CN101346376A - Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase - Google Patents

Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase Download PDF

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CN101346376A
CN101346376A CNA2006800487374A CN200680048737A CN101346376A CN 101346376 A CN101346376 A CN 101346376A CN A2006800487374 A CNA2006800487374 A CN A2006800487374A CN 200680048737 A CN200680048737 A CN 200680048737A CN 101346376 A CN101346376 A CN 101346376A
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substituted
low
alkyl group
group
carbonyl
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吉田弘志
川筋孝
大司照彦
垰田善之
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Abstract

The invention provides a compound with antivirus function, especially HIV integrase inhibition activity, and medicine containing the compound, especially HIV inhibiting medicine. The compound is expressed by the general formula (I) in which, R1 expresses hydrogen or low grade alkyl radical; X expresses low grade alkylidene radical; R2 expresses substitutable aryl radical; R3 expresses hydrogen, halogen, hydroxyl radical; R4 expresses hydrogen and substitutable low grade alkyl radical; broken line expresses existing or dis-existing; one of B1 and B2 is CR20R21, the other one is NR22, here the broken line does not exist; or B1 and B2 separated from each other are C, CR23 or N, B1 and B2 can be partly formed into substitutable heterocycle; R20, R21, R22 and R23 are independent from each other, express hydrogen, substitutable low grade alkyl radical, substitutable cycloalkyl radical and substitutable cycloalkyl low grade alkyl radical.

Description

Have hiv integrase and suppress active polycyclic carbamoylpyridone derivative
Technical field
The present invention relates to have the novel cpd of antivirus action, more particularly, relate to and have hiv integrase and suppress active polycyclic carbamoylpyridone derivative and contain the medicine of this derivative, particularly anti-HIV medicine.
Background technology
In the virus, known a kind of human immunodeficiency virus (being designated hereinafter simply as HIV) as retrovirus is the reason of acquired immune deficiency syndrome (AIDS) (being designated hereinafter simply as acquired immune deficiency syndrome (AIDS) (AIDS)).Curative as this acquired immune deficiency syndrome (AIDS), present main flow medicine is reverse transcriptase inhibitors (AZT, 3TC etc.) and proteinase inhibitor (Indinavir etc.), but recognized that they have side effect such as kidney obstacle or problem such as virus resistance occurs, people's expectation can be developed the anti-HIV medicine with mechanism of action different with them.
In the treatment of acquired immune deficiency syndrome (AIDS), owing to resistance virus occurs easily, therefore, present report is that the multi-form conjoint therapy is comparatively effective.In the anti-HIV medicine, reverse transcriptase inhibitors, proteinase inhibitor are applied in clinical for two kinds, and still, the medicine with same function mechanism usually shows crossed resistance, perhaps only show additional effect, people wish to develop the anti-HIV medicine of the different mechanisms of action.
Under above-mentioned condition, as the anti-HIV medicine of novel mechanism, integrase inhibitor is subjected to people's attention (with reference to patent documentation 1,2).Known anti-HIV medicine with same purpose also has: formamyl substituted hydroxy pyrimidone derivatives (with reference to patent documentation 3,4), formamyl substituted hydroxy pyrrolidinone derivatives (with reference to patent documentation 5).The somebody has proposed formamyl substituted hydroxy Pyridione derivatives (with reference to patent documentation 6, embodiment 8).
In addition, as other carbamoylpyridone derivative, known have 5-alkoxy pyridines-3-carboxamides derivatives or gamma-pyrone-3-carboxamides derivatives, but they are plant growth inhibitor or weedicide (with reference to patent documentation 7~9).
Nitrogenous fused ring compound as hiv integrase inhibitor also makes known (with reference to patent documentation 10).
The applicant had once applied for the dicyclo carbamoylpyridone derivative (with reference to patent documentation 11) as hiv integrase inhibitor.
Patent documentation 1:WO03/0166275
Patent documentation 2:WO2004/024693
Patent documentation 3:WO03/035076
Patent documentation 4:WO03/035076
Patent documentation 5:WO2004/004657
Patent documentation 6: Japanese Patent Application 2003-32772
Patent documentation 7: Japanese kokai publication hei 2-108668
Patent documentation 8: Japanese kokai publication hei 2-108683
Patent documentation 9: Japanese kokai publication hei 2-96506
Patent documentation 10:WO2005/016927
Patent documentation 11:WO2006/088173
Summary of the invention
Invent problem to be solved
Under above-mentioned condition, people wish can development of new integrase inhibitor.
Solve the method for problem
The inventor etc. have carried out deep research to this, found that: novel polycyclic carbamoylpyridone derivative has intensive hiv integrase restraining effect.And find: compound of the present invention can be used as antiviral drug (for example anti-retroviral medicine, anti-HIV medicine, anti-HTLV-1 (human T-cell leukemia virus I type) medicine, anti-FIV (cat AIDS poison) medicine, anti-SIV (simian acquired immunodeficiency syndrome poison) medicine) with the medicine that contains this compound, can be used as the curative of anti-HIV medicine, anti-AIDS medicine or its relative disease etc. especially, thereby finished the present invention shown below.
(1) acceptable salt or their solvate in the compound shown in the following formula, its pharmacy:
[Chemical formula 1]
Figure A20068004873700131
(in the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
R 4Be hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O, S, SO, SO 2, NR a(R aBe hydrogen or low alkyl group) ,-N=and=heteroatom group of N-);
Dotted line is represented the existence or the non-existence of key;
B 1And B 2Wherein any one party is represented CR 20R 21, the opposing party represents NR 22, in this case, dotted line does not exist;
B 2Be NR 22The time, R 4And R 22Can form together can substituted heterocycle;
B 2Be CHR 21The time, R 4And R 21Can form together can substituted heterocycle;
B 1And B 2Independent separately, be C, CR 23Or N, at this moment, B 1And B 2Part can form together can substituted heterocycle;
R 20, R 21, R 22And R 23Independent separately, expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O, S, SO, SO 2, NR 5(R 5With R 4Independent, be selected from and R 4Identical substituting group group);-N=and=heteroatom group of N-); hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl).
(2) acceptable salt or their solvate in the compound of above-mentioned (1), its pharmacy, described compound is expressed from the next:
[Chemical formula 2]
Figure A20068004873700141
(in the formula,
G ring expression can substituted heterocycle;
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, maybe can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
R 14Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O, S, SO, SO 2, NR 5(R 5With R 4Independent, be selected from and R 4Identical substituting group group);-N=and=heteroatom group of N-); hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl.
(3) acceptable salt or their solvate in the compound of above-mentioned (1), its pharmacy, described compound is by shown in the following formula:
[chemical formula 3]
Figure A20068004873700161
(in the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
R 4Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocycle, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O, S, SO, SO 2, NR a(R aBe hydrogen or low alkyl group) ,-N=and=heteroatom group of N-);
B 1And B 2Wherein a side is CR 20R 21, the opposing party is NR 22
R 20, R 21And R 22Independent separately, expression hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted low-grade alkenyl; can substituted lower alkoxy; can substituted low-grade alkenyl oxygen base; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted aryloxy; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted heterocyclyloxy base; hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl).
(4) acceptable salt or their solvate, wherein B in the compound of above-mentioned (3), its pharmacy 1Be CR 20R 21, B 2Be NR 22(R 20, R 21And R 22Identical with the situation implication of above-mentioned (3)).
(5) acceptable salt or their solvate, wherein B in the compound of above-mentioned (3), its pharmacy 1Be NR 22, B 2Be CR 20R 21(R 20, R 21And R 22Identical with the situation implication of above-mentioned (3)).
(6) acceptable salt or their solvate, wherein B in the compound of above-mentioned (3), its pharmacy 1Be NR 22(R 22Identical with the situation implication of above-mentioned (3)), B 2Be CH 2
(7) acceptable salt or their solvate, wherein B in the compound of above-mentioned (3), its pharmacy 1Be NR 22(R 22Expression hydrogen, can substituted low alkyl group, low-grade alkenyl, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted lower alkylcarbonyl, can substituted aryl carbonyl, replacement (sulphur) urea or substituted sulphonyl); B 2Be CH 2
(8) acceptable salt or their solvate, wherein R in the compound of above-mentioned (3), its pharmacy 4For can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group.
(9) acceptable salt or their solvate, wherein B in the compound of above-mentioned (3), its pharmacy 1Be NR 22(R 22For hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted lower alkylcarbonyl, can substituted aryl carbonyl, replacement (sulphur) urea or substituted sulphonyl); B 2Be CH 2R 4For can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group.
(10) acceptable salt or their solvate, wherein B in the compound of above-mentioned (3), its pharmacy 1Be NR 22(R 22Expression hydrogen, can substituted low alkyl group (substituting group: amino, low-grade alkyl amino, lower alkoxy, aryloxy, cyano group, halogen, (replacement) formamyl, acyl amino, low-grade alkynyl, hydroxyl), cycloalkyl, cycloalkyl low-grade alkyl, can substituted phenyl, can substituted benzyl, can substituted 5~6 yuan of aromatic heterocyclic radicals, can substituted 5~6 yuan of heterocyclic radical low alkyl groups, can substituted lower alkylcarbonyl (substituting group: lower alkoxy), can substituted benzoyl (substituting group: lower alkoxy), substituted sulphonyl (substituting group: low alkyl group, aryl, heterocyclic radical); B 2Be CH 2R 4For can substituted low alkyl group (substituting group: amino, low-grade alkyl amino, lower alkoxy, aryloxy), cycloalkyl, cycloalkyl low-grade alkyl, phenyl, benzyl, 5~6 yuan of aromatic heterocyclic radicals, 5~6 yuan of heterocyclic radical low alkyl groups).
(11) acceptable salt or their solvate in the compound of above-mentioned (1), its pharmacy, described compound is expressed from the next:
[chemical formula 4]
(in the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
C ring expression can substituted heterocycle or can substituted carbocyclic ring;
B 1And B 2Independent separately, expression C, CR 23Or N;
R 23Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted lower alkylcarbonyl, can substituted naphthene base carbonyl, can substituted cycloalkyl low-grade alkyl carbonyl, can substituted elementary alkoxy carbonyl, can substituted aryl carbonyl, can substituted aromatic yl elementary alkyl carbonyl, can substituted aryloxy carbonyl, can substituted heterocyclic radical carbonyl, can substituted heterocyclic radical lower alkylcarbonyl, can substituted heterocyclyloxy base carbonyl, can substituted aminocarboxyl, replace (sulphur) urea, or substituted sulphonyl;
Dotted line is represented the existence or the non-existence of key;
R 4Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from CO, O, S, SO, SO 2, NR a(R aBe hydrogen or low alkyl group) ,-N=and=heteroatom group of N-).
(12) acceptable salt or their solvate in the compound of above-mentioned (1), its pharmacy, described compound is expressed from the next:
[chemical formula 5]
Figure A20068004873700201
(in the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
H ring expression can substituted heterocycle;
R 24Expression hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted low-grade alkenyl; can substituted lower alkoxy; can substituted low-grade alkenyl oxygen base; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted aryloxy; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted heterocyclyloxy base; hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl).
(13) acceptable salt or their solvate, wherein R in each compound, its pharmacy in above-mentioned (1)~(12) 1Be hydrogen or low alkyl group.
(14) acceptable salt or their solvate in each compound, its pharmacy in above-mentioned (1)~(12), wherein X is a low-grade alkylidene; R 2Be phenyl or the phenyl that replaced by halogen at least.
(15) acceptable salt or their solvate, wherein R in each compound, its pharmacy in above-mentioned (1)~(12) 3Be hydrogen.
(16) acceptable salt or their solvate, wherein R in each compound, its pharmacy in above-mentioned (1)~(12) 1Be hydrogen or low alkyl group; X is a low-grade alkylidene; R 2For phenyl or by the phenyl of 1~2 halogen replacement; R 3Be hydrogen.
(17) pharmaceutical composition, this pharmaceutical composition contain in above-mentioned (1)~(16) acceptable salt or their solvate on each the compound, its pharmacy.
(18) pharmaceutical composition of above-mentioned (17), this pharmaceutical composition are anti-HIV medicines.
The present invention also provides the methods of treatment of viral infectious disease, it is characterized in that: with the above-claimed cpd administration of human.The present invention provides the preparation method of the medicine of viral infectious disease again, it is characterized in that: use above-claimed cpd.
The invention effect
Compound of the present invention to virus, particularly HIV has integrase inhibiting activities and/or cell inhibitory effect activity.Therefore, can be used for the prevention or the treatment of various diseases relevant or viral infectious disease (for example acquired immune deficiency syndrome (AIDS)) etc. with intergrase.Preferred compound is also effective for the resistance virus strain.And the internal metabolism kinetics of preferred compound is good.
The best mode that carries out an invention
The following explanation of the term that uses in this specification sheets.Each term can have following implication separately or with other term.
" low-grade alkylidene " is meant a straight chain shape or a catenate low-grade alkylidene of 1~6 of carbonatoms, for example has: methylene radical, ethylidene, trimethylene, propylene, tetramethylene, ethyl ethylidene, pentamethylene or hexamethylene etc.Preferred carbonatoms 1-4 straight chain shape low-grade alkylidene for example has methylene radical, ethylidene, trimethylene or tetramethylene.More preferably methylene radical or ethylidene.
" rudimentary alkylene group " is meant a straight chain shape or a rudimentary alkylene group of catenate of 2~6 of carbonatomss that have one or more pairs key in above-mentioned " low-grade alkylidene ", for example has: vinylene, propenylene or 1.Be preferably carbonatoms 2-3 the rudimentary alkylene group of straight chain shape, vinylene or propenylene are for example arranged.
" alkyl " is meant a straight chain shape or a catenate alkyl of 1~10 of carbonatoms, for example has: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, positive decyl etc.The low alkyl group that preferred carbonatoms is 1~6, more preferably the low alkyl group of 1~4 of carbonatoms for example has: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl.
Low alkyl group with-N=or=when the form of N-exists, can have two keys, for example can form-CH 2-N=CH 2,-CH=N-CH 3Deng.
" alkenyl " is a straight chain shape or a chain alkenyl that has 2~8 of the carbonatomss of one or more pairs key in above-mentioned " alkyl ", for example have: vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 3-butenyl, 1,3-butadiene base, 3-methyl-2-butene base etc.The low-grade alkenyl that preferred carbonatoms is 2~6, the more preferably low-grade alkenyl of 2~4 of carbonatomss.
" low-grade alkenyl oxygen base " is meant the oxygen base that is combined with above-mentioned " low-grade alkenyl ", for example have: vinyl oxygen base, 1-propenyl oxygen base, 2-propenyl oxygen base, 1-butylene base oxygen base, crotyl oxygen base, 3-butenyl oxygen base, 1,3-butadiene base oxygen base, 3-methyl-2-butene base oxygen base etc.
" cycloalkyl " is meant 3~20 of carbonatomss, preferred 3~15, more preferably 3~10 cyclic saturated hydrocarbon base, for example has: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, adamantyl, polyhedron (for example: cubane, dodecahedrane) etc.The cycloalkyl that further preferred carbonatoms is 3~6.
" cycloalkyl low-grade alkyl " is meant the low alkyl group that is substituted with above-mentioned cycloalkyl, for example has: cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, cyclohexyl ethyl etc.The cycloalkyl low-grade alkyl that preferred carbonatoms is 3~6.
" aryl " is meant monocyclic aromatic alkyl (phenyl) and polycyclic aromatic alkyl (for example having: 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl etc.).Preferred phenyl or naphthyl (1-naphthyl, 2-naphthyl).
" aralkyl " or " aryl lower alkyl " is meant above-mentioned " low alkyl group " that is substituted with 1-3 above-mentioned " aryl ", and benzyl, diphenyl methyl, trityl group, styroyl, 1-naphthyl methyl, 2-naphthyl methyl etc. are for example arranged) etc.Preferred benzyl.
" aryloxy " is meant the oxygen base that is combined with above-mentioned " aryl ", for example has: 1-naphthyl oxygen base, 2-naphthyl oxygen base, 1-anthryl oxygen base, 2-anthryl oxygen base, 9-anthryl oxygen base, 1-phenanthryl oxygen base, 2-phenanthryl oxygen base, 3-phenanthryl oxygen base, 4-phenanthryl oxygen base, 9-phenanthryl oxygen base etc.Preferred phenyl oxygen base or naphthyl oxygen base (for example: 1-naphthyl oxygen base, 2-naphthyl oxygen base).
" heterocyclic radical " is meant " heterocycle " or " heteroaryl ".
" heterocycle " is to have 1 above nitrogen-atoms in the finger ring at least, Sauerstoffatom, phosphorus atom and/or sulphur atom, on commutable position arbitrarily, have the non-aromatic heterocycle (preferred 5~7 yuan of rings) of key, for example have: the 1-pyrrolinyl, the 2-pyrrolinyl, the 3-pyrrolinyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 1-imidazolinyl, the 2-imidazolinyl, the 4-imidazolinyl, the 1-imidazolidyl, the 2-imidazolidyl, the 4-imidazolidyl, the 1-pyrazolinyl, the 3-pyrazolinyl, the 4-pyrazolinyl, the 1-pyrazolidyl, the 3-pyrazolidyl, the 4-pyrazolidyl, piperidino-(1-position only), the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-piperazinyl, the 2-piperazinyl, the 2-morpholinyl, morpholinyl, the morpholino base, THP trtrahydropyranyl etc.Need to prove, " non-aromatic heterocycle " so long as non-aromatics get final product, can be saturated also can be unsaturated.
" heteroaryl " is meant monocyclic aromatic heterocyclic radical and fused aromatic heterocyclic radical.
The monocyclic aromatic heterocyclic radical is meant by 5~8 yuan of aromatic ring deutero-that can contain 1~4 Sauerstoffatom, sulphur atom, phosphorus atom and/or nitrogen-atoms in the ring, can has the group of key on commutable optional position.
The fused aromatic heterocyclic radical is the group that can contain 5~8 yuan of aromatic rings of 1~4 Sauerstoffatom, sulphur atom, phosphorus atom and/or nitrogen-atoms and 1~4 5~8 yuan of aromatic carbocyclic or other 5~8 yuan of aromatic heterocycle condensed in the finger ring, can have key in commutable optional position.
" heteroaryl " for example has: furyl (2-furyl for example, the 3-furyl), thienyl (2-thienyl for example, the 3-thienyl), pyrryl (1-pyrryl for example, the 2-pyrryl, the 3-pyrryl), imidazolyl (1-imidazolyl for example, the 2-imidazolyl, the 4-imidazolyl,), pyrazolyl (1-pyrazolyl for example, the 3-pyrazolyl, the 4-pyrazolyl), triazolyl (for example 1,2, the 4-triazol-1-yl, 1,2,4-triazole-3-base, 1,2,4-triazole-4-yl), tetrazyl (1-tetrazyl for example, the 2-tetrazyl, the 5-tetrazyl) oxazolyl (2-oxazolyl for example, the 4-oxazolyl, the 5-oxazolyl) isoxazolyl (3-isoxazolyl for example, the 4-isoxazolyl, the 5-isoxazolyl), thiazolyl (2-thiazolyl for example, the 4-thiazolyl, the 5-thiazolyl), thiadiazolyl group, isothiazolyl (3-isothiazolyl for example, the 4-isothiazolyl, the 5-isothiazolyl), pyridyl (2-pyridyl for example, the 3-pyridyl, the 4-pyridyl), pyridazinyl (3-pyridazinyl for example, the 4-pyridazinyl), pyrimidyl (2-pyrimidyl for example, the 4-pyrimidyl, the 5-pyrimidyl), furazan base (for example 3-furazan base), pyrazinyl (for example 2-pyrazinyl) oxadiazole base (for example 1,3,4-oxadiazole-2-yl), benzofuryl (2-benzo [b] furyl for example, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzothienyl (2-benzo [b] thienyl for example, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzimidazolyl-(1-benzimidazolyl-for example, the 2-benzimidazolyl-, the 4-benzimidazolyl-, the 5-benzimidazolyl-), dibenzofuran group benzoxazolyl, quinoxalinyl (2-quinoxalinyl for example, the 5-quinoxalinyl, the 6-quinoxalinyl), cinnolines base (3-cinnolines base for example, 4-cinnolines base, 5-cinnolines base, 6-cinnolines base, 7-cinnolines base, 8-cinnolines base), quinazolyl (2-quinazolyl for example, the 4-quinazolyl, the 5-quinazolyl, the 6-quinazolyl, the 7-quinazolyl, the 8-quinazolyl), quinolyl (2-quinolyl for example, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, the 7-quinolyl, the 8-quinolyl), phthalazinyl (1-phthalazinyl for example, the 5-phthalazinyl, the 6-phthalazinyl), isoquinolyl (1-isoquinolyl for example, the 3-isoquinolyl, the 4-isoquinolyl, the 5-isoquinolyl, the 6-isoquinolyl, the 7-isoquinolyl, the 8-isoquinolyl), purine radicals, pteridyl (2-pteridyl for example, the 4-pteridyl, the 6-pteridyl, the 7-pteridyl), carbazyl, phenanthridinyl, acridyl (1-acridyl for example, the 2-acridyl, the 3-acridyl, the 4-acridyl, the 9-acridyl), indyl (1-indyl for example, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 6-indyl), pseudoindoyl, phenazinyl (1-phenazinyl for example, the 2-phenazinyl) or phenothiazinyl (1-phenothiazinyl for example, the 2-phenothiazinyl, the 3-phenothiazinyl, the 4-phenothiazinyl) etc.
" heterocyclic radical low alkyl group " is meant the low alkyl group that is substituted with above-mentioned " heterocyclic radical ".
" heterocyclyloxy base " is meant the oxygen base that is combined with above-mentioned " heterocyclic radical ".
" heterocycle " is meant the heterocycle that can form above-mentioned heterocyclic radical.
" lower alkoxy " is meant the oxygen base that is combined with above-mentioned " low alkyl group ", and methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc. are for example arranged.
" lower alkylcarbonyl ", " naphthene base carbonyl ", " cycloalkyl low-grade alkyl carbonyl ", " elementary alkoxy carbonyl ", " aryl carbonyl ", " aromatic yl elementary alkyl carbonyl ", " aryloxy carbonyl ", " heterocyclic radical carbonyl ", " heterocyclic radical lower alkylcarbonyl ", " heterocyclyloxy base carbonyl " refers to be combined with above-mentioned " low alkyl group " respectively, " cycloalkyl ", " cycloalkyl low-grade alkyl ", " lower alkoxy ", " aryl ", " aromatic yl elementary alkyl ", " aryloxy ", " heterocyclic radical ", the carbonyl of " heterocyclic radical low alkyl group ".
" can substituted low alkyl group ", " can substituted cycloalkyl ", " can substituted cycloalkyl low-grade alkyl ", " can substituted low-grade alkenyl ", " can substituted lower alkoxy ", " can substituted aryl ", " can substituted aromatic yl elementary alkyl ", " can substituted aryloxy ", " can substituted aryloxy low alkyl group ", " can substituted heterocycle ", " can substituted heterocyclic radical ", " can substituted heterocyclic radical low alkyl group ", " can substituted heterocyclyloxy base ", " can substituted low-grade alkenyl oxygen base ", " can substituted lower alkylcarbonyl ", " can substituted naphthene base carbonyl ", " can substituted cycloalkyl low-grade alkyl carbonyl ", " can substituted elementary alkoxy carbonyl ", " can substituted aryl carbonyl ", " can substituted aromatic yl elementary alkyl carbonyl ", " can substituted aryloxy carbonyl ", " can substituted heterocyclic radical carbonyl ", " can substituted heterocyclic radical lower alkylcarbonyl ", " can substituted heterocyclyloxy base carbonyl ", " can substituted low-grade alkylidene ", " can substituted rudimentary alkylene group ", " can substituted phosphoric acid residue ", when " can substituted carbocyclic ring " or " can substituted heterocycle " etc. has substituting group, can be that the position is replaced by 1~4 identical or different group that is selected from substituting group group B respectively arbitrarily.
The example of substituting group group B for example has: hydroxyl, carboxyl, halogen (F, Cl, Br, I), junior alkyl halides (CF for example 3, CH 2CF 3, CH 2CCl 3), halogenated lower alkoxy (OCF for example 3, OCH 2CF 3, OCH 2CCl 3); low alkyl group (methyl for example; ethyl; sec.-propyl; the tertiary butyl); low-grade alkenyl (for example vinyl); low-grade alkynyl (for example ethynyl); cycloalkyl (for example cyclopropyl); cycloalkenyl (for example cyclopropenyl radical); lower alkoxy (methoxyl group for example; oxyethyl group; propoxy-; butoxy); low-grade alkenyl oxygen base (vinyl oxygen base for example; allyl group oxygen base); elementary alkoxy carbonyl (methoxycarbonyl for example; ethoxy carbonyl; tert-butoxycarbonyl); nitro; nitroso-group; can substituted amino (alkylamino (methylamino for example for example; ethylamino; dimethylamino); acyl amino (kharophen for example; benzamido); aryl alkyl amino (benzylamino for example; trityl amino); hydroxyl amino); azido-; aryl (for example phenyl); aralkyl (for example benzyl); cyano group; isocyano-; the isocyanide acyl; thiocyanogen; isothiocyano; sulfydryl; alkylthio (for example methylthio group); alkyl sulphonyl (methylsulfonyl for example; ethylsulfonyl); can substituted alkyl sulfonyl-amino (methylsulfonyl amino for example; ethylsulfonylamino; N-methyl sulphonyl-N '-methylamino); can substituted formamyl (alkyl-carbamoyl (methylamino formyl radical for example for example; the ethylamino formyl radical; formyl-dimethylamino)); sulphonamide; acyl group (formyl radical for example; ethanoyl); formyl radical oxygen base; the halo formyl radical; oxalyl; thioformyl; thiocarboxyl group; dithiocarboxy; thiocarbamoyl; sulfino; sulfo group; sulfoamino-; diazanyl; azido-; urea groups; amidino groups; guanidine radicals; phthalic imidine; the oxo base; the phosphoric acid residue; the low alkyl group (can have heteroatoms) that is replaced by the phosphoric acid residue; the aryl that is replaced by the phosphoric acid residue; the aralkyl that is replaced by the phosphoric acid residue; hydroxyl low-grade alkyl etc., more preferably hydroxyl; carboxyl; halogen (F; Cl; Br; I); junior alkyl halides (for example: CF 3, CH 2CF 3, CH 2CCl 3), halogenated lower alkoxy (for example: OCF 3, OCH 2CF 3, OCH 2CCl 3), low alkyl group (for example: methyl, ethyl, sec.-propyl, the tertiary butyl), lower alkoxy (for example: methoxyl group, oxyethyl group, propoxy-, butoxy), can substituted amino (for example: alkylamino (for example: methylamino, ethylamino, dimethylamino)), oxo base or phosphoric acid residue etc.
The substituting group of " can substituted amino " or " can substituted formamyl " for example can be: single or two low alkyl groups; lower alkylcarbonyl or low alkyl group alkylsulfonyl; can substituted low alkyl group (methyl for example; ethyl; sec.-propyl; benzyl; formamyl alkyl (for example carbamyl ylmethyl); list or two elementary alkyl amido formyl radical low alkyl group (for example formyl-dimethylamino ethyl); hydroxyl low-grade alkyl; heterocyclic radical low alkyl group (morpholino base ethyl for example; the THP trtrahydropyranyl ethyl); alkoxy carbonyl low alkyl group (example: ethoxy carbonyl methyl; the ethoxy carbonyl ethyl); list or two elementary alkyl amido low alkyl group (for example dimethyl aminoethyl)); lower alkoxy low alkyl group (methoxy ethyl for example; ethoxyl methyl; ethoxyethyl group; isopropoxy ethyl etc.); acyl group (formyl radical for example; can substituted lower alkylcarbonyl (ethanoyl for example; propionyl; butyryl radicals; isobutyryl; pentanoyl; isovaleryl; valeryl; caproyl; capryloyl; the methoxy ethyl carbonyl; 2; 2; 2-trifluoroethyl carbonyl; ethoxy carbonyl methyl carbonyl); lower alkoxy lower alkylcarbonyl (for example methoxy ethyl carbonyl); elementary alkyl amido methanoyl lower alkylcarbonyl (for example methylamino formyl radical ethyl carbonyl); the alkoxy carbonyl ethanoyl); can substituted aryl carbonyl (benzoyl for example; toluyl); can substituted aralkyl (benzyl for example; the 4-luorobenzyl); hydroxyl; can substituted low alkyl group alkylsulfonyl (methylsulfonyl for example; ethylsulfonyl; the sec.-propyl alkylsulfonyl; 2; 2,2-trifluoro ethylsulfonyl; the benzyl alkylsulfonyl; the methoxy ethyl alkylsulfonyl); the low alkyl group or the aryl sulfonyl that can be replaced by halogen (benzenesulfonyl for example; tosyl group; 4-fluorobenzene alkylsulfonyl); cycloalkyl (for example cyclopropyl); the aryl that can be replaced by low alkyl group (phenyl for example; trityl); low-grade alkyl amino alkylsulfonyl (methylamino alkylsulfonyl for example; the dimethylamino alkylsulfonyl); low-grade alkyl amino carbonylic (for example dimethylamino carbonyl); elementary alkoxy carbonyl (for example ethoxy carbonyl); naphthene base carbonyl (cyclopropyl carbonyl for example; cyclohexyl-carbonyl); can substituted sulphonamide (sulphonamide for example; the methyl sulphonamide; the dimethylamino sulphonyl); lower alkylcarbonyl amino (for example methyl carbonylamino); heterocyclic radical (morpholino base for example; THP trtrahydropyranyl); can substituted amino (for example list or dialkyl amido (for example dimethylamino); formyl radical amino) etc.
" can substituted amino " or " can substituted formamyl ", " can's substituted formamyl carbonyl " amino can be 2 amino substituting groups can contain sulphur atom and/or Sauerstoffatom in adjacent nitrogen-atoms forms ring nitrogen heterocycle (preferred 5~7 yuan of rings; also preferably saturated), this ring also can be replaced by oxo base or hydroxyl.The sulphur atom that forms ring can be replaced by the oxo base.For example preferred piperazinyl, piperidino-(1-position only), morpholino base, pyrrolidyl, thiazine-2-base, 2-oxo-piperidine subbase, 2-oxo-pyrrolidine base, 1,5 yuan of 1-two oxo bridges-1,2-thiazines-2-base, 4-hydroxymorpholine Dai Ji etc. or 6 yuan of rings etc.
The phosphoric acid residue is meant by-PO (OH) 2Shown group can substituted phosphoric acid residue be meant that the hydrogen partial of its OH part and/or OH can substituted phosphoric acid residue, preferably by shown in the following formula.
[chemical formula 6]
(in the formula, R AAnd R BIndependent separately, OR C, NR DR E(in the formula, R C, R DAnd R EIndependent separately, expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted aryl or can substituted heterocyclic radical, perhaps R DAnd R EForm together contain adjacent nitrogen atom can substituted heterocycle (preferred 5~6 yuan of rings)) or R AAnd R BForm together contain adjacent phosphorus atom can substituted heterocycle (preferred 5~6 yuan of rings)).
More preferably R AAnd R BBe OR C, perhaps wherein a side is OR C, the opposing party is NR DR E
R C, R DAnd R EPreferably independent separately, be low alkyl group (for example methyl, ethyl).
R AAnd R BForm together contain adjacent phosphorus atom can substituted heterocycle, can obtain for example following structure:
[chemical formula 7]
Figure A20068004873700282
(in the formula, the part of dotted line representative ring)
By can be substituted the hydroxyl that replaces of phosphoric acid residue be preferably by the hydroxyl that can be replaced, more preferably Yi Xia group by the phosphoric acid residue that two low alkyl groups replace:
[chemical formula 8]
Figure A20068004873700283
By can be substituted the amino that replaces of phosphoric acid residue be preferably by the amino that can be replaced, more preferably Yi Xia group by the phosphoric acid residue that two low alkyl groups replace:
[chemical formula 9]
The A ring is can substituted heterocycle.This heterocycle is preferably 5~7 yuan of rings that contain 1~3, preferred 2~3 O, S and/or N atom, more preferably is selected from above-mentioned heterocycle.Can have 1 or 2 heteroatoms as required on the arc of A ring, its position is not particularly limited.One of preferred version of A ring is can substituted following ring:
[Chemical formula 1 0]
Figure A20068004873700292
(Z is CH 2, O, S, SO, SO 2Or NR 19).
One of preferred version of Z is Z=O or NR 19
Z=NR 19The time, R 19Preferably: 1) hydrogen, 2) can substituted low alkyl group (substituent example: but the amino that coverlet or two low alkyl groups replace, cycloalkyl, hydroxyl, can substituted heterocyclic radical (preferred 5~7 yuan of rings of heterocycle, for example furyl, thienyl, thiazolyl, pyridyl, morpholino base, imidazoles; Substituent example: low alkyl group; halogen); can substituted heterocyclic radical carbonyl (preferred 5~7 yuan of rings of heterocycle, for example morpholino base carbonyl); can substituted phenyl (substituting group: low alkyl group; amino; low-grade alkyl amino; hydroxyl; halogen; junior alkyl halides; lower alkoxy; halogenated lower alkoxy; lower alkylthio; the low alkyl group alkylsulfonyl); acetylamino; formamyl; list or two low alkyl group substituted-amino formyl radicals; the low alkyl group sulfuryl amino; lower alkoxy; carbonyl; halogen; thiol; lower alkylthio); 3) low-grade alkenyl; 4) acyl group (for example lower alkylcarbonyl); 5) low alkyl group alkylsulfonyl.
Other substituting group on the A ring can exemplify one or more the identical or different substituting group that is selected from substituting group group S2, preferred low alkyl group etc.Substituting group on A ring part can further form fused rings or volution with adjacent atom, and preferably can form can substituted carbocyclic ring (preferred 5~6 yuan of rings) or can substituted heterocycle (preferred 5~6 yuan of rings).
Substituting group group S2: hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted lower alkylcarbonyl, can substituted naphthene base carbonyl, can substituted cycloalkyl low-grade alkyl carbonyl, can substituted elementary alkoxy carbonyl, can substituted aryl carbonyl, can substituted aromatic yl elementary alkyl carbonyl, can substituted aryloxy carbonyl, can substituted heterocyclic radical carbonyl, can substituted heterocyclic radical lower alkylcarbonyl, can substituted heterocyclyloxy base carbonyl, can substituted aminocarboxyl, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by the aralkyl that can substituted phosphoric acid residue replaces, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, perhaps by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from CO, O, S, SO, SO 2, NR 5(R 5With R 4Independent, be selected from and R 4Identical substituting group group) ,-N=and=heteroatom group of N-), the oxo base.
R 1Be hydrogen or low alkyl group, preferred hydrogen.
X is a singly-bound, is selected from O, S, SO, SO 2Maybe can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group with the heteroatom group of NH (following represent) with M.Here, " existence " be meant this heteroatom group 1) be present in the situation between the carbon atom that constitutes alkylidene group or alkylene group; 2) with the N atom bonded situation of X adjacent amino groups formyl radical; And/or 3) with the R adjacent with X 2The bonded situation.This heteroatom group (M) can be identical or different one or more groups, for example, when having heteroatoms in low-grade alkylidene, can exemplify-M-CH 2-,-CH 2-M-CH 2-,-CH 2-M-,-CH 2-M-M-CH 2-etc.X is preferably the spacer groups that 1~3 atom is formed by connecting.Low-grade alkylidene or rudimentary alkylene group or O that X more preferably can have heteroatom group to exist, rudimentary alkylene group or O that further preferred 1~3 low-grade alkylidene of carbonatoms or carbonatoms are 2~3, preferred especially methylene radical or O.
R 2For can substituted aryl, preferred phenyl.Substituting group on the aryl is preferably selected from halogen; hydroxyl; amino; low-grade alkyl amino; cyano group; carboxyl; formyl radical; the oxo base; low alkyl group; lower alkoxy; lower alkylthio; formamyl; and elementary alkyl amido methanoyl; with substituting group group S1 (for example can substituted phosphoric acid residue; by can be substituted the aryl that replaces of phosphoric acid residue; by can be substituted the aralkyl that replaces of phosphoric acid residue; by can be substituted the hydroxyl that replaces of phosphoric acid residue; by can be substituted the amino that replaces of phosphoric acid residue; by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O; S; SO; SO 2, NR 5(R 5With R 4Independent, be selected from and R 4Identical substituting group group);-N=and=heteroatom group of N-); the lower alkoxy low alkyl group; but the amino low alkyl group that coverlet or two low alkyl groups replace; junior alkyl halides; lower alkoxy; but the formamyl that coverlet or two low alkyl groups replace; can substituted low alkyl group sulfuryl amino; halogenated lower alkoxy; hydroxyl low-grade alkyl) identical or different 1~3; preferred 1~2 substituting group; more preferably be selected from halogen; hydroxyl; amino; cyano group; low alkyl group; with lower alkoxy and substituting group group S1, be preferably the group that is selected from halogen (for example F) and/or substituting group group S1 especially.When the substituting group on the aryl was 1, its optimum seeking site was 4.R 2More preferably phenyl or the phenyl that replaced by halogen at least, preferred especially 4-halogenophenyl (for example 4-F-phenyl) or 2,4-dihalogenated phenyl (for example 2,4-F-phenyl).
R 2More preferably can be by the phenyl of 1~3 R replacement of aftermentioned.
In all compounds of the present invention ,-X-R 2Part preferably is expressed from the next:
[Chemical formula 1 1]
R is independent separately, for being selected from the group of halogen and substituting group group S1.
Substituting group group S1: can substituted phosphoric acid residue, by the aryl that can substituted phosphoric acid residue replaces, by the aralkyl that can substituted phosphoric acid residue replaces, by the hydroxyl that can substituted phosphoric acid residue replaces, by the amino that can substituted phosphoric acid residue replaces, (can be existed in this low alkyl group and be selected from CO, O, S, SO, SO by the low alkyl group that can substituted phosphoric acid residue replaces 2, NR a(R aBe hydrogen or low alkyl group);-N=and=heteroatom group of N-); the lower alkoxy low alkyl group; can substituted amino low alkyl group (substituting group: single or two low alkyl groups; lower alkylcarbonyl; or low alkyl group alkylsulfonyl); junior alkyl halides; lower alkoxy; can substituted formamyl (substituting group: single or two low alkyl groups; lower alkylcarbonyl; or low alkyl group alkylsulfonyl); can substituted low alkyl group sulfuryl amino; halogenated lower alkoxy; and hydroxyl low-grade alkyl.
M is 0~3 integer, is preferably 0 or 1~2.M is 1 o'clock, and R is preferably halogen, and m is 2 o'clock, and R is preferably 2 halogens or halogen and group in addition.
R preferably is present in 4 on the phenyl ring and is present in other position (for example 2) as required.
During m=2, R more preferably is selected from the identical or different group of halogen, low alkyl group, lower alkoxy, lower alkoxy low alkyl group, junior alkyl halides, halogenated lower alkoxy, low alkyl group sulfuryl amino, formamyl and elementary alkyl amido methanoyl.Be preferably 2 F especially.
