CN102372711B - 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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CN102372711B
CN102372711B CN201110245003.8A CN201110245003A CN102372711B CN 102372711 B CN102372711 B CN 102372711B CN 201110245003 A CN201110245003 A CN 201110245003A CN 102372711 B CN102372711 B CN 102372711B
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cancer
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quinoline
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CN102372711A (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 preparation 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 cytogenetics substance change, cause genetic expression not normal, abnormal cell proliferation and the true tumor that forms.Tumour cell loses normal growth regulatory function, has independently or relatively autonomous energy for growth, still can continued growth after the tumorigenesis factor stops, consuming in a large number the nutritive substance of human body.If find and treat not in time, cancer cells also can be transferred to whole body growth and breeding everywhere, and discharges multiple toxin, causes human body sale, anaemia, the impaired extremely death of organ function.
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, and therefore the status of pharmacological agent in oncotherapy is more and more obvious.Traditional antineoplastic thing cannot be distinguished tumour cell and normal tissue cell, often cause severe side effect, targeted drug is using cancer cells as specificity target spot, can accurately act on tumour, improve greatly treatment level, and alleviated untoward reaction rate, and for example make the median survival time of advanced CRC increase by 66.7%, the treated effect of advanced breast cancer improves 71.3%.
Because each drugmaker accelerates the development of target class antitumour drug, add market sought-after to the antitumour drug of this classification, molecular targeted agents has become fastest-rising unit in global antitumor drug market.PI3K path is the place of the most often morphing in human cancer cell, can cause cell proliferation, activation, amplifying signal.Phosphatidylinositol3 3 kinase (PI3K) and Mammals rapamycin target protein (mTOR) are the important kinases of PI3K signal path.
Phosphatidylinositol3 3 kinase (PI3K) is fat kinases family member, can produce Phosphatidyl inositol triphosphate fat (PIP3) by 3 of a phosphatidyl alcohol phosphorylation and regulate cellular metabolism and growth.The second messenger PIP3 of this lipid can make effector (particularly Akt) the pairing combination in P13K and downstream, thereby causes film to be raised and phosphorylation, cell proliferation, activation.Therefore inhibition of phosphatidylinositol3 3 kinases, can affect PI3K path, thus anticancer propagation, activation.
MTOR is a kind of protein serine/threonine being present in endochylema, belong to Phosphoinoside kinase related protein kinase enzyme family, exist with the form of two kinds of mixtures in vivo, i.e. mTORC1 (action target spot of rapamycin) and mTORC2 (not suppressed by rapamycin).MTOR is a kind of cell signalling albumen, the reaction of its regulate tumor cell to nutrient and somatomedin, and by the effect to vascular endothelial growth factor, control the blood supply of tumour.MTOR inhibitors can make cancer cells hunger, and by the effect that suppresses mTOR, gross tumor volume is dwindled.
In the patent WO2006122806 of Novartis (open day 2006.11.23) and the patent WO201003816 of Pfizer (open day 2010.04.08), all report the validity of PI3K/mTOR double inhibitor in oncotherapy.At present, without the listing of PI3K/mTOR double inhibitor class medicine, therefore, need to research and develop more PI3K/mTOR double inhibitor structure type temporarily, the good compound of effectiveness of selection and security, for the treatment of 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 as follows:
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer:
X is O, S, or NH;
R 1for hydrogen, or be not substituted or by least one R 6athe C replacing 1-6alkyl, C 3-8cycloalkyl, C 3-8thiazolinyl, C 3-8alkynyl, 3-14 unit heterocyclic radical, 6-12 unit volution base;
R 2for hydrogen, or be not substituted or by least one R 6bthe C replacing 1-6alkyl, C 3-8cycloalkyl, 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' be independently hydrogen respectively, halogen, cyano group, 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 5for hydrogen ,-(CH 2) ns (O) mr 8, or be not substituted or by least one R 6cthe C replacing 1-6alkyl;
R 6a, R 6b, R 6cbe independently hydroxyl respectively, halogen, cyano group ,-(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 least one R 9the C replacing 1-6alkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkoxyl group, C 3-8cycloalkyl, aryl, 3-14 unit heterocyclic radical;
R 7aand R 7bbe independently respectively hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl, C 3-8cycloalkyl, aryl, 3-14 unit heterocyclic radical;
R 8for hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group, C 3-8cycloalkyl, aryl, 3-14 unit heterocyclic radical;
R 9for hydroxyl, halogen, cyano group, trifluoromethyl, C 1-6alkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkoxyl group, C 3-8cycloalkyl, 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 10bbe independently hydrogen respectively, C 1-6alkyl, C 3-8cycloalkyl, aryl, or 3-14 unit heterocyclic radical;
R 11for C 1-6alkyl, C 3-8cycloalkyl, aryl, or 3-14 unit heterocyclic radical;
M is 1 or 2;
N is 0～4.
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer, preferred technical scheme is:
X is O;
R 1for not being substituted or by least one R 6athe C replacing 1-6alkyl, C 3-8cycloalkyl, 4-10 unit heterocyclic radical, 7-10 unit volution base;
R 2for not being substituted or by least one R 6bthe C replacing 1-6alkyl, C 3-8cycloalkyl, 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' be independently hydrogen respectively, halogen, cyano group ,-(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 5for hydrogen, or be not substituted or by least one R 6cthe C replacing 1-6alkyl;
R 6a, R 6b, R 6cbe independently 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 least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group, C 3-8cycloalkyl, aryl, 4-10 unit heterocyclic radical;
R 7aand R 7bbe independently respectively hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl;
R 8for hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group, C 3-8cycloalkyl, aryl, 4-10 unit heterocyclic radical;
R 9for hydroxyl, halogen, cyano group, trifluoromethyl, C 1-6alkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkoxyl group, C 3-8cycloalkyl, aryl, 4-10 unit heterocyclic radical, or-(CH 2) nnR 10ar 10b;
R 10aand R 10bbe independently hydrogen respectively, C 1-6alkyl, C 3-8cycloalkyl, aryl, or 4-10 unit heterocyclic radical;
M is 1 or 2;
N is 0～4.
