CN102372712B - Imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor - Google Patents

Imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor Download PDF

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CN102372712B
CN102372712B CN 201110245010 CN201110245010A CN102372712B CN 102372712 B CN102372712 B CN 102372712B CN 201110245010 CN201110245010 CN 201110245010 CN 201110245010 A CN201110245010 A CN 201110245010A CN 102372712 B CN102372712 B CN 102372712B
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naphthyridine
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glyoxalidine
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CN102372712A (en
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention relates to the technical field of medicine, and in particular to an imidazodiazanaphthalene PI3K (phosphatidyl inositol 3 kinase) and mTOR (mammalian target of rapamycin) dual inhibitor represented by a general formula (I), a pharmaceutically acceptable salt or a stereomer thereof, wherein R1, R2, R3, R3', R4, R5 and X are defined in the description; and the invention further relates to a preparation method of the compounds, a pharmaceutical preparation containing the compounds, a pharmaceutical composition containing the compounds, and application of the compounds in preparation of medicines for treating and/or preventing proliferative diseases.

Description

Imidazo naphthyridine class PI3K and mTOR double inhibitor
1, technical field
The invention belongs to medical technical field, be specifically related to imidazo naphthyridine class 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, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent 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, abnormal cell proliferation and the true tumor that forms.Tumour cell loses the 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 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 with cancer cells as the specificity target spot, can accurately act on tumour, improved greatly treatment level, and alleviated the 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 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.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 phosphorylations of phosphatidyl alcohol 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 the PI3K path, thus anticancer propagation, activation.
MTOR is a kind of protein serine/threonine that is present in the endochylema, belong to Phosphoinoside kinase related protein kinase enzyme family, form with two kinds of mixtures exists in vivo, i.e. mTORCl (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 somatomedin, and by the effect to vascular endothelial growth factor, the blood supply of control tumour.MTOR inhibitors can make cancer cells hungry, and by the effect that suppresses mTOR gross tumor volume is dwindled.
Among the 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, temporarily without the listing of PI3K/mTOR double inhibitor class medicine, therefore, need the more PI3K/mTOR double inhibitor structure type of research and development, effectiveness of selection and security be compound preferably, is used for the treatment of cancer.
3, summary of the invention
The object of the present invention is to provide a class effectiveness of selection and security preferably PI3K and mTOR double inhibitor.
Technical scheme of the present invention is as follows:
Compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Figure BSA00000562950400021
X is O, NH, or S;
R 1Be hydrogen, or be not substituted or by at least one R 6aThe C that replaces 1-6Alkyl, C 3-8Cycloalkyl, C 3-8Thiazolinyl, C 3-8Alkynyl, 3-14 unit heterocyclic radical, 6-12 unit volution base, aryl;
R 2Be hydrogen, or be not substituted or by at least one R 6bThe C that replaces 1-6Alkyl, C 3-8Cycloalkyl, aryl, 3-14 unit heterocyclic radical;
R 3And R 3' independently be hydrogen respectively, 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 4Be hydrogen, 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 5Be hydrogen ,-(CH 2) nS (O) mR 8, or be not substituted or by at least one R 6cThe C that replaces 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be 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, 3-14 unit heterocyclic radical, or be not substituted or by at least one R 9The C that replaces 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 hydrogen independently respectively, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 3-8Cycloalkyl, aryl, 3-14 unit heterocyclic radical;
R 8Be hydrogen, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Cycloalkyl, aryl, 3-14 unit heterocyclic radical;
R 9Be 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 10bIndependently be hydrogen respectively, C 1-6Alkyl, C 3-8Cycloalkyl, aryl, or 3-14 unit heterocyclic radical;
R 11Be 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 the 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 at least one R 6aThe C that replaces 1-6Alkyl, C 3-8Cycloalkyl, 4-10 unit heterocyclic radical, aryl, 7-10 unit volution base;
R 2For not being substituted or by at least one R 6bThe C that replaces 1-6Alkyl, C 3-8Cycloalkyl, aryl, 4-10 unit heterocyclic radical;
R 3And R 3' independently be hydrogen respectively ,-(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 4Be hydrogen, 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 5Be hydrogen, or be not substituted or by at least one R 6cThe C that replaces 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, the single heterocyclic radical of 4-10 unit, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Cycloalkyl, aryl, 4-10 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Cycloalkyl, 4-10 unit heterocyclic radical, aryl;
R 9Be 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 10bIndependently be 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 the 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 at least one R 6aThe C that replaces 1-6Alkyl, C 4-7Cycloalkyl, 5-10 unit heterocyclic radical, aryl;
R 2For not being substituted or by at least one R 6bThe aryl that replaces, 5-10 unit heterocyclic radical;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be hydrogen, or be not substituted or by at least one R 6cThe C that replaces 1-6Alkyl;
R 6a, R 6b, R 6cIndependently be hydroxyl respectively ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nS (O) mR 8,-(CH 2) nS (O) mNR 7aR 7b,-(CH 2) nNR 7aS (O) mR 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, the single heterocyclic radical of 5-6 unit, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Cycloalkyl, phenyl, 5-10 unit heterocyclic radical;
R 7aAnd R 7bBe hydrogen independently respectively, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Cycloalkyl, 5-10 unit heterocyclic radical, phenyl;
R 9Be 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 10bIndependently be 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 the 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 at least one R 6aThe C that replaces 4-7Cycloalkyl, the single heterocyclic radical of 5-6 unit, phenyl, naphthyl;
R 2For not being substituted or by at least one R 6bThe phenyl that replaces, naphthyl, the single heterocyclic radical of 5-6 unit, 9-10 unit fused heterocycle base;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be hydrogen, or C 1-6Alkyl;
R 6a, R 6bIndependently be hydroxyl respectively, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, single heterocyclic radical that 5-6 unit is saturated, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-6Alkyl;
R 8Be hydrogen, or be not substituted or by at least one R 9The C that replaces 1-6Alkyl, C 1-6Alkoxyl group, C 4-7Cycloalkyl;
R 9Be hydroxyl, cyano group, trifluoromethyl, C 1-6Alkyl, C 1-6Alkoxyl group, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, or C 1-6Alkyl;
N is 0～3.
Compound shown in the 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 at least one R 6aThe cyclopentyl, cyclohexyl, piperidyl, piperazinyl, tetrahydrofuran base, morpholinyl, pyridyl, pyrimidyl, pyrazolyl, the phenyl that replace;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, piperazinyl, piperidyl, or be not substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-4Alkoxyl group;
R 2For not being substituted or by at least one R 6bThe phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, indyl, the Pyrazolopyridine base that replace;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-4Alkoxyl group;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be hydrogen, or C 1-4Alkyl;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-4Alkyl;
R 8For not being substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-4Alkoxyl group;
R 9Be hydroxyl, cyano group, trifluoromethyl, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, or C 1-4Alkyl;
N is 0～2.