As R 3Only otherwise the pharmacologically active of compound (I) is produced detrimentally affect to get final product, can be various substituting groups, for example have hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino." can be substituted " substituting group has halogen, hydroxyl, amino, low-grade alkyl amino, cyano group, carboxyl, formyl radical, oxo base, low alkyl group, lower alkoxy, lower alkylthio, formamyl, elementary alkyl amido methanoyl, aryl, heterocyclic radical, lower alkylcarbonyl, lower alkylcarbonyl oxygen base, elementary alkoxy carbonyl, halogenated lower alkyl, halogenated lower alkoxyl group etc., more preferably halogen, hydroxyl, amino, low-grade alkyl amino, low alkyl group, lower alkoxy etc.R 3More preferably hydrogen, halogen, hydroxyl, low alkyl group, low-grade alkenyl, lower alkoxy, low-grade alkenyl oxygen base or can substituted amino, further preferred hydrogen or low alkyl group (for example methyl), preferred especially hydrogen.
The invention provides compound shown below (each symbol if no special instructions, in various is identical with above-mentioned implication).
[Chemical formula 1 2]
R 1Be hydrogen or low alkyl group, preferred hydrogen.
X is a singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group; Preferred singly-bound, O, S, maybe can there be low-grade alkylidene (the more preferably C1~C3) of O or S.
R 2For can substituted aryl;
R 3For hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino.More preferably hydrogen or can substituted low alkyl group.
R 4Be hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O, S, SO, SO 2, NR a(R aBe hydrogen or low alkyl group) ,-N=and=heteroatom group of N-).More preferably hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group.
Dotted line is represented the existence or the non-existence of key.
B 1And B 2Wherein a side is CR 20R 21, the opposing party is NR 22, do not have dotted line this moment.
B 2Be NR 22The time, R 4And R 22Can form together can substituted heterocycle (for example G ring).
B 2Be CHR 21The time, R 4And R 21Can form together can substituted heterocycle (for example H ring).
B 1And B 2Independent separately, be C, CR 23Or N.B 1And B 2Part can form together can substituted heterocycle (for example C ring), at this moment, and B 1And B 2Independent separately, be CR 23Or during N, dotted line is represented the non-existence of key.
R 20, R 21, R 22And R 23Independent separately, be selected from hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue (can exist in this low alkyl group and be selected from O, S, SO, SO 2, NR 5(R 5With R 4Independent, be selected from and R 4Identical substituting group group);-N=and=heteroatom group of N-); hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl.
R 20, R 21, R 22And R 23More preferably be selected from hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl.
Above-claimed cpd (I) comprises compound shown below (I-10), (I-6), (I-9) and (I-12).
[Chemical formula 1 3]
Figure A20068004873700351
The G ring is 5~7 yuan of rings that contain 2~3 O, S and/or N atom, contains 2 N atoms at least.More preferably be selected from above-mentioned heterocycle, can exemplify following ring:
[Chemical formula 1 4]
Figure A20068004873700361
(Z is CH 2, O, S, SO, SO 2Or NR described later 19)
Substituting group on the G ring can exemplify one or more the identical or different substituting groups that are selected from above-mentioned substituting group group S2.Substituting group on G ring part can further form fused rings or volution with adjacent atom, and preferably can form can substituted carbocyclic ring (preferred 5~6 yuan of rings) or can substituted heterocycle (preferred 5~6 yuan of rings).
One of substituent preferred version on the G ring is: low alkyl group (for example methyl, sec.-propyl), lower alkoxy low alkyl group (for example 2-methoxy ethyl) or can substituted amino (substituent example: low alkyl group (for example methyl), lower alkylcarbonyl (for example ethanoyl)).
R 3Be preferably hydrogen or can substituted low alkyl group, more preferably hydrogen.
R 14Can exemplify and above-mentioned R 20, R 21, R 22And R 23The group that situation is same; but be preferably hydrogen; can substituted low alkyl group (substituting group: amino; low-grade alkyl amino; lower alkoxy; aryloxy; cyano group; halogen; (replacement) formamyl; acyl amino; low-grade alkynyl; hydroxyl); cycloalkyl; cycloalkyl low-grade alkyl; phenyl; benzyl; 5~6 Yuans aromatic heterocyclic radicals; 5~6 element heterocycle base low alkyl groups; can substituted lower alkylcarbonyl (substituting group: lower alkoxy); can substituted benzoyl (substituting group: lower alkoxy); substituted sulphonyl (substituting group: low alkyl group; aryl; heterocyclic radical), more preferably hydrogen or can substituted low alkyl group.
[Chemical formula 1 5]
Figure A20068004873700371
Preferred B 1Be CR 20R 21, B 2Be NR 22(R 20, R 21And R 22Identical with above-mentioned implication).
Also preferred B 1Be NR 22, B 2Be CR 20R 21(R 20, R 21And R 22Identical with above-mentioned implication).
R 3Be preferably hydrogen or can substituted low alkyl group, more preferably hydrogen.
R 20, R 21And R 22Preferably independent separately, be hydrogen; can substituted low alkyl group (substituent example: amino; low-grade alkyl amino; rudimentary carbonylamino; lower alkoxy; aryloxy; cyano group; halogen; acyl amino (for example rudimentary carbonylamino); low-grade alkynyl; hydroxyl; elementary alkoxy carbonyl; can substituted heterocyclic radical carbonyl (substituent example: low alkyl group; lower alkoxy); low-grade alkenyl; can substituted formamyl (substituent example: low alkyl group); lower alkylcarbonyl oxygen base; low alkyl group oxygen base carbonyl; lower alkylcarbonyl amino; the oxo base; low-grade alkynyl); cycloalkyl; cycloalkyl low-grade alkyl; can substituted aryl (substituent example: low alkyl group; halogen; low alkyl group oxygen base; nitro); can substituted aromatic yl elementary alkyl (substituent example: low alkyl group; halogen; low alkyl group oxygen base; nitro; the oxo base); can substituted heterocyclic radical (substituent example: low alkyl group; halogen; low alkyl group oxygen base; nitro); can substituted heterocyclic radical low alkyl group (substituent example: low alkyl group; halogen; low alkyl group oxygen base; nitro; the oxo base); can substituted lower alkylcarbonyl (substituting group: lower alkoxy; halogen); naphthene base carbonyl; can substituted benzoyl (substituting group: lower alkoxy; halogen); substituted sulphonyl (substituting group: low alkyl group; aryl; heterocyclic radical (preferred 5~6 Yuans aromatic heterocyclic radicals)).
More preferably R 20And R 21Be hydrogen.
In the compound (I-6), more preferably: R 1Be hydrogen or low alkyl group, more preferably hydrogen; X is a low-grade alkylidene; R 2Be phenyl or the phenyl that replaced by halogen atom at least, more preferably the phenyl that is replaced by 1~2 halogen atom (for example F); R 3Be hydrogen; B 1Be CH 2Or NR 22B 2Be NR 22Or CH 2, more preferably B 1Be NR 22B 2Be CH 2
R 4Being preferably can substituted low alkyl group (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl; Substituent example: hydroxyl, amino, low-grade alkyl amino, lower alkoxy, aryloxy, the oxo base, elementary alkoxy carbonyl, can substituted heterocyclic radical carbonyl (substituent example: low alkyl group, lower alkoxy)), specifically have: low-grade alkyl amino low alkyl group (2-dimethyl aminoethyl for example, 2-diethylamino ethyl), lower alkoxy low alkyl group (1-methoxy ethyl for example, the 2-methoxy-propyl, the 2-methoxy ethyl, the 3-methoxy-propyl, 4-methoxyl group butyl, the 2-ethoxyethyl group, the 3-ethoxycarbonyl propyl, 4-oxyethyl group butyl, 2-propoxy-ethyl, 3-propoxy-propyl group, 4-propoxy-butyl) or aryloxy low alkyl group (2-phenoxy group ethyl for example, the 3-phenoxy propyl); Can substituted cycloalkyl (for example cyclopropyl); Can substituted cycloalkyl low-grade alkyl (for example cyclopropyl methyl, 1-adamantyl methyl, 2-adamantyl methyl, dodecahedrane methyl, cubane methyl); Can substituted aryl (phenyl for example; Substituent example: can there be the low-grade alkylidene of heteroatoms (for example O) in low alkyl group, halogen, low alkyl group oxygen base, nitro or substituting group part); Can substituted aromatic yl elementary alkyl (benzyl for example; Substituent example: can there be the low-grade alkylidene of heteroatoms (for example O) in low alkyl group, halogen, low alkyl group oxygen base, nitro or substituting group part); Can substituted heterocyclic radical (preferred 5~6 yuan of rings) (for example picolyl, pyridyl; Substituent example: low alkyl group, halogen, low alkyl group oxygen base, nitro); Or can substituted heterocyclic radical (preferred 5~6 yuan of rings) low alkyl group (for example piperonyl methyl, 2-morpholino base ethyl, thienyl methyl, furfuryl, tetrahydrofuran methyl, diox methyl, tetrahydropyrans methyl, thiazole methyl, oxazole methyl, 1,2,4-oxadiazole methyl, 1,3,4-oxadiazole methyl; Substituent example: low alkyl group, halogen, low alkyl group oxygen base, nitro; This heterocycle can condense with phenyl ring).
R 22Being preferably can substituted alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, neo-pentyl; Substituent example: amino, low-grade alkyl amino, lower alkoxy, aryloxy, cyano group, halogen, (replacement) formamyl, acyl amino, the oxo base), be specially: low-grade alkyl amino low alkyl group (2-dimethyl aminoethyl for example, 2-diethylamino ethyl), lower alkoxy low alkyl group (1-methoxy ethyl for example, the 2-methoxy-propyl, the 2-methoxy ethyl, the 3-methoxy-propyl, 4-methoxyl group butyl, the 2-ethoxyethyl group, the 3-ethoxycarbonyl propyl, 4-oxyethyl group butyl, 2-propoxy-ethyl, 3-propoxy-propyl group, 4-propoxy-butyl), aryloxy low alkyl group (2-phenoxy group ethyl for example, the 3-phenoxy propyl), cyano-lower alkyl group (for example cyano methyl), junior alkyl halides (methyl fluoride for example, 2,2, the 2-trifluoromethyl), or carborane methyl, acyl amino low alkyl group (for example 2-kharophen ethyl); Low-grade alkenyl (for example allyl group, propargyl, crot(on)yl); Cycloalkyl low-grade alkyl (for example 3-cyclopropyl, cyclopropyl methyl, 1-adamantyl methyl, 2-adamantyl methyl, dodecahedrane methyl, cubane methyl); Can substituted aryl (phenyl for example; The substituting group part can be the low-grade alkylidene that can have heteroatoms (for example O)); Can substituted aromatic yl elementary alkyl (benzyl for example; The substituting group part can be the low-grade alkylidene that can have heteroatoms (for example O)); Can substituted heterocyclic radical (for example picolyl, pyridyl; Substituent example: low alkyl group); Can substituted heterocyclic radical low alkyl group (for example piperonyl methyl, morpholino base ethyl, furfuryl, tetrahydrofuran methyl, diox methyl, tetrahydropyrans methyl, triazole methyl, tetrazole methyl, thiazole methyl, oxazole methyl, 1,2,4-oxadiazole methyl, 1,3,4-oxadiazole methyl, isoxazole methyl, imidazoles methyl, methylpyrrole methyl, hexaoxacyclooctadecane-6 methyl; Substituent example: low alkyl group); Can substituted lower alkylcarbonyl (ethanoyl for example; Substituent example: lower alkoxy (for example methoxyl group)); Can substituted aryl carbonyl (benzoyl for example; Substituent example: lower alkoxy); Replace (sulphur) urea (for example urea, low alkyl group urea (for example dimethyl urea), dimethyl thiourea); Or substituted sulphonyl (for example alkyl sulphonyl (for example methylsulfonyl), aryl sulfonyl (for example benzenesulfonyl), heterocyclic radical alkylsulfonyl (for example thiophen sulfuryl)).
[Chemical formula 1 6]
Figure A20068004873700391
C ring expression can substituted carbocyclic ring or can substituted heterocycle.When the C ring is heterocycle, B 1And B 2Independent separately, be C, CH or N.But work as B 1And B 2Independent separately, be CR 23Or during N, dotted line is represented the non-existence of key.When the C ring is heterocycle, can exemplify and above-mentioned A ring or the same heterocycle of G ring, the substituting group on the C ring too.That is, the substituting group on the C ring can exemplify one or more the identical or different substituting group that is selected from above-mentioned substituting group group S2.Substituting group on C ring part can further form fused rings or volution with adjacent atom, and preferably can form can substituted carbocyclic ring (preferred 5~6 yuan of rings) or can substituted heterocycle (preferred 5~6 yuan of rings).
When the C ring is carbocyclic ring, B 1And B 2Independent separately is C or CH, can exemplify 5~7 yuan of rings as carbocyclic ring.
Dotted line is represented the existence or the non-existence of key, but preferably represents non-existence.
The C ring comprises following ring, preferred (i), (l):
[Chemical formula 1 7]
Figure A20068004873700411
(Z is CH 2, O, S, SO, SO 2Or NR 19)
One of substituent preferred version on the C ring is: low alkyl group (for example methyl, sec.-propyl), lower alkoxy low alkyl group (for example 2-methoxy ethyl), can substituted amino (substituent example: low alkyl group (for example methyl), lower alkylcarbonyl (for example ethanoyl)).
R 19More preferably hydrogen, low alkyl group, lower alkoxy low alkyl group.
R 3Be preferably hydrogen or can substituted low alkyl group, more preferably hydrogen.
In the compound (I-9), R 4Preferably exemplify R with compound (I-6) 4Same group.
[Chemical formula 1 8]
Figure A20068004873700421
The H ring is meant the heterocycle that encircles same implication with above-mentioned A, preferred 5~7 yuan of rings, and the substituting group on each ring also can exemplify the same substituting group of situation with the A ring.That is, the substituting group on the H ring can exemplify one or more the identical or different substituting group that is selected from above-mentioned substituting group group S2.Substituting group on H ring part can further form fused rings or volution with adjacent atom, and preferably can form can substituted carbocyclic ring (preferred 5~6 yuan of rings) or can substituted heterocycle (preferred 5~6 yuan of rings).
R 3Be preferably hydrogen or can substituted low alkyl group, more preferably hydrogen.
R 24Can exemplify and above-mentioned R 20, R 21, R 22And R 23Same group; preferred hydrogen; can substituted low alkyl group (substituting group: amino; low-grade alkyl amino; lower alkoxy; aryloxy; cyano group; halogen; (replacement) formamyl; acyl amino; low-grade alkynyl; hydroxyl); cycloalkyl; cycloalkyl low-grade alkyl; phenyl; benzyl; 5~6 yuan of aromatic heterocyclic radicals; 5~6 yuan of heterocyclic radical low alkyl groups; can substituted lower alkylcarbonyl (substituting group: lower alkoxy; halogen); can substituted benzoyl (substituting group: lower alkoxy; halogen); substituted sulphonyl (substituting group: low alkyl group; aryl; heterocyclic radical (preferred 5~6 yuan of aromatic heterocyclic radicals)), more preferably hydrogen or can substituted low alkyl group.
The chemical structure of compound (I) has following feature at least.
(1) have on the annelated heterocycles as main framing the oxo base (=O), hydroxyl (OH) and oxo base (=O) replace.
(2) adjacent regions of the oxo base on the heterocycle has substituted formamyl (CONR 1XR 2).
By having said structure, can show very strong intergrase restraining effect and/or cell inhibitory effect activity especially for the virus that contains HIV.Preferred compound is also effective for the resistance virus strain.On the other hand, the structure degree of freedom of other parts is bigger, can have various substituting groups, can also form fused rings, and this fused rings can also further be substituted.
The present invention also provides acceptable salt and their solvate in compound (I) pharmacy.Possible in theory all tautomers of The compounds of this invention, geometrical isomer, optical isomer, racemic modification etc. are also within the scope of the invention.
Acceptable salt in the pharmacy as The compounds of this invention, basic salt for example has an alkali metal salts such as sodium salt, sylvite; Alkaline earth salt such as calcium salt, magnesium salts; Ammonium salt; Aliphatic amine salt such as front three amine salt, triethylamine salt, dicyclohexyl amine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; N, aralkyl amine salt such as N-dibenzyl-ethylenediamin, Benethamine diacetale salt; Heterocyclic aromatic amine salt such as pyridinium salt, picoline salt, quinolinium, isoquinoline 99.9 salt; Quaternary ammonium salts such as tetramethyl ammonium, tetraethyl-ammonium salt, benzyl trimethyl ammonium salt, benzyl triethyl ammonium ammonium salt, benzyl tributyl ammonium salt, methyl trioctylphosphine ammonium salt, 4-butyl ammonium; Alkaline amino acid salt such as arginic acid salt, lysine salt etc.Acid-salt for example has inorganic acid salts such as hydrochloride, vitriol, nitrate, phosphoric acid salt, carbonate, supercarbonate, perchlorate; Organic acid salts such as acetate, propionic salt, lactic acid salt, maleate, fumarate, tartrate, malate, Citrate trianion, ascorbate salt; Sulfonate such as mesylate, isethionate, benzene sulfonate, tosilate; Acidic amino acid such as aspartate, glutaminate etc.
The solvate of The compounds of this invention has alcohol adduct or hydrate etc.
The conventional preparation method of The compounds of this invention can exemplify following.
(feedstock production method)
[chemical formula 41]
Figure A20068004873700441
(in the formula, L 1Expression leavings group (for example halogen); P 1, P 2The blocking group of expression hydroxyl; P 3The blocking group (for example low alkyl group) of expression carboxyl; R a, R bSubstituting group on expression hydrogen or the amino).
Blocking group (the P of hydroxyl 1, P 2) for example have: acyl group (for example ethanoyl, pivaloyl, benzoyl), aralkyl (for example benzyl), low alkyl group (for example methyl), alkoxyalkyl (for example methoxymethyl, methoxy ethyl), low alkyl group alkylsulfonyl (for example methylsulfonyl), aryl sulfonyl (for example benzenesulfonyl, tosyl group), alkoxy carbonyl (for example methoxycarbonyl) etc.
Blocking group (the P of carboxyl 3) for example have: low alkyl group (for example methyl, ethyl), aralkyl (for example benzyl).
(step 1)
This step is to make compound (II) and compound (III) condensation, the reaction of synthetic compound (IV).Reaction can be carried out according to the condition of the amidate action of the carboxylic acid that carries out usually.Compound (II) can make its direct reaction, also can be transformed into corresponding acyl chlorides or active ester, reacts then.Preferably in the presence of condensing agent, in appropriate solvent, carry out.
Condensing agent can use dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride etc.Also can add alkali such as reagent such as I-hydroxybenzotriazole or N-hydroxy-succinamide, triethylamine, N-methylmorpholine, pyridine as required.
Temperature of reaction is 0~150 ℃, preferred room temperature~70 ℃.
Reaction solvent can be extensive use of non-protonic solvent, preferred tetrahydrofuran (THF) (THF), 1,4-diox, dimethyl formamide (DMF), methylene dichloride, chloroform etc.
Reaction times is several minutes~tens of hours, preferred 9~17 hours.
(step 2)
This step is to import protection hydroxyl (OP in compound (IV) 1), the reaction of preparation compound (V).Reaction can be carried out according to the conditions such as alkoxylation of carrying out usually.
For example, by making metal alkoxides (for example sodium methylate) and compound (IV) reaction, can synthesize P 1Compound (V) for methyl.
Temperature of reaction is 0~200 ℃, preferred 80~120 ℃.
Reaction solvent can exemplify alcohol, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO).
Reaction times is several minutes~tens of hours, preferred 5~10 hours.
(step 3)
This step is the hydroxyl of protection compound (V), the reaction of preparation compound (VI).Reaction can be carried out according to the protective reaction condition of the hydroxyl that carries out usually.For example, use diisopropyl azo-2-carboxylic acid or diethylazodicarboxylate, can synthesize P thus with pure and mild various phosphines 2Compound (VI) for alkyl.
Temperature of reaction is 0~100 ℃, preferred 0 ℃~room temperature.
Reaction solvent can exemplify THF, toluene, methylene dichloride etc.
Reaction times is several minutes~tens of hours, preferred 1~3 hour.
(step 4)
This step is the nitrogen-atoms oxidation that makes compound (VI), the reaction of preparation compound (VII).Reaction can be carried out according to oxidation reaction condition that carry out usually, the use oxygenant.
Temperature of reaction is 0~100 ℃, preferred ice-cooled time~room temperature.
Reaction solvent can exemplify chloroform, methylene dichloride, acetate etc.
Oxygenant can exemplify metachloroperbenzoic acid, hydrogen peroxide etc.
Reaction times is several minutes~tens of hours, preferred 1~5 hour.
(step 5)
This step is to make the methyl of compound (VII) carry out hydroxylated reaction.Preferably, carry out acetoxylation (0~150 ℃ of temperature of reaction, preferred 120~140 ℃), hydrolysis then (for example using alkali (for example alkali hydroxide metal) to handle) with acetic anhydride.
Reaction times is several minutes~tens of hours, and preferred acetylize needs 0.5~2 hour, is hydrolyzed to 0.5~1 hour.
(step 6)
This step is to make the hydroxyl of compound (VIII) carry out oxidation, the reaction of synthetic compound (IX).
Temperature of reaction is 0~150 ℃, preferred room temperature~70 ℃.
Reaction solvent can exemplify chloroform etc.
Oxygenant can exemplify dimethyl sulfoxide (DMSO) etc.
Reaction times is several minutes~tens of hours, preferred 0.1~1 hour.
(step 7)
This step is the formyl radical oxidation that makes compound (IX), the reaction of synthetic compound (X).
Temperature of reaction is 0~150 ℃, preferred ice-cooled time~room temperature.
Reaction solvent can exemplify alcohol etc.
Oxygenant can exemplify potassium hydroxide and iodine.
Reaction times is several minutes~tens of hours, preferred 0.5~3 hour.
(step 8)
This step is the OP with compound (X) 2The part deprotection, the reaction of synthetic compound (XI).Reaction can be carried out according to the deprotection reaction condition of the hydroxyl protecting group that carries out usually.
Temperature of reaction is 0~150 ℃, preferred ice-cooled time~room temperature.
Reaction solvent can exemplify acetonitrile, methylene dichloride, THF etc.
Reaction times is several minutes~tens of hours, preferred 1~3 hour.
(step 9)
This step is the OP with compound (XI) 1The part deprotection, the reaction of synthetic compound (I-A).Reaction is preferably handled with Lewis acid (for example aluminum chloride).
Temperature of reaction is 0~150 ℃, preferred 10~50 ℃.
Reaction solvent can exemplify methylene dichloride, THF etc.
Reaction times is several minutes~tens of hours, preferred 1~3 hour.
(step 10)
This step is the ester moiety (COOP with compound (X) 3) deprotection, the reaction of synthesis of carboxylic acid (XII).Preferably use alkali (for example NaOH) to be hydrolyzed.
Temperature of reaction is 0~150 ℃, preferred 10~50 ℃.
Reaction solvent can exemplify methyl alcohol, water etc.
Reaction times is several minutes~tens of hours, preferred several minutes~2 hours.
Carboxylic acid (XII) can be transformed into various derivatives (for example acid amides).
(step 11)
This step is to make various amine and compound (XII) reaction, the reaction of synthetic compound (XIII).Reaction can be carried out according to the amidation reaction condition of the carboxylic acid that carries out usually, for example can similarly react with step 1.
Temperature of reaction is 0~150 ℃, preferred room temperature~70 ℃.
Reaction solvent can be extensive use of non-protonic solvent, preferred tetrahydrofuran (THF) (THF), 1,4-diox, dimethyl formamide (DMF), methylene dichloride, chloroform etc.
Reaction times is several minutes~tens of hours, preferred several minutes~3 hours.
The amide moieties of gained compound (XIII) can further carry out chemical modification (for example N-alkylation).
(step 12)
This step is the OP with compound (XIII) 1And OP 2The part deprotection, the reaction of synthetic compound (I-B).Reaction can be carried out according to the deprotection reaction condition of the blocking group of the hydroxyl that carries out usually.
When for example using pyridine hydrochloride, temperature of reaction is 0~200 ℃, preferred 150~180 ℃.
Reaction times is several minutes~tens of hours, preferred 1~5 minute.
(step 13)
This step is the ester moiety (COOP with compound (XI) 3) deprotection, the reaction of synthesis of carboxylic acid (XIV).Preferably use alkali (for example lithium hydroxide) hydrolysis.
Temperature of reaction is 0~150 ℃, preferred 10~50 ℃.
Reaction solvent can exemplify methyl alcohol, water etc.
Reaction times is several minutes~tens of hours, preferred several minutes~3 hours.
(step 14)
This step is the OP with compound (XIV) 1Part is carried out deprotection, the reaction of synthetic compound (I-C).Reaction is preferably handled with Lewis acid (for example boron tribromide).
Temperature of reaction is 0~150 ℃, and is preferably ice-cooled~room temperature.
Reaction solvent can exemplify methylene dichloride etc.
Reaction times is several minutes~tens of hours, preferred several minutes~5 hours.
The above-mentioned monocycle carbamoylpyridone derivative that obtains is derived by following method and is the dicyclo compound.
(preparation method 6)
[chemical formula 47]
(in the formula, each symbol is identical with above-mentioned implication)
(step 35)
According to the amidate action of routine, make protected hydrazine reagent and compound (XIV) reaction, obtain compound (XIV-1) thus.Protected hydrazine reagent for example can be synthetic according to the method for Pol.J.Chem.2003.77.315~319.Compound (XIV) can make its direct reaction, but also can be transformed into corresponding acyl chlorides or active ester, reaction then.Preferably in the presence of condensing agent, in appropriate solvent, carry out.
Condensing agent can use dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride etc.Also can add alkali such as reagent such as I-hydroxybenzotriazole or N-hydroxy-succinamide, triethylamine, N-methylmorpholine, pyridine as required.
Temperature of reaction is about 0~150 ℃, preferred room temperature~70 ℃.
Reaction solvent can be extensive use of non-protonic solvent, preferred tetrahydrofuran (THF) (THF), 1,4-diox, dimethyl formamide (DMF), methylene dichloride, chloroform etc.
Reaction times is several minutes~tens of hours, preferred 10 minutes~5 hours.
(step 36)
P with compound (XIV-1) 2The part deprotection obtains compound (XIV-2) thus.
Temperature of reaction is about 0~150 ℃ usually, preferred room temperature~60 ℃.
Reaction solvent can exemplify ethyl acetate, 1,4-diox, THF.
Reaction times is several minutes~tens of hours, preferred several minutes~5 hours.
(step 37)
Aminal according to routine forms reaction, makes carbonyl compound and compound (XIV-2) reaction, obtains compound (XIV-3) thus.
Temperature of reaction is about 0~100 ℃ usually, preferred room temperature~60 ℃.
Reaction solvent can exemplify methylene dichloride, THF, toluene.
Reaction times is several minutes~tens of hours, preferred several minutes~5 hours.
This reaction is preferably carried out in the presence of acid catalyst (for example acetate, tosic acid).
(step 38)
By P with compound (XIV-3) 1The part deprotection obtains compound (XIV-4).
Temperature of reaction is about 0~180 ℃ usually, preferred room temperature~60 ℃.
Reaction solvent can exemplify THF, 1,4-diox, methylene dichloride.
Reaction times is several minutes~a few hours, preferred several minutes~5 hours.
In the above-mentioned reaction, by using R 4And R 22The compound that forms ring can synthesize the three ring property compounds (forming the G ring) as above-mentioned compound (I-10) as protected hydrazine reagent together.
(preparation method 7)
[chemical formula 48]
Figure A20068004873700511
(in the formula, each symbol is identical with above-mentioned implication)
(step 39)
According to step 35, amine reagent and compound (XIV) are reacted, obtain compound (XIV-5) thus.
(step 40)
Make N-amination reagent and compound (XIV-5) reaction, obtain compound (XIV-6) thus.The preparation of N-amination reagent and N-ammoxidation for example can be according to J.Med.Chem.1984, and the method for record is carried out in 27,1103~1108.
(step 41)
According to step 37, make carbonyl compound and compound (XIV-6) reaction, obtain compound (XIV-7) thus.
(step 42)
Partly carry out various modifications by NH, obtain compound (XIV-8) thus compound (XIV-6).Method of modifying can exemplify common N-alkylation, uses halid alkylation, use reductive amination, acylations or the sulfonylation etc. of carbonyl compound.
(step 43)
According to step 38, to the P of compound (XIV-8) 1The part deprotection obtains compound (XIV-9) thus.
(preparation method 8)
[chemical formula 49]
(in the formula, each symbol is identical with above-mentioned implication; N is 1~4 integer; R and R ' are substituting group arbitrarily; Each X 1Can be identical or different, X 1The part of (when being C, N) can be substituted; N is preferably 1~4 integer).
(step 44)
Compound (XIV-10) is carried out conventional acetal deprotection reaction, obtain compound (XIV-11) thus.This reaction is preferably carried out under acidic conditions.
Temperature of reaction is about 0~120 ℃ usually, preferred room temperature~60 ℃.
Reaction solvent can exemplify THF, 1,4-diox, water, methyl alcohol.
Reaction times is several minutes~tens of hours, preferred several minutes~5 hours.
Compound (XIV-10) can make to have substituent hydrazine reagent of protected aldehyde type and compound (VIV) reaction acquisition according to step 35.
(step 45)
According to step 38, to the P of compound (XIV-11) 1The part deprotection obtains compound (XIV-12) (forming the C ring) thus.
(preparation method 9)
[chemical formula 50]
Figure A20068004873700531
(in the formula, each symbol is identical with above-mentioned implication; L is a leavings group, and R and R ' are substituting group arbitrarily)
(step 46)
Aminal according to routine forms reaction, makes carbonyl compound and compound (XIV-6) reaction, obtains compound (XIV-13) thus.
(step 47)
Make compound (XIV-13) at intramolecular cyclization, obtain compound (XIV-14) thus.Reaction can be carried out according to common alkylated reaction or condition proximate with it.
(step 48)
According to step 38, to the P of compound (XIV-14) 1The part deprotection obtains compound (XIV-15) (forming the C ring) thus.
(preparation method 11)
[chemical formula 51]
Figure A20068004873700541
(in the formula, each symbol is identical with above-mentioned implication)
(step 52)
According to step 35, make amine reagent and compound (XIV) reaction, obtain compound (XIV-19) thus.
(step 53)
Make N-amination reagent and compound (XIV-19) reaction, obtain compound (XIV-20) thus.The preparation of N-amination reagent and N-ammoxidation for example can be according to J.Med.Chem.1984, and the method for 27,1103~1108 records is carried out.
(step 54)
According to step 44, make compound (XIV-20) carry out conventional acetal deprotection reaction, obtain compound (XIV-21) thus.
(step 55)
The NH of compound (XIV-21) is partly carried out various modifications, obtain compound (XIV-22) thus.Method of modifying can exemplify common N-alkylation, uses halid alkylation, use reductive amination, acylations or the sulfonylation etc. of carbonyl compound.
(step 56)
According to step 38, to the P of compound (XIV-22) 1The part deprotection obtains compound (XIV-23) thus.
The The compounds of this invention of above-mentioned gained further can be carried out chemical modification, synthesize other compound.In the above-mentioned reaction, there are reactive functional groups (for example OH, COOH, NH at chain portion etc. 2) time, can before reaction, protect deprotection after reaction as required.
The compounds of this invention for example can be used as the medicine of antiviral drug etc.Compound of the present invention has significant inhibitory effect for the intergrase of virus.Therefore, at least the viral caused various diseases of producing intergrase and propagation when compound of the present invention is expected to for infection in zooblast has prevention or result of treatment, for example as being useful, be useful as anti-HIV medicine etc. to the integrase inhibitor of retrovirus (for example HIV-1, HIV-2, HTLV-1, SIV, FIV etc.).
The compounds of this invention can make up with the anti-HIV medicine that has with different mechanisms of action such as reverse transcriptase inhibitors and/or proteinase inhibitor, as conjoint therapy.Particularly present, integrase inhibitor is not still gone public, and is useful with The compounds of this invention and reverse transcriptase inhibitors and/or proteinase inhibitor combination, as conjoint therapy.
Above-mentioned application is not limited only to anti-HIV combination medicine, as drug cocktail therapy (treatment) etc., also comprises so that the form of the combination medicine that the HIV (human immunodeficiency virus)-resistant activity of other anti-HIV medicine improves is used.
In field of gene, when the retrovirus vector that uses based on HIV or MLV, the infection that The compounds of this invention can be used for preventing retrovirus vector to destination organization with external diffusion., when turning back in the body more afterwards the carrier cells infected, give The compounds of this invention in advance particularly in vitro, then can prevent intravital unnecessary infection.
The compounds of this invention can oral or non-orally give.During orally give, The compounds of this invention can be with solid preparations such as common preparation, for example tablet, powder, granule, capsules; Aqua; The oiliness suspensoid; Or any formulation of liquid preparations such as syrup or elixir is used.During non-orally give, The compounds of this invention can be as water-based or oiliness suspensoid injectio, nasal drops.When it prepares, can use vehicle commonly used, tackiness agent, lubricant, aqueous solvent, oil-based solvent, emulsifying agent, suspensoid, sanitas, stablizer etc. arbitrarily.The special preferred oral preparation of anti-HIV medicine.Preparation of the present invention can be by will treating significant quantity The compounds of this invention acceptable carrier or thinner in pharmacy make up (for example mixing) preparation.
The administered dose of The compounds of this invention is according to the kind that gives method, patient's age, body weight, state and disease and different, but during common orally give, the about 0.05mg~3000mg of per day for adults, preferably about 0.1mg~1000mg, gradation gives as required.During non-orally give, the about 0.01mg~1000mg of per day for adults, preferably about 0.05mg~500mg.
Below provide embodiment.
Embodiment A-1) 9-hydroxyl-2-(2-methoxyl group-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Embodiment B-1) 9-hydroxyl-2-(2-methoxyl group-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
[chemical formula 52]
Figure A20068004873700571
1) 189g (1.5mol) maltol 1 is dissolved in the 1890mL dimethyl formamide, adds 184mL (1.5mol) bromotoluene.Solution was stirred 15 minutes down at 80 ℃, add 228g (1.65mol) salt of wormwood then, stirred 1 hour.Reaction solution is cooled to room temperature, and the filtering inorganic salt heat up in a steamer filtrate under the decompression then.Add the 1000mL tetrahydrofuran (THF) in the inorganic salt of separating out once more, filter, heat up in a steamer filtrate under the decompression, obtaining 329g thus is the crude product (>100%) of the 3-benzyloxy-2-methyl-pyrans-4-ketone 2 of brown oil.
NMR(CDCl 3)δ:2.09(3H,s),5.15(2H,s),6.36(1H,d,J=5.6Hz),7.29-7.41(5H,m),7.60(1H,d,J=5.6Hz).
2) 162.2g (750mmol) above-claimed cpd 2 is dissolved in the 487mL ethanol, adds 974mL ammoniacal liquor (28%) and 150mL (900mmol) 6 Equivalent Hydrogen aqueous solution of sodium oxide.Reaction solution was stirred 1 hour down at 90 ℃, in ice-cooled cooling down, add 58g (1080mmol) ammonium chloride then then.In reaction solution, add chloroform, extract, organic layer is washed with saturated sodium bicarbonate water, use anhydrous sodium sulfate drying then.Heat up in a steamer under the decompression and desolvate, in resistates, add Virahol and diethyl ether, the crystal that leaching is separated out, obtaining 69.1g is the 3-benzyloxy-2-methyl isophthalic acid H-pyridine-4-ketone 3 (43%) of pale yellow crystals.
NMR(DMSO-d 6)δ:2.05(3H,s),5.04(2H,s),6.14(1H,d,J=7.0Hz),7.31-7.42(5H,m),7.46(1H,d,J=7.2Hz),11.29(1H,brs).
3) 129g (599mmol) above-claimed cpd 3 is suspended in the 1300mL acetonitrile, adds 117g (659mmol) N-bromine succinimide, at room temperature stirred 90 minutes.The crystal that leaching is separated out, with acetonitrile and diethyl ether washing, obtaining 154g thus is the 3-benzyloxy-5-bromo-2-methyl-pyridine-4-alcohol 4 (88%) of clear crystal.
NMR(DMSO-d 6)δ:2.06(3H,s),5.04(2H,s),7.32-7.42(5H,m),8.03(1H,d,J=5.5Hz),11.82(1H,brs).
4) at room temperature, close palladium and 30.8g (516mmol) 1 to 88g (300mmol) above-claimed cpd 4,13.4g (60mmol) acetate, add 264mL methyl alcohol and 210mL (1.5mol) triethylamine in the 660mL dimethyl formamide solution of two (diphenyl phosphine) propane of 3-.With replacing with carbon monoxide in the reaction vessel, at room temperature stirred 30 minutes, stirred 18 hours down at 80 ℃ then.At the ice-cooled container that has added 1500mL ethyl acetate, 1500mL saturated aqueous ammonium chloride and 1500mL water that stirs down, to wherein adding reaction solution, the leaching throw out.With 300mL water, 300mL ethyl acetate and the washing of 300mL diethyl ether, obtaining 44.9g thus is the 5-benzyloxy-4-hydroxyl-6-methyl-nicotinic acid methyl ester 5 (55%) of clear crystal.
NMR(DMSO-d 6)δ:2.06(3H,s),3.72(3H,s),5.02(2H,s),7.33-7.42(5H,m),8.07(1H,s).
5) the 134mL solution of acetic anhydride with 19.1g (70mmol) above-claimed cpd 5 stirred 40 minutes down at 130 ℃, heated up in a steamer under the decompression then and desolvated, and obtaining 19.9g thus is skin-color crystalline 4-acetoxyl group-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6 (90%).
NMR(CDCl 3)δ:2.29(3H,s),2.52(3H,s),3.89(3H,s),4.98(2H,s),7.36-7.41(5H,m),8.85(1H,s).
6) ice-cooled following, in the 370mL chloroformic solution of 46.2g (147mmol) above-claimed cpd 6, repeatedly add 42.8g (161mmol) metachloroperbenzoic acid (65%) on a small quantity, at room temperature stirred 90 minutes, in reaction solution, add 10% wet chemical, stirred 10 minutes, and used chloroform extraction then.Organic layer is washed successively according to the order of 10% wet chemical, saturated aqueous ammonium chloride, saturated aqueous common salt, use anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, resistates is washed with Di Iso Propyl Ether, obtaining 42.6g thus is the 4-acetoxyl group-5-benzyloxy-6-methyl isophthalic acid oxygen base-nicotinic acid methyl ester 7 (87%) of clear crystal.
NMR(CDCl 3)δ:2.30(3H,s),2.41(3H,s),3.90(3H,s),5.02(2H,s),7.37-7.39(5H,m),8.70(1H,s).
7) with 2 minutes time, 42.6g (129mmol) above-claimed cpd 7 is joined 500mL in the diacetyl oxide of 130 ℃ of following heated and stirred, stirred then 20 minutes.Heat up in a steamer under the decompression and desolvate, obtaining 49.6g thus is the 4-acetoxyl group-6-acetoxy-methyl-5-benzyloxy-nicotinic acid methyl ester 8 (>100%) of dark oil thing.
NMR(CDCl 3)δ:2.10(3H,s),2.28(3H,s),3.91(3H,s),5.07(2H,s),5.20(2H,s),7.35-7.41(5H,m),8.94(1H,s).