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer, preferred technical scheme is:
X is O;
R 1for not being substituted or by least one R 6athe C replacing 1-6alkyl, C 4-7cycloalkyl, 5-10 unit heterocyclic radical;
R 2for not being substituted or by least one R 6bthe phenyl, naphthyl, the 5-10 unit heterocyclic radical that replace;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5for hydrogen, or be not substituted or by least one R 6cthe C replacing 1-6alkyl;
R 6a, R 6b, R 6cbe independently 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 least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group, C 4-7cycloalkyl, phenyl, 5-10 unit heterocyclic radical;
R 7aand R 7bbe independently respectively hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl;
R 8for hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group, C 4-7cycloalkyl, phenyl, 5-10 unit heterocyclic radical;
R 9for hydroxyl, fluorine, chlorine, cyano group, trifluoromethyl, C 1-6alkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkoxyl group, C 4-7cycloalkyl, phenyl, 5-10 unit heterocyclic radical, or-(CH 2) nnR 10ar 10b;
R 10aand R 10bbe independently hydrogen respectively, C 1-6alkyl, C 4-7cycloalkyl, phenyl, or 5-10 unit heterocyclic radical;
M is 1 or 2;
N is 0～3.
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer, preferred technical scheme is:
X is O;
R 1for not being substituted or by least one R 6athe C replacing 4-7cycloalkyl, the single heterocyclic radical of 5-6 unit;
R 2for not being substituted or by least one R 6bthe phenyl, the single heterocyclic radical of 5-6 unit, the 9-10 unit fused heterocycle base that replace;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5for hydrogen, or C 1-6alkyl;
R 6a, R 6bbe independently 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 least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group;
R 7aand R 7bbe independently hydrogen respectively, or C 1-6alkyl;
R 8for hydrogen, or be not substituted or by least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group;
R 9for hydroxyl, fluorine, chlorine, cyano group, or trifluoromethyl;
N is 0～2.
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer, preferred technical scheme is:
X is O;
R 1for not being substituted or by least one R 6athe cyclopentyl, cyclohexyl, piperidyl, piperazinyl, imidazolidyl, pyrazolidyl, tetrahydrofuran base, morpholinyl, pyridyl, pyrimidyl, the pyrazolyl that replace;
R 6afor 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 least one R 9the C replacing 1-4alkyl, C 1-4alkoxyl group;
R 2for not being substituted or by least one R 6bthe phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, indyl, the Pyrazolopyridine base that replace;
R 6bfor hydroxyl, trifluoromethyl, or be not substituted or by least one R 9the C replacing 1-6alkyl, C 1-6alkoxyl group;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5for hydrogen, or C 1-4alkyl;
R 7aand R 7bbe independently hydrogen respectively, or C 1-4alkyl;
R 8for not being substituted or by least one R 9the C replacing 1-4alkyl, C 1-4alkoxyl group;
R 9for hydroxyl, cyano group, or trifluoromethyl;
N is 0～2.
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer, preferred technical scheme is:
X is O;
R 1for not being substituted or by least one R 6athe cyclopentyl, cyclohexyl, piperidyl, piperazinyl, pyridyl, the pyrimidyl that replace;
R 6afor 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 least one R 9the C replacing 1-3alkyl, C 1-2alkoxyl group;
R 2for not being substituted or by least one R 6bthe phenyl, pyridyl, pyrimidyl, indazolyl, quinolyl, indyl, the Pyrazolopyridine base that replace;
R 6bfor hydroxyl, trifluoromethyl, or be not substituted or by least one R 9the C replacing 1-3alkyl, C 1-2alkoxyl group;
R 3, R 3', R 4, R 4' be respectively hydrogen;
R 5for hydrogen, methyl, ethyl or propyl group;
R 7aand R 7bindependent is respectively hydrogen, methyl or ethyl;
R 8for not being substituted or by least one R 9the C replacing 1-4alkyl, C 1-3alkoxyl group;
R 9for hydroxyl, cyano group, or trifluoromethyl;
N is 0～2.
Compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer, preferred technical scheme is:
X is O;
R 1for not being substituted or by 1～3 R 6athe cyclohexyl, piperidyl, the pyridyl that replace;
R 6afor 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 9the C replacing 1-3alkyl, C 1-2alkoxyl group;
R 2for not being substituted or by 1～3 R 6bthe pyridyl, the Pyrazolopyridine base that replace;
R 6bfor hydroxyl, trifluoromethyl, C 1-3alkyl, or C 1-2alkoxyl group;
R 3, R 3', R 4, R 4' be independently hydrogen respectively;
R 5for methyl;
R 7aand R 7bbe independently hydrogen respectively, methyl or ethyl;
R 8for not being substituted or by 1～3 R 9the C replacing 1-4alkyl;
R 9for hydroxyl;
N is 0 or 1.
Table 1 part of compounds of the present invention
" halogen " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention 1-6alkyl " the hydrocarbon part that refers to contain 1-6 carbon atom removes the alkyl of the derivative straight or branched of hydrogen atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, 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 respectively the specific examples that contains 1-4, a 1-3 carbon atom in above-mentioned example.