Compound shown in the 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 at least one R 6aThe cyclopentyl, cyclohexyl, piperidyl, piperazinyl, pyridyl, pyrimidyl, the phenyl that replace;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, piperazinyl, or be not substituted or by at least one R 9The C that replaces 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by at least one R 6bThe phenyl, pyridyl, pyrimidyl, indazolyl, quinolyl, indyl, the Pyrazolopyridine base that replace;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9The C that replaces 1-3Alkyl, C 1-2Alkoxyl group;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be hydrogen, methyl, ethyl, or propyl group;
R 7aAnd R 7bIndependently be hydrogen respectively, methyl, or ethyl;
R 8For not being substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-3Alkoxyl group;
R 9Be hydroxyl, cyano group, or trifluoromethyl;
N is 0～2.
Compound shown in the 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, pyridyl, the phenyl that replace;
R 6aBe trifluoromethyl ,-C (O) R 8,-C (O) OR 8,-NR 7aC (O) R 8, piperazinyl, or be not substituted or by 1～3 R 9The C that replaces 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by 1～3 R 6bThe pyridyl, the Pyrazolopyridine base that replace;
R 6bBe hydroxyl, trifluoromethyl, C 1-3Alkyl, or C 1-2Alkoxyl group;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be methyl;
R 7aBe hydrogen, methyl, or ethyl;
R 8For not being substituted or by 1～3 R 9The C that replaces 1-4Alkyl;
R 9Be hydroxyl, cyano group, or trifluoromethyl.
Table 1 part of compounds of the present invention
Figure BSA00000562950400061
Figure BSA00000562950400071
Figure BSA00000562950400081
Figure BSA00000562950400091
" 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 the derivative straight or branched of a hydrogen atom; such as methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2,3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl 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 the above-mentioned example.
" C of the present invention 3-8Cycloalkyl " refer to contain the cyclic alkyl of 3-8 carbon atom, such 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 the above-mentioned example.
" C of the present invention 2-8Thiazolinyl " carbonatoms that refers to contain two keys is the straight or branched of 2-8 or the thiazolinyl of ring-type; such 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 the above-mentioned example.
" C of the present invention 2-8Alkynyl " carbonatoms that refers to contain three key is the alkynyl of the straight or branched of 2-8, such 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 the above-mentioned example.
" C of the present invention 1-6Alkoxyl group " refer to " C 1-6Alkyl " group that is connected with other structures by Sauerstoffatom, such as methoxyl group, oxyethyl group, 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 the above-mentioned example.
" aryl " of the present invention refer to aromatic ring such as phenyl, replacement phenyl (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 contain whole saturated, the fractional saturation of 3-14 annular atoms (wherein containing at least 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 ", its described single heterocycle can be all saturated, fractional saturation, undersaturated, example has: ethylenimine, the 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1, the 2-diazetidine, azete, 1, the 2-diazetine, the pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4, the 5-glyoxalidine, imidazolidine, pyrazoles, 4, the 5-pyrazoline, pyrazolidine, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, pyridine, the 2-pyridone, the 4-pyridone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3, the 5-triazine, 1,2,4, the 5-tetrazine, the nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, the nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, tetrahydrofuran (THF), thiophene, 2, the 5-dihydro-thiophene, tetramethylene sulfide, 1, the 3-dioxolane, 1,3-dioxole-2-ketone, 1, the 2-dithiole, 1,3-dithiolane, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, the 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, Isosorbide-5-Nitrae-oxathiin, Isosorbide-5-Nitrae-dioxane, 1, the 3-dioxane, 1, the 3-oxathiane, oxepin, the thia cycloheptatriene, Isosorbide-5-Nitrae-dioxane sarohornene, oxaza propane oxazole, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 2, the 3-dihydro-isoxazole, 1,2,3-oxadiazole, 1,2, the 5-oxadiazole, thiazole, 4,5-thiazoline, isothiazole, 1,2, the 3-thiadiazoles, 1,2,4-thiadiazoles, 1,3, the 4-thiadiazoles, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 5,6-dihydro-4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1, the 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 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, example has indoles, isoindole, carbazole, benzoglyoxaline, indazole, benzotriazole, imidazolidine also [4,5-c] pyridine, quinoline, isoquinoline 99.9, the 2-quinolinone, the 4-quinolinone, the 1-isoquinolines, acridine, phenanthridines, cinnolines, phthalazines, quinazoline, 3, the 4-dihydroquinazoline, quinoxaline, 1, the 2-dihydro-quinoxaline, 1, the 8-naphthyridines, 1, the 7-naphthyridines, 1, the 6-naphthyridines, 1, the 5-naphthyridines, 2, the 7-naphthyridines, 2, the 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, the 3-dihydroisobenzofuran, 2H-chromogen alkene, 2H-chromogen alkene-2-ketone, the 4H-chromene, 4H-chromene-4-ketone, chroman benzoxazole, benzothiazole, 4H-1, the 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 is not limited to contain the specific examples of 9-10 annular atoms in " 6-14 unit fused heterocycle base ".
" 4-10 unit heterocyclic radical " of the present invention, " 5-10 unit heterocyclic radical " refer to respectively contain in above-mentioned " 3-14 unit heterocyclic radical " cyclic group of 4-10 annular atoms (containing at least a heteroatoms), a 5-10 annular atoms (containing at least a heteroatoms), comprise all monocycles or condensed ring, and ring can be whole saturated, fractional saturation, undersaturated.
" 6-12 unit volution " of the present invention refers to that a class has that two rings share that atoms form at least contains 6-12 carbon atom 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, specific examples comprise but not only for
Figure BSA00000562950400121
6-12 unit fractional saturation volution refers to that having a ring in this volution at least is undersaturated cyclic group, and specific examples includes but are not limited to:
Figure BSA00000562950400122
Figure BSA00000562950400131
" 7-10 unit volution base " of the present invention refers to contain in " 6-12 unit volution base " structure of 7-10 annular atoms, comprises saturated, fractional saturation.
Of the present invention " by at least one R 6aReplace ", " by at least one R 6bReplace ", " by at least one R 6c, by at least one R 9Replace ", " at least one " in the term such as " by at least one halogen, hydroxyl, carboxyl substituted "; referring to have one or more substituting groups on the substituted group; its maximum substituent numbers depend on the number of the position that can be replaced by corresponding substituting group that all chemistry on the substituted group are feasible; 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 describing in the following flow process to synthesize, but is not limited only to following methods.
Compound shown in the general formula (I), when X is O,
Figure BSA00000562950400132
Reactions steps:
The preparation of step 1 compound a
Raw material a, raw material b are joined in the alcohol, the reactant stirring and refluxing, cooling, crystallization filters, and filtration cakes torrefaction gets compound a.
