CN102382128A - Three-ring fused PI3K and mTOR dual inhibitor - Google Patents

Three-ring fused PI3K and mTOR dual inhibitor Download PDF

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CN102382128A
CN102382128A CN2011102592433A CN201110259243A CN102382128A CN 102382128 A CN102382128 A CN 102382128A CN 2011102592433 A CN2011102592433 A CN 2011102592433A CN 201110259243 A CN201110259243 A CN 201110259243A CN 102382128 A CN102382128 A CN 102382128A
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pyridine
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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 medicine and specifically relates to a three-ring fused PI3K and mTOR dual inhibitor, its pharmaceutically acceptable salt or stereoisomer shown by the general formula (I), in which R1, R2, R3, R4 and X are defined as in the instruction. The invention also relates to preparation methods of the compounds, pharmaceutical preparations containing the compounds, combinations containing the compounds and applications of the compounds in the preparation of drugs for treating and/or preventing proliferative diseases.

Description

Three and the ring PI3K and mTOR double inhibitor
1, technical field
The invention belongs to medical technical field; Be specifically related to three and the ring 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 contains these compound compositions, 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 BSA00000568042500021
Wherein
X is O, S, or NH;
R 1Be hydrogen, or be not substituted or by at least one R 5aSubstituted C 1-6Alkyl, C 3-8Naphthenic base, C 3-8Thiazolinyl, C 3-8Alkynyl, aryl, 3-14 unit heterocyclic radical, 6-12 unit volution base;
R 2Be hydrogen, or be not substituted or by at least one R 5bSubstituted C 1-6Alkyl, C 3-8Naphthenic base, C 2-8Thiazolinyl, C 2-8Alkynyl, aryl, 3-14 unit heterocyclic radical;
R 3Be hydrogen, hydroxyl, carboxyl, cyanic acid ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nS (O) mR 7,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 4Be hydrogen ,-(CH 2) nS (O) mR 7, or be not substituted or by at least one R 5cSubstituted C 1-6Alkyl;
R 5a, R 5b, R 5cIndependently be hydroxyl respectively, halogen, cyanic acid, carboxyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nS (O) mR 7,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 6aAnd R 6bBe hydrogen independently respectively, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, heterocyclic radical;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 8Be 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 9aR 9b,-(CH 2) nC (O) R 10,-(CH 2) nC (O) NR 9aR 9b,-(CH 2) nS (O) mR 10,-(CH 2) nS (O) mNR 9aR 9b,-(CH 2) nNR 9aS (O) mR 10,-(CH 2) nOC (O) R 10,-(CH 2) nC (O) OR 11,-(CH 2) nNR 9aC (O) R 10, or-(CH 2) nNR 9aC (O) NR 9aR 9b
R 9aAnd R 9bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 3-14 unit heterocyclic radical;
R 10Be 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 5aSubstituted C 3-8Naphthenic base, aryl, the single heterocyclic radical of 5-6 unit;
R 2For not being substituted or by at least one R 5bSubstituted aryl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3Be hydrogen ,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 4Be hydrogen, or be not substituted or by at least one R 5cSubstituted C 1-6Alkyl;
R 5a, R 5b, R 5cIndependently be hydroxyl respectively, halogen ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nS (O) mR 7,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit;
R 6aAnd R 6bBe hydrogen independently respectively, or be not substituted or by at least one R 8Substituted C 1-6Alkyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C1-6 alkyl, C1-6 alkoxyl group, C3-8 naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit;
R 8Be hydroxyl, halogen, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit, or-(CH 2) nNR 9aR 9b
R 9aAnd R 9bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, phenyl, or the single heterocyclic radical of 5-6 unit;
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 5aSubstituted C 5-7Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit;
R 2For not being substituted or by at least one R 5bSubstituted phenyl, naphthyl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3Be hydrogen;
R 4Be hydrogen, or C 1-6Alkyl;
R 5aBe hydroxyl, halogen ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, the single heterocyclic radical of 5-6 unit, C 5-7Naphthenic base, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 5bBe hydroxyl, halogen ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 6aAnd R 6bIndependently be hydrogen respectively, or C 1-6Alkyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 8Be hydroxyl, halogen, cyanic acid, trifluoromethyl, or-(CH 2) nNR 9aR 9b
R 9aAnd R 9bBe respectively hydrogen, or C 1-6Alkyl;
N is 0 or 1.
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 5aSubstituted cyclopentyl, cyclohexyl, phenyl, piperidyl, piperazinyl, imidazolidyl, pyrazolidyl, tetrahydrofuran base, morpholinyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, pyrryl;
R 2For not being substituted or by at least one R 5bSubstituted phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, quinazolyl, indyl, Pyrazolopyridine base, benzotriazole base;
R 3Be hydrogen;
R 4Be hydrogen, or C 1-4Alkyl;
R 5aBe hydroxyl, halogen, trifluoromethyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, piperazinyl, piperidyl, imidazolyl, pyrazolyl, triazolyl, cyclopentyl, cyclohexyl, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 5bBe hydroxyl, halogen, trifluoromethyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 6aAnd R 6bIndependently be hydrogen respectively, or C 1-4Alkyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 8Be hydroxyl, cyanic acid, trifluoromethyl, or-(CH 2) nNR 9aR 9b
R 9aAnd R 9bBe respectively hydrogen, or C 1-4Alkyl;
N is 0 or 1.