" C of the present invention 3-8cycloalkyl " refer to the cyclic alkyl that contains 3-8 carbon atom, as cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane, cyclooctane etc." C of the present invention 4-7cycloalkyl " refer to the specific examples that contains 4-7 carbon atom in above-mentioned example.
" C of the present invention 2-8thiazolinyl " refer to straight or branched that the carbonatoms that contains two keys is 2-8 or the thiazolinyl of ring-type; as vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1; 3-divinyl, 1-pentenyl, pentenyl, 3-pentenyl, 1; 3-pentadiene, 1; 4-pentadiene, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1; 4-hexadiene, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc.C of the present invention 3-8thiazolinyl refers to the specific examples that contains 3-8 carbon atom in above-mentioned example.
" C of the present invention 2-8alkynyl " refer to the alkynyl of the straight or branched that the carbonatoms that contains triple bond is 2-8, as ethynyl, proyl, 2-butyne base, valerylene base, 3-pentynyl, 4-methyl-valerylene base, 2-hexin base, 3-hexin base, 5-methyl-2-hexin base, 2-heptyne base, 5-methyl-2-heptyne base, 2-octyne base, 3-octyne base etc.C of the present invention 3-8alkynyl refers to the specific examples that contains 3-8 carbon atom in above-mentioned example.
" C of the present invention 1-6alkoxyl group " refer to " C 1-6alkyl " group that is connected with other structures by Sauerstoffatom, as 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 respectively 1-4,1-3, the specific examples of a 1-2 carbon atom of containing in above-mentioned example.
" aryl " of the present invention refer to the such as phenyl of phenyl, replacement of aromatic ring (such as benzyl, styroyl) and thick and fragrant cyclic group (such as naphthyl, phenanthrene) etc.
" 3-14 unit heterocyclic radical " of the present invention refers to whole saturated, the fractional saturation that contains 3-14 annular atoms (wherein at least containing a heteroatoms), undersaturated cyclic group, and described " heteroatoms " refers to nitrogen-atoms, Sauerstoffatom, sulphur atom etc." the first heterocyclic radical of assorted 3-14 " comprises the 3-8 single heterocyclic radical of unit and 6-14 unit fused heterocycle base.
Described " the single heterocyclic radical of 3-8 unit ", the single heterocycle described in it can be all saturated, fractional saturation, undersaturated, example 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-triazines, 1,2,4,5-tetrazine, nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, Isosorbide-5-Nitrae-diazacyclo heptantriene, nitrogen heterocyclic octatetraene, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-diazacyclo sarohornene, oxyethane, dioxirane, thiirane, trimethylene oxide, 1,2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, tetrahydrofuran (THF), thiophene, 2,5-dihydro-thiophene, tetramethylene sulfide, 1,3-dioxolane, 1,3-dioxole-2-ketone, 1,2-dithiole, 1,3-dithiolane, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, Isosorbide-5-Nitrae-Dioxin, Isosorbide-5-Nitrae-dithia cyclohexadiene, Isosorbide-5-Nitrae-oxathiin, Isosorbide-5-Nitrae-dioxane, 1,3-dioxane, 1,3-oxathiane, oxepin, thia cycloheptatriene, Isosorbide-5-Nitrae-dioxane sarohornene, oxaza propane, 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 whole saturated, fractional saturation, undersaturated, and the example comprises and being not limited in " the single heterocyclic radical of 3-8 unit ", the specific examples that contains 5-6 annular atoms.
Described " 6-14 unit fused heterocycle base ", the fused heterocycle described in it can be all saturated, fractional saturation, undersaturated, example has indoles, isoindole, carbazole, benzoglyoxaline, indazole, benzotriazole, imidazolidine is [4,5-c] pyridine also, 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 whole saturated, fractional saturation, undersaturated, and the example comprises and being not limited in " 6-14 unit fused heterocycle base ", the specific examples that contains 9-10 annular atoms.
" 4-10 unit heterocyclic radical " of the present invention, " 5-10 unit heterocyclic radical " refer to respectively the cyclic group that contains 4-10 annular atoms (at least containing a heteroatoms), a 5-10 annular atoms (at least containing a heteroatoms) in above-mentioned " 3-14 unit heterocyclic radical ", comprise all monocycles or condensed ring, and ring can be whole saturated, fractional saturation, undersaturated.
What " 6-12 unit volution " of the present invention referred to that a class has that two rings share that atoms form at least contains 6-12 carbon atom and/or heteroatomic structure, and 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, refers to that all rings in this volution are saturated cyclic group, and specific examples includes but are not limited to: deng.
6-12 unit fractional saturation volution, refers to that in this volution, having a ring at least is undersaturated cyclic group, and specific examples includes but are not limited to: deng.
" 7-10 unit volution base " of the present invention refers to the structure that contains 7-10 annular atoms in " 6-12 unit volution base ", comprises saturated, fractional saturation.
Of the present invention " by least one R 6areplace ", " by least one R 6breplace ", " by least one R 6c, by least one R 9replace ", " at least one " in the term such as " by least one halogen, hydroxyl, carboxyl substituted "; referring on substituted group to have one or more substituting groups; its maximum substituent numbers depend on the number of the feasible position that can be replaced by corresponding substituting group of all chemistry on substituted group; in general, be preferably 1-3 substituting group.
Above-claimed cpd of the present invention can adopt method and/or other technology known to persons of ordinary skill in the art of in following flow process, describing to synthesize, but is not limited only to following methods.
Compound shown in general formula (I), in the time that X is O,
Reactions steps:
The preparation of step 1TM-a adds SM-a in the mixture of the cooling ice of ice bath and NaOH, and stirring reaction under room temperature, adds solution in ice and concentrated hydrochloric acid, makes solution A, prepares to drop into immediately in next step reaction.