The preparation of step 2 compound b
Compound a is added in the phenyl ether, and reflux after raw material reaction is complete, is cooled to room temperature, and reaction solution is poured in the sherwood oil, filters, and after the drying, gets compound b.
The preparation of step 3 compound c
Compound b is dissolved among the DMF, adds raw material c, two (triphenyl phosphorus) palladium chloride (II) and Na 2CO 3, heated and stirred, reaction mixture NaHCO 3The saturated aqueous solution cancellation, with ethyl acetate extraction twice, organic layer is washed with saturated common salt, through anhydrous sodium sulfate drying, filters and evaporated under reduced pressure, and resistates silicagel column column chromatography purification gets the product compound c.
The preparation of step 4 compound d
Compound c is added stirring and refluxing in the phosphorus oxychloride, after raw material reaction is complete, mixture is chilled to room temperature, unnecessary phosphorus oxychloride is removed in underpressure distillation, and residuum is carefully poured in the frozen water, extraction, drying, the solid column chromatography that obtains, evaporated under reduced pressure gets the product compound d.
The preparation of step 5 Verbindung
Compound d and raw material d are together joined in the methylene dichloride, add triethylamine, stirred overnight at room temperature.Vacuum rotary steam is removed methylene dichloride, and the syrupy shape solid column chromatography purification that obtains gets the product Verbindung.
The preparation of step 6 compound f
Verbindung is dissolved in the alcohol, adds NaOH solution, stirred overnight at room temperature, pressure reducing and steaming ethanol, residuum is dissolved in water, and adds dilute hydrochloric acid, has solid to generate, and filters, and gets solid product compound f.
The preparation of step 7 compound g
Compound f is added among the DMF, drips triethylamine, room temperature reaction for some time, under the ice-water bath to wherein adding DPPA, room temperature reaction for some time, temperature reaction for some time, after raw material reaction was complete, cool to room temperature was poured in the frozen water, ethyl acetate extraction, drying is spin-dried for, and gets product compound g.
The preparation of step 8 compound h
Compound g, raw material e and Tetrabutyl amonium bromide are joined in the methylene dichloride, add the NaOH aqueous solution, stirring at room, add the aqueous solution that methyl iodide and NaOH are made into, continue to stir the cancellation of reaction mixture water, with twice of dichloromethane extraction, organic phase salt water washing, anhydrous sodium sulfate drying filters and evaporate to dryness filtrate namely gets product compound h.
Compound shown in the general formula (I) when X is S or NH, can prepare with reference to aforesaid method.
In the reaction equation, R 1, R 2, R 3, R 4, R 5Define such as preamble.
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, perhaps can be protected, then remove in whole or in part protecting group according to the method for routine.For example, if there is amino acid proton, " amino protecting group " of available routine protected, the example of described " amino protecting group " comprising: methyl, encircle the third methyl, 1-methyl isophthalic acid-ring the third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, ethyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, the 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, the 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, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 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, to methoxy-benzyl, 3, the 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, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, the p-acyloxy benzyl of meta-chloro-, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the 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, the isonicotine base, the S-benzyl, N '-piperidino carbonyl, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the 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, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoxy ylmethyl) benzoyl and p-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-pyrrolidin-3-yl; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 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; benzylidene; to the methoxyl group benzylidene; to nitrobenzal; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; the 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; the dimethyl sulphur-based phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; phenacyl alkylsulfonyl etc.
" pharmacy acceptable salt " of formula of the present invention (I) compound refers to have formula (I) compound and mineral acid shape, organic acid or the formed salt of organic protonic acid of basic nitrogen atom.
" steric isomer " of formula of the present invention (I) compound, refer to that there is unsymmetrical carbon in formula of the present invention (I) compound, 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 be made pharmaceutically acceptable pharmaceutical preparation with one or more pharmaceutical carriers, are applied to the patient who needs this treatment in modes such as oral, parenterals.During oral administration, can make conventional solid preparation with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc., such as tablet, capsule, pill, granule etc.; When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.
The 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 is 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; 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 includes but are not limited to Topotecan; The 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 purposes in the medicine of proliferative disease in preparation.
Described proliferative disease comprises cancer and non-Cancerous disease, and 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, the 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 by 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 this should 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 Example 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 (IC50)
Figure BSA00000562950400171
Experiment conclusion
As can be seen from Table 1, the compounds of this invention has good external the enzyme activity.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.
Embodiment 1 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] also The preparation of naphthyridine (compound 1)
The preparation of embodiment 1-a (6-bromo-2-chloropyridine-3-is amino) methylene malonic acid diethyl ester
Figure BSA00000562950400172
20.7g (100mmol) 6-bromo-3-Amino-2-Chloropyridine and 21.6g (100mmol) ethoxy methylene diethyl are added in the 200mL dehydrated alcohol stirring and refluxing 5 hours, cooling, separate out solid, filter, get white solid 36.0g, productive rate 95.3%.
Embodiment 1-b 8-chloro-6-bromo-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester preparation
Figure BSA00000562950400181
30.2g (80mmol) (6-bromo-2-chloropyridine-3-is amino) methylene malonic acid diethyl ester reflux in the 200mL phenyl ether was stirred 2 hours, then will reflect that mixture pours in the sherwood oil, have yellow solid to separate out, filtration drying gets product 24.5g, productive rate 92.4%.
The preparation of embodiment 1-c 8-chloro-6-(2-methoxypyridine-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400182
With 16.6g (50mmol) 8-chloro-6-bromo-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester, 9.18g (60mmol) 2-methoxypyridine-4-boric acid, two (triphenyl phosphorus) palladium chlorides (II) of 1.6g and 50mL 1M Na 2CO 3Solution adds among the 150mL DMF, stirring at room 2h, with mixture with saturated NaHCO 3Then aqueous solution cancellation uses ethyl acetate extraction, and the salt solution washing is through Na 2SO 4Drying is filtered and evaporated under reduced pressure, gets product 15.6g, productive rate 86.7%.
The preparation of embodiment 1-d 6-(2-methoxypyridine-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400183
7.2g (20mmol) 8-chloro-6-(2-methoxypyridine-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester is added in the 100mL methyl alcohol, add 2g Pd/C, pass into H 2, stirred overnight at room temperature is filtered, and the filtrate decompression evaporate to dryness gets product 6.28g, productive rate 96.5%.
Embodiment 1-e 4-chloro-6-(6-chloropyridine-3-yl)-1, the preparation of 7-naphthyridines-3-carboxylic acid, ethyl ester
Figure BSA00000562950400184
1.2g (3.7mmol) 6-(2-methoxypyridine-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester is added in the 25mL phosphorus oxychloride reflux 3h, vacuum rotary steam is removed phosphorus oxychloride, with simple silicagel column column chromatography purification, get light yellow solid 0.6g, yield 45%.