8) in the 140mL methanol solution of 46.8g (125mmol) above-claimed cpd 8, add 376mL 2 Equivalent Hydrogen aqueous solution of sodium oxide down ice-cooled, stirred 40 minutes down at 50 ℃ then.Under ice-cooled, in reaction solution, add diethyl ether and 2 equivalent hydrochloric acid, the crystal that leaching is separated out.With gained crystal water and diethyl ether washing, obtaining 23.3g thus is the 5-benzyloxy-4-hydroxyl-6-hydroxymethyl-nicotinic acid 9 (68%) of clear crystal.
NMR(DMSO-d 6)δ:4.49(2H,s),5.19(2H,s),5.85(1H,brs),7.14-7.20(2H,m),7.33-7.43(7H,m),8.30(1H,s),10.73(1H,t,J=5.8Hz),11.96(1H,brs).
9) in the 1300mL dimethyl formamide solution of 131g (475mmol) above-claimed cpd 9,219g (1140mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and 128g (950mmol) I-hydroxybenzotriazole, add 109mL (950mmol) 4-flunamine, stirred 1.5 hours down at 80 ℃.Reaction solution is cooled to room temperature, adds hydrochloric acid then, use ethyl acetate extraction.Extraction liquid with 5% wet chemical, saturated aqueous ammonium chloride and saturated common salt water washing, is used anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, obtain the mixture of 175g 10 and 11 thus.The gained mixture is dissolved in 1050mL acetate and the 1050mL water, adds 31.1g (475mmol) zinc, reflux 1 hour.Reaction solution is cooled to room temperature, adds 10% wet chemical then, use ethyl acetate extraction.Extraction liquid with saturated aqueous ammonium chloride, saturated common salt water washing, is used anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, with the diethyl ether washing, obtaining 107g thus is 5-benzyloxy-N-(4-fluoro-the benzyl)-4-hydroxyl-6-hydroxymethyl-niacinamide 10 (59%) of clear crystal then.
NMR(DMSO-d 6)δ:4.45(2H,d,J=4.3Hz),4.52(2H,d,J=5.8Hz),5.09(2H,s),6.01(1H,brs),7.36-7.43(5H,m),8.31(1H,s),12.63(1H,brs).
10) in the 490mL chloroform suspension of 9.8g (25.6mmol) above-claimed cpd 10, add 49g Manganse Dioxide, at room temperature stirred then 1 hour.Reaction solution was stirred 20 minutes down at 60 ℃, carry out C ore deposit (Celite) then and filter, with the chloroform washing that is heated to 50 ℃.Heat up in a steamer filtrate under the decompression, obtaining 8.2g thus is 5-benzyloxy-N-(4-fluoro-the benzyl)-6-formyl radical-4-hydroxyl-niacinamide 12 (84%) of pale yellow crystals.
NMR(DMSO-d 6)δ:4.53(2H,d,J=5.8Hz),5.38(2H,s),7.15-7.21(2H,m),7.35-7.46(7H,m),8.33(1H,s),9.90(1H,s),10.35(1H,t,J=5.8Hz),12.49(1H,brs).
11) in the 105mL aqueous solution of 7.73g (78.8mmol) clorox, 7.65g (78.8mmol) thionamic acid, add the 630mL tetrahydrofuran solution of 15.0g (39.4mmol) above-claimed cpd 12 down ice-cooled, at room temperature stirred then 1 hour.In reaction solution, add 2500mL water, then the leaching crystal of separating out.With the diethyl ether washing, obtaining 14.0g thus is 3-benzyloxy-5-(4-fluoro-benzylamino the formyl radical)-4-hydroxyl-pyridine-2-formic acid 13 (90%) of clear crystal.
NMR(DMSO-d 6)δ:4.52(2H,d,J=5.8Hz),5.13(2H,s),7.14-7.19(2H,m),7.31-7.40(5H,m),7.47-7.49(2H,m),8.31(1H,d,J=4.5Hz),10.44(1H,t,J=5.9Hz),12.47(1H,brs).
12) at room temperature, 3mL dimethyl formamide solution with 198mg (0.500mmol) above-claimed cpd 13,115mg (0.600mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and 81mg (0.600mmol) I-hydroxybenzotriazole stirred 1.5 hours.Then add 3mL methyl alcohol and 153 μ L (1.10mmol) triethylamines, reflux is 1.5 hours then.Reaction solution is diluted with ethyl acetate, use saturated sodium bicarbonate water, 10% aqueous citric acid solution, saturated common salt water washing then, use anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, resistates is washed with diethyl ether, obtaining 140mg thus is 3-benzyloxy-5-(4-fluoro-benzylamino the formyl radical)-4-hydroxyl-pyridine-2-methyl-formiate 14 (69%) of clear crystal.
NMR(DMSO-d 6)δ:3.85(3H,s),4.52(2H,d,J=6.0Hz),5.15(2H,s),7.13-7.21(2H,m),7.31-7.47(7H,m),8.33(1H,s),10.41(1H,t,J=6.0Hz),12.59(1H,brs).
13) in the 54mL dimethyl formamide solution of 4.79g (16.5mmol) above-claimed cpd 14 and 8.09g (24.8mmol) cesium carbonate, add 2.15mL (24.8mmol) 3-bromopropylene, at room temperature stirred then 4.5 hours.Add aqueous ammonium chloride solution in reaction solution, use ethyl acetate extraction, anhydrous sodium sulfate drying is used in water and saturated common salt water washing.Heat up in a steamer under the decompression and desolvate, resistates is washed with diethyl ether, obtaining 6.15g thus is 1-allyl group-3-benzyloxy-5-(4-fluoro-benzylamino the formyl radical)-4-oxo-1 of clear crystal, 4-dihydro-pyridine-2-methyl-formiate 15 (83%).
NMR(CDCl 3)δ:3.76(3H,s),4.54(2H,d,J=6.0Hz),4.60(2H,d,J=6.0Hz),5.20-5.37(2H,m),5.25(2H,s),5.80-5.93(1H,m),6.98-7.04(2H,m),7.31-7.35(7H,m),8.45(1H,s),10.41(1H,m).
14) to the 228mL 1 of 7.6g (16.9mmol) above-claimed cpd 15, add the 38mL aqueous solution of 372mg (1.01mmol) potassium osmate dihydrate in the 4-dioxane solution, and then add 14.5g (67.6mmol) sodium metaperiodate, at room temperature stirred 2 hours.Under agitation in the container that has added 300mL ethyl acetate and 300mL water, add reaction solution.With organic layer water, 5% aqueous solution of sodium bisulfite and saturated common salt water washing, use anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, resistates is washed with diethyl ether, obtaining 5.39g thus is 3-benzyloxy-5-(4-fluoro-benzylamino the formyl radical)-4-oxo-1-(2-oxo-ethyl)-1 of clear crystal, 4-dihydro-pyridine-2-methyl-formiate 16 (71%).
NMR(CDCl 3)δ:3.74(3H,s),4.60(2H,d,J=5.9Hz),4.87(2H,s),5.27(2H,s),6.98-7.04(2H,m),7.30-7.40(7H,m),8.39(1H,s),9.58(1H,s),10.38(1H,s).
15) in the 12mL dichloromethane solution of 400mg (0.884mmol) above-claimed cpd 16, add 77 μ L (0.884mmol) 2-methoxyethyl amine and 18 μ L acetate, at room temperature stirred then 5 minutes.Reacted 30 minutes down at 140 ℃ by the microwave reaction device then.Heat up in a steamer under the decompression and desolvate, resistates is passed through silica gel column chromatography, to carrying out concentrating under reduced pressure with the component of toluene-acetone wash-out, obtaining 226mg thus is the 9-benzyloxy-2-(2-methoxyl group-ethyl)-1 of yellow solid, 8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides 17-1 (54%).
NMR(CDCl 3)δ:3.35(3H,s),3.65(2H,t,J=5.1Hz),3.97(2H,t,J=4.5Hz),4.63(2H,d,J=5.7Hz),5.28(2H,s),6.56(2H,m),7.01(2H,t,J=8.7Hz),7.38-7.30(5H,m),7.65(2H,d,J=6.6Hz),10.63(1H,s).
Carry out the synthetic of following compound after the same method.
Compound 17-2) 9-benzyloxy-2-(2-dimethylamino-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:2.68(6H,s),3.33(2H,t,J=6.6Hz),4.28(2H,t,J=6.6Hz),4.62(2H,d,J=6.0Hz),5.25(2H,s),6.85-6.92(2H,m),7.03(2H,t,J=8.7Hz),7.31-7.40(5H,m),7.62(2H,d,J=6.3Hz),8.65(1H,s),10.63(1H,t,J=6.0Hz).
Compound 17-3) 9-benzyloxy-2-(2-morpholine-4-base-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR (CDCl 3) δ: 2.59 (4H, s), 2.74 (2H, s), 3.73 (4H, s), 3.95 (2H, s), 4.62 (2H, d, J=6.0Hz), 5.28 (1H, s), 6.53 (1H, d, J=6.0Hz), 6.63 (1H, d, J=6.0Hz), 7.01 (2H, t, J=8.7Hz), 7.26-7.38 (5H, m), 7.64 (2H, d, J=6.9Hz), 8.61 (1H, s), 10.61 (1H, t, J=5.4Hz). and compound 17-4) 9-benzyloxy-1,8-dioxo-2-(2-piperidines-1-base-ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.55-1.76(6H,m),2.71-2.87(6H,m),4.13(2H,brs),4.62(2H,d,J=6Hz),5.28(2H,s),6.62(1H,d,J=6.2Hz),6.77(1H,m),6.97-7.04(2H,m),7.30-7.39(5H,m),7.62-7.63(2H,m),8.59(1H,s),10.56-10.61(1H,m).
Compound 17-5) 9-benzyloxy-2-(2-methyl-butyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:0.92-0.99(6H,m),1.17-1.26(1H,m),1.44-1.50(1H,m),1.88-1.92(1H,m),3.52-3.59(1H,m),3.68-3.75(1H,m),4.62(2H,d,J=6Hz),5.29(2H,s),6.36(1H,d,J=6Hz),6.59(1H,d,J=6Hz),6.98-7.04(2H,m),7.29-7.37(5H,m),7.62-7.65(2H,m),8.57(1H,s),10.62(1H,m).
Compound 17-6) 9-benzyloxy-2-(2-isopropoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.12(6H,d,J=6Hz),3.51-3.59(1H,m),3.68(2H,t,J=4.8Hz),3.96(2H,t,J=4.8Hz),4.62(2H,d,J=6Hz),5.28(2H,s),6.58-6.64(2H,m),6.98-7.04(2H,m),7.30-7.39(5H,m),7.64-7.66(2H,m),8.59(1H,brs),10.63(1H,brs).
Compound 17-7) 9-benzyloxy-2-sec.-propyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.31(6H,d,J=6.9Hz),4.62(2H,d,J=6.0Hz),5.08-5.17(1H,m),5.27(2H,s),6.39(1H,d,J=6.3Hz),6.73(1H,d,J=6.3Hz),6.98-7.04(2H,m),7.16-7.39(5H,m),7.66-7.68(2H,m),8.66(1H,s),10.67(1H,t,J=5.5Hz).
Compound 17-8) 9-benzyloxy-2-cyclohexyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.15-1.92(10H,m),4.62(2H,d,J=6.1Hz),4.70-4.78(1H,m),5.27(2H,s),6.43(1H,d,J=6.4Hz),6.69(1H,d,J=6.3Hz),7.01-7.16(2H,m),7.18-7.37(5H,m),7.66-7.68(2H,m),8.63(1H,s),10.67(1H,t,J=5.5Hz).
Compound 17-9) 9-benzyloxy-2-(4-fluoro-benzyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:4.61(2H,d,J=6.0Hz),4.92(2H,s),5.31(2H,s),6.28(1H,d,J=6.1Hz),6.62(1H,d,J=6.3Hz),6.97-7.09(4H,m),7.25-7.38(7H,m),7.62-7.66(2H,m),8.60(1H,s),10.59(1H,t,J=6.0Hz).
Compound 17-10) 9-benzyloxy-1,8-dioxo-2-[2-(propyl group-toluoyl base-amino)-ethyl]-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.09(3H,t,J=6.6Hz),2.29(3H,s),3.28-3.32(2H,m),3.61-3.65(2H,m),3.94-3.98(2H,m),4.62(2H,d,J=5.7Hz),5.31(2H,s),6.21(1H,d,J=6.0Hz),6.49(1H,d,J=6.0Hz),6.54(3H,brs),6.89-7.04(2H,m),7.08-7.39(6H,m),7.66(2H,d,J=6.3Hz),8.54(1H,s),10.57-10.62(1H,m).
Compound 17-11) 9-benzyloxy-1,8-dioxo-2-[3-(2-oxo base-tetramethyleneimine-1-yl)-propyl group]-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.96(2H,t,J=6.6Hz),2.07(2H,t,J=7.5Hz),2.42(2H,t,J=7.8Hz),3.36(2H,t,J=6.6Hz),3.43(2H,t,J=6.9Hz),3.76(2H,t,J=6.6Hz),4.62(2H,d,J=6.0Hz),5.28(2H,s),6.62(1H,d,J=6.3Hz),6.78(1H,d,J=6.3Hz),6.98-7.04(2H,m),7.30-7.38(5H,m),7.63-7.65(2H,m),8.59(1H,s),10.59-10.63(1H,m).
Compound 17-12) 9-benzyloxy-1,8-dioxo-2-(2-tetrahydrochysene-furans-2-ylmethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.48-1.62(1H,m),1.87-1.98(2H,m),2.05-2.17(1H,m),3.47(1H,dd,J=14.1,8.1Hz),3.73-3.82(1H,m),3.84-3.92(1H,m),4.12-4.21(1H,m),4.21(1H,dd,J=13.8,2.4Hz),4.62(2H,d,J=6.0Hz),5.28(2H,s),6.58(1H,d,J=6.2Hz),6.67(1H,d,J=6.2Hz),6.97-7.05(2H,m),7.28-7.39(5H,m),7.62-7.66(2H,m),8.58(1H,m),10.60-10.68(1H,m).
Compound 17-13) 9-benzyloxy-1,8-dioxo-2-pyridin-4-yl methyl isophthalic acid, 8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:4.63(2H,d,J=6.0Hz),5.00(2H,s),5.31(2H,s),6.37(1H,d,J=6.1Hz),6.68(1H,d,J=6.1Hz),6.97-7.06(2H,m),7.28-7.38(7H,m),7.56-7.61(2H,m),8.61(1H,s),8.62-8.66(2H,m),10.50(1H,t,J=6.0Hz).
Compound 17-14) 4-[9-benzyloxy-7-(4-fluoro-benzylamino formyl radical)-1,8-dioxo-1,8-dihydro-pyrido [1,2-a] pyrazine-2-yl]-piperidines-1-ethyl formate
NMR(CDCl 3)δ:1.26(3H,t,J=7.0Hz),1.62-1.69(2H,m),1.84-1.87(2H,m),2.88-2.96(2H,m),4.16(2H,q,J=7.0Hz),4.35(2H,brs),4.62(2H,d,J=5.9Hz),5.27(2H,s),6.37(1H,d,J=6.3Hz),6.69(1H,d,J=5.6Hz),6.98-7.04(2H,m),7.16-7.40(5H,m),7.64-7.67(2H,m),8.62(1H,brs),10.59(1H,brs).
Compound 17-15) 9-benzyloxy-2-methyl isophthalic acid, 8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:3.40(3H,s),4.62(2H,d,J=6.0Hz),5.27(2H,s),6.37(1H,d,J=6.0Hz),6.64(1H,d,J=6.0Hz),6.97-7.05(2H,m),7.28-7.40(5H,m),7.63-7.68(2H,m),8.60(1H,brs),10.61(1H,brs).
Compound 17-16) 2-(2-acetylamino-ethyl)-9-benzyloxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.76(3H,s),3.33(2H,s),3.79(2H,s),4.55(2H,d,J=5.1Hz),5.05(2H,s),6.89(1H,d,J=6.0Hz),7.17(2H,t,J=8.4Hz),7.30-7.50(5H,m),7.61(2H,d,J=5.1Hz),7.96(1H,s),8.93(1H,s),10.61(1H,s).
Compound 17-17) 9-benzyloxy-2-(3-isopropoxy-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.15(6H,d,J=6.1Hz),1.93-2.02(2H,m),3.45(2H,t,J=5.7Hz),3.55(1H,sep,J=6.1Hz),3.90(2H,d,J=6.8Hz),4.62(2H,d,J=6.0Hz),5.28(2H,s),6.49(1H,d,J=6.3Hz),6.59(1H,d,J=6.3Hz),6.97-7.05(2H,m),7.27-7.38(5H,m),7.62-7.65(2H,m),8.58(1H,s),10.58-10.65(1H,m).
Compound 17-18) 9-benzyloxy-2-(4-dimethylamino-benzyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:2.98(6H,s),4.62(2H,d,J=6.0Hz),4.88(2H,s),5.31(2H,s),6.35(1H,d,J=6.2Hz),6.54(1H,d,J=6.2Hz),6.77(2H,brs),6.87-7.05(2H,m),7.19-7.25(2H,m),7.29-7.41(2H,m),7.65-7.70(2H,m),8.54(1H,s),10.62(1H,t,J=5.6Hz).
Compound 17-19) 9-benzyloxy-1,8-dioxo-2-(4-sulphonamide-1-benzyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:4.62(2H,s),5.04(2H,s),5.28(2H,s),6.51(1H,d,J=6.3Hz),6.87(1H,d,J=6.3Hz),7.00-7.06(2H,m),7.20-7.40(5H,m),7.44-7.47(2H,m),7.59-7.62(2H,m),7.90-7.93(2H,m),8.63(1H,s).
Compound 17-20) 9-benzyloxy-2-[3-(4-methyl-piperazine-1-yl)-propyl group]-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.87-1.97(2H,m),2.34(3H,s),2.42(2H,d,J=6.8Hz),2.54(8H,brs),3.85(2H,d,J=6.9Hz),4.62(2H,d,J=5.9Hz),5.28(2H,s),6.52(1H,d,J=6.3Hz),6.60(1H,d,J=6.3Hz),6.95-7.05(2H,m),7.28-7.38(5H,m),7.61-7.66(2H,m),8.59(1H,s),10.61(1H,t,J=5.9Hz).
Compound 17-21) 9-benzyloxy-2-(3-methoxyl group-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.99(2H,quin,J=5.7Hz),3.34(3H,s),3.60(2H,t,J=6.3Hz),3.95(2H,t,J=6.3Hz),4.62(2H,d,J=5.7Hz),5.28(2H,s),6.45(1H,d,J=6.3Hz),6.61(1H,d,J=6.3Hz),7.01(2H,t,J=6.6Hz),7.28-7.38(5H,m),7.64(2H,d,J=6.6Hz),8.59(1H,s),10.62(1H,s).
Compound 17-22) 9-benzyloxy-1,8-dioxo-2-(2-propoxy--ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:0.89(3H,t,J=7.5Hz),1.55(2H,m),3.38(2H,t,J=6.6Hz),3.68(2H,t,J=4.8Hz),3.98(2H,t,J=4.5Hz),4.62(2H,d,J=5.7Hz),5.28(2H,s),6.57(1H,d,J=5.7Hz),6.60(1H,d,J=5.7Hz),7.01(2H,t,J=8.7Hz),7.30-7.38(5H,m),7.65(2H,d,J=6.9Hz),8.59(1H,s),10.63(1H,s).
Compound 17-23) 9-benzyloxy-1,8-dioxo-2-(2-phenoxy group-ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:4.17-4.20(2H,m),4.25-4.28(2H,m),4.62(2H,d,J=5.6Hz),5.28(2H,s),6.60-6.66(1H,m),6.86(2H,d,J=8.0Hz),6.95-7.04(2H,m),7.28-7.37(8H,m),7.64(2H,d,J=7.0Hz),8.59(1H,s),10.60(1H,brs).
Compound 17-24) 9-benzyloxy-1,8-dioxo-2-(2-pyridin-3-yl-ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:3.04(2H,t,J=7.2Hz),4.00(2H,t,J=7.2Hz),4.62(2H,d,J=6.0Hz),5.29(2H,s),6.10(1H,d,J=6.3Hz),6.52(1H,d,J=6.3Hz),7.01(2H,m),7.24(1H,m),7.30-7.39(5H,m),7.53(1H,m),7.62-7.66(2H,m),8.46(1H,m),8.52(1H,dd,J=1.5Hz,4.5Hz),8.56(1H,s),10.57(1H,brt,J=6.0Hz).
Compound 17-25) 9-benzyloxy-2-formyl-dimethylamino methyl isophthalic acid, 8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:3.01(3H,s),3.13(3H,s),4.59(2H,s),4.63(2H,d,J=6.0Hz),5.26(2H,s),6.42(1H,d,J=6.0Hz),6.64(1H,d,J=6.0Hz),7.01(2H,m),7.29-7.36(5H,m),7.64(2H,m),8.60(1H,s),10.59(1H,brt,J=6.0Hz).
Compound 17-26) 9-benzyloxy-2-(2-oxyethyl group-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.18(3H,t,J=7.0Hz),3.49(2H,q,J=7.0Hz),3.66-3.71(2H,m),3.96-4.00(2H,m),4.63(2H,d,J=6.0Hz),5.28(2H,s),6.57(1H,d,J=5.9Hz),6.61(1H,d,J=5.9Hz),6.98-7.06(2H,m),7.29-7.40(5H,m),7.63-7.67(2H,m),8.59(1H,s),10.60-10.68(1H,m).
Compound 17-27) 9-benzyloxy-2-furans-2-ylmethyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:4.55(2H,d,J=5.7Hz),4.99(2H,s),5.07(2H,s),6.44(1H,dd,J=1.8Hz,3.0Hz),6.51(1H,dd,J=0.9Hz,3.0Hz),6.99(1H,d,J=6.3Hz),7.17(2H,m),7.31-7.41(4H,m),7.46(1H,d,J=6.6Hz),7.58-7.62(2H,m),7.65(1H,dd,J=0.9Hz,1.8Hz),8.89(1H,s),10.57(1H,brt,J=5.7Hz).
Compound 17-28) 9-benzyloxy-2-[2-(4-chloro-phenyl)-ethyl]-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:3.00(2H,t,J=7.2Hz),3.98(2H,t,J=7.2Hz),4.62(2H,d,J=5.4Hz),5.30(2H,s),6.06(1H,d,J=6.3Hz),6.46(1H,d,J=6.3Hz),7.01(2H,m),7.11(2H,m),7.17-7.40(9H,m),7.64(2H,m),8.53(1H,s),10.58(1H,brt,J=5.4Hz).
Compound 17-29) 9-benzyloxy-2-(1-benzyl-tetramethyleneimine-3-yl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.75(1H,m),2.21(1H,m),2.44-2.55(2H,m),2.87(1H,brd,J=10.8Hz),3.15(1H,brt,J=8.7Hz),3.56(1H,d,J=9.9Hz),3.69(1H,d,J=9.9Hz),4.62(2H,d,J=5.7Hz),5.25(2H,s),6.66(1H,d,J=6.3Hz),6.98(1H,d,J=6.3Hz),7.00(2H,m),7.15-7.38(10H,m),7.62-7.66(2H,m),8.58(1H,s),10.63(1H,brt,J=5.7Hz).
Compound 17-30) 9-benzyloxy-1,8-dioxo-2-thiophene-2-ylmethyl-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:4.63(2H,d,J=5.2Hz),5.13(2H,s),5.32(2H,s),6.43-6.44(1H,m),6.58-6.60(1H,m),6.98-7.04(3H,m),7.13-7.14(1H,m),7.28-7.39(6H,m),7.65-7.67(2H,m),8.56(1H,s),10.58(1H,brs).
Compound 17-31) 9-benzyloxy-2-(3-dimethylamino-2,2-dimethyl-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:0.99(6H,brs),1.62(1H,brs),2.22(1H,brs),2.33(6H,brs),3.83(2H,brs),4.62(2H,d,J=6.0Hz),5.29(2H,s),6.56(1H,d,J=6.3Hz),6.64(1H,brs),7.01(2H,t,J=8.1Hz),7.27-7.36(5H,m),7.62(2H,d,J=8.1Hz),8.57(1H,s),10.62(1H,t,J=5.7Hz).
Compound 17-32) 9-benzyloxy-2-(3-morpholine-4-base-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl 3)δ:1.92(2H,tt,J=6.6Hz,6.9Hz),2.39(2H,t,J=6.6Hz),2.43(4H,brt,J=4.8Hz),3.70(4H,brt,J=4.8Hz),3.86(2H,t,J=6.9Hz),4.62(2H,d,J=6.0Hz),5.28(2H,s),6.50(1H,d,J=6.3Hz),6.61(1H,d,J=6.3Hz),7.01(2H,m),7.29-7.38(5H,m),7.62-7.65(2H,m),8.60(1H,s),10.62(1H,brt,J=6.0Hz).
16) in 140mg (0.293mmol) above-claimed cpd 17-1, add the 1.4mL trifluoroacetic acid down ice-cooled, stirred 5 minutes down, at room temperature stirred then 1.5 hours at 0 ℃.Heat up in a steamer under the decompression and desolvate,, join in the frozen water then with the chloroform dilution.With saturated sodium bicarbonate water, 10% aqueous citric acid solution and water washing, use anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate,, obtain the embodiment A that 89mg is a yellow crystals-1 (79%) thus resistates dichloromethane-ethanol recrystallization.
Fusing point: 223-224 ℃
NMR(DMSO-d 6)δ:3.25(3H,s),3.58(2H,t,J=5.4Hz),3.92(2H,t,J=5.1Hz),4.53(2H,d,J=5.7Hz),6.87(1H,d,6.3Hz),7.14(2H,t,J=9.0Hz),7.33-7.38(2H,m),7.47(1H,d,J=6.0Hz),8.77(1H,s),10.56(1H,t,J=6.0Hz),12.00(1H,brs).
17) 157mg (0.329mmol) above-claimed cpd 17-1 is dissolved in 18mL dimethyl formamide and the 1mL methyl alcohol, adds 31mg 10% palladium on carbon powder, under nitrogen atmosphere, at room temperature stirred 20 hours.Reaction solution is filtered with the C ore deposit, and decompression is concentrated filtrate down.Resistates is dissolved in the chloroform, and then filters with the C ore deposit, decompression is concentrated filtrate down.With resistates dichloromethane-ethanol recrystallization, obtaining 66mg thus is brown crystalline Embodiment B-1 (52%).Fusing point: 197 ℃-199 ℃
NMR(DMSO-d 6)δ:3.27(3H,s),3.55(2H,t,J=5.1Hz),3.68(2H,t,J=5.1Hz),3.79(2H,s),4.36(2H,s),4.51(2H,d,J=5.7Hz),7.15(2H,t,J=8.7Hz),7.32-7.37(2H,m),8.38(1H,s),10.46(1H,t,J=5.4Hz),12.41(1H,s).
According to carrying out the synthetic of following embodiment compd A-2~A-29, A-31~A-32 with the same method of embodiment A-1.
Embodiment A-2) 2-(2-dimethylamino-ethyl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 224 ℃-225 ℃
NMR(DMSO-d 6)δ:2.24(6H,s),2.59(2H,t,J=6.0Hz),3.87(2H,t,J=6.0Hz),4.55(2H,d,J=6.0Hz),6.94(1H,d,J=6.3Hz),7.17(2H,t,J=6.9Hz),7.35-7.40(2H,m),7.50(1H,d,J=6.3Hz),8.80(1H,s),10.59(1H,t,J=6.0Hz),12.05(1H,s).
Embodiment A-3) 9-hydroxyl-2-(2-morpholine-4-base-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 212-215 ℃
NMR(DMSO-d 6)δ:2.51(4H,s),2.38(3H,s),3.55(4H,s),3.90(2H,s),4.55(2H,d,J=6.0Hz),6.95(1H,d,J=6.3Hz),7.17(2H,t,J=8.7Hz),7.35-7.40(2H,m),7.50(1H,d,J=6.3Hz),10.58(1H,t,J=6.3Hz),12.10(1H,s).
Embodiment A-4) 9-hydroxyl-1,8-dioxo-2-(2-piperidines-1-base-ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 217-218 ℃
Ultimate analysis: C 23H 25FN 4O 4
Calculated value (%): C, 62.72; H, 5.72; F, 4.31; N, 12.72.
Analytical value (%): C, 58.98; H, 5.46; F, 6.16; N, 11.66.
NMR(DMSO-d 6)δ:1.41-1.51(6H,m),2.49-2.73(6H,m),3.91(2H,m),4.54(2H,d,J=6Hz),6.93(1H,d,J=6Hz),7.13-7.19(2H,m),7.35-7.39(2H,m),7.50(1H,d,J=6Hz),8.80(1H,s),10.57(1H,t,J=5.7Hz),12.14(1H,brs).
Embodiment A-5) 9-hydroxyl-2-(2-methyl-butyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 242-243 ℃
Ultimate analysis: C 21H 22FN 3O 4
Calculated value (%): C, 63.15; H, 5.55; F, 4.76; N, 10.52.
Analytical value (%): C, 63.14; H, 5.57; F, 4.63; N, 10.54.
NMR(DMSO-d 6)δ:0.86-0.94(6H,m),1.08-1.20(1H,m),1.33-1.55(1H,m),1.81-1.90(1H,m),3.51-3.58(1H,m),3.65-3.71(1H,m),4.54(2H,d,J=6Hz),6.92(1H,d,J=6.3Hz),7.13-7.20(2H,m),7.34-7.39(2H,m),7.50(1H,d,J=6.3Hz),8.79(1H,s),10.60(1H,t,J=5.7Hz),12.13(1H,brs).
Embodiment A-6) 9-hydroxyl-2-(2-isopropoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 209-210 ℃
Ultimate analysis: C 21H 22FN 3O 5
Calculated value (%): C, 60.72; H, 5.34; F, 4.57; N, 10.12.
Analytical value (%): C, 60.78; H, 5.29; F, 4.34; N, 10.11.
NMR(DMSO-d 6)δ:1.06(6H,d,J=6.3Hz),3.54-3.64(3H,m),3.90(2H,t,J=5.4Hz),6.89(1H,d,J=6.3Hz),7.13-7.19(2H,m),7.35-7.39(2H,m),7.47(1H,d,J=6.3Hz),8.77(1H,s),10.58(1H,t,J=5.7Hz),12.04(1H,brs).
Embodiment A-7) 9-hydroxyl-2-sec.-propyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 282-283 ℃
NMR(DMSO-d 6)δ:1.29(6H,d,J=6.9Hz),4.54(2H,d,J=5.9Hz),4.83-4.92(1H,m),7.04(1H,d,J=6.4Hz),7.13-7.19(2H,m),7.35-7.40(2H,m),7.56(1H,d,J=6.4Hz),8.80(1H,s),10.61(1H,t,J=5.8Hz),12.26(1H,brs).
Embodiment A-8) 2-cyclohexyl-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point:>300 ℃
NMR(DMSO-d 6)δ:1.15-1.84(10H,m),4.43-4.49(1H,m),4.53(2H,d,J=5.8Hz),7.05(1H,d,J=6.4Hz),7.13-7.19(2H,m),7.34-7.39(2H,m),7.53(1H,d,J=6.4Hz),8.79(1H,s),10.61(1H,t,J=5.8Hz),12.23(1H,brs).
Embodiment A-9) 9-hydroxyl-1,8-dioxo-2-[2-(propyl group-toluoyl base-amino)-ethyl]-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 190-192 ℃
NMR(CDCl 3)δ:1.10-1.16(3H,m),2.29(3H,s),3.29-3.38(2H,m),3.63-3.69(2H,m),3.94-3.99(2H,m),4.62(2H,d,J=6.0Hz),6.13-6.19(1H,m),6.52-6.61(4H,m),6.96-7.40(2H,m),6.96-7.04(2H,m),7.04-7.17(1H,m),7.29-7.36(2H,m),8.47(1H,s),10.56(1H,brs),11.89(1H,brs).
Embodiment A-10) 9-hydroxyl-1,8-dioxo-2-[3-(2-oxo base-tetramethyleneimine-1-yl)-propyl group]-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 262-264 ℃
NMR(CDCl 3)δ:1.93-2.04(2H,m),2.04-2.15(2H,m),2.39-2.46(2H,m),3.35-3.46(4H,m),3.75-3.81(2H,m),4.62(2H,d,J=5.7Hz),6.69(1H,d,J=6.3Hz),6.78(1H,d,J=6.3Hz),6.95-7.04(2H,m),7.29-7.37(2H,m),8.53(1H,s),10.58(1H,brs),11.89(1H,brs).
Embodiment A-11) 9-hydroxyl-1,8-dioxo-2-(2-tetrahydrochysene-furans-2-ylmethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 248-249 ℃
NMR(CDCl 3)δ:1.52-1.66(1H,m),1.90-2.00(2H,m),2.06-2.18(1H,m),3.52-3.61(1H,m),3.71-3.83(1H,m),3.85-3.94(1H,m),4.12-4.24(1H,m),4.63(2H,d,J=6.0Hz),6.59(1H,d,J=6.5Hz),6.66(1H,d,J=6.5Hz),6.96-7.04(2H,m),7.29-7.37(2H,m),8.52(1H,s),10.61(1H,brs),11.97(1H,brs).
Embodiment A-12) 9-hydroxyl-1,8-dioxo-2-pyridin-4-yl methyl isophthalic acid, 8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 265-268 ℃
NMR(DMSO-d 6)δ:4.55(2H,d,J=5.4Hz),5.02(2H,s),7.02(1H,d,J=6.5Hz),7.13-7.22(2H,m),7.34-7.42(4H,m),7.56(1H,d,J=6.51Hz),8.54-8.57(2H,m),8.83(1H,s),10.54-10.56(1H,m),11.78(1H,s).
Embodiment A-13) 4-[7-(4-fluoro-benzylamino formyl radical)-9-hydroxyl-1,8-dioxo-1,8-dihydro-pyrido [1,2-a] pyrazine-2-yl]-piperidines-1-ethyl formate
Fusing point: 288-289 ℃
NMR(CDCl 3)δ:1.29(3H,t,J=7.0Hz),1.64-1.75(2H,m),1.86-1.92(2H,m),2.89-2.97(2H,m),4.16(2H,q,J=7.0Hz),4.30-4.50(2H,m),4.62(2H,d,J=5.8Hz),4.80-4.88(1H,m),6.33(1H,d,J=6.6Hz),6.76(1H,d,J=6.6Hz),6.97-7.03(2H,m),7.31-7.35(2H,m),8.56(1H,s),10.57(1H,brs),11.98(1H,brs).
Embodiment A-14) 9-hydroxy-2-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 276-279 ℃
NMR(CDCl 3)δ:3.43(3H,s),4.63(2H,d,J=5.7Hz),6.33(1H,d,J=6.2Hz),6.71(1H,d,J=6.2Hz),6.86-7.05(2H,m),7.30-7.37(2H,m),8.53(1H,s),10.59(1H,brs),11.95(1H,brs).
Embodiment A-15) 2-(2-acetylamino-ethyl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point:>300 ℃
NMR(DMSO-d 6)δ:1.76(3H,s),3.37(2H,t,J=5.7Hz),3.79(2H,t,J=5.7Hz),4.54(2H,d,J=5.7Hz),6.85(1H,d,J=6.3Hz),7.16(2H,m),7.37(2H,m),7.48(1H,d,J=6.3Hz),7.95(1H,brt,J=5.7Hz),8.82(1H,s),10.58(1H,brt,J=5.7Hz),12.07(1H,s).
Embodiment A-16) 9-hydroxyl-2-(3-isopropoxy-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 180-181 ℃
NMR(CDCl 3)δ:1.14(6H,d,J=6.1Hz),1.94-2.04(2H,m),3.48(2H,t,J=5.7Hz),3.55(1H,sep,J=6.1Hz),3.92(2H,t,J=6.6Hz),4.63(2H,d,J=6.0Hz),6.42(1H,d,J=6.2Hz),6.67(1H,d,J=6.2Hz),6.96-7.04(2H,m),7.30-7.37(2H,m),8.52(1H,s),10.61(1H,brs),12.05(1H,brs).
Embodiment A-17) 2-(4-dimethylamino-benzyl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 245-247 ℃
NMR(CDCl 3)δ:2.98(6H,s),4.62(2H,d,J=5.7Hz),4.87(2H,s),6.32(1H,d,J=6.2Hz),6.63(1H,d,J=6.2Hz),6.79(2H,brs),6.96-7.23(2H,m),7.21-7.25(2H,m),7.30-7.36(2H,m),8.49(1H,s),10.61(1H,t,J=5.7Hz),12.08(1H,brs).
Embodiment A-18) 9-hydroxyl-2-(3-methoxyl group-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 197-199 ℃
NMR(CDCl 3)δ:1.96-2.04(2H,m),3.34(3H,s),3.45(2H,t,J=5.4Hz),3.90(2H,t,J=6.9Hz),4.62(2H,d,J=5.7Hz),5.11(2H,s),6.38(1H,d,J=6.0Hz),6.70(1H,d,J=6.0Hz),6.97-7.03(2H,m),7.31-7.35(2H,m),8.55(1H,s),10.61(1H,brs),12.03(1H,brs).
Embodiment A-19) 9-hydroxyl-1,8-dioxo-2-(2-propoxy--ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 215-217 ℃
NMR(CDCl 3)δ:0.90(3H,t,J=7.5Hz),1.58(2H,m),3.41(2H,t,J=6.6Hz),3.69(2H,t,J=4.7Hz),3.97(2H,t,J=4.6Hz),4.63(2H,d,J=5.8Hz),6.53(1H,d,J=6.3Hz),6.67(1H,d,J=6.3Hz),6.97-7.03(2H,m),7.31-7.36(2H,m),8.54(1H,s),10.62(1H,brs),11.97(1H,brs).
Embodiment A-20) 9-hydroxyl-1,8-dioxo-2-(2-phenoxy group-ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 237-239 ℃
NMR(CDCl 3)δ:4.18-4.21(2H,m),4.26-4.29(2H,m),4.62(2H,d,J=5.8Hz),6.57(1H,d,J=6.3Hz),6.71(1H,d,J=6.3Hz),6.86(2H,d,J=8.1Hz),6.97-7.02(3H,m),7.29-7.35(4H,m),8.56(1H,s),10.58(1H,t,J=5.7Hz),11.84(1H,brs).
Embodiment A-21) 9-hydroxyl-1,8-dioxo-2-(2-pyridin-3-yl-ethyl)-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 256-257 ℃
NMR(CDCl 3)δ:3.00(2H,t,J=7.5Hz),4.02(2H,t,J=7.5Hz),4.54(2H,d,J=6.0Hz),6.89(1H,d,J=6.3Hz),7.16(2H,m),7.30-7.39(3H,m),7.48(1H,d,J=6.3Hz),7.70(1H,m),8.44(1H,dd,J=1.8Hz,5.1Hz),8.48(1H,m),8.78(1H,s),10.56(1H,t,J=6.0Hz),11.98(1H,s).