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 5aSubstituted cyclopentyl, cyclohexyl, phenyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, pyrryl;
R 2For not being substituted or by at least one R 5bSubstituted phenyl, pyridyl, pyrimidyl, indazolyl, quinolyl, quinazolyl, indyl, Pyrazolopyridine base;
R 3Be hydrogen;
R 4Be hydrogen, methyl, or ethyl;
R 5aBe hydroxyl, fluorine, chlorine, trifluoromethyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, piperazinyl, piperidyl, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 5bBe hydroxyl, fluorine, chlorine, trifluoromethyl ,-NR 6aR 6b,-C (O) R 7,-OC (O) R 7,-C (O) OR 7,-NR 6aC (O) R 7, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 6aAnd R 6bIndependently be hydrogen respectively, methyl, or ethyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 8Be hydroxyl, cyanic acid, trifluoromethyl, or-NR 9aR 9b
R 9aAnd R 9bBe respectively hydrogen, methyl, or ethyl;
N is 0 or 1.
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 5aSubstituted cyclopentyl, cyclohexyl, phenyl, piperidyl, pyridyl, pyrimidyl;
R 2For not being substituted or by 1～3 R 5bSubstituted phenyl, pyridyl, pyrimidyl, indazolyl, indyl, Pyrazolopyridine base;
R 3Be hydrogen;
R 4Be hydrogen, methyl, or ethyl;
R 5aBe hydroxyl, fluorine, chlorine, trifluoromethyl ,-C (O) R 7,-C (O) NR 6aR 6b,-OC (O) R 7,-C (O) OR 7,-NR 6aC (O) R 7,-NR 6aC (O) NR 6aR 6b, piperazinyl, or be not substituted or by 1～3 R 8Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 5bBe hydroxyl, fluorine, chlorine, trifluoromethyl, or be not substituted or by 1～3 R 8Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 6aAnd R 6bIndependent respectively is hydrogen, methyl, or ethyl;
R 7Be hydrogen, or be not substituted or by 1～3 R Russia 8Substituted C 1-4Alkyl;
R 8Be hydroxyl, cyanic acid, or trifluoromethyl;
N is 0 or 1.
Table 1 part of compounds of the present invention:
Figure BSA00000568042500061
Figure BSA00000568042500071
Figure BSA00000568042500081
Figure BSA00000568042500091
Figure BSA00000568042500101
Figure BSA00000568042500111
" 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 " refer to the specific examples that contains 1～4 carbon atom in the above-mentioned instance.
" C of the present invention 3-8Naphthenic base " refer to contain the cyclic alkyl of 3～8 carbon atoms, like Trimetylene base, tetramethylene base, pentamethylene base, cyclohexyl, suberane, cyclooctane etc." C of the present invention 5-7Naphthenic base " refer to the specific examples that contains 5～7 carbon atoms in the above-mentioned instance.
" C of the present invention 2-8Thiazolinyl " be meant that the carbonatoms that contains two keys is 2～8 straight or branched or cyclic thiazolinyl; 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 atoms in the above-mentioned instance.
" C of the present invention 2-8Alkynyl " be meant and contain the alkynyl that the triple-linked carbonatoms is 2～8 straight or branched, 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 atoms 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 " refer to the specific examples that contains 1～4 carbon atom in the above-mentioned instance.
" 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 ".
" 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 BSA00000568042500131
Figure BSA00000568042500132
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 BSA00000568042500133
Figure BSA00000568042500134
Of the present invention " by at least one R 5aSubstituted ", " by at least one R 5bSubstituted ", " by at least one R 5c, by at least one R 8Substituted ", " 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 to following method.
General formula (I) compound, when X is O,
Figure BSA00000568042500141
(1) being prepared in the dry single port bottle of midbody 1 joins raw material 2 in the ethanolic soln of raw material 1, is heated to backflow, and reaction finishes, and revolves dried solvent, and column chromatography gets midbody 1.
(2) preparation of midbody 2 is dissolved in midbody 1 in alcohol and the THF, adding sodium hydroxide (or Lithium Hydroxide MonoHydrate) solution, and stirring at room is reacted and is finished, and regulates pH, and filtration gets bullion, uses a spot of pure wash solids then, gets midbody 2.
(3) in the preparation exsiccant reaction flask of midbody 3, adding midbody 2, zinc powder, ammonium chloride is dissolved in methyl alcohol and tetrahydrofuran solution, stirs under the room temperature, and reaction finishes, suction filtration, methanol wash, filtrating concentrates, and gets midbody 3.
(4) preparation of midbody 4 is suspended in midbody 3 in the toluene, adds tertiary amine (like triethylamine), and stirring at room drips DPPA to system, heating reflux reaction, and cooling concentrates, and column chromatography gets midbody 4.
(5) preparation of midbody 5 is with midbody 4; Phase-transfer catalyst such as Tetrabutyl amonium bromide and sodium hydroxide (about 1.2 equivalents) are dissolved in the mixed solvent of methylene dichloride and water, and ice bath adds raw material 3 (about 1.2 equivalents), stirred overnight at room temperature down; Concentrating under reduced pressure, column chromatography get midbody 5.
(6) preparation of midbody 6 with raw material 3 (about 1.3 equivalents) through with SOCl 2Perhaps the oxalyl chloride effect is converted into acyl chlorides, adds midbody 5 then and is dissolved in the pyridine, and room temperature or heating reaction down after the end, concentrates, and column chromatography gets midbody 6.
(7) preparation of formula (I) compound joins midbody 6 and Lawesson ' s reagent among the DME, refluxes.Reaction finishes, and cooling concentrates, and column chromatography gets formula (I) compound.
General formula (I) compound, when X is S or NH, can be with reference to method for preparing.
R in the reaction equation 1, R 2, R 3, R 4With X such as preamble definition, the Y in the raw material 4 is OH, halogen etc.Work as R 4During for hydrogen, can omit the preparation of midbody 5.
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 steric 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 ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.
