CN104418853A - Substituted naphthyridine-2-ketone compound, preparation method, application and pharmaceutical composition - Google Patents

Substituted naphthyridine-2-ketone compound, preparation method, application and pharmaceutical composition Download PDF

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CN104418853A
CN104418853A CN201310382278.5A CN201310382278A CN104418853A CN 104418853 A CN104418853 A CN 104418853A CN 201310382278 A CN201310382278 A CN 201310382278A CN 104418853 A CN104418853 A CN 104418853A
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formula
compound
compound shown
cancer
base
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CN104418853B (en
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易崇勤
许恒
陶晶
林松文
韩方斌
钟学超
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New Founder Holdings Development Co ltd
Peking University Medical Management Co ltd
Peking University Founder Group Co Ltd
PKU Healthcare Industry Group
PKUCare Pharmaceutical R&D Center
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Peking University Founder Group Co Ltd
PKU International Healthcare Group Co Ltd
PKUCare Pharmaceutical R&D Center
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Priority to PCT/CN2014/085286 priority patent/WO2015027914A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention provides a compound as shown in formula I in the specification, and pharmaceutically acceptable salt, a preparation method, an application and a pharmaceutical composition. The compound as shown in the formula I is relatively excellent in anti-cancer or anti-tumor function and can inhibit multiple kinases, including PI3-K kinase and mTOR kinase, in cells and on the surfaces of cells simultaneously, so that relatively high anti-cancer or anti-tumor functions are achieved. The composition provided by the invention can be used for treating cerebral cancer, glioblastoma, head and neck cancer, lung cancer, melanin tumor, liver cancer, kidney cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, bone marrow paraplasm syndrome, esophagus cancer, sarcoma, osteosarcoma and rhabdomyoma.

Description

Naphthyridines-2-the ketone compound replaced, preparation method, purposes and pharmaceutical composition
Technical field
The invention belongs to medicinal chemistry art, in particular to a kind of naphthyridines-2-ketone compound of replacement, preparation method, purposes and pharmaceutical composition.
Background technology
The research and development of antitumor drug are rich in challenge in current life science and far reaching field.In recent years, along with molecular biological develop rapidly and people cancer is occurred, development, mechanism of action further understanding, the various primary processes such as the interaction of the signal transduction in malignant cell, the regulation and control of cell cycle, apoptotic induction, vasculogenesis and cell and extracellular matrix are progressively illustrated.Therefore find and find that selectively acting has become one of key areas of current medical research and development in efficient, low toxicity, high specificity the new type antineoplastic medicine of specific target spot, thereby produce a new cancer therapy drug field-molecular targeted agents.
Molecular targeted agents refers to for enzyme crucial in the acceptor of cell carcinogenesis or transductive process, from the Therapeutic mode of molecular level Tumor suppression growth.It, decreases Normocellular toxic side effect for target spot with the characteristic molecular of tumour cell while performance antitumor action.
Phosphoinositide 3-kinase (PI3-K) catalyze phospholipid acyl inositol (PI) second messenger PI(3) P, PI(3,4) P2 and PI(3,4,5) synthesis of P3 (PIP3).Under suitable cellular environment, these three kinds of lipids control multiplely to comprise Growth of Cells, survival, differentiation and chemotactic physiological processes.Main PI3-kinases in cancer is the I class PI3-K α be made up of catalytic subunit (p110 α) and adjustment subunit (p85) with merit iso series.The several components of PI3-K/Akt/PTEN path relates to tumour and is formed, comprise Cycle Regulation, hyperplasia, survival, apoptosis and motion many cell processes regulation and control in play a significant role, and be the important component of the molecular mechanism of the diseases such as such as cancer, diabetes and immune inflammation.
Therefore, PI3-K α is the target of the attractive and prospect of exploitation cancer drug, and this type of medicine by anticancer hyperplasia, and avoids the damage of cellulotoxic preparation to body, and cancer cells is to the tolerance of cellulotoxic preparation.But it is comparatively large that existing PI3-K alpha inhibitor exists toxic side effect, therefore the defect that in clinical trial, result for the treatment of is not high is needed the PI3-K alpha inhibitor that exploitation is new at present badly, is applied to field of cancer as cancer treatment drugs.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of naphthyridines-2-ketone compound of replacement, preparation method, purposes and pharmaceutical composition.
Specifically, the invention provides:
(1) compound shown in a kind of formula I or its pharmacy acceptable salt:
Wherein,
R 1be selected from C 1-C 10alkyl, C 3-C 10cycloalkyl or C 3-C 10heterocyclylalkyl, wherein said C 3-C 10cycloalkyl or C 3-C 10heterocyclylalkyl is optionally by-OR 2replaced, wherein R 2be selected from hydrogen, C 1-C 6alkyl or C 1-C 6hydroxyalkyl; And
R 3be selected from hydrogen or-NHSO 2r 4, wherein, R 4be selected from C 1-C 6alkyl, C 3-C 10cycloalkyl, C 5-C 10aryl or C 5-C 10heteroaryl, wherein said C 1-C 6alkyl, C 3-C 10cycloalkyl, C 5-C 10aryl or C 5-C 10heteroaryl is optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.
(2) compound shown in the formula I Gen Ju (1) or its pharmacy acceptable salt, wherein, R 1group for as follows:
Wherein, R 6, R 7be selected from hydrogen or C independently of one another 1-C 4alkyl; Be preferably selected from hydrogen or methyl.
(3) compound shown in the formula I Gen Ju (1) or its pharmacy acceptable salt, wherein, R 1be selected from C 3-C 6cycloalkyl or C 3-C 6heterocyclylalkyl, it is optionally by-OR 2replaced.
(4) compound shown in the formula I Gen Ju (1) or its pharmacy acceptable salt, wherein, preferably, R 1be selected from cyclopropyl, cyclopentyl, cyclohexyl or oxacyclohexyl, it is optionally by-OR 2replaced.
(5) compound shown in the formula I Gen Ju (1) or its pharmacy acceptable salt, wherein, R 2for C 1-C 6hydroxyalkyl; Be more preferably-CH 2-CH 2-OH.
(6) compound shown in the formula I Gen Ju (1) or its pharmacy acceptable salt, wherein, R 3for-NHSO 2r 4, wherein,
R 4be preferably selected from C 1-C 4alkyl, C 3-C 5cycloalkyl, C 5-C 6aryl or C 5-C 6heteroaryl, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl, C 5-C 6aryl or C 5-C 6heteroaryl is optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.
(7) compound shown in the formula I Gen Ju (6) or its pharmacy acceptable salt, wherein, R 4be selected from C 1-C 4alkyl, C 3-C 5cycloalkyl, aryl or 5 yuan of heteroaryls, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl, aryl or 5 yuan of heteroaryls are optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group; 5 yuan of described heteroaryls are preferably containing a sulphur atom.
(8) compound shown in the formula I Gen Ju (6) or its pharmacy acceptable salt, wherein, R 4be selected from aryl or 5 yuan of heteroaryls, described aryl or 5 yuan of heteroaryls are optionally by 1-5 R 5replaced, be preferably by 1-2 R 5replaced; Described R 5be selected from halogen, cyano group ,-CF 3or C 1-C 4alkoxyl group.
(9) compound shown in the formula I Gen Ju (6) or its pharmacy acceptable salt, wherein, R 4be selected from C 1-C 4alkyl or C 3-C 5cycloalkyl, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl is optionally by 1-5 R 5replaced, be more preferably by 1-3 R 5replaced; Described R 5for halogen.
(10) compound shown in the formula I Gen Ju (1) or its pharmacy acceptable salt, wherein, the compound shown in formula I is selected from following compounds:
Compound 1:
Compound 2:
Compound 3:
Compound 4:
Compound 5:
Compound 6:
Compound 7:
Compound 8:
Compound 9:
Compound 10:
Compound 11:
Compound 12:
Compound 13:
Compound 14:
Compound 15:
Compound 16:
Compound 17:
Compound 18:
Compound 19:
Compound 20:
Compound 21:
and
Compound 22:
(11) according to the preparation method of the compound shown in formula I in (1)-(10) described in any one, it comprises: make the compound shown in the compound shown in formula A and formula B occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula I:
Wherein, R 1and R 3as (1) define; X is halogen, is preferably bromine; And R 8for or
(12) method Gen Ju (11), wherein, described palladium catalyst is two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride.
(13) method Gen Ju (11), wherein, the compound shown in formula A prepares by the following method:
Make the compound shown in formula L and N-N-halosuccinimides that following halogenating reaction occur, thus obtain the compound shown in formula A:
(14) method Gen Ju (13), wherein, the compound shown in formula L prepares by the following method:
Make the compound shown in formula K and oxammonium hydrochloride that following deprotection reaction occur, thus obtain the compound shown in formula L:
(15) method Gen Ju (14), wherein, the compound shown in formula K prepares by the following method:
Under the existence of potassium tert.-butoxide and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, make the compound shown in formula J that following cyclization reaction occur, thus obtain the compound shown in formula K:
(16) method Gen Ju (15), wherein, the compound shown in formula J prepares by the following method:
Make the compound shown in formula H and ethyl propenoate occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula J:
Wherein, X is halogen, is preferably bromine; Described palladium catalyst is preferably tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, is more preferably tetrakis triphenylphosphine palladium.
(17) method Gen Ju (16), wherein, the compound shown in formula H prepares by the following method:
Make the compound shown in the compound shown in formula F and formula G occur to react as follows under the existence of acid binding agent diisopropyl ethyl amine, thus obtain the compound shown in formula H:
Wherein, X is halogen, is preferably bromine.
(18) method Gen Ju (17), wherein, the compound shown in formula F prepares by the following method:
Make the compound shown in formula E and iodine, under the existence of lithium diisopropyl amido, following iodide reaction occur, thus obtain the compound shown in formula F:
Wherein, X is halogen, is preferably bromine.
(19) method Gen Ju (18), wherein, the compound shown in formula E prepares by the following method:
Make the compound shown in the compound shown in formula C and formula D occur to react as follows under the existence of catalyzer tosic acid, thus obtain the compound shown in formula E:
Wherein, X is halogen, is preferably bromine.
(20) method Gen Ju (11), wherein,
Work as R 8for time, the compound shown in formula B prepares by the following method:
Make the compound shown in the compound shown in formula M and formula N that following reaction occur under the existence of catalyzer [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, thus obtain the compound shown in formula B:
(21) according to the compound shown in formula I in (1)-(10) described in any one or its pharmacy acceptable salt for the preparation of the purposes treated and/or prevented in the medicine of the disease that PI3-K kinases and/or mTOR kinases cause.
(22) purposes Gen Ju (21), wherein, described PI3-K kinases is PI3-K alpha kinase.
(23) purposes Gen Ju (21), wherein, described disease is cancer or tumour.
(24) purposes Gen Ju (21), wherein, described disease be selected from the cancer of the brain, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney, acute leukemia, chronic leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colon and rectum carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, sarcoma, osteosarcoma and rhabdomyoma one or more.
(25) a kind of pharmaceutical composition being used for the treatment of and/or preventing the disease that PI3-K kinases and/or mTOR kinases cause, comprise in described pharmaceutical composition (1)-(10) in the compound shown in formula I described in any one and/or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
The present invention compared with prior art has the following advantages and positively effect:
The present invention provides the new naphthyridines-2-ketone compound of a class first, with existing Compound Phase ratio, compound shown in formula I of the present invention has more outstanding anticancer or function of tumor, can suppress multiple is present in cell and the kinases of cell surface simultaneously, comprise PI3-K kinases and mTOR kinases, therefore have quite or more potent anticancer or function of tumor.
Pharmaceutical composition of the present invention can be used for treating the cancer of the brain, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney, acute leukemia, chronic leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colon and rectum carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, sarcoma, osteosarcoma and rhabdomyoma.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
In specification sheets of the present invention and claims, compound, all according to chemical structural formula and naming, if the name of compound and chemical structural formula are not inconsistent when representing same compound, is as the criterion with chemical structural formula or chemical equation.
In the present invention, described " Me " is methyl.
Wavy line in the present invention, in substituting group " " implication be that the group of substituent group and main chain (such as, phenyl ring) on the position of wavy line is connected by chemical bond.
The present inventor has carried out studying in large quantities to the compound with PI3-K kinase inhibiting activity, have been surprisingly found that by the 1-nitrogen-atoms in the compound shown in formula a is replaced to carbon atom, namely replace with Kui Linpyrimido quinoline pyridine ring, the compound of gained can be made simultaneously to possess PI3K and mTOR two kinds of kinase whose inhibit activities.
Wherein R is substituting group, may be the same or different.The present inventor, on the basis that this finds, has carried out screening further and optimizing to substituent R wherein, to obtain the kinase whose higher inhibit activities of PI3K and mTOR two kinds, thus obtains technical scheme of the present invention further.
Specifically, the invention provides:
(1) compound shown in formula I
The present invention provide firstly the compound shown in a kind of formula I or its pharmacy acceptable salt:
Wherein,
R 1be selected from C 1-C 10alkyl, C 3-C 10cycloalkyl or C 3-C 10heterocyclylalkyl, wherein said C 3-C 10cycloalkyl or C 3-C 10heterocyclylalkyl is optionally by-OR 2replaced, wherein R 2be selected from hydrogen, C 1-C 6alkyl or C 1-C 6hydroxyalkyl; And
R 3be selected from hydrogen or i.e.-NHSO 2r 4, wherein, R 4be selected from C 1-C 6alkyl, C 3-C 10cycloalkyl, C 5-C 10aryl or C 5-C 10heteroaryl, wherein said C 1-C 6alkyl, C 3-C 10cycloalkyl, C 5-C 10aryl or C 5-C 10heteroaryl is optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.