Embodiment A-22) 2-formyl-dimethylamino methyl-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point:>300 ℃
NMR(DMSO-d 6)δ:2.87(3H,s),3.03(3H,s),4.55(2H,d,J=6.0Hz),4.71(2H,s),6.80(1H,d,J=6.3Hz),7.16(2H,m),7.38(2H,m),7.48(1H,d,J=6.3Hz),8.82(1H,s),10.54(1H,brt,J=6.0Hz),11.83(1H,s).
Embodiment A-23) 2-(2-oxyethyl group-ethyl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 212-214 ℃
NMR(CDCl 3)δ:1.19(3H,t,J=7.0Hz),3.51(2H,q,J=7.0Hz),3.67-3.72(2H,m),3.95-4.01(2H,m),4.63(2H,d,J=5.7Hz),6.54(1H,d,J=6.0Hz),6.65(1H,d,J=6.0Hz),6.96-7.02(2H,m),7.29-7.36(2H,m),8.52(1H,s),10.62(1H,brs),11.97(1H,brs).
Embodiment A-24) 2-furans-2-ylmethyl-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 234-237 ℃
NMR(DMSO-d 6)δ:4.54(2H,d,J=6.0Hz),4.98(2H,s),6.45(1H,dd,J=2.1Hz,3.3Hz),6.53(1H,dd,J=0.6Hz,3.3Hz),6.93(1H,d,J=6.3Hz),7.16(2H,m),7.36(2H,m),7.47(1H,d,J=6.3Hz),7.65(1H,dd,J=0.6Hz,2.1Hz),8.74(1H,s),10.56(1H,brt,J=6.0Hz),11.85(1H,s).
Embodiment A-25) 2-[2-(4-chloro-phenyl)-ethyl]-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 288-291 ℃
NMR(DMSO-d 6)δ:2.96(2H,t,J=7.5Hz),2.98(2H,t,J=7.5Hz),4.54(2H,d,J=6.0Hz),6.87(1H,d,J=6.3Hz),7.16(2H,m),7.30(2H,m),7.34-7.39(4H,m),7.47(1H,d,J=6.3Hz),8.78(1H,s),10.57(1H,brt,J=6.0Hz),12.01(1H,s).
Embodiment A-26) 2-(1-benzyl-tetramethyleneimine-3-yl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 218-219 ℃
NMR(CDCl 3)δ:1.82(1H,m),2.24(1H,q,J=8.4Hz),2.36(1H,m),2.56(1H,m),2.83(1H,m),3.00(1H,m),3.63(2H,s),4.54(2H,d,J=6.0Hz),5.19(1H,m),7.11(1H,d,J=6.3Hz),7.16(2H,m),7.23-7.39(7H,m),7.56(1H,d,J=6.3Hz),8.78(1H,s),10.58(1H,t,J=6.0Hz),12.14(1H,s).
Embodiment A-27) 9-hydroxyl-1,8-dioxo-2-thiophene-2-ylmethyl-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 233-236 ℃
NMR(CDCl 3)δ:4.61(2H,d,J=6.0Hz),5.11(2H,s),6.37(1H,d,J=6.3Hz),6.72(1H,d,J=6.3Hz),6.96-7.04(3H,m),7.15(1H,d,J=3.3Hz),7.32-7.36(3H,m),8.56(1H,s),10.56(1H,brs),11.87(1H,brs).
Embodiment A-28) 2-(3-dimethylamino-2,2-dimethyl-propyl group)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 208-210 ℃
NMR(DMSO-d 6)δ:0.91(6H,s),2.17(2H,s),2.25(6H,s),3.70(2H,s),4.54(2H,d,J=5.7Hz),6.84(1H,d,J=6.0Hz),7.14-7.19(2H,m),7.35-7.39(2H,m),7.46(1H,d,J=6.0Hz),8.81(1H,s),10.60(1H,t,J=6.3Hz),12.18(1H,brs).
Embodiment A-29) 9-hydroxyl-2-(3-morpholine-4-base-propyl group)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 197-198 ℃
NMR(CDCl 3)δ:1.81(2H,tt,J=6.3Hz,6.9Hz),2.31(4H,brs),2.33(2H,t,J=6.3Hz),3.49(4H,brt,J=4.5Hz),3.80(2H,t,J=6.9Hz),4.54(2H,d,J=6.0Hz),6.95(1H,d,J=6.3Hz),7.16(2H,m),7.34(2H,m),7.50(1H,d,J=6.3Hz),8.80(1H,s),10.59(1H,t,J=6.0Hz),12.16(1H,s).
Embodiment A-30) 2-(4-luorobenzyl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-luorobenzyl acid amides
[chemical formula 53]
Figure A20068004873700771
1) 95.6g (0.625mol) 4-hydroxyl-6-methylnicotinic acid is dissolved in 950mL acetate and the 190mL water, with 15 minutes adding 39mL (0.750mol) bromines.Solution was stirred 5 hours down at 60 ℃, heat up in a steamer under the decompression then and desolvate, add 200mL methyl alcohol, the leaching crystal.Heat up in a steamer solution under the decompression, in resistates, add methyl alcohol, leaching crystal once more.Merge, obtaining 142.2g is the 5-bromo-4-hydroxyl-6-methylnicotinic acid 20 (98%) of clear crystal.
NMR(DMSO-d 6)δ:2.53(3H,s),8.56(1H,s),13.45(1H,brs),14.80(1H,brs).
2) 138g (0.596mol) above-claimed cpd 20,148g (0.775mol) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 100g (0.656mol) I-hydroxybenzotriazole are dissolved in the 970mL dimethyl formamide, add 79mL (0.715mol) 4-flunamine.At room temperature reaction solution was stirred 9 hours, add 2000mL water then, the leaching crystal washs with ether.Obtaining 156g is 5-bromo-N-(4-the luorobenzyl)-4-hydroxyl-6-methylnicotinamide 21 (77%) of clear crystal.
NMR(DMSO-d 6)δ:2.47(3H,s),4.50(2H,d,J=5.9Hz),7.12-7.20(m,2H),7.32-7.39(m,2H),8.38(1H,s),10.50(1H,t,J=5.9Hz),12.72(1H,brs).
3) 75.2g (222mmol) above-claimed cpd 21 and 21.1g (111mmol) cupric iodide (I) are dissolved in the 750mL dimethyl formamide, add 216mL (888mmol) 28% sodium methylate-methanol solution, stirred 100 minutes down at 105 ℃.The cooling back adds the 800mL frozen water, and filtering does not need material.In solution, add 443mL 2M hydrochloric acid, the leaching crystal.Obtain the N-that 56.0g is a clear crystal (4-luorobenzyl)-4-hydroxy-5-methyl oxygen base-6-methylnicotinamide 22 (87%).
NMR(DMSO-d 6)δ:2.26(3H,s),3.74(3H,s),4.49(2H,d,J=6.0Hz),7.10-7.19(2H,m),7.30-7.38(2H,m),8.24(1H,s),10.68(1H,t,J=6.0Hz),12.21(1H,brs).
4) ice-cooled following, in the 1000mL tetrahydrofuran solution of 100g (344mmol) above-claimed cpd 22,46mL (447mmol) benzylalcohol and 128mL (516mmol) tributylphosphine, add 280mL (516mmol) 40% diisopropyl azodiformate-toluene solution with 30 fens clock times.Ice-cooled stirring down 30 minutes is warming up to room temperature then, further stirs 2 hours.Heat up in a steamer under the decompression and desolvate, in resistates, add 100mL toluene and 2000mL hexane, the crystal that filtering is separated out.Heat up in a steamer under the decompression and desolvate, in resistates, add 200mL diethyl ether and 2000mL hexane, the crystal that filtering is separated out, heat up in a steamer under the decompression and desolvate, with resistates silica gel column chromatography (hexane/ethyl acetate) purifying, obtaining 68.5g is 4-benzyloxy-N-(4-the luorobenzyl)-5-methoxyl group-6-methylnicotinamide 23 (52%) of clear crystal.
NMR(CDCl 3)δ:2.58(3H,s),3.86(3H,s),4.40(2H,d,J=5.7Hz),5.21(2H,s),6.91-7.00(2H,m),7.08-7.14(2H,m),7.19-7.27(2H,m),7.32-7.40(3H,m),7.87(1H,brs),8.97(1H,s).
5), add the 350mL chloroformic solution of 49.5g (186mmol) metachloroperbenzoic acid (65%) in the 350mL chloroformic solution with 30 fens clockwise 67.5g (177mmol) above-claimed cpds 23 ice-cooled following.Ice-cooled stirring down 45 minutes is warming up to room temperature then, stirs 75 minutes.In reaction solution, add saturated sodium bicarbonate water, use chloroform extraction.Wash organic layer with saturated sodium bicarbonate water, use anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, in resistates, add 200mL diethyl ether, the crystal that leaching 47.8g separates out.Heat up in a steamer under the decompression and desolvate, resistates with silica gel column chromatography (toluene/acetone) purifying, is obtained the 2.65g crystal.Merge, obtaining 50.5g is 4-benzyloxy-N-(4-the luorobenzyl)-5-methoxyl group-6-methyl isophthalic acid-oxygen base niacinamide 24 (72%) of clear crystal.
NMR(CDCl 3)δ:2.55(3H,s),3.90(3H,s),4.40(2H,d,J=5.7Hz),5.16(2H,s),6.93-6.70(2H,s),6.90-7.19(5H,m),7.30-7.38(2H,m),7.94(1H,brs),8.81(1H,s).
6) 49.4g (125mmol) above-claimed cpd 24 is dissolved in the 350mL diacetyl oxide, stirred 30 minutes down at 80 ℃.Heat up in a steamer under the decompression and desolvate, be dissolved in then in the 500mL methyl alcohol, the ice-cooled 7.5mL (31.3mmol) of adding down 28% sodium methylate-methanol solution at room temperature stirred 1 hour.Adding An Bailaite IR-120B in reaction solution, is neutral until solution, then the elimination solid matter.Heat up in a steamer under the decompression and desolvate, resistates is passed through silica gel column chromatography (hexane/ethyl acetate) purifying.Obtaining 25.4g is 4-benzyloxy-N-(4-the luorobenzyl)-6-hydroxymethyl-5-methoxyl group niacinamide 25 (51%) of clear crystal.
NMR(CDCl 3)δ:3.42(1H,brs),3.89(3H,s),4.41(2H,d,J=5.7Hz),4.83(2H,s),5.23(2H,s),6.92-6.99(2H,m),7.09-7.14(2H,m),7.19-7.23(2H,m),7.28-7.37(3H,m),7.85(1H,brs),9.03(1H,s).
7) ice-cooled following, in the 250mL chloroformic solution of 25.0g (63.1mmol) above-claimed cpd 25,44.8mL (631mmol) dimethyl sulfoxide (DMSO) and 44.3mL (378mmol) triethylamine, add 50.2g (315mmol) sulfur trioxide pyridine complex, at room temperature stirred 20 minutes.Add entry in reaction solution, it is imitative to heat up in a steamer dechlorination under the decompression, uses the ethyl acetate extraction resistates.With the extraction liquid washing, use anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, in resistates, add diethyl ether, leaching 17.7g crystal.Heat up in a steamer under the decompression and desolvate, resistates by purification by silica gel column chromatography, is obtained the 3.16g crystal.Merge, obtaining 20.9g is 4-benzyloxy-N-(4-the luorobenzyl)-6-formyl radical-5-methoxyl group niacinamide 26 (84%) of clear crystal.
NMR(CDCl 3)δ:4.02(3H,s),4.41(2H,d,J=5.7Hz),5.30(2H,s),6.93-6.70(2H,m),7.09-7.15(2H,m),7.20-7.27(2H,m),7.31-7.40(3H,m),7.83(1H,brs),9.20(1H,s),10.26(1H,s).
8) ice-cooledly down in the 1mL methanol solution of 300mg (0.761mmol) above-claimed cpd 26, add the 1mL methanol solution of 111mg (1.99mmol) potassium hydroxide, add the 4mL methanol solution of 251mg (1.00mmol) iodine again, under this temperature, stirred 1 hour.In reaction solution, add 5% aqueous solution of sodium bisulfite and water, the crystal that leaching is separated out.Obtaining 275mg is 4-benzyloxy-5-(the 4-luorobenzyl formamyl)-3-Methoxy Pyridine-2-methyl-formiate (85%) of clear crystal.
NMR(CDCl 3)δ:3.99(3H,s),4.02(3H,s),7.40(2H,d,J=5.7Hz),5.26(2H,s),6.92-6.99(2H,m),7.10-7.15(2H,m),7.19-7.23(2H,m),7.25-7.39(3H,m),7.81(1H,brs),9.09(1H,s).
9) in the 50mL acetonitrile suspension of 5.51g (36.8mmol) sodium iodide, add 4.66mL (36.8mmol) chlorine trimethyl silane, at room temperature stirred 10 minutes.In this solution, add 2.60g (6.13mmol) above-claimed cpd 27 down ice-cooled, under this temperature, stirred 20 minutes then.In reaction solution, add 5% aqueous solution of sodium bisulfite, use ethyl acetate extraction.Extraction liquid with saturated sodium bicarbonate water, saturated common salt water washing, is used anhydrous sodium sulfate drying.Heat up in a steamer under the decompression and desolvate, make gained solid matter recrystallization (acetone-Di Iso Propyl Ether), obtain the 5-that 1.73g is a clear crystal (4-luorobenzyl formamyl)-3-methoxyl group-4-oxo-1,4-dihydropyridine-2-methyl-formiate 28 (84%).
NMR(CDCl 3)δ:4.04(6H,s),4.60(2H,d,J=6.0Hz),6.96-7.03(2H,m),7.29-7.35(2H,m),8.63(1H,s),9.68(1H,brs),10.34(1H,brs).
10) 900mg (2.12mmol) above-claimed cpd 28 is dissolved in the 8mL methyl alcohol, adds 4mL 2N aqueous sodium hydroxide solution.Solution was at room temperature stirred 2 hours, add 3mL 2M hydrochloric acid then, the leaching crystal.Obtaining 474mg is 4-benzyl oxygen base-5-(4-fluoro-benzylamino the formyl radical)-3-methoxyl group-pyridine-2-formic acid 29 (54%) of clear crystal.
NMR(CDCl 3)δ:4.05(3H,s),4.40(2H,d,J=5.6Hz),5.36(2H,s),6.94-7.01(2H,m),7.08-7.12(2H,m),7.21-7.24(2H,m),7.29-7.41(3H,m),7.87(1H,brs),9.03(1H,s).
11), obtain the thick purified product of 932mg compound 30 by 641mg (2mmol) above-claimed cpd 29 according to the method for step 21.At room temperature, in Gai dioxane solution of 6mL, add 3mL2 equivalent aqueous hydrochloric acid, under 70 ℃, heated 30 minutes then, be cooled to room temperature, add sodium bicarbonate.The crystal that washing is separated out, drying obtains 513mg compound 31 (61%).
1H-NMR(DMSO-d 6)δ:3.58(1H,brs),3.82(3H,s),3.83(1H,brs),4.51(2H,d,J=6.0Hz),4.60(1H,brs),4.70(1H,brs),5.84(1H,brs),7.10-7.20(4H,m),7.30-7.42(4H,m),7.68(1H,brs),8.57(1H,s),10.41(1H,brs).
12) in the 5mL acetonitrile solution of 513mg (1.1mmol) above-claimed cpd 31, add 520mg (2.2mmol) Burgess reagent, under 70 ℃, heated 1.5 hours.Add entry after being cooled to room temperature, stopped reaction is used chloroform extraction, uses dried over mgso after the washing.Heat up in a steamer under the decompression and desolvate, resistates is carried out silica gel column chromatography, will obtain 95mg compound 32 (19%) with the component concentrating under reduced pressure of chloroform-methanol wash-out.
1H-NMR(CDCl 3)δ:4.08(3H,s),4.60(2H,d,J=5.8Hz),4.95(2H,s),6.38(1H,d,J=6.1Hz),6.62(1H,d,J=6.1Hz),6.95-7.10(4H,m),7.27-7.40(4H,m),8.57(1H,s),10.54(1H,brs).
13) in 95mg (0.2mmol) above-claimed cpd 32, add the 2g pyridine hydrochloride, under 180 ℃, heated 5 minutes.Add entry after being cooled to room temperature, the crystal that washing is separated out, drying obtains 86mg embodiment A-30 (93%).
Fusing point: 290-293 ℃
Ultimate analysis: C 23H 17F 2N 3O 4と て
Calculated value (%): C, 63.16; H, 3.92; F, 8.69; N, 9.61.
Analytical value (%): C, 62.97; H, 3.87; F, 8.36; N, 9.65.
1H-NMR(DMSO-d 6)δ:4.54(2H,d,J=5.6Hz),4.95(2H,s),7.02(1H,d,J=5.6Hz),7.10-7.22(4H,m),7.30-7.57(5H,m),8.78(1H,s),10.57(1H,t,J=5.9Hz),11.9(1H,brs).
Embodiment A-31) 2-[3-(3-chloro-5-trifluoromethyl-pyridine-2-base is amino)-propyl group]-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 281-283 ℃
NMR(DMSO-d 6)δ:1.97-2.00(2H,m),3.43-3.51(2H,m),3.83(2H,t,J=6.8Hz),4.54(2H,d,J=5.6Hz),6.97(1H,d,J=6.0Hz),7.14-7.18(2H,m),7.30(1H,t,J=5.2Hz),7.35-7.39(2H,m),7.50(1H,d,J=6.0Hz),7.93(1H,s),8.27(1H,s),8.78(1H,s),10.58(1H,t,J=5.6Hz),12.05(1H,s).
Embodiment A-32) 2-(2-benzyloxy-ethyl)-9-hydroxyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 191 ℃
NMR(DMSO-d 6)δ:3.76(2H,t,J=5.0Hz),3.98(2H,t,J=5.2Hz),4.52(2H,s),4.63(2H,d,J=5.8Hz),6.49(1H,d,J=6.4Hz),6.63(1H,d,J=6.3Hz),6.98-7.03(2H,m),7.25-7.36(7H,m),8.53(1H,s),10.60-10.64(1H,m),11.92(1H,brs).
Embodiment A-33) 9-hydroxyl-2-(2-hydroxyl-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 287 ℃
NMR(DMSO-d 6)δ:3.63-3.68(2H,m),3.81-3.84(2H,m),4.54(2H,d,J=5.8Hz),4.95(1H,t,J=5.5Hz),6.90(1H,d,J=5.9Hz),7.14-7.20(2H,m),7.35-7.38(2H,m),7.48(1H,d,J=5.8Hz),8.81(1H,s),10.60(1H,t,J=5.9Hz),12.12(1H,brs).
According to the method same with Embodiment B-1, synthetic following embodiment compd B-2~B-28.
Embodiment B-2) 2-(2-dimethylamino-ethyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 218-220 ℃
NMR(DMSO-d 6)δ:2.19(6H,s),3.60(2H,t,J=6.3Hz),3.79(2H,s),4.37(2H,s),4.52(2H,d,J=4.5Hz),7.15(2H,t,J=9.0Hz),7.32-7.37(2H,m),8.40(1H,s),10.45(1H,t,J=6.3Hz),12.40(1H,s).
Embodiment B-3) 9-hydroxyl-2-(2-morpholine-4-base-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 205-207 ℃
NMR(DMSO-d 6)δ:2.43(2H,s),2.50(4H,s),3.54(4H,s),3.63(2H,s),3.81(2H,s),4.40(2H,s),4.52(2H,d,J=6.0Hz),7.16(2H,t,J=9.0Hz),7.33-7.37(2H,m),8.43(1H,s),10.45(1H,t,J=5.7Hz),12.48(1H,s).
Embodiment B-4) 9-hydroxyl-1,8-dioxo-2-(2-piperidines-1-base-ethyl)-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 232-235 ℃
Ultimate analysis: C 23H 27FN 4O 4
Calculated value (%): C, 62.43; H, 6.15; F, 4.29; N, 12.66.
Analytical value (%): C, 61.78; H, 5.76; F, 4.04; N, 12.50.
NMR(DMSO-d 6)δ:1.37-1.46(6H,m),2.38-2.50(6H,m),3.61(2H,t,J=6.6Hz),3.79(2H,m),4.37(2H,m),4.52(2H,d,J=6Hz),7.12-7.18(2H,m),7.32-7.37(2H,m),8.41(1H,s),10.44(1H,t,J=6Hz),12.50(1H,brs).
Embodiment B-5) 9-hydroxyl-2-(2-methyl-butyl)-1,8-dioxo-1,8-dihydro-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 278-280 ℃
Ultimate analysis: C 21H 24FN 3O 4
Calculated value (%): C, 62.83; H, 6.03; F, 4.73; N, 10.47.
Analytical value (%): C, 62.45; H, 6.00; F, 4.50; N, 10.43.
NMR(DMSO-d 6)δ:0.86-0.93(6H,m),1.08-1.18(1H,m),1.37-1.44(1H,m),1.78-1.84(1H,m),3.30-3.38(2H,m),3.73-3.77(2H,m),4.37-4.44(2H,m),4.52(2H,d,J=6Hz),7.12-7.18(2H,m),7.32-7.37(2H,m),8.41(1H,s),10.46(1H,t,J=6Hz),12.54(1H,brs).
Embodiment B-6) 9-hydroxyl-2-(2-isopropoxy-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 210-212 ℃
Ultimate analysis: C 21H 24FN 3O 5
Calculated value (%): C, 60.42; H, 5.80; F, 4.55; N, 10.07.
Analytical value (%): C, 59.77; H, 5.66; F, 4.42; N, 10.01.
NMR(DMSO-d 6)δ:1.08(6H,d,J=6Hz),3.54-3.66(5H,m),3.79-3.83(2H,m),4.35-4.39(2H,m),4.52(2H,d,J=6Hz),7.12-7.18(2H,m),7.32-7.37(2H,m),8.40(1H,s),10.44(1H,t,J=6Hz),12.42(1H,brs).
Embodiment B-7) 9-hydroxyl-2-sec.-propyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 286-287 ℃
NMR(DMSO-d 6)δ:1.17(6H,d,J=6.9Hz),3.64-3.70(2H,m),4.36-4.38(2H,m),4.52(2H,d,J=6.0Hz),4.70-4.79(1H,m),7.13-7.19(2H,m),7.33-7.37(2H,m),8.43(1H,s),10.47(1H,t,J=6.0Hz),12.60(1H,brs).
Embodiment B-8) 2-cyclohexyl-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point:>300 ℃
NMR(DMSO-d 6)δ:1.03-1.81(10H,m),3.69-3.72(2H,m),4.29-4.36(3H,m),4.52(2H,d,J=6.1Hz),7.13-7.19(2H,m),7.33-7.37(2H,m),8.43(1H,s),10.47(1H,t,J=5.8Hz),12.59(1H,brs).
Embodiment B-9) 2-(4-fluoro-benzyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 271-272 ℃
NMR(DMSO-d 6)δ:3.71-3.75(2H,m),4.37-4.41(2H,m),4.52(2H,d,J=6.0Hz),4.71(2H,s),7.13-7.23(4H,m),7.33-7.45(4H,m),8.41(1H,s),10.44(1H,t,J=5.9Hz),12.36(1H,brs).
Embodiment B-10) 9-hydroxyl-1,8-dioxo-2-[2-(propyl group-toluoyl base-amino)-ethyl]-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 185-188 ℃
NMR(CDCl 3)δ:1.12-1.18(3H,m),2.26(3H,s),3.30-4.40(10H,m),4.60(2H,d,J=5.4Hz),6.57(2H,brs),6.97-7.02(2H,m),7.04-7.16(1H,m),7.26-7.34(3H,m),8.23(1H,s),10.43(1H,brs),12.29(1H,brs).
Embodiment B-11) 9-hydroxyl-1,8-dioxo-2-[3-(2-oxo base-tetramethyleneimine-1-yl)-propyl group]-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 207-209 ℃
NMR(CDCl 3)δ:1.92-1.96(2H,m),2.05-2.10(2H,m),2.40(2H,t,J=8.1Hz),3.35(2H,t,J=6.6Hz),3.43(2H,t,J=6.9Hz),3.55(2H,t,J=6.6Hz),3.82-3.86(2H,m),4.26-4.30(2H,m),4.60(2H,d,J=6.0Hz),6.96-7.02(2H,m),7.30-7.35(2H,m),8.32(1H,s),10.43-10.47(1H,m),12.26(1H,brs).
Embodiment B-12) 9-hydroxyl-1,8-dioxo-2-(2-tetrahydrochysene-furans-2-ylmethyl)-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 250-251 ℃
NMR(CDCl 3)δ:1.50-1.59(2H,m),1.89-1.98(2H,m),2.03-2.14(1H,m),3.25(1H,dd,J=8.4Hz,13.8Hz),4.25-3.73(7H,m),4.59(2H,d,J=5.1Hz),7.00(2H,d,J=8.4Hz),7.32(2H,dd,J=5.4Hz,8.4Hz),8.31(1H,s),10.47(1H,t,5.1Hz),12.29(1H,brs).
Embodiment B-13) 4-[7-(4-fluoro-benzylamino formyl radical)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-pyrido [1,2-a] pyrazine-2-yl]-piperidines-1-ethyl formate
Fusing point: 258-260 ℃
NMR(CDCl 3)δ:1.28(3H,t,J=7.2Hz),1.54-1.92(4H,m),4.14-4.43(6H,m),4.60(2H,d,J=5.4Hz),6.97-7.05(2H,m),7.29-7.34(2H,m),8.32(1H,s),10.43(1H,t,J=5.4Hz),12.27(1H,brs).
Embodiment B-14) 2-(2-acetylamino-ethyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 249-251 ℃
NMR(CDCl 3)δ:1.93(3H,s),3.48-3.52(2H,m),3.67-3.71(2H,m),3.82-3.86(2H,m),4.28-4.32(2H,m),4.59(2H,s),6.99-7.04(2H,m),7.30-7.33(2H,m),8.30(1H,s).
Embodiment B-15) 9-hydroxyl-2-(3-isopropoxy-propyl group)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 239-241 ℃
NMR(CDCl 3)δ:1.10(6H,d,J=6.0Hz),1.88-1.96(2H,m),3.48-3.57(3H,m),3.69(2H,t,J=6.6Hz),3.77-3.81(2H,m),4.21-4.24(2H,m),4.60(2H,d,J=5.7Hz),6.96-7.02(2H,m),7.30-7.35(2H,m),8.30(1H,s),10.45-10.49(1H,m),12.42(1H,brs).
Embodiment B-16) 2-(4-dimethylamino-benzyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 260-262 ℃
NMR(CDCl 3)δ:2.97(6H,s),3.59-3.63(2H,m),4.09-4.13(2H,m),4.59(2H,d,J=5.7Hz),4.67(2H,s),6.70-6.78(2H,m),6.96-7.02(2H,m),7.19(2H,d,J=8.7Hz),7.29-7.34(2H,m),8.27(1H,s),10.46(1H,t,J=5.7Hz),12.45(1H,brs).
Embodiment B-17) 9-hydroxyl-1,8-dioxo-2-(4-sulphonamide-1-benzyl)-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 266-270 ℃
NMR(DMSO-d 6)δ:3.75-3.81(2H,m),4.41-4.45(2H,m),4.52(2H,d,J=6.0Hz),4.80(2H,s),7.13-7.19(2H,m),7.33-7.37(4H,m),7.56(2H,d,J=8.1Hz),7.81(2H,d,J=8.1Hz),8.44(1H,s),10.44(1H,t,J=6.0Hz),12.28(1H,brs).
Embodiment B-18) 9-hydroxyl-2-(3-methoxyl group-propyl group)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 238-240 ℃
NMR(CDCl 3)δ:1.93(2H,quin,J=5.7Hz),3.31(3H,s),3.47(2H,t,J=5.7Hz),3.68(2H,t,J=6.9Hz),3.75-3.79(2H,m),4.21-4.24(2H,m),4.60(2H,d,J=5.7Hz),6.97-7.02(2H,m),7.30-7.35(2H,m),8.31(1H,s),10.46(1H,t,J=7.8Hz),12.38(1H,brs).
Embodiment B-19) 9-hydroxyl-1,8-dioxo-2-(2-propoxy--ethyl)-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 196-197 ℃
NMR(CDCl 3)δ:0.91(3H,t,J=7.5Hz),1.52-1.63(2H,m),3.41(2H,t,J=7.5Hz),3.67(2H,t,J=4.2Hz),3.76(2H,t,J=4.2Hz),3.88-3.92(2H,m),4.19-4.23(2H,m),4.60(2H,d,J=6.0Hz),6.97-7.03(2H,m),7.30-7.35(2H,m),8.32(1H,s),10.47(1H,t,J=5.7Hz),12.29(1H,brs).
Embodiment B-20) 9-hydroxyl-1,8-dioxo-2-(2-phenoxy group-ethyl)-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 200-201 ℃
NMR(CDCl 3)δ:3.96-4.02(4H,m),4.20-4.28(4H,m),4.60(2H,d,J=6.0Hz),6.86-6.89(2H,m),6.96-7.02(3H,m),7.28-7.34(4H,m),8.31(1H,s),10.43(1H,brs),12.15(1H,brs).
Embodiment B-21) 2-formyl-dimethylamino methyl-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 245 ℃
NMR(CDCl 3)δ:3.00(3H,s),3.08(3H,s),3.83-3.87(2H,m),4.37-4.41(2H,m),4.42(2H,s),4.60(2H,s),6.98-7.04(2H,m),7.30-7.34(2H,m),8.33(1H,s).
Embodiment B-22) 2-(2-oxyethyl group-ethyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 201-202 ℃
NMR(CDCl 3)δ:1.19(3H,t,J=7.2Hz),3.51(2H,q,J=7.2Hz),3.67(2H,t,J=5.4Hz),3.76(2H,t,J=5.4Hz),3.88-3.92(2H,m),4.20-4.23(2H,m),4.60(2H,d,J=5.7Hz),6.96-7.02(2H,m),7.30-7.34(2H,m),8.31(1H,s),10.46(1H,brs),12.28(1H,brs).
Embodiment B-23) 9-hydroxyl-1,8-dioxo-2-styroyl-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 241 ℃
NMR(CDCl 3)δ:3.00(2H,t,J=6.3Hz),3.41(2H,brs),3.82(2H,t,J=6.6Hz),3.97(2H,brs),4.59(2H,d,J=5.1Hz),6.96-7.02(2H,m),7.22-7.36(7H,m),8.24(1H,brs),10.45(1H,brs),12.31(1H,brs).
Embodiment B-24) 2-(3-dimethylamino-2,2-dimethyl-propyl group)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 212-214 ℃
NMR(CDCl 3)δ:1.03(6H,s),2.25(2H,brs),2.37(6H,s),3.55(2H,s),3.86-3.90(2H,m),4.20-4.24(2H,m),4.60(2H,d,J=6.0Hz),6.96-7.02(2H,m),7.29-7.34(2H,m),8.30(1H,s),10.46(1H,t,J=4.5Hz),12.43(1H,brs).
Embodiment B-25) 9-hydroxyl-2-(3-morpholine-4-base-propyl group)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 181-185 ℃
NMR(CDCl 3)δ:2.08(2H,brs),2.73(6H,brs),3.67(2H,t,J=6.6Hz),3.80-3.84(6H,m),4.22-4.26(2H,m),4.61(2H,d,J=6.0Hz),6.98-7.04(2H,m),7.33-7.38(2H,m),8.28(1H,s),10.41(1H,t,J=6.0Hz),12.19(1H,brs).
Embodiment B-26) the 8-tetrahydropyridine is [1,2-a] pyrazine-2-yl also for 2-[7-(4-luorobenzyl formamyl)-9-hydroxyl-1,8-dioxo-1,3,4] and ethyl } the sulfonic acid diethyl ester
NMR(DMSO-d 6)δ:1.24(6H,d,J=7.0Hz),2.1-2.23(2H,m),3.64-3.72(2H,m),3.79-3.82(2H,m),3.99-4.06(4H,m),4.37-4.41(2H,m),7.52(2H,d,J=5.7Hz),7.12-7.18(2H,m),7.33-7.38(2H,m),8.42(1H,s),10.43(1H,t,J=5.7Hz),12.34(1H,s).
Embodiment B-27) 2-(3-tertiary butyl amino-propyl group)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 216 ℃
NMR(DMSO-d 6)δ:1.40(9H,s),2.18(2H,s),2.92(2H,s),3.40(2H,s),3.90(2H,s),4.39(2H,s),4.59(2H,s),7.01(2H,t,J=11.6Hz),7.31(2H,m),8.34(1H,s),10.48(1H,s).
Embodiment B-28) 9-hydroxyl-2-(2-hydroxyl-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-a] pyrazine-7-formic acid 4-fluoro-benzyl acid amides
Fusing point: 213 ℃
NMR(DMSO-d 6)δ:3.57-3.63(4H,m),3.80-3.84(2H,m),4.36-4.41(2H,m),4.52(2H,d,J=5.8Hz),4.89(1H,t,J=5.5Hz),7.13-7.20(2H,m),7.32-7.38(2H,m),8.42(1H,s),10.46(1H,t,J=5.8Hz),12.52(1H,brs).
Embodiment K-1) 2-(4-luorobenzyl)-9-hydroxy-4-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-luorobenzyl acid amides
[chemical formula 64]
[chemical formula 91]
Figure A20068004873701061
Z=NR C(R C=-CH 2CH 2OCH 3)
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
Figure A20068004873700891
1) at room temperature, the dimethyl formamide that in the 30mL dichloromethane solution of 3.00g (7.57mmol) compound 13, adds 0.79mL (9.08mmol) oxalyl chloride and catalytic amount, directly stirred 1.5 hours, at 0 ℃ of 30mL dichloromethane solution that adds 2.00g (8.33mmol) N '-(4-fluoro-benzyl)-hydrazine t-butyl formate and 1.16mL (8.33mmol) triethylamine down, be warming up to room temperature, stirred 1.5 hours.Add aqueous ammonium chloride solution, use chloroform extraction, the washing organic layer is used anhydrous sodium sulfate drying, heats up in a steamer under the decompression and desolvates.With resistates by silica gel column chromatography (elutriant: normal hexane-ethyl acetate) purifying, obtain 133mg compound 59, yield is 85%.
NMR(CDCl 3)δ:4.20(1H,brs),4.61(2H,d,J=6.0Hz),5.00(2H,brs),5.60(1H,brs),6.82(1H,s),6.91(2H,t,J=8.4Hz),7.01(2H,t,J=8.7Hz),7.10(2H,dd,J=5.4Hz,8.7Hz),7.22-7.36(7H,m),8.52(1H,d,J=6.6Hz),10.24(1H,s),10.47(1H,t,J=5.7Hz).
2) N '-(4-fluoro-benzyl)-hydrazine formic acid tertiary butyl ester according to the method for document record synthetic (J.Med.Chem.1996,39,3203-3216).Under 0 ℃, in 597mg (0.966mmol) compound 59, add 4 normal hydrochloric acid (ethyl acetate solution), be warming up to room temperature, stirred 1 hour.Add sodium bicarbonate aqueous solution and neutralize, use ethyl acetate extraction.The washing organic layer is used anhydrous sodium sulfate drying, heats up in a steamer under the decompression and desolvates, and obtains 500mg compound 60, and yield is 100%.
NMR(CDCl 3)δ:4.53(4H,s),5.20(2H,s),6.81-7.35(13H,m),8.48(1H,s),10.60(1H,s),11.80(1H,s).
3) under 0 ℃, in the 1.8mL dichloromethane solution of 180mg (0.347mmol) compound 60, add 26 μ L (0.417mmol) acetaldehyde and 40 μ L (0.694mmol) acetate, be warming up to room temperature, stirred 4 hours.Decompression is concentration of reaction solution down, with resistates by silica gel column chromatography (elutriant: purifying chloroform-methanol), obtain 165mg compound 61, yield is 87%.
NMR(CDCl 3)δ:0.83(3H,s),3.46(1H,s),4.31(1H,s),4.58(2H,d,J=5.4Hz),4.89(1H,s),5.11(2H,s),6.07(1H,s),6.96-7.67(13H,m),8.00(1H,s),10.22(1H,s).
4) according to the synthetic embodiment compound K-1 of the synthetic method of Embodiment B-1.
Fusing point: 247-249 ℃
NMR(CDCl 3)δ:1.24(3H,m),4.54(3H,m),4.80(2H,m),6.22(1H,s),7.06(4H,m),7.37(4H,m),8.03(1H,s),10.09(1H,s),11.57(1H,s).
According to the method same with embodiment K-1, synthetic following embodiment compound K-2~K-6.
Embodiment K-2) 2-(4-luorobenzyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-luorobenzyl acid amides
Fusing point:>300 ℃
NMR(DMSO-d 6)δ:4.50(2H,d,J=5.7Hz),4.68(2H,s),5.16(2H,d,J=7.2Hz),6.83(1H,t,J=7.8Hz),7.14(4H,m),7.36(4H,m),8.38(1H,s),10.39(1H,t,J=5.7Hz),11.20(1H,s).
Embodiment K-3) 2-(4-luorobenzyl)-9-hydroxyl-4-isobutyl--1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-luorobenzyl acid amides
Fusing point: 206 ℃
NMR(DMSO-d 6)δ:0.64(3H,d,J=6.0Hz),0.80(3H,d,J=6.0Hz),1.23(2H,s),1.55(1H,t,J=9.3Hz),4.50(3H,m),4.89(1H,d,14.1Hz),5.50(1H,s),7.06(1H,s),7.33-7.44(4H,m),8.43(1H,s),10.40(1H,t,J=5.7Hz),11.44(1H,s).
Embodiment K-4) 2-(4-luorobenzyl)-9-hydroxyl-4-sec.-propyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-luorobenzyl acid amides
Fusing point: 207 ℃
NMR(DMSO-d 6)δ:0.64(3H,d,J=6.6Hz),0.69(3H,d,J=6.6Hz),1.89(1H,m),4.51(2H,d,J=6.3Hz),4.60(1H,d,J=14.4Hz),4.79(1H,d,J=14.4Hz),5.10(1H,d,J=8.1Hz),7.01(1H,s),7.13-7.22(4H,m),7.33-7.44(4H,m),8.40(1H,s),10.42(1H,t,J=6.0Hz),11.44(1H,s).
Embodiment K-5) 4-cyclopropyl-2-(4-luorobenzyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-luorobenzyl acid amides
Fusing point: 235 ℃
NMR(DMSO-d 6)δ:0.30-0.57(4H,m),1.09(1H,m),4.51(2H,d,J=6.0Hz),4.60(1H,d,J=14.4Hz),4.78(1H,s),4.83(1H,d,J=14.4Hz),7.10-7.22(4H,m),7.33-7.46(4H,m),8.52(1H,s),10.38(1H,t,J=6.0Hz),11.39(1H,s).
Embodiment K-6) the 4-tertiary butyl-2-(4-luorobenzyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-luorobenzyl acid amides
Fusing point: 270 ℃
NMR(DMSO-d 6)δ:0.91(9H,s),4.45(1H,d,J=14.4Hz),4.52(2H,d,J=6.0Hz),5.03(1H,d,J=14.4Hz),5.27(1H,d,J=3.3Hz),7.05(1H,d,J=3.3Hz),7.13-7.24(4H,m),7.33-7.46(4H,m),8.41(1H,s),10.40(1H,t,J=5.7Hz),11.51(1H,s).
The present invention further comprises following compound.