The 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
Trial-product
The compounds of this invention, self-control, its chemical name and structural formula are seen the preparation embodiment of each compound;
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 3 times of kinase tracer of 5 μ L;
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
Figure BSA00000568042500171
+++expression IC 50Be 0～300nM, ++ expression IC 50Be 0.3-3 μ M ,+expression IC 50Be＞3 μ M
Experiment conclusion
Can find out that by table 1 The compounds of this invention has the good in vitro the enzyme activity.
4, embodiment
Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.
Embodiment 12-(6-methoxypyridine-3-yl)-6-methyl-8-(piperidin-4-yl)-6H-imidazo [4,5-d] thiazole is [5,4-b] pyrrole also The preparation of pyridine-7 (8H)-ketone (compound 1)
Figure BSA00000568042500181
The preparation of (1) 4,6-dihydroxyl Nikithan
Figure BSA00000568042500182
With 3-keto-glutaric acid diethyl ester (10.0g, 49.5mmol), diacetyl oxide (10.11g; 99mmol) and triethyl orthoformate (7.34g, mixing solutions 49.5mmol) is at 120 ℃ of following heating 2h, concentrating under reduced pressure; Under ice bath, in resistates, add the ammoniacal liquor of 20mL 25%, stir half a hour, suction filtration; Obtain faint yellow solid 6.5g, yield 71.7%.
The preparation of (2) 4,6-dihydroxyl-5-nitro Nikithan
Figure BSA00000568042500183
With 4, (6.5g 35.5mmol) is dissolved in 25mL acetate to 6-dihydroxyl Nikithan, is heated to 60 ℃; (3.44g 35.5mmol), is warming up to 90 ℃ to the nitric acid of dropping 65% then, reacts 20 hours; Be cooled to 0 ℃, filter, obtain faint yellow solid 4.8g, yield 59.2%.
The preparation of (3) 4,6-two chloro-5-nitro Nikithans
Figure BSA00000568042500191
With 4, and 6-dihydroxyl-5-nitro Nikithan (4.8g, 21.0mmol) and N, accelerine (3mL) adds in the POCl3 (35mL); Reaction backflow 5h, cooling, decompression steams POCl3, and residuum is poured in the frozen water; Transfer pH ≈ 8, use dichloromethane extraction then, anhydrous sodium sulfate drying concentrates; Silica gel column chromatography (sherwood oil: ETHYLE ACETATE=8: 1), obtain faint yellow solid 3.5g, yield 62.9%.
(4) 4-(preparation of 1-((tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-chloro-5-nitro Nikithan
Figure BSA00000568042500192
With 4, (3.5g is 13.2mmol) with 4-amino piperidine-1-carboxylic acid tert-butyl ester (2.65g for 6-two chloro-5-nitro Nikithans; 13.2mmol) be dissolved in the ethanol (25mL), in system, add triethylamine (2.68g, 26.5mmol); Room temperature reaction 20h, concentrating under reduced pressure, silica gel column chromatography (sherwood oil: ETHYLE ACETATE=3: 1); Faint yellow solid 3.9g, yield 68.9%.
(5) 4-(preparation of 1-((tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-chloro-5-nitro nicotinic acid
Figure BSA00000568042500193
With 4-(1-((tertbutyloxycarbonyl) piperidin-4-yl amino)-6-chloro-5-nitro Nikithan (3.9g, 9.1mmol), LiOHH 2(1.0g 23.8mmol) joins THF (25mL) and H to O 2In the mixing solutions of O (25mL), stirred 15 hours under the room temperature, THF is removed in decompression, adds 50mL water, transfers pH to 6 with 2N HCl, uses dichloromethane extraction, the saturated common salt washing, and anhydrous sodium sulfate drying concentrates, and obtains the 3.3g faint yellow solid, yield 90.1%.
(6) preparation of 5-amino-4-(1-(tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-chlorine apellagrin
Figure BSA00000568042500194
With 4-(1-((tertbutyloxycarbonyl) piperidin-4-yl amino)-6-chloro-5-nitro nicotinic acid (3.0g, 7.5mmol), zinc powder (4.9g; 75mmol) and ammonia chloride (4.0g 75mmol) is dissolved in 20mL methyl alcohol, the 20mL THF, 20 ℃ the reaction 20h; Suction filtration; Revolve driedly, obtain the 2.5g brown solid, productive rate 89.3%.
(7) preparation of 4-(7-amino-6-chloro-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000568042500201
Adding 5-amino-4-(1-(tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-chlorine apellagrin in 40mL toluene (2.2g, 5.9mmol), triethylamine (1.2g; 11.9mmol), DPPA (3.3g, 12.0mmol); 110 ℃ of reaction 4h are until reacting completely concentrating under reduced pressure, silica gel column chromatography (methylene dichloride: methyl alcohol=80: 1); Obtain white solid 1.09g, yield 50.2%.
(8) preparation of 4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000568042500202
With 4-(7-amino-6-chloro-2-oxo-2; 3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester (1.09g, 2.96mmol); Tetrabutyl amonium bromide (0.114g; 0.354mmol) and sodium hydroxide (0.140g 3.50mmol) is dissolved in 20mL methylene dichloride and the 3mL water, and ice bath adds down CH 3I (0.51g, 3.59mmol), stirring at room 15h, concentrating under reduced pressure, silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain white solid 1.01g, yield 89.2%.
(9) preparation of 4-(6-chloro-7-(6-methoxyl group nicotinoyl amido) 3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000568042500203
The preparation of 6-methoxyl group nicotinoyl chlorine: (1.0g 6.5mmol) is dissolved in 25mL SOCl with 6-methoxyl group nicotinic acid 2, 80 ℃ of heating 5h spin off SOCl then 2, obtain the 1.05g white products, yield 93.8%.