Preferably, R 1group for as follows:
Wherein, R 6, R 7be selected from hydrogen or C independently of one another 1-C 4alkyl; It is further preferred that R 6, R 7be selected from hydrogen or methyl independently of one another.
Preferably, R 1be selected from C 3-C 6cycloalkyl or C 3-C 6heterocyclylalkyl, it is optionally by-OR 2replaced.
Preferably, R 1be selected from cyclopropyl, cyclopentyl, cyclohexyl or oxacyclohexyl, it is optionally by-OR 2replaced.
Preferably, R 1be selected from or it is optionally by-OR 2replaced.
Preferably, R 2for C 1-C 6hydroxyalkyl.It is further preferred that R 2for-CH 2-CH 2-OH.
Preferably, R 3for i.e.-NHSO 2r 4.
The present inventor be have been surprisingly found that by the cocrystallization x-ray diffraction pattern analyzing PI3K γ, the action site of 2-methoxypyridine and PI3K γ acceptor and the compound GSK2126458(Knight of GlaxoSmithKline PLC company, S.D.et.al.Discovery of GSK2126458, a highlypotent inhibitor of PI3K and the mammalian target of rapamycin.ACS Med.Chem.Lett.2010, 1, 39 – 43) similar, therefore introduce sulfoamido substituting group in its 3-position and can produce hydrogen bond action with the Lys833 of PI3K γ acceptor, thus strengthen the activity of compound.Particularly produce Van der Waals at its 3-position introducing 2,4 difluorobenzene sulfoamido and PI3K kinases hydrophobic pocket to interact, the activity of compound can be strengthened further.
Preferably, R 4be preferably selected from C 1-C 4alkyl, C 3-C 5cycloalkyl, C 5-C 6aryl or C 5-C 6heteroaryl, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl, C 5-C 6aryl or C 5-C 6heteroaryl is optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.
It is further preferred that R 4be selected from C 1-C 4alkyl, C 3-C 5cycloalkyl, aryl or 5 yuan of heteroaryls, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl, aryl or 5 yuan of heteroaryls are optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.It is further preferred that described 5 yuan of heteroaryls contain a sulphur atom.
It is further preferred that R 4be selected from aryl or 5 yuan of heteroaryls, described aryl or 5 yuan of heteroaryls are optionally by 1-5 R 5replaced, be more preferably by 1-2 R 5replaced; Described R 5be selected from halogen, cyano group ,-CF 3or C 1-C 4alkoxyl group.
Preferably, R 4be selected from C 1-C 4alkyl or C 3-C 5cycloalkyl, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl is optionally by 1-5 R 5replaced, be more preferably by 1-3 R 5replaced; Described R 5for halogen.
Preferably, the compound shown in formula I is selected from following compounds:
Compound 1:
Compound 2:
Compound 3:
Compound 4:
Compound 5:
Compound 6:
Compound 7:
Compound 8:
Compound 9:
Compound 10:
Compound 11:
Compound 12:
Compound 13:
Compound 14:
Compound 15:
Compound 16:
Compound 17:
Compound 18:
Compound 19:
Compound 20:
Compound 21:
and
Compound 22:
The pharmacy acceptable salt of the compound shown in formula I of the present invention is selected from:
A) mineral acid and organic acid salt, described acid is selected from: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol;
B) salt of organic and mineral alkali, described positively charged ion is selected from: the ammonium cation that alkali metal cation, alkaline earth metal cation, ammonium cation, aliphatic group replace, and the ammonium cation that aromatic base replaces.
(2) preparation method of the compound shown in formula I:
Secondly the present invention provides the preparation method of the compound shown in a kind of formula I, and it comprises:
Make the compound shown in the compound shown in formula A and formula B occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula I:
Wherein, R 1and R 3as claim 1 define; X is halogen, is preferably bromine; And R 8for or
Preferably, described palladium catalyst is two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride.
Preferably, the compound shown in formula A prepares by the following method:
Make the compound shown in formula L and N-N-halosuccinimides that following halogenating reaction occur, thus obtain the compound shown in formula A:
It is further preferred that the compound shown in formula L prepares by the following method:
Make the compound shown in formula K and oxammonium hydrochloride that following deprotection reaction occur, thus obtain the compound shown in formula L:
It is further preferred that the compound shown in formula K prepares by the following method:
Under the existence of potassium tert.-butoxide and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, make the compound shown in formula J that following cyclization reaction occur, thus obtain the compound shown in formula K:
It is further preferred that the compound shown in formula J prepares by the following method:
Make the compound shown in formula H and ethyl propenoate occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula J:
Wherein, X is halogen, is preferably bromine; More preferably, described palladium catalyst is tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, be preferably tetrakis triphenylphosphine palladium.
It is further preferred that the compound shown in formula H prepares by the following method:
Make the compound shown in the compound shown in formula F and formula G occur to react as follows under the existence of acid binding agent diisopropyl ethyl amine, thus obtain the compound shown in formula H:
Wherein, X is halogen, is preferably bromine.
It is further preferred that the compound shown in formula F prepares by the following method:
Make the compound shown in formula E and iodine, under the existence of lithium diisopropyl amido, following iodide reaction occur, thus obtain the compound shown in formula F:
Wherein, X is halogen, is preferably bromine.
It is further preferred that the compound shown in formula E prepares by the following method:
Make the compound shown in the compound shown in formula C and formula D occur to react as follows under the existence of catalyzer tosic acid, thus obtain the compound shown in formula E:
Wherein, X is halogen, is preferably bromine.
In a preferred embodiment of the invention, the compound shown in formula A prepares by the following method:
1) make the compound shown in the compound shown in formula C and formula D occur to react as follows under the existence of catalyzer tosic acid, thus obtain the compound shown in formula E:
Wherein, X is halogen, is preferably bromine;
2) make the compound shown in formula E and iodine, under the existence of lithium diisopropyl amido, following iodide reaction occur, thus obtain the compound shown in formula F:
Wherein, X is halogen, is preferably bromine;
3) make the compound shown in the compound shown in formula F and formula G occur to react as follows under the existence of acid binding agent diisopropyl ethyl amine, thus obtain the compound shown in formula H:
Wherein, X is halogen, is preferably bromine;
4) make the compound shown in formula H and ethyl propenoate occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula J:
Wherein, X is halogen, is preferably bromine; More preferably, described palladium catalyst is tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, be preferably tetrakis triphenylphosphine palladium;
5) under the existence of potassium tert.-butoxide and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, make the compound shown in formula J that following cyclization reaction occur, thus obtain the compound shown in formula K:
6) make the compound shown in formula K and oxammonium hydrochloride that following deprotection reaction occurs, thus obtain the compound shown in formula L:
; And
7) make the compound shown in formula L and N-N-halosuccinimides that following halogenating reaction occurs, thus obtain the compound shown in formula A:
Preferably, R is worked as 8for time, the compound shown in formula B prepares by the following method:
Make the compound shown in the compound shown in formula M and formula N that following reaction occur under the existence of catalyzer [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, thus obtain the compound shown in formula B:
(3) compound shown in formula I or the purposes of its pharmacy acceptable salt
The present invention again provides the compound shown in formula I or its pharmacy acceptable salt for the preparation of the purposes treated and/or prevented in the medicine of the disease that PI3-K kinases and/or mTOR kinases cause.
Compound shown in formula I of the present invention is a kind of multi-kinase inhibitor, can suppress multiple simultaneously and be present in cell and the kinases of cell surface, comprise: PI3-K kinases and mTOR kinases.It is further preferred that described PI3-K kinases is PI3-K alpha kinase.
Preferably, described disease is cancer or tumour.
Preferably, described disease be selected from the cancer of the brain, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney, acute leukemia, chronic leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colon and rectum carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, sarcoma, osteosarcoma and rhabdomyoma one or more.
(4) pharmaceutical composition of the disease that PI3-K kinases and/or mTOR kinases cause is used for the treatment of and/or prevents
The present invention finally provides a kind of pharmaceutical composition being used for the treatment of and/or preventing the disease that PI3-K kinases and/or mTOR kinases cause, compound shown in contained I and/or its pharmacy acceptable salt in described pharmaceutical composition, and pharmaceutically acceptable auxiliary material.
Preferably, the formulation of described pharmaceutical composition is injection, oral preparations, cutaneous permeable agent or suppository.
Mode below by way of example further explains and describes content of the present invention, but these embodiments are not to be construed as limiting the scope of the invention.
In following example, if no special instructions, each reagent all commercially, such as, can derive from lark prestige Science and Technology Ltd., AlfaAesar (Tianjin) Chemical Co., Ltd. or Beijing coupling Science and Technology Ltd..
In following example, the calculation formula of yield is: yield=products weight × feed molar quality/(raw material weight × product molar quality).
Embodiment 1:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (compound 1)
Preparation method:
The synthesis of the bromo-6-of step 1:3-(2,5-methyl isophthalic acid H-pyrroles-1-base)-2-picoline
The bromo-6-picoline (38.2g, 204mmol) of 2-amino-5-will be housed, 2,5-hexanedione (36mL, 306mmol), the there-necked flask of a hydration tosic acid (1.94g, 10.2mmol) and 380mL toluene connects water trap and prolong and by reaction mixture refluxed 6h.After being cooled to room temperature, with ethyl acetate (500mL) diluted reaction mixture, with water (200mL × 2) and saturated aqueous common salt (200mL × 2) washing, with anhydrous sodium sulfate drying, filter, concentrated.With column chromatography (silica gel, petrol ether/ethyl acetate=100:1, v/v) purification residues, obtaining product is brown oil (41.4g, yield is 76%).
1H NMR(400MHz，DMSO-d 6)δ8.17(d，J=8.4Hz，1H)，7.21(d，J=8.4Hz，1H)，5.80(s，2H)，2.60(s，3H)，2.06(s，6H).
The synthesis of the bromo-6-of step 2:3-(2,5-methyl isophthalic acid H-pyrroles-1-base) the iodo-2-picoline of-4-
Under argon gas atmosphere, by n-Butyl Lithium (69.69mmol, be mixed with the hexane solution 29mL of 2.4M) be added drop-wise to-30 DEG C at the solution of Diisopropylamine (9.83mL, 69.69mmol) in anhydrous tetrahydro furan (60mL) in, and reaction mixture is stirred 30min at-30 DEG C.After being cooled to-78 DEG C, dripping 3-bromo-6-(2, the 5-methyl isophthalic acid H-pyrroles-1-base) solution of-2-picoline (16.8g, 63.36mmol) in anhydrous tetrahydro furan (120mL), and reaction mixture is stirred 30min at-78 DEG C.Drip iodine (17.7g, the 69.69mmol) solution in anhydrous tetrahydro furan (120mL), and reaction mixture is stirred 30min at-78 DEG C.With saturated ammonium chloride solution cancellation reaction mixture, with water (400mL) dilution, be extracted with ethyl acetate (200mL × 3).With the organic layer that water (200mL × 2) and saturated aqueous common salt (200mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.With column chromatography (silica gel, petrol ether/ethyl acetate=150:1, v/v) purification residues, obtaining product is yellow solid (13.09g, yield 53%).
1H NMR(400MHz，DMSO-d 6)δ7.84(s，1H)，5.80(s，2H)，2.71(s，3H)，2.08(s，6H)
The synthesis of the bromo-N-cyclopentyl of step 3:3--6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-amine
In sealed tube, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles-1-base) the iodo-2-picoline of-4-(9.5g, 24.3mmol), cyclopentamine (6.21g, 72.9mmol), the solution of diisopropylethylamine (9.42g, 72.9mmol) in N-Methyl pyrrolidone (95mL) stirs 24 hours at 160 DEG C.After being cooled to room temperature, with water (500mL) diluted reaction mixture, be extracted with ethyl acetate (200mL × 3).With the organic layer that water (200mL × 2) and saturated aqueous common salt (200mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=80:1, then petrol ether/ethyl acetate=50:1, v/v) purification residues is yellow solid (6.0g, yield is 56%).
1H NMR(400MHz，DMSO-d 6)δ6.44(s，1H)，5.75(s，2H)，5.66(d，J=7.2Hz，1H)，3.95-3.91(m，1H)，2.47(s，3H)，2.06(s，6H)，1.99-1.95(m，2H)，1.68-1.55(m，6H)
MS(ESI+)m/z348.0[M+H] +
Step 4:(E) synthesis of-3-(4-(Cyclohexylamino)-6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-3-base) ethyl propenoate
In sealed tube, by bromo-for 3-N-cyclopentyl-6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-amine (7.2g, 20.67mmol) and the solution of ethyl propenoate (6.6mL, 62.01mmol) in triethylamine (70mL) is with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (2.39g, 2.067mmol), again mixture is sealed tubule with bubbling argon 5min.Reaction soln is stirred at 135 DEG C and spends the night, cool and concentrate.Add water (200mL), the mixture produced with ethyl acetate (100mL × 3) extraction.With the organic layer that water (100mL × 2) and saturated common salt washing (100mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=50:1, then petrol ether/ethyl acetate=12:1, v/v) purification residues is yellow oil (6.46g, yield 85%).
1H NMR(400MHz，DMSO-d 6)δ7.62(d，J=16.4Hz，1H)，6.40(s，1H)，6.29(d，J=16.4Hz，1H)，6.05(d，J=6.8Hz，1H)，5.75(s，2H)，4.21(q，J=7.2Hz，2H)，3.88-3.84(m，1H)，2.38(s，3H)，2.08(s，6H)，1.91-1.97(m，2H)，1.50-1.47(m，6H)，1.28(t，J=7.2Hz，3H).
