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CN102372711A - Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor - Google Patents

Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor Download PDF

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CN102372711A
CN102372711A CN2011102450038A CN201110245003A CN102372711A CN 102372711 A CN102372711 A CN 102372711A CN 2011102450038 A CN2011102450038 A CN 2011102450038A CN 201110245003 A CN201110245003 A CN 201110245003A CN 102372711 A CN102372711 A CN 102372711A
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methyl
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quinoline
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CN102372711B (en
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor disclosed in a general formula (I) and clinically-acceptable salt or stereoisomer thereof, wherein R1, R2, R3, R3', R4, R4', R5 and X are defined as in a specification. The invention also relates to a preparation method of the compounds, a medicine preparation containing the compounds and the application of the compounds in preparing medicines capable of treating and/ or preventing proliferative diseases.

Description

Imidazoquinolines PI3K and mTOR double inhibitor
1, technical field
The invention belongs to medical technical field; Be specifically related to imidazoquinolines PI3K and mTOR double inhibitor, its pharmacy acceptable salt or its steric isomer; The preparation method of these compounds; The pharmaceutical prepn that contains these compounds, and these compounds treat and/or prevent the application in the medicine of proliferative disease in preparation.
2, background technology
Tumour be body under the effect of the various tumorigenesis factor, cause the cytogenetics substance change, cause genetic expression not normal, cellular abnormality propagation and the true tumor that forms.Tumour cell loses the normal growth regulatory function, has independently or autonomous relatively energy for growth, still can continued growth after the tumorigenesis factor stops, and the nutritive substance of mass consumption human body.If find and treat untimely, cancer cells also can be transferred to whole body growth and breeding everywhere, and discharges multiple toxin, causes human body sale, anaemia, organ function impaired to dead.
The method of oncotherapy mainly comprises three aspects: pharmacological agent, operative treatment and radiotherapy.Because operative treatment, radiotherapy are difficult to thoroughly eradicate tumour, and the effect of centering patients with advanced cancer is not obvious, so the status of pharmacological agent in oncotherapy is more and more obvious.The traditional antineoplastic thing can't be distinguished tumour cell and normal tissue cell; Often cause severe side effect, targeted drug as the specificity target spot, can accurately act on tumour with cancer cells; Improved treatment level greatly; And alleviated the untoward reaction rate, for example make the median survival time of advanced CRC increase by 66.7%, the efficient raising 71.3% of the treatment of advanced breast cancer.
Because it is sought-after to the antitumour drug of this classification that each drugmaker, adds market to the development acceleration of target class antitumour drug, molecular targeted agents has become fastest-rising unit in the global antitumor drug market.The PI3K path is the place of the most often morphing among the human cancer cell, can cause cell proliferation, activation, amplifying signal.PI 3 kinases (PI3K) and Mammals rapamycin target protein (mTOR) are the important kinases of PI3K signal path.
PI 3 kinases (PI3K) are fat kinases family members, can produce PI triphosphoric acid fat (PIP3) through 3 phosphorylations of phosphatidyl alcohol and regulate cellular metabolism and growth.The second messenger PIP3 of this lipid can make P13K combine with effector (particularly Akt) pairing in downstream, thereby causes film to be raised and phosphorylation, cell proliferation, activation.Therefore inhibition of phosphatidylinositol3 3 kinases can influence the PI3K path, thus anticancer propagation, activation.
MTOR is a kind of protein serine/threonine that is present in the endochylema; Belong to phosphoinositide kinase-associated protein kinases family; Form with two kinds of mixtures exists in vivo, i.e. mTORC1 (action target spot of rapamycin) and mTORC2 (not suppressed by rapamycin).MTOR is a kind of cell signalling albumen, and its regulate tumor cell is to the reaction of nutrient and growth factor, and through the effect to VEGF, the blood supply of control tumour.The mTOR suppressor factor can make cancer cells hungry, and through the effect that suppresses mTOR gross tumor volume is dwindled.
Among patent WO2006122806 of Novartis (open day 2006.11.23) and the patent WO201003816 of Pfizer (open day 2010.04.08), all reported the validity of PI3K/mTOR double inhibitor in oncotherapy.At present, do not have the listing of PI3K/mTOR double inhibitor class medicine temporarily, therefore, need the more PI3K/mTOR double inhibitor structure type of research and development, select validity and better security compound, be used for treatment for cancer.
3, summary of the invention
The object of the present invention is to provide a kind of PI3K and mTOR double inhibitor.
Technical scheme of the present invention is following:
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Figure BSA00000562951200021
X is O, S, or NH;
R 1Be hydrogen, or be not substituted or by at least one R 6aSubstituted C 1-6Alkyl, C 3-8Naphthenic base, C 3-8Thiazolinyl, C 3-8Alkynyl, 3-14 unit heterocyclic radical, 6-12 unit volution base;
R 2Be hydrogen, or be not substituted or by at least one R 6bSubstituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 3' be hydrogen, hydroxyl, carboxyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 3, R 4, R 4' independently be hydrogen respectively, halogen, cyanic acid, hydroxyl, carboxyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 5Be hydrogen ,-(CH 2) nS (O) mR 8, or be not substituted or by at least one R 6cSubstituted C 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively, halogen, cyanic acid ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 9Be hydroxyl, halogen, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical ,-(CH 2) nNR 10aR 10b,-(CH 2) nC (O) R 11,-(CH 2) nC (O) NR 10aR 10b,-(CH 2) nS (O) mR 11,-(CH 2) nS (O) mNR 10aR 10b,-(CH 2) nNR 10aS (O) mR 11,-(CH 2) nOC (O) R 11,-(CH 2) nC (O) OR 11,-(CH 2) nNR 10aC (O) R 11, or-(CH 2) nNR 10aC (O) NR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 3-14 unit heterocyclic radical;
R 11Be C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 3-14 unit heterocyclic radical;
M is 1 or 2;
N is 0～4.
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer, optimized technical scheme is:
X is O;
R 1For not being substituted or by at least one R 6aSubstituted C 1-6Alkyl, C 3-8Naphthenic base, 4-10 unit heterocyclic radical, 7-10 unit volution base;
R 2For not being substituted or by at least one R 6bSubstituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical;
R 3' be hydrogen ,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 3, R 4, R 4' independently be hydrogen respectively, halogen, cyanic acid ,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 5Be hydrogen, or be not substituted or by at least one R 6cSubstituted C 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9Substituted C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical;
R 9Be hydroxyl, halogen, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 4-10 unit heterocyclic radical;
M is 1 or 2;
N is 0～4.
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer, optimized technical scheme is:
X is O;
R 1For not being substituted or by at least one R 6aSubstituted C 1-6Alkyl, C 4-7Naphthenic base, 5-10 unit heterocyclic radical;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, naphthyl, 5-10 unit heterocyclic radical;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, or be not substituted or by at least one R 6cSubstituted C 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Naphthenic base, phenyl, 5-10 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9Substituted C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Naphthenic base, phenyl, 5-10 unit heterocyclic radical;
R 9Be hydroxyl, fluorine, chlorine, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 4-7Naphthenic base, phenyl, 5-10 unit heterocyclic radical, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 4-7Naphthenic base, phenyl, or 5-10 unit heterocyclic radical;
M is 1 or 2;
N is 0～3.
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer, optimized technical scheme is:
X is O;
R 1For not being substituted or by at least one R 6aSubstituted C 4-7Naphthenic base, the single heterocyclic radical of 5-6 unit;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, or C 1-6Alkyl;
R 6a, R 6bIndependently be hydroxyl respectively, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 9Be hydroxyl, fluorine, chlorine, cyanic acid, or trifluoromethyl;
N is 0～2.
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer, optimized technical scheme is:
X is O;
R 1For not being substituted or by at least one R 6aSubstituted cyclopentyl, cyclohexyl, piperidyl, piperazinyl, imidazolidyl, pyrazolidyl, tetrahydrofuran base, morpholinyl, pyridyl, pyrimidyl, pyrazolyl;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by at least one R 9Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, indyl, Pyrazolopyridine base;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, or C 1-4Alkyl;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-4Alkyl;
R 8For not being substituted or by at least one R 9Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 9Be hydroxyl, cyanic acid, or trifluoromethyl;
N is 0～2.
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer, optimized technical scheme is:
X is O;
R 1For not being substituted or by at least one R 6aSubstituted cyclopentyl, cyclohexyl, piperidyl, piperazinyl, pyridyl, pyrimidyl;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by at least one R 9Substituted C 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, pyridyl, pyrimidyl, indazolyl, quinolyl, indyl, Pyrazolopyridine base;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9Substituted C 1-3Alkyl, C 1-2Alkoxyl group;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, methyl, ethyl or propyl group;
R 7aAnd R 7bIndependent respectively is hydrogen, methyl or ethyl;
R 8For not being substituted or by at least one R 9Substituted C 1-4Alkyl, C 1-3Alkoxyl group;
R 9Be hydroxyl, cyanic acid, or trifluoromethyl;
N is 0～2.