With 4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester (1.0g; 2.62mmol), (0.63g 3.67mmol) is dissolved in the 15mL pyridine 6-methoxyl group nicotinoyl chlorine; 80 ℃ of reaction 6h concentrate silica gel column chromatography (methylene dichloride: methyl alcohol=50: 1); Obtain white solid 1.08g, yield 79.8%.
(10) 4-(2-(6-methoxypyridine-3-the yl)-6-methyl-also preparation of [5,4-b] pyridines-8 (7H)-yl) piperidines-1-carboxylic acid tert-butyl ester of 7-oxo-6H-imidazo [4,5-d] thiazole
Figure BSA00000568042500204
With 4-(6-chloro-7-(6-methoxyl group nicotinoyl amido) 3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester (1.0g; 1.93mmol), (1.02g 2.51mmol) is dissolved among the 25mL DME Lawesson reagent; 80 ℃ of reaction 10h concentrate silica gel column chromatography (methylene dichloride: ETHYLE ACETATE=4: 1); Re-crystallizing in ethyl acetate obtains white solid 173mg, yield 18.0%.
(11) 2-(6-methoxypyridine-3-yl)-also preparation of [5,4-b] pyridines-7 (8H)-keto hydrochloride of 6-methyl-8-(piperidin-4-yl)-6H-imidazo [4,5-d] thiazole
Figure BSA00000568042500211
(2-(6-methoxypyridine-3-yl)-6-methyl-7-oxo-6H-imidazo [4,5-d] thiazole is [5,4-b] pyridines-8 (7H)-yl) piperidines-1-carboxylic acid tert-butyl ester (100mg also with 4-; 0.201mmol) be dissolved in the methylene dichloride (10mL), logical hydrogen chloride gas half a hour in system, separate out solid; Suction filtration; With methylene dichloride, ether washing, recrystallizing methanol obtains 34mg solid (hydrochloride), yield 39.1% successively.
Molecular formula: C 19H 20N 6O 2S molecular weight: 396.14 mass spectrums (M+H): 397.1
1H-NMR(d 6-DMSO，400MHz)δ9.49-9.39(1H，m)，9.10(1H，d)，8.54(2H，s)，8.50(1H，dd)，7.04(1H，d)，5.40-5.25(1H，m)，3.98(3H，s)，3.53-3.44(2H，m)，3.46(3H，s)，3.31-3.15(2H，m)，2.90-2.72(2H，m)，2.16-2.03(2H，m).
Embodiment 2 (R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-2-(6-methoxypyridine-3-yl)-6-methyl-6H-imidazo [4,5-d] thiazole is the preparation of [5,4-b] pyridines-7 (8H)-ketone (compound 2) also
Figure BSA00000568042500212
With 2-(6-methoxypyridine-3-yl)-6-methyl-8-(piperidin-4-yl)-6H-imidazo [4,5-d] thiazole [5,4-b] pyridines-7 (8H)-keto hydrochloride (compound 1) (200mg also; 0.46mmol) be dissolved in methylene dichloride (5mL), add respectively triethylamine (93mg, 0.92mmol); (R)-lactic acid (52mg, 0.58mmol), the 1-hydroxy benzo triazole (76mg, 0.560mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (142mg; 0.74mmol), reaction was at room temperature stirred 2 hours, and (methylene dichloride: methyl alcohol=12: 1) demonstration reacts completely TLC; Reaction solution is used saturated sodium carbonate solution, water, saturated common salt water washing successively, and organic layer is used anhydrous sodium sulfate drying, concentrates; The preparative chromatograph separation and purification obtains the 98mg white solid, yield 45.7%.
Molecular formula: C 22H 24N 6O 4S molecular weight: 468.16 mass spectrums (M+H): 469.2
1H-NMR(d 6-DMSO，400MHz)δ8.86(1H，s)，8.53(1H，s)，8.38-8.24(1H，m)，7.02(1H，dd)，5.76(1H，s)，5.11-4.85(2H，m)，4.74-4.43(2H，d)，4.31-4.10(1H，m)，3.96(3H，s)，3.48(3H，s)，2.93-2.59(3H，m)，1.92-1.69(2H，m)，1.25(3H，d).
Embodiment 32-(6-methoxypyridine-3-yl)-6-methyl-8-[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl]-6H-imidazo [4,5-d] thiazole is the preparation of [5,4-b] pyridines-7 (8H)-ketone (compound 3) also
Figure BSA00000568042500221
(1) preparation of 4-(4-(2-chloro-5-(ethoxy carbonyl)-3-nitropyridine-4-base is amino)-2-(trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester
With 4, and 6-two chloro-5-nitro Nikithans ((3) among the embodiment 1 are seen in preparation) (3.5g, 13.2mmol) and 4-(4-amino-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (4.56g; 13.2mmol) be dissolved in the ethanol (25mL), in system, add triethylamine (2.68g, 26.5mmol); Room temperature reaction 18h separates out solid, further cooling; Suction filtration gets faint yellow solid 5.4g, yield 71.2%.
(2) preparation of 4-(4-(4-(tertbutyloxycarbonyl) piperazine-1-yl)-3-(trifluoromethyl) anilino)-6-chloro-5-nitro nicotinic acid
Figure BSA00000568042500223
With 4-(4-(2-chloro-5-(ethoxy carbonyl)-3-nitropyridine-4-base amino)-2-(trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester (4.0g, 6.97mmol), LiOHH 2(0.878g 20.9mmol) joins THF (25mL) and H to O 2In the mixing solutions of O (25mL), stirred 15 hours under the room temperature, THF is removed in decompression, adds 50mL water, transfers pH to 6 with 2N HCl, uses dichloromethane extraction, the saturated common salt washing, and anhydrous sodium sulfate drying concentrates, and obtains the 3.6g faint yellow solid, yield 94.7%.