The preparation of step 2TM-b by SM-b at H 2in the solution of O-HC1, stir, filter, make solution B, will under solution A and solution B room temperature, merge, stirring reaction, filtering precipitation, washes with water, is drying to obtain.
The preparation of step 3TM-c adds potassium acetate and diacetyl oxide in TM-b, and return stirring reaction, leaches precipitation, is washed till filtrate colourless with acetic acid, then washes with water, is drying to obtain.
TM-c is joined stirring and refluxing in phosphorus oxychloride by the preparation of step 4TM-d, and mixture is chilled to room temperature, and unnecessary phosphorus oxychloride is removed in underpressure distillation, short silicagel column column chromatography for the solid obtaining, eluent petroleum ether-ethyl acetate, evaporated under reduced pressure and get final product.
The preparation of step 5TM-e together joins TM-d and SM-c in methylene dichloride, adds triethylamine, stirred overnight at room temperature.Vacuum rotary steam is removed methylene dichloride, and the syrupy shape solid column chromatography purification obtaining, to obtain final product.
The preparation of step 6TM-f joins TM-e to go back in original reagent, reduces and get final product.
The preparation of step 7TM-g joins TM-f in methylene dichloride, drips triethylamine, adds SM-d (1,1-carbonyl dimidazoles) under ice-water bath, refluxes, and adds saturated NaHCO 3the aqueous solution, stirs, separatory, organic phase anhydrous sodium sulfate drying, solvent evaporated and get final product.
The preparation of step 8TM-h joins TM-g, SM-e and Tetrabutyl amonium bromide in methylene dichloride, add the NaOH aqueous solution, stirring at room temperature, the aqueous solution that adds methyl iodide and NaOH to be made into, continues to stir the cancellation of reaction mixture water, with twice of dichloromethane extraction, organic phase salt water washing, anhydrous sodium sulfate drying, filters and evaporate to dryness filtrate obtain product.
The preparation of step 9 compound i is dissolved in TM-h in DMF, adds SM-f, two (triphenyl phosphorus) palladium chloride (II) and Na 2cO 3, heated and stirred, reaction mixture NaHCO 3saturated aqueous solution cancellation, ethyl acetate extracting twice, organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying, filters and evaporated under reduced pressure, and resistates silicagel column column chromatography purification, to obtain final product.
Compound shown in general formula (I), in the time that X is S or NH, can prepare with reference to aforesaid method.
In reaction equation, represent raw material with SM, represent product with TM, R 1, R 2, R 3, R 4, R 4', R 5as defined above.Work as R 5during for hydrogen, TM-g directly can be reacted with SM-f, obtain formula of the present invention (I) compound.
In reaction process, the functional group that should not participate in the starting compound of reaction can be not report the form of protecting to exist, or can be protected, then removes in whole or in part protecting group according to conventional method.For example, if there is amino acid proton, " amino protecting group " of available routine protected, and the example of described " amino protecting group " comprising: methyl, encircle the third methyl, 1-methyl isophthalic acid-ring the 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-methylsulfonylethyl, 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-(3,5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-, tri-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-(Isosorbide-5-Nitrae-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4,6-trimethyl benzyl, to methoxy-benzyl, 3,5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, chlorobenzyl, 2,4-dichloro benzyl, to cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, m-chloro-p-acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (O-Nitrophenylfluorone) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, isonicotine base, S-benzyl, N '-piperidino carbonyl, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl, formyl radical, ethanoyl, ethanoyl-pyridine, (N '-dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(O-Nitrophenylfluorone) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoxy ylmethyl) benzoyl and p-P-benzoyl, phthaloyl, 2, the sub-acid amides of ring of 3-phenylbenzene maleoyl and dithio succinyl, allyl group, allyloxy carbonyl, tert-butoxycarbonyl, to nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, phenacyl, 3-acetoxyl group propyl group, 4-nitro-1-cyclohexyl-2-oxo-3-pyrrolidin-3-yl, quaternary ammonium salt, methoxymethyl, 2-chloroethoxy methyl, benzyloxymethyl, valeryl methyl, [1-(alkoxycarbonyl amido)]-2,2,2, trifluoroethyl, [1-Trifluoromethyl-1-(to 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-bis-phenylpropyl alcohol suberane bases, (N ', N '-dimethylaminomethylene), N, N '-isopropylidene, benzylidene, to methoxyl group benzylidene, to nitrobenzal, salicylidene, 5-chlorine salicylidene, diphenylmethylene, (the chloro-2-hydroxyphenyl of 5-) 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, dimethyl sulphur-based phosphinyl, hexichol sulfenyl phosphinyl, diethyl 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, refers to and has formula (I) compound of basic nitrogen atom and the salt that mineral acid shape, organic acid or organic protonic acid form.
" steric isomer " of formula of the present invention (I) compound, refer to that formula of the present invention (I) compound exists unsymmetrical carbon, carbon-carbon double bond 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 make pharmaceutically acceptable pharmaceutical preparation with one or more pharmaceutical carriers, is applied to the patient who needs this treatment in modes such as oral, parenterals.When oral administration, can make conventional solid preparation with conventional weighting agent, tackiness agent, disintegrating agent, lubricant, thinner etc., as tablet, capsule, pill, granule etc.; During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.While making injection, can adopt the ordinary method in existing pharmacy field to produce, when preparation injection, can not add additives, also can add suitable additives according to the character of medicine.