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer, optimized technical scheme is:
X is O;
R 1For not being substituted or by 1～3 R 6aSubstituted cyclohexyl, piperidyl, pyridyl;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nC (O) R 8,-(CH 2) nC (O) NR 7aR 7b,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by 1～3 R 9Substituted C 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by 1～3 R 6bSubstituted pyridyl, Pyrazolopyridine base;
R 6bBe hydroxyl, trifluoromethyl, C 1-3Alkyl, or C 1-2Alkoxyl group;
R 3, R 3', R 4, R 4' independently be hydrogen respectively;
R 5Be methyl;
R 7aAnd R 7bIndependently be hydrogen respectively, methyl or ethyl;
R 8For not being substituted or by 1～3 R 9Substituted C 1-4Alkyl;
R 9Be hydroxyl;
N is 0 or 1.
Table 1 part of compounds of the present invention
Figure BSA00000562951200061
Figure BSA00000562951200071
Figure BSA00000562951200081
Figure BSA00000562951200091
Figure BSA00000562951200101
" halogen " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention 1-6Alkyl " hydrocarbon that refers to contain 1-6 carbon atom partly removes the alkyl of a Wasserstoffatoms deutero-straight or branched; like methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methylbutyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc." C of the present invention 1-4Alkyl ", " C 1-3Alkyl " refer to the specific examples that contains 1-4, a 1-3 carbon atom in the above-mentioned instance respectively.
" C of the present invention 3-8Naphthenic base " refer to contain the cyclic alkyl of 3-8 carbon atom, like Trimetylene base, tetramethylene base, pentamethylene base, cyclohexyl, suberane, cyclooctane etc." C of the present invention 4-7Naphthenic base " refer to the specific examples that contains 4-7 carbon atom in the above-mentioned instance.
" C of the present invention 2-8Thiazolinyl " be meant that the carbonatoms that contains two keys is straight or branched or the cyclic thiazolinyl of 2-8; like vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1,3-butadiene, 1-pentenyl, pentenyl, 3-pentenyl, 1,3-pentadiene, 1; 4-pentadiene, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1; 4-hexadiene, cyclopentenyl, 1 base, cyclohexenyl, 1 base, cycloheptenyl, 1; 4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc.C of the present invention 3-8Thiazolinyl is meant the specific examples that contains 3-8 carbon atom in the above-mentioned instance.
" C of the present invention 2-8Alkynyl " be meant and contain the alkynyl that the triple-linked carbonatoms is the straight or branched of 2-8, like ethynyl, proyl, 2-butyne base, valerylene base, 3-pentynyl, 4-methyl-valerylene base, 2-hexyn, 3-hexyn, 5-methyl-2-hexyn, 2-heptyne base, 5-methyl-2-heptyne base, 2-octyne base, 3-octyne base etc.C of the present invention 3-8Alkynyl is meant the specific examples that contains 3-8 carbon atom in the above-mentioned instance.
" C of the present invention 1-6Alkoxyl group " refer to " C 1-6Alkyl " group that is connected with other structures through Sauerstoffatom, like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Term " C 1-4Alkoxyl group ", C 1-3Alkoxyl group ", " C 1-2Alkoxyl group " refer to 1-4,1-3, the specific examples of a 1-2 carbon atom of containing in the above-mentioned instance respectively.
" aryl " of the present invention be meant aromatic ring for example phenyl, substituted phenyl (for example benzyl, styroyl) and thick and fragrant cyclic group (for example naphthyl, phenanthrene) etc.
" 3-14 unit heterocyclic radical " of the present invention is meant whole saturated, the fractional saturation that contains 3-14 annular atoms (wherein containing a heteroatoms at least), undersaturated cyclic group, and said " heteroatoms " is meant nitrogen-atoms, Sauerstoffatom, sulphur atom etc." the first heterocyclic radical of assorted 3-14 " comprises 3-8 single heterocyclic radical of unit and 6-14 unit fused heterocycle base.
Described " the single heterocyclic radical of 3-8 unit ", its described single heterocycle can be all saturated, fractional saturation, undersaturated, instance has: ethylenimine, 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1,2-diazetidine, azete, 1,2-diazetine, pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4; 5-glyoxalidine, imidazolidine, pyrazoles, 4,5-pyrazoline, pyrazolidine, 1,2,3-triazoles, 1,2; 4-triazole, tetrazolium, pyridine, 2-pyridone, 4-pyridone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1; 3,5-triazine, 1,2,4,5-tetrazine, nitrogen heterocyclic heptantriene, 1; 2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene, oxyethane, dioxirane, thiirane, trimethylene oxide, 1; 2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, THF, thiophene, 2,5-dihydro-thiophene, THTP, 1,3-dioxolane, 1,3-dioxole-2-ketone, 1; 2-dithia cyclopentenes, 1,3-dithiolane, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1,4-Dioxin, 1,4-dithia cyclohexadiene, 1; 4-oxathiin, 1,4-dioxane, 1,3-dioxane, 1,3-oxathiane, oxepin, thia cycloheptatriene, 1,4-dioxane sarohornene, oxaza Bing Wan 、 oxazole, 4; 5-dihydro-oxazole 、 isoxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2,3-oxadiazole, 1; 2,5-oxadiazole, thiazole, 4,5-thiazoline, isothiazole, 1,2,3-thiadiazoles, 1; 2,4-thiadiazoles, 1,3,4-thiadiazoles, 2H-1,2-oxazine, 4H-1; 2-oxazine, 6H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 5; 6-dihydro-4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1; 4-oxazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-1; 3-thiazine, 6H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,4-thiazine, morpholine etc.Be preferably " 5-6 unit single heterocyclic radical ", its ring can be all saturated, fractional saturation, undersaturated, and the example comprises and is not limited to contain the specific examples of 5-6 annular atoms in " the single heterocyclic radical of 3-8 unit ".
Described " 6-14 unit fused heterocycle base ", its described fused heterocycle can be all saturated, fractional saturation, undersaturated, instance has indoles, isoindole, carbazole, benzoglyoxaline, indazole, benzotriazole, imidazolidine also [4,5-c] pyridine, quinoline, isoquinoline 99.9,2-quinolinone, 4-quinolinone, 1-isoquinolines, acridine, phenanthridines, cinnolines, phthalazines, quinazoline, 3; 4-dihydroquinazoline, quinoxaline, 1,2-dihydro-quinoxaline, 1,8-naphthyridines, 1; 7-naphthyridines, 1,6-naphthyridines, 1,5-naphthyridines, 2; 7-naphthyridines, 2,6-naphthyridines, purine, pteridine, azophenlyene, benzo [b] furans, different benzo [b] furans, dibenzo [b] furans, benzo [b] thiophene, benzo [c] thiophene, benzo [d] [1,3] dioxole, 3-oxo-1; 3-dihydroisobenzofuran, 2H-chromogen alkene, 2H-chromogen alkene-2-ketone, 4H-chromene, 4H-chromene-4-ketone, chroman, benzoxazole, benzothiazole, 4H-1,3-benzoxazine, azophenlyene, thiodiphenylamine, 4,6-dihydro-1H-furo [3; 4-d] imidazoles, 3a, 4,6; 6a-tetrahydrochysene-1H-furo [3,4-d] imidazoles, 4,6-dihydro-1H-thieno-[3; 4-d] imidazoles, 4,6-dihydro-1H-pyrrolo-[3,4-d] imidazoles, 4; 5,6,7-tetrahydrochysene-1H-benzo [d] imidazoles etc.Be preferably " 9-10 unit fused heterocycle base ", its ring can be all saturated, fractional saturation, undersaturated, and the example comprises and is not limited to contain the specific examples of 9-10 annular atoms in " 6-14 unit fused heterocycle base ".
" 4-10 unit heterocyclic radical " of the present invention, " 5-10 unit heterocyclic radical " are meant the cyclic group that contains 4-10 annular atoms (containing a heteroatoms at least), a 5-10 annular atoms (containing a heteroatoms at least) in above-mentioned " 3-14 unit heterocyclic radical " respectively; Comprise all monocycles or condensed ring, and ring can be all saturated, fractional saturation, undersaturated.
" 6-12 unit volution " of the present invention be meant one type have that two rings share that atoms form at least contain 6-12 carbon atom or heteroatomic structure, described heteroatoms has nitrogen, oxygen and sulphur etc.6-12 unit volution comprises the saturated volution of 6-12 unit, 6-12 unit fractional saturation volution.
The saturated volution of 6-12 unit; Be meant that all rings in this volution are saturated cyclic group, specific examples includes but are not limited to:
Figure BSA00000562951200121
Figure BSA00000562951200122
etc.
6-12 unit fractional saturation volution; Be meant that having a ring in this volution at least is undersaturated cyclic group, specific examples includes but are not limited to:
Figure BSA00000562951200124
Figure BSA00000562951200131
etc.