(3) preparation of 5-amino-4-(4-(4-(tertbutyloxycarbonyl) piperazine-1-yl)-3-(trifluoromethyl) anilino)-6-chlorine apellagrin
Figure BSA00000568042500231
With 4-(4-(4-(tertbutyloxycarbonyl) piperazine-1-yl)-3-(trifluoromethyl) anilino)-6-chloro-5-nitro nicotinic acid (3.6g, 6.6mmol), zinc powder (4.32g; 66mmol) and ammonium chloride (3.53g 66mmol) is dissolved in 25mL methyl alcohol, the 25mL THF, 20 ℃ the reaction 19h; Suction filtration; Revolve driedly, obtain the 3.06g brown solid, productive rate 89.8%.
(4) preparation of 4-(4-(7-amino-6-chloro-2-oxo-2,3-dihydro-1H-imidazoles [4,5-c] pyridine-1-yl)-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
Figure BSA00000568042500232
Adding 5-amino-4-(4-(4-(tertbutyloxycarbonyl) piperazine-1-yl)-3-(trifluoromethyl) anilino)-6-chlorine apellagrin in 40mL toluene (3.06g, 5.93mmol), triethylamine (1.2g; 11.9mmol), DPPA (3.27g, 11.9mmol); 110 ℃ of reaction 5h are until reacting completely concentrating under reduced pressure, silica gel column chromatography (methylene dichloride: methyl alcohol=85: 1); Obtain white solid 1.37g, yield 45.0%.
(5) preparation of 4-(4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazoles [4,5-c] pyridine-1-yl)-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
Figure BSA00000568042500233
With 4-(4-(7-amino-6-chloro-2-oxo-2; 3-dihydro-1H-imidazoles [4,5-c] pyridine-1-yl)-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (1.37g, 2.67mmol); Tetrabutyl amonium bromide (0.114g; 0.354mmol) and sodium hydroxide (0.14g 3.50mmol) is dissolved in 25mL methylene dichloride and the 4mL water, and ice bath adds down CH 3I (0.51g, 3.59mmol), stirring at room 20h, concentrating under reduced pressure, silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1), obtain white solid 1.21g, yield 86.1%.
(6) 4-(preparation of 4-(6-chloro-7-(6-methoxyl group vitamin PP-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl)-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
Figure BSA00000568042500241
With 4-(4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazoles [4,5-c] pyridine-1-yl)-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (1.20g; 2.28mmol), (0.63g 3.67mmol) is dissolved in the 16mL pyridine 6-methoxyl group nicotinoyl chlorine; 80 ℃ of reaction 7h concentrate silica gel column chromatography (methylene dichloride: methyl alcohol=60: 1); Obtain white solid 0.60g, yield 39.9%.
(7) 4-(preparation of 4-(2-(6-methoxypyridine-3-yl)-6-methyl-7-oxo-6H-imidazoles [4,5-d] thiazole is [5,4-b] pyridines-8 (7H)-yl)-2-(trifluoromethyl) phenyl also) piperazine-1-t-butyl formate
Figure BSA00000568042500242
With 4-(4-(6-chloro-7-(6-methoxyl group vitamin PP-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl)-2-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.60g; 0.91mmol), (0.53g 1.31mmol) is dissolved among the 25mLDME Lawesson reagent; 80 ℃ of reaction 14h concentrate silica gel column chromatography (methylene dichloride: ETHYLE ACETATE=8: 1); Obtain white solid 60mg, yield 10.3%.
(8) 2-(6-methoxypyridine-3-yl)-6-methyl-8-(4-piperazine-1-yl)-3-(trifluoromethyl) phenyl)-the also preparation of [5,4-b] pyridines-7 (8H)-keto hydrochloride of 6H-imidazoles [4,5-d] thiazole
With 4-(4-(2-(6-methoxypyridine-3-yl)-6-methyl-7-oxo-6H-imidazoles [4,5-d] thiazole is [5,4-b] pyridines-8 (7H)-yl)-2-(trifluoromethyl) phenyl also) piperazine-1-t-butyl formate (60mg; 0.094mmol) be dissolved in the methylene dichloride (10mL), logical hydrogen chloride gas half a hour in system, separate out solid; Suction filtration; With methylene dichloride, ether washing, obtain 34mg white solid (hydrochloride), yield 62.8% successively.
Molecular formula: C 25H 22F 3N 7O 2S molecular weight: 541.15 mass spectrums (M+H): 542.2
1H-NMR(d 6-DMSO，400MHz)δ8.90(2H，s)，8.69(1H，d)，8.65(1H，s)，8.11(1H，d)，8.05(1H，d)，8.03(1H，d)，7.79(1H，d)，6.97(1H，d)，3.94(3H，s)，3.56(3H，s)，3.32-3.24(4H，m)，3.23-3.16(4H，m).
Embodiment 4 (R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-6-methyl-2-(6-picoline-3-yl)-6H-imidazo [4,5-d] thiazole is the preparation of [5,4-b] pyridines-7 (8H)-ketone (compound 12) also
Figure BSA00000568042500251
(1) preparation of 4-[6-chloro-3-methyl-7-(6-picoline-2-formamido-)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl] piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000568042500252
4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester 764mg (2.0mmol) is thrown in (9) in the concrete operations reference implementation example 1, gets product 0.328g, yield 32.7%.