Embodiment 1-f 4-(1-(tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-(6-chloropyridine-3-yl)-1, the preparation of 7-naphthyridines-3-carboxylic acid, ethyl ester
Figure BSA00000562950400191
With 4-chloro-6-(6-chloropyridine-3-yl)-1,7-naphthyridines-3-carboxylic acid, ethyl ester (0.6g, 1.7mmol), triethylamine (1.3mL, 8.7mmol) and 4-amino piperidine-1-carboxylic acid tert-butyl ester (0.7g, 3.4mmol) join among the toluene 50mL, backflow is spent the night, be cooled to room temperature, filter to get product 0.5g, productive rate 58%.
Embodiment 1-g 4-(1-(tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-(6-chloropyridine-3-yl)-1, the preparation of 7-naphthyridines-3-carboxylic acid
Figure BSA00000562950400192
With 4-(1-(tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-(6-chloropyridine-3-yl)-1,7-naphthyridines-3-carboxylic acid, ethyl ester (0.5g, 1mmol) and lithium hydroxide monohydrate (0.083g, 2mmol) add to stir in the mixed solution of second alcohol and water (10mL/2mL) and spend the night the reaction solution evaporate to dryness, soluble in water, regulate pH=4, separate out solid, filtration drying, get product 0.4g, productive rate 83%.
The preparation of embodiment 1-h 4-(8-(6-chloropyridine-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazo [4,5-c] [1,7] naphthyridines-1-yl) piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000562950400193
With 4-(1-(tertbutyloxycarbonyl) piperidin-4-yl is amino)-6-(6-chloropyridine-3-yl)-1,7-naphthyridines-3-carboxylic acid (400mg, 0.83mmol), triethylamine (0.25mL, 1.67mmol) add among the 6mL DMF, stirred 30 minutes, drip diphenyl phosphate azide (459mg, 1.67mmol), stir 3h, be warming up to 60 ℃, stir 2h, be cooled to room temperature, separate out solid, wash with ethyl acetate, dry product 0.2g, the productive rate 51% of getting.
The preparation of embodiment 1-i 4-(8-(6-chloropyridine-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-imidazo [4,5-c] [1,7] naphthyridines-1-yl) piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000562950400194
With 4-(8-(6-chloropyridine-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazo [4,5-c] [1,7] naphthyridines-1-yl) piperidines-1-carboxylic acid tert-butyl ester (200mg, 0.42mmol), Tetrabutyl amonium bromide (50mg, 0.154mmol) and methyl iodide (119mg, 0.84mmol) add in the 10mL methylene dichloride, drip the aqueous sodium hydroxide solution of 2N, mixture stirs and spends the night reaction solution water and dichloromethane extraction, the dry evaporate to dryness of organic layer gets product 180mg, yield: 87%.
The preparation of embodiment 1-j 4-(8-(6-methoxyl group-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-imidazo [4,5-c] [1,7] naphthyridines-1-yl) piperidines-1-carboxylic acid tertiary butyl
Figure BSA00000562950400201
4-(8-(6-chloropyridine-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-imidazo [4,5-c] [1,7] naphthyridines-1-yl) piperidines-1-carboxylic acid tert-butyl ester (180mg, 0.36mmol) is dissolved in the 4mL toluene, adds NaOCH 3/ CH 3OH (500mg, 5mL) flows through night next time in nitrogen protection, water and dichloromethane extraction, and organic layer is dry, crosses the silicagel column purifying and gets product 160mg, yield 91%.
The preparation of embodiment 1-k compound 1
Figure BSA00000562950400202
In the 20mL methylene dichloride, add 4-(8-(6-methoxyl group-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-imidazo [4,5-c] [1,7] naphthyridines-1-yl) piperidines-1-carboxylic acid tertiary butyl (80mg, 0.16mmol), under ice bath, add trifluoroacetic acid (0.5mL), stirring at room 2h, evaporate to dryness gets oily matter, be dissolved in the methyl alcohol, be added dropwise to crystallization in the ether, get white solid 40mg, yield: 64%.
Molecular formula: C 21H 22N 6O 2Molecular weight: 390.44 MS:391 (M+H +)
1H?NMR(d 6-DMSO)δ6.99(d，1H)，8.48-8.51(m，1H)，9.0(d，1H)，9.0(s，1H)，9.41(s，1H)，8.41(s，1H)，5.13-5.19(m，1H)，3.93(s，3H)，3.51(s，3H)，3.41-3.47(m，3H)，3.33-3.35(m，2H)，2.82-2.92(m，2H)，2.22(d，2H)
Embodiment 2 8-(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] [1,7] naphthyridine (compound 2) also
With 8-(6-methoxypyridine-3-yl)-3-methyl isophthalic acid-(piperidin-4-yl)-1H-imidazo [4,5-c] [1,7] naphthyridines-2 (3H)-ketone (100mg, 0.25mmol), I-hydroxybenzotriazole (90mg, 0.67mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (120mg, 0.63mmol) and D-ALPHA-Hydroxypropionic acid (72mg, 0.8mmol) add in the 20mL methylene dichloride, stirred overnight at room temperature, evaporate to dryness, cross column purification and get product 15mg, yield 13%.
Molecular formula: C 24H 26N 6O 4Molecular weight: 462.5 MS:463 (M+H +)
1H?NMR(400MHz，d 6-DMSO)δ9.43(s，1H)，9.03(s，1H)，9.02(s，1H)，8.43(s，1H)，8.48(d，1H)，7.01(d，1H)，5.17(s，1H)，4.95(dd，1H)，4.50-4.58(m，2H)，4.37-4.40(m，1H)，3.94(s，3H)，3.53(s，3H)，2.93-2.99(m，1H)，2.59-2.67(m，1H)，2.01-2.06(m，2H)，1.28(s，3H)
Embodiment 3 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[4-(piperazine-N-yl)-3-trifluoromethyl]-2,3- Glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 3) also
Embodiment 3-f 4-(4-(4-(tertbutyloxycarbonyl) piperidin-1-yl)-3-(trifluoromethyl) phenyl amino)-6-(6-chloropyridine-3-yl)-1, the preparation of 7-naphthyridines-3-carboxylic acid, ethyl ester
Figure BSA00000562950400212
The preparation method is with reference to embodiment 1-f, throw 1g (2.9mmol) 4-chloro-6-(6-chloropyridine-3-yl)-1,7-naphthyridines-3-carboxylate methyl ester and 2.1g (5.8mmol) 4-(N-tertbutyloxycarbonyl-piperazine-4-yl)-3 trifluoromethyl phenylaminos, triethylamine (1.3mL, 8.7mmol), get product 1.6g, productive rate 85%.