The pharmaceutical composition of the claimed formula of the present invention (I) compound, its pharmacy acceptable salt or its steric isomer and one or more antineoplastic agents and immunosuppressor; drug combination, for the preparation of 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, pemetrexed disodium; Growth factor receptor inhibitors, includes but are not limited to pazopanib, imatinib, erlotinib, lapatinibditosylate, Gefitinib, 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; Alkylating agent class, includes but are not limited to endoxan, carmustine; Metal platinum class, includes but are not limited to carboplatin, cis-platinum, oxaliplatin; Topoisomerase enzyme inhibitor, includes but are not limited to Topotecan; Immunosuppression class, includes but are not limited to everolimus, sirolimus, special cancer suitable.
The claimed formula of the present invention (I) compound, 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, described 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.
Further set forth below the beneficial effect of the compounds of this invention by the experiment in vitro of part the compounds of this invention, other compound of the present invention has identical beneficial effect with part the compounds of this invention cited in test, but this should be interpreted as to the compounds of this invention only has following beneficial effect.
the external zymetology of experimental example the compounds of this invention suppresses active
Trial-product the compounds of this invention, self-control, its chemical name and structural formula are shown in the Preparation Example of each compound;
Disclosed compd B GT-226 and BEZ-235 in WO2006122806 (open day 2006.11.23), with reference to patented method preparation, product in contrast.
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 doubly kinase buffer liquor, kinase tracer antibody 6nM;
1.4 test compounds 10mM liquid storages.
2. experimental procedure
2.1 test compounds 30 μ M, with 4 times of gradient dilutions of kinase buffer liquid;
In 2.2384 orifice plates, every hole adds the compound of 5 μ L serial dilutions;
2.3 every hole adds 5 μ L3 times kinase tracer;
2.4 every holes add 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
As can be seen from Table 2, the compounds of this invention has good restraining effect to PI3K α and mTOR enzyme, better than contrast medicine BGT-226 and BEZ-235, the compounds of this invention is described compared with prior art, has significant progress.
4, embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.
embodiment 18-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2,3-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 the cooling 28g ice of ice bath and 12.4g (310mmol) NaOH, 0 DEG C is stirred 1 hour, then under room temperature, stir 1 hour, solution is added at 0 DEG C in 22.4g ice and 32.8mL concentrated hydrochloric acid (37%) (solution A), prepare to drop into immediately in next step reaction.
The benzoic preparation of the bromo-2-of step 1-b 5-(2-nitro-vinyl amino)
By the bromo-phenylformic acid of 10g (46.3mmol) 2-amino-5-at H 2in the solution of O-HCl (37%) (10: 1), stir 2 hours, then filter, make solution B, will under solution A and solution B room temperature, merge, stir 18 hours, leach yellow mercury oxide, wash with water, be dried to obtain product 10.2g, yield 76.8%.
The preparation of the bromo-4-hydroxyl-3-of step 1-c 6-nitroquinoline
Add 6.1g (62.7mmol) potassium acetate and 70mL diacetyl oxide to the bromo-2-of 15g (52.3mmol) 5-(2-nitro-vinyl amino)-phenylformic acid, 120 DEG C of return stirrings 2 hours, leach precipitation, be washed till filtrate with acetic acid colourless, then wash with water, be dried to obtain product 7.77g, yield 55.2%.
The preparation of the chloro-3-nitroquinoline of the bromo-4-of step 1-d 6-
The bromo-4-hydroxyl-3-of 2.5g (9.3mmol) 6-nitroquinoline is added in 50mL phosphorus oxychloride to stirring and refluxing 2 hours, mixture is chilled to room temperature, unnecessary phosphorus oxychloride is removed in underpressure distillation, short silicagel column column chromatography for the solid obtaining, the about 600mL of petroleum ether-ethyl acetate for eluent (3: 1), evaporated under reduced pressure obtains product 2.1g, yield 78.5%.
The preparation of step 1-e 4-(the bromo-3-nitroquinoline-4-of 6-base amino) piperidines-1-tertiary butyl carbonic ether
The chloro-3-nitroquinoline of the bromo-4-of 7.6g (26mmol) 6-, 5.6g triethylamine (55mmol) and 7.9g (40mmol) 4-amino piperidine-1-tertiary butyl carbonic ether are together added in 50mL methylene dichloride to stirred overnight at room temperature.Vacuum rotary steam is removed methylene dichloride, and the syrupy shape solid column chromatography purification obtaining, obtains product 8.7g, yield 75%.
The preparation of step 1-f 4-(3-amino-6-bromoquinoline-4-base amino) piperidines-1-tertiary butyl carbonic ether
2.25g (5mmol) 4-(the bromo-3-nitroquinoline-4-of 6-base amino) piperidines-1-tertiary butyl carbonic ether is added to H 2o-CH 3in OH (15: 25) mixed solution, add Zn (1.3g, 20mmol) and NH 4cl (0.4g), is heated to 55 DEG C, stirs 2h, and purifying obtains product 0.7g, yield 34%.
The preparation of step 1-g 4-(the bromo-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether
1.8g (4.3mmol) 4-(3-amino-6-bromoquinoline-4-base amino) piperidines-1-tertiary butyl carbonic ether is added in 50mL methylene dichloride, drip 2 triethylamines, under ice-water bath, drip two phosgene (1.0g, 4.8mmol), stir 2h, add saturated NaHCO 3aqueous solution cancellation, stirs 5 minutes, separatory, and organic phase anhydrous sodium sulfate drying, solvent evaporated obtains product 0.86g, productive rate 46%.