" 7-10 unit volution base " of the present invention is meant the structure that contains 7-10 annular atoms in " 6-12 unit volution base ", comprises saturated, fractional saturation.
Of the present invention " by at least one R 6aSubstituted ", " by at least one R 6bSubstituted ", " by at least one R 6c, by at least one R 9Substituted ", " at least one " in term such as " by at least one halogen, hydroxyl, carboxyl substituted "; being meant to have one or more substituting groups on the substituted group; its maximum substituent numbers depend on all chemistry on the substituted group feasible can be by the number of the substituted position of corresponding substituting group; in general, be preferably 1-3 substituting group.
Above-claimed cpd of the present invention can adopt method and/or known other technology of those of ordinary skills of describing in the following flow process to synthesize, but is not limited only to following method.
Compound shown in the general formula (I), when X is O,
Reactions step:
The preparation of step 1TM-a adds SM-a in the mixture of ice bath refrigerative ice and NaOH, and stirring reaction under room temperature adds solution in ice and the concentrated hydrochloric acid, processes solution A, prepares to drop into immediately in next step reaction.
The preparation of step 2TM-b with SM-b at H 2Stir in the solution of O-HC1, filter, process solution B, with merging under solution A and the solution B room temperature, stirring reaction, filtering precipitate is used water washing, is drying to obtain.
The preparation of step 3TM-c adds potassium acetate and diacetyl oxide in TM-b, the refluxing and stirring reaction leaches deposition, and it is colourless to be washed till filtrating with acetate, uses water washing then, is drying to obtain.
The preparation of step 4TM-d joins stirring and refluxing in the POCl3 with TM-c, and mixture is chilled to room temperature, and unnecessary POCl3 is removed in underpressure distillation, and the solid that obtains is with short silicagel column column chromatography, and eluent is used petroleum ether-ethyl acetate, and evaporated under reduced pressure promptly gets.
The preparation of step 5TM-e together joins TM-d and SM-c in the methylene dichloride, adds triethylamine, stirred overnight at room temperature.Vacuum rotary steam is removed methylene dichloride, and the syrupy shape solid that obtains is used column chromatography purification, promptly gets.
The preparation of step 6TM-f joins TM-e and goes back in the original reagent, and reduction promptly gets.
The preparation of step 7TM-g joins TM-f in the methylene dichloride, drips triethylamine, and ice-water bath adds SM-d (1, the 1-carbonyl dimidazoles) down, refluxes, and adds saturated NaHCO 3The aqueous solution stirs, separatory, and organic phase is used anhydrous sodium sulfate drying, and solvent evaporated promptly gets.
The preparation of step 8TM-h joins TM-g, SM-e and Tetrabutyl amonium bromide in the methylene dichloride, adds the NaOH aqueous solution, stirring at room; Add the aqueous solution that methyl iodide and NaOH are made into, continue to stir the cancellation of reaction mixture water; With twice of dichloromethane extraction; Organic phase is used brine wash, and anhydrous sodium sulfate drying filters and evaporate to dryness filtrating promptly gets product.
The preparation of step 9 compound i is dissolved in TM-h among the DMF, adds SM-f, two (triphenyl phosphorus) palladium chloride (II) and Na 2CO 3, heated and stirred, reaction mixture is used NaHCO 3The saturated aqueous solution cancellation, ethyl acetate extraction twice, organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying, filters and evaporated under reduced pressure, and resistates is used the silicagel column column chromatography purification, promptly gets.
Compound shown in the general formula (I), when X is S or NH, can be with reference to method for preparing.
In the reaction equation, represent raw material, represent product, R with TM with SM 1, R 2, R 3, R 4, R 4', R 5Such as preamble definition.Work as R 5During for hydrogen, can TM-g directly be reacted with SM-f, obtain formula of the present invention (I) compound.
In the reaction process, the functional group of the starting compound that should not participate in reacting can exist not report the form of protecting, and perhaps can be protected, then according to all or part of protection base of removing of the method for routine.For example; If there is amino acid proton; " amino protecting group " of available routine protected; The instance of said " amino protecting group " comprising: methyl, ring third methyl, 1-methyl isophthalic acid-ring third methyl, diisopropyl methyl, 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2,2-trichloromethyl, 2-halogenated methyl, ethyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1; 1-dimethyl--3-(N; N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3; The 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1; 1-dimethyl--2,2,2-three chloroethyls, 1; 1-dimethyl--2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2; 4,6-tri-tert phenyl, m-nitro base, S-phenyl, 8-quinolyl, N-hydroxy piperidine base, 4-(1,4-lupetidine base), 4; 5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2; 4, the 6-trimethyl benzyl is to methoxy-benzyl, 3; The 5-dimethoxy-benzyl, to the last of the ten Heavenly stems oxy-benzyl, to nitrobenzyl, adjacent nitrobenzyl, 3; 4-dimethoxy-6-nitrobenzyl, to bromobenzyl, benzyl chloride base, 2, the 4-dichloro benzyl, to cyanic acid benzyl, neighbour's (N, N-dimethylformamide base) benzyl ,-chloro-is right-acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to the carbamate of (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, isonicotine base, S-benzyl, N '-piperidino carbonyl, N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical; Ethanoyl; Ethanoyl-pyridine; (N '-the dithio benzyloxycarbonyl amino) ethanoyl; 3-phenyl propionyl group; 3-(to phenylor) propionyl group; 3-(ortho-nitrophenyl base) propionyl group; 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl group; 2-methyl-2-(adjacent phenylazo-phenoxy) propionyl group; 4-chloro butyryl radicals; Isobutyryl; Adjacent nitro cinnamoyl; The pyridine formyl radical; N '-acetyl methionyl; N '-benzoyl--phenylalkyl; Benzoyl-; To the phenyl benzoyl-; To anisoyl; O-nitrobenzoyl; The acid amides of adjacent (benzoyloxy methyl) benzoyl-and right-P-benzoyl-; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Allyl group, allyloxy carbonyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, phenacyl-, 3-acetoxyl group propyl group, 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base, quaternary ammonium salt, methoxymethyl, 2-chloroethoxy methyl, benzyloxymethyl, valeryl methyl, [1-(alkoxycarbonyl amido)]-2; 2; 2; Trifluoroethyl, [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl, 2-THP trtrahydropyranyl, 2; 4-dinitrophenyl, benzyl, 3; 4-dimethoxy-benzyl, adjacent nitrobenzyl, two (p-methoxyphenyl) methyl, trityl, (p-methoxyphenyl) diphenyl methyl, phenylbenzene-4-pyridylmethyl, 2-picolyl N '-oxide compound, 5-two phenylpropyl alcohol suberane bases, (N '; N '-dimethylaminomethylene), N; N '-isopropylidene, tolylene, to the methoxyl group tolylene, to nitro tolylene, salicylidene, 5-chlorine salicylidene, diphenylmethylene, (5-chloro-2-phenylor) phenylmethylene, acyl group vinyl, 5,6-dimethyl--3-oxo-1-cyclohexenyl, borine, [phenyl (pentacarbonyl chromium or tungsten)] carbonyl, copper or chelates of zinc, nitro, nitroso-group, oxide compound, diphenylphosphino, diformazan sulfenyl phosphinyl, hexichol sulfenyl phosphinyl, diethylammonium phosphoryl, dibenzyl phosphoryl, diphenylphosphine acyl group, phosphoryl, trimethyl silyl, thiophenyl, ortho-nitrophenyl sulfenyl, 2,4-dinitrobenzene sulfenyl, 2-nitro-4-anisole sulfenyl, three benzylthios, benzenesulfonyl, to anisole alkylsulfonyl, 2; 4,6-Three methyl Benzene alkylsulfonyl, methyl sulphonyl, benzene methylsulfonyl, to toluene methylsulfonyl, trifluoromethyl sulfonyl, phenacyl-alkylsulfonyl etc.
" pharmacy acceptable salt " of formula of the present invention (I) compound is meant formula (I) compound and mineral acid shape, organic acid or the formed salt of organic protonic acid with basic nitrogen atom.
" steric isomer " of formula of the present invention (I) compound; Be meant that there is unsymmetrical carbon in formula of the present invention (I) compound; Carbon-carbon double bonds etc., its all enantiomers, diastereomer, racemization isomer, cis-trans-isomer, tautomer and composition thereof include in the present invention.
Formula of the present invention (I) compound, its pharmacy acceptable salt or its isomer can be processed pharmaceutically acceptable pharmaceutical prepn with one or more pharmaceutical carriers, are applied to the patient who needs this treatment with modes such as oral, parenterals.During oral administration, can process conventional solid preparation with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc., like tablet, capsule, pill, granule etc.; When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When processing injection, can adopt the conventional method production in the existing pharmaceutical field, during the preparation injection, can not add additives, also can add suitable additives based on the character of medicine.
The present invention requires the pharmaceutical composition of protection (I) compound, its pharmacy acceptable salt or its steric isomer and one or more antineoplastic agents and immunosuppressor, and drug combination is used to prepare the medicine that treats and/or prevents proliferative disease.