Embodiment 3-g to 3-j 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[4-(N-tertbutyloxycarbonyl-piperazine-4-yl)-3-trifluoromethyl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
Figure BSA00000562950400213
The preparation method is with reference to embodiment 1-f to 1-i, throw 4-(4-(4-(tertbutyloxycarbonyl) piperidin-1-yl)-3-(trifluoromethyl) phenyl amino)-6-(6-chloropyridine-3-yl)-1,7-naphthyridines-3-carboxylic acid, ethyl ester 1.6g (2.4mmol), get product 133mg, overall yield 8.7%.
The preparation of embodiment 3-k compound 3
Figure BSA00000562950400221
The preparation method is with reference to embodiment 2-k, throw 60mg (0.09mmol) 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[4-(N-tertbutyloxycarbonyl-piperazine-4-yl)-3-trifluoromethyl]-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine, get product 33mg, productive rate 66%.
Molecular formula: C 27H 24F 3N 7O 2Molecular weight: 535.52 MS:536 (M+H +)
1H?NMR(d 6-DMSO)δ9.41(s，1H)，9.16(s，1H)，8.42(d，1H)，8.16(d，1H)，8.07(d，1H)，7.87(s，1H)，7.89(dd，1H)，7.33(s，1H)，6.92(d，1H)，6.88(d，1H)，3.84(s，3H)，3.59(s，3H)，3.25-3.27(m，4H)，3.21-3.23(m，4H)
Embodiment 4 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[4-(2-acetonitrile-base propane 2-yl) phenyl]-2, the 3-dihydro The preparation of imidazo [4,5-c] [1,7] naphthyridine (compound 4)
Embodiment 4-f 6-(2-methoxypyridine-5-yl)-4-[4-(2-acetonitrile-base propane-2-yl) phenylamino] preparation of [1,7] naphthyridine-3-carboxylic acid, ethyl ester
The preparation method is with reference to embodiment 1-f, throw 3.44g (10mmol) 6-(2-methoxypyridine-5-yl)-4-chlorine [1,7] naphthyridine-3-carboxylic acid, ethyl ester and 1.76g (11mmol) 4-(2-acetonitrile-base propane-2-yl) phenylamino, the 5mL triethylamine, get product 4.26g, productive rate 91.2%.
Embodiment 4-g to 4-h 8-(2-methoxypyridine-5-yl)-2-oxo-1-[4-(2-acetonitrile-base propane-2-yl) phenyl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
The preparation method is with reference to embodiment 1-g to 1-h, throw 4.68g (10mmol) 6-(2-methoxypyridine-5-yl)-4-[4-(2-acetonitrile-base propane-2-yl) phenylamino] [1,7] naphthyridine-3-carboxylic acid, ethyl ester gets product 2.10g, overall yield 48.2%.
The preparation of embodiment 4-i compound 4
Figure BSA00000562950400232
The preparation method is with reference to embodiment 1-i, throws 4.36g (10mmol) 8-(2-methoxypyridine-5-yl)-2-oxo-1-[4-(2-acetonitrile-base propane-2-yl) phenyl]-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine gets product 3.77g, productive rate 83.7%.
Molecular formula: C 26H 22N 6O 2Molecular weight: 450.49 MS:451 (M+H +)
Theoretical value: C, 69.32%; H, 4.92%; N, 18.66%;
Measured value: C, 69.25%; H, 4.98%; N, 18.60%;
Embodiment 5 8-(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] [1,7] naphthyridine (compound 5) also
The preparation of embodiment 5f 6-(2-methoxypyridine-5-yl)-4-(N-glycoloyl phenylpiperidines-4-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400233
The preparation method is with reference to embodiment 1-f; throw 3.44g (10mmol) 6-(2-methoxypyridine-5-yl)-4-chlorine [1,7] naphthyridine-3-carboxylic acid, ethyl ester and 1.74g (11mmol) N-glycoloyl phenylpiperidines-4-ammonia, the 5mL triethylamine; get product 4.28g, productive rate 92.0%.
Embodiment 5-g to 5-h 8-(2-methoxypyridine-5-yl)-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
Figure BSA00000562950400241
The preparation method throws 4.66g (10mmol) 6-(2-methoxypyridine-5-yl)-4-(N-glycoloyl phenylpiperidines-4-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester with reference to embodiment 1-g to 1-h, gets product 2.00g, overall yield 46.1%.
The preparation of embodiment 5-i compound 5
Figure BSA00000562950400242
The preparation method is with reference to embodiment 1-i, throws 4.34g (10mmol) 8-(2-methoxypyridine-5-yl)-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 3.57g, productive rate 79.6%.
Molecular formula: C 23H 24N 6O 4Molecular weight: 448.47 MS:449 (M+H +)
Theoretical value: C, 61.60%; H, 5.39%; N, 18.74%;
Measured value: C, 61.53%; H, 5.44%; N, 18.70%;
Embodiment 6 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine And the preparation of [4,5-c] [1,7] naphthyridine (compound 6)
The preparation of embodiment 6-f 6-(2-methoxypyridine-5-yl)-4-(N-methoxycarbonyl piperidines-4-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400243
Preparation Method is with reference to embodiment 1-f, throw 3.44g (10mmol) 6-(2-methoxypyridine-5-yl)-4-chlorine [1,7] naphthyridine-3-carboxylic acid, ethyl ester and 1.74g (11mmol) N-methoxycarbonyl piperidines-4-ammonia, the 5mL triethylamine, get product 4.33g, productive rate 93.1%.
Embodiment 6-g to 6-h 8-(2-methoxypyridine-5-yl)-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
Figure BSA00000562950400251
The preparation method throws 4.66g (10mmol) 6-(2-methoxypyridine-5-yl)-4-(N-methoxycarbonyl piperidines-4-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester with reference to embodiment 1-g to 1-h, gets product 2.05g, overall yield 47.3%.
The preparation of embodiment 6-i compound 6
Figure BSA00000562950400252
The preparation method is with reference to embodiment 1-i, throws 4.34g (10mmol) 8-(2-methoxypyridine-5-yl)-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine gets product 3.83g, productive rate 85.3%.
Molecular formula: C 23H 24N 6O 4Molecular weight: 448.47 MS:449 (M+H +)
Theoretical value: C, 61.60%; H, 5.39%; N, 18.74%;
Measured value: C, 61.57%; H, 5.46%; N, 18.69%;
Embodiment 7 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] [1,7] naphthyridine (compound 7)
The preparation of embodiment 7-f 6-(2-methoxypyridine-5-yl)-4-(N-ethanoyl piperidines-4-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400253
Preparation Method is with reference to embodiment 1-f; throw 3.44g (10mmol) 6-(2-methoxypyridine-5-yl)-4-chlorine [1,7] naphthyridine-3-carboxylic acid, ethyl ester and 1.56g (11mmol) N-ethanoyl piperidines-4-ammonia, the 5mL triethylamine; get product 3.97g, productive rate 91.7%.