The preparation of step 1-h 4-(the bromo-3-methyl-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether
By 1.78g (4mmol) 4-(the bromo-2-of 8-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 adds in 15mL methylene dichloride and 10%NaOH 50mL is configured to the aqueous solution, stirring at room temperature 2h, with dichloromethane extraction twice, organic phase salt water washing, anhydrous sodium sulfate drying, filter also evaporate to dryness filtrate and obtain 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
By 1.1g (2.4mmol) 4-(the bromo-3-methyl-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) piperidines-1-tertiary butyl carbonic ether is dissolved in 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, be heated to 100 DEG C and stir 2 hours, reaction mixture NaHCO 3saturated aqueous solution cancellation, is extracted with ethyl acetate twice, and organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying, filters and evaporated under reduced pressure, and resistates silicagel column column chromatography purification, obtains product 0.45g, productive rate 38%.
The preparation of step 1-j compound 1
2mL trifluoroacetic acid is added to (455mg under ice bath, 0.9mmol) 4-(8-(6-methoxypyridine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) in the 15mL dichloromethane solution of piperidines-1-tertiary butyl carbonic ether, stir 2h, reaction solution washing, dry organic phase, obtain 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)-2-hydroxyl propionyl] piperidin-4-yl]-2,3- glyoxalidine is the preparation of [4,5-c] quinoline (compound 2) also
By 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-ALPHA-Hydroxypropionic acid (72mg, 0.8mmol), reaction solution stirring at room temperature 17h, reaction solution evaporate to dryness, cross preparation liquid phase and obtain 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
By 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 temperature 48h, reaction solution evaporate to dryness, crosses preparation liquid phase and obtains 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)-2,3-glyoxalidine and the preparation of [4,5-c] quinoline (compound 4)
Compound 1 (130mg 0.33mmol), triethylamine (50mg, 0.5mmol) and methyl-chloroformate (31.1mg, 0.33mmol) are added in 10mL methylene dichloride, ice bath stirs 2h, reaction solution evaporate to dryness, crosses preparation liquid phase and obtains 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)-2,3-glyoxalidine also the preparation of [4,5-c] quinoline (compound 5)
Compound 1 (130mg 0.33mmol), triethylamine (50mg, 0.5mmol) and Acetyl Chloride 98Min. (26mg, 0.33mmol) are added in 10mL methylene dichloride, ice bath stirs 2h, reaction solution evaporate to dryness, crosses preparation liquid phase and obtains 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]-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 6) also
Preparation method is with reference to embodiment 1-e, throw the chloro-3-nitroquinoline of the bromo-4-of 2.88g (10mmol) 6-and 2.49g (10mmol) 5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-PA, 5mL triethylamine, obtains product 3.29g, productive rate 65.8%.
The bromo-3-methyl-2-of step 6-f to 6-h 8-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2,3-glyoxalidine is the preparation of [4,5-c] quinoline also
Preparation method, with reference to embodiment step 1-f to 1-h, throws the bromo-4-[5-of 3.5g (6.96mmol) 6-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-amino]-3-nitroquinoline, obtain product 1.14g, overall yield 32.1%.
Step 6-i preparation method is with reference to embodiment 1-i
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]-2,3-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, obtain 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)-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 7) also
The preparation of the bromo-4-of step 7-e 6-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-3-nitroquinoline
Preparation method is with reference to embodiment step 1-e, throw the chloro-3-nitroquinoline of the bromo-4-of 2.88g (10mmol) 6-and 1.87g (10mmo1) 3,5-dimethyl-4-hydroxyl-oxethyl-1-aminocyclohexane, 5mL triethylamine, obtain product 2.82g, productive rate 64.4%.
The bromo-3-methyl-2-of step 7-f to 7-h 8-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2,3-glyoxalidine is the preparation of [4,5-c] quinoline also
Preparation method, with reference to embodiment step 1-f to 1-h, throws the bromo-4-of 3.1g (6.96mmol) 6-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-3-nitroquinoline, obtains product 1.43g, overall yield 45.9%.
The preparation of step 7-i compound 7
Preparation method is with reference to embodiment step 1-i, throw the bromo-3-methyl-2-of 89mg (0.2mmol) 8-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2,3-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, obtain 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)-2-hydroxyl propionyl] piperidin-4-yl]-23-bis- the preparation of hydrogen imidazo [4,5-c] quinoline (compound 8)
Can make compound 8 with reference to embodiment 1 and 2.
Preparation method is with reference to embodiment 1-i; throw the bromo-3-methyl-2-of 86mg (0.2mmol) 8-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline; 41mg (0.3mmol) 2-picoline-5-boric acid; obtain 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)-2,3-glyoxalidine and the preparation of [4,5-c] quinoline (compound 9)
Can make compound 9 with reference to embodiment 1 and 2.
Preparation method is with reference to embodiment 1-i; throw 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; obtain 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)-2,3-glyoxalidine also the preparation of [4,5-c] quinoline (compound 10)
Can make compound 10 with reference to embodiment 1 and 2.
Preparation method is with reference to embodiment 1-i, throw 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, obtain 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)-2,3-glyoxalidine also the preparation of [4,5-c] quinoline (compound 11)
Can make compound 11 with reference to embodiment 1 and 2.
Preparation method is with reference to embodiment 1-i; throw 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; obtain 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)-2,3-glyoxalidine is [4,5-c] quinoline also the preparation of (compound 12)
Can make compound 12 with reference to embodiment 1.
Preparation method is with reference to embodiment 1-j, throw 4.74g (10mmol) 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-tertbutyloxycarbonyl-piperidin-4-yl)-2,3-glyoxalidine is [4,5-c] quinoline also, obtain 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]-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 13) also
Can make compound 13 with reference to embodiment 6.