[chemical formula 77]
Figure A20068004873700921
Z=C,Ra=H
Figure A20068004873700922
[chemical formula 78]
Figure A20068004873700931
Z=C,Rb=H
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 79]
Figure A20068004873700941
Z=O,Ra=H
[chemical formula 80]
Figure A20068004873700951
Z=O,Rb=H
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 81]
Z=NR C(R C=-CH 3) Ra=H
Figure A20068004873700962
[chemical formula 82]
Figure A20068004873700971
Z=NR C(R C=-CH 3) Rb=H
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 83]
Figure A20068004873700981
Z=NR C(R C=-CH(CH 3) 2) Ra=H
Figure A20068004873700982
[chemical formula 84]
Figure A20068004873700991
Z=NR C(R C=-CH(CH 3) 2) Rb=H
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 85]
Figure A20068004873701001
Z=NR C(R C=-CH 2CH 2OCH 3) Ra=H
Figure A20068004873701002
[chemical formula 86]
Figure A20068004873701011
Z=NR C(R C=-CH 2CH 2OCH 3) Rb=H
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 87]
Figure A20068004873701021
Z=C
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 88]
Figure A20068004873701031
Z=O
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 89]
Figure A20068004873701041
Z=NR C(R C=-CH 3)
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 90]
Figure A20068004873701051
Z=NR C(R C=-CH(CH 3) 2)
No (R)m R a R 4 No (R)m R a R 4
1 4-F -CH 3 CH 3 27 2-F, 3-Cl -CH(CH 3) 2 CH 2CH 2OCH 3
2 4-F -CH(CH 3) 2 CH 3 28 2-F, 3-Cl - CH 2CH 2OCH 3 CH 2CH 2OCH 3
3 4-F -CH 2CH 2OCH 3 CH 3 29 2-F, 3-Cl -N(CH 3)CO CH 3 CH 2CH 2OCH 3
4 4-F -N(CH 3)CO CH 3 CH 3 30 2-F, 3-Cl -N(CH 3) 2 CH 2CH 2OCH 3
5 4-F -N(CH 3) 2 CH 3 31 4-F -CH 3 -CH 2(4-F-Ph)
6 2,4-F -CH 3 CH 3 32 4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
7 2,4-F -CH(CH 3) 2 CH 3 33 4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
8 2,4-F -CH 2CH 2OCH 3 CH 3 34 4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
9 2,4-F -N(CH 3)CO CH 3 CH 3 35 4-F -N(CH 3) 2 -CH 2(4-F-Ph)
10 2,4-F -N(CH 3) 2 CH 3 36 2,4-F -CH 3 -CH 2(4-F-Ph)
11 2-F, 3-Cl -CH 3 CH 3 37 2,4-F -CH(CH 3) 2 -CH 2(4-F-Ph)
12 2-F, 3-Cl -CH(CH 3) 2 CH 3 38 2,4-F - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
13 2-F, 3-Cl -CH 2CH 2OCH 3 CH 3 39 2,4-F -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
14 2-F, 3-Cl -N(CH 3)CO CH 3 CH 3 40 2,4-F -N(CH 3) 2 -CH 2(4-F-Ph)
15 2-F, 3-Cl -N(CH 3) 2 CH 3 41 2-F, 3-Cl -CH 3 -CH 2(4-F-Ph)
16 4-F -CH 3 CH 2CH 2OCH 3 42 2-F, 3-Cl -CH(CH 3) 2 -CH 2(4-F-Ph)
17 4-F -CH(CH 3) 2 CH 2CH 2OCH 3 43 2-F, 3-Cl - CH 2CH 2OCH 3 -CH 2(4-F-Ph)
18 4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3 44 2-F, 3-Cl -N(CH 3)CO CH 3 -CH 2(4-F-Ph)
19 4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3 45 2-F, 3-Cl -N(CH 3) 2 -CH 2(4-F-Ph)
20 4-F -N(CH 3) 2 CH 2CH 2OCH 3
21 2,4-F -CH 3 CH 2CH 2OCH 3
22 2,4-F -CH(CH 3) 2 CH 2CH 2OCH 3
23 2,4-F -CH 2CH 2OCH 3 CH 2CH 2OCH 3
24 2,4-F -N(CH 3)CO CH 3 CH 2CH 2OCH 3
25 2,4-F -N(CH 3) 2 CH 2CH 2OCH 3
26 2-F, 3-Cl -CH 3 CH 2CH 2OCH 3
[chemical formula 92]
Figure A20068004873701071
(R)m=4-F
No R a R b
1 H H
2 -CH 3 H
3 -CH(CH 3) 2 H
4 -CH 2CH 2OCH 3 H
5 H -CH 3
6 -CH 3 -CH 3
7 -CH(CH 3) 2 -CH 3
8 -CH 2CH 2OCH 3 -CH 3
9 H -CH(CH 3) 2
10 -CH 3 -CH(CH 3) 2
11 -CH(CH 3) 2 -CH(CH 3) 2
12 -CH 2CH 2OCH 3 -CH(CH 3) 2
13 H -CH 2CH 2OCH 3
14 -CH 3 -CH 2CH 2OCH 3
15 -CH(CH 3) 2 -CH 2CH 2OCH 3
16 -CH 2CH 2OCH 3 -CH 2CH 2OCH 3
17 H -N(CH 3) 2
18 -CH 3 -N(CH 3) 2
19 -CH(CH 3) 2 -N(CH 3) 2
20 -CH 2CH 2OCH 3 -N(CH 3) 2
21 H -N(CH 3)CO CH 3
22 -CH 3 -N(CH 3)CO CH 3
23 -CH(CH 3) 2 -N(CH 3)CO CH 3
24 -CH 2CH 2OCH 3 -N(CH 3)CO CH 3
[chemical formula 93]
Figure A20068004873701081
(R)m=2,4-F
No R a R b
1 H H
2 -CH 3 H
3 -CH(CH 3) 2 H
4 -CH 2CH 2OCH 3 H
5 H -CH 3
6 -CH 3 -CH 3
7 -CH(CH 3) 2 -CH 3
8 -CH 2CH 2OCH 3 -CH 3
9 H -CH(CH 3) 2
10 -CH 3 -CH(CH 3) 2
11 -CH(CH 3) 2 -CH(CH 3) 2
12 -CH 2CH 2OCH 3 -CH(CH 3) 2
13 H -CH 2CH 2OCH 3
14 -CH 3 -CH 2CH 2OCH 3
15 -CH(CH 3) 2 -CH 2CH 2OCH 3
16 -CH 2CH 2OCH 3 -CH 2CH 2OCH 3
17 H -N(CH 3) 2
18 -CH 3 -N(CH 3) 2
19 -CH(CH 3) 2 -N(CH 3) 2
20 -CH 2CH 2OCH 3 -N(CH 3) 2
21 H -N(CH 3)CO CH 3
22 -CH 3 -N(CH 3)CO CH 3
23 -CH(CH 3) 2 -N(CH 3)CO CH 3
24 -CH 2CH 2OCH 3 -N(CH 3)CO CH 3
[chemical formula 94]
Figure A20068004873701091
(R)m=2-F,3-Cl
No R a R b
1 H H
2 -CH 3 H
3 -CH(CH 3) 2 H
4 -CH 2CH 2OCH 3 H
5 H -CH 3
6 -CH 3 -CH 3
7 -CH(CH 3) 2 -CH 3
8 -CH 2CH 2OCH 3 -CH 3
9 H -CH(CH 3) 2
10 -CH 3 -CH(CH 3) 2
11 -CH(CH 3) 2 -CH(CH 3) 2
12 -CH 2CH 2OCH 3 -CH(CH 3) 2
13 H -CH 2CH 2OCH 3
14 -CH 3 -CH 2CH 2OCH 3
15 -CH(CH 3) 2 -CH 2CH 2OCH 3
16 -CH 2CH 2OCH 3 -CH 2CH 2OCH 3
17 H -N(CH 3) 2
18 -CH 3 -N(CH 3) 2
19 -CH(CH 3) 2 -N(CH 3) 2
20 -CH 2CH 2OCH 3 -N(CH 3) 2
21 H -N(CH 3)CO CH 3
22 -CH 3 -N(CH 3)CO CH 3
23 -CH(CH 3) 2 -N(CH 3)CO CH 3
24 -CH 2CH 2OCH 3 -N(CH 3)CO CH 3
[chemical formula 95]
Figure A20068004873701101
(R)m=4-F
No R a R b
1 H H
2 -CH 3 H
3 -CH(CH 3) 2 H
4 -CH 2CH 2OCH 3 H
5 H -CH 3
6 -CH 3 -CH 3
7 -CH(CH 3) 2 -CH 3
8 -CH 2CH 2OCH 3 -CH 3
9 H -CH(CH 3) 2
10 -CH 3 -CH(CH 3) 2
11 -CH(CH 3) 2 -CH(CH 3) 2
12 -CH 2CH 2OCH 3 -CH(CH 3) 2
13 H -CH 2CH 2OCH 3
14 -CH 3 -CH 2CH 2OCH 3
15 -CH(CH 3) 2 -CH 2CH 2OCH 3
16 -CH 2CH 2OCH 3 -CH 2CH 2OCH 3
17 H -N(CH 3) 2
18 -CH 3 -N(CH 3) 2
19 -CH(CH 3) 2 -N(CH 3) 2
20 -CH 2CH 2OCH 3 -N(CH 3) 2
21 H -N(CH 3)CO CH 3
22 -CH 3 -N(CH 3)CO CH 3
23 -CH(CH 3) 2 -N(CH 3)CO CH 3
24 -CH 2CH 2OCH 3 -N(CH 3)CO CH 3
[chemical formula 96]
Figure A20068004873701111
(R)m=2,4-F
No R a R b
1 H H
2 -CH 3 H
3 -CH(CH 3) 2 H
4 -CH 2CH 2OCH 3 H
5 H -CH 3
6 -CH 3 -CH 3
7 -CH(CH 3) 2 -CH 3
8 -CH 2CH 2OCH 3 -CH 3
9 H -CH(CH 3) 2
10 -CH 3 -CH(CH 3) 2
11 -CH(CH 3) 2 -CH(CH 3) 2
12 -CH 2CH 2OCH 3 -CH(CH 3) 2
13 H -CH 2CH 2OCH 3
14 -CH 3 -CH 2CH 2OCH 3
15 -CH(CH 3) 2 -CH 2CH 2OCH 3
16 -CH 2CH 2OCH 3 -CH 2CH 2OCH 3
17 H -N(CH 3) 2
18 -CH 3 -N(CH 3) 2
19 -CH(CH 3) 2 -N(CH 3) 2
20 -CH 2CH 2OCH 3 -N(CH 3) 2
21 H -N(CH 3)CO CH 3
22 -CH 3 -N(CH 3)CO CH 3
23 -CH(CH 3) 2 -N(CH 3)CO CH 3
24 -CH 2CH 2OCH 3 -N(CH 3)CO CH 3
[chemical formula 97]
Figure A20068004873701121
(R)m=2-F,3-Cl
No R a R b
1 H H
2 -CH 3 H
3 -CH(CH 3) 2 H
4 -CH 2CH 2OCH 3 H
5 H -CH 3
6 -CH 3 -CH 3
7 -CH(CH 3) 2 -CH 3
8 -CH 2CH 2OCH 3 -CH 3
9 H -CH(CH 3) 2
10 -CH 3 -CH(CH 3) 2
11 -CH(CH 3) 2 -CH(CH 3) 2
12 -CH 2CH 2OCH 3 -CH(CH 3) 2
13 H -CH 2CH 2OCH 3
14 -CH 3 -CH 2CH 2OCH 3
15 -CH(CH 3) 2 -CH 2CH 2OCH 3
16 -CH 2CH 2OCH 3 -CH 2CH 2OCH 3
17 H -N(CH 3) 2
18 -CH 3 -N(CH 3) 2
19 -CH(CH 3) 2 -N(CH 3) 2
20 -CH 2CH 2OCH 3 -N(CH 3) 2
21 H -N(CH 3)CO CH 3
22 -CH 3 -N(CH 3)CO CH 3
23 -CH(CH 3) 2 -N(CH 3)CO CH 3
24 -CH 2CH 2OCH 3 -N(CH 3)CO CH 3
[Chemical formula 1 03]
Figure A20068004873701131
No (R)m R a
1 4-F H
2 4-F -CH 3
3 4-F -CH(CH 3) 2
4 4-F -CH 2CH 2OCH 3
5 2,4-F H
6 2,4-F -CH 3
7 2,4-F -CH(CH 3) 2
8 2,4-F -CH 2CH 2OCH 3
9 2-F,3-Cl H
10 2-F,3-Cl -CH 3
11 2-F,3-Cl -CH(CH 3) 2
12 2-F,3-Cl -CH 2CH 2OCH 3
Further synthesized following compound.
A scheme of compound (I-10)
[Chemical formula 1 04]
Figure A20068004873701132
A scheme of compound (I-6)
[Chemical formula 1 05]
Figure A20068004873701141
Below provide concrete compound." Ex No. " expression embodiment numbering.
[Chemical formula 1 06]
Figure A20068004873701151
[Chemical formula 1 07]
Figure A20068004873701161
[Chemical formula 1 08]
[Chemical formula 1 09]
Figure A20068004873701181
[Chemical formula 1 10]
[Chemical formula 1 11]
Figure A20068004873701201
[Chemical formula 1 12]
Figure A20068004873701211
[Chemical formula 1 13]
Figure A20068004873701221
[Chemical formula 1 14]
Figure A20068004873701231
[Chemical formula 1 15]
Figure A20068004873701241
[Chemical formula 1 16]
[Chemical formula 1 17]
Figure A20068004873701261
[Chemical formula 1 18]
Figure A20068004873701271
[Chemical formula 1 19]
Figure A20068004873701281
[Chemical formula 1 20]
Figure A20068004873701291
[Chemical formula 1 21]
Figure A20068004873701301
[Chemical formula 1 22]
Figure A20068004873701311
[Chemical formula 1 23]
Figure A20068004873701321
[Chemical formula 1 24]
[Chemical formula 1 25]
Figure A20068004873701341
[Chemical formula 1 26]
[Chemical formula 1 27]
Figure A20068004873701361
[Chemical formula 1 28]
Figure A20068004873701371
Below provide the rerum natura of above-claimed cpd.Embodiment compound K-7~K-41 is according to synthetic with the same method of embodiment K-1.
Embodiment K-7) 2-(4-fluoro-benzyl)-9-hydroxyl-4-(2-hydroxyl-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.68(1H,dd,J=6.6Hz,12.3Hz),3.15(2H,m),4.51(2H,d,J=6.3Hz),4.55(1H,d,J=14.7Hz),4.64(1H,s),4.83(1H,d,J=14.7Hz),5.47(1H,m),7.01(1H,d,2.7Hz),7.13-7.43(8H,m),8.34(1H,s),10.39(1H,t,J=6.0Hz).
Embodiment K-8) 4-(2-acetylamino-ethyl)-2-(4-fluoro-benzyl)-9-hydroxyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.69(2H,m),1.78(3H,s),2.87(1H,m),4.52(1H,s),4.72(1H,s),5.42(1H,s),7.02(1H,s),7.16-7.43(8H,m),7.82(1H,s),8.48(1H,s),10.40(1H,s),11.57(1H,s).
Embodiment K-9) 5-hydroxyl-9-isobutyl--6,10-dioxo-1,2,3,4,6,10-six hydrogen-4a, 8a, 9a-three azepines-anthracene-7-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.92(6H,t,J=6.0Hz),1.46-1.86(7H,m),2.75-3.08(3H,m),4.41(1H,m),4.52(2H,m),5.56(1H,m),7.16(2H,t,J=9.0Hz),7.35(2H,dd,J=6.0Hz,8.7Hz),8.39(1H,s),10.44(1H,t,J=6.0Hz),11.88(1H,s).
Embodiment K-10) 5-hydroxyl-6,10-dioxo-1,2,3,4,6,10-six hydrogen-4a, 8a, 9a-three azepines-anthracene-7-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.56(2H,m),1.79(2H,m),2.94(2H,t,J=4.5Hz),3.70(2H,m),4.52(2H,d,J=6.0Hz),5.38(1H,s),7.16(2H,t,J=6.0Hz),7.34(2H,dd,J=5.4Hz,8.7Hz),8.40(1H,s),10.40(1H,t,J=6.0Hz),11.73(1H,s).
Embodiment K-11) 8-hydroxyl-7,9-dioxo-2,3,7,9-tetrahydrochysene-1H-3a, 4a, 9a-three azepines-ring penta [b] naphthalene-6-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.19(2H,t,J=6.6Hz),3.19(2H,t,J=6.0Hz),7.06(1H,m),7.25(1H,m),7.41(1H,m),8.49(1H,s),10.37(1H,t,J=5.7Hz),11.63(1H,s).
Embodiment K-12) 9-hydroxyl-2-sec.-propyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.05(6H,t,J=5.4Hz),4.20-4.43(3H,m),5.01(1H,d,J=12.6Hz),5.38(1H,d,J=13.2Hz),6.01(1H,s),6.89(1H,m),7.07(1H,m),7.23(1H,m),8.14(1H,s),10.30(1H,s).
Embodiment K-13) 9-hydroxyl-2-(2-methoxyl group-ethyl)-3-methyl isophthalic acid, 8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.61(3H,s),3.33(3H,s),3.54(3H,m),3.98(1H,s),4.55(1H,s),5.19(1H,m),5.38(1H,s),7.08(1H,m),7.24(1H,m),7.42(1H,m),8.41(1H,s),10.39(1H,t,J=6.0Hz),11.10(1H,s).
Embodiment K-14) 9-hydroxyl-2,3-pair-(2-methoxyl group-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:3.21(3H,s),3.26(3H,s),3.43(7H,m),4.07(1H,m),4.55(1H,s),5.15(1H,d,J=12.6Hz),5.46(1H,d,J=13.2Hz),7.07(1H,m),7.24(1H,m),7.42(1H,m),8.39(1H,s),10.39(1H,t,J=5.4Hz),10.97(1H,s).
Embodiment K-15) 8-hydroxyl-7,9-dioxo-2,3,7,9-tetrahydrochysene-1H-3a, 4a, 9a-three azepines-ring penta [b] naphthalene-6-formic acid 4-fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.19(2H,quint,J=7.5Hz),3.19(2H,t,J=6.6Hz),3.76(2H,t,J=6.9Hz),4.52(2H,d,J=6.0Hz),5.17(2H,s),7.15(1H,t,J=9.0Hz),7.35(2H,dd,J=5.7Hz,8.7Hz),8.47(1H,s),10.35(1H,t,J=5.7Hz),11.61(1H,s).
Embodiment K-16) [7-(2,4-two fluoro-benzylamino formyl radicals)-9-hydroxy-2-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-d] [1,2,4] triazine-3-yl]-acetate
NMR(DMSO-d 6)δ:3.18(3H,s),3.70(2H,s),4.54(2H,d,J=6.0Hz),5.42(2H,s),7.06(1H,m),7.23(1H,m),7.40(1H,m),8.43(1H,s),10.36(1H,t,J=5.7Hz),11.10(1H,s).
Embodiment K-17) 9-hydroxy-2-methyl-3-(2-morpholine-4-base-2-oxo-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:3.16(3H,s),3.55(4H,s),3.84(2H,s),4.54(2H,d,J=4.5Hz),5.39(2H,s),7.07(1H,m),7.29(1H,m),7.41(1H,m),8.35(1H,s),10.41(1H,t,J=4.5Hz),11.19(1H,s).
Embodiment K-18) 3-formyl-dimethylamino methyl-9-hydroxy-2-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.81(3H,s),2.90(3H,s),3.16(3H,s),3.81(2H,s),4.54(2H,d,J=5.7Hz),5.41(2H,s),7.07(1H,m),7.25(1H,m),7.40(1H,m),8.37(1H,s),10.39(1H,t,J=6.3Hz),11.10(1H,s).
Embodiment K-19) 9-hydroxy-2-methyl-3-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.16(3H,s),2.25(2H,m),3.15(3H,s),3.40(2H,s),3.81(1H,s),4.54(2H,d,J=6.0Hz),5.38(2H,s),7.07(1H,m),7.28(1H,m),7.41(1H,m),8.32(1H,s),10.43(1H,t,J=6.0Hz),11.08(1H,s).
Embodiment K-20) acetate 2-[7-(2,4-two fluoro-benzylamino formyl radicals)-9-hydroxy-2-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-d] [1,2,4] triazine-3-yl]-ethyl ester
NMR(DMSO-d 6)δ:3.11(2H,t,J=6.3Hz),3.14(3H,s),3.34(2H,t,J=6.3Hz),4.07(1H,s),4.15(1H,s),4.56(2H,d,J=6.0Hz),5.42(2H,s),7.06(1H,m),7.25(1H,m),7.41(1H,m),8.42(1H,s),10.40(1H,t,J=6.0Hz),11.04(1H,s).
Embodiment K-21) 9-hydroxyl-3-(2-hydroxyethyl-ethyl)-2-methyl isophthalic acid, 8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.90(2H,s),3.17(3H,s),3.53(2H,d,J=4.2Hz),4.54(2H,d,J=5.7Hz),4.81(1H,t,J=4.8Hz),5.37(1H,br s),5.42(1H,br s),7.06(1H,m),7.24(1H,m),7.42(1H,m),8.40(1H,s),10.39(1H,t,J=5.7Hz),11.10(1H,s).
Embodiment K-22) acetate 2-[7-(2,4-two fluoro-benzylamino formyl radicals)-9-hydroxy-3-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-pyrido [1,2-d] [1,2,4] triazine-2-yl]-ethyl ester
NMR(DMSO-d 6)δ:2.00(3H,s),2.61(3H,s),3.47(1H,m),4.22(3H,m),4.55(2H,br s),5.22(1H,br s),5.37(1H,br s),7.06(1H,m),7.24(1H,m),7.40(1H,m),8.40(1H,s),10.38(1H,t,J=6.3Hz),11.00(1H,s).
Embodiment K-23) 9-hydroxyl-2-(2-hydroxyl-ethyl)-3-methyl isophthalic acid, 8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.61(3H,s),3.20(1H,br s),3.62(2H,br s),3.89(1H,br s),4.55(2H,d,J=5.4Hz),4.83(1H,t,J=5.7Hz),5.27(1H,br s),5.34(1H,br s),7.06(1H,m),7.23(1H,m),7.42(1H,m),8.39(1H,s),10.41(1H,t,J=6.0Hz),11.22(1H,s).
Embodiment K-24) 9-hydroxyl-3-hydroxymethyl-2-(2-methoxyl group-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:3.26(3H,s),3.55(2H,m),4.15(1H,br s),4.51(2H,m),4.53(1H,d,J=6.0Hz),5.21(1H,br s),5.57(1H,br s),6.11(1H,t,J=7.2Hz),7.05(1H,m),7.23(1H,m),7.42(1H,m),8.35(1H,s),10.41(1H,t,J=6.0Hz),11.12(1H,s).
Embodiment K-25) [7-(2,4-two fluoro-benzylamino formyl radicals)-9-hydroxy-3-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-pyrido [1,2-d] [1,2,4] triazine-2-yl]-methyl acetate
NMR(DMSO-d 6)δ:2.63(3H,s),4.28(1H,br s),4.56(1H,br s),4.56(1H,d,J=5.7Hz),5.34(1H,br s),5.35(1H,br s),7.07(1H,m),7.25(1H,m),7.42(1H,m),8.41(1H,s),10.34(1H,t,J=5.7Hz),10.60(1H,s).
Embodiment K-26) 3-(2-oxyethyl group-ethyl)-9-hydroxy-2-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.09(3H,t,J=6.6Hz),3.03(2H,br s),3.37(2H,q,J=6.6Hz),3.47(2H,s),4.54(1H,d,J=6.0Hz),5.36(1H,br s),5.38(1H,br s),7.07(1H,m),7.25(1H,m),7.41(1H,m),8.38(1H,s),10.39(1H,t,J=6.0Hz),11.09(1H,br s).
Embodiment K-27) 9-hydroxyl-3-(3-methoxyl group-propyl group)-2-methyl isophthalic acid, 8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.72(2H,br s),2.86(2H,br s),3.16(3H,s),3.21(2H,br s),4.55(1H,d,J=5.7Hz),5.37(1H,br s),5.43(1H,br s),7.06(1H,m),7.25(1H,m),7.41(1H,m),8.50(1H,s),10.37(1H,t,J=5.7Hz),11.10(1H,br s).
Embodiment K-28) 3-(2-acetylamino-ethyl)-9-hydroxy-2-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.80(3H,s),2.86(2H,t,J=6.6Hz),3.15(3H,s),3.21(2H,t,J=6.6Hz),4.54(2H,d,J=4.8Hz),5.36(2H,br s),7.06(1H,m),7.24(1H,m),7.42(1H,m),7.93(1H,t,J=5.1Hz),8.42(1H,s),10.42(1H,t,J=4.8Hz),11.18(1H,br s).
Embodiment K-29) 3-(2-dimethylamino-ethyl)-9-hydroxy-2-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.10(6H,s),2.38(2H,s),2.85(2H,s),3.16(3H,s),4.54(2H,d,J=5.7Hz),5.31(1H,br s),5.45(1H,br s),7.07(1H,m),7.25(1H,m),7.40(1H,m),8.35(1H,s),10.46(1H,t,J=5.7Hz),11.03(1H,br s).
Embodiment K-30) 9-hydroxyl-3-(2-methoxyl group-ethyl)-1,8-dioxo-2-propyl group-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.89(3H,t,J=7.2Hz),1.64(2H,m),3.00(2H,t,J=5.14Hz),3.07(1H,m),3.20(3H,s),3.20(1H,m),3.42(2H,m),4.54(2H,s),5.22(1H,d,12.6Hz),5.48(1H,d,12.6Hz),7.09(1H,m),7.24(1H,m),7.40(1H,m),8.39(1H,s),10.39(1H,t,J=5.7Hz),11.13(1H,br s).
Embodiment K-31) 9-hydroxyl-2,3-dimethyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides
NMR(CDCl3)δ:2.72(3H,s),3.26(3H,s),4.61(2H,d,J=2.7Hz),6.97-7.03(2H,m),7.26-7.35(2H,m),8.32(1H,s),10.40(1H,brs).
Embodiment K-32) 9-hydroxyl-2,3-dimethyl-1,8-dioxo-4-(tetrahydrochysene-furans-3-yl)-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides (non-enantiomer mixture 1: 1)
1H-NMR(DMSO-d6)δ:1.60-1.70(1H,m),3.15(3H,d,J=7.1Hz),3.14-3.83(m),4.49-4.53(2H,m)5.40-5.50(1H,m),7.12-7.18(2H,m),7.33-7.38(2H,m),8.43 and8.53(1H,s),10.30-10.40(1H,brt),11.30(1H,brs).
Embodiment K-33) 9-hydroxyl-2,3-dimethyl-4-morpholine-4-ylmethyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:2.79(3H,s),3.27(3H,s),4.03-3.66(m),4.58(2H,d,J=5.71Hz),6.09(1H,s),7.26-7.16(2H,m),7.45-7.36(2H,m),8.57(1H,s),10.34(1H,t,J=6.04Hz),11.44(1H,br s).
Embodiment K-34) 9-hydroxyl-2,3-dimethyl-1,8-dioxo-4-styroyl-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:2.72(3H,s),3.15-3.52(m),,4.53(2H,d,J=2.7Hz),7.11-7.18(2H,m),7.32-7.37(2H,m),8.31(1H,s),8.51(1H,brs),10.29(1H,brs).
Embodiment K-35) 9-hydroxyl-4-sec.-propyl-2,3-dimethyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 4-fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:0.70 and 1.02(each 3H,d,J=6.2Hz),2.63(3H,s),,3.16(3H,s),3.25-3.52(1H,m),4.51(2H,m),5.18(1H,d,J=8.4Hz),7.12-7.18(2H,m),7.33-7.38(2H,m),8.46(1H,s),10.30-10.40(1H,m),11.27(1H,brs).
Embodiment K-36) 9-hydroxy-2-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:3.18(3H,s),4.50-4.70(3H,m),5.47(1H,brs),6.13(1H,t,J=7.0Hz),7.03-7.09(1H,m),7.19-7.27(1H,m),7.36-7.44(1H,m),8.36(1H,s),10.41(1H,t,J=5.9Hz),11.26(1H,brs).
Embodiment K-37) 9-hydroxyl-3-(2-methoxyl group-ethyl)-2-methyl isophthalic acid, 8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:2.98-3.14(2H,m),3.27(3H,s),3.33(3H,s),3.46-3.62(2H,m),4.64(2H,d,J=5.9Hz),5.20-5.27(2H,m),6.75-6.90(2H,m),7.26-7.41(1H,m),8.26(1H,s)10.30-10.40(1H,brt).
Embodiment K-38) 3-ethyl-9-hydroxy-2-methyl-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(CDCl3)δ:1.21(3H,t,J=7.0Hz),2.85-3.08(2H,m),3.31(3H,s),4.64(2H,d,J=5.9Hz),4.83-5.37(2H,m),6.75-6.87(2H,m),7.32-7.43(1H,m),8.34(1H,brs),10.30-10.45(1H,m),11.13-11.31(1H,m).
Embodiment K-39) 2-ethyl-9-hydroxyl-3-(2-methoxyl group-ethyl)-1,8-dioxo-1,3,4,8-tetrahydrochysene-2H-pyrido [1,2-d] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.35(1H,t,J=7.13Hz),3.28-2.90(1H,m),3.37(3H,s),3.53(3H,s),3.75-3.58(1H,m),4.28-4.08(1H,m),4.69(2H,d,J=5.88Hz),5.48-5.05(2H,m),6.90-6.80(2H,m),7.47-7.36(1H,m),8.31(1H,s),0.50-10.41(1H,m).
Embodiment K-40) 1-hydroxyl-2,11-dioxo-2,6,7,9,10,11-six hydrogen-8-oxa--4a, 5a, 10a-three azepines-ring heptan [b] naphthalene-3-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.41(2H,br s),3.82(2H,br s),4.12(2H,br s),4.55(2H,br s),4.64(2H,d,J=6.0Hz),4.95(1H,br s),5.32(1H,br s),6.75-6.83(2H,m),7.31-7.41(1H,m),10.39(1H,t,J=6.0Hz),11.31(1H,br s).
Embodiment K-41) 1-hydroxyl-2,11-dioxo-2,7,8,9,10,11-six hydrogen-6H-4a, 5a, 10a-three azepines-ring heptan [b] naphthalene-3-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.68(1H,br s),1.91(4H,br s),2.92(1H,br s),3.00(1H,br s),3.21(1H,br s),4.39(1H,br s),4.63(2H,d,J=6.0Hz),4.82(1H,br s),5.22(1H,br s),6.79-6.82(2H,m),7.27-7.40(1H,m),8.30(1H,s),10.40(1H,t,J=6.0Hz),11.39(1H,br s).
Embodiment N-1) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-(pyridine-2-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
O-1) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
[Chemical formula 1 29]
1) use is according to the synthetic method synthetic compound 67 of compound 65, according to following order synthetic compound 68.
In the 230mL DMF solution of 23.3g (49.4mmol) above-claimed cpd 67, add 13.7g (98.8mmol) salt of wormwood, at room temperature stirred 90 minutes.Then add 10.8g (54.4mmol) O-(2, the 4-dinitrophenyl)-azanol, at room temperature stirred 2 hours.In reaction solution, add entry, use ethyl acetate extraction, use dried over sodium sulfate.Heat up in a steamer and desolvate, the gained crystal is washed with diethyl ether, obtain 21.7g 1-amino-3-benzyl oxygen base-5-[3-(2,4-two fluoro-phenyl)-propyl group]-4-oxo-1,4-dihydro-pyridine-2-formic acid (2-methoxyl group-ethyl)-acid amides 68 (yield 90%).
NMR(CDCl3)δ:3.25(3H,s),3.42(2H,t,J=4.9Hz),3.48(2H,t,J=4.9Hz),4.60(2H,d,J=4.8Hz),4.60(2H,br s),5.27(3H,s),6.74-6.84(2H,m),7.34-7.43(6H,m),7.77(1H,br s),9.37(1H,br s),10.38(1H,t,J=4.8Hz).
2) in the 300mL toluene solution of 10g (20.6mmol) above-claimed cpd 68, add 790mg (26.3mmol) paraformaldehyde and 3.16g (52.6mmol) acetate, 80 ℃ of following heated and stirred 40 minutes.Heat up in a steamer after the cooling and desolvate.Need not the purifying residue, be dissolved among the 500mL DMF, ice-cooled 25.7g (78.9mmol) cesium carbonate that adds down stirred 30 minutes.In reaction solution, add entry, use ethyl acetate extraction, use dried over sodium sulfate after the washing.Heat up in a steamer and desolvate, the gained crystal is washed with diethyl ether, obtain 9.85g 5-benzyl oxygen base-7-[3-(2,4-two fluoro-phenyl)-propyl group]-3-(2-methoxyl group-ethyl)-2,3-dihydro-1H-pyrido [2,1-f] [1,2,4] triazine-4,6-diketone 69 (yield 96%).
NMR(CDCl3)δ:3.34(3H,s),3.55(2H,t,J=4.7Hz),3.62(2H,t,J=4.7Hz),4.51(2H,d,J=7.9Hz),4.62(2H,d,J=5.9Hz),5.29(2H,s),5.88(1H,br s),6.76-6.86(2H,m),7.29-7.42(4H,m),7.54-7.58(2H,m),8.51(1H,s)10.41(1H,t,J=5.9Hz).
3) according to the synthetic method of compound 15, obtain 76.3mg 5-benzyl oxygen base-7-[3-(2 by 72.2g compound 69,4-two fluoro-phenyl)-propyl group]-3-(2-methoxyl group-ethyl)-1-pyridine-2-ylmethyl-2,3-dihydro-1H-pyrido [2,1-f] [1,2,4] triazine-4,6-diketone 70 (89%).
NMR(CDCl3)δ:3.28(3H,s),3.66(2H,s),3.80(2H,br s),3.30(2H,br s),4.61(2H,d,J=6.0Hz),4.69(2H,br s),5.35(1H,br s),6.76-6.86(2H,m),7.29-7.39(7H,m),7.59-7.62(2H,m),7.74(1H,d,J=1.9Hz,7.7Hz),8.32(1H,s),8.62(1H,d,J=4.2Hz),10.38(1H,t,J=6.0Hz).
4) according to the synthetic method of embodiment A-1, obtain 44.3mg embodiment N-1 (69%) by 76.3mg compound 70.
1H-NMR(CDCl3)δ:3.32(3H,s),3.64(2H,t,J=4.8Hz),3.79(2H,br s),4.41(2H,br s),4.59(2H,d,J=5.9Hz),4.88(2H,br s),6.75-6.84(2H,m),7.28-7.42(2H,m),7.84(1H,dd,J=7.6Hz,7.6Hz),8.21(1H,s),8.63(1H,d,J=4.4Hz),10.28(1H,t,J=5.9Hz),11.67(1H,br s).
5) according to the synthetic method of embodiment A-1, obtain 54.3mg embodiment O-1 (66%) by 100g compound 69.
1H-NMR(CDCl3)δ:3.37(3H,s),3.59(2H,t,J=4.5Hz),3.70(2H,t,J=4.5Hz),4.62(2H,d,J=6.0Hz),4.72(2H,d,J=8.2Hz),5.91(1H,t,J=8.2Hz),6.76-6.84(2H,m),7.32-7.40(1H,m),8.43(1H,s),10.29(1H,t,J=6.0Hz).
According to the method same with embodiment N-1, synthetic following examples compound N-2~N-57.
Embodiment N-2) 3-(4-fluoro-benzyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.71(3H,s),4.53(2H,d,J=5.7Hz),4.68(2H,s),4.80(2H,br s),7.02-7.48(7H,m),8.24(1H,s),10.34(1H,t,J=5.7Hz),11.58(1H,br s).
Embodiment N-3) 5-hydroxyl-3-sec.-propyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.19(6H,d,J=6.9Hz),2.83(3H,s),4.53(2H,d,J=5.7Hz),4.66(1H,m),4.79(2H,s),7.07(1H,m),7.27(1H,m),7.40(1H,m),8.28(1H,s),10.37(1H,t,J=5.7Hz),11.94(1H,br s).
Embodiment N-4) 5-hydroxyl-1-methyl-4,6-dioxo-3-thiophene-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.67(3H,s),4.53(2H,d,J=5.7Hz),4.87(4H,br s),7.00-7.50(5H,m),7.52(1H,d,J=1.5Hz),8.27(1H,s),10.28(1H,t,J=5.7Hz),11.40(1H,br s).
Embodiment N-5) 5-hydroxyl-3-(3-methoxyl group-propyl group)-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.82(2H,quint,J=6.6Hz),2.86(3H,s),3.24(3H,s),3.40(2H,t,J=6.0Hz),3.52(2H,t,J=7.5Hz),4.53(2H,d,J=6.0Hz),4.80(2H,br s),7.06(1H,m),7.23(1H,m),7.36(1H,m),8.26(1H,s),10.35(1H,t,J=5.4Hz),11.79(1H,br s).
Embodiment N-6) 5-hydroxyl-1-methyl-4,6-dioxo-3-(tetrahydrochysene-furans-2-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.54-1.97(4H,m),2.88(3H,s),3.49(1H,dd,J=7.8Hz,14.4Hz),3.68(2H,m),3.79(1H,dd,J=8.1Hz,15.0Hz),4.07(1H,m),4.53(2H,d,J=6.0Hz),4.84(2H,br s),7.06(1H,m),7.26(1H,m),7.36(1H,m),8.26(1H,s),10.35(1H,t,J=6.0Hz),11.69(1H,br s).
Embodiment N-7) 5-hydroxyl-3-(2-isopropoxy-ethyl)-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.06(6H,d,J=6.0Hz),2.88(3H,s),3.37(1H,m),3.60(4H,m),4.53(2H,d,J=6.0Hz),4.82(2H,br s),7.06(1H,m),7.23(1H,m),7.41(1H,m),8.28(1H,s),10.33(1H,t,J=5.7Hz),11.74(1H,br s).
Embodiment N-8) 5-hydroxyl-3-(3-isopropoxy-propyl group)-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.07(6H,d,J=6.0Hz),1.81(2H,m),2.87(3H,s),3.38(1H,m),3.43(2H,t,J=6.0Hz),3.53(2H,t,J=6.3Hz),4.53(2H,d,J=6.0Hz),4.81(2H,br s),7.06(1H,m),7.23(1H,m),7.39(1H,m),8.27(1H,s),10.35(1H,t,J=6.0Hz),11.84(1H,br s).
Embodiment N-9) 3-furans-2-ylmethyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.70(3H,s),4.53(2H,d,J=6.0Hz),4.74(1H,s),4.83(2H,br s),6.45(1H,d,J=3.0Hz),6.50(1H,d,J=2.4Hz),7.06(1H,m),7.21(1H,m),7.44(1H,m),7.61(s,1H),8.28(1H,s),10.29(1H,t,J=6.0Hz),11.50(1H,br s).
Embodiment N-10) 3-diamantane-1-ylmethyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.52(8H,m),1.94(3H,br s),2.88(3H,s),3.28(2H,br s),4.53(2H,d,J=6.0Hz),4.84(2H,br s),7.06(1H,m),7.24(1H,m),7.38(1H,m),8.24(1H,s),10.38(1H,t,J=6.0Hz),11.71(1H,br s).