Antineoplastic agent and immunosuppressor are selected from metabolic antagonist, include but are not limited to capecitabine, gemcitabine, Tifolar; Growth factor receptor inhibitors includes but are not limited to handkerchief azoles handkerchief Buddhist nun, imatinib, erlotinib, lapatinibditosylate, ZD1939, ZD6474; Antibody includes but are not limited to Trastuzumab, rhuMAb-VEGF; Mitotic inhibitor includes but are not limited to taxol, vinorelbine, docetaxel, Dx; Antitumor hormones includes but are not limited to letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; The alkylating agent class includes but are not limited to endoxan, carmustine; The metal platinum class includes but are not limited to carboplatin, cis-platinum, oxaliplatin; Topoisomerase enzyme inhibitor, it is special willing to include but are not limited to topology; The immunosuppression class includes but are not limited to SDZ-RAD, sirolimus, special cancer and fits.
The present invention requires protection (I) compound, its pharmacy acceptable salt or its steric isomer to treat and/or prevent the purposes in the medicine of proliferative disease in preparation.
Described proliferative disease comprises cancer and non-Cancerous disease, and said cancer is selected from brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, bladder cancer, cancer of the stomach, ovarian cancer, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, cervical cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, neurospongioma, glioblastoma multiforme, glioma sarcomatosum, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, histocytic lymphoma, neurofibromatosis, osteocarcinoma, skin carcinoma, the cancer of the brain, colorectal carcinoma, carcinoma of testis, small cell lung cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, multiple myeloma, melanoma, glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, sarcoma; Non-Cancerous disease is selected from skin or prostatic hyperplasia of prostate.
Below further set forth the beneficial effect of The compounds of this invention through the experiment in vitro of part The compounds of this invention; Cited part The compounds of this invention has identical beneficial effect in other compound of the present invention and the test, but should this be interpreted as that The compounds of this invention only has following beneficial effect.
The external zymetology of experimental example The compounds of this invention suppresses active
The trial-product The compounds of this invention, self-control, its chemical name and structural formula are seen the preparation embodiment of each compound;
Disclosed compd B GT-226 and BEZ-235 among the WO2006122806 (open day 2006.11.23) are with reference to the patented process preparation, as reference substance.
Figure BSA00000562951200161
Experimental technique
1. reagent final concentration and compound preparation
1.1PI3K alpha kinase solution 8.469nM, kinase tracer1710,57.29nM;
1.2mTOR (24.72nM) kinase solution, kinase tracer314,32.50nM;
1.35 kinase buffer liquor doubly, kinase tracer antibody 6nM;
1.4 test compounds 10mM liquid storage.
2. experimental procedure
2.1 test compounds 30 μ M are with 4 times of gradient dilutions of kinase buffer liquid;
2.2384 every hole adds the compound of 5 μ L serial dilutions in the orifice plate;
2.3 every hole adds 5 μ L3 times kinase tracer;
2.4 every hole adds 5 μ L kinases/kinase tracer antibody-solutions;
2.5PI3K α incubated at room 50min, mTOR is hatched 40min;
2.6Envision reading of data (excitation wavelength 340nM, emission wavelength 615 and 665nM).
3. data processing
Inhibiting rate %=(100%Emission ratio-sample Emission ratio)/(100% Emission ratio-0%Emission ratio) * 100;
Input GraphPad Prism5.0 mapping obtains curve and IC50.
Experimental result
The external zymetology determination of activity of table 2 The compounds of this invention (IC50)
Experiment conclusion
Can be found out that by table 2 The compounds of this invention has the good restraining effect to PI3K α and mTOR enzyme, comparison is better according to medicine BGT-226 and BEZ-235, explains that The compounds of this invention compared with prior art, has obvious improvement.
4, embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.
Embodiment 18-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] quinoline also The preparation of (compound 1)
The preparation of step 1-a 2-nitro-1-hydroxyl amino ethene
6.4g (105mmol) Nitromethane 99Min. is added in the mixture of ice bath refrigerative 28g ice and 12.4g (310mmol) NaOH; 0 ℃ was stirred 1 hour; Under room temperature, stirred 1 hour then; Solution is added under 0 ℃ in 22.4g ice and the 32.8mL concentrated hydrochloric acid (37%) (solution A), prepare to drop into immediately in next step reaction.
The benzoic preparation of step 1-b 5-bromo-2-(2-nitro-vinyl is amino)
Figure BSA00000562951200182
With 10g (46.3mmol) 2-amino-5-bromo-phenylformic acid at H 2Stirred 2 hours in the solution of O-HCl (37%) (10: 1), filter then, process solution B,, stirred 18 hours, leach yellow mercury oxide, use water washing, dry product 10.2g, the yield 76.8% of getting merging under solution A and the solution B room temperature.
The preparation of step 1-c 6-bromo-4-hydroxyl-3-nitroquinoline
Figure BSA00000562951200183
Add 6.1g (62.7mmol) potassium acetate and 70mL diacetyl oxide to 15g (52.3mmol) 5-bromo-2-(2-nitro-vinyl amino)-phenylformic acid, 120 ℃ of refluxing and stirring 2 hours leach deposition; It is colourless to be washed till filtrating with acetate; Use water washing then, dry product 7.77g, the yield 55.2% of getting.
The preparation of step 1-d 6-bromo-4-chloro-3-nitroquinoline
Figure BSA00000562951200184
2.5g (9.3mmol) 6-bromo-4-hydroxyl-3-nitroquinoline was added in the 50mL POCl3 stirring and refluxing 2 hours; Mixture is chilled to room temperature; Unnecessary POCl3 is removed in underpressure distillation, and the solid that obtains is with short silicagel column column chromatography, and eluent is with the about 600mL of petroleum ether-ethyl acetate (3: 1); Evaporated under reduced pressure gets product 2.1g, yield 78.5%.
The preparation of step 1-e 4-(6-bromo-3-nitroquinoline-4-base is amino) piperidines-1-tertiary butyl carbonic ether
Figure BSA00000562951200185
7.6g (26mmol) 6-bromo-4-chloro-3-nitroquinoline, 5.6g triethylamine (55mmol) and 7.9g (40mmol) 4-amino piperidine-1-tertiary butyl carbonic ether are together added in the 50mL methylene dichloride stirred overnight at room temperature.Vacuum rotary steam is removed methylene dichloride, and the syrupy shape solid that obtains is used column chromatography purification, gets product 8.7g, yield 75%.
The preparation of step 1-f 4-(3-amino-6-bromoquinoline-4-base is amino) piperidines-1-tertiary butyl carbonic ether
Figure BSA00000562951200191
2.25g (5mmol) 4-(6-bromo-3-nitroquinoline-4-base is amino) piperidines-1-tertiary butyl carbonic ether is added H 2O-CH 3In OH (15: the 25) mixed solution, add Zn (1.3g, 20mmol) and NH 4Cl (0.4g) is heated to 55 ℃, stirs 2h, and purifying gets product 0.7g, yield 34%.
The preparation of step 1-g 4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether
Figure BSA00000562951200192
1.8g (4.3mmol) 4-(3-amino-6-bromoquinoline-4-base is amino) piperidines-1-tertiary butyl carbonic ether is added in the 50mL methylene dichloride, drip 2 triethylamines, ice-water bath drips two phosgene down, and (1.0g 4.8mmol), stirs 2h, adds saturated NaHCO 3Aqueous solution cancellation was stirred 5 minutes, separatory, and organic phase is used anhydrous sodium sulfate drying, and solvent evaporated gets product 0.86g, productive rate 46%.
The preparation of step 1-h 4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether
Figure BSA00000562951200193
1.78g (4mmol) 4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether, 0.8g (6mmol) methyl iodide and 0.2g tetrabutylammonium iodide are added the aqueous solution that is configured to 10%NaOH 50mL in the 15mL methylene dichloride; Stirring at room 2h; With dichloromethane extraction twice, organic phase is used brine wash, anhydrous sodium sulfate drying; Filtering also, evaporate to dryness filtrating promptly gets product 1.1g, yield 61%.
The preparation of step 1-i 4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether
Figure BSA00000562951200201
With 1.1g (2.4mmol) 4-(8-bromo-3-methyl-2-oxo-2; 3-dihydro-1H-imidazo [4; 5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether is dissolved among the 10mL DMF, adds 0.81g (4.8mmol) 2-methoxypyridine-5-boric acid, two (triphenyl phosphorus) palladium chlorides (II) of 100mg and 6mL 1M Na 2CO 3, being heated to 100 ℃ and stirring 2 hours, reaction mixture is used NaHCO 3The saturated aqueous solution cancellation, with ethyl acetate extraction twice, organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying, filters and evaporated under reduced pressure, and resistates is used the silicagel column column chromatography purification, obtains product 0.45g, productive rate 38%.