MS(ESI+)m/z368.2[M+H] +
Step 5:1-cyclopentyl-7-(2,5-dimethyl-1H-pyrroles-1-base)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(4-(clopentylamino)-6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-3-base) ethyl propenoate (279mg, 0.76mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene (568 μ L, 3.8mmol) and potassium tert.-butoxide (43mg, solution 0.38mmol) in DMF (6mL) stirs and spends the night at 150 DEG C.After being cooled to room temperature, with water (30mL) diluted reaction mixture, be extracted with ethyl acetate (20mL × 3).With the organic layer that water (20mL × 2) and saturated aqueous common salt (20mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=10:1, then petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow oil (66mg, yield is 27%).
1H NMR(400MHz，DMSO-d 6)δ8.14(d，J=9.8Hz，1H)，7.47(s，1H)，6.65(d，J=9.7Hz，1H)，5.83(s，2H)，5.48-5.28(m，1H)，2.74(s，3H)，2.19-2.04(m，2H)，2.11(s，6H)，1.90(dd，J=16.7，10.2Hz，4H)，1.73-1.57(m，2H).
MS(ESI+)m/z322.1[M+H] +
Step 6:7-amino-1-cyclopentyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 1-cyclopentyl-7-(2,5-dimethyl-1H-pyrroles-1-base)-5-methyl isophthalic acid, the mixture backflow in second alcohol and water (4mL:0.4mL) of 6-naphthyridines-2 (1H)-one (66mg, 0.21mmol) and oxammonium hydrochloride (73mg, 1.05mmol) is spent the night.It is yellow blister solid (22mg, yield is 44%) that concentrated reaction mixture also obtains product with column chromatography (silica gel, petrol ether/ethyl acetate=1:3, then ethyl acetate/triethylamine=100:1, v/v) purification residues.
MS(ESI+)m/z244.0[M+H] +
The bromo-1-cyclopentyl of step 7:7-amino-3--5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By N-bromo-succinimide (56mg, 0.315mmol) be added to 7-amino-1-cyclopentyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.315mmol) is at N, in the solution of dinethylformamide (2mL), and reaction soln is at room temperature stirred 1h.Add 20mL water, the mixture produced with ethyl acetate (20mL × 5) extraction.With the organic layer that water (20mL × 2) and saturated common salt washing (20mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (20mg, yield 76%).
1H NMR(400MHz，DMSO-d 6)δ8.29(s，1H)，6.50(s，2H)，6.29(s，1H)，5.27(p，J=8.8Hz，1H)，2.19-1.93(m，4H)，1.92-1.75(m，2H)，1.73-1.56(m，2H).
MS(ESI+)m/z321.9[M+H] +
The synthesis of step 8:N-(the bromo-2-methoxypyridine of 5--3-base)-2,4 difluorobenzene sulphonamide
By 2,4-difluoro chloride (510mg, 2.4mmol, methylene dichloride (5mL) solution 1.2eq) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residue is yellow solid (590mg, yield is 78%).
1H NMR(400MHz，DMSO-d 6)δ10.46(s，1H)，8.13(d，J=2.3Hz，1H)，7.84-7.70(m，2H)，7.64-7.51(m，1H)，7.23(td，J=8.5，2.0Hz，1H)，3.61(s，3H).
The synthesis of step 9:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron ring penta-2-base) pyridin-3-yl)-2,4 difluorobenzene sulphonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-2,4-difluorobenzenesulfonamide (576mg, 1.52mmol), Glacial acetic acid potassium (300mg, 3.04mmol) degassed with connection pinacol borate (466mg, the 1.84mmol) mixture in dioxane (7mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (56mg, 0.076mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 3 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (480mg, yield is 74%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ10.18(s，1H)，8.20(d，J=1.5Hz，1H)，7.80-7.63(m，2H)，7.56(dd，J=14.3，5.5Hz，1H)，7.20(t，J=7.5Hz，1H)，3.61(s，3H)，1.29(s，12H).
The synthesis of step 10:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (90mg, 0.28mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (143mg, 0.336mmol) degassed with the mixture of salt of wormwood (166mg, 1.2mmol) in DMF and water (3mL/0.6mL), and two (triphenylphosphine) palladium chloride (20mg, 0.028mmol) are added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=1:1 then petrol ether/ethyl acetate=1:2, v/v) purification residues is yellow solid (103mg, yield is 68%).
1H NMR(400MHz，DMSO-d 6)δ10.19(s，1H)，8.28(d，J=2.4Hz，1H)，7.94(s，1H)，7.92(d，J=2.4Hz，1H)，7.76-7.70(m，1H)，7.62-7.52(m，1H)，7.20(td，J=8.4，2.4Hz，1H)，6.44(s，2H)，6.30(s，1H)，5.38-5.29(m，1H)，3.63(s，3H)，2.57(s，3H)，2.18-2.12(m，2H)，2.08-2.01(m，2H)，1.90-1.82(m，2H)，1.71-1.64(m，2H)
MS(ESI+)m/z541.9[M+H] +.
Embodiment 2:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-cvanobenzenesulfonamide (compound 2)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-4-cvanobenzenesulfonamide
By 4-cyanobenzenesulfonyl chloride (482mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred 4h.Water (25mL) is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) separating residue is yellow solid (699mg, yield is 95%).
1H NMR(300MHz，DMSO-d 6)δ10.49(s，1H)，8.12(d，J=2.3Hz，1H)，8.07(d，J=8.5Hz，2H)，7.90(d，J=8.5Hz，2H)，7.76(d，J=2.3Hz，1H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-cvanobenzenesulfonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-4-cvanobenzenesulfonamide (368mg, 1.0mmol), Glacial acetic acid potassium (196mg, 2mmol) with connection pinacol borate (bis (pinacolato) diboron) (304mg, mixture 1.2mmol) in dioxane (7mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=6:1, v/v) purification residues is yellow solid (360mg, yield is 87%).
1H NMR(400MHz，DMSO-d 6)δ10.22(s，1H)，8.24(d，J=1.6Hz，1H)，7.73(d，J=1.6Hz，1H)，7.30(d，J=4.0Hz，1H)，7.21(d，J=4.0Hz，1H)，3.71(s，3H)，1.30(s，12H).
MS(ESI+)m/z333.9[M+H] +
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-cvanobenzenesulfonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-cvanobenzenesulfonamide (100mg, 0.24mmol, 1.2eq) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide-water (5mL:0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (75mg, yield is 71%).
1H NMR(400MHz，DMSO-d 6)δ10.23(s，1H)，8.26(d，J=2.2Hz，1H)，8.07(d，J=8.6Hz，2H)，7.94(s，1H)，7.92(d，J=2.2Hz，1H)，7.91(d，J=8.6Hz，2H)，6.45(s，2H)，6.30(s，1H)，5.40-5.26(m，1H)，3.60(s，3H)，2.57(s，3H)，2.21-2.10(m，2H)，2.09-1.99(m，2H)，1.92-1.80(m，2H)，1.73-1.61(m，2H).
Embodiment 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-(trifluoromethyl) benzsulfamide (compound 3)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-4-(trifluoromethyl) benzsulfamide
By 4-(trifluoromethyl) benzene sulfonyl chloride (587mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred 4h.Water (25mL) is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid (690mg, yield is 84%).
1H NMR(400MHz，DMSO-d 6)δ10.42(s，1H)，8.11(d，J=2.4Hz，1H)，7.98(d，J=8.8Hz，2H)，7.94(d，J=8.8Hz，2H)，7.76(d，J=2.4Hz，1H)，3.54(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-(trifluoromethyl) benzsulfamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-4-(trifluoromethyl) benzsulfamide (411mg, 1.0mmol), Glacial acetic acid potassium (196mg, 2mmol) with connection pinacol borate (304mg, mixture 1.2mmol) in dioxane (7mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (390mg, yield is 85%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ10.14(s，1H)，8.20(d，J=1.6Hz，1H)，7.96(d，J=8.4Hz，2H)，7.87(d，J=8.4Hz，2H)，7.69(d，J=1.6Hz，1H)，3.54(s，3H)，1.29(s，12H)
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-(trifluoromethyl) benzsulfamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-(trifluoromethyl) benzsulfamide (110mg, 0.24mmol, 1.2eq) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide-water (5mL:0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=60:1, v/v) purification residues is yellow solid (91mg, yield is 78%).
1H NMR(400MHz，DMSO-d 6)δ10.18(s，1H)，8.26(d，J=2.2Hz，1H)，8.03-7.90(m，6H)，6.45(s，2H)，6.30(s，1H)，5.41-5.27(m，1H)，3.57(s，3H)，2.57(s，3H)，2.23-2.10(m，2H)，2.10-1.95(m，2H)，1.94-1.78(m，2H)，1.74-1.58(m，2H).
Embodiment 4:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2-(trifluoromethyl) benzsulfamide (compound 4)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-2-(trifluoromethyl) benzsulfamide
By 2-(trifluoromethyl) benzene sulfonyl chloride (587mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred 4h.Water (25mL) is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid (660mg, yield is 80%).
1H NMR(400MHz，CD 3OD)δ8.07-7.89(m，3H)，7.88-7.62(m，3H)，3.69(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-2-(trifluoromethyl) benzsulfamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-4-(trifluoromethyl) benzsulfamide (411mg, 1.0mmol), Glacial acetic acid potassium (196mg, 2mmol) with connection pinacol borate (304mg, mixture 1.2mmol) in dioxane (7mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (349mg, yield is 76%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ9.96(s，1H)，8.19(d，J=1.6Hz，1H)，8.06-7.96(m，1H)，7.96-7.90(m，1H)，7.88-7.77(m，2H)，7.72(d，J=1.6Hz，1H)，3.56(s，3H)，1.28(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2-(trifluoromethyl) benzsulfamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-(trifluoromethyl) benzsulfamide (110mg, 0.24mmol, 1.2eq) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide and water (5mL/0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (76mg, yield is 67%).
1H NMR(400MHz，DMSO-d 6)δ10.00(s，1H)，8.26(d，J=2.2Hz，1H)，8.05-7.98(m，2H)，7.92(d，J=2.2Hz，1H)，7.91(s，1H)，7.87-7.78(m，2H)，6.44(s，2H)，6.30(s，1H)，5.44-5.22(m，1H)，3.59(s，3H)，2.56(s，3H)，2.22-2.09(m，2H)，2.09-1.96(m，2H)，1.92-1.78(m，2H)，1.74-1.59(m，2H).
Embodiment 5:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2-(trifluoromethyl) benzsulfamide (compound 5)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-3-(trifluoromethyl) benzsulfamide
By 3-(trifluoromethyl) benzene sulfonyl chloride (588mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow solid (320mg, yield is 39%).
1H NMR(400MHz，DMSO-d 6)δ10.43(s，1H)，8.12(d，J=2.3Hz，1H)，8.09-8.05(m，2H)，8.00(d，J=8.0Hz，1H)，7.82(t，J=8.0Hz，1H)，7.77(d，J=2.3Hz，1H)，3.54(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-3-(trifluoromethyl) benzsulfamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-3-(trifluoromethyl) benzsulfamide (270mg, 0.66mmol), Glacial acetic acid potassium (130mg, 1.32mmol) with connection pinacol borate (167mg, mixture 0.79mmol) in dioxane (6mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (25mg, 0.033mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (220mg, yield is 73%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=3:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ10.20(s，1H)，8.18(d，J=1.7Hz，1H)，8.05(d，J=7.9Hz，1H)，8.00(s，1H)，7.95(d，J=7.9Hz，1H)，7.81(t，J=7.9Hz，1H)，7.71(d，J=1.7Hz，1H)，3.57(s，3H)，1.29(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-3-(trifluoromethyl) benzsulfamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-3-(trifluoromethyl) benzsulfamide (110mg, 0.24mmol) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide and water (4mL:0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (101mg, yield is 88%).
1H NMR(400MHz，DMSO-d 6)δ10.19(s，1H)，8.25(d，J=2.1Hz，1H)，8.11(s，1H)，8.08-7.97(m，3H)，7.95(s，1H)，7.81(t，J=7.8Hz，1H)，6.45(s，2H)，6.30(s，1H)，5.44-5.28(m，1H)，3.58(s，3H)，2.57(s，3H)，2.22-2.10(m，2H)，2.10-1.99(m，2H)，1.94-1.79(m，2H)，1.75-1.58(m，2H).
Embodiment 6:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide (compound 6)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-4-fluorobenzenesulfonamide
By 4-fluorophenylsulfonyl chloride (467mg, 2.4mmol, methylene dichloride (5mL) solution 1.2eq) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residue is yellow solid (590mg, yield is 82%).
1H NMR(400MHz，DMSO-d 6)δ10.21(s，1H)，8.08(d，J=2.3Hz，1H)，7.82(dd，J=8.9，5.2Hz，2H)，7.72(d，J=2.3Hz，1H)，7.43(t，J=8.9Hz，2H)，3.63(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-fluorobenzenesulfonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-4-fluorobenzenesulfonamide (550mg, 1.52mmol), Glacial acetic acid potassium (300mg, 3.04mmol) with connection pinacol borate (466mg, mixture 1.84mmol) in dioxane (7mL) is degassed, and [1,1'-two (diphenylphosphino) ferrocene] palladium chloride (56mg, 0.076mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow solid (374mg, yield is 60%).
1H NMR(400MHz，DMSO-d 6)δ9.92(s，1H)，8.17(d，J=1.6Hz，1H)，7.82(dd，J=8.9，5.2Hz，2H)，7.71(d，J=1.6Hz，1H)，7.40(t，J=8.9Hz，2H)，3.61(s，3H)，1.29(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-fluorobenzenesulfonamide (103mg, 0.24mmol, 1.2eq) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide-water (4mL:0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (56mg, yield is 53%).