(2) preparation of 4-[6-methyl-2-(6-picoline-3-yl)-7-oxo-6H-imidazo [4,5-d] thiazole is [5,4-b] pyridines-8 (7H)-yl also] piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000568042500253
(10) in the concrete operations reference implementation example 1; Throw 4-[6-chloro-3-methyl-7-(6-picoline-2-formamido-)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl] piperidines-1-carboxylic acid tert-butyl ester 0.781g (1.56mmol); Get product 0.092g, yield 12.3%.
(3) 6-methyl-2-(6-picoline-3-yl)-also preparation of [5,4-b] pyridines-7 (8H)-keto hydrochloride of 8-(piperidin-4-yl)-6H-imidazo [4,5-d] thiazole
Figure BSA00000568042500261
(11) in the concrete operations reference implementation example 1; Throw 4-[6-methyl-2-(6-picoline-3-yl)-7-oxo-6H-imidazo [4,5-d] thiazole is [5,4-b] pyridines-8 (7H)-yl also] piperidines-1-carboxylic acid tert-butyl ester 0.092g (0.191mmol); Get product 0.068g, yield 85.3%.
(4) (R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-6-methyl-2-(6-picoline-3-yl)-also preparation of [5,4-b] pyridines-7 (8H)-ketone of 6H-imidazo [4,5-d] thiazole
Concrete operations reference implementation example 2 is thrown also [5,4-b] pyridines-7 (8H)-keto hydrochloride 0.068g (0.163mmol) of 6-methyl-2-(6-picoline-3-yl)-8-(piperidin-4-yl)-6H-imidazo [4,5-d] thiazole, gets product 40mg, yield 54.3%.
Molecular formula: C 22H 24N 6O 3S molecular weight: 452.53 mass spectrums (M+H): 453
Embodiment 5 (R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-6-methyl-2-(1H-pyrazolo [3,4-b] pyridine-5-yl)-6H- The also preparation of [5,4-b] pyridines-7 (8H)-ketone (compound 21) of imidazo [4,5-d] thiazole
Figure BSA00000568042500263
(1) preparation of 4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester
4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester 764mg (2.0mmol) is thrown in (9) in the concrete operations reference implementation example 1, gets product 0.971g, yield 75.2%.
(2) preparation of 4-[2-[1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine-5-yl]-6-methyl-7-oxo-6H-imidazo [4,5-d] thiazole is [5,4-b] pyridines-8 (7H)-yl also] piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000568042500272
4-(7-amino-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-yl) piperidines-1-carboxylic acid tert-butyl ester 0.971g (1.50mmol) is thrown in (10) in the concrete operations reference implementation example 1, gets product 0.607g, yield 64.6%.
(3) 6-methyl-8-(piperidin-4-yl)-2-(1H-pyrazolo [3,4-b] pyridine-5-yl)-also preparation of [5,4-b] pyridines-7 (8H)-ketone of 6H-imidazo [4,5-d] thiazole
With 4-[2-[1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine-5-yl]-6-methyl-7-oxo-6H-imidazo [4,5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] piperidines-1-carboxylic acid tert-butyl ester 0.607g (0.969mmol) joins among the 15mL TFA, and stirring at room 3 days is revolved dried solvent; Preparation liquid phase purifying; Get product, get product 0.225g, yield 57.1%.
(4) (R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-6-methyl-2-(1H-pyrazolo [3,4-b] pyridine-5-yl)-also preparation of [5,4-b] pyridines-7 (8H)-ketone of 6H-imidazo [4,5-d] thiazole
Concrete operations reference implementation example 2 is thrown also [5,4-b] pyridines-7 (8H)-ketone 0.225g (0.553mmol) of 6-methyl-8-(piperidin-4-yl)-2-(1H-pyrazolo [3,4-b] pyridine-5-yl)-6H-imidazo [4,5-d] thiazole, gets product 0.115g, yield 43.6%.
Molecular formula: C 22H 22N 8O 3S molecular weight: 478.53 mass spectrums (M+H): 479
With reference to aforesaid method, can also prepare following compound:
Figure BSA00000568042500281
formula; (I-1)
Figure BSA00000568042500282
formula; (I-2)
Figure BSA00000568042500283
formula; (I-3)
Substituent R in above-mentioned formula (I-1), formula (I-2), the formula (I-3) 1, be respectively following group:
Table 3
Figure BSA00000568042500284
Figure BSA00000568042500291
Figure BSA00000568042500292
formula; (I-4) formula; (I-5)
Figure BSA00000568042500294
formula; (I-6)
Figure BSA00000568042500295
formula; (I-7)
Figure BSA00000568042500296
formula; (I-8)
Figure BSA00000568042500297
formula; (I-9)
Substituent R in above-mentioned formula (I-4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), the formula (I-9) 1, be respectively following group:
Table 4
Figure BSA00000568042500298
Figure BSA00000568042500301

Claims (10)

1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Figure FSA00000568042400011
Wherein
X is O, S, or NH;
R 1Be hydrogen, or be not substituted or by at least one R 5aSubstituted C 1-6Alkyl, C 3-8Naphthenic base, C 3-8Thiazolinyl, C 3-8Alkynyl, aryl, 3-14 unit heterocyclic radical, 6-12 unit volution base;
R 2Be hydrogen, or be not substituted or by at least one R 5bSubstituted C 1-6Alkyl, C 3-8Naphthenic base, C 2-8Thiazolinyl, C 2-8Alkynyl, aryl, 3-14 unit heterocyclic radical;
R3 is a hydrogen, hydroxyl, carboxyl, cyanic acid ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nS (O) mR 7,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 4Be hydrogen ,-(CH 2) nS (O) mR 7, or be not substituted or by at least one R 5cSubstituted C 1-6Alkyl;