Embodiment 7-g to 7-h 8-(2-methoxypyridine-5-yl)-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
Figure BSA00000562950400261
The preparation method throws 4.50g (10mmol) 6-(2-methoxypyridine-5-yl)-4-(N-ethanoyl piperidines-4-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester with reference to embodiment 1-g to 1-h, gets product 1.98g, overall yield 47.2%.
The preparation of embodiment 7-i compound 7
Figure BSA00000562950400262
The preparation method is with reference to embodiment 1-i, throws 4.18g (10mmol) 8-(2-methoxypyridine-5-yl)-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 3.61g, productive rate 83.4%.
Molecular formula: C 23H 24N 6O 3Molecular weight: 432.48 MS:433 (M+H +)
Theoretical value: C, 63.88%; H, 5.59%; N, 19.43%;
Measured value: C, 63.80%; H, 5.66%; N, 19.40%;
Embodiment 8 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine -2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 8) also
Embodiment 8-f 6-(2-methoxypyridine-5-yl)-4-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-is amino] preparation of [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400263
Preparation Method is with reference to embodiment 1-f, throw 3.44g (10mmol) 6-(2-methoxypyridine-5-yl)-4-chlorine [1,7] naphthyridine-3-carboxylic acid, ethyl ester and 2.74g (11mmol) 5-(2-hydroxyl propionamido-)-4-trifluoromethyl-PA, the 5mL triethylamine, get product 4.93g, productive rate 88.6%.
Embodiment 8-g to 8-h 8-(2-methoxypyridine-5-yl)-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
Figure BSA00000562950400271
The preparation method is with reference to embodiment 1-g to 1-h, throw 5.56g (10mmol) 6-(2-methoxypyridine-5-yl)-4-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-amino] [1,7] naphthyridine-3-carboxylic acid, ethyl ester gets product 2.39g, overall yield 45.5%.
The preparation of embodiment 8-i compound 8
Figure BSA00000562950400272
The preparation method is with reference to embodiment 1-i, throw 5.25g (10mmol) 8-(2-methoxypyridine-5-yl)-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-yl]-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine, get product 4.21g, productive rate 78.1%.
Molecular formula: C 25H 20F 3N 7O 4Molecular weight: 539.47 MS:540 (M+H +)
Theoretical value: C, 55.66%; H, 3.74%; N, 18.17%;
Measured value: C, 55.60%; H, 3.79%; N, 18.14%;
Embodiment 9 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1- Base)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 9) also
The preparation of embodiment 9-f 6-(2-methoxypyridine-5-yl)-4-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400273
Preparation Method is with reference to embodiment 1-f, throw 3.44g (10mmol) 6-(2-methoxypyridine-5-yl)-4-chlorine [1,7] naphthyridine-3-carboxylic acid, ethyl ester and 2.06g (11mmol) 3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-is amino, the 5mL triethylamine, get product 4.52g, productive rate 91.3%.
Embodiment 9-g to 9-h 8-(2-methoxypyridine-5-yl)-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine also
Figure BSA00000562950400281
The preparation method is with reference to embodiment 1-g to 1-h, throw 4.95g (10mmol) 6-(2-methoxypyridine-5-yl)-4-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-is amino) [1,7] naphthyridine-3-carboxylic acid, ethyl ester, get product 2.17g, overall yield 46.9%.
The preparation of embodiment 9-i compound 9
Figure BSA00000562950400282
The preparation method throws 4.64g (10mmol) 8-(2-methoxypyridine-5-yl)-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2 with reference to embodiment 1-i, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also, get product 3.81g, productive rate 79.8%.
Molecular formula: C 26H 31N 5O 4Molecular weight: 477.56 MS:478 (M+H +)
Theoretical value: C, 65.39%; H, 6.54%; N, 14.66%;
Measured value: C, 65.31%; H, 6.60%; N, 14.60%;
Embodiment 10 8-(2-picoline-5-yl)-3-methyl 2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2,3-two The preparation of hydrogen imidazo [4,5-c] [1,7] naphthyridine (compound 10)
Can make compound 10 with reference to embodiment 1.
The preparation of embodiment 10-c 8-chloro-6-(2-picoline-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester
Figure BSA00000562950400291
The preparation method is with reference to embodiment 1-c, throw 16.6g (50mmol) 8-chloro-6-bromo-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester, 8.22g (60mmol) 2-picoline-4-boric acid, two (triphenyl phosphorus) palladium chlorides (II) of 1.6g, get product 14.7g, yield 85.6%.
The preparation of embodiment 10-i compound 10
The preparation method is with reference to embodiment 1-i, throws 4.32g (10mmol) 8-(2-picoline-5-yl)-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2,3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 3.63g, yield 81.3%.
Molecular formula: C 24H 26N 6O 3Molecular weight: 446.5 MS:447 (M+H +)
Theoretical value: C, 64.56%; H, 5.87%; N, 18.82%;
Measured value: C, 64.50%; H, 5.90%; N, 18.77%;
Embodiment 11 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2, the 3-glyoxalidine And the preparation of [4,5-c] [1,7] naphthyridine (compound 11)
Can make compound 11 with reference to embodiment 5.
Figure BSA00000562950400293
The preparation method is with reference to embodiment 5-i, throws 4.18g (10mmol) 8-(2-picoline-5-yl)-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 3.51g, productive rate 81.2%.
Molecular formula: C 23H 24N 6O 3Molecular weight: 432.48 MS:433 (M+H +)
Theoretical value: C, 63.88%; H, 5.59%; N, 19.43%;
Measured value: C, 63.81%; H, 5.65%; N, 19.39%;
Embodiment 12 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] [1,7] naphthyridine (compound 12)
Can make compound 12 with reference to embodiment 6.
Figure BSA00000562950400301
The preparation method is with reference to embodiment 6-i, throws 4.18g (10mmol) 8-(2-picoline-5-yl)-2-oxo-1-(N methoxycarbonyl piperidin-4-yl)-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine gets product 3.61g, productive rate 83.5%.
Molecular formula: C 23H 24N 6O 3Molecular weight: 432.48 MS:433 (M+H +)
Theoretical value: C, 63.88%; H, 5.59%; N, 19.43%;
Measured value: C, 63.80%; H, 5.67%; N, 19.37%;
Embodiment 13 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] [1,7] naphthyridine (compound 13)
Can make compound 13 with reference to embodiment 7.
Figure BSA00000562950400302
The preparation method is with reference to embodiment 7-i, throws 4.02g (10mmol) 8-(2-picoline-5-yl)-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2,3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 3.44g, productive rate 82.7%.