1H NMR(400MHz，DMSO-d 6)δ9.93(s，1H)，8.23(d，J=2.2Hz，1H)，7.92(d，J=2.2Hz，1H)，7.91(s，1H)，7.82(dd，J=8.9，5.2Hz，2H)，7.41(t，J=8.8Hz，2H)，6.44(s，2H)，6.30(s，1H)，5.41-5.23(m，1H)，3.65(s，3H)，2.57(s，3H)，2.22-2.09(m，2H)，2.08-2.00(m，2H)，1.92-1.81(m，2H)，1.71-1.61(m，2H).
Embodiment 7:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide (compound 7)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-2-fluorobenzenesulfonamide
By 2-fluorophenylsulfonyl chloride (467mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid (588mg, yield is 82%).
1H NMR(400MHz，DMSO-d 6)δ10.40(s，1H)，8.11(d，J=2.3Hz，1H)，7.76-7.66(m，3H)，7.49-7.42(m，1H)，7.34(td，J=7.8，1.0Hz，1H)，3.59(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-2-fluorobenzenesulfonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-2-fluorobenzenesulfonamide (580mg, 1.60mmol), Glacial acetic acid potassium (315mg, 3.20mmol) with connection pinacol borate (490mg, mixture 1.92mmol) in dioxane (7mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (59mg, 0.08mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (350mg, yield is 54%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=6:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ10.12(s，1H)，8.18(d，J=1.7Hz，1H)，7.72(d，J=1.7Hz，1H)，7.71-7.60(m，2H)，7.49-7.40(m，1H)，7.34-7.25(m，1H)，3.59(s，3H)，1.29(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.30mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-2-fluorobenzenesulfonamide (148mg, 0.36mmol) with salt of wormwood (125mg, mixture 0.90mmol) in DMF and water (5mL:0.30mL) is degassed, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (22mg, 0.03mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=50:1, v/v) purification residues is yellow solid (120mg, yield is 76%).
1H NMR(400MHz，DMSO-d 6)δ10.12(s，1H)，8.25(d，J=2.0Hz，1H)，7.93(d，J=2.0Hz，1H)，7.92(s，1H)，7.73-7.64(m，2H)，7.51-7.40(m，1H)，7.30(t，J=7.6Hz，1H)，6.44(s，2H)，6.30(s，1H)，5.41-5.26(m，1H)，3.59(s，3H)，2.57(s，3H)，2.24-2.10(m，2H)，2.10-2.00(m，2H)，1.95-1.77(m，2H)，1.75-1.59(m，2H).
MS(ESI+)m/z524.0[M+H] +
Embodiment 8:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-3-fluorobenzenesulfonamide (compound 8)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-3-fluorobenzenesulfonamide
By 3-fluorophenylsulfonyl chloride (467mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residue is yellow solid (560mg, yield is 74%).
1H NMR(400MHz，DMSO-d 6)δ10.33(s，1H)，8.10(d，J=2.2Hz，1H)，7.72(d，J=2.3Hz，1H)，7.69-7.50(m，4H)，3.63(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-3-fluorobenzenesulfonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-3-fluorobenzenesulfonamide (550mg, 1.52mmol), Glacial acetic acid potassium (300mg, 3.04mmol) with connection pinacol borate (466mg, mixture 1.84mmol) in dioxane (7mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (59mg, 0.08mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow solid (400mg, yield is 65%).
1H NMR(400MHz，DMSO-d 6)δ10.06(s，1H)，8.18(d，J=1.6Hz，1H)，7.72(d，J=1.6Hz，1H)，7.67-7.57(m，1H)，7.56-7.47(m，3H)，3.62(s，3H)，1.29(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-3-fluorobenzenesulfonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (81mg, 0.25mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-3-fluorobenzenesulfonamide (123mg, 0.30mmol) with salt of wormwood (103mg, mixture 0.75mmol) in DMF and water (4mL:0.25mL) is degassed, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (20mg, 0.025mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=50:1, v/v) purification residues is yellow solid (104mg, yield is 80%).
1H NMR(400MHz，DMSO-d 6)δ10.06(s，1H)，8.22(d，J=2.0Hz，1H)，7.94(d，J=2.0Hz，1H)，7.92(s，1H)，7.65-7.48(m，5H)，6.44(s，2H)，6.30(s，1H)，5.41-5.24(m，1H)，3.65(s，3H)，2.56(s，3H)，2.24-2.10(m，2H)，2.10-1.96(m，2H)，1.94-1.78(m，2H)，1.74-1.58(m，2H).
Embodiment 9:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-5-chlorothiophene-2-sulphonamide (compound 9)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-5-chlorothiophene-2-sulphonamide
By the chloro-thiophene of 5--2-SULPHURYL CHLORIDE (521mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred 4h.Water (25mL) is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) separating residue is yellow solid (755mg, yield is 98%).
1H NMR(300MHz，CD 3OD)δ8.01(d，J=2.1Hz，1H)，7.88(d，J=2.1Hz，1H)，7.33(d，J=3.9Hz，1H)，7.02(d，J=3.9Hz，1H)，3.79(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-5-chlorothiophene-2-sulphonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-5-chlorothiophene-2-sulphonamide (595mg, 1.55mmol), Glacial acetic acid potassium (306mg, 3.1mmol) with connection pinacol borate (472mg, mixture 1.86mmol) in dioxane (10mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (60mg, 0.08mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid (458mg, yield is 69%).
1H NMR(400MHz，DMSO-d 6)δ10.22(s，1H)，8.24(d，J=1.7Hz，1H)，7.73(d，J=1.7Hz，1H)，7.30(d，J=4.1Hz，1H)，7.21(d，J=4.1Hz，1H)，3.71(s，3H)，1.30(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-5-chlorothiophene-2-sulphonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-5-chlorothiophene-2-sulphonamide (104mg, 0.24mmol) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide and water (4mL:0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (64mg, yield is 59%).
1H NMR(400MHz，DMSO-d 6)δ10.23(s，1H)，8.30(d，J=2.1Hz，1H)，7.97(d，J=2.1Hz，1H)，7.96(s，1H)，7.39(d，J=4.1Hz，1H)，7.22(d，J=4.1Hz，1H)，6.44(s，2H)，6.31(s，1H)，5.44-5.24(m，1H)，3.74(s，3H)，2.58(s，3H)，2.21-2.11(m，2H)，2.11-1.99(m，2H)，1.92-1.80(m，2H)，1.72-1.60(m，2H).
Embodiment 10:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) amsacrine (compound 10)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base) amsacrine
By methane sulfonyl chloride (275mg, 2.4mmol, 1.2eq) methylene dichloride (5mL) solution be added drop-wise to the bromo-2-methoxypyridine (0.406g, 2mmol) of 3-amino-5-and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, v/v) separating residue is yellow solid (498mg, yield is 89%).
1H NMR(400MHz，DMSO-d 6)δ9.49(s，1H)，8.09(d，J=2.3Hz，1H)，7.78(d，J=2.3Hz，1H)，3.91(s，3H)，3.10(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) amsacrine
By N-(the bromo-2-methoxypyridine of 5--3-base) amsacrine (490mg, 1.74mmol), Glacial acetic acid potassium (315mg, 3.20mmol) with connection pinacol borate (531mg, mixture 2.09mmol) in dioxane (10mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (64mg, 0.087mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=2:1, v/v) purification residues is yellow solid (410mg, yield is 72%).
1H NMR(400MHz，DMSO-d 6)δ9.25(s，1H)，8.21(d，J=1.7Hz，1H)，7.77(d，J=1.7Hz，1H)，3.94(s，3H)，3.01(s，3H)，1.30(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) amsacrine
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (97mg, 0.30mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) amsacrine (119mg, 0.36mmol) with salt of wormwood (125mg, mixture 0.90mmol) in DMF and water (5mL:0.30mL) is degassed, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (22mg, 0.03mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1 then methylene dichloride/10% ammoniacal liquor methanol solution=80:1, v/v) purification residues is yellow solid (84mg, yield is 64%).
1H NMR(400MHz，DMSO-d 6)δ9.26(s，1H)，8.26(d，J=2.2Hz，1H)，7.96(s，1H)，7.95(d，J=2.1Hz，1H)，6.44(s，2H)，6.29(s，1H)，5.47-5.29(m，1H)，3.95(s，3H)，3.04(s，3H)，2.57(s，3H)，2.23-2.11(m，2H)，2.11-1.97(m，2H)，1.93-1.77(m，2H)，1.74-1.56(m，2H).
Embodiment 11:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) cyclopropanesulfonamide (compound 11)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base) cyclopropanesulfonamide
By cyclopropanesulfonyl chloride (338mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, v/v) purification residues is yellow solid (493mg, yield is 81%).
1H NMR(400MHz，DMSO-d 6)δ9.54(s，1H)，8.10(d，J=2.3Hz，1H)，7.79(d，J=2.3Hz，1H)，3.91(s，3H)，2.78(s，1H)，0.99-0.87(m，4H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) cyclopropanesulfonamide
By N-(the bromo-2-methoxypyridine of 5--3-base) cyclopropanesulfonamide (485mg, 1.58mmol), Glacial acetic acid potassium (311mg, 3.16mmol) with connection pinacol borate (482mg, mixture 1.90mmol) in dioxane (8mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (60mg, 0.079mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (510mg, yield is 91%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=3:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ9.28(s，1H)，8.21(d，J=1.7Hz，1H)，7.79(d，J=1.7Hz，1H)，3.94(s，3H)，2.70-2.58(m，1H)，1.30(s，12H)，0.98-0.79(m，4H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) cyclopropanesulfonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (60mg, 0.186mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl) cyclopropanesulfonamide (80mg, 0.223mmol) with salt of wormwood (77mg, 0.558mmol) at N, mixture in dinethylformamide and water (2.0mL:0.186mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (15mg, 0.0186mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=50:1, v/v) purification residues is yellow solid (40mg, yield is 46%).
1H NMR(400MHz，DMSO-d 6)δ9.27(s，1H)，8.26(d，J=2.2Hz，1H)，7.99(d，J=2.1Hz，1H)，7.96(s，1H)，6.45(s，2H)，6.29(s，1H)，5.44-5.33(m，1H)，3.95(s，3H)，2.71-2.64(m，1H)，2.57(s，3H)，2.22-2.11(m，2H)，2.11-2.00(m，2H)，1.91-1，80(m，2H)，1.71-1，60(m，2H)，0.97-0.88(m，4H).
MS(ESI+)m/z470.1[M+H] +.
Embodiment 12:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-3-chloropropane-1-sulphonamide (compound 12)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-3-chloropropane-1-sulphonamide
By 3-chloropropane-1-SULPHURYL CHLORIDE (425mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residue is yellow solid (402mg, yield is 58%).
1H NMR(400MHz,DMSO-d 6)δ9.70(s,1H),8.12(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,1H),3.91(s,3H),3.75(t,J=6.5Hz,2H),3.29(t,J=7.6Hz,2H),2.23-2.10(m,2H).
The synthesis of the chloro-N-of step 2:3-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) propane-1-sulphonamide
By N-(the bromo-2-methoxypyridine of 5--3-base)-3-chloropropane-1-sulphonamide (400mg, 1.16mmol), Glacial acetic acid potassium (228mg, 2.32mmol) with connection pinacol borate (325mg, mixture 1.28mmol) in dioxane (5mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (42mg, 0.058mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow solid (308mg, yield is 68%).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.22(d,J=1.6Hz,1H),7.78(d,J=1.6Hz,1H),3.94(s,3H),3.74(t,J=6.5Hz,2H),3.26-3.13(m,2H),2.24-2.10(m,2H),1.30(s,12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-3-chloropropane-1-sulphonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), the chloro-N-of 3-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) propane-1-sulphonamide (94mg, 0.24mmol, 1.2eq) and salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide and water (4mL:0.20mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (50mg, yield is 50%).
1H NMR(400MHz，DMSO-d 6)δ8.37(d，J=2.2Hz，1H)，8.04(d，J=2.2Hz，1H)，7.98(s，1H)，6.44(s，2H)，6.30(s，1H)，5.42-5.29(m，1H)，3.94(s，3H)，3.74(t，J=6.4Hz，2H)，3.37(t，J=7.4Hz，2H)，2.58(s，3H)，2.48-2.39(m，2H)，2.24-2.11(m，2H)，2.08-2.00(m，2H)，1.90-1.80(m，2H)，1.72-1.61(m，2H).
Embodiment 13:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) butane-1-sulphonamide (compound 13)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base) butane-1-sulphonamide
By butane-1-SULPHURYL CHLORIDE (376mg, 2.4mmol, methylene dichloride (5mL) solution 1.2eq) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) with pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred and spends the night.25mL water is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid (469mg, yield is 73%).
1H NMR(400MHz，DMSO-d 6)δ9.50(s，1H)，8.09(d，J=2.3Hz，1H)，7.77(d，J=2.3Hz，1H)，3.90(s，3H)，3.15(t，J=7.6Hz，2H)，1.74-1.61(m，2H)，1.43-1.32(m，2H)，0.87(t，J=7.4Hz，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) butane-1-sulphonamide
By N-(the bromo-2-methoxypyridine of 5--3-base) butane-1-sulphonamide (400mg, 1.24mmol), Glacial acetic acid potassium (244mg, 2.48mmol) with connection pinacol borate (347mg, mixture 1.36mmol) in dioxane (6mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (46mg, 0.062mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Product yellow solid (401mg, yield is 87%) is obtained with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ9.27(s，1H)，8.20(d，J=1.7Hz，1H)，7.78(d，J=1.6Hz，1H)，3.93(s，3H)，3.05(t，J=7.4Hz，2H)，1.75-1.62(m，2H)，1.43-1.32(m，2H)，1.30(s，12H)，0.86(t，J=7.4Hz，3H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) butane-1-sulphonamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) butane-1-sulphonamide (89mg, 0.24mmol) and salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide and water (4mL:0.20mL) is degassed, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride PdCl 2(dppf) (16mg, 0.02mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (67mg, yield is 69%).