R 5a, R 5b, R 5cIndependently be hydroxyl respectively, halogen, cyanic acid, carboxyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nS (O) mR 7,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 6aAnd R 6bBe hydrogen independently respectively, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 3-8Naphthenic base, aryl, heterocyclic radical;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, aryl, 3-14 unit heterocyclic radical;
R 8Be 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 9aR 9b,-(CH 2) nC (O) R 10,-(CH 2) nC (O) NR 9aR 9b,-(CH 2) nS (O) mR 10,-(CH 2) nS (O) mNR 9aR 9b,-(CH 2) nNR 9aS (O) mR 10,-(CH 2) nOC (O) R 10,-(CH 2) nC (O) OR 11,-(CH 2) nNR 9aC (O) R 10, or-(CH 2) nNR 9aC (O) NR 9aR 9b
R 9aAnd R 9bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, aryl, or 3-14 unit heterocyclic radical;
R 10Be 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 5aSubstituted C 3-8Naphthenic base, aryl, the single heterocyclic radical of 5-6 unit;
R 2For not being substituted or by at least one R 5bSubstituted aryl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3Be hydrogen ,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7, or be not substituted or by the C of at least one halogen, hydroxyl, carboxyl substituted 1-6Alkyl, C 1-6Alkoxyl group;
R 4Be hydrogen, or be not substituted or by at least one R 5cSubstituted C 1-6Alkyl;
R 5a, R 5b, R 5cIndependently be hydroxyl respectively, halogen ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nS (O) mR 7,-(CH 2) nS (O) mNR 6aR 6b,-(CH 2) nNR 6aS (O) mR 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit;
R 6aAnd R 6bBe hydrogen independently respectively, or be not substituted or by at least one R 8Substituted C 1-6Alkyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit;
R 8Be hydroxyl, halogen, cyanic acid, trifluoromethyl, C 1-6Alkyl, C 2-8Thiazolinyl, C 2-8Alkynyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit, or-(CH 2) nNR 9aR 9b
R 9aAnd R 9bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Naphthenic base, phenyl, or the single heterocyclic radical of 5-6 unit;
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 5aSubstituted C 5-7Naphthenic base, phenyl, the single heterocyclic radical of 5-6 unit;
R 2For not being substituted or by at least one R 5bSubstituted phenyl, naphthyl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3Be hydrogen;
R 4Be hydrogen, or C 1-6Alkyl;
R 5aBe hydroxyl, halogen ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, the single heterocyclic radical of 5-6 unit, C 5-7Naphthenic base, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 5bBe hydroxyl, halogen ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 6aAnd R 6bIndependently be hydrogen respectively, or C 1-6Alkyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 8Be hydroxyl, halogen, cyanic acid, trifluoromethyl, or-(CH 2) nNR 9aR 9b
R 9aAnd R 9bBe respectively hydrogen, or C 1-6Alkyl;
N is 0 or 1.
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 5aSubstituted cyclopentyl, cyclohexyl, phenyl, piperidyl, piperazinyl, imidazolidyl, pyrazolidyl, tetrahydrofuran base, morpholinyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, pyrryl;
R 2For not being substituted or by at least one R 5bSubstituted phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, quinazolyl, indyl, Pyrazolopyridine base, benzotriazole base;
R 3Be hydrogen;
R 4Be hydrogen, or C 1-4Alkyl;
R 5aBe hydroxyl, halogen, trifluoromethyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, piperazinyl, piperidyl, imidazolyl, pyrazolyl, triazolyl, cyclopentyl, cyclohexyl, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 5bBe hydroxyl, halogen, trifluoromethyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 6aAnd R 6bIndependently be hydrogen respectively, or C 1-4Alkyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 8Be hydroxyl, cyanic acid, trifluoromethyl, or-(CH 2) nNR 9aR 9b
R 9aAnd R 9bBe respectively hydrogen, or C 1-4Alkyl;
N is 0 or 1.
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 5aSubstituted cyclopentyl, cyclohexyl, phenyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, pyrryl;
R 2For not being substituted or by at least one R 5bSubstituted phenyl, pyridyl, pyrimidyl, indazolyl, quinolyl, quinazolyl, indyl, Pyrazolopyridine base;
R 3Be hydrogen;
R 4Be hydrogen, methyl, or ethyl;
R 5aBe hydroxyl, fluorine, chlorine, trifluoromethyl ,-(CH 2) nNR 6aR 6b,-(CH 2) nC (O) R 7,-(CH 2) nC (O) (CH 2) nNR 6aR 6b,-(CH 2) nOC (O) R 7,-(CH 2) nC (O) OR 7,-(CH 2) nNR 6aC (O) R 7,-(CH 2) nNR 6aC (O) NR 6aR 6b, piperazinyl, piperidyl, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 5bBe hydroxyl, fluorine, chlorine, trifluoromethyl ,-NR 6aR 6b,-C (O) R 7,-OC (O) R 7,-C (O) OR 7,-NR 6aC (O) R 7, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 6aAnd R 6bIndependently be hydrogen respectively, methyl, or ethyl;
R 7Be hydrogen, or be not substituted or by at least one R 8Substituted C 1-6Alkyl, C 1-6Alkoxyl group;
R 8Be hydroxyl, cyanic acid, trifluoromethyl, or-NR 9aR 9b
R 9aAnd R 9bBe respectively hydrogen, methyl, or ethyl;
N is 0 or 1.