Embodiment N-11) 3-cyclopropyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.81(4H,m),2.80(1H,m),2.81(3H,s),4.53(2H,d,J=5.7Hz),4.72(2H,br s),7.05(1H,m),7.23(1H,m),7.39(1H,m),8.26(1H,s),10.34(1H,t,J=6.0Hz),11.87(1H,br s).
Embodiment N-12) 3-(3-chloro-2-fluoro-benzyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.81(3H,s),4.53(2H,d,J=6.0Hz),4.80(2H,s),4.88(2H,br s),7.03-7.59(6H,m),8.31(1H,s),10.28(1H,t,J=65.7Hz),11.46(1H,br s).
Embodiment N-13) 3-cyclopropyl methyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.33(2H,d,J=4.8Hz),0.51(2H,d,J=6.6Hz),1.12(1H,m),2.89(3H,s),3.36(2H,d,J=7.2Hz),4.53(2H,d,J=5.4Hz),4.88(2H,br s),7.09(1H,m),7.23(1H,m),7.41(1H,m),8.28(1H,s),10.34(1H,t,J=5.7Hz),11.76(1H,br s).
Embodiment N-14) 1,3-pair-cyclopropyl methyl-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.31-1.09(6H,m),3.33(4H,br s),4.54(2H,d,J=5.4Hz),4.97(2H,br s),7.08(1H,m),7.22(1H,m),7.39(1H,m),8.31(1H,s),10.34(1H,t,J=5.1Hz),11.80(1H,br s).
Embodiment N-15) 5-hydroxyl-1-methyl-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.56-1.90(4H,m),3.44-4.07(5H,m),4.53(2H,d,J=6.0Hz),4.82(2H,br s),7.09(1H,m),7.28(1H,m),7.41(1H,m),8.23(1H,s),10.39(1H,t,J=6.0Hz),11.71(1H,br s).
Embodiment N-16) 5-hydroxyl-1-methyl-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.54-1.97(4H,m),2.88(3H,s),3.49(1H,dd,J=7.8Hz,14.4Hz),3.68(2H,m),3.79(1H,dd,J=8.1Hz,15.0Hz),4.07(1H,m),4.53(2H,d,J=6.0Hz),4.84(2H,br s),7.06(1H,m),7.26(1H,m),7.36(1H,m),8.26(1H,s),10.35(1H,t,J=6.0Hz),11.69(1H,br s).
Embodiment N-17) 3-benzo [1,3] dioxole-5-ylmethyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.71(3H,s),4.54(2H,d,J=5.7Hz),4.60(2H,s),4.77(2H,br s),6.00(2H,s),6.90(2H,s),6.98(1H,s),7.05(1H,m),7.28(1H,m),7.40(1H,m),8.22(1H,s),10.37(1H,t,J=5.7Hz),11.65(1H,br s).
Embodiment N-18) 3-(2-oxyethyl group-ethyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.10(3H,t,J=6,9Hz),2.88(3H,s),3.46(2H,q,J=6.6Hz),3.60(2H,d,J=4.8Hz),3.66(2H,br s),4.53(2H,d,J=5.7Hz),4.83(2H,br s),7.05(1H,m),7.24(1H,m),7.41(1H,m),8.31(1H,s),10.31(1H,t,J=5.7Hz),11.72(1H,br s).
Embodiment N-19) 5-hydroxyl-1-methyl-4,6-dioxo-3-[3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.79(2H,m),1.93(2H,m),2.22(2H,t,J=8.1Hz),2.90(3H,s),3.23(2H,t,J=6.6Hz),3.42(4H,m),4.54(2H,d,J=6.0Hz),4.84(2H,br s),7.06(1H,m),7.21(1H,m),7.41(1H,m),8.32(1H,s),10.32(1H,t,J=5.7Hz),11.76(1H,br s).
Embodiment N-20) 3-(3-dodecyloxy-propyl group)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.85(3H,t,J=6.3Hz),1.22(20H,br s),1.44(2H,m),1.82(2H,m),2.88(3H,s),3.39(2H,t,J=6.0Hz),3.54(2H,t,J=5.7Hz),4.53(2H,d,J=6.0Hz),4.82(2H,br s),7.07(1H,m),7.25(1H,m),7.41(1H,m),8.31(1H,s),10.32(1H,t,J=6.0Hz),11.85(1H,br s).
Embodiment N-21) 3-[1,4] diox-2-ylmethyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.89(3H,s),3.25-3.81(9H,m),4.54(2H,d,J=5.7Hz),4.84(2H,brs),7.06(1H,m),7.27(1H,m),7.42(1H,m),8.31(1H,s),10.31(1H,t,J=6.0Hz),11.64(1H,br s).
Embodiment N-22) 3-(2,3-dihydro-benzo [1,4] dioxine-6-ylmethyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.72(3H,s),4.23(4H,s),4.54(2H,m),4.55(2H,s),4.78(1H,brs),6.78-7.41(6H,m),8.25(1H,s),10.35(1H,s),11.66(1H,br s).
Embodiment N-23) 3-[3-(2-ethyl-hexyloxy)-propyl group]-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.82-1.40(17H,m),1.82(2H,m),2.88(3H,s),3.24(2H,d,5.7Hz),3.41(2H,t,J=6.0Hz),3.54(2H,t,J=7.2Hz),4.53(2H,d,J=5.7Hz),4.82(2H,br s),7.06(1H,m),7.25(1H,m),7.41(1H,m),8.31(1H,s),10.32(1H,t,J=5.7Hz),11.85(1H,br s).
Embodiment N-24) 1-butyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:0.99(3H,t,J=7.39Hz),1.79-1.34(4H,m),3.14-3.00(2H,m),3.41(3H,s),3.83-3.62(4H,m),4.69(2.2H,d,J=6.21Hz),4.95-4.71(1H,m),6.92-6.79(1H,m),7.49-7.37(1H,m),8.51(1H,s),10.47(1H,brt,J=6.21Hz),11.82-11.53(1H,brs).
Embodiment N-25) 5-hydroxyl-1-sec.-propyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.19-1.01(6H,brm),3.38(3H,s),3.48(1H,s),3.68-3.61(2H,m),3.76-3.70(2H,m),4.67(2H,d,J=6.88Hz),4.91-4.83(2H,m),6.90-6.77(2H,m),7.46-7.35(1H,m),8.44(1.4H,s),10.40(1H,brt,J=6.88Hz),11.58(1H,brs).
Embodiment N-26) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.79(2H,br s),3.19(1H,br s),3.35(3H,s),3.38(3H,s),3.47(2H,t,J=5.77Hz),3.65(2H,t,J=4.53Hz),3.74(2H,br s),4.66(2H,d,J=5.77Hz),4.94-4.70(2H,m),6.91-6.76(2H,m),7.45-7.34(1H,m),8.46(1H,s),10.39(1H,br s),11.77-11.46(1H,m).
Embodiment N-27) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-(3-pyrroles-1-base-propyl group)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.97(2H,br s),2.96(2H,t,J=7.22Hz),3.32(3H,s),3.73-3.57(4H,m),4.06(2H,br s),4.67(2H,d,J=4.20Hz),5.03-4.60(2H,m),6.19(2H,t,J=2.0Hz),6.65(2H,t,J=2.0Hz),6.91-6.79(2H,m),7.47-7.34(1H,m),8.46(1H,s),10.43-10.31(1H,m),11.68-11.47(1H,m).
Embodiment N-28) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-(5-methyl-isoxazole-3-base methyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.50(3H,s),3.38(3H,s),3.87-3.60(6H,m),4.27(1H,br s),4.66(2H,d,J=6.04Hz),4.77(1H,br s),6.13(1H,s),6.92-6.75(2H,m),7.49-7.32(2H,m),8.45(1H,s),10.37(1H,br s),11.69(1H,br s).
Embodiment N-29) 1-(2,4-dinitrobenzene-phenyl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:3.22(2H,br s),3.36(3H,s),3.60(2H,br s),4.55(2H,d,J=9.40Hz),5.41(2H,br s),7.12-7.03(1H,m),7.26(1H,d,J=9.74Hz),7.31-7.21(1H,m),7.49-7.36(1H,m),8.47-8.38(1H,m),8.49(1H,s),9.01(1H,d,J=9.74Hz),10.23-10.20(1H,m),11.56(1H,br s).
Embodiment N-30) 1-ethyl-5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.19(3H,t,J=7.60Hz),1.99-1.91(2H,m),3.13(2H,q,J=15.19,7.60Hz),3.35(3H,s),3.49(2H,t,J=5.62Hz),3.66(2H,t,J=7.22Hz),4.67(2H,d,J=7.72Hz),8.49(1H,s),10.41(1H,br s),11.73(1H,br s).
Embodiment N-31) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-(2-nitro-phenyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.94(3H,s),3.39-3.32(2H,m),3.66(2H,br s),4.62(2H,d,J=6.21Hz),6.87-6.77(3H,m),7.41-7.31(1H,m),7.48(1H,dt,J=10.63,3.99Hz),7.60(1H,td,J=7.76,1.62Hz),8.09(1H,dd,J=8.14,1.59Hz),8.42(1H,s),10.26(1H,t,J=6.21Hz).
Embodiment N-32) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-pyrimidine-2-base-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.39(3H,s),3.72-3.41(3H,m),4.14-4.01(2H,m),4.71(2H,d,J=5.37Hz),5.25(1H,d,J=13.60Hz),6.15(1H,d,J=13.60Hz),6.92-6.81(2H,m),7.13(1H,t,J=4.11Hz),7.50-7.40(1H,m),8.57(2H,d,J=4.11Hz),8.60(1H,s),10.51-10.37(1H,m),11.49(1H,br s).
Embodiment N-33) 3-cyclopropyl methyl-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:0.42-0.33(2H,m),0.70-0.60(2H,m),1.22-1.02(1H,m),3.54(2H,d,J=7.05Hz),4.41(2H,br s),4.65(2H,d,J=6.29Hz),4.93(2H,br s),6.90-6.79(2H,m),7.46-7.33(3H,m),7.84(1H,td,J=7.76,1.79Hz),8.34(1H,s),8.66(1H,d,J=4.87Hz),10.36(1H,t,J=6.29Hz),11.83(1H,br s).
Embodiment N-34) 3-cyclopropyl-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.07-0.94(4H,m),2.90-2.80(1H,m),4.24(2H,s),4.64(2H,d,J=6.21Hz),4.74(2H,br s),6.91-6.77(2H,m),7.46-7.32(3H,m),7.80(1H,td,J=7.68,1.73Hz),8.38(1H,s),8.64(1H,d,J=5.87Hz),10.36(1H,t,J=5.71Hz),12.06-11.70(1H,m).
Embodiment N-35) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-(4-nitro-phenyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:3.07(3H,s),3.37-3.30(2H,m),3.56(2H,br s),4.58(1H,d,J=5.87Hz),5.84-5.41(2H,m),7.15-7.07(1H,m),7.18(2H,d,J=10.24Hz),7.36-7.24(1H,m),7.52-7.42(1H,m),8.24(2H,d,J=9.40Hz),8.35(1H,s),10.37-10.21(1H,m),11.63-11.34(1H,m).
Embodiment N-36) 5-hydroxyl-1-(2-methoxyl group-ethyl)-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.14-1.92(4H,m),3.35-3.15(1H,m),3.37(3H,s),3.63-3.48(2H,m),3.95-3.73(2H,m),4.19-3.98(2H,m),4.67(1H,d,J=5.54Hz),4.84(1H,br s),4.98(1H,br s),6.91-6.77(1H,m),7.47-7.32(1H,m),8.54(1H,s),10.46-10.36(1H,m),11.91-11.45(1H,m).
Embodiment N-37) 3-(3-chloro-2-fluoro-benzyl)-5-hydroxyl-1-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.24-3.01(2H,m),3.34(3H,s),3.55-3.49(2H,m),4.66(2H,d,J=7.22Hz),4.81(2H,br s),4.85(2H,br s),6.89-6.77(3H,m),7.20-7.13(1H,m),7.49-7.32(2H,m),8.51(1H,s),10.44-10.28(1H,m).
Embodiment N-38) 5-hydroxyl-1-(2-methoxyl group-ethyl)-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.14-1.92(4H,m),3.35-3.15(1H,m),3.37(3H,s),3.63-3.48(2H,m),3.95-3.73(2H,m),4.19-3.98(2H,m),4.67(1H,d,J=5.54Hz),4.84(1H,br s),4.98(1H,br s),6.91-6.77(1H,m),7.47-7.32(1H,m),8.54(1H,s),10.46-10.36(1H,m),11.91-11.45(1H,m).
Embodiment N-39) 3-benzo [1,3] two oxazoles-5-ylmethyl-5-hydroxyl-1-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.06(2H,br s),3.33(3H,s),3.46(4H,t,J=5.00Hz),4.72-4.62(2H,m),6.01(2H,s),6.89-6.78(2H,m),7.45-7.32(1H,m),8.49(1H,s),10.39-10.36(1H,m),11.93-11.50(1H,m).
Embodiment N-40) 5-hydroxyl-3-(2-isopropoxy-ethyl)-1-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.17(6H,d,J=6.21Hz),3.38(3H,s),3.82-3.50(5H,m),4.67(2H,d,J=5.87Hz),4.89(2H,br s),6.88-6.78(2H,m),7.44-7.34(1H,m),8.53(1H,s),10.41(1H,t,J=5.87Hz).
Embodiment N-41) 1-(4,6-two fluoro-benzothiazole-2-yl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.34(3H,s),3.54(3H,br s),4.03(1H,br s),4.66(2H,d J=5.7Hz),5.30(1H,br s),5.92(1H,s),6.78-6.88(2H,m),6.96-7.03(1H,m),7.19-7.23(1H,m),7.35-7.43(1H,m),8.64(1H,s),10.17(1H,t,J=5.7Hz),11.52(1H,s).
Embodiment N-42) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-Propargyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.49(1H,t,J=2.5Hz),3.38(3H,s),3.69(2H,t,J=4.5Hz),3.77(2H,t,J=4.5Hz),3.96(2H,d,J=2.5Hz),4.68(2H,d,J=5.9Hz),4.88(2H,s),6.80-6.90(2H,m),7.37-7.45(1H,m),8.53(1H,s),10.32(1H,t,J=5.9Hz),11.62(1H,br s).
Embodiment N-43) 1-furans-3-ylmethyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.35(3H,s),3.63(2H,d,J=3.9Hz),3.70(2H,br s),4.06(2H,br s),4.62(2H,d,J=6.0Hz),4.74(2H,br s),6.45(1H,s),6.76-6.85(2H,m),7.31-7.39(1H,m),7.48(1H,t,J=1.8Hz),10.31(1H,t,J=6.0Hz),11.60(1H,br s).
Embodiment N-44) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.34(3H,s),3.62(2H,t,J=3.9Hz),3.69(2H,br s),4.20(2H,br s),4.61(2H,d,J=6.2Hz),4.78(2H,br s),6.76-6.85(2H,m),7.09(1H,dd,J=1.3Hz,5.0Hz),7.14(1H,dd,J=2.9Hz,5.0Hz),8.22(1H,s),10.28(1H,J=6.2Hz),11.60(1H,br s).
Embodiment N-45) 1-furans-2-ylmethyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.36(3H,s),3.64(2H,t,J=4.8Hz),3.74(2H,br s),4.20(2H,s),4.61(2H,d,J=6.0Hz),4.76(2H,br s),6.27(1H,d,J=3.2Hz),6.34(1H,dd,J=1.9Hz,3.2Hz),6.76-6.84(2H,m),7.30-7.38(1H,m),7.45(1H,dd,J=0.8Hz,1.9Hz),8.20(1H,s),10.29(1H,t,J=6.0Hz).
Embodiment N-46) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-thiophene-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.49(3H,s),3.67(2H,t,J=4.5Hz),3.76(2H,br s),4.43(2H,br s),4.67(2H,d,J=5.5Hz),4.78(2H,br s),6.80-6.90(2H,m),6.96-7.04(2H,m),7.36-7.44(1H,m),7.44(1H,dd,J=1.5Hz,5.1Hz),8.41(1H,br s),10.37(1H,br s).
Embodiment N-47) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-methylamino formyl radical methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.89(3H,d,J=4.5Hz),3.35(3H,s),3.63(2H,t,J=4.8Hz),3.72(2H,br s),4.61(2H,d,J=5.7Hz),4.87(2H,br s),6.72(1H,br s),6.76-6.85(2H,m),7.31-7.39(1H,m),8.49(1H,s),10.23(1H,t,J=5.7Hz),11.63(1H,br s).
Embodiment N-48) 1-methyl fluoride-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.44(3H,s),3.72(4H,br s),4.61(2H,d,J=5.4Hz),4.80(2H,s),4.90(2H,s),4.77-4.87(2H,m),7.36-7.44(1H,m),8.52(1H,s),10.10(1H,s),11.65(1H,br s).
Embodiment N-49) 1-(4-fluoro-benzyl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.32(3H,s),3.61(2H,br s),3.68(2H,br s),4.15(2H,s),4.60(2H,d,J=5.7Hz),4.81(2H,br s),6.75-6.85(2H,m),7.07(2H,t,J=5.6Hz),7.23-7.36(3H,m),8.27(1H,s),10.24(1H,t,J=5.7Hz),11.60(1H,br s).
Embodiment N-50) 5-hydroxyl-1-(4-methoxyl group-benzyl)-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.32(3H,s),3.59(2H,t,J=4.5Hz),3.68(2H,br s),3.80(3H,s),4.61(2H,d,J=5.7Hz),4.65(2H,br s),6.75-6.85(2H,m),6.89(2H,d,J=8.6Hz),7.17(2H,d,J=8.6Hz),7.29-7.37(1H,m),8.28(1H,s),10.30(1H,t,J=5.7Hz),11.61(1H,br s).
Embodiment N-51) 1-benzyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.31(3H,s),3.60(2H,t,J=4.2Hz),3.68(2H,br s),4.17(2H,s),4.60(2H,d,J=5.7Hz),4.68(2H,br s),6.75-6.85(2H,m),7.25-7.39(6H,m),8.27(1H,s),10.28(1H,t,J=5.7Hz),11.61(1H,br s).
Embodiment N-52) 5-hydroxyl-1,3-pair-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.34(3H,s),3.35(3H,s),3.54(2H,t,J=4.5Hz),3.61(2H,t,J=4.5Hz),3.72(2H,br s),4.64(2H,d,J=5.9Hz),4.84(2H,br s),6.75-6.84(2H,m),7.32-7.40(1H,m),8.51(1H,s),10.38(1H,br s),11.62(1H,br s).
Embodiment N-53) 1-formyl-dimethylamino methyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.04(3H,s),3.05(3H,s),3.35(3H,s),3.65(2H,t,J=4.6Hz),3.77(2H,br s),3.96(2H,br s),4.68(2H,d,J=5.9Hz),5.02(2H,s),6.80-6.89(2H,m),7.37-7.45(1H,m),8.56(1H,s),10.39(1H,br s),11.60(1H,br s).
Embodiment N-54) 5-hydroxyl-1-(2-hydroxyl-ethyl)-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.25(2H,br s),3.37(3H,s),3.66(2H,t,J=4.2Hz),3.73(2H,br s),3.82(2H,t,J=4.2Hz),4.63(2H,d,J=5.7Hz),4.90(2H,s),6.76-6.85(2H,m),7.33-7.41(1H,m),8.63(1H,br s),10.45(1H,br s),11.6(1H,br s).
Embodiment N-55) 1-cyclopropyl methyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:0.00(2H,br s),0.60(2H,m),0.94(1H,m),2.93(2H,br s),3.38(3H,s),3.65(2H,t,J=4.5Hz),3.74(2H,t,J=4.5Hz),4.67(2H,d,J=5.9Hz),4.83(2H,br s),6.79-6.88(2H,m),7.36-7.44(1H,m),8.56(1H,s),10,42(1H,J=5.9Hz),11.61(1H,br s).
Embodiment N-56) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-pyridin-3-yl methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.37(3H,s),3.68(2H,br s),3.75(2H,br s),4.38(2H,br s),4.63(2H,d,J=5.9Hz),4.88(2H,br s),6.79-6.88(2H,m),7.32-7.41(1H,m),7.56-7.61(1H,m),7.94-7.97(1H,m),8.34(1H,s),8.74(1H,br s),10.26(1H,t,J=5.9Hz).
Embodiment N-57) 1-ethyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.17(3H,t,7.13),3.11(2H,q,J=7.1Hz),3.36(3H,s),3.63(2H,t,J=4.5Hz),3.71(2H,br s),4.64(2H,d,J=5.9Hz),4.78(2H,br s),6.76-6.85(2H,m),7.33-7.41(1H,m),8.45(1H,s),10.38(1H,t,J=5.9Hz),11.59(1H,br s).
According to the method synthetic following embodiment compound O-2~O-13 same with embodiment O-1.
Embodiment O-2) 3-(4-fluoro-benzyl)-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:4.52(2H,d,J=5.4Hz),4.64(4H,br s),7.02-7.44(7H,m),7.64(1H,t,J=5.4Hz),7.98(1H,s),10.52(1H,s).
Embodiment O-3) 5-hydroxyl-3-sec.-propyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.19(6H,d,J=6.9Hz),4.62(1H,m),4.68(2H,d,J=8.1Hz),7.06(1H,m),7.26(1H,m),7.40(1H,m),7.53(1H,t,J=7.2Hz),8.12(1H,s),10.41(1H,t,J=5.7Hz),11.94(1H,br s).
Embodiment O-4) 3-furans-2-ylmethyl-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:4.52(2H,d,J=5.7Hz),4.68(4H,s),6.44(2H,m),7.06(1H,m),7.27(2H,m),7.40(2H,m),7.64(2H,s),8.06(1H,s),10.43(1H,t,J=5.7Hz),11.56(1H,br s).
Embodiment O-5) 5-hydroxyl-4,6-dioxo-3-thiophene-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:4.53(1H,d,J=3.8Hz),4.76(2H,d,J=7.8Hz),4.85(2H,s),7.00-7.40(5H,m),7.50(1H,d,J=3.6Hz),7.65(1H,t,J=7.8Hz),8.15(1H,s),10.32(1H,t,J=5.7Hz),11.58(1H,br s).
Embodiment O-6) 5-hydroxyl-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.52-1.94(4H,m),3.46(1H,dd,J=7.5Hz,14.1Hz),3.66(2H,m),3.79(1H,dd,J=6.9Hz,14.4Hz),4.04(1H,m),4.54(2H,d,J=5.7Hz),6.75(2H,d,J=16.0Hz),7.07(1H,m),7.25(1H,m),7.39(1H,m),7.61(1H,t,J=8.1Hz),8.15(1H,s),10.37(1H,t,J=5.7Hz),11.72(1H,br s).
Embodiment O-7) 5-hydroxyl-3-(2-morpholine-4-base-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.43(2H,br s),3.55(4H,br s),3.60(2H,t,J=5.7Hz),4.54(2H,d,J=6.0Hz),4.78(2H,d,J=8.1Hz),7.07(1H,m),7.24(1H,m),7.40(1H,m),7.55(1H,t,J=8.1Hz),8.18(1H,s),10.35(1H,t,J=6.2Hz),11.79(1H,br s).
Embodiment O-8) 5-hydroxyl-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.52-1.94(4H,m),3.46(1H,dd,J=7.5Hz,14.1Hz),3.66(2H,m),3.79(1H,dd,J=6.9Hz,14.4Hz),4.04(1H,m),4.54(2H,d,J=5.7Hz),6.75(2H,d,J=16.0Hz),7.07(1H,m),7.25(1H,m),7.39(1H,m),7.61(1H,t,J=8.1Hz),8.15(1H,s),10.37(1H,t,J=5.7Hz),11.72(1H,br s).
Embodiment O-9) 5-hydroxyl-3-(2-isopropoxy-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.08(2H,d,J=6.0Hz),3.56(2H,t,J=5.7Hz),3.58(1H,m),3.60(2H,t,J=5.7Hz),4.54(2H,d,J=6.0Hz),4.75(2H,d,J=8.1Hz),7.06(1H,m),7.28(1H,m),7.38(1H,m),7.55(1H,t,J=8.4Hz),8.17(1H,s),10.36(1H,t,J=5.7Hz),11.73(1H,br s).
Embodiment O-10) 5-hydroxyl-3-(3-isopropoxy-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.06(6H,d,J=6.3Hz),1.78(2H,m),3.43(2H,t,J=6.3Hz),3.53(3H,m),4.53(2H,d,J=6.3Hz),4.72(2H,d,J=13.5Hz),7.09(1H,m),7.24(1H,m),7.38(1H,m),7.57(1H,t,J=8.1Hz),8.17(1H,s),10.36(1H,t,J=6.3Hz),11.87(1H,br s).
Embodiment O-11) 5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.59(1H,m),3.01(3H,s),3.15(2H,t,J=8.1Hz),3.28(2H,t,J=8.1Hz),4.31(2H,d,J=5.7Hz),4.50(2H,d,J=8.1Hz),6.85(1H,m),7.03(1H,m),7.19(1H,m),7.36(1H,t,J=8.1Hz),7.95(1H,s),10.14(1H,t,J=6.0Hz),11.63(1H,br s).
Embodiment O-12) 3-benzo [1,3]-dioxole-5-ylmethyl-5-hydroxyl-4,6-dioxy base-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:4.52(6H,br s),5.98(2H,s),6.84-7.77(7H,m),10.73(1H,br s).
Embodiment O-13) 5-hydroxyl-4,6-dioxo-3-(2-pyridine-2-base-ethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(DMSO-d6)δ:2.62-2.50(2H,m),3.10(1H,t,J=7.30Hz),3.87(1H,t,J=7.39Hz),4.49(1H,d,J=6.88Hz),4.57(3H,d,J=5.88Hz),4.75(2H,d,J=7.89Hz),6.59-6.57(1H,m),7.12-7.09(2H,m),7.33-7.23(1H,m),7.48-7.36(1H,m),7.58(1H,t,J=7.89Hz)7.76(1H,td,J=7.64,1.85Hz),8.18(1H,s),8.54(1H,d,J=3.86Hz),10.42(1H,t,J=5.71Hz),11.71(1H,br s).
Embodiment P-1) 1-[2-(ethanoyl-methyl-amino)-ethyl]-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [21-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
[Chemical formula 1 30]
Figure A20068004873701601
1) use is according to the synthetic method synthetic compound 71 of compound 70, and synthetic compound 72 in the following order.
Under ice-cooled, in the 10mL THF solution of 200mg (0.369mmol) compound 71, add 145mg (0.553mmol) triphenyl phosphine, 251 μ L (0.553mmol) diethylazodicarboxylates' 40%wt toluene solution, 120mg (0.553mmol) N-methyl-ortho-nitrophenyl sulphonamide, at room temperature stirred 2 hours.Heat up in a steamer and desolvate, the gained resistates is passed through purification by silica gel column chromatography.By with hexane/ethyl acetate (1: 19v/v) obtain N-{2-[5-benzyl oxygen base-7-[3-(2 that 143mg is an oily matter in the component of wash-out, 4-two fluoro-phenyl)-propyl group]-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-pyrido [2,1-f] [1,2,4] triazine-1-yl]-ethyl }-N-methyl-adjacent nitro-benzsulfamide 72 (yield 52%).
NMR(CDCl3)δ:2.94(3H,s),3.13(1H,br s),3.34(1H,br s),3.37(3H,s),3.62(6H,br s),4.64(2H,d,J=6.0Hz),4.72(2H,s),5.29(1H,br s),5.35(1H,br s),6.77-6.87(2H,m),7.30-7.42(4H,m),7.57(2H,dd,J=1.5Hz,7.9Hz),7.64-7.70(1H,m),7.71-7.77(2H,m),8.08-8.05(1H,m),8.55(1H,s),10.40(1H,t,J=6.0Hz).
2) at room temperature, in the 5mL DMF solution of 106.6mg (0.144mmol) compound 72 and 99.5mg (0.72mmol) salt of wormwood, add 23.8mg (0.216mmol) benzenethiol, stirred 16 hours.In reaction solution, add entry, use ethyl acetate extraction, use dried over mgso after the washing.Heat up in a steamer and desolvate, the gained resistates is passed through purification by silica gel column chromatography.By with chloroform/methanol (85: 15v/v) obtain 5-benzyl oxygen base-7-[3-(2 that 39.1mg is an oily matter in the component of wash-out, 4-two fluoro-phenyl)-propyl group]-3-(2-methoxyl group-ethyl)-1-(2-methylamino-ethyl)-2,3-dihydro-1H-pyrido [2,1-f] [1,2,4] triazine-4,6-diketone 73 (yield 49%).
NMR(CDCl3)δ:2.56(3H,s),3.29(2H,br s),3.33(3H,s),3.65(6H,br s),4.62(2H,d,J=6.6Hz),4.72(2H,br s),5.32(2H,br s),6.76-6.88(2H,m),7.29-7.40(4H,m),7.55-7.61(2H,m),8.61(1H,s),10.47(1H,t,J=6.6Hz).
3) in the 5mL dichloromethane solution of 45mg (0.081mmol) compound 73, add 24.6mg (0.243mmol) triethylamine and 16.5mg (0.162mmol) diacetyl oxide down ice-cooled, at room temperature stirred 30 minutes.Heat up in a steamer and desolvate, the gained resistates is passed through purification by silica gel column chromatography.By with chloroform-methanol (95: 5v/v) obtain N-{2-[5-benzyl oxygen base-7-[3-(2 that 48.0mg is an oily matter in the component of wash-out, 4-two fluoro-phenyl)-propyl group]-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-pyrido [2,1-f] [1,2,4] triazine-1-yl]-ethyl }-N-methyl-ethanamide 74 (yield 100%).
NMR(CDCl3)δ:2.14(3H,s),3.10(3H,s),3.34(3H,s),3.36(4H,br s),3.61(2H,brs),3.70(2H,br s),4.63(2H,d,J=5.9Hz),4.73(2H,s),5.31(2H,br s),6.77-6.87(2H,m),7.29-7.41(4H,m),7.55-7.58(2H,m),10.43(1H,t,J=5.9Hz).
4) according to the synthetic method of embodiment A-1, obtain 46.1mg embodiment P-1 (75%) by 72.2mg compound 74.
2.13(3H,s),3.09(3H,s),3.56(3H,s),3.64(2H,t,J=4.8Hz),3.75(2H,br s),4.64(2H,d,J=6.4Hz),4.89(2H,s),6.77-6.85(2H,m),7.32-7.40(1H,m),8.40(1H,s),10.38(1H,t,J=6.4Hz),11.65(1H,br s).
Embodiment Q-1) 5-hydroxyl-1-(2-methoxyl group-ethanoyl)-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
[Chemical formula 1 31]
Figure A20068004873701621
1) at room temperature, in the 2mL THF solution of 150mg (0.301mmol) compound 69, adds 327mg (3.010mmol) methoxyacetyl chloride and 47.6mg (0.602mmol) pyridine, stirred 30 minutes down at 60 ℃.Use the saturated sodium bicarbonate aqueous solution chilling, use ethyl acetate extraction, use the saturated common salt water washing, use dried over sodium sulfate.Heat up in a steamer and desolvate, with the gained resistates by purification by silica gel column chromatography, by with chloroform-methanol (97: 3v/v) obtain the title compound 75 that 168.0mg is an oily matter (yield 98%) in the component of wash-out.
1H-NMR(CDCl3)δ:3.37(3H,s),3.46(3H,s),3.60(3H,br s),3.86(1H,br s),4.27(2H,br s),4.67(2H,d,J=6.04Hz),5.06-4.88(2H,m),5.51-5.20(2H,m),5.73-5.56(1H,m),6.92-6.79(4H,m),7.47-7.31(4H,m),7.64-7.57(2H,m),8.43(1H,s),10.28(1H,t,J=5.96Hz).
2) according to the synthetic method of embodiment A-1, obtain 80g embodiment Q-1 (57%) by 168mg compound 75.
1H-NMR(CDCl3)δ:3.42(3H,s),3.49(3H,s),3.49(3H,s),3.69-3.60(2H,m),3.87-3.70(2H,m),4.27(2H,s),4.69(2H,d,J=5.88Hz),5.25-5.04(1H,br m),5.88-5.69(1H,br m),6.93-6.79(2H,m),7.48-7.35(1H,m),8.42(1.3H,s),10.23(1H,br s),11.55-11.27(1H,m).
According to the method same with embodiment Q-1, synthetic following embodiment compound Q-2~Q-15.
Embodiment Q-2) 1-ethanoyl-3-(4-fluoro-benzyl)-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.00(3H,s),4.45(2H,d,J=5.7Hz),4.63(1H,br s),4.71(1H,br s),5.29(1H,br s),5.55(1H,br s),7.03-7.44(7H,m),8.26(1H,s),10.25(1H,t,J=6.3Hz),11.23(1H,br s).
Embodiment Q-3) 3-(4-fluoro-benzyl)-5-hydroxyl-1-(2-methoxyl group-ethanoyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:3.21(3H,s),4.02(2H,m),4.53(2H,d,J=6.0Hz),4.72(2H,m),5.22(1H,br s),5.38(1H,br s),7.04-7.46(7H,m),8.11(1H,s),10.39(1H,t,J=6.0Hz).
Embodiment Q-4) 1-benzoyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.05(3H,s),3.65-3.31(4H,m),4.69(2H,d,J=4.87Hz),5.58-5.22(2H,m),6.93-6.79(2H,m),7.48-7.36(2H,m),7.67-7.56(2H,m),7.78-7.69(2H,m),7.88-7.76(2H,m),8.46(1H,s),10.28(1H,brt,J=4.87Hz),11.58-11.34(1H,m).
Embodiment Q-5) 5-hydroxyl-1-(4-methoxyl group-benzoyl)-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.04(3H,s),3.61-3.31(4H,m),3.92(3H,s),4.65(1H,d,J=7.32Hz),5.55-5.27(2H,m),6.90-6.75(2H,m),7.03(2H,d,J=8.69Hz),7.45-7.29(1H,m),7.76(2H,d,J=8.69Hz),8.39(1H,s),10.29(1H,br s),11.61-11.30(1H,m).
Embodiment Q-6) 1-(4-fluoro-benzoyl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.09(3H,s),3.44(2H,br s),3.57(2H,br s),4.69(0.9H,d,J=5.29Hz),5.49-5.34(0.8H,m),6.91-6.80(2H,m),7.35-7.26(2H,m),7.47-7.36(1H,m),7.92-7.79(2H,m),8.45(1H,s),10.27(1H,t,J=5.29Hz),11.44(1H,br s).
Embodiment Q-7) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-(4-methyl-benzoyl)--4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.51(3H,s),3.07(2.9H,s),3.46-3.36(2H,m),3.63-3.49(2H,m),4.69(1H,d,J=6.04Hz),5.42(1H,br s),6.91-6.79(1.1H,m),7.40(2H,d,J=8.23Hz),7.45-7.39(1H,m),7.70(2H,d,J=8.23Hz),8.46(1H,s),10.31(1H,t,J=6.04Hz),11.47(1H,br s).
Embodiment Q-8) 5-hydroxyl-1-isobutyryl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.29-1.19(4H,m),2.81(1H,t,J=6.97Hz),3.41(3H,s),3.74-3.59(3H,m),3.96-3.82(1H,m),4.68(2H,d,J=5.71Hz),5.09(0H,d,J=10.91Hz),5.65(1H,d,J=12.09Hz),6.93-6.80(2H,m),7.47-7.36(1H,m),8.44(1H,s),10.24(1H,t,J=12.09Hz),11.39(1H,br s).
Embodiment Q-9) 1-cyclopropane carbonyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:1.17-0.96(6H,m),1.51(1H,s),3.40(3H,s),3.62(3H,br s),4.08-3.96(1H,m),4.69(1H,d,J=7.39Hz),5.07-5.02(1H,br m),5.81-5.78(1H,brm),6.92-6.80(2H,m),7.48-7.36(1H,m),8.58(1H,s),10.25(1H,t,J=7.39Hz),11.47(1H,br s).
Embodiment Q-10) 1-(Flurane-2-carbonyl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.16(3H,s),3.51(2H,br s),3.68(2H,br s),4.67(2H,d,J=6.71Hz),5.36(1H,br s),6.02(1H,br s),6.68(1H,s),6.90-6.78(2H,m),7.46-7.34(1H,m),7.68(1H,s),8.43(1H,s),10.27(1H,br s),11.41(1H,br s).
Embodiment Q-11) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-(thiophene-2-carbonyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.12(3H,s),3.54-3.44(2H,m),3.69-3.61(2H,m),4.67(2H,d,J=6.55Hz),5.53-5.25(1H,m),5.88-5.62(1H,m),6.94-6.76(2H,m),7.25(1H,dd,J=5.04,4.40Hz),7.45-7.34(1H,m),7.71(1H,dd,J=4.40,1.10Hz),7.81(1H,dd,J=5.04,1.10Hz),8.43(1H,s),10.30-10.24(1H,m).
Embodiment Q-12) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-1-(2-oxo base-2-thiophene-2-base-acetoxyl group)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.11(3H,s),3.52(2H,br s),3.70(1H,br s),3.78(1H,br s),4.64(2H,d,J=5.9Hz),5.28(1H,br s),5.75(1H,br s),6.77-6.87(2H,m),7.25-7.27(1H,m),7.33-7.41(1H,m),7.95(1H,d,J=4.9Hz),8.04(1H,br s),8.44(3H,s),10,20(1H,br s).
Embodiment Q-13) 5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-pyrido [2,1-f] [1,2,4] triazine-1,7-dioctyl phthalate 7-(2,4-two fluoro-benzyl acid amides) 1-dimethylformamide
1H-NMR(CDCl3)δ:3.08(6H,s),3.35(3H,s),3.57(2H,t,J=4.5Hz),3.69(2H,brs),4.63(2H,d,J=5.7Hz),5.07(2H,s),6.76-6.85(2H,m),7.31-7.39(1H,m),8.30(1H,s),10.33(1H,t,J=5.7Hz),11.40(1H,br s).
Embodiment Q-14) 5-hydroxyl-1-methylsulfonyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:3.18(3H,s),3.38(3H,s),3.64(2H,s),3.70(1H,br s),3.87(1H,m),4.64(2H,d,J=5.7Hz),5.15(1H,d,J=13.2Hz),5.49(1H,d,J=13.2Hz),6.77-6.86(2H,m),7.33-7.41(1H,m),8.55(1H,s),10.10(1H,t,5.7Hz),11.55(1H,br s).
Embodiment Q-15) 1-ethanoyl-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl3)δ:2.20(3H,s),3.37(3H,s),3.60(2H,br s),3.67(1H,br s),3.81(1H,br s),4.64(2H,d,J=5.9Hz),5.02(1H,br s),5.61(1H,br s),6.77-6.86(2H,m),7.33-7.41(1H,m),8.43(1H,s),10.17(1H,t,J=5.9Hz),11.39(1H,br s).
The present invention further provides following compound.