1H NMR(400MHz，DMSO-d 6)δ9.27(s，1H)，8.26(d，J=2.2Hz，1H)，7.96(d，J=2.2Hz，1H)，7.95(s，1H)，6.44(s，2H)，6.30(s，1H)，5.43-5.29(m，1H)，3.94(s，3H)，3.16-3.02(t，J=7.6Hz，2H)，2.57(s，3H)，2.26-2.10(m，2H)，2.10-1.97(m，2H)，1.93-1.78(m，2H)，1.80-1.58(m，4H)，1.47-1.32(m，2H)，0.88(t，J=7.6Hz，3H).
Embodiment 14:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) benzsulfamide (compound 14)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base) benzsulfamide
By benzene sulfonyl chloride (424mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred 4hr.Water (25mL) is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=10:1, v/v) purification residues is yellow solid (580mg, yield is 85%).
1H NMR(300MHz，DMSO-d 6)δ10.16(s，1H)，8.05(d，J=2.2Hz，1H)，7.81-7.38(m，6H)，3.62(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) benzsulfamide
By N-(the bromo-2-methoxypyridine of 5--3-base) benzsulfamide (580mg, 1.69mmol), Glacial acetic acid potassium (332mg, 3.38mmol) with connection pinacol borate (515mg, mixture 2.03mmol) in dioxane (10mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (62mg, 0.0845mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=9:1, v/v) purification residues is yellow solid (470mg, yield is 71%).
1H NMR(300MHz，DMSO-d 6)δ9.86(s，1H)，8.15(d，J=1.3Hz，1H)，7.77-7.49(m，6H)，3.60(s，3H)，1.29(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base) benzsulfamide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) benzsulfamide (94mg, 0.24mmol) with salt of wormwood (83mg, mixture 0.60mmol) in DMF-water (4mL:0.20mL) is degassed, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) is added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (84mg, yield is 83%).
1H NMR(400MHz，DMSO-d 6)δ9.87(s，1H)，8.21(d，J=2.2Hz，1H)，7.94(d，J=2.1Hz，1H)，7.91(s，1H)，7.77(dd，J=7.4，1.4Hz，2H)，7.64(t，J=7.4Hz，1H)，7.56(t，J=7.5Hz，2H)，6.44(s，2H)，6.31(s，1H)，5.44-5.25(m，1H)，3.63(s，3H)，2.57(s，3H)，2.27-2.11(m，2H)，2.11-2.00(m，2H)，1.98-1.76(m，2H)，1.77-1.57(m，2H).
Embodiment 15:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-methoxybenzenesulphoismide (compound 15)
The synthesis of step 1:N-(the bromo-2-methoxypyridine of 5--3-base)-4-methoxybenzenesulphoismide
By 4-Methoxybenzenesulfonyl chloride (496mg, methylene dichloride (5mL) solution 2.4mmol) is added drop-wise to the bromo-2-methoxypyridine of 3-amino-5-(0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of methylene dichloride (5mL), reaction mixture is at room temperature stirred 4h.Water (25mL) is added in reaction mixture, the mixture (30mL × 3) produced with dichloromethane extraction.With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) separating residue is yellow solid (668mg, yield is 90%).
1H NMR(400MHz，DMSO-d 6)δ9.99(s，1H)，8.02(d，J=2.4Hz，1H)，7.70(d，J=9.0Hz，2H)，7.67(d，J=2.4Hz，1H)，7.09(d，J=9.0Hz，2H)，3.82(s，3H)，3.67(s，3H).
The synthesis of step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-methoxybenzenesulphoismide
By N-(the bromo-2-methoxypyridine of 5--3-base)-4-methoxybenzenesulphoismide (373mg, 1.0mmol), Glacial acetic acid potassium (196mg, 2mmol) with connection pinacol borate (304mg, mixture 1.2mmol) in dioxane (7mL) is degassed, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (62mg, 0.0845mmol) is added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow solid (370mg, yield is 88%).
1H NMR(400MHz，DMSO-d 6)δ9.67(s，1H)，8.13(d，J=1.6Hz，1H)，7.72(d，J=1.6Hz，1H)，7.61(d，J=9.0Hz，2H)，7.05(d，J=9.0Hz，2H)，3.80(s，3H)，3.65(s，3H)，1.29(s，12H).
The synthesis of step 3:N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-4-methoxybenzenesulphoismide
By the bromo-1-cyclopentyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-4-methoxybenzenesulphoismide (101mg, 0.24mmol, 1.2eq) with salt of wormwood (83mg, 0.60mmol) at N, mixture in dinethylformamide and water (4mL:0.20mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, stir 5 hours at 100 DEG C under argon atmosphere.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (84mg, yield is 79%).
1H NMR(400MHz，DMSO-d 6)δ9.68(s，1H)，8.18(d，J=2.0Hz，1H)，7.91(d，J=2.0Hz，1H)，7.88(s，1H)，7.71(d，J=8.9Hz，2H)，7.06(d，J=8.9Hz，2H)，6.43(s，2H)，6.30(s，1H)，5.43-5.22(m，1H)，3.81(s，3H)，3.68(s，3H)，2.56(s，3H)，2.21-2.10(m，2H)，2.10-2.00(m，2H)，1.92-1.80(m，2H)，1.77-1.56(m，2H).
Embodiment 16:7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (compound 16)
Step 1: the synthesis of trans-4-(the bromo-6-of 3-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-base is amino) hexalin
In sealed tube, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles-1-base) the iodo-2-picoline of-4-(7.8g, 20mmol), trans-4-Trans-4-Amino Cyclohexanol (4.6g, 40mmol), the solution of diisopropyl ethyl amine (7.76g, 60mmol) in N-Methyl pyrrolidone (80mL) stirs 24 hours at 160 DEG C.After being cooled to room temperature, with water (400mL) diluted reaction mixture, be extracted with ethyl acetate (200mL × 3).With the organic layer that water (200mL × 2) and saturated aqueous common salt (200mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, then petrol ether/ethyl acetate=4:1, v/v) purification residues is yellow solid (4.90g, yield is 65%).
1H NMR(400MHz，DMSO-d 6，)δ6.52(s，1H)，5.75(s，2H)，5.51(d，J=8.4Hz，1H)，4.56(d，J=4.0Hz，1H)，3.57-3.35(m，2H)，2.46(s，3H)，2.05(s，6H)，1.90-1.73(m，4H)，1.49-1.27(m，4H).
MS(ESI+)m/z378.0[M+H] +.
The synthesis of step 2:2-(trans-4-(the bromo-6-of 3-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-base is amino) cyclohexyloxy) ethanol
By sodium hydride (70% dispersion liquid in oil, 686mg, 20mmol) be added to trans-4-(the bromo-6-(2 of 3-at 0 DEG C, 5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-base amino) hexalin (3.78g, 10mmol) at N, in solution in dinethylformamide (38mL), and the reaction mixture produced is stirred 2.5 hours at 0 DEG C.Add 1,3,2-dioxazole thiophene-2,2-dioxide (1.86g, 15mmol), and the reaction mixture produced is stirred 2 hours at 0 DEG C.With methyl alcohol (2mL) cancellation reaction mixture, evaporated under reduced pressure.With 150mL dioxane and 3.78mL water dilution residue.Add tosic acid monohydrate (3.80g, 20mmol), the reaction mixture produced is stirred 3 hours at 40 DEG C.Concentrated reaction mixture, with the dilution of 100mL water, with dichloromethane extraction (50mL × 3).With the organic layer that water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, then petrol ether/ethyl acetate=3:1, v/v) purification residues is yellow oil (760mg, yield is 18%).
1H NMR(300MHz,DMSO-d 6)δ6.53(s,1H),5.74(s,2H),5.56(d,J=8.4Hz,1H),4.54(t,J=5.4Hz,1H),3.59-3.36(m,5H),3.29-3.15(m,1H),2.46(s,3H),2.05(s,6H),1.95-1.85(m,4H),1.55-1.26(m,4H).
MS(ESI+)m/z422.0[M+H] +
Step 3:(E) synthesis of-3-(6-(2,5-dimethyl-1H-pyrroles-1-base)-4-(trans-4-(2-hydroxyl-oxethyl) Cyclohexylamino)-2-picoline-3-base) ethyl propenoate
In sealed tube, by 2-(trans-4-(the bromo-6-(2 of 3-, 5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-base amino) cyclohexyloxy) ethanol (0.76g, 1.8mmol) and the solution of ethyl propenoate (575 μ L, 5.40mmol) in triethylamine (15mL) with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (0.208g, 0.18mmol), again mixture is sealed tubule with bubbling argon 5min.Reaction soln is stirred at 130 DEG C and spends the night, cool and concentrate.Add 50mL water, the mixture produced with ethyl acetate (50mL × 3) extraction.With the organic layer that water (50mL × 2) and saturated common salt washing (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=3:2, v/v) purification residues is yellow oil (770mg, yield is 97%).
1H NMR(400MHz,DMSO-d 6)δ7.60(d,J=16.0Hz,1H),6.47(s,1H),6.28(d,J=16.0Hz,1H),5.89(d,J=8.0Hz,1H),5.74(s,2H),4.53(t,J=5.6Hz,1H),4.21(q,J=7.2Hz,2H),3.55-3.36(m,5H),3.25-3.16(m,1H),2.37(s,3H),2.07(s,6H),2.01-1.78(m,4H),1.47-1.30(m,4H),1.28(t,J=7.2Hz,3H).
MS(ESI+)m/z442.1[M+H] +
Step 3:7-(2,5-dimethyl-1H-pyrroles-1-base)-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles-1-base)-4-(trans-4-(2-hydroxyl-oxethyl) Cyclohexylamino)-2-picoline-3-base) ethyl propenoate (0.77g, 1.74mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene (1.3mL, 8.70mmol) with potassium tert.-butoxide (98mg, solution 0.87mmol) in N,N-dimethylacetamide (10mL) stirs and spends the night at 150 DEG C.After being cooled to room temperature, with 50mL water diluted reaction mixture, be extracted with ethyl acetate (30mL × 3).With the organic layer that water (30mL × 2) and saturated aqueous common salt (30mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=1.5:1, then petrol ether/ethyl acetate=1:1, v/v) purification residues is yellow oil (0.25g, yield is 36%).
1H NMR(300MHz，DMSO-d 6)δ8.12(d，J=9.6Hz，1H)，6.61(d，J=9.6Hz，1H)，5.84(s，2H)，4.53(t，J=5.2Hz，1H)，3.55-3.40(m，5H)，3.35-3.27(m，1H)，2.73(s，3H)，2.70-2.55(m，2H)，2.12(s，6H)，2.08-1.97(m，2H)，1.70-1.40(m，4H).
MS(ESI+)m/z396.0[M+H] +
Step 4:7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles-1-base)-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (250mg, mixture backflow 0.63mmol) with oxammonium hydrochloride (218mg, 3.15mmol) in second alcohol and water (5mL:0.5mL) is spent the night.It is yellow blister solid (100mg, yield is 50%) that concentrated reaction mixture also obtains product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=20:1, then methylene dichloride/10% ammoniacal liquor methanol solution=15:1, v/v) purification residues.
1H NMR(300MHz，DMSO-d 6)δ7.79(d，J=9.9Hz，1H)，6.45(s，1H)，6.28(s，2H)，6.08(d，J=9.9Hz，1H)，4.57(t，J=5.1Hz，1H)，3.54-3.43(m，5H)，3.42-3.25(m，1H)，2.68-2.54(m，2H)，2.48(s，3H)，2.18-2.05(m，2H)，1.63-1.50(m，2H)，1.40-1.20(m，2H).
MS(ESI+)m/z318.1[M+H] +
The bromo-1-of step 5:7-amino-3-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By N-bromo-succinimide (56mg, 0.315mmol) be added to 7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.315mmol) in the solution of DMF (4mL).Reaction soln is at room temperature stirred 1 hour.Add 50mL water, the mixture produced with ethyl acetate (20mL × 5) extraction.With the organic layer that water (20mL × 2) and saturated common salt washing (20mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=30:1, then methylene dichloride/10% ammoniacal liquor methanol solution=20:1, v/v) purification residues is yellow solid (30mg, yield 32%).
1H NMR(400MHz，DMSO-d 6)δ8.27(s，1H)，6.50-6.37(m，3H)，4.57(s，1H)，3.55-3.35(m，6H)，2.62-2.53(m，2H)，2.49(s，3H)，2.18-2.08(m，2H)，1.73-1.67(m，2H)，1.38-1.25(m，2H)
MS(ESI+)m/z395.9[M+H] +.
Step 6:7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By the bromo-1-of 7-amino-3-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (30mg, 0.076mmol), 6-methoxypyridine-3-ylboronic acid (17.4mg, 0.115mmol) with salt of wormwood (166mg, mixture 1.20mmol) in DMF and water (3mL:0.6mL) is degassed.Two (triphenylphosphine) palladium chloride (11mg, 0.0152mmol) are added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, stir 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=20:1, v/v) purification residues is yellow solid (29mg, yield is 90%).