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]-2,3-glyoxalidine also [4,5-c] quinoline, 41mg (0.3mmol) 2-picoline-5-boric acid, obtain 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)-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 14) also
Can make compound 14 with reference to embodiment 7.
Preparation method is with reference to embodiment 1-i, throw the bromo-3-methyl-2-of 81mg (0.2mmol) 8-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, obtains 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)-2-hydroxyl propionyl] piperidines -4-yl]-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 15) also
Can make compound 15 with reference to embodiment 1 and 2.
By the bromo-3-methyl-2-of 86mg (0.2mmol) 8-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] quinoline is dissolved in 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, be heated to 100 DEG C and stir 1 hour, reaction mixture NaHCO 3saturated aqueous solution cancellation, is extracted with ethyl acetate twice, and organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying, filter and evaporated under reduced pressure resistates silicagel column column chromatography purification, obtain white solid, then this solid is dissolved in to 10mL methyl alcohol, add 50mg Pd/C, 1 formic acid, passes into hydrogen, stirring at room temperature 5h, filter and collect filtrate, evaporated under reduced pressure, obtains 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)-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 16) also
Can make compound 16 with reference to embodiment 1 and 2.
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; 3-glyoxalidine also [4; 5-c] quinoline; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, obtain 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.
Preparation method is with reference to embodiment 15, throw 84mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2,3-glyoxalidine also [4,5-c] quinoline, 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid, obtain 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-bis- the preparation of hydrogen imidazo [4,5-c] quinoline (compound 18)
Can make compound 18 with reference to embodiment 1 and 2.
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; 3-glyoxalidine also [4; 5-c] quinoline; 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-boric acid, obtain 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)-2,3-glyoxalidine is also the preparation of [4,5-c] quinoline (compound 19)
Can make compound 19 with reference to embodiment 1 and 2.
Preparation method is with reference to embodiment 15, throw 92mg (0.2mmol) 8-bromo-3-methyl-2-oxo-1-(N-tertbutyloxycarbonyl-piperidin-4-yl)-2,3-glyoxalidine also [4,5-c] quinoline, 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid, obtain white solid intermediate product 88mg, productive rate 88.6%.This intermediate product drops in 5mL methylene dichloride, adds 1mLTFA, stirring at room temperature 1h, and evaporated under reduced pressure solvent, obtains 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]-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 20) also
Can make compound 20 with reference to embodiment 6.
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]-2,3-glyoxalidine also [4,5-c] quinoline, 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid, obtain 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)-2,3-glyoxalidine is the preparation of [4,5-c] quinoline (compound 21) also
Can make compound 21 with reference to embodiment 7.
Preparation method is with reference to embodiment 15, throw the bromo-3-methyl-2-of 90mg (0.2mmol) 8-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2,3-glyoxalidine also [4,5-c] quinoline, 75.9mg (0.3mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid, obtain 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) piperidin-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo the preparation of [4,5-c] quinoline-2 (3H)-one (compound 22)
By 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) and Pfansteihl (250mg, 2.8mmol) add in 20mL methylene dichloride, reaction solution stirring at room temperature 17h, reaction solution evaporate to dryness, crosses preparation liquid phase and obtains 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) piperidin-1-yl) preparation of ethanamide (compound 23)
By compound 1 (130mg, 0.33mmol), triethylamine 0.3mL, 2-iodo-acid amide (1.84g 10mmol) joins in 20mL acetonitrile, is heated to reflux, and stirs 2h, react the mixed solution extraction of complete water and methylene dichloride, dry organic phase, crosses preparation liquid phase and obtains 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) 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)-one (compound 24) also
By 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) with 2-methyl-2 hydroxy propanoic acid (67.6mg, 0.65mmol) add in 20mL methylene dichloride, reaction solution stirring at room temperature 48h, reaction solution evaporate to dryness, cross preparation liquid phase and obtain 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) cyclohexyl) preparation of propionic acid amide (compound 25)
Step a-d is with embodiment step 1-a to 1-d.
The preparation of step 25-e 4-(the bromo-3-nitroquinoline-4-of 6-base amino) cyclohexyl tertiary butyl carbonic ether
By the chloro-3-nitroquinoline of bromo-6-4-(6.4g, 22.5mmol), triethylamine (6.6g, 66mmol) with 4-aminocyclohexyl tertiary butyl carbonic ether (6.4g, 30mmol) add in 50mL methylene dichloride, stirring at room temperature 15 hours, reaction solution is spin-dried for, and crosses silicagel column purifying and obtains product 7.8g, productive rate: 74%.
The preparation of step 25-f 4-(3-amino-6-bromoquinoline-4-base amino) cyclohexyl tertiary butyl carbonic ether
4-(the bromo-3-nitroquinoline-4-of 6-base amino) cyclohexyl tertiary butyl carbonic ether (7.8g, 16.8mmol), zinc powder (4.36g, 67.2mmol), ammonium chloride (3.5g, 67mmol) are joined to H 2o-CH 3in the solution of OH (50: 150), be warming up to 75C, stir 2h, reaction solution is extracted with ethyl acetate, and washes with water, and dry, evaporate to dryness, purifies and obtain product 2.9g with silicagel column, productive rate: 40%.
The preparation of step 25-g 4-(the bromo-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether
By 4-(3-amino-6-bromoquinoline-4-base amino) cyclohexyl tertiary butyl carbonic ether (2.9g, 6.6mmol) be dissolved in 60mL methylene dichloride under ice bath, in 40 minutes, be added dropwise to 30mL triphosgene (2.96g, in dichloromethane solution 10mmol), control the stable 2h of stirring, use saturated NaHCO 3solution cancellation, washes with water, and organic layer is dry, and evaporate to dryness is crossed silicagel column purifying and obtained product 2.4g, yield: 80%.