[Chemical formula 1 32]
Figure A20068004873701661
[Chemical formula 1 33]
Figure A20068004873701671
[Chemical formula 1 34]
Figure A20068004873701681
[Chemical formula 1 35]
[Chemical formula 1 36]
Figure A20068004873701701
[Chemical formula 1 37]
Figure A20068004873701711
[Chemical formula 1 38]
Figure A20068004873701721
[Chemical formula 1 39]
[Chemical formula 1 40]
Figure A20068004873701741
[Chemical formula 1 41]
Figure A20068004873701751
[Chemical formula 1 42]
Figure A20068004873701761
[Chemical formula 1 43]
Figure A20068004873701771
[Chemical formula 1 44]
[Chemical formula 1 45]
Figure A20068004873701791
[Chemical formula 1 46]
Figure A20068004873701801
[Chemical formula 1 47]
Figure A20068004873701811
[Chemical formula 1 48]
Figure A20068004873701821
[Chemical formula 1 49]
Figure A20068004873701831
[Chemical formula 1 50]
Figure A20068004873701841
[Chemical formula 1 51]
Figure A20068004873701851
[Chemical formula 1 52]
Figure A20068004873701861
Below provide the chemical name and the rerum natura of above-claimed cpd.
Embodiment N-59-1) 5-hydroxyl-1-(3-hydroxy-3-methyl-butyl)-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.28(6.0H,s),1.60-1.78(2.0H,m),3.27(2.0H,br s),3.41(3.0H,s),3.63-3.82(4.0H,m),4.68(2.0H,d,J=5.71Hz),4.83(2.0H,br s),6.80-6.90(2.0H,m),7.38-7.45(1.0H,m),8.50(1.0H,s),10.41(1.0H,t,J=5.62Hz).
Embodiment N-60-1) 5-hydroxyl-1-(5-methyl-isoxazole-3-base methyl)-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.56-1.62(1.0H,m),1.92-2.01(2.0H,m),2.07-2.15(1.0H,m),2.50(3.0H,s),3.26(1.0H,br s),3.70-3.80(1.0H,m),3.82-3.92(1.0H,m),4.01-4.19(3.0H,m),4.30(1.0H,br s),4.66(1.0H,br s),4.67(2.0H,d,J=5.37Hz),4.91(1.0H,br s),6.12(1.0H,s),6.79-6.90(2.0H,m),7.35-7.43(1.0H,m),8.44(1.0H,s),10.30-10.40(1.0H,m),11.70(1.0H,br s).
Embodiment N-61) 5-hydroxyl-4,6-dioxo-1-propine-2-base-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.54-1.61(1.0H,m),1.92-2.01(2.0H,m),2.06-2.20(1.0H,m),2.51(1.0H,t,J=2.47Hz),3.20(2.0H,dd,J=13.73,8.52Hz),3.75-3.83(1.0H,m),3.88-3.96(2.0H,m),4.03-4.20(2.0H,m),4.67(2.0H,d,J=5.77Hz),4.87(1.0H,d,J=13.46Hz),5.02(1.0H,d,J=13.46Hz),6.78-6.88(2.0H,m),7.35-7.43(1.0H,m),8.58(1.0H,s),10.36(1.0H,t,J=7.00Hz).
Embodiment N-62) 5-hydroxyl-1-(3-methoxyl group-propyl group)-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.55-1.63(2.0H,m),1.75-1.87(1.0H,m),1.90-2.00(2.0H,m),2.05-2.17(1.0H,m),3.17-3.28(2.0H,m),3.35(3.0H,s),3.70-4.15(6.0H,m),4.67(2.0H,d,J=5.71Hz),4.78(1.0H,br s),4.93(1.0H,br s),6.79-6.90(2.0H,m),7.35-7.44(1.0H,m),8.47(1.0H,s),10.41(1.0H,t,J=7.00Hz).
Embodiment N-63) 5-hydroxyl-3-(2-isopropoxy-ethyl)-1-(5-methyl-isoxazole-3-base methyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.15(6.0H,d,J=6.04Hz),2.50(3.0H,s),3.48-3.55(1.0H,m),3.59-3.65(2.0H,m),3.65-3.72(2.0H,m),3.77(1.0H,br s),4.28(1.0H,br s),4.67(2.0H,d,J=5.71Hz),4.67(1.0H,br s),4.79(1.0H,br s),6.12(1.0H,s),6.80-6.90(2.0H,m),7.37-7.42(1.0H,m),8.44(1.0H,br s),10.36(1.0H,br s).
Embodiment N-64) 5-hydroxyl-3-(3-methoxyl group-propyl group)-1-(5-methyl-isoxazole-3-base methyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.93-2.01(2.0H,m),2.51(3.0H,s),3.33(3.0H,s),3.50(2.0H,t,J=7.00Hz),3.69(2.0H,br s),4.26(1.0H,br s),4.60-4.70(1.0H,m),4.68(2.0H,d,J=6.04Hz),6.14(1.0H,s),6.80-6.90(2.0H,m),7.35-7.46(1.0H,m),8.50(1.0H,s),10.37(1.0H,br s),11.80(1.0H,br s).
Embodiment N-65) 5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.92-2.01(2.0H,m),2.08-2.16(1.0H,m),3.31(1.0H,br s),3.75(1.0H,q,J=7.50Hz),3.86(1.0H,q,J=7.39Hz),4.05-4.21(2.0H,m),4.39(1.0H,s),4.64(2.0H,d,J=5.71Hz),4.73-4.92(2.0H,m),4.95-5.06(2.0H,m),6.80-6.88(2.0H,m),7.28-7.42(3.0H,m),7.81(1.0H,t,J=6.88Hz),8.26(1.0H,s),8.65(1.0H,d,J=4.03Hz),10.32-10.35(1.0H,m).
Embodiment N-66) 5-hydroxyl-3-(2-methoxyl group-ethyl)-1-(6-methyl-pyridine-2-ylmethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:2.62(3.0H,s),3.37(3.0H,s),3.69(2.0H,t,J=4.62Hz),3.81(2.0H,br s),4.35(2.0H,br s),4.64(2.0H,d,J=5.71Hz),4.90(2.0H,br s),6.81-6.88(2.0H,m),7.15(1.0H,d,J=7.72Hz),7.23(1.0H,d,J=7.72Hz),7.32-7.42(1.0H,m),7.69(1.0H,t,J=7.81Hz),8.21(1.0H,s),10.33(1.0H,s).
Embodiment N-67) 5-hydroxyl-1-(5-methyl-isoxazole-3-base methyl)-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.56-1.62(1.0H,m),1.92-2.01(2.0H,m),2.07-2.15(1.0H,m),2.50(3.0H,s),3.26(1.0H,br s),3.70-3.80(1.0H,m),3.82-3.92(1.0H,m),4.01-4.19(3.0H,m),4.30(1.0H,br s),4.66(1.0H,br s),4.67(2.0H,d,J=5.37Hz),4.91(1.0H,br s),6.12(1.0H,s),6.79-6.90(2.0H,m),7.35-7.43(1.0H,m),8.44(1.0H,s),10.30-10.40(1.0H,m),11.70(1.0H,br s).
Embodiment N-68) 5-hydroxyl-4,6-dioxo-1-propine-2-base-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.54-1.61(1.0H,m),1.92-2.01(2.0H,m),2.06-2.20(1.0H,m),2.51(1.0H,t,J=2.47Hz),3.20(2.0H,dd,J=13.73,8.52Hz),3.75-3.83(1.0H,m),3.88-3.96(2.0H,m),4.03-4.20(2.0H,m),4.67(2.0H,d,J=5.77Hz),4.87(1.0H,d,J=13.46Hz),5.02(1.0H,d,J=13.46Hz),6.78-6.88(2.0H,m),7.35-7.43(1.0H,m),8.58(1.0H,s),10.36(1.0H,t,J=7.00Hz).
Embodiment N-69) 5-hydroxyl-1-(3-methoxyl group-propyl group)-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.55-1.63(2.0H,m),1.75-1.87(1.0H,m),1.90-2.00(2.0H,m),2.05-2.17(1.0H,m),3.17-3.28(2.0H,m),3.35(3.0H,s),3.70-4.15(6.0H,m),4.67(2.0H,d,J=5.71Hz),4.78(1.0H,br s),4.93(1.0H,br s),6.79-6.90(2.0H,m),7.35-7.44(1.0H,m),8.47(1.0H,s),10.41(1.0H,t,J=7.00Hz).
Embodiment N-70) 5-hydroxyl-1-(6-methyl-pyridine-2-ylmethyl)-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.52-1.61(1.0H,m),1.90-2.00(2.0H,m),2.05-2.19(1.0H,m),2.57(3.0H,s),3.75(1.0H,q,J=7.23Hz),3.85(1.0H,q,J=7.42Hz),4.00-4.20(2.0H,m),4.34(1.0H,br s),4.62(2.0H,d,J=5.77Hz),4.77-5.05(4.0H,m),6.78-6.86(2.0H,m),7.12(1.0H,d,J=7.69Hz),7.18(1.0H,d,J=7.97Hz),7.25-7.40(1.0H,m),7.64(1.0H,t,J=7.83Hz),8.20(1.0H,br s),10.33(1.0H,br s).
Embodiment N-71) 5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.92-2.01(2.0H,m),2.08-2.16(1.0H,m),3.31(1.0H,br s),3.75(1.0H,q,J=7.50Hz),3.86(1.0H,q,J=7.39Hz),4.05-4.21(2.0H,m),4.39(1.0H,s),4.64(2.0H,d,J=5.71Hz),4.73-4.92(2.0H,m),4.95-5.06(2.0H,m),6.80-6.88(2.0H,m),7.28-7.42(3.0H,m),7.81(1.0H,t,J=6.88Hz),8.26(1.0H,s),8.65(1.0H,d,J=4.03Hz),10.32-10.35(1.0H,m).
Embodiment N-72) 5-hydroxyl-1-(6-methyl-pyridine-2-ylmethyl)-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.52-1.61(1.0H,m),1.90-2.00(2.0H,m),2.05-2.19(1.0H,m),2.57(3.0H,s),3.75(1.0H,q,J=7.23Hz),3.85(1.0H,q,J=7.42Hz),4.00-4.20(2.0H,m),4.34(1.0H,br s),4.62(2.0H,d,J=5.77Hz),4.77-5.05(4.0H,m),6.78-6.86(2.0H,m),7.12(1.0H,d,J=7.69Hz),7.18(1.0H,d,J=7.97Hz),7.25-7.40(1.0H,m),7.64(1.0H,t,J=7.83Hz),8.20(1.0H,br s),10.33(1.0H,br s).
Embodiment N-73) 5-hydroxyl-3-(2-isopropoxy-ethyl)-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.13(6.0H,d,J=6.21Hz),3.56-3.64(1.0H,m),3.68-3.71(2.0H,m),3.81(2.0H,br s),4.41(2.0H,br s),4.62(2.0H,d,J=6.21Hz),4.92(2.0H,br s),6.79-6.86(2.0H,m),7.31-7.42(3.0H,m),7.83(1.0H,t,J=7.97Hz),8.21(1.0H,s),8.65-8.67(1.0H,m),10.31(1.0H,t,J=10.00Hz).
Embodiment N-74) 3-(3-oxyethyl group-propyl group)-5-hydroxyl-1-(5-methyl-isoxazole-3-base methyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.14(3.0H,t,J=6.97Hz),1.90-2.00(2.0H,m),2.50(3.0H,s),3.46(2.0H,q,J=7.05Hz),3.53(2.0H,t,J=5.62Hz),3.70(2.0H,br s),4.26(2.0H,br s),4.60-4.71(2.0H,m),4.66(2.0H,d,J=6.04Hz),6.14(1.0H,s),6.78-6.88(2.0H,m),7.35-7.44(1.0H,m),8.49(1.0H,br s),10.39(1.0H,br s).
Embodiment N-75) 5-hydroxyl-4, the 6-dioxo-3-[(R)-1-(tetrahydrochysene-furans-2-yl) methyl]-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.50-1.66(1.0H,m),1.89-2.03(2.0H,m),2.06-2.21(1.0H,m),3.20(1.0H,br s),3.78(1.0H,dd,J=15.19,6.97Hz),3.83-3.93(1.0H,m),3.97-4.18(2.0H,m),4.25(2.0H,br s),4.59-4.66(1.0H,m),4.65(2.0H,d,J=5.54Hz),4.89(1.0H,br s),6.79-6.90(2.0H,m),7.13(1.0H,d,J=5.04Hz),7.19(1.0H,d,J=2.01Hz),7.33-7.41(1.0H,m),7.41-7.46(1.0H,m),8.25(1.0H,br s),10.30-10.34(1.0H,brm),11.69(1.0H,br s).
Embodiment N-76) 5-hydroxyl-4, the 6-dioxo-3-[(S)-1-(tetrahydrochysene-furans-2-yl) methyl]-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.50-1.66(1.0H,m),1.89-2.03(2.0H,m),2.06-2.21(1.0H,m),3.20(1.0H,br s),3.78(1.0H,dd,J=15.19,6.97Hz),3.83-3.93(1.0H,m),3.97-4.18(2.0H,m),4.25(2.0H,br s),4.59-4.66(1.0H,m),4.65(2.0H,d,J=5.54Hz),4.89(1.0H,br s),6.79-6.90(2.0H,m),7.13(1.0H,d,J=5.04Hz),7.19(1.0H,d,J=2.01Hz),7.33-7.41(1.0H,m),7.41-7.46(1.0H,m),8.25(1.0H,br s),10.30-10.34(1.0H,brm),11.69(1.0H,br s).
Embodiment N-77) 1-furans-2-ylmethyl-5-hydroxyl-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.51-1.68(1.0H,m),1.91-2.02(2.0H,m),2.06-2.20(1.0H,m),3.22(1.0H,s),3.79(1.0H,dd,J=15.36,6.97Hz),3.85-3.95(1.0H,m),4.01-4.35(4.0H,m),4.64(2.0H,d,J=5.87Hz),4.94(2.0H,br s),6.29(1.0H,d,J=3.02Hz),6.35(1.0H,d,J=1.85Hz),6.78-6.87(2.0H,m),7.32-7.42(1.0H,m),7.47(1.0H,d,J=1.85Hz),8.20(1.0H,s),10.31(1.0H,t,J=7.00Hz).
Embodiment N-78) 1-furans-2-ylmethyl-5-hydroxyl-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrochysene-furans-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.51-1.68(1.0H,m),1.91-2.02(2.0H,m),2.06-2.20(1.0H,m),3.22(1.0H,s),3.79(1.0H,dd,J=15.36,6.97Hz),3.85-3.95(1.0H,m),4.01-4.35(4.0H,m),4.64(2.0H,d,J=5.87Hz),4.94(2.0H,br s),6.29(1.0H,d,J=3.02Hz),6.35(1.0H,d,J=1.85Hz),6.78-6.87(2.0H,m),7.32-7.42(1.0H,m),7.47(1.0H,d,J=1.85Hz),8.20(1.0H,s),10.31(1.0H,t,J=7.00Hz).
Embodiment N-79) 3-(2-oxyethyl group-ethyl)-1-furans-2-ylmethyl-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.22(3.0H,t,J=6.97Hz),3.55(2.0H,q,J=6.99Hz),3.68-3.84(3.0H,m),4.26(2.0H,s),4.65(2.0H,d,J=5.88Hz),4.85(2.0H,br s),6.30(1.0H,d,J=3.36Hz),6.38(1.0H,t,J=2.43Hz),6.79-6.90(2.0H,m),7.33-7.43(1.0H,m),7.48(1.0H,t,J=0.92Hz),8.22(1.0H,s),10.32(1.0H,t,J=7.00Hz),11.66(1.0H,brs).
Embodiment N-80) 3-(3-oxyethyl group-propyl group)-1-furans-2-ylmethyl-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.16(3.0H,t,J=7.05Hz),1.90-2.01(2.0H,m),3.47(2.0H,q,J=6.99Hz),3.54(2.0H,t,J=5.62Hz),3.70(2.0H,br s),4.23(2.0H,s),4.65(2.0H,d,J=5.54Hz),6.32(1.0H,d,J=2.85Hz),6.38(1.0H,dd,J=3.27,1.76Hz),6.79-6.87(2.0H,m),7.32-7.44(1.0H,m),7.48(1.0H,dd,J=1.93,0.76Hz),8.29(1.0H,s),10.34(1.0H,t,J=7.00Hz).
Embodiment N-81) 1-furans-2-ylmethyl-5-hydroxyl-4,6-dioxo-3-(3-propoxy--propyl group)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:0.92(3.0H,t,J=7.39Hz),1.53-1.65(2.0H,m),1.92-2.03(2.0H,m),3.39(2.0H,t,J=6.71Hz),3.55(2.0H,t,J=5.54Hz),3.71(2.0H,br s),4.24(2.0H,s),4.61-4.85(2.0H,m),4.66(2.0H,d,J=5.88Hz),6.33(1.0H,d,J=3.36Hz),6.39(1.0H,br s),6.80-6.91(2.0H,m),7.33-7.44(1.0H,m),7.49(1.0H,br s),8.30(1.0H,s),10.33-10.36(1.0H,br m).
Embodiment N-82) 5-hydroxyl-3-(2-methyl-ethyl)-4,6-dioxo-1-(3-oxo base-butyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:2.22(2H,t),2.24(3H,s),2.74(2H,br),3.40(3H,s),3.68(2H,t,J=3.68Hz),3.78(2H,t,J=3.68Hz),4.68(2H,s,J=5.71Hz),4.77(2H,br),6.77-6.91(2H,m),7.36(1.0H,m),8.40(1.0H,s),10.35(1.0H,s),11.66(1.0H,br).
Embodiment N-83) 1-ethyl-5-hydroxyl-3-(3-sec.-propyl-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.16(6H,d,J=6.2Hz),1.21(3H,t,J=7.22Hz),1.91-1.99(2H,m),3.15(2H,q,J=7.16Hz),3.58(2H,t,J=5.71Hz),3.59(1H,q,J=6.2Hz),3.70(2H,t,J=6.71Hz),4.71(2H,d,J=5.88Hz),4.74(2H,br),6.81-6.90(2H,m),7.38-7.46(1H,m),8.50(1.0H,s),10.43(1H,s),11.74(1H,s).
Embodiment N-84) 5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-3-thiophene-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:4.21(2H,s),4.64(2H,d,J=5.88Hz),4.79(2H,s),5.01(1H,s),6.82-6.86(1.0H,m),7.03(1H,dd,J=5.20,3.53Hz),7.11-7.12(1H,m),7.20(1H,d,J=7.72Hz),7.36-7.38(2.0H,m),7.77(1H,td,J=7.68,1.73Hz),8.28(1H,s),8.65(1H,d,J=5.04Hz),10.30(1H,t,J=6.04Hz).
Embodiment N-85) 3-furans-2-ylmethyl-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:4.24(2H,s),4.64(2H,d,J=5.88Hz),4.82(2H,br),4.85(2H,s)6.40(1H,dd,J=3.27,1.93Hz),6.45(1H,d,J=3.36Hz),6.80-6.89(2H,m),7.27(1H,d,J=7.72Hz),7.34-7.39(2H,m),7.41-7.42(1H,m),7.77(1H,td,J=7.72,1.68Hz),8.28(1.0H,s),8.65(1H,d,J=4.70Hz),10.30(0.6H,t,J=5.71Hz).
Embodiment N-86) 3-diamantane-1-ylmethyl-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.58-1.77(15H,m),2.03(2H,s),4.34(2H,s),4.64(2H,d,J=5.88Hz),4.80(2H,br),6.79-6.88(2H,m),7.33-7.40(3H,m),7.78(1H,dt,J=7.55,1.68Hz),8.32(1H,s),8.63-8.66(1H,m),10.36(1H,t,J=5.88Hz),11.73(1H,br).
Embodiment N-87) 2-[7-(2,4-two fluoro-benzylamino formyl radicals)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-pyrido [2,1-f] [1,2,4] triazine-1-yl]-ethyl }-diethyl phosphonate
1H-NMR(CDCl 3)δ:1.37(6H,t,J=7.14Hz),2.00(2H,s),3.34(2H,br)3.41(3H,s),3.66(2H,br),3.74(2H,br),4.15(4H,q,J=7.14Hz),4.67(2H,d,J=6.04Hz),4.82(2H,s),6.79-6.88(2.1H,m),7.37-7.42(1.0H,m),8.51(1.0H,s),10.36(1.0H,t,J=5.91Hz),11.58(1H,br).
Embodiment N-88) 3-benzo [1,3] dioxole-5-ylmethyl-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:4.18(2H,s),4.64(2H,d,J=5.88Hz),4.69(2H,br),4.73(2H,s),6.01(2H,s),6.80(1H,s),6.83-6.88(2H,m),7.21(1H,d,J=7.72Hz),7.32-7.45(3H,m),7.75(1H,td,J=7.68,1.79Hz),8.30(1H,s),8.63(1H,d,J=5.04Hz),10.32(1H,t,J=5.88Hz).
Embodiment N-89) 3-(2,3-dihydro-cumarone-5-ylmethyl)-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:3.22(2H,t,J=8.73Hz),4.19(2H,s),4.60(2.0H,t,J=8.64Hz),4.73(4H,s),6.75(1H,d,J=7.39Hz),6.78-6.87(2H,m),7.07(1H,d,J=8.06Hz),7.17-7.22(2H,m),7.31-7.41(2H,m),7.78(1H,t,J=7.30Hz),8.24(1H,s),8.63(1H,d,J=4.70Hz),10.29(1H,t,J=8.73Hz),11.78(1H,br).
Embodiment N-90) 3-(2,3-dihydro-benzo [1,4] dioxane is alkene-6-ylmethyl)-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:4.23(3H,s),4.27(4H,s),4.62(2H,d,J=6.04Hz),4.71(4H,s),6.78-6.87(5H,m),7.22(1H,d,J=7.72Hz),7.34-7.42(2H,m),7.79(1H,d,J=6.71Hz),8.23(1H,s),8.65(1H,d,J=4.87Hz),10.30(1H,d,J=6.04Hz),11.81(1H,br).
Embodiment N-91) 3-[1,4] diox-2-ylmethyl-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:3.32-3.98(9H,m),4.43(2H,br),4.63(2H,d,J=5.87Hz),4.94(2H,br),6.80-6.88(2H,m),7.32-7.45(3H,m),7.86(1H,t,J=8.73Hz),8.27(1H,s),8.66(1H,d,J=4.87Hz),10.30(1.0H,d,J=5.87Hz),11.60(1H,br).
Embodiment N-92) 1-(2-diethylamino-ethyl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.03(6.0H,t,J=7.05Hz),2.56(4H,q,J=7.23Hz),2.66(2H,t,J=4.89Hz),3.16(2H,br),3.38(3H,s),3.65(2H,t,J=5.20Hz),3.76(2H,br),4.66(2H,d,J=5.87Hz),4.90(2H,s),6.79-6.88(2H,m),7.35-7.43(1H,m),8.54(1H,s),10.40(1.0H,t,J=5.79Hz).
Embodiment N-93) 5-hydroxyl-3-(3-sec.-propyl-propyl group)-4,6-dioxo-1-propine-2-base-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.13(6H,d,J=6.04Hz),1.91-1.99(2H,m),2.55(1H,t,J=2.52Hz),3.54(2H,t,J=5.71Hz),3.58(1H,t,J=6.21Hz),3.70(2H,t,J=6.71Hz),3.94(2H,d,J=2.35Hz),4.67(2H,d,J=5.87Hz),4.85(2H,s),6.79-6.88(2H,m),7.36-7.44(1H,m),8.57(1H,s),10.38(1H,br),11.74(1H,br).
Embodiment N-94) 1-(4-ethyl-4-hydroxyl-hexyl)-5-hydroxyl-3-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:0.89(6H,t,J=7.39Hz),1.50(4H,q,J=7.39Hz),1.46-1.57(4H,m),3.09(2H,br),3.39(3H,s),3.66(2H,t,J=4.12Hz),3.74(2H,br),4.67(2H,d,J=5.54Hz),4.80(2H,br),6.80-6.87(2H,m),7.36-7.43(1H,m),8.50(1H,s),10.41(1.0H,t,J=5.54Hz),11.60(1H,br).
Embodiment N-95) 5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.13(6H,d,J=6.13Hz),1.92-2.01(2H,m),3.52-3.60(3H,m),3.75(2H,br),4.36(2H,br),4.66(2H,d,J=5.88Hz),4.81(2H,br),6.81-6.90(2.0H,m),7.35-7.43(3H,m),7.77-7.84(1H,m),8.36(1.0H,s),8.66(1H,d,J=4.03Hz),10.38(1H,s),11.87(1H,br).
Embodiment N-96) 5-hydroxyl-3-(2-methoxy ethyl)-4,6-dioxo-1-thiazole-4-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:3.39(3H,s),3.70(2H,t,J=4.53Hz),3.83(2H,t,J=4.03Hz),4.43(2H,br),4.65(2H,d,J=5.88Hz),4.90(2H,br),6.81-6.88(2H,m),7.34-7.42(1H,m),8.23(1H,s),8.90(1H,d,J=1.51Hz),10.32(1H,t,J=5.21Hz),11.68(1H,br).
Embodiment N-97) 5-hydroxyl-3-(2-methoxy ethyl)-1-[1,2,4] oxadiazole-3-ylmethyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:3.34(3H,s),3.66(2H,t,J=4.50Hz),3.75(2H,br),4.44(2H,br),4.62(2H,d,J=5.95Hz),4.89(2H,br),6.78-6.85(2H,m),7.31-7.38(1H,m),8.39(1H,s),8.80(1H,s),10.25(1H,t,J=5.64Hz).
Embodiment N-98) 5-hydroxyl-3-(2-methoxy ethyl)-1-(2-methylthiazol-4-ylmethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:2.74(3H,s),3.35(3H,s),3.65(2H,t,J=4.50Hz),3.76(2H,t,J=4.27Hz),4.27(2H,br),4.60(2H,d,J=5.80Hz),4.86(2H,br),6.76-6.85(2H,m),6.98(1H,s),7.29-7.37(1H,m),8.16(1.0H,s),10.26(1H,t,J=5.95Hz),11.65(1H,br).
Embodiment N-99) 1-(3,5-dimethyl isoxazole-4-ylmethyl)-5-hydroxyl-3-(2-methoxy ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:2.26(3H,s),2.31(3H,s),3.35(3H,s),3.63(3H,br),3.97(3H,br),4.62(2H,d,J=5.64Hz),4.75(2H,br),6.77-6.86(2H,m),7.31-7.39(1H,m),8.21(1H,s),10.22(1H,t,J=5.64Hz),11.57(1H,br).
Embodiment N-100) 1-cyclopropyl methyl-5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:0.00(2H,br),0.58(2H,br),0.84-0.97(1H,m),1.10(3H,s),1.12(3H,s),1.86-1.94(2H,m),2.91(2H,br),3.47-3.57(3H,m),3.65(2H,br),4.64(2H,d,J=5.80Hz),4.77(2H,br),6.76-6.85(2H,m),7.32-7.40(1H,m),8.52(1H,s),10.38(1H,t,J=5.80Hz),11.70(1H,br).
Embodiment N-101) 5-hydroxyl-3-(3-isopropoxide propyl)-1-[1,2,4] oxadiazole-3-ylmethyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.13(6H,d,J=6.04Hz),1.93-2.01(2H,m),3.4-3.59(3H,m),3.75(2H,br),4.49(2H,br),4.67(2H,d,J=5.54Hz),4.86(2H,br),6.82-6.89(2H,m),7.37-7.45(1H,m),8.48(1H,s),8.85(1H,s),10.32(1H,br).
Embodiment N-102) 5-hydroxyl-3-(3-isopropoxide propyl)-1-(2-methoxy ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.13(6H,d,J=6.04Hz),1.88-1.97(2H,m),3.25(2H,br),3.38(3H,s),3.52(2H,t,J=5.54Hz),3.56-3.60(2H,m),3.67(2H,br),4.67(2H,d,J=6.21Hz),4.82(2H,br),6.79-6.88(2H,m),7.35-7.43(1H,m),8.51(1H,s),10.42(1H,t,J=6.04Hz),11.79(1H,br).
Embodiment N-103) 5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-1-thiazole-4-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.12(6H,d,J=6.04Hz),1.91-2.00(2H,m),3.52-3.59(3H,m),3.74(2H,br),4.40(2H,br),4.64(2H,d,J=5.71Hz),4.82(2H,br),6.80-6.87(2H,m),7.31-7.41(1H,m),8.26(1H,s),8.89(1H,s),10.34(1H,t,J=5.71Hz),11.84(1H,br).
Embodiment N-104) 1-(3,5-dimethyl isoxazole-4-ylmethyl)-5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.09(6H,d,J=6.21Hz),1.87-1.95(2H,m),2.30(3H,s),3.34(3H,s),3.49-3.57(3H,m),3.99(2H,br),4.65(2H,d,J=5.71Hz),4.65(2H,br),6.79-6.89(2H,m),7.34-7.42(1H,m),8.29(1H,s),10.29(1H,t,J=5.71Hz),11.77(1H,br).
Embodiment N-105) 5-hydroxyl-3-(3-isopropoxide propyl)-1-(3-methoxy-propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.14(6H,d,J=6.04Hz),1.78(2H,br),1.88-1.97(2H,m),3.17(2H,t,J=6.71Hz),3.35(3H,s),3.46-3.58(5H,m),3.68(2H,br),4.66(2H,d,J=6.04Hz),4.71(2H,br),6.80-6.87(2.4H,m),7.36-7.44(1H,m),8.46(1H,s),10.41(1H,t,J=6.71Hz),11.75(1H,br).
Embodiment N-106) 5-hydroxyl-3-(3-isopropoxide propyl)-1-(5-methyl-isoxazole-3-ylmethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.10(6H,d,J=6.04Hz),1.88-1.96(2H,m),2.50(3H,s),3.50-3.56(3H,m),3.71(2H,br),4.25(2H,br),4.66(2H,d,J=6.21Hz),4.66(2H,br),6.79-6.89(2H,m),7.35-7.43(1H,m),8.48(1H,s),10.37(1H,t,J=6.21Hz),11.85(1H,br).
Embodiment N-107) 5-hydroxyl-3-sec.-propyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.30(6H,d,J=6.71Hz),4.27(2H,br),4.60(2H,d,J=5.80Hz),4.76(2H,s),4.90(1H,q,J=6.71Hz),6.75-6.84(2H,m),7.28-7.37(3H,m),7.77(1H,dd,J=8.54,6.86Hz),8.22(1H,s),8.61(1H,d,J=4.12Hz),10.31(1H,t,J=6.71Hz),11.89(1H,br).
Embodiment N-108) 5-hydroxyl-3-sec.-propyl-1-[1,2,4] oxadiazole-3-ylmethyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.32(6H,d,J=6.71Hz),4.35(2H,br),4.62(2H,d,J=5.80Hz),4.78(2H,br),4.92(1H,q,J=6.79Hz),6.76-6.85(2H,m),7.31-7.39(1H,m),8.43(1H,s),8.82(1H,s),10.27(1H,t,J=6.79Hz).
Embodiment N-109) 1-furans-3-ylmethyl-5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.09(6H,d,J=6.10Hz),1.83-1.91(2H,m),3.48-3.55(3H,m),3.62(2H,br),4.06(2.5H,s),4.62(2H,d,J=5.80Hz),4.62(2H,br),6.45(1H,s),6.76-6.84(2H,m),7.31-7.39(3H,m),7.48(1H,d,J=1.68Hz),8.38(1H,s),10.33(1H,t,J=5.80Hz),11.75(2H,br).
Embodiment N-110) 1-furans-3-ylmethyl-5-hydroxyl-3-(3-methoxy-propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.85-1.94(2H,m),3.30(3H,s),3.46(2H,t,J=5.64Hz),3.61(2H,br),4.05(2H,br),4.62(2H,d,J=5.80Hz),4.62(2H,br),6.45(1H,d,J=1.07Hz),6.76-6.85(2H,m),7.30-7.40(3H,m),7.48(1H,t,J=1.68Hz),8.37(1H,s),10.31(1H,t,J=5.80Hz),11.70(1H,br).
Embodiment N-111) 3-(2-ethoxyethyl group)-5-hydroxyl-1-(5-methyl-isoxazole-3-ylmethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.15(3.0H,t,J=7.02Hz),2.46(3H,s),3.48(2.4H,q,J=7.02Hz),3.65(2H,t,J=4.12Hz),3.75(2H,br),4.23(2H,br),4.63(2H,d,J=5.95Hz),4.74(2H,br),6.09(1H,s),6.76-6.85(2H,m),7.31-7.39(1H,m),8.40(1H,s),10.31(1H,t,J=5.95Hz),11.66(1H,br).
Embodiment N-112) 5-hydroxyl-3-sec.-propyl-1-(5-methyl-isoxazole-3-ylmethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.33(6H,d,J=7.22Hz),2.52(3H,s),4.22(2H,br),4.67(2H,d,J=5.88Hz),4.67(2H,br),4.91(1H,q,J=7.22Hz),6.15(1H,s),6.80-6.90(2H,m),7.36-7.44(1H,m),8.48(1H,s),10.38(1H,t,J=5.54Hz),11.89(1H,br).
Embodiment N-113) 1-furans-3-ylmethyl-5-hydroxyl-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrofuran (THF)-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.93-2.03(3H,m),2.09-2.18(1H,m),3.19(1H,br),3.76-3.84(1H,m),3.87-3.94(1H,m),4.02-4.17(4H,m),4.66(2H,d,J=5.54Hz),4.66(1H,br),4.89(1H,br),6.49(1H,s),6.80-6.89(2H,m),7.35-7.44(2H,m),7.54(1H,s),8.38(1H,s),10.35(1H,br),11.67(1H,br).
Embodiment N-114) 5-hydroxyl-1-(5-methyl-isoxazole-3-ylmethyl)-4,6-dioxo-3-thiophene-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:2.47(3H,s),4.12(2H,br),4.65(2H,d,J=5.54Hz),4.65(2H,br),4.96(2H,br),6.01(1H,s),6.79-6.88(2H,m),7.01(1H,dd,J=5.20,3.36Hz),7.10(1H,d,J=2.85Hz),7.21-7.41(2H,m),8.41(1H,s),10.31(1H,br),11.56(1H,br).
Embodiment N-115) 3-furans-2-ylmethyl-5-hydroxyl-1-(5-methyl-isoxazole-3-ylmethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:2.48(3H,s),4.17(2H,br),4.67(2H,d,J=6.21Hz),4.73(2H,br),4.81(2H,br),6.07(1.H,s),6.40(1H,dd,J=3.36,1.85Hz),6.45(1H,d,J=3.36Hz),6.81-6.90(2H,m),7.35-7.43(2H,m),8.44(1H,s),10.32(1H,br),11.58(1H,br).
Embodiment N-116) 1-furans-3-ylmethyl-5-hydroxyl-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrofuran (THF)-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.93-2.03(3H,m),2.09-2.18(1H,m),3.19(1H,br),3.76-3.84(1H,m),3.87-3.94(1H,m),4.02-4.17(4H,m),4.66(2H,d,J=5.54Hz),4.66(1H,br),4.89(1H,br),6.49(1H,s),6.80-6.89(2H,m),7.35-7.44(2H,m),7.54(1H,s),8.38(1H,s),10.35(1H,br),11.67(1H,br).
Embodiment N-117) 1-furans-2-ylmethyl-5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.12(6H,d,J=6.04Hz),1.90-1.98(2H,m),3.51-3.59(3H,m),3.70(2H,br),4.24(2H,s),4.65(2H,d,J=5.71Hz),4.70(2H,br),6.32(1H,d,J=3.19Hz),6.37-6.39(1H,m),6.79-6.88(2H,m),7.34-7.42(1H,m),7.48(1H,d,J=1.68Hz),8.30(1H,s),10.35(1H,br),11.80(2H,br).
Embodiment N-118) 5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-1-thiophene-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMS0-d 6)δ:1.85(2H,m),3.24(3H,s),3.40(2H,t,J=6.0Hz),3.54(2H,t,J=7.2Hz),4.46(2H,d),4.47(2H,s),4.98(2H,br s),6.98-7.59(6H,m),7.81(1H,s),10.17(1H,t,J=5.9Hz),11.86(1H,s).
Embodiment N-119) 5-hydroxyl-1-methyl-4,6-dioxo-3-(3-propoxy--propyl group)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.85(3H,t,J=7.3Hz),1.49(2H,q,J=7.1Hz),1.82(2H,t,J=6.7Hz),2.87(3H,s),3.29(2H,t,J=10Hz),3.42(2H,t,J=5.8Hz),3.51-3.55(2H,m),4.53(2H,d,J=6.0Hz),4.80(2H,s),7.08(01H,d,J=8.8Hz),7.24(1H,s),7.40(1H,d,J=7.1Hz),8.27(1H,s),10.37(1H,s).
Embodiment N-120) 3-(2,3-dihydro-cumarone-5-ylmethyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.69(3H,s),3.16(2H,t,J=8.8Hz),4.54(6H,m),4.76(2H,s),6.73(1H,d,J=8.06Hz),7.10(2H,m),7.23(2H,m),7.39(1H,m),8.22(1H,s),10.35(1H,s).
Embodiment N-121) 5-hydroxyl-1-methyl-4,6-dioxo-3-(tetrahydrochysene-furans-3-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.61(1H,m),1.91-2.01(1H,m),2.61(1H,m),2.88(3H,s),3.42-3.51(6H,m),4.54(2H,d,J=5.7Hz),4.84(2H,s),7.04-7.10(1H,m),7.20-7.28(1H,m),7.41(1H,m),8.25(1H,s),10.38(1H,s).
Embodiment N-122) 3-furans-3-ylmethyl-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.72(3H,s),4.52(2H,s),4.56(2H,s),4.80(1H,s),6.54(1H,s),7.06(1H,td,J=8.5,2.6Hz),7.20-7.29(1H,m),7.40(1.0H,dd,J=15.4,8.6Hz),7.67(1H,s),7.75(1H,s),8.24(1H,s),10.30(1H,t,J=6.0Hz).
Embodiment N-123) 3-(2,3-dihydro-cumarone-2-ylmethyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.82(3H,s),3.01(1H,dd,J=16.2,6.6Hz),3.56-3.85(2H,m),4.50(2H,d,J=5.7Hz),4.78-5.12(4H,m),6.77-6.86(2H,m),7.03-7.12(2H,m),7.24(2H,m),7.40(1H,dd,J=15.3,8.6Hz),8.21(1H,s),10.39(1H,s),11.59(1H,brs).
Embodiment N-124) 5-hydroxyl-1-methyl-4,6-dioxo-3-(3-phenoxy group-propyl group)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [[1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.06(2H,dd,J=10.6,4.0Hz),2.88(3H,s),3.65(2H,t,J=7.0Hz),4.04(2H,t,J=6.1Hz),4.53(2H,d,J=5.9Hz),4.84(2H,s),6/90-7.30(m,8H),8.26(1H,s),10.36(1H,s).
Embodiment N-125) 5-hydroxyl-1-methyl-4,6-dioxo-3-(tetrahydrochysene-pyrans-4-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.24(2H,m),1.58(1H,d,J=12.4Hz),1.91(1H,m),2.91(3H,s),3.36(4H,m),3.85(2H,d,J=9.4Hz),4.53(2H,d,J=5.5Hz),4.83(2H,s),7.06(1H,dd,J=9.5,7.1Hz),7.19-7.27(1H,m),7.40(1H,dd,J=15.4,8.6Hz),8.29(1H,s),10.35(1H,t,J=5.5Hz).