The preparation of step 1-j compound 1
Figure BSA00000562951200202
The 2mL trifluoroacetic acid is added (455mg, 0.9mmol) 4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4 under ice bath; 5-c] quinoline-1-yl) in the 15mL dichloromethane solution of piperidines-1-tertiary butyl carbonic ether; Stir 2h, reaction solution washing, dry organic phase; Get product 0.3g, productive rate 86%.
Molecular formula: C 22H 23N 5O 2Molecular weight: 389.45MS:390 (M+H +)
1H?NMR(400MHz，DMSO+D 2O)δ8.83(d，1H)，8.59(d，1H)，8.28(s，1H)，7.91-8.17(m，2H)，7.93(dd，1H)，6.98(d，1H)，5.11-5.17(m，1H)，3.89(s，3H)，3.44-3.46(m，5H)，3.19(t，2H)，2.83-2.92(m，2H)，2.18(d，2H).
Embodiment 28-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-and 2-hydroxyl propionyl group] piperidin-4-yl]-2,3- Glyoxalidine is the preparation of [4,5-c] quinoline (compound 2) also
Figure BSA00000562951200203
With compound 1 (160mg, 0.41mmol), I-hydroxybenzotriazole (100mg, 1.1mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (150mg; 0.8mmol), triethylamine (360mg) and D-lactic acid (72mg; 0.8mmol), reaction solution stirring at room 17h, reaction solution evaporate to dryness; Cross the preparation liquid phase and get product 18mg, productive rate 9.5%.
Molecular formula: C 25H 27N 5O 4Molecular weight: 461.51MS:462 (M+H +)
1H?NMR(d 6-DMSO)δ1.19(2H，m)，1.21(3H，s)，2.02-2.07(2H，m)，2.56(1H，m)，2.87(1H，m)，3.50(3H，s)，3.92(3H，s)，4.16-4.20(1H，m)，4.49-4.57(2H，m)，5.13(1H，m)，7.01(1H，d)，8.24(1H，dd)，8.72(1H，d)，8.79(1H，d)，9.00(1H，s)，9.26(1H，d).
Embodiment 38-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2,3-dihydro miaow Azoles is the preparation of [4,5-c] quinoline (compound 3) also
With compound 1 (130mg 0.33mmol), I-hydroxybenzotriazole (100mg; 1.1mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (120mg, 0.63mmol), triethylamine (350mg) and oxyacetic acid (50mg, 0.66mmo1); Reaction solution stirring at room 48h; The reaction solution evaporate to dryness is crossed the preparation liquid phase and is got product 18mg, productive rate 12.3%.
Molecular formula: C 24H 25N 5O 4Molecular weight: 447.49MS:448 (M+H +)
1H?NMR(CDC1 3)δ8.73(s，1H)，8.46(d，1H)，8.25(s，1H)，8.24(s，1H)，7.86(dd，1H)，7.79-7.82(m，1H)，6.92(d，1H)，5.10(s，1H)，4.93-4.95(m，1H)，4.22-4.30(m，2H)，4.02(s，3H)，3.79-3.83(m，1H)，3.60(s，3H)，3.20-3.26(m，1H)，2.76-2.92(m，3H)，2.10(d，2H)
Embodiment 48-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine And the preparation of [4,5-c] quinoline (compound 4)
Figure BSA00000562951200212
With compound 1 (130mg 0.33mmol), triethylamine (50mg, 0.5mmol) and methyl-chloroformate (31.1mg 0.33mmol) adds in the 10mL methylene dichloride, and ice bath stirs 2h, and the reaction solution evaporate to dryness is crossed the preparation liquid phase and got product 128mg, productive rate 87%.
Molecular formula: C 24H 25N 5O 4Molecular weight: 447.49MS:448 (M+H +)
Theoretical value: C, 62.42%; H, 5.63%; N, 15.65%;
Measured value: C, 62.30%; H, 5.78%; N, 15.55%
Embodiment 58-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] quinoline (compound 5)
With compound 1 (130mg 0.33mmol), triethylamine (50mg, 0.5mmol) and Acetyl Chloride 98Min. (26mg 0.33mmol) adds in the 10mL methylene dichloride, and ice bath stirs 2h, and the reaction solution evaporate to dryness is crossed the preparation liquid phase and got product 115mg, productive rate 81%.
Molecular formula: C 24H 25N 5O 3Molecular weight: 431.49MS:432 (M+H +)
1H?NMR(CDCl 3)δ8.72(s，1H)，8.48(d，1H)，8.25(s，1H)，8.23(s，1H)，7.86(dd，1H)，7.81(dd，1H)，6.93(d，1H)，4.96-5.06(m，2H)，4.07-4.10(m，1H)，4.02(s，3H)，3.60(s，3H)，3.25-3.31(m，1H)，2.74-2.76(m，1H)，2.69-2.71(m，2H)，2.16(s，3H)，2.03-2.07(m，2H)
Embodiment 68-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine -2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 6) also
Figure BSA00000562951200222
The preparation method throws 2.88g (10mmol) 6-bromo-4-chloro-3-nitroquinoline and 2.49g (10mmol) 5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-2-EL-970 with reference to embodiment 1-e, and the 5mL triethylamine gets product 3.29g, productive rate 65.8%.
Step 6-f to 6-h 8-bromo-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline also
Figure BSA00000562951200231
The preparation method throws 3.5g (6.96mmol) 6-bromo-4-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-is amino]-3-nitroquinoline with reference to embodiment step 1-f to 1-h, gets product 1.14g, overall yield 32.1%.
Step 6-i preparation method is with reference to embodiment 1-i
Figure BSA00000562951200232
The preparation method is with reference to embodiment step 1-i; Throw 102mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2; The 3-glyoxalidine is [4,5-c] quinoline and 46mg (0.3mmol) 2-methoxypyridine-5-boric acid, two (triphenyl phosphorus) palladium chlorides (II) of 8mg and 0.5mL 1M Na also 2CO 3, get product 64mg, productive rate 59.9%.
Molecular formula: C 26H 21F 3N 6O 4Molecular weight: 538.48MS:539 (M+H +)
Theoretical value: C, 57.99%; H, 3.93%; N, 15.61%;
Measured value: C, 57.89%; H, 3.99%; N, 15.55%;
Embodiment 78-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1- Base)-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 7) also
The preparation of step 7-e 6-bromo-4-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-3-nitroquinoline
The preparation method throws 2.88g (10mmol) 6-bromo-4-chloro-3-nitroquinoline and 1.87g (10mmo1) 3 with reference to embodiment step 1-e, 5-dimethyl--4-hydroxyl-oxethyl-1-aminocyclohexane, and the 5mL triethylamine gets product 2.82g, productive rate 64.4%.
Step 7-f to 7-h 8-bromo-3-methyl-2-oxo-1-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline also
Figure BSA00000562951200241
The preparation method throws 3.1g (6.96mmol) 6-bromo-4-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-3-nitroquinoline with reference to embodiment step 1-f to 1-h, gets product 1.43g, overall yield 45.9%.
The preparation of step 7-i compound 7
Figure BSA00000562951200242
The preparation method is with reference to embodiment step 1-i; Throw 89mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(3; 5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2; The 3-glyoxalidine is [4,5-c] quinoline and 46mg (0.3mmol) 2-methoxypyridine-5-boric acid, two (triphenyl phosphorus) palladium chlorides (II) of 8mg and 0.5mL 1M Na also 2CO 3, get product 69mg, productive rate 72.6%.
Molecular formula: C 27H 32N 4O 4Molecular weight: 476.57MS:477 (M+H +)
Theoretical value: C, 68.05%; H, 5.77%; N, 11.76%;
Measured value: C, 67.98%; H, 5.86%; N, 11.70%
Embodiment 88-(2-picoline-5-yl)-3-methyl-2-oxo-1-[N-[(R)-and 2-hydroxyl propionyl group] piperidin-4-yl]-23-two The preparation of hydrogen imidazo [4,5-c] quinoline (compound 8)
Can make compound 8 with reference to embodiment 1 and 2.
Figure BSA00000562951200243
The preparation method is with reference to embodiment 1-i, throws 86mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl group] piperidin-4-yl]-2,3-glyoxalidine also [4; 5-c] quinoline; 41mg (0.3mmol) 2-picoline-5-boric acid gets white solid product 72mg, productive rate 81.2%.
Molecular formula: C 25H 27N 5O 3Molecular weight: 445.51MS:446 (M+H +)
Theoretical value: C, 67.40%; H, 6.11%; N, 15.72%;
Measured value: C, 67.32%; H, 6.17%; N, 15.66%
Embodiment 98-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2, the 3-glyoxalidine And the preparation of [4,5-c] quinoline (compound 9)
Can make compound 9 with reference to embodiment 1 and 2.
Figure BSA00000562951200251
The preparation method is with reference to embodiment 1-i, throws 84mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] quinoline; 41mg (0.3mmol) 2-picoline-5-boric acid gets white solid product 72mg, productive rate 83.4%.