1H NMR(400MHz，DMSO-d 6)δ8.42(d，J=2.4Hz，1H)，7.99(dd，J=8.4，2.4Hz，1H)，7.93(s，1H)，6.83(d，J=8.4Hz，1H)，6.48(s，1H)，6.35(s，2H)，4.58(s，1H)，3.88(s，3H)，3.55-3.45(m，5H)，3.45-3.30(m，1H)，2.70-2.57(m，2H)，2.56(s，3H)，2.20-2.10(m，2H)，1.68-1.60(m，2H)，1.40-1.26(m，2H)
MS(ESI+)m/z425.0[M+H] +
Embodiment 17:N-(5-(7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (compound 17)
By the bromo-1-of 7-amino-3-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (79.2mg, 0.2mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-2, 4-difluorobenzenesulfonamide (102.3mg, 0.24mmol) with salt of wormwood (138mg, 1.0mmol) at N, mixture in dinethylformamide and water (2.5mL:0.5mL) is degassed, and by two (triphenylphosphine) palladium chloride (14mg, 0.02mmol) be added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=20:1, v/v) purification residues is yellow solid (43mg, yield is 35%).
1H NMR(400MHz，DMSO-d 6)δ10.18(s，1H)，8.27(d，J=2.4Hz，1H)，7.93(s，1H)，7.91(s，1H)，7.73(td，J=8.4，6.4Hz，1H)，7.66-7.49(td，J=10.0，2.4Hz，1H)，7.20(td，J=8.4，2.1Hz，1H)，6.47(s，1H)，6.38(s，2H)，4.58(t，J=4.8Hz，1H)，3.63(s，3H)，3.56-3.45(m，4H)，3.45-3.35(m，1H)，3.36-3.27(m，1H)，2.74-2.52(m，2H)，2.56(s，3H)，2.15(d，J=10.0Hz，2H)，1.65(d，J=10.8Hz，2H)，1.41-1.28(m，2H).
MS(ESI+)m/z615.90[M+H] +
Embodiment 18:N-(5-(7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (compound 18)
Step 1:(E)-3-(6-(2,5-dimethyl-1H-pyrroles-1-base)-4-(trans-4-hydroxy-cyclohexyl amino)-2-picoline-3-base) synthesis of ethyl propenoate
In sealed tube, by trans-4-(the bromo-6-(2 of 3-, 5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-base amino) hexalin (4.86g, 12.85mmol) and the solution of ethyl propenoate (2.73mL, 25.70mmol) in triethylamine (97mL) with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (1.48g, 1.285mmol), again mixture is sealed tubule with bubbling argon 5min.Reaction soln is stirred at 130 DEG C and spends the night, cool and concentrate.Add 50mL water, the mixture produced with ethyl acetate (50mL × 3) extraction.With the organic layer that water (50mL × 2) and saturated common salt washing (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=3:2, v/v) purification residues is yellow oil (3.77g, yield is 74%).
1H NMR(400MHz，DMSO-d 6)δ7.59(d，J=16.4Hz，1H)，6.45(s，1H)，6.28(d，J=16.4Hz，1H)，5.85(d，J=8.4Hz，1H)，5.74(s，2H)，4.54(d，J=4.0Hz，1H)，4.21(q，J=7.2Hz，2H)，3.45-3.35(m，2H)，2.37(s，3H)，2.07(s，6H)，1.88-1.71(m，4H)，1.45-1.20(m，4H)，1.28(t，J=7.2Hz，3H)
MS(ESI+)m/z398.0[M+H] +
Step 2:7-(2,5-dimethyl-1H-pyrroles-1-base)-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles-1-base)-4-(trans-4-hydroxy-cyclohexyl is amino)-2-picoline-3-base) ethyl propenoate (3.37g, 8.48mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene DBU(6.4mL, 42.4mmol) and potassium tert.-butoxide (475mg, solution 4.24mmol) in N,N-dimethylacetamide (35mL) stirs 4h at 150 DEG C.After being cooled to room temperature, with 150mL water diluted reaction mixture, be extracted with ethyl acetate (50mL × 3).With the organic layer that water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=1.5:1, then petrol ether/ethyl acetate=1:1, v/v) purification residues is yellow oil (1.02g, yield is 31%).
1H NMR(300MHz，DMSO-d 6)δ8.11(d，J=9.6Hz，1H)，7.69-7.49(m，1H)，6.60(d，J=9.6Hz，1H)，5.84(s，2H)，4.60(d，J=3.9Hz，1H)，3.60-3.40(m，1H)，2.72(s，3H)，2.69-2.54(m，2H)，2.12(s，6H)，1.95-1.75(m，2H)，1.69-1.36(m，4H).
MS(ESI+)m/z352.1[M+H] +
Step 3:7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles-1-base)-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (1.01g, mixture backflow 2.87mmol) with oxammonium hydrochloride (998mg, 14.35mmol) in second alcohol and water (20mL:2mL) is spent the night.It is yellow blister solid (100mg, yield is 50%) that concentrated reaction mixture also obtains product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=50:1, then methylene dichloride/10% ammoniacal liquor methanol solution=40:1, v/v) purification residues.
1H NMR(300MHz，DMSO-d 6)δ7.79(d，J=9.6Hz，1H)，6.44(s，1H)，6.30(s，2H)，6.07(d，J=9.6Hz，1H)，4.67(d，J=4.2Hz，1H)，4.10(q，J=5.1Hz，1H)，3.66-3.44(m，1H)，2.74-2.52(m，2H)，2.47(s，3H)，2.05-1.86(m，2H)，1.64-1.45(m，2H)，1.41-1.20(m，2H).
MS(ESI+)m/z274.1[M+H] +
The bromo-1-of step 4:7-amino-3-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By N-bromo-succinimide (228mg, 1.28mmol) be added to 7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (538mg, 1.97mmol) is in the solution of DMF (10mL).Reaction soln is at room temperature stirred 1 hour.Add 50mL water, the mixture produced with ethyl acetate (20mL × 5) extraction.With the organic layer that water (20mL × 2) and saturated common salt washing (20mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=50:1, v/v) purification residues is yellow solid (312mg, yield is 45%).
1H NMR(300MHz，DMSO-d 6)δ8.27(s，1H)，6.45(s，2H)，5.76(s，1H)，4.69(d，J=4.2Hz，1H)，3.62-3.44(m，1H)，2.66-2.52(m，2H)，2.49(s，3H)，2.02-1.90(m，2H)，1.63-1.50(m，2H)，1.43-1.25(m，2H).
MS(ESI+)m/z352.0[M+H] +.
The synthesis of step 5:N-(5-(7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
By the bromo-1-of 7-amino-3-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.284mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (145mg, 0.115mmol) degassed with the mixture of salt of wormwood (276mg, 2mmol) in DMF and water (5mL:1mL), and two (triphenylphosphine) palladium chloride (20mg, 0.0284mmol) are added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 3h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=60:1, v/v) purification residues is yellow solid (19mg, yield is 12%).
1H NMR(400MHz，DMSO-d 6)δ10.18(s，1H)，8.26(s，1H)，7.94-7.89(m，2H)，7.73(td，J=8.8，6.4Hz，1H)，7.58(t，J=8.8Hz，1H)，7.21(td，J=9.2，2.4Hz，1H)，6.48(s，1H)，6.39(s，2H)，4.69(d，J=4.0Hz，1H)，3.63(s，3H)，2.56(s，3H)，2.55(m，2H)，1.98(d，J=8.8Hz，2H)，1.60(d，J=10.8Hz，2H)，1.41-1.30(m，2H).
MS(ESI+)m/z571.9[M+H] +
The synthesis (compound 19) of embodiment 19:7-amino-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one
The synthesis of the bromo-6-of step 1:3-(2,5-dimethyl-1H-pyrroles-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino) pyridine
In sealed tube, by bromo-for 3-6-(2,5-dimethyl-1H-pyrroles-1-base) the iodo-2-picoline of-4-(6.00g, 15.35mmol), tetrahydrochysene-2H-pyrans-4-amine (3.11g, 30.70mmol), the solution of diisopropyl ethyl amine (5.95g, 46.05mmol) in METHYLPYRROLIDONE (60mL) heats 24 hours at 160 DEG C.After being cooled to room temperature, add 300mL water, be extracted with ethyl acetate produced mixture (150mL × 3).With the organic layer that water (150mL × 2) and salt solution (150mL × 2) washing merge, with anhydrous sodium sulfate drying, filter and concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid (1.52g, yield 27%).
1H NMR(400MHz，DMSO-d 6)δ6.62(s，1H)，5.75(s，2H)，5.70(d，J=7.2Hz，1H)，3.89-3.82(m，2H)，3.80-3.72(m，1H)，3.43(t，J=10.9Hz，2H)，2.48(s，3H)，2.05(s，6H)，1.95-1.85(m，2H)，1.70-1.56(m，2H).
MS(ESI+)m/z364.0[M+H] +.
Step 2:(E)-3-(6-(2,5-dimethyl-1H-pyrroles-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-4-base amino) pyridin-3-yl) synthesis of ethyl propenoate
In sealed tube, by bromo-for 3-6-(2,5-dimethyl-1H-pyrroles-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino) pyridine (1.71g, 4.69mmol) and the solution of ethyl propenoate (1.50mL, 14.07mmol) in triethylamine (30mL) with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (0.542g, 0.47mmol), again mixture is sealed tubule with bubbling argon 5min.Reaction soln is stirred at 130 DEG C and spends the night, cool and concentrate.Add 100mL water, the mixture produced with ethyl acetate (50mL × 3) extraction.With the organic layer that water (50mL × 2) and saturated common salt washing (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=10:1, then petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow oil (540mg, yield 30%).
1H NMR(400MHz，DMSO-d 6)δ7.52(d，J=16.4Hz，1H)，6.40(s，1H)，6.35(d，J=16.4Hz，1H)，6.05(d，J=6.8Hz，1H)，5.75(s，2H)，4.21(q，J=7.2Hz，2H)，3.90-3.77(m，2H)，3.75-3.62(m，1H)，3.43(t，J=11.2Hz，2H)，2.38(s，3H)，2.08(s，6H)，1.84-1.72(m，2H)，1.65-1.51(m，2H)，1.28(t，J=7.2Hz，3H).
MS(ESI+)m/z384.1[M+H] +.
The synthesis of step 3:7-(2,5-dimethyl-1H-pyrroles-1-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino) pyridin-3-yl) ethyl propenoate (313mg, 0.82mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene (627 μ L, 4.1mmol) and potassium tert.-butoxide (46mg, solution 0.41mmol) in N,N-dimethylacetamide (5mL) stirs 7 hours at 150 DEG C.After being cooled to room temperature, with 30mL water diluted reaction mixture, be extracted with ethyl acetate (20mL × 3).With the organic layer that water (20mL × 2) and saturated aqueous common salt (20mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, then petrol ether/ethyl acetate=2:1, v/v) purification residues is yellow oil (72mg, yield is 26%).
1H NMR(400MHz，CDCl 3)δ7.94(d，J=9.7Hz，1H)，7.28(s，1H)，6.73(d，J=9.7Hz，1H)，5.96(s，2H)，5.30-5.09(m，1H)，4.19-4.09(m，2H)，3.55(t，J=11.2Hz，2H)，3.00-2.84(m，2H)，2.82(s，3H)，2.21(s，6H)，1.72-1.62(m，2H).
The synthesis of step 4:7-amino-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles-1-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one (721mg, mixture backflow 2.14mmol) with oxammonium hydrochloride (743mg, 10.7mmol) in alcohol-water (15mL:1.5mL) is spent the night.It is yellow solid (684mg, thick yield is 114%) that concentrated reaction mixture also obtains crude product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=50:1, then methylene dichloride/10% ammoniacal liquor methanol solution=25:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ7.82(d，J=9.6Hz，1H)，6.52(s，1H)，6.35(s，2H)，6.10(d，J=9.6Hz，1H)，5.20-4.90(m，1H)，4.01(dd，J=11.2，4.0Hz，2H)，3.45(t，J=11.2Hz，2H)，2.85-2.70(m，2H)，2.48(s，3H)，1.53-1.46(m，2H).
The synthesis of the bromo-5-methyl isophthalic acid of step 5:7-amino-3--(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one
By N-bromo-succinimide (294mg, 1.65mmol) be added to 7-amino-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one crude product (564mg, 2.18mmol) is in the solution of DMF (17mL).Reaction soln is at room temperature stirred 1h.Add 100mL water, the mixture produced with ethyl acetate (50mL × 5) extraction.With the organic layer that water (50mL × 2) and saturated common salt washing (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=25:1, v/v) purification residues is yellow solid (335mg, yield 46%).
1H NMR(300MHz，DMSO-d 6)δ8.30(s，1H)，6.52(s，1H)，6.50(s，2H)，4.90-4.70(m，1H)，4.01(dd，J=11.2，4.1Hz，2H)，3.45(t，J=11.2Hz，2H)，2.84-2.65(m，2H)，2.50(s，3H)，1.60-1.50(m，2H).
Step 6:7-amino-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one
By bromo-for 7-amino-3-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one (101mg, 0.3mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (154mg, 0.36mmol) degassed with the mixture of salt of wormwood (138mg, 1mmol) in DMF and water (2.5mL:0.5mL), and two (triphenylphosphine) palladium chloride (21mg, 0.03mmol) are added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 4h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=30:1, v/v) purification residues is yellow solid (103mg, yield is 68%).
1H NMR(400MHz，DMSO-d 6)δ10.20(s，1H)，8.27(s，1H)，7.94(d，J=6.9Hz，2H)，7.73(dd，J=14.8，8.4Hz，1H)，7.58(t，J=8.8Hz，1H)，7.20(t，J=8.5Hz，1H)，6.54(s，1H)，6.45(s，2H)，5.02-4.89(m，1H)，4.04(dd，J=11.2，4.0Hz，2H)，3.62(s，3H)，3.47(t，J=11.2Hz，2H)，2.87-2.74(d，J=9.0Hz，2H)，2.57(s，3H)，1.57(dd，J=11.2，2.0Hz，2H).