Molecular formula: C 23H 24N 6O 2Molecular weight: 416.48 MS:417 (M+H +)
Theoretical value: C, 66.33%; H, 5.81%; N, 20.18%;
Measured value: C, 66.25%; H, 5.89%; N, 20.10%;
Embodiment 14 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] also The preparation of naphthyridine (compound 14)
Can make compound 14 with reference to embodiment 1.
Figure BSA00000562950400311
The preparation method is with reference to embodiment 2-j, throws 4.75g (10mmol) 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-tertbutyloxycarbonyl-piperidin-4-yl)-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine gets product 3.71g, productive rate 99.2%.
Molecular formula: C 21H 22N 6O molecular weight: 374.44 MS:375 (M+H +)
Theoretical value: C, 67.36%; H, 5.92%; N, 22.44%;
Measured value: C, 67.30%; H, 5.95%; N, 22.41%;
Embodiment 15 8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine -2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 15) also
Can make compound 15 with reference to embodiment 8.
Figure BSA00000562950400312
The preparation method is with reference to embodiment 8-i, throw 5.09g (10mmol) 8-(2-picoline-5-yl)-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-yl]-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine, get product 4.00g, productive rate 76.4%.
Molecular formula: C 25H 20F 3N 7O 3Molecular weight: 523.47 MS:524 (M+H +)
Theoretical value: C, 57.36%; H, 3.85%; N, 18.73%;
Measured value: C, 57.28%; H, 3.93%; N, 18.66%;
Embodiment 16 8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1- Base)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 16) also
Can make compound 16 with reference to embodiment 9.
Figure BSA00000562950400321
The preparation method throws 4.48g (10mmol) 8-(2-picoline-5-yl)-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2 with reference to embodiment 9-i, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also, get product 3.67g, productive rate 79.5%.
Molecular formula: C 26H 31N 5O 3Molecular weight: 461.56 MS:462 (M+H +)
Theoretical value: C, 67.66%; H, 6.77%; N, 15.17%;
Measured value: C, 67.60%; H, 6.85%; N, 15.12%;
Embodiment 17 8-(1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidines -4-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 17) also
The preparation of embodiment 17-c 8-chloro-6-(1H-pyrazolo [3,4-b] pyridine-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester
The preparation method is with reference to embodiment 1-c, 16.6g (50mmol) 8-chloro-6-bromo-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester, 15.2g (60mmol) 1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-boric acid and two (triphenyl phosphorus) palladium chlorides (II) of 1.6g, get product 4.05g, yield 88.1%
Embodiment 17-d to 17-i 8-(1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2; the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 17-i) also
Figure BSA00000562950400323
The preparation method throws 4.60g (10mmol) 8-chloro-6-(1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-yl)-4-hydroxyl [1,7] naphthyridine-3-carboxylic acid, ethyl ester with reference to embodiment 1-d to 1-i, gets product 1.65g, total recovery 29.4%.
The preparation of embodiment 17-j compound 17
Figure BSA00000562950400331
With 5.63g (10mmol) 8-(1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2; 3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine adds in the 50mL methyl alcohol; the careful 3g Pd/C that adds, 2mL formic acid passes into H 2, stirring at room 6h filters reaction mixture, and filtrate concentrates evaporate to dryness, gets khaki color solid product 4.38g, yield 92.7%.
Molecular formula: C 24H 24N 8O 3Molecular weight: 472.5 MS:473 (M+H +)
Theoretical value: C, 61.01%; H, 5.12%; N, 23.72%;
Measured value: C, 60.95%; H, 5.20%; N, 23.68%;
Embodiment 18 8-(1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(N-glycoloyl phenylpiperidines-4- Base)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 18) also
Can make compound 18 with reference to embodiment 17-j.
Figure BSA00000562950400332
The preparation method is with reference to embodiment 17-j; throw 5.49g (10mmol) 8-(1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 4.37g, productive rate 95.4%.
Molecular formula: C 23H 22N 8O 3Molecular weight: 458.47 MS:459 (M+H +)
Theoretical value: C, 60.25%; H, 4.84%; N, 24.44%;
Measured value: C, 60.19%; H, 4.92%; N, 24.40%;
Embodiment 19 8-(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] [1,7] naphthyridine (compound 19) also
Can make compound 19 with reference to embodiment 17-j.
Figure BSA00000562950400341
The preparation method is with reference to embodiment 17-j, throw 5.49g (10mmol) 8-(1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine gets product 4.41g, productive rate 96.1%.
Molecular formula: C 23H 22N 8O 3Molecular weight: 458.47 MS:459 (M+H +)
Theoretical value: C, 60.25%; H, 4.84%; N, 24.44%;
Measured value: C, 60.17%; H, 4.96%; N, 24.39%;
Embodiment 20 8-(1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2,3-two The preparation of hydrogen imidazo [4,5-c] [1,7] naphthyridine (compound 20)
Can make compound 20 with reference to embodiment 17-j.
Figure BSA00000562950400342
The preparation method is with reference to embodiment 17-j; throw 5.33g (10mmol) 8-(1-benzyl-1H-pyrazolo [3; 4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2; 3-glyoxalidine also [4; 5-c] [1; 7] naphthyridine gets product 4.14g, productive rate 93.6%.
Molecular formula: C 23H 22N 8O 2Molecular weight: 442.47 MS:443 (M+H +)
Theoretical value: C, 62.43%; H, 5.01%; N, 25.32%;
Measured value: C, 62.38%; H, 5.11%; N, 25.29%;
Embodiment 21 8-(1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine also The preparation of [4,5-c] [1,7] naphthyridine (compound 21)
Can make compound 21 with reference to embodiment 17-j.
Figure BSA00000562950400343
The preparation method throws 4.91g (10mmol) 8-(1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2 with reference to embodiment 17-j, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also, get product 3.73g, productive rate 93.2%.
Molecular formula: C 21H 20N 8O molecular weight: 400.44 MS:401 (M+H +)
Theoretical value: C, 62.99%; H, 5.03%; N, 27.98%;
Measured value: C, 62.91%; H, 5.10%; N, 27.92%;
Embodiment 22 8-(1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-trifluoro Picoline-2-yl]-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 22) also
Can make compound 22 with reference to embodiment 17-j.
Figure BSA00000562950400351
The preparation method is with reference to embodiment 17-j, throw 6.40g (10mmol) 8-(1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-yl]-2,3-glyoxalidine also [4,5-c] [1,7] naphthyridine gets product 5.00g, productive rate 90.9%.