Molecular formula: C 24H 25N 5O 3Molecular weight: 431.49MS:432 (M+H +)
Theoretical value: C, 66.81%; H, 5.84%; O, 16.23%;
Measured value: C, 66.74%; H, 5.88%; O, 16.20%
Embodiment 108-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] quinoline (compound 10)
Can make compound 10 with reference to embodiment 1 and 2.
Figure BSA00000562951200252
The preparation method is with reference to embodiment 1-i, throws 84mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] quinoline; 41mg (0.3mmol) 2-picoline-5-boric acid gets pale solid product 74mg, productive rate 85.7%.
Molecular formula: C 24H 25N 5O 3Molecular weight: 431.49MS:432 (M+H +)
Theoretical value: C, 66.81%; H, 5.84%; O, 16.23%;
Measured value: C, 66.70%; H, 5.92%; O, 16.16%
Embodiment 118-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] quinoline (compound 11)
Can make compound 11 with reference to embodiment 1 and 2.
Figure BSA00000562951200261
The preparation method is with reference to embodiment 1-i, throws 81mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] quinoline; 41mg (0.3mmol) 2-picoline-5-boric acid gets white solid product 75mg, productive rate 89.6%.
Molecular formula: C 24H 25N 5O 2Molecular weight: 415.49MS:416 (M+H +)
Theoretical value: C, 69.38%; H, 6.06%; N, 16.86%;
Measured value: C, 69.32%; H, 6.12%; N, 16.80%
Embodiment 128-(2-picoline-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] quinoline also The preparation of (compound 12)
Can make compound 12 with reference to embodiment 1.
Figure BSA00000562951200262
The preparation method throws 4.74g (10mmol) 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-tertbutyloxycarbonyl-piperidin-4-yl)-2 with reference to embodiment 1-j, and the 3-glyoxalidine is [4,5-c] quinoline also, gets product 3.61g, productive rate 96.7%.
Molecular formula: C 22H 23N 5O molecular weight: 373.45MS:374 (M+H +)
Theoretical value: C, 70.76%; H, 6.21%; N, 18.75%;
Measured value: C, 70.71%; H, 6.28%; N, 18.70%
Embodiment 138-(2-picoline-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine -2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 13) also
Can make compound 13 with reference to embodiment 6.
Figure BSA00000562951200271
The preparation method is with reference to embodiment 1-i; Throw 102mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2; The 3-glyoxalidine is [4,5-c] quinoline also, 41mg (0.3mmol) 2-picoline-5-boric acid; Get gray solid product 83mg, productive rate 79.1%.
Molecular formula: C 26H 21F 3N 6O 3Molecular weight: 522.48MS:523 (M+H +)
Theoretical value: C, 59.77%; H, 4.05%; N, 16.08%;
Measured value: C, 59.73%; H, 4.09%; N, 16.02%
Embodiment 148-(2-picoline-5-yl)-3-methyl 2-oxo-1-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1- Base)-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 14) also
Can make compound 14 with reference to embodiment 7.
Figure BSA00000562951200272
The preparation method is with reference to embodiment 1-i; Throw 81mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2,3-glyoxalidine also [4; 5-c] quinoline; 41mg (0.3mmol) 2-picoline-5-boric acid gets white solid product 69mg, productive rate 75.1%.
Molecular formula: C 27H 32N 4O 3Molecular weight: 460.57MS:461 (M+H +)
Theoretical value: C, 70.41%; H, 7.00%; N, 12.16%;
Measured value: C, 70.35%; H, 7.10%; N, 12.10%
Embodiment 158-[1H-pyrazolo [3,4-b] pyridine-5-yl]-3-methyl-2-oxo-1-[N-[(R)-and 2-hydroxyl propionyl group] piperidines -4-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 15) also
Can make compound 15 with reference to embodiment 1 and 2.
Figure BSA00000562951200281
With 86mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl group] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline is dissolved among the 2mL DMF; Add 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid, two (triphenyl phosphorus) palladium chlorides (II) of 8mg and 0.5mL 1M Na 2CO 3, being heated to 100 ℃ and stirring 1 hour, reaction mixture is used NaHCO 3The saturated aqueous solution cancellation, with ethyl acetate extraction twice, organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying; Filter and evaporated under reduced pressure, resistates is used the silicagel column column chromatography purification, obtains white solid, then this solid is dissolved in 10mL methyl alcohol; Add 50mg Pd/C, 1 formic acid feeds hydrogen, stirring at room 5h; Filter and collect filtrating, evaporated under reduced pressure gets solid phase prod 76.5mg, yield 81%.
Molecular formula: C 25H 25N 7O 3Molecular weight: 471.51MS:472 (M+H +)
Theoretical value: C, 63.68%; H, 5.34%; N, 20.79%;
Measured value: C, 63.61%; H, 5.38%; N, 20.74%
Embodiment 168-[1H-pyrazolo [3,4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(N-glycoloyl phenylpiperidines-4- Base)-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 16) also
Can make compound 16 with reference to embodiment 1 and 2.
The preparation method is with reference to embodiment 15; Throw 84mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] quinoline also; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, get white solid product 71mg, productive rate 78.0%.
Molecular formula: C 24H 23N 7O 3Molecular weight: 457.48MS:458 (M+H +)
Theoretical value: C, 63.01%; H, 5.07%; N, 21.43%;
Measured value: C, 62.96%; H, 5.18%; N, 21.37%
Embodiment 178-[1H-pyrazolo [3,4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2,3- Glyoxalidine is the preparation of [4,5-c] quinoline (compound 17) also
Can make compound 17 with reference to embodiment 1 and 2.
Figure BSA00000562951200291
The preparation method is with reference to embodiment 15; Throw 84mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] quinoline also; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, get white solid product 74mg, productive rate 81.3%.
Molecular formula: C 24H 23N 7O 3Molecular weight: 457.48MS:458 (M+H +)
Theoretical value: C, 63.01%; H, 5.07%; N, 21.43%;
Measured value: C, 62.95%; H, 5.12%; N, 21.36%
Embodiment 188-[1H-pyrazolo [3,4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2,3-two The preparation of hydrogen imidazo [4,5-c] quinoline (compound 18)
Can make compound 18 with reference to embodiment 1 and 2.
Figure BSA00000562951200292
The preparation method is with reference to embodiment 15; Throw 81mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] quinoline also; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, get white solid product 76mg, productive rate 85.7%.
Molecular formula: C 24H 23N 7O 2Molecular weight: 441.49MS:442 (M+H +)
Theoretical value: C, 65.29%; H, 5.25%; N, 22.21%;
Measured value: C, 65.23%; H, 5.34%; N, 22.15%
Embodiment 198-[1H-pyrazolo [3,4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] quinoline (compound 19)
Can make compound 19 with reference to embodiment 1 and 2.
Figure BSA00000562951200301
The preparation method is with reference to embodiment 15; Throw 92mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-tertbutyloxycarbonyl-piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] quinoline also; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, get white solid intermediate product 88mg, productive rate 88.6%.This intermediate product drops in the 5mL methylene dichloride, adds 1mLTFA, stirring at room 1h, and the evaporated under reduced pressure solvent gets yellow solid 68mg, two step total recoverys 85.5%.
Molecular formula: C 22H 21N 7O molecular weight: 399.45MS:400 (M+H +)
Theoretical value: C, 66.15%; H, 5.30%; N, 24.55%;
Measured value: C, 66.10%; H, 5.36%; N, 24.50%
Embodiment 208-[1H-pyrazolo [3.4-b] pyridine-5-yl]-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoro Methyl-pyridine-2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 20) also
Can make compound 20 with reference to embodiment 6.
Figure BSA00000562951200302
The preparation method is with reference to embodiment 15; Throw 102mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2, the 3-glyoxalidine is [4,5-c] quinoline also; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, get yellow solid product 80mg, productive rate 73.4%.
Molecular formula: C 26H 19F 3N 8O 3Molecular weight: 548.48MS:549 (M+H +)
Theoretical value: C, 56.94%; H, 3.49%; N, 20.43%;
Measured value: C, 56.90%; H, 3.55%; N, 20.37%
Embodiment 218-[1H-pyrazolo [3,4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(3,5-dimethyl--4-'-hydroxyethoxy basic ring Hexane-1-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 21) also
Can make compound 21 with reference to embodiment 7.
Figure BSA00000562951200311
The preparation method throws 90mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(3,5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2 with reference to embodiment 15; 3-glyoxalidine also [4; 5-c] quinoline, 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid; Get yellow solid product 75mg, productive rate 76.6%.
Molecular formula: C 27H 30N 6O 3Molecular weight: 486.57MS:487 (M+H +)
Theoretical value: C, 66.65%; H, 6.21%; N, 17.27%;
Measured value: C, 66.61%; H, 6.26%; N, 17.22%
Embodiment 22 (S)-1-(1-(2-hydroxyl propionyl group) piperidin-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo The preparation of [4,5-c] quinoline-2 (3H)-ketone (compound 22)
Figure BSA00000562951200312
With compound 1 (200mg, 0.5mmol), I-hydroxybenzotriazole (200mg, 2.2mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (230mg; 1.2mmol), triethylamine (300mg, 2.9mmol) (250mg 2.8mmol) adds in the 20mL methylene dichloride with L-lactic acid; Reaction solution stirring at room 17h; The reaction solution evaporate to dryness is crossed the preparation liquid phase and is got product 19mg, productive rate 8.3%.