Embodiment N-126) 5-hydroxyl-1-methyl-4,6-dioxo-3-(2-propoxy--ethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.84(3H,t,J=7.8Hz),1.48(2H,m),2.87(3H,s),3.35(2H,m),3.60(2H,m),4.53(2H,d,J=5.7Hz),4.83(2H,s),7.09(1H,m),7.26(1H,m),7.41(1H,m),8.28(1H,s),10.34(1H,t,J=5.7Hz),11.73(1H,br s).
Embodiment N-127) 5-hydroxyl-1-methyl-4,6-dioxo-3-(2-phenoxy group-ethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.87(3H,s),3.89(2H,s),4.21(2H,t,J=4.7Hz),4.53(2H,d,J=6.4Hz),4.95(2H,s),7.18(8H,m),8.31(1H,s,),10.32(1H,t,J=6.0Hz).
Embodiment N-128) 3-(3-oxyethyl group-propyl group)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.08(3H,t,J=6.9Hz),1.82(2H,t,J=6.6Hz),2.87(3H,s),3.42(4H,m),3.53(2H,t,J=7.2Hz),4.53(2H,d,J=6.0Hz),4.82(2H,s),7.06(1H,m),7.24(1H,m),7.40(1H,m),8.30(1H,s),10.33(1H,t,J=6.0Hz).
Embodiment N-129) 3-(2-dimethylamino-ethyl)-5-hydroxyl-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:2.10(6H,s),2.82(3H,s),3.59(2H,s),4.54(2H,d,J=5.9Hz),4.85(2H,s),7.04-7.10(1H,m),7.25(1H,m),7.41(1H,m),8.31(1H,s),10.32(1H,t,J=5.9Hz),11.81(1H,br s).
Embodiment N-130) 5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.81-1.90(2H,m),3.24(3.6H,s),3.39(2H,t,J=7.13Hz),3.55(2H,t,J=7.13Hz),4.35(2H,s),4.47(2H,d,J=5.7Hz),4.93(2H,s),7.04-7.10(1H,m),7.19-7.36(3H,m),7.50(1H,d,J=7.7Hz),7.81(2H,td,J=7.6,1.7Hz),8.49(1H,dd,J=4.9,0.8Hz),10.18(1H,t,J=6.0Hz),11.80(1H,br s).
Embodiment N-131) 5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-1-propine-2-base-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.85(2H,m),3.22(3H,s),3.38(2H,t,J=6.0Hz),3.51(2H,t,J=7.5Hz),3.53(1H,s),4.12(2H,s),4.54(2H,d,J=5.9Hz),4.93(2H,s),7.07(1H,m),7.20-7.28(1H,m),7.40(1H,dd,J=15.36,8.64Hz),8.34(1H,s),10.28(1H,t,J=5.9Hz),11.79(1H,br s).
Embodiment N-132) 3-(2-oxyethyl group-ethyl)-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.07(3H,t,J=7.1Hz),3.39-3.70(6H,m),4.36(2H,s),4.47(2H,d,J=6.0Hz),4.97(2H,s),7.04-7.10(1H,m),7.19-7.36(3H,m),7.50(1H,d,J=7.7Hz),7.77(1H,s),7.81(1H,t,J=8.0,2.2Hz),8.49(1H,dd,J=4.9,0.8Hz),10.16(1H,t,J=5.9Hz),11.73(1H,s).
Embodiment N-133) 3-(3-oxyethyl group-propyl group)-5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.08(3H,t,J=7.0Hz),1.80-1.89(2H,m),3.39-3.45(4H,m),3.56(2H,t,J=7.1Hz),4.35(2H,s),4.46(2H,d,J=5.8Hz),4.93(1H,s),7.06(1H,dt,J=11.6,4.3Hz),7.27(3H,m),7.49(1H,d,J=7.8Hz),7.80(2H,td,J=7.7,1.8Hz),8.48(1H,d,J=4.0Hz),10.17(1H,t,J=5.9Hz),11.81(1H,s).
Embodiment N-134) 1-cyclopropyl methyl-5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.00(2H,m),0.37(2H,s),0.88(1.H,m),1.76-1.85(2H,m),3.36(3H,s),3.49(2H,dd,J=13.7,6.4Hz),4.53(2H,d,J=5.8Hz),4.89(2H,s),7.06(1H,m),7.24(1H,m),7.39(1H,m),8.30(1H,s),10.30(1H,t,J=5.9Hz).
Embodiment N-135) 5-hydroxyl-1-(2-methoxyl group-ethyl)-3-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.76-1.85(2H,m),3.16(3H,s),3.21(3H,s),3.33(6H,m),3.49(2H,dd,J=12.2,5.0Hz),4.53(2H,d,J=5.6Hz),4.84(2H,s),7.02-7.09(1H,m),7.20-7.27(1H,m),7.38(1H,dd,J=15.3,8.6Hz),8.20(1H,s),10.34(1H,s).
Embodiment N-136) 5-hydroxyl-1,3-pair-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.66(2H,m),1.76-1.85(2H,m),3.0(2H,m),3.18(3H,s),3.23(3H,s),3.35-3.62(6H,m),4.53(2H,d,J=5.4Hz),4.87(2H,s),7.04-7.10(1H,m),7.21-7.28(1H,m),7.36-7.44(1H,m),8.19(1H,s),10.33(1H,t,J=5.5Hz).
Embodiment N-137) 5-hydroxyl-3-((S)-2-methoxyl group-1-methyl-ethyl)-1-methyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.15(3H,d,J=6.9Hz),2.78(3H,s),3.25(3H,s),3.33-3.43(3H,m),4.52(2H,d,J=5.7Hz),4.81(2H,m),7.05(1H,td,J=8.3,2.1Hz),7.23(1H,dt,J=13.7,5.2Hz),7.39(1H,dd,J=15.3,8.5Hz),8.23(1H,s),10.38(1H,s),11.82(1H,s).
Embodiment N-138) 5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-1-thiazole-4-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.88(2H,m),3.24(3H,s),3.40(2H,t,J=6.0Hz),3.56(2H,t,J=7.1Hz),4.42(s,2H),4.45(2H,d,J=5.7Hz),4.96(2H,s),7.07(1H,m),7.19-7.27(1H,m),7.33(1H,dd,J=15.3,8.6Hz),7.68(1H,s),7.69(1H,s),9.10(1H,d,J=1.7Hz),10.17(1H,t,J=6.0Hz),11.84(1H,s).
Embodiment N-139) 5-hydroxyl-3-((S)-2-methoxyl group-1-methyl-ethyl)-4,6-dioxo-1-pyridine-2-ylmethyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.20(3H,br s),3.25(3H,s),3.32(2H,m),3.44(1H,m),4.31(1H,br s),4.45(2H,d,J=5.6Hz),4.79(1H,m),4.95(2H,s),7.04-7.09(1H,m),7.19-7.34(3H,m),7.48(1H,d,J=7.6Hz),7.67(1H,s),7.80(1H,td,J=7.6,1.8Hz),8.48(1H,d,J=4.0Hz),10.14(1H,t,J=6.0Hz),11.88(1H,s).
Embodiment N-140) 5-hydroxyl-3-((S)-2-methoxyl group-1-methyl-ethyl)-1-(5-methyl-isoxazole-3-base methyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.18(3H,br s),2.38(3H,s),3.21(3H,s),3.42-3.54(3H,m),4.30(2H,br s),4.50(2H,d,J=5.7Hz),4.82(2H,m),6.41(1H,s),7.04-7.09(1H,m),7.24(1H,dt,J=13.7,5.3Hz),7.37(1H,dd,J=15.4,8.7Hz),8.00(1H,s),10.19(1H,t,J=6.0Hz),11.84(1H,s).
Embodiment N-141) 5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.84(2H,m),3.25(3H,s),3.40(2H,t,J=6.1Hz),3.55(2H,t,J=7.2Hz),4.27(2H,s),4.48(2H,d,J=5.9Hz),4.84(2H,br s),7.04-7.39(5H,m),7.57(1H,dd,J=4.9,2.9Hz),7.79(1H,s),10.19(1H,t,J=5.9Hz),11.85(1H,s).
Embodiment N-142) 5-hydroxyl-3-(3-isopropoxy-propyl group)-4,6-dioxo-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.46(6H,d,J=6.0Hz),1.76-1.84(2H,m),3.49(4H,m),4.26(2H,s),4.47(2H,d,J=5.7Hz),4.83(2H,m),7.03-7.39(6H,m),7.56(1H,dd,J=5.0,2.9Hz),7.80(1H,s),10.19(1H,t,J=5.9Hz),11.90(1H,s).
Embodiment N-143) 5-hydroxyl-3-((S)-2-methoxyl group-1-methyl-ethyl)-4,6-dioxo-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.19(3H,s),3.27(3H,s),3.37-3.62(3H,m),4.21(2H,s),4.46(2H,d,J=6.0Hz),4.74-4.90(2H,m),7.02-7.35(5H,m),7.57(1H,dd,J=5.0,2.9Hz),7.68(1H,s),10.16(1H,t,J=5.9Hz),11.92(1H,s).
Embodiment N-144) 5-hydroxyl-4,6-dioxo-1-pyridine-2-ylmethyl-3-(tetrahydrochysene-pyrans-4-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.26(2H,m),1.61(2H,d,J=12.4Hz),1.95(1H,m),3.23(4H,m),3.85(2H,d,J=9.7Hz),4.37(2H,s),4.47(2H,d,J=5.4Hz),4.96(2H,br s),7.07(1H,t,J=7.7Hz),7.29(3H,m),7.54(1H,d,J=7.7Hz),7.82(1H,s),7.85(1H,s),8.52(1H,d,J=3.9Hz),10.18(1H,t,J=6.0Hz),11.80(1H,s).
Embodiment N-145) 5-hydroxyl-4,6-dioxo-3-[3-(2-oxo-1-yl)-propyl group]-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.76-1.98(4H,m),2.22(2H,t,J=8.1Hz),3.22-3.44(6H,m),4.28(2H,s),4.47(2H,d,J=5.7Hz),4.95(2H,br s),7.02-7.38(5H,m),7.56(1H,dd,J=5.0,2.9Hz),7.76(1H,s),10.16(1H,t,J=6.0Hz),11.82(1H,s).
Embodiment N-146) 1-ethyl-5-hydroxyl-3-((S)-2-methoxyl group-1-methyl-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.06(3H,t,J=6.9Hz),1.15(3H,d,J=6.9Hz),3.05(2H,m),3.26(3H,s),3.43-3.56(3H,m),4.55(2H,d,J=5.9Hz),4.75(1H,m),4.84(2H,s),7.08(1H,td,J=8.6,2.6Hz),7.21-7.29(1H,m),7.42(1H,dd,J=15.4,8.6Hz),8.23(1H,d,J=13.6Hz),10.31(1H,t,J=5.8Hz),11.85(1H,s).
Embodiment N-147) 3-[1,4] diox-2-ylmethyl-1-ethyl-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:3.10-3.78(3H,m),3.07-3.75(11H,m),4.51(2H,d,J=6.0Hz),4.84(2H,s),7.05-7.11(1H,m),7.21-7.28(1H,m),7.41(1H,dd,J=15.4,8.6Hz),8.20(1H,s),10.35(1H,t,J=6.0Hz).
Embodiment N-148) 5-hydroxyl-1-(2-methoxyl group-ethyl)-4,6-dioxo-3-(tetrahydrochysene-pyrans-4-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.15-1.29(2H,m),1.57(2H,d,J=12.4Hz),1.91(1H,m),3.19(3H,s),3.25(8H,m),3.84(2H,d,J=11.3Hz),4.51(2H,d,J=5.7Hz),4.90(2H,brs),7.06(1H,dt,J=11.6,4.2Hz),7.20-7.27(1H,m),7139(1H,dd,J=15.4,8.6Hz),8.26(1H,s),10.28(1H,t,J=6.0Hz),11.73(1H,s).
Embodiment N-149) 3-[1,4] diox-2-ylmethyl-5-hydroxyl-1-(2-methoxyl group-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:3.20(3H,s),3.40-3.79(13H,m),4.53(2H,d,J=5.7Hz),4.89(2H,m),7.03-7.44(3H,m),8.25(1H,s),10.28(1H,t,J=6.0Hz),11.58(1H,s).
Embodiment N-150) 5-hydroxyl-4,6-dioxo-3-(3-propoxy--propyl group)-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.84(3H,t,J=7.4Hz),1.48(2H,td,J=14.0,7.2Hz),1.82(2H,m),3.31(2H,t,J=6.6Hz),3.42(2H,t,J=6.0Hz),3.55(2H,s),4.26(2H,s),4.47(2H,d,J=5.6Hz),4.68-5.00(2H,br s),7.02-7.39(5H,m),7.56(1H,dd,J=4.9,2.9Hz),7.79(1H,s),10.18(1H,t,J=6.0Hz),11.87(1H,s).
Embodiment N-151) 5-hydroxyl-4,6-dioxo-3-(2-propoxy--ethyl)-1-thiene-3-yl-methyl-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:0.84(3H,s),1.48(2H,s),3.64(4H,m),4.26(2H,s),4.47(2H,s),7.25-7.37(5H,m),7.56(1H,s),7.76(1H,s),10.17(1H,s),11.79(1H,s).
Embodiment Q-16) 1-ethanoyl-5-hydroxyl-3-(2-isopropoxy-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
1H-NMR(CDCl 3)δ:1.18(6.0H,d,J=6.21Hz),2.23(3.0H,s),3.59-3.67(4.0H,m),3.96(1.0H,br s),4.67(2.0H,d,J=5.71Hz),4.95-5.11(2.0H,m),6.80-6.88(2.0H,m),7.35-7.45(1.0H,m),8.47(1.0H,s),10.21(1.0H,t,J=7.00Hz).
Embodiment Q-17) 1-ethanoyl-5-hydroxyl-3-(3-isopropoxide propyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
1H-NMR(CDCl 3)δ:1.12(6H,d,J=6.21Hz),1.88-1.96(2H,m),2.15(3H,s),3.49-3.59(3H,m),3.58(1H,br),4.67(2H,d,J=5.87Hz),4.93(1H,br),5.63(1H,br),6.81-6.89(2H,m),7.36-7.44(1H,br),8.51(1H,s),10.22(1H,t,J=5.87Hz),11.62(1H,br).
Embodiment Q-18) 1-ethanoyl-5-hydroxyl-4, the 6-dioxo-3-[(R)-and 1-(tetrahydrofuran (THF)-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
NMR(DMSO-d 6)δ:1.47-1.59(1H,m),1.79-1.99(3H,m),2.51(3H,s),3.40-3.49(1H,m),3.64-3.73(2H,m),3.77-3.85(1H,m),4.06(1H,br),4.55(2H,d,J=5.64Hz),5.37(1H,br),5.63(1H,br),7.07(1H,t,J=8.54Hz),7.25(1H,dd,J=16.40,6.02Hz),7.41(1H,dd,J=15.56,8.54Hz),8.32(1H,s),10.20(1H,t,J=5.72Hz),11.38(1H,br).
Embodiment Q-19) 1-ethanoyl-5-hydroxyl-3-((S)-2-methoxyl group-1-methyl-ethyl)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:1.16(3H,br s),2.27(3H,br s),3.24(3H,s),3.38(2H,m),4.54(2H,d,J=5.8Hz),4.67(1H,br s),5.12(1H,br s),5.68(1H,br s),7.03-7.44(3H,m),8.28(1H,s),10.28(1H,s).
Embodiment Q-20) 1-ethanoyl-5-hydroxyl-4,6-dioxo-3-(tetrahydrochysene-pyrans-4-ylmethyl)-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:
1.21(2H,m),1.52(2H,m),1.89(1H,m),2.25(3H,br s),3.21(4H,m),3.84(2H,d,J=9.0Hz),4.54(2H,d,J=5.88Hz),5.31-5.65(2H,m,),7.04-7.10(1H,m),7.20-7.28(1H,m),7.41(1H,dd,J=15.3,8.6Hz),8.38(1H,s),10.22(1H,t,J=5.8Hz),11.44(1H,s).
Embodiment Q-21) 1-ethanoyl-3-[1,4] diox-2-ylmethyl-5-hydroxyl-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:
2.30(3H,s),3.19-3.77(9H,m),4.54(2H,d,J=5.7Hz),5.31-5.44(2H,m),7.04-7.45(3H,m),8.25(1H,s),10.27(1H,s).
Embodiment Q-22) 1-ethanoyl-5-hydroxyl-3-(3-methoxyl group-propyl group)-4,6-dioxo-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-two fluoro-benzyl acid amides
NMR(DMSO-d 6)δ:
1.79(2H,m),2.24(3H,m),3.21(3H,s),3.52(2H,m),4.54(2H,d,J=5.5Hz),5.24-5.61(2H,m),7.06(1H,m),7.24(1H,m),7.41(1H,m),8.37(1H,s),10.26(1H,s).
Embodiment Q-23) 1-ethanoyl-5-hydroxyl-4, the 6-dioxo-3-[(S)-and 1-(tetrahydrofuran (THF)-2-yl) methyl]-2,3,4,6-tetrahydrochysene-1H-pyrido [2,1-f] [1,2,4] triazine-7-formic acid 2,4-difluorobenzyl acid amides
NMR(DMSO-d 6)δ:1.47-1.59(1H,m),1.79-1.99(3H,m),2.51(3H,s),3.40-3.49(1H,m),3.64-3.73(2H,m),3.77-3.85(1H,m),4.06(1H,br),4.55(2H,d,J=5.64Hz),5.37(1H,br),5.63(1H,br),7.07(1H,t,J=8.54Hz),7.25(1H,dd,J=16.40,6.02Hz),7.41(1H,dd,J=15.56,8.54Hz),8.32(1H,s),10.20(1H,t,J=5.72Hz),11.38(1H,br).
The present invention further provides following compound.
[Chemical formula 1 53]
Figure A20068004873702091
In the compound (I-6), R 4And R 22Be selected from following substituting group, the invention provides all compounds that are combined to form by them.
R 4
Methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, cyclopropyl, the cyclopropyl methyl, 1-adamantyl methyl, 2-adamantyl methyl, the dodecahedrane methyl, methoxy ethyl, methoxy-propyl, methoxy ethyl, methoxy-propyl, the methoxyl group butyl, ethoxyethyl group, ethoxycarbonyl propyl, the oxyethyl group butyl, the propoxy-ethyl, the propoxy-propyl group, the propoxy-butyl, phenyl, picolyl, the piperonyl methyl, benzyl, dimethyl aminoethyl, the diethylamino ethyl, the morpholino ethyl, the phenoxy group ethyl, phenoxy propyl, the cubane methyl, thenyl, furfuryl, tetrahydrofuran methyl diox methyl, the tetrahydropyrans methyl, pyridyl, thiazole methyl oxazole methyl, 1,2,4-oxadiazole methyl, 1,3,4-oxadiazole methyl
R 22
Methyl; ethyl; n-propyl; sec.-propyl; normal-butyl; cyclopropyl; the cyclopropyl methyl; 1-adamantyl methyl; 2-adamantyl methyl; the dodecahedrane methyl; methoxy ethyl; methoxy-propyl; methoxy ethyl; methoxy-propyl; the methoxyl group butyl; ethoxyethyl group; ethoxycarbonyl propyl; the oxyethyl group butyl; the propoxy-ethyl; the propoxy-propyl group; the propoxy-butyl; phenyl; picolyl; the piperonyl methyl; benzyl; dimethyl aminoethyl; the diethylamino ethyl; the morpholino ethyl; the phenoxy group ethyl; phenoxy propyl; the cubane methyl; thenyl; furfuryl; tetrahydrofuran methyl diox methyl; the tetrahydropyrans methyl; pyridyl; ethanoyl; the methoxyl group ethanoyl; benzoyl; cyano methyl; 2; 2; the 2-trifluoromethyl; triazole methyl; tetrazole methyl; thiazole methyl oxazole methyl; 1; 2; 4-oxadiazole methyl; 1; 3,4-oxadiazole methyl; neo-pentyl; the carborane methyl; methyl fluoride; dimethyl urea; methylsulfonyl; benzenesulfonyl; thiophen sulfuryl; the acetamido ethyl; allyl group; propargyl isoxazole methyl; dimethyl thiourea; crot(on)yl; methoxymethyl; the hexaoxacyclooctadecane-6 methyl; the imidazoles methyl; the methylpyrrole methyl
Test example 1
According to the following study on determination method hiv integrase restraining effect that provides.
(1) preparation of dna solution
According to the identical method of being put down in writing with WO2004/024693 number test example 1 of method, preparation 2pmol/ μ L substrate dna solution and 5pmol/ μ L target DNA solution.Each solution of target DNA boils earlier, slowly reduces temperature then, makes between the complementary strand and anneals, and uses then.Each sequence of substrate DNA and target DNA is tested as described in the example as this.
(2) inhibiting rate (IC 50Value) mensuration
Streptavidin (preparation of Vector Aaboratories company) is dissolved in the 0.1M carbonic acid buffer (to be formed: 90mM Na 2CO 3, 10mM NaHCO 3), concentration is 40 μ g/mL.This solution of each 50mL is joined in the hole of immune plate (preparation of NUNC company),, make its absorption 4 ℃ of following standing over night.Then each hole (is formed: 13.7mM NaCl, 0.27mM KCl, 0.43mM Na with phosphoric acid buffer 2HPO 4, 0.14mM KH 2PO 4) wash 2 times, add the phosphoric acid buffer that 300 μ L contain 1% skimming milk then, sealed 30 minutes.Again each hole is washed 2 times with phosphoric acid buffer, add 50 μ L substrate dna solutions (2pmol/ μ L) then, vibrate down, at room temperature adsorbed 30 minutes, then with phosphoric acid buffer washing 2 times, then once with distilled water wash.
Adding 12 μ L damping fluids in each hole of preparation according to the method described above (forms: 150mMMOPS (pH 7.2), 75mM MnCl 2, 50mM 2 mercapto ethanol, 25% glycerine, 500 μ g/ml bovine serum albumin-component V), 51 μ L are by the reaction soln of 39 μ L distilled water preparations.Then add 9 μ L intergrase solution (30pmol), thorough mixing.In the hole as negative contrast (NC), add 9 μ L diluents (forming: 20mM MOPS (pH 7.2), 400mM Potassium glutamate, 1mM EDTA, 0.1%NP-40,20% glycerine, 1mM DTT, 4M urea), use immune plate mixing tank thorough mixing.
Plate 30 ℃ of following incubations 60 minutes, is removed reaction solution then, with 250 μ L lavation buffer solutions (forming: 150mM MOPS (pH 7.2), 50mM 2 mercapto ethanol, 25% glycerine, 500 μ g/ml bovine serum albumin-component V) washing three times.
Then, adding 12 μ L damping fluids in each hole (forms: 150mM MOPS (pH 7.2), 75mM MgCl 2, 50mM 2 mercapto ethanol, 25% glycerine, 500 μ g/ml bovine serum albumin-component V), 53 μ L are by the reaction soln of 41 μ L distilled water preparations.The DMSO solution that adds the tested compound of 6 μ L again in each hole to as over against according to adding 6 μ L DMSO in the hole of (PC), is used plate mixing tank thorough mixing.Plate 30 ℃ of following incubations 30 minutes, is added 1 μ L target DNA (5pmol/ μ L) then, use plate mixing tank thorough mixing.
Each plate after 10 minutes, is removed reaction solution at 30 ℃ of following incubations, with phosphoric acid buffer washing 2 times.Then the anti-digoxigenin antibody (sheep Fab fragment: Boehringer company prepares) with alkali phosphatase enzyme mark is 2000 times with the antibody diluent dilution, add 100 μ L, under 30 ℃ in conjunction with 1 hour, then successively with the phosphoric acid buffer washing that contains 0.05% polysorbas20 2 times, more once with the phosphoric acid buffer washing.Then, adding 150 μ L alkaline phosphatases colour developing damping fluid (forms: 10mM p-nitrophenyl phosphate (preparation of Vector Laboratories company), 5mMMgCl 2, 100mM NaCl, 100mM Tris-hydrochloric acid (pH 9.5)), 30 ℃ of down reactions 2 hours, add 50 μ L 1N NaOH solution, stopped reaction is measured the absorbancy (OD405nm) in each hole then, obtains inhibiting rate (IC according to following calculating formula 50).
Inhibiting rate (%)=100[1-{ (C abs.-NC abs.)/(PC abs.-NC abs.) }]
C abs.: the absorbancy in the hole of compound
The absorbancy of NC abs.:NC
The absorbancy of PC abs.:PC
Compound of the present invention shows strong intergrase restraining effect to HIV.
[table 1]
Ex No IC50(nM)
O-07 4.8
O-06 3.8
N-15 3.3
N-16 2.6
Formulation example
The term of " activeconstituents " is meant acceptable salt or their solvate in compound of the present invention, its tautomer, their pharmacy.
(formulation example 1)
Hard gelatine capsule uses following composition preparation.
Consumption
(mg/ capsule)
Activeconstituents 250
Starch (drying) 200
Magnesium Stearate 10
Add up to 460mg
(formulation example 2)
Tablet uses the following compositions preparation:
Consumption
(mg/ tablet)
Activeconstituents 250
Mierocrystalline cellulose (crystallite) 400
Silica 10
(sootiness, fumed)
Stearic acid 5
Add up to 665mg
Composition is mixed, and the tablet that each weight is 665mg is made in compression.

Claims (18)

1. acceptable salt or their solvate in the compound shown in the following formula, its pharmacy:
[Chemical formula 1]
Figure A2006800487370002C1
In the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
R 4Be hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue, can exist in this low alkyl group to be selected from O, S, SO, SO 2, NR a,-N=and=heteroatom group of N-, wherein R aBe hydrogen or low alkyl group;
Dotted line is represented the existence or the non-existence of key;
B 1And B 2Wherein any one party is represented CR 20R 21, the opposing party represents NR 22, in this case, dotted line does not exist;
B 2Be NR 22The time, R 4And R 22Can form together can substituted heterocycle;
B 2Be CHR 21The time, R 4And R 21Can form together can substituted heterocycle;
B 1And B 2Independent separately, be C, CR 23Or N, at this moment, B 1And B 2Part can form together can substituted heterocycle;
R 20, R 21, R 22And R 23Independent separately; expression hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted low-grade alkenyl; can substituted lower alkoxy; can substituted low-grade alkenyl oxygen base; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted aryloxy; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted heterocyclyloxy base; can substituted phosphoric acid residue; by can be substituted the aryl that replaces of phosphoric acid residue; by can be substituted the aralkyl that replaces of phosphoric acid residue; by can be substituted the hydroxyl that replaces of phosphoric acid residue; by can be substituted the amino that replaces of phosphoric acid residue; or by can be substituted the low alkyl group that replaces of phosphoric acid residue; hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl, described quilt can be substituted can exist in the low alkyl group that replaces of phosphoric acid residue and is selected from O; S; SO; SO 2, NR 5,-N=and=heteroatom group of N-, wherein R 5With R 4Independently, be selected from and R 4Identical substituting group group.
2. acceptable salt or their solvate in the compound of claim 1, its pharmacy, described compound is expressed from the next:
[Chemical formula 2]
In the formula,
G ring expression can substituted heterocycle;
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, maybe can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
R 14Expression hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted low-grade alkenyl; can substituted lower alkoxy; can substituted low-grade alkenyl oxygen base; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted aryloxy; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted heterocyclyloxy base; can substituted phosphoric acid residue; by can be substituted the aryl that replaces of phosphoric acid residue; by can be substituted the aralkyl that replaces of phosphoric acid residue; by can be substituted the hydroxyl that replaces of phosphoric acid residue; by can be substituted the amino that replaces of phosphoric acid residue; or by can be substituted the low alkyl group that replaces of phosphoric acid residue; hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl, described quilt can be substituted can exist in the low alkyl group that replaces of phosphoric acid residue and is selected from O; S; SO; SO 2, NR 5,-N=and=heteroatom group of N-, wherein R 5With R 4Independently, be selected from and R 4Identical substituting group group.
3. acceptable salt or their solvate in the compound of claim 1, its pharmacy, described compound is by shown in the following formula:
[chemical formula 3]
Figure A2006800487370005C1
In the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
R 4Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocycle, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue, can exist in this low alkyl group to be selected from O, S, SO, SO 2, NR a,-N=and=heteroatom group of N-, wherein R aBe hydrogen or low alkyl group;
B 1And B 2Wherein a side is CR 20R 21, the opposing party is NR 22
R 20, R 21And R 22Independent separately, expression hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted low-grade alkenyl; can substituted lower alkoxy; can substituted low-grade alkenyl oxygen base; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted aryloxy; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted heterocyclyloxy base; hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl.
4. acceptable salt or their solvate, wherein B in the compound of claim 3, its pharmacy 1Be CR 20R 21, B 2Be NR 22, described R 20, R 21And R 22Identical with the situation implication of claim 3.
5. acceptable salt or their solvate, wherein B in the compound of claim 3, its pharmacy 1Be NR 22, B 2Be CR 20R 21, described R 20, R 21And R 22Identical with the situation implication of claim 3.
6. acceptable salt or their solvate, wherein B in the compound of claim 3, its pharmacy 1Be NR 22, described R 22Identical with the situation implication of claim 3; B 2Be CH 2
7. acceptable salt or their solvate, wherein B in the compound of claim 3, its pharmacy 1Be NR 22, described R 22Expression hydrogen, can substituted low alkyl group, low-grade alkenyl, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted lower alkylcarbonyl, can substituted aryl carbonyl, replacement (sulphur) urea or substituted sulphonyl; B 2Be CH 2
8. acceptable salt or their solvate, wherein R in the compound of claim 3, its pharmacy 4For can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group.
9. acceptable salt or their solvate, wherein B in the compound of claim 3, its pharmacy 1Be NR 22, described R 22For hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted lower alkylcarbonyl, can substituted aryl carbonyl, replacement (sulphur) urea or substituted sulphonyl; B 2Be CH 2R 4For can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group.
10. acceptable salt or their solvate, wherein B in the compound of claim 3, its pharmacy 1Be NR 22, described R 22Expression hydrogen, can substituted low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl, can substituted phenyl, can substituted benzyl, can substituted 5~6 yuan of aromatic heterocyclic radicals, can substituted 5~6 yuan of heterocyclic radical low alkyl groups, can substituted lower alkylcarbonyl, can substituted benzoyl, substituted sulphonyl, substituting group that wherein can substituted low alkyl group is: amino, low-grade alkyl amino, lower alkoxy, aryloxy, cyano group, halogen, (replacement) formamyl, the acyl amino low-grade alkynyl, hydroxyl, substituting group that can substituted lower alkylcarbonyl is: lower alkoxy, substituting group that can substituted benzoyl is: lower alkoxy, and the substituting group of substituted sulphonyl is: low alkyl group, aryl, heterocyclic radical; B 2Be CH 2R 4For can substituted low alkyl group, cycloalkyl, cycloalkyl low-grade alkyl, can substituted phenyl, can substituted benzyl, can substituted 5~6 yuan of aromatic heterocyclic radicals, can substituted 5~6 yuan of heterocyclic radical low alkyl groups, substituting group that wherein can substituted low alkyl group is: amino, low-grade alkyl amino, lower alkoxy, aryloxy.
11. acceptable salt or their solvate in the compound of claim 1, its pharmacy, described compound is expressed from the next:
[chemical formula 4]
Figure A2006800487370008C1
In the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
C ring expression can substituted heterocycle or can substituted carbocyclic ring;
B 1And B 2Independent separately, expression C, CR 23Or N;
R 23Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted lower alkylcarbonyl, can substituted naphthene base carbonyl, can substituted cycloalkyl low-grade alkyl carbonyl, can substituted elementary alkoxy carbonyl, can substituted aryl carbonyl, can substituted aromatic yl elementary alkyl carbonyl, can substituted aryloxy carbonyl, can substituted heterocyclic radical carbonyl, can substituted heterocyclic radical lower alkylcarbonyl, can substituted heterocyclyloxy base carbonyl, can substituted aminocarboxyl, replace (sulphur) urea, or substituted sulphonyl;
Dotted line is represented the existence or the non-existence of key;
R 4Expression hydrogen, can substituted low alkyl group, can substituted cycloalkyl, can substituted cycloalkyl low-grade alkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted aryl, can substituted aromatic yl elementary alkyl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclic radical low alkyl group, can substituted heterocyclyloxy base, hydroxyl, can substituted amino, can substituted phosphoric acid residue, by can be substituted the aryl that replaces of phosphoric acid residue, by can be substituted the aralkyl that replaces of phosphoric acid residue, by can be substituted the hydroxyl that replaces of phosphoric acid residue, by can be substituted the amino that replaces of phosphoric acid residue, or by can be substituted the low alkyl group that replaces of phosphoric acid residue, can exist in this low alkyl group to be selected from CO, O, S, SO, SO 2, NR a,-N=and=heteroatom group of N-, wherein R aBe hydrogen or low alkyl group.
12. acceptable salt or their solvate in the compound of claim 1, its pharmacy, described compound is expressed from the next:
[chemical formula 5]
Figure A2006800487370009C1
In the formula,
R 1Expression hydrogen or low alkyl group;
X represents singly-bound, is selected from O, S, SO, SO 2With the heteroatom group of NH, perhaps can there be the low-grade alkylidene or the rudimentary alkylene group of this heteroatom group;
R 2Expression can substituted aryl;
R 3Expression hydrogen, halogen, hydroxyl, can substituted low alkyl group, can substituted cycloalkyl, can substituted low-grade alkenyl, can substituted lower alkoxy, can substituted low-grade alkenyl oxygen base, can substituted aryl, can substituted aryloxy, can substituted heterocyclic radical, can substituted heterocyclyloxy base or can substituted amino;
H ring expression can substituted heterocycle;
R 24Expression hydrogen; can substituted low alkyl group; can substituted cycloalkyl; can substituted cycloalkyl low-grade alkyl; can substituted low-grade alkenyl; can substituted lower alkoxy; can substituted low-grade alkenyl oxygen base; can substituted aryl; can substituted aromatic yl elementary alkyl; can substituted aryloxy; can substituted heterocyclic radical; can substituted heterocyclic radical low alkyl group; can substituted heterocyclyloxy base; hydroxyl; can substituted amino; can substituted lower alkylcarbonyl; can substituted naphthene base carbonyl; can substituted cycloalkyl low-grade alkyl carbonyl; can substituted elementary alkoxy carbonyl; can substituted aryl carbonyl; can substituted aromatic yl elementary alkyl carbonyl; can substituted aryloxy carbonyl; can substituted heterocyclic radical carbonyl; can substituted heterocyclic radical lower alkylcarbonyl; can substituted heterocyclyloxy base carbonyl; can substituted aminocarboxyl; replace (sulphur) urea; or substituted sulphonyl.
13. acceptable salt or their solvate, wherein R in each compound, its pharmacy in the claim 1~12 1Be hydrogen or low alkyl group.
14. acceptable salt or their solvate in each compound, its pharmacy in the claim 1~12, wherein X is a low-grade alkylidene; R 2Be phenyl or the phenyl that replaced by halogen at least.
15. acceptable salt or their solvate, wherein R in each compound, its pharmacy in the claim 1~12 3Be hydrogen.
16. acceptable salt or their solvate, wherein R in each compound, its pharmacy in the claim 1~12 1Be hydrogen or low alkyl group; X is a low-grade alkylidene; R 2For phenyl or by the phenyl of 1~2 halogen replacement; R 3Be hydrogen.
17. pharmaceutical composition, this pharmaceutical composition contain in the claim 1~16 acceptable salt or their solvate on each the compound, its pharmacy.
18. the pharmaceutical composition of claim 17, this pharmaceutical composition are anti-HIV medicines.
CNA2006800487374A 2005-10-27 2006-10-26 Polycyclic carbamoylpyridone derivative having inhibitory activity on HIV integrase Pending CN101346376A (en)

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CN102803260A (en) * 2009-06-15 2012-11-28 盐野义制药株式会社 Substituted polycyclic carbamoylpyridone derivative
CN102858771A (en) * 2010-02-26 2013-01-02 日本烟草产业株式会社 1,3,4,8-tetrahydro-2h-pyrido[1,2-a]pyrazine derivative and use of same as HIV integrase inhibitor
CN103228653A (en) * 2010-09-24 2013-07-31 盐野义制药株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug
CN104903323A (en) * 2012-12-27 2015-09-09 日本烟草产业株式会社 Substituted spiropyrido[1,2-a]pyrazine derivative and medicinal use thereof as HIV integrase inhibitor
CN108473494A (en) * 2015-12-31 2018-08-31 默沙东公司 Fused tricyclic heterocycles compound as hiv integrase inhibitor
WO2020221294A1 (en) * 2019-04-30 2020-11-05 上海拓界生物医药科技有限公司 Bridge ring-3,4-dihydro-pyrido[1,2-a]pyrazine-1,8-dione compound and pharmaceutical use thereof
CN114426540A (en) * 2020-10-29 2022-05-03 上海拓界生物医药科技有限公司 Pyrido [1,2-a ] pyrazine-1, 8-diketone prodrug derivatives, preparation method and application thereof
WO2023006087A1 (en) * 2021-07-30 2023-02-02 南京明德新药研发有限公司 Macrocyclic pyridone compound and application thereof

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102803260A (en) * 2009-06-15 2012-11-28 盐野义制药株式会社 Substituted polycyclic carbamoylpyridone derivative
CN102803260B (en) * 2009-06-15 2016-02-10 盐野义制药株式会社 The polycyclic carbamoylpyridone derivative be substituted
CN102858771A (en) * 2010-02-26 2013-01-02 日本烟草产业株式会社 1,3,4,8-tetrahydro-2h-pyrido[1,2-a]pyrazine derivative and use of same as HIV integrase inhibitor
CN103228653A (en) * 2010-09-24 2013-07-31 盐野义制药株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug
CN103228653B (en) * 2010-09-24 2016-03-16 盐野义制药株式会社 The prodrug of the polycyclic carbamoylpyridone derivative be substituted
CN104903323A (en) * 2012-12-27 2015-09-09 日本烟草产业株式会社 Substituted spiropyrido[1,2-a]pyrazine derivative and medicinal use thereof as HIV integrase inhibitor
CN108473494A (en) * 2015-12-31 2018-08-31 默沙东公司 Fused tricyclic heterocycles compound as hiv integrase inhibitor
WO2020221294A1 (en) * 2019-04-30 2020-11-05 上海拓界生物医药科技有限公司 Bridge ring-3,4-dihydro-pyrido[1,2-a]pyrazine-1,8-dione compound and pharmaceutical use thereof
CN113795491A (en) * 2019-04-30 2021-12-14 上海拓界生物医药科技有限公司 Bridged ring-3, 4-dihydro-pyrido [1,2-a ] pyrazine-1, 8-dione compound and pharmaceutical use thereof
CN114426540A (en) * 2020-10-29 2022-05-03 上海拓界生物医药科技有限公司 Pyrido [1,2-a ] pyrazine-1, 8-diketone prodrug derivatives, preparation method and application thereof
WO2023006087A1 (en) * 2021-07-30 2023-02-02 南京明德新药研发有限公司 Macrocyclic pyridone compound and application thereof

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