The preparation of step 25-h 4-(the bromo-3-methyl-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether
By 4-(the bromo-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether (2.4g, dichloromethane solution 20mL 5.3mmol) adds in the 10%NaOH solution that contains methyl iodide (0.76g, 5.3mmol), tetrabutyl iodate amine 500mg, stirs 2h, with the mixed solution extraction of methylene dichloride and water, organic layer is dry, crosses silicagel column purifying and obtains 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
By 2-methoxyl group-5-pyridine boric acid (1.4g, 3mmol), Pd 2(dba) 3140mg and 4-(the bromo-3-methyl-2-of 8-oxo-2,3-dihydro-1H-imidazo [4,5-c] quinoline-1-yl) cyclohexyl tertiary butyl carbonic ether (0.6g, 3mmol) adds the NaCO of 15mL DMF and 10mL 1M 3in solution, under nitrogen protection, be warming up to 100 DEG C, stir 2h, react the mixed solution extraction of complete water and ethyl acetate, separate organic layer, dry, cross silicagel column purifying and obtain 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)-one
By 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 (0.6g, 1.2mmol) be dissolved in 15mL dichloromethane solution, add 2mL trifluoroacetic acid, stir 2h, reaction solution evaporate to dryness obtains crude product 0.2g, yield 70%.
The preparation of step 25-k compound 25
By 1-(4-aminocyclohexyl)-8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid H-imidazo [4,5-c] quinoline-2 (3H)-one (200mg, 0.5mmol), I-hydroxybenzotriazole (200mg, 2.2mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (230mmg, 1.2mmol), triethylamine (360mg) and Pfansteihl (72mg, 0.8mmol), reaction solution stirring at room temperature 17h, reaction solution evaporate to dryness, cross preparation liquid phase and obtain 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 be prepared as follows compound:
formula (I-1) formula (I-2)
formula (I-3)
Substituent R in above-mentioned formula (I-1), (I-2), (I-3) 1, be respectively following group:
Table 4
formula (I-4) formula (I-5)
formula (I-6) formula (I-7)
formula (I-8) formula (I-9)
Substituent R in above-mentioned formula (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) 1, be respectively following group:
Table 5

Claims (4)

1. compound as described below or its pharmacy acceptable salt, described compound is selected from:
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2,3-glyoxalidine is [4,5-c] quinoline also,
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2,3-glyoxalidine is [4,5-c] quinoline also,
2. contain the pharmaceutical preparation of compound claimed in claim 1 or its pharmacy acceptable salt, it is characterized in that comprising one or more pharmaceutical carriers.
3. contain the pharmaceutical composition of compound claimed in claim 1 or its pharmacy acceptable salt, it is characterized in that comprising one or more antineoplastic agents and immunosuppressor, described antineoplastic agent and immunosuppressor are selected from metabolic antagonist, growth factor receptor inhibitors, antibody, mitotic inhibitor, antitumor hormones, alkylating agent class, metal platinum class, topoisomerase enzyme inhibitor, immunosuppression class
Described metabolic antagonist, is selected from capecitabine, gemcitabine, pemetrexed disodium; Described growth factor receptor inhibitors, is selected from pazopanib, imatinib, erlotinib, lapatinibditosylate, Gefitinib, ZD6474; Described antibody, is selected from Trastuzumab, rhuMAb-VEGF; Described mitotic inhibitor, is selected from taxol, vinorelbine, docetaxel, Dx; Described antitumor hormones, is selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; Described alkylating agent class, is selected from endoxan, carmustine; Described metal platinum class, is selected from carboplatin, cis-platinum, oxaliplatin; Described topoisomerase enzyme inhibitor is selected from Topotecan; Described immunosuppression class, is selected from everolimus, sirolimus, special cancer suitable.
4. compound claimed in claim 1 or its pharmacy acceptable salt treat and/or prevent the purposes in the medicine of proliferative disease in preparation, described proliferative disease comprises cancer and non-Cancerous disease, described cancer is selected from lung cancer, bladder cancer, cancer of the stomach, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, osteocarcinoma, skin carcinoma, the cancer of the brain, colorectal carcinoma, carcinoma of testis, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma, non-Cancerous disease is selected from skin or prostatic hyperplasia of prostate.
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WO2017076898A1 (en) * 2015-11-05 2017-05-11 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer

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WO2023143282A1 (en) * 2022-01-26 2023-08-03 正大天晴药业集团股份有限公司 Hydrazino group-containing compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1655788A (en) * 2002-05-21 2005-08-17 诺瓦提斯公司 1H-imidazo[4,5-c]quinoline derivatives in the treatment of protein kinase dependent diseases
CN101495477A (en) * 2005-05-20 2009-07-29 诺瓦提斯公司 Imidazoquinolines as lipid kinase inhibitors
CN101616672A (en) * 2007-02-20 2009-12-30 诺瓦提斯公司 Imidazoquinolines as lipid kinase and mTOR double inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1655788A (en) * 2002-05-21 2005-08-17 诺瓦提斯公司 1H-imidazo[4,5-c]quinoline derivatives in the treatment of protein kinase dependent diseases
CN101495477A (en) * 2005-05-20 2009-07-29 诺瓦提斯公司 Imidazoquinolines as lipid kinase inhibitors
CN101616672A (en) * 2007-02-20 2009-12-30 诺瓦提斯公司 Imidazoquinolines as lipid kinase and mTOR double inhibitor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017076898A1 (en) * 2015-11-05 2017-05-11 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer

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