Molecular formula: C 25H 27N 5O 4Molecular weight: 461.51MS:462 (M+H +)
1H?NMR(d 6-DMSO)δ8.87(s，1H)，8.67(s，1H)，8.35(s，1H)，8.17(d，1H)，8.12(d，1H)，7.93(d，1H)，7.01(d，1H)，5.15(s，1H)，4.93-4.98(m，1H)，4.50-4.62(m，2H)，4.21(s，1H)，3.93(s，3H)，3.49(s，3H)，3.29-3.35(m，2H)，2.87-2.92(m，1H)，2.63-2.66(m，1H)，2.03-2.05(m，2H)，1.21(d，3H)
Embodiment 232-(4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1- Base) preparation of ethanamide (compound 23) piperidines-1-yl)
Figure BSA00000562951200321
With compound 1 (130mg, 0.33mmol), triethylamine 0.3mL, 2-iodo-acid amide (1.84g 10mmol) joins in the 20mL acetonitrile; Be heated to backflow, stir 2h, react the mixed solution extraction of finish water and methylene dichloride; Dry organic phase is crossed the preparation liquid phase and is got product 27mg, yield: 18.4%.
Molecular formula: C 24H 26N 6O 3Molecular weight: 447.49MS:448 (M+H +)
1H?NMR(400MHz，DMSO)δ8.89(s，1H)，8.68(d，1H)，8.41-8.52(m，1H)，8.22(d，1H)，8.12(d，1H)，7.95(d，1H)，7.12-7.17(m，2H)，7.01(d，1H)，4.81-4.92(m，1H)，3.92(s，3H)，3.50(s，3H)，3.03-3.05(m，2H)，2.97(s，2H)，2.69-2.79(m，2H)，2.22-2.48(m，2H)，1.91-1.99(m，2H).
Embodiment 241-(1-(2-hydroxy-2-methyl propionyl group) piperidin-4-yl)-8-(6-methoxypyridine 3-yl)-3-methyl isophthalic acid H-miaow Azoles is the preparation of [4,5-c] quinoline-2 (3H)-ketone (compound 24) also
Figure BSA00000562951200322
With compound 1 (130mg, 0.33mmol), I-hydroxybenzotriazole (100mg, 1.1mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (120mg; 0.63mmol), triethylamine (300mg, 2.9mmol) (67.6mg 0.65mmol) adds in the 20mL methylene dichloride with 2-methyl-2 hydroxy propanoic acid; Reaction solution stirring at room 48h; The reaction solution evaporate to dryness is crossed the preparation liquid phase and is got product 26mg, productive rate 20.3%.
Molecular formula: C 26H 29N 5O 4Molecular weight: 475.22MS:476 (M+H +)
1H?NMR(400MHz，DMSO)δ8.90(s，1H)，8.68(s，1H)，8.39(s，1H)，8.15(d，1H)，7.96(dd，1H)，7.79-7.82(m，1H)，6.99(d，1H)，5.47(s，1H)，4.67-5.78(m，1H)，3.94(s，3H)，3.51(s，3H)，2.50-2.51(m，2H)，2.01-2.07(m，2H)，1.66(s，2H)，δ1.33(s，6H)
Embodiment 25 (R)-2-hydroxy-n-(4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dioxy-1H-imidazo [4,5-c] quinoline-1-yl) preparation of propionic acid amide (compound 25) cyclohexyl)
Step a-d is with embodiment step 1-a to 1-d.
The preparation of step 25-e 4-(6-bromo-3-nitroquinoline-4-base is amino) cyclohexyl tertiary butyl carbonic ether
Figure BSA00000562951200331
With 6-bromo-4-chloro-3-nitroquinoline (6.4g, 22.5mmol), triethylamine (6.6g, 66mmol) with 4-aminocyclohexyl tertiary butyl carbonic ether (6.4g; 30mmol) add in the 50mL methylene dichloride, stirring at room 15 hours, reaction solution revolves dried; Cross the silicagel column purifying and get product 7.8g, productive rate: 74%.
The preparation of step 25-f 4-(3-amino-6-bromoquinoline-4-base is amino) cyclohexyl tertiary butyl carbonic ether
Figure BSA00000562951200332
With 4-(6-bromo-3-nitroquinoline-4-base amino) cyclohexyl tertiary butyl carbonic ether (7.8g, 16.8mmol), zinc powder (4.36g, 67.2mmol), (3.5g 67mmol) joins H to ammonium chloride 2O-CH 3In the solution of OH (50: 150), be warming up to 75C, stir 2h, reaction solution is used ethyl acetate extraction, with washing, and drying, evaporate to dryness gets product 2.9g with the silicagel column purifying, productive rate: 40%.
The preparation of step 25-g 4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether
Figure BSA00000562951200333
With 4-(3-amino-6-bromoquinoline-4-base is amino) cyclohexyl tertiary butyl carbonic ether (2.9g; 6.6mmol) be dissolved in the 60mL methylene dichloride under ice bath, (2.96g is in dichloromethane solution 10mmol) to be added dropwise to the 30mL TRIPHOSGENE 99.5 in 40 minutes; Control stabilization stirs 2h, uses saturated NaHCO 3The solution cancellation, with washing, organic layer is dry, and evaporate to dryness is crossed the silicagel column purifying and is got product 2.4g, yield: 80%.
The preparation of step 25-h 4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether
Figure BSA00000562951200334
With 4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether (2.4g; 5.3mmol) dichloromethane solution 20mL add contain methyl iodide (0.76g, 5.3mmol), in the 10%NaOH solution of tetrabutyl iodate amine 500mg, stir 2h; Mixed solution extraction with methylene dichloride and water; Organic layer is dry, crosses the silicagel column purifying and gets product 2.0g, productive rate: 81%.
The preparation of step 25-i 4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether
Figure BSA00000562951200341
With 2-methoxyl group-5-pyridine boric acid (1.4g, 3mmol), Pd 2(dba) 3140mg and 4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether (0.6g, 3mmol) NaCO of adding 15mL DMF and 10mL 1M 3In the solution, be warming up to 100 ℃ under the nitrogen protection, stir 2h, react the mixed solution extraction of finish water and ETHYLE ACETATE, separate organic layer, drying is crossed the silicagel column purifying and is got product 0.6g, productive rate: 90%.
The preparation of step 25-j 1-(4-aminocyclohexyl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo [4,5-c] quinoline-2 (3H)-ketone
With 4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2; 3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) (0.6g 1.2mmol) is dissolved in the 15mL dichloromethane solution cyclohexyl tertiary butyl carbonic ether; Add the 2mL trifluoroacetic acid; Stir 2h, the reaction solution evaporate to dryness gets bullion 0.2g, yield 70%.
The preparation of step 25-k compound 25
Figure BSA00000562951200343
With 1-(4-aminocyclohexyl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo [4,5-c] quinoline-2 (3H)-ketone (200mg, 0.5mmol), I-hydroxybenzotriazole (200mg; 2.2mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (230mmg, 1.2mmol), triethylamine (360mg) and L-lactic acid (72mg, 0.8mmol); Reaction solution stirring at room 17h; The reaction solution evaporate to dryness is crossed the preparation liquid phase and is got product 58mg, productive rate 30%.