MS(ESI+)m/z557.9[M+H] +.
The synthesis (compound 20) of embodiment 20:7-amino-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one
By bromo-for 7-amino-3-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one (101mg, 0.3mmol), pyridine-4-boric acid (55mg, 0.36mmol) degassed with the mixture of salt of wormwood (138mg, 1mmol) in DMF-water (2.5mL:0.5mL), and two (triphenylphosphine) palladium chloride (21mg, 0.03mmol) are added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 4 hours.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=30:1, v/v) purification residues is yellow solid (70mg, yield is 64%).
1H NMR(400MHz，DMSO-d 6)δ8.43(d，J=2.2Hz，1H)，8.00(dd，J=8.6，2.2Hz，1H)，7.95(s，1H)，6.84(d，J=8.6Hz，1H)，6.54(s，1H)，6.41(s，2H)，5.03-4.79(m，1H)，4.02(dd，J=11.2，4.0Hz，2H)，3.88(s，3H)，3.47(t，J=11.4Hz，2H)，2.88-2.75(m，2H)，2.57(s，3H)，1.57(dd，J=11.2，2.0Hz，2H).
MS(ESI+)m/z367.0[M+H] +.
The synthesis (compound 21) of embodiment 21:N-(5-(7-amino-1-sec.-propyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
The synthesis of the bromo-6-of step 1:3-(2,5-dimethyl-1H-pyrroles-1-base)-N-sec.-propyl-2-picoline-4-amine
In sealed tube, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles-1-base) the iodo-2-picoline (15g, 38.5mmol) of-4-and the solution of diisopropyl ethyl amine (4.96g, 38.5mmol) in Isopropylamine (75mL) stirs 24 hours at 160 DEG C.After being cooled to room temperature, concentrating under reduced pressure reaction mixture.Be extracted with ethyl acetate (500mL) and dissolve the residue produced, with water (200mL × 2) and saturated aqueous common salt (200mL × 2) washing, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=150:1, then petrol ether/ethyl acetate=50:1, v/v) purification residues is yellow solid (7.5g, yield is 61%).
1H NMR(400MHz，DMSO-d 6)δ6.44(s，1H)，5.74(s，2H)，5.60(d，J=8.3Hz，1H)，3.87-3.77(m，1H)，2.47(s，3H)，2.06(s，6H)，1.20(d，J=6.3Hz，6H).
MS(ESI+)m/z322.0[M+H] +.
Step 2:(E) synthesis of-3-(6-(2,5-dimethyl-1H-pyrroles-1-base-)-4-(isopropylamino)-2-picoline-3-base) ethyl propenoate
In sealed tube, by bromo-for 3-N-cyclopentyl-6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-amine (7.5g, 23.4mmol) and the solution of ethyl propenoate (5.0mL, 46.7mmol) in triethylamine (55mL) is with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (1.35g, 11.68mmol), again mixture is sealed tubule with bubbling argon 5min.Reaction soln is stirred at 130 DEG C and spends the night, cool and concentrate.Add 200mL water, the mixture produced with ethyl acetate (100mL × 3) extraction.With the organic layer that water (100mL × 2) and saturated common salt washing (100mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.The crude product produced is that yellow oil (8.00g, yield 100%) is directly used in next step without being further purified.
1H NMR(400MHz，DMSO-d 6)δ7.61(d，J=16.2Hz，1H)，6.40(s，1H)，6.30(d，J=16.2Hz，1H)，5.94(d，J=8.1Hz，1H)，5.74(s，2H)，4.22(q，J=7.1Hz，2H)，3.81-3.70(m，1H)，2.38(s，3H)，2.07(s，6H)，1.28(t，J=7.1Hz，3H)，1.17(d，J=6.3Hz，6H).
MS(ESI+)m/z342.1[M+H] +
Step 3:7-(2,5-dimethyl-1H-pyrroles-1-base)-1-sec.-propyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles-1-base-)-4-(isopropylamino)-2-picoline-3-base) ethyl propenoate (8.0g, 23.5mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene (17.5mL, 117.3mmol) and potassium tert.-butoxide (1.32g, solution 11.75mmol) in N,N-dimethylacetamide (80mL) stirs and spends the night at 150 DEG C.After being cooled to room temperature, with 400mL water diluted reaction mixture, be extracted with ethyl acetate (200mL × 3).With the organic layer that water (200mL × 2) and saturated aqueous common salt (200mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=10:1, then petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow oil (2.7g, yield is 39%).
1H NMR(400MHz，DMSO-d 6)δ8.13(d，J=9.8Hz，1H)，7.46(s，1H)，6.63(d，J=9.8Hz，1H)，5.83(s，2H)，5.38-5.17(m，1H)，2.73(s，3H)，2.11(s，6H)，1.51(d，J=6.8Hz，6H).
Step 4:7-amino-1-sec.-propyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles-1-base)-1-sec.-propyl-5-methyl isophthalic acid, the mixture backflow in second alcohol and water (40mL/4mL) of 6-naphthyridines-2 (1H)-one (2.7g, 9.2mmol) and oxammonium hydrochloride (3.2g, 4.58mmol) is spent the night.It is yellow blister solid (1.3g, yield is 65%) that concentrated reaction mixture also obtains product with column chromatography (silica gel, petrol ether/ethyl acetate=1:3, then ethyl acetate/triethylamine=100:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ7.80(d，J=9.6Hz，1H)，6.43(s，1H)，6.30(s，2H)，6.09(d，J=9.6Hz，1H)，5.32(q，J=7.2Hz，1H)，2.48(s，3H)，1.49(d，J=7.2Hz，6H).
The bromo-1-sec.-propyl of step 5:7-amino-3--5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
N-bromo-succinimide (1.14g, 6.41mmol add in three batches) is added to 7-amino-1-sec.-propyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (1.39g, 6.41mmol) is in the solution of DMF (14mL).Reaction soln is at room temperature stirred 1 hour.Add 60mL water, the mixture produced with ethyl acetate (30mL × 3) extraction.With the organic layer that water (50mL × 2) and saturated common salt washing (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=3:1, then petrol ether/ethyl acetate/triethylamine=50:50:1, v/v) purification residues is yellow solid (1.02g, yield 54%).
1H NMR(400MHz，CDCl 3)δ8.15(s，1H)，6.30(s，1H)，4.70(br s，2H)，4.12(q，J=7.2Hz，1H)，2.60(s，3H)，1.60(d，J=7.2Hz，6H).
MS(ESI+)m/z296.0，298.0[M+H] +.
The synthesis of step 6:N-(5-(7-amino-1-sec.-propyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
By the bromo-1-sec.-propyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.34mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-2, 4-difluorobenzenesulfonamide (173mg, 0.41mmol) with salt of wormwood (110mg, 1.02mmol) at N, dinethylformamide-water (4mL:0.34mL, mixture 12:1) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (25mg, 0.034mmol) be added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 5h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (40mg, yield is 23%).
1H NMR(400MHz，DMSO-d 6)δ10.18(s，1H)，8.28(d，J=1.9Hz，1H)，7.93(d，J=2.0Hz，1H)，7.92(s，1H)，7.73(dt，J=8.4，6.5Hz，1H)，7.63-7.52(m，1H)，7.27-7.12(m，1H)，6.45(s，1H)，6.39(s，2H)，5.35-5.30(m，1H)，3.62(s，3H)，2.56(s，2H)，1.53(d，J=7.0Hz，6H).
MS(ESI+)m/z516.1[M+H] +.
Embodiment 22:N-(5-(7-amino-1-cyclopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (compound 22)
The synthesis of the bromo-N-cyclopropyl of step 1:3--6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-amine
In sealed tube, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles-1-base) the iodo-2-picoline (6g, 15.4mmol) of-4-and DIEA(1.98g, 15.4mmol) solution in cyclopropylamine (30mL) stirs 48 hours at 90 DEG C.After being cooled to room temperature, concentrating under reduced pressure reaction mixture.Be extracted with ethyl acetate (200mL) and dissolve the residue produced, with water (100mL × 2) and saturated aqueous common salt (100mL × 2) washing, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=150:1 then petrol ether/ethyl acetate=50:1, v/v) purification residues is yellow solid (1.6g, yield is 33%).
1H NMR(400MHz，DMSO-d 6)δ6.63(s，1H)，6.62(brs，1H)，5.76(s，2H)，2.47(s，3H)，2.09(s，6H)，2.02-1.95(m，1H)，0.83-0.76(m，2H)，0.61-0.51(m，2H).
MS(ESI+)m/z320.0[M+H] +.
Step 2:(E) synthesis of-3-(4-(cyclopropylamino)-6-(2,5-dimethyl-1H-pyrroles-1-base-)-2-picoline-3-base) ethyl propenoate
In sealed tube, by bromo-for 3-N-cyclopropyl-6-(2,5-dimethyl-1H-pyrroles-1-base)-2-picoline-4-amine (1g, 3.1mmol) and the solution of ethyl propenoate (0.68mL, 6.2mmol) in triethylamine (10mL) is with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (0.362g, 0.31mmol), again mixture is sealed tubule with bubbling argon 5min.Reaction soln is stirred at 130 DEG C and spends the night, cool and concentrate.Add 50mL water, the mixture produced with ethyl acetate (50mL × 3) extraction.With the organic layer that water (50mL × 2) and saturated common salt washing (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=50:1 then petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow oil (0.58g, yield is 55%).
1H NMR(400MHz，CDCl 3)δ7.67(d，J=16.4Hz，1H)，6.76(s，1H)，6.24(d，J=16.4Hz，1H)，5.88(s，2H)，5.03(s，1H)，4.30(q，J=7.1Hz，2H)，2.48(s，3H)，2.46-2.39(m，1H)，2.20(s，6H)，1.36(t，J=7.1Hz，3H)，0.92-0.77(m，2H)，0.63-0.52(m，2H).
Step 3:1-cyclopropyl-7-(2,5-dimethyl-1H-pyrroles-1-base)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(4-(cyclopropylamino)-6-(2,5-dimethyl-1H-pyrroles-1-base-)-2-picoline-3-base) ethyl propenoate (1.08g, 3.2mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene DBU(2.36mL, 15.9mmol) and potassium tert.-butoxide (0.179g, solution 1.6mmol) in N,N-dimethylacetamide (20mL) stirs and spends the night at 150 DEG C.After being cooled to room temperature, with 100mL water diluted reaction mixture, be extracted with ethyl acetate (50mL × 3).With the organic layer that water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, then petrol ether/ethyl acetate=2:1, v/v) purification residues is yellow oil (0.42g, yield is 45%).
1H NMR(400MHz，DMSO-d 6)δ8.11(d，J=9.8Hz，1H)，7.49(s，1H)，6.61(d，J=9.8Hz，1H)，5.84(s，2H)，3.05-2.91(m，1H)，2.72(s，3H)，2.15(s，6H)，1.35-1.24(m，2H)，0.83-0.70(m，2H).
Step 4:7-amino-1-cyclopropyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 1-cyclopropyl-7-(2,5-dimethyl-1H-pyrroles-1-base)-5-methyl isophthalic acid, the mixture backflow in alcohol-water (5mL/0.5mL) of 6-naphthyridines-2 (1H)-one (0.42g, 1.43mmol) and oxammonium hydrochloride (0.498g, 7.17mmol) is spent the night.It is yellow blister solid (273mg, yield is 89%) that concentrated reaction mixture also obtains product with column chromatography (silica gel, petrol ether/ethyl acetate=1:3, then ethyl acetate/triethylamine=100:1, v/v) purification residues.
1H NMR(400MHz，DMSO-d 6)δ7.79(d，J=9.6Hz，1H)，6.53(s，1H)，6.38(s，2H)，6.06(d，J=9.6Hz，1H)，2.80-2.68(m，1H)，2.46(s，3H)，1.20-1.15(m，2H)，0.75-0.62(m，2H).
The bromo-1-cyclopropyl of step 5:7-amino-3--5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
N-bromo-succinimide (181mg, 0.8eq) is added to 7-amino-1-cyclopropyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (273mg, 1.27mmol) is in the solution of DMF (4mL).Reaction soln is at room temperature stirred 1h.Add 20mL water, the mixture produced with ethyl acetate (20mL × 3) extraction.With the organic layer that water (20mL × 2) and saturated common salt washing (20mL × 2) washing merge, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=1:1, then petrol ether/ethyl acetate: triethylamine=50:50:1, v/v) purification residues is yellow solid (200g, yield 53%).
1H NMR(400MHz，CDCl 3)δ8.26(s，1H)，6.54(s，2H)，6.53(s，1H)，2.92-2.79(m，1H)，2.48(s，3H)，1.30-1.16(m，2H)，0.77-0.66(m，2H).
The synthesis of step 6:N-(5-(7-amino-1-cyclopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide
By the bromo-1-cyclopropyl of 7-amino-3--5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (60mg, 0.205mmol), N-(2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolan alkane-2-base) pyridin-3-yl)-2, 4-difluorobenzenesulfonamide (105mg, 0.246mmol) with salt of wormwood (85mg, 0.615mmol) at N, mixture in dinethylformamide-water (4mL:0.3mL) is degassed, and by [1, 1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (15mg, 0.021mmol) be added in mixture.By degassed for the reaction mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 5h.After cooling, 30mL water is added in reaction mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With the organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, with anhydrous sodium sulfate drying, filter, concentrated.Obtaining product with column chromatography (silica gel, methylene dichloride/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues is yellow solid (20mg, yield is 19%).