6. compound as claimed in claim 5, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by 1～3 R 5aSubstituted cyclopentyl, cyclohexyl, phenyl, piperidyl, pyridyl, pyrimidyl;
R 2For not being substituted or by 1～3 R 5bSubstituted phenyl, pyridyl, pyrimidyl, indazolyl, indyl, Pyrazolopyridine base;
R 3Be hydrogen;
R 4Be hydrogen, methyl, or ethyl;
R 5aBe hydroxyl, fluorine, chlorine, trifluoromethyl ,-C (O) R 7,-C (O) NR 6aR 6b,-OC (O) R 7,-C (O) OR 7,-NR 6aC (O) R 7,-NR 6aC (O) NR 6aR 6b, piperazinyl, or be not substituted or by 1～3 R 8Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 5bBe hydroxyl, fluorine, chlorine, trifluoromethyl, or be not substituted or by 1～3 R 8Substituted C 1-4Alkyl, C 1-4Alkoxyl group;
R 6aAnd R 6bIndependent respectively is hydrogen, methyl, or ethyl;
R 7Be hydrogen, or be not substituted or by 1～3 R 8Substituted C 1-4Alkyl;
R 8Be hydroxyl, cyanic acid, or trifluoromethyl;
N is 0 or 1.
7. compound as claimed in claim 6, its pharmacy acceptable salt or its steric isomer, said compound is selected from:
Figure FSA00000568042400051
2-(6-methoxypyridine-3-yl)-6-methyl-8-(piperidin-4-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400052
(R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-2-(6-methoxypyridine-3-yl)-6-methyl-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400053
2-(6-methoxypyridine-3-yl)-6-methyl-8-[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl]-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400054
2-[4-[2-(6-methoxypyridine-3-yl)-6-methyl-7-oxo-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] phenyl]-2-methyl propionitrile
Figure FSA00000568042400061
8-[1-(2-hydroxyacetyl) piperidin-4-yl]-2-(6-methoxypyridine-3-yl)-6-methyl-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400062
4-[2-(6-methoxypyridine-3-yl)-6-methyl-7-oxo-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] piperidines-1-carboxylate methyl ester
8-(1-ethanoyl piperidin-4-yl)-2-(6-methoxypyridine-3-yl)-6-methyl-8; 8b-dihydro-3aH-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (6H)-ketone
Figure FSA00000568042400064
2-hydroxy-n-[6-[2-(6-methoxypyridine-3-yl)-6-methyl-7-oxo-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl]-4-(trifluoromethyl) pyridin-3-yl] propionic acid amide
8-[4-(2-hydroxyl-oxethyl)-3; The 5-Dimethylcyclohexyl]-2-(6-methoxypyridine-3-yl)-6-methyl-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400072
6-methyl-2-(6-picoline-3-yl)-8-[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl]-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400073
2-methyl-2-[4-[6-methyl-2-(6-picoline-3-yl)-7-oxo-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] phenyl] propionitrile
Figure FSA00000568042400074
(R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-6-methyl-2-(6-picoline-3-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
8-[1-(2-hydroxyacetyl) piperidin-4-yl]-6-methyl-2-(6-picoline-3-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400082
4-[6-methyl-2-(6-picoline-3-yl)-7-oxo-6H-imidazoles [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] piperidines-1-carboxylate methyl ester
Figure FSA00000568042400083
8-(1-ethanoyl piperidin-4-yl)-6-methyl-2-(6-picoline-3-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400084
6-methyl-2-(6-picoline-3-yl)-8-(piperidin-4-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
2-hydroxy-n-[6-[6-methyl-2-(6-picoline-3-yl)-7-oxo-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl]-4-(trifluoromethyl) pyridin-3-yl] propionic acid amide
8-[4-(2-hydroxyl-oxethyl)-3; The 5-Dimethylcyclohexyl]-6-methyl-2-(6-picoline-3-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
6-methyl-8-[4-(piperazine-1-yl)-3-(trifluoromethyl) phenyl]-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400093
2-methyl-2-[4-[6-methyl-7-oxo-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] phenyl] propionitrile
Figure FSA00000568042400094
(R)-8-[1-(2-hydroxyl propionyl group) piperidin-4-yl]-6-methyl-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400101
8-[1-(2-hydroxyacetyl) piperidin-4-yl]-6-methyl-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400102
4-[6-methyl-7-oxo-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl] piperidines-1-carboxylate methyl ester
Figure FSA00000568042400103
8-(1-ethanoyl piperidin-4-yl)-6-methyl-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400104
6-methyl-8-(piperidin-4-yl)-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-7 (8H)-ketone
Figure FSA00000568042400105
2-hydroxy-n-[6-[6-methyl-7-oxo-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole also [5; 4-b] pyridine-8 (7H)-yl]-4-(trifluoromethyl) pyridin-3-yl] propionic acid amide
Figure FSA00000568042400111
8-[4-(2-hydroxyl-oxethyl)-3; The 5-Dimethylcyclohexyl]-6-methyl-2-(1H-pyrazolo [3; 4-b] pyridine-5-yl)-6H-imidazo [4; 5-d] thiazole [5,4-b] pyridines-7 (8H)-ketone also.
8. contain the pharmaceutical prepn of each described compound of claim 1～7, its pharmacy acceptable salt or its steric isomer, it is characterized in that comprising one or more pharmaceutical carriers.
9. the pharmaceutical composition that contains each described compound of claim 1～7, 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.
10. each described compound of claim 1～7, 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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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101495477A (en) * 2005-05-20 2009-07-29 诺瓦提斯公司 Imidazoquinolines as lipid kinase inhibitors
WO2010038165A1 (en) * 2008-09-30 2010-04-08 Pfizer Inc. Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101495477A (en) * 2005-05-20 2009-07-29 诺瓦提斯公司 Imidazoquinolines as lipid kinase inhibitors
WO2010038165A1 (en) * 2008-09-30 2010-04-08 Pfizer Inc. Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions

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