Molecular formula: C 26H 29N 5O 4Molecular weight: 475.22MS:476 (M+H +)
1H NMR (d 6-DMSO) δ 8.88 (s, 1H), 8.66 (d, 1H), 8.31 (s, 1H), 8.14 (d, 1H), 7.93 (d; 1H), 7.60 (d, 1H), 7.02 (d, 1H), 5.49-5.50 (m, 1H), 4.93-4.98 (m, 1H); 3.93 (s, 3H), 3.41-3.45 (m, 1H), 3.39 (s, 3H), 2.56-2.60 (m, 2H), 2.01-2.07 (m; 1H), 1.90-1.93 (m, 2H), 1.60-1.63 (m, 2H), 1.21-1.23 (m 5H) with reference to aforesaid method, can also prepare following compound:
Figure BSA00000562951200351
formula; (I-1)
Figure BSA00000562951200352
formula; (I-2)
Figure BSA00000562951200353
formula (I-3)
Substituent R among above-mentioned formula (I-1), (I-2), (I-3) 1, be respectively following group:
Table 4
Figure BSA00000562951200354
formula; (I-4)
Figure BSA00000562951200363
formula; (I-5)
Figure BSA00000562951200364
formula; (I-6)
Figure BSA00000562951200365
formula; (I-7)
Figure BSA00000562951200366
formula; (I-8) formula; (I-9)
Substituent R among above-mentioned formula (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) 1, be respectively following group:
Table 5
Figure BSA00000562951200368
Figure BSA00000562951200371

Claims (12)

1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Figure FSA00000562951100011
Wherein
X is O, S, or NH;
R 1Be hydrogen, or be not substituted or by at least one R 6aSubstituted C 1-6Alkyl, C 3-8Naphthenic base, C 3-8Thiazolinyl, C 3-8Alkynyl, 3-14 unit heterocyclic radical, 6-12 unit volution base;
R 2Be hydrogen, or be not substituted or by at least one R 6bSubstituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 3' be hydrogen, hydroxyl, carboxyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 3, R 4, R 4' independently be hydrogen respectively, halogen, cyanic acid, hydroxyl, carboxyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) nR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 5Be hydrogen ,-(CH 2) nS (O) mR 8, or be not substituted or by at least one R 6cSubstituted C 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively, halogen, cyanic acid ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 9Be hydroxyl, halogen, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical ,-(CH 2) nNR 10aR 10b,-(CH 2) nC (O) R 11,-(CH 2) nC (O) NR 10aR 10b,-(CH 2) nS (O) mR 11,-(CH 2) nS (O) mNR 10aR 10b,-(CH 2) nNR 10aS (O) mR 11,-(CH 2) nOC (O) R 11,-(CH 2) nC (O) OR 11,-(CH 2) nNR 10aC (O) R 11, or-(CH 2) nNR 10aC (O) NR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 3-14 unit heterocyclic radical;
R 11Be C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 3-14 unit heterocyclic radical;
M is 1 or 2;
N is 0～4.
2. compound as claimed in claim 1, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by at least one R 6aSubstituted C 1-6Alkyl, C 3-8Naphthenic base, 4-10 unit heterocyclic radical, 7-10 unit volution base;
R 2For not being substituted or by at least one R 6bSubstituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical;
R 3' be hydrogen ,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 3, R 4, R 4' independently be hydrogen respectively, halogen, cyanic acid ,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 5Be hydrogen, or be not substituted or by at least one R 6cSubstituted C 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9Substituted C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical;
R 9Be hydroxyl, halogen, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 4-10 unit heterocyclic radical, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 4-10 unit heterocyclic radical;
M is 1 or 2;
N is 0～4.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by at least one R 6aSubstituted C 1-6Alkyl, C 4-7Naphthenic base, 5-10 unit heterocyclic radical;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, naphthyl, 5-10 unit heterocyclic radical;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, or be not substituted or by at least one R 6cSubstituted C 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Naphthenic base, phenyl, 5-10 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9Substituted C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Naphthenic base, phenyl, 5-10 unit heterocyclic radical;
R 9Be hydroxyl, fluorine, chlorine, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 4-7Naphthenic base, phenyl, 5-10 unit heterocyclic radical, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 4-7Naphthenic base, phenyl, or 5-10 unit heterocyclic radical;
M is 1 or 2;
N is 0～3.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by at least one R 6aSubstituted C 4-7Naphthenic base, the single heterocyclic radical of 5-6 unit;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, or C 1-6Alkyl;
R 6a, R 6bIndependently be hydroxyl respectively, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 9Be hydroxyl, fluorine, chlorine, cyanic acid, or trifluoromethyl;
N is 0～2.
5. compound as claimed in claim 4, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by at least one R 6aSubstituted cyclopentyl, cyclohexyl, piperidyl, piperazinyl, imidazolidyl, pyrazolidyl, tetrahydrofuran base, morpholinyl, pyridyl, pyrimidyl, pyrazolyl;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by at least one R 9Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, indyl, Pyrazolopyridine base;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, or C 1-4Alkyl;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-4Alkyl;
R 8For not being substituted or by at least one R 9Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 9Be hydroxyl, cyanic acid, or trifluoromethyl;
N is 0～2.
6. compound as claimed in claim 5, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by at least one R 6aSubstituted cyclopentyl, cyclohexyl, piperidyl, piperazinyl, pyridyl, pyrimidyl;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by at least one R 9Substituted C 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by at least one R 6bSubstituted phenyl, pyridyl, pyrimidyl, indazolyl, quinolyl, indyl, Pyrazolopyridine base;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9Substituted C 1-3Alkyl, C 1-2Alkoxyl group;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5Be hydrogen, methyl, ethyl or propyl group;
R 7aAnd R 7bIndependent respectively is hydrogen, methyl or ethyl;
R 8For not being substituted or by at least one R 9Substituted C 1-4Alkyl, C 1-3Alkoxyl group;
R 9Be hydroxyl, cyanic acid, or trifluoromethyl;
N is 0～2.
7. compound as claimed in claim 6, its pharmacy acceptable salt or its steric isomer, said compound is selected from:
Wherein
X is O;
R 1For not being substituted or by 1～3 R 6aSubstituted cyclohexyl, piperidyl, pyridyl;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nC (O) R 8,-(CH 2) nC (O) NR 7aR 7b,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8, or be not substituted or by 1～3 R 9Substituted C 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by 1～3 R 6bSubstituted pyridyl, Pyrazolopyridine base;
R 6bBe hydroxyl, trifluoromethyl, C 1-3Alkyl, or C 1-2Alkoxyl group;
R 3, R 3', R 4, R 4' independently be hydrogen respectively;
R 5Be methyl;
R 7aAnd R 7bIndependently be hydrogen respectively, methyl or ethyl;
R 8For not being substituted or by 1～3 R 9Substituted C 1-4Alkyl;
R 9Be hydroxyl;
N is 0 or 1.
8. compound as claimed in claim 7, its pharmacy acceptable salt or its steric isomer, said compound is selected from:
Figure FSA00000562951100051
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100052
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-and 2-hydroxyl propionyl group] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100061
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100062
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100071
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(3; 5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-[N-[(R)-and 2-hydroxyl propionyl group] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100073
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100074
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100075
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100082
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(3; 5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100084
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-[N-[(R)-and 2-hydroxyl propionyl group] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100091
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100092
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100093
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100094
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100095
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline
Figure FSA00000562951100101
8-[1H-pyrazolo [3; 4-b] pyridine-5-yl]-3-methyl-2-oxo-1-(3; 5-dimethyl--4-hydroxyl-oxethyl hexanaphthene-1-yl)-2; The 3-glyoxalidine is [4,5-c] quinoline also.
9. compound as claimed in claim 7, its pharmacy acceptable salt or its steric isomer, said compound is selected from:
Figure FSA00000562951100102
(S)-1-(1-(2-hydroxyl propionyl group) piperidin-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo [4; 5-c] quinoline-2 (3H)-ketone
Figure FSA00000562951100103
2-(4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2; 3-dihydro-1H-imidazo [4; 5-c] quinoline-1-yl) piperidines-1-yl) ethanamide
Figure FSA00000562951100104
1-(1-(2-hydroxy-2-methyl propionyl group) piperidin-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo [4; 5-c] quinoline-2 (3H)-ketone
Figure FSA00000562951100111
(R)-2-hydroxy-n-(4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2; 3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) propionic acid amide cyclohexyl).
10. contain the pharmaceutical prepn of each described compound of claim 1～9, its pharmacy acceptable salt or its steric isomer, it is characterized in that comprising one or more pharmaceutical carriers.
11. contain the pharmaceutical composition of each described compound of claim 1～9, its pharmacy acceptable salt or its steric isomer; It is characterized in that comprising one or more antineoplastic agents and immunosuppressor; Described antineoplastic agent and immunosuppressor are metabolic antagonist, comprise capecitabine, gemcitabine, Tifolar; Be growth factor receptor inhibitors, comprise handkerchief azoles handkerchief Buddhist nun, imatinib, erlotinib, lapatinibditosylate, ZD1939, ZD6474; Be antibody, comprise Trastuzumab, rhuMAb-VEGF; Be mitotic inhibitor, comprise taxol, vinorelbine, docetaxel, Dx; Be antitumor hormones, comprise letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; Be the alkylating agent class, comprise endoxan, carmustine; Be the metal platinum class, comprise carboplatin, cis-platinum, oxaliplatin; Be topoisomerase enzyme inhibitor, comprise that topology is special willing; Be the immunosuppression class, comprise that SDZ-RAD, sirolimus, special cancer fit.
12. each described compound of claim 1～9, its pharmacy acceptable salt or its steric isomer treat and/or prevent the purposes in the medicine of proliferative disease in preparation; Described proliferative disease comprises cancer and non-Cancerous disease, and said cancer is selected from brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, bladder cancer, cancer of the stomach, ovarian cancer, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, cervical cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, neurospongioma, glioblastoma multiforme, glioma sarcomatosum, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, histocytic lymphoma, neurofibromatosis, osteocarcinoma, skin carcinoma, the cancer of the brain, colorectal carcinoma, carcinoma of testis, small cell lung cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, multiple myeloma, melanoma, glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, sarcoma; Non-Cancerous disease is selected from skin or prostatic hyperplasia of prostate.
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