1H NMR(400MHz，DMSO-d 6)δ10.18(s，1H)，8.29(d，J=2.2Hz，1H)，7.93(d，J=2.2Hz，1H)，7.92(s，1H)，7.73(td，J=8.5，6.4Hz，1H)，7.66-7.49(m，1H)，7.20(td，J=8.5，2.3Hz，1H)，6.55(s，1H)，6.49(s，2H)，3.62(s，3H)，2.87-2.80(m，1H)，2.55(s，3H)，1.30-1.13(m，2H)，0.79-0.66(m，2H).
Embodiment 23 biological chemistry detects PI3K-alpha active
Vitro kinase test experience is used to assess the usefulness of compound of the present invention to PI3K-α.Use ADP-Glo tMkinase assay test kit, measures the external activity of PI3K-α by detecting the ADP level produced in kinase reaction.In kinase assay experiment, kinases consumes ATP generation ADP, ADP-Glo reagent and will stop kinase reaction and by remaining ATP completely consumed, finally add kinase assay reagent, and ADP is converted into new ATP.Luciferase in detection reagent is at ATP and O 2participate in lower can catalytic fluorometry plain, produce the fluorescein of oxidized form, AMP and produce photon, thus chemical signal is transferred to optical signal (Luminecence), in the intensity of optical signal and kinase reaction, ADP generation is proportionate, thus can the activity of detection by quantitative kinases PI3K-α.ADP-Glo tMkinase assay test kit is purchased from Promega company.
All test experience are all at room temperature carried out, use Corning3674 white 384 orifice plates, kinases PI3K-α is from BPS Biosciences, and kinase substrate is P1P2/PS (Invitrogen), uses microplate reader EnVision (Perkin Elmer) to read optical signal.Detect damping fluid and comprise 40mM Tris-HCl (pH7.5), 3mM MgCl 2and 0.01%BSA; Kinases PI3K-α is used and detects the kinase reaction solution that buffer is 4nM concentration; Substrate reactions solution comprises 100uM P1P2/PS and 100uM ATP.First compound dissolved dilution in 100%DMSO, to 2mM, is re-used detection damping fluid and is diluted to 0.05mM.In check-out console, first add compound and 2 μ L kinase reaction solution that 1 μ L concentration is 0.05mM, mix rear room temperature lucifuge and hatch 15min; Add 2 μ L kinase reaction solution subsequently, reaction cumulative volume is 5 μ L, by reaction mixture at room temperature lucifuge reaction 45min; Add subsequently and the isopyknic 5 μ LADP-Glo of reaction tMreagent termination reaction, mixes rear room temperature and places 40min; Finally add 10 μ L kinase assay reagent, room temperature lucifuge places 30min, then reading numerical values on Envision.
Inhibition percentage is based on following formulae discovery:
Inhibition percentage=[1-(RLU compound-RLU min)/(RLU max-RLU min)] × 100%
Wherein RLU compoundfor the cold light reading under given compound concentration, RLU minfor not adding the cold light reading in kinase whose situation, RLU maxfor not adding cold light reading when compound.By using the IC carrying out computerized compound in Excel in XLfit program 50.
Experimental result is in table 1.
It is active that embodiment 24 biological chemistry detects mTOR
Use vitro kinase calibrating experimental evaluation compound for the usefulness of mTOR.The kinase activity of mTOR is measured by the phosphorylation level measuring substrate 4E-BP1.In temporal resolution resonance energy transfer experiment, mTOR kinases is by the substrate GFP-4E-BP1 of phosphorylation GFP label, and when substrate is excessive, the content of phosphorylated substrate is higher.Specific antibody Tb-chelate labeled anti-4E-BP1 [pT46] of Tb mark can termination reaction, and induced fluorescence energy is calculated from Tb resonance transfer to the phosphorylation of GFP, 4E-BP1 substrate by the energy proportion being transferred to GFP from Tb.MTOR TR-FRET kinase assay test kit is purchased from Invitrogen company.
All test experience are all at room temperature carried out, use black 384 orifice plate that PE company article No. is Greiner784076, kinases mTOR is from Invitrogen, kinase substrate is GFP-4E-BP1 (Invitrogen), uses microplate reader Envision (Perkin Elmer) to read fluorescent signal.Detect damping fluid and comprise 50mM HEPES, 5mM MgCl 2, 0.01%BSA, 1mM DTT, 1mM EGTA and 0.01%Triton X-100; Kinases mTOR is used and detects the kinase reaction solution that buffer is 0.31ng/ μ L concentration; Substrate reactions solution comprises 0.8uM GFP-4E-BP1 and 60uM ATP.First compound dissolved dilution in 100%DMSO, to 1mM, is then carried out the serial dilution of 3 times, dilute 10 concentration point altogether, re-use detection damping fluid and be diluted to 100uM.In check-out console, first add compound and 2 μ L kinase reaction solution that 0.5 μ L concentration is 100uM, mix rear room temperature lucifuge and hatch 15min; Add 2.5 μ L kinase reaction solution subsequently, reaction cumulative volume is 5 μ L, by reaction mixture at room temperature lucifuge reaction 40min; Add subsequently and isopyknic 5 μ L TR-FRET detection reagent (comprising the EDTA of 2nMTb-chelate labeled anti-4E-BP1 [pT46] and the 30mM) termination reactions of reaction, mix rear room temperature lucifuge and place 60min; Then on Envision instrument, 340nm reads the numerical value under 495 and 520nm utilizing emitted light respectively after exciting.
Inhibition percentage is based on following formulae discovery:
Inhibition percentage=[1-(compound-min)/(max-min)] × 100%
Wherein " compound " is the fluorescence reading ratio under given compound concentration, and min is the fluorescence ratio do not added in kinase whose situation, and max is fluorescence ratio when not adding compound.By using the IC carrying out computerized compound in Excel in XLfit program 50.
Experimental result is in table 1 and table 2.
Table 1PI3K-α biological data
As can be seen from the data of table 1, all compounds of the present invention all have obvious restraining effect to PI3K.Wherein, the IC of compound 12 50value is 1.725 μMs; The IC of compound 3,4,14,15 50value reaches 100-200nM; The IC of all the other compounds 50value reaches 1-100nM.
Table 2mTOR biological data
As can be seen from the data of table 2, all compounds of the present invention have obvious restraining effect equally to mTOR.Wherein, the IC of compound 11 and 21 50value reaches 100-200nM; The IC of all the other compounds 50value reaches 1-100nM.

Claims (25)

1. the compound shown in a formula I or its pharmacy acceptable salt:
Wherein,
R 1be selected from C 1-C 10alkyl, C 3-C 10cycloalkyl or C 3-C 10heterocyclylalkyl, wherein said C 3-C 10cycloalkyl or C 3-C 10heterocyclylalkyl is optionally by-OR 2replaced, wherein R 2be selected from hydrogen, C 1-C 6alkyl or C 1-C 6hydroxyalkyl; And
R 3be selected from hydrogen or-NHSO 2r 4, wherein, R 4be selected from C 1-C 6alkyl, C 3-C 10cycloalkyl, C 5-C 10aryl or C 5-C 10heteroaryl, wherein said C 1-C 6alkyl, C 3-C 10cycloalkyl, C 5-C 10aryl or C 5-C 10heteroaryl is optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.
2. the compound shown in formula I according to claim 1 or its pharmacy acceptable salt, wherein, R 1group for as follows:
Wherein, R 6, R 7be selected from hydrogen or C independently of one another 1-C 4alkyl; Be preferably selected from hydrogen or methyl.
3. the compound shown in formula I according to claim 1 or its pharmacy acceptable salt, wherein, R 1be selected from C 3-C 6cycloalkyl or C 3-C 6heterocyclylalkyl, it is optionally by-OR 2replaced.
4. the compound shown in formula I according to claim 1 or its pharmacy acceptable salt, wherein, preferably, R 1be selected from cyclopropyl, cyclopentyl, cyclohexyl or oxacyclohexyl, it is optionally by-OR 2replaced.
5. the compound shown in formula I according to claim 1 or its pharmacy acceptable salt, wherein, R 2for C 1-C 6hydroxyalkyl; Be more preferably-CH 2-CH 2-OH.
6. the compound shown in formula I according to claim 1 or its pharmacy acceptable salt, wherein, R 3for-NHSO 2r 4, wherein,
R 4be preferably selected from C 1-C 4alkyl, C 3-C 5cycloalkyl, C 5-C 6aryl or C 5-C 6heteroaryl, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl, C 5-C 6aryl or C 5-C 6heteroaryl is optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group.
7. the compound shown in formula I according to claim 6 or its pharmacy acceptable salt, wherein, R 4be selected from C 1-C 4alkyl, C 3-C 5cycloalkyl, aryl or 5 yuan of heteroaryls, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl, aryl or 5 yuan of heteroaryls are optionally by one or more R 5replaced, described R 5be selected from halogen, cyano group, C independently of one another 1-C 6haloalkyl, C 1-C 6alkoxyl group; 5 yuan of described heteroaryls are preferably containing a sulphur atom.
8. the compound shown in formula I according to claim 6 or its pharmacy acceptable salt, wherein, R 4be selected from aryl or 5 yuan of heteroaryls, described aryl or 5 yuan of heteroaryls are optionally by 1-5 R 5replaced, be preferably by 1-2 R 5replaced; Described R 5be selected from halogen, cyano group ,-CF 3or C 1-C 4alkoxyl group.
9. the compound shown in formula I according to claim 6 or its pharmacy acceptable salt, wherein, R 4be selected from C 1-C 4alkyl or C 3-C 5cycloalkyl, wherein said C 1-C 4alkyl, C 3-C 5cycloalkyl is optionally by 1-5 R 5replaced, be more preferably by 1-3 R 5replaced; Described R 5for halogen.
10. the compound shown in formula I according to claim 1 or its pharmacy acceptable salt, wherein, the compound shown in formula I is selected from following compounds:
Compound 1:
Compound 2:
Compound 3:
Compound 4:
Compound 5:
Compound 6:
Compound 7:
Compound 8:
Compound 9:
Compound 10:
Compound 11:
Compound 12:
Compound 13:
Compound 14:
Compound 15:
Compound 16:
Compound 17:
Compound 18:
Compound 19:
Compound 20:
Compound 21:
and
Compound 22:
The preparation method of 11. compounds according to the formula I in claim 1-10 described in any one, it comprises: make the compound shown in the compound shown in formula A and formula B occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula I:
Wherein, R 1and R 3as claim 1 define; X is halogen, is preferably bromine; And R 8for or
12. methods according to claim 11, wherein, described palladium catalyst is two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride.
13. methods according to claim 11, wherein, the compound shown in formula A prepares by the following method:
Make the compound shown in formula L and N-N-halosuccinimides that following halogenating reaction occur, thus obtain the compound shown in formula A:
14. methods according to claim 13, wherein, the compound shown in formula L prepares by the following method:
Make the compound shown in formula K and oxammonium hydrochloride that following deprotection reaction occur, thus obtain the compound shown in formula L:
15. methods according to claim 14, wherein, the compound shown in formula K prepares by the following method:
Under the existence of potassium tert.-butoxide and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, make the compound shown in formula J that following cyclization reaction occur, thus obtain the compound shown in formula K:
16. methods according to claim 15, wherein, the compound shown in formula J prepares by the following method:
Make the compound shown in formula H and ethyl propenoate occur to react as follows under the existence of palladium catalyst, thus obtain the compound shown in formula J:
Wherein, X is halogen, is preferably bromine; Described palladium catalyst is preferably tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, is more preferably tetrakis triphenylphosphine palladium.
17. methods according to claim 16, wherein, the compound shown in formula H prepares by the following method:
Make the compound shown in the compound shown in formula F and formula G occur to react as follows under the existence of acid binding agent diisopropyl ethyl amine, thus obtain the compound shown in formula H:
Wherein, X is halogen, is preferably bromine.
18. methods according to claim 17, wherein, the compound shown in formula F prepares by the following method:
Make the compound shown in formula E and iodine, under the existence of lithium diisopropyl amido, following iodide reaction occur, thus obtain the compound shown in formula F:
Wherein, X is halogen, is preferably bromine.
19. methods according to claim 18, wherein, the compound shown in formula E prepares by the following method:
Make the compound shown in the compound shown in formula C and formula D occur to react as follows under the existence of catalyzer tosic acid, thus obtain the compound shown in formula E:
Wherein, X is halogen, is preferably bromine.
20. methods according to claim 11, wherein,
Work as R 8for time, the compound shown in formula B prepares by the following method:
Make the compound shown in the compound shown in formula M and formula N that following reaction occur under the existence of catalyzer [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, thus obtain the compound shown in formula B:
21. compounds according to the formula I in claim 1-10 described in any one or its pharmacy acceptable salt are for the preparation of the purposes treated and/or prevented in the medicine of the disease that PI3-K kinases and/or mTOR kinases cause.
22. purposes according to claim 21, wherein, described PI3-K kinases is PI3-K alpha kinase.
23. purposes according to claim 21, wherein, described disease is cancer or tumour.
24. purposes according to claim 21, wherein, described disease be selected from the cancer of the brain, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney, acute leukemia, chronic leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colon and rectum carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, sarcoma, osteosarcoma and rhabdomyoma one or more.
25. 1 kinds of pharmaceutical compositions being used for the treatment of and/or preventing the disease that PI3-K kinases and/or mTOR kinases cause, the compound shown in the formula I in claim 1-10 described in any one and/or its pharmacy acceptable salt is comprised in described pharmaceutical composition, and pharmaceutically acceptable auxiliary material.
CN201310382278.5A 2013-08-28 2013-08-28 Substituted naphthyridines-2-ketonic compound, preparation method, purposes and pharmaceutical composition Expired - Fee Related CN104418853B (en)

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