Molecular formula: C 25H 18F 3N 9O 3Molecular weight: 549.46 MS:550 (M+H +)
Theoretical value: C, 54.65%; H, 3.30%; N, 22.94%;
Measured value: C, 54.58%; H, 3.41%; N, 22.90%;
Embodiment 23 8-(1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl-4-'-hydroxyethoxy basic ring Hexane-1-yl)-2, the 3-glyoxalidine is the preparation of [4,5-c] [1,7] naphthyridine (compound 23) also
Can make compound 23 with reference to embodiment 17-j.
Figure BSA00000562950400352
The preparation method is with reference to embodiment 17-j, throw 5.64g (10mmol) 8-(1-benzyl-1H-pyrazolo [3,4-b] pyridine-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also, get product 4.44g, productive rate 91.1%.
Molecular formula: C 26H 29N 7O 3Molecular weight: 487.55 MS:488 (M+H +)
Theoretical value: C, 64.05%; H, 6.00%; N, 20.11%;
Measured value: C, 63.98%; H, 6.10%; N, 20.06%;
With reference to aforesaid method, can also be prepared as follows compound:
Figure BSA00000562950400361
Substituent R among above-mentioned formula (I-1), (I-2), (I-3) 1, be respectively following group:
Table 3
Figure BSA00000562950400362
Figure BSA00000562950400371
Figure BSA00000562950400372
Substituent R among above-mentioned formula (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) 1, be respectively following group:
Table 4
Figure BSA00000562950400373
Figure BSA00000562950400381

Claims (8)

1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Figure DEST_PATH_FSB00001037892400011
Wherein
X is O;
R 1For not being substituted or by at least one R 6aThe cyclopentyl, cyclohexyl, piperidyl, the piperazinyl that replace;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-4Alkoxyl group;
R 2For not being substituted or by at least one R 6bThe phenyl, pyridyl, pyrimidyl, the pyrazolyl that replace;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-4Alkoxyl group;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be hydrogen, or C 1-4Alkyl;
R 7aAnd R 7bIndependently be hydrogen respectively, or C 1-4Alkyl;
R 8For not being substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-4Alkoxyl group;
R 9Be hydroxyl, cyano group, trifluoromethyl, or-(CH 2) nNR 10aR 10b
R 10aAnd R 10bIndependently be hydrogen respectively, or C 1-4Alkyl;
N is 0～2.
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 6aThe cyclopentyl, cyclohexyl, piperidyl, the piperazinyl that replace;
R 6aBe hydroxyl, trifluoromethyl ,-(CH 2) nNR 7aR 7b,-(CH 2) nC (O) R 8,-(CH 2) nC (O) (CH 2) nNR 7aR 7b,-(CH 2) nOC (O) R 8,-(CH 2) nC (O) OR 8,-(CH 2) nNR 7aC (O) R 8,-(CH 2) nNR 7aC (O) NR 7aR 7b, or be not substituted or by at least one R 9The C that replaces 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by at least one R 6bThe phenyl, pyridyl, the pyrimidyl that replace;
R 6bBe hydroxyl, trifluoromethyl, or be not substituted or by at least one R 9The C that replaces 1-3Alkyl, C 1-2Alkoxyl group;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be hydrogen, methyl, ethyl, or propyl group;
R 7aAnd R 7bIndependently be hydrogen respectively, methyl, or ethyl;
R 8For not being substituted or by at least one R 9The C that replaces 1-4Alkyl, C 1-3Alkoxyl group;
R 9Be hydroxyl, cyano group, or trifluoromethyl;
N is 0～2.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R 1For not being substituted or by 1～3 R 6aThe cyclohexyl, the piperidyl that replace;
R 6aBe trifluoromethyl ,-C (O) R 8,-C (O) OR 8,-NR 7aC (O) R 8, or be not substituted or by 1～3 R 9The C that replaces 1-3Alkyl, C 1-2Alkoxyl group;
R 2For not being substituted or by 1～3 R 6bThe pyridyl that replaces;
R 6bBe hydroxyl, trifluoromethyl, C 1-3Alkyl, or C 1-2Alkoxyl group;
R 3, R 3', R 4Be respectively hydrogen;
R 5Be methyl;
R 7aBe hydrogen, methyl, or ethyl;
R 8For not being substituted or by 1～3 R 9The C that replaces 1-4Alkyl;
R 9Be hydroxyl, cyano group, or trifluoromethyl.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer, described compound is selected from:
Figure DEST_PATH_FSB00001037892400021
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400022
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400031
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400032
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400033
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400034
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxyl propionyl] piperidin-4-yl]-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400042
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-methoxycarbonyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400044
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(N-ethanoyl piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400045
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400051
8-(2-picoline-5-yl)-3-methyl-2-oxo-1-(3,5-dimethyl-4-hydroxyl-oxethyl hexanaphthene-1-yl)-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also.
5. compound as described below, its pharmacy acceptable salt or its steric isomer,
Figure DEST_PATH_FSB00001037892400052
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[4-(piperazine-N-yl)-3-trifluoromethyl]-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400053
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[4-(2-acetonitrile-base propane-2-yl) phenyl]-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl-propionamido-)-4-trifluoromethyl-pyridine-2-yl]-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also,
Figure DEST_PATH_FSB00001037892400061
8-(2-methoxypyridine-5-yl)-3-methyl-2-oxo-1-[5-(2-hydroxyl propionamido-)-4-5-flumethiazine-2-yl]-2, the 3-glyoxalidine is [4,5-c] [1,7] naphthyridine also.
6. contain the pharmaceutical preparation of each described compound of claim 1～5, its pharmacy acceptable salt or its steric isomer, it is characterized in that comprising one or more pharmaceutical carriers.
7. the pharmaceutical composition that contains each described compound of claim 1～5, 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 selected from the metabolic antagonist of capecitabine, gemcitabine, pemetrexed disodium; Be selected from the growth factor receptor inhibitors of pazopanib, imatinib, erlotinib, lapatinibditosylate, Gefitinib, ZD6474; Be selected from the antibody of Trastuzumab, rhuMAb-VEGF; Be selected from the mitotic inhibitor of taxol, vinorelbine, docetaxel, Dx; Be selected from the antitumor hormones of letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; Be selected from the alkylating agent class of endoxan, carmustine; Be selected from the metal platinum class of carboplatin, cis-platinum, oxaliplatin; Be selected from the Topotecan topoisomerase enzyme inhibitor; Be selected from everolimus, sirolimus, the suitable immunosuppression class of special cancer.
8. each described compound of claim 1～5, its pharmacy acceptable salt or its steric isomer treat and/or prevent purposes in the medicine of the proliferative disease relevant with PI3K and mTOR in preparation, described proliferative disease comprises cancer and non-Cancerous disease, and described cancer is selected from brain tumor, 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, the female reproductive tract cancer, carcinoma in situ, lymphoma, histocytic 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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CN102399218A (en) * 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 Triheterocyclic compounds and their use as PI3K inhibitors

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