CN104151311A - Fused ring compound or pharmaceutically acceptable salt thereof as well as preparation method and application of fused ring compound - Google Patents

Fused ring compound or pharmaceutically acceptable salt thereof as well as preparation method and application of fused ring compound Download PDF

Info

Publication number
CN104151311A
CN104151311A CN201410027270.1A CN201410027270A CN104151311A CN 104151311 A CN104151311 A CN 104151311A CN 201410027270 A CN201410027270 A CN 201410027270A CN 104151311 A CN104151311 A CN 104151311A
Authority
CN
China
Prior art keywords
alkyl
hexa
fused ring
group
atomic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410027270.1A
Other languages
Chinese (zh)
Other versions
CN104151311B (en
Inventor
佘能芳
黄伟
卓林胜
董欢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huazhong Normal University
Original Assignee
Huazhong Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Huazhong Normal University filed Critical Huazhong Normal University
Priority to CN201410027270.1A priority Critical patent/CN104151311B/en
Publication of CN104151311A publication Critical patent/CN104151311A/en
Application granted granted Critical
Publication of CN104151311B publication Critical patent/CN104151311B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Abstract

The invention discloses a fused ring compound or pharmaceutically acceptable salt thereof as well as a preparation method and application of the fused ring compound. The fused ring compound has a structure shown in a formula (I) and has a good inhibiting effect on activities of multiple kinases, for example, the fused ring compound has good inhibitory activity on kinases such as c-kit, VEGFR-2 and PDGFR-beta and has no inhibiting effect on a kinase c-Met but shows certain selectivity; meanwhile, the fused ring compound which is of the structure shown in the formula (I) and prepared by adopting the preparation method disclosed by the invention has an inhibiting effect on proliferation of multiple tumour cells. The formula (I) is described in the specification.

Description

One class fused ring compound or its pharmacy acceptable salt and its preparation method and application
Technical field
The present invention relates to biomedicine field, be particularly related to a class fused ring compound or its pharmacy acceptable salt and preparation method thereof, the invention still further relates to such fused ring compound or its pharmacy acceptable salt as the application of tyrosine kinase inhibitor or serine-threonine kinase inhibitor.
Background technology
Between mammalian cell, there is similar molecular mechanism, within the whole cell cycle, regulate propagation, differentiation and the death of cell.Wherein, protein tyrosine kinase and albumen serine/threonine kinase have vital role in Normocellular signal transduction mechanism, their unconventionality expression will cause the generation of numerous disease, as tumour, arteriosclerosis, psoriasis and inflammatory reaction etc., thereby regulate and control these kinase whose activity, recover physiological equilibrium and can be used as a kind of new treatment means.
Family tyrosine kinase with transmembrane receptor (receptor tyrosine kinase, RTKs) or kytoplasm form (nonreceptor tyrosine kinase CTKs) participates in cell signalling widely.In human genome, protein kinase group comprises 30 kinds of family tyrosine kinases, contains altogether 90 kinds of different protein tyrosine kinases, and wherein 58 kinds is receptor tyrosine kinase.
Known receptor tyrosine kinase is contained 20Ge family, and many be oncogene (Blume-Jensen P, Nature, 2001,411:355).The receptor tyrosine kinase sustained activation that numerous disease causes to this sudden change and PTKs false demonstration or overexpression are relevant.In the characterization of molecules process of malignant tumour, find nearly half known PTKs, such as c-Met, EGFR, ErbB2, Ret, Kit, Src, Abl, PDGFR, VEGF1/2/3, FGFR1/2/3 etc., all exists and suddenlys change or the situation of overexpression.Meanwhile, the overexpression of clinical studies show Tyrosylprotein kinase or imbalance to prediction tumour patient and symptom have important references be worth (Madhusudan S, et al, Clin Biochem, 2004,37:618).From the above mentioned, Tyrosylprotein kinase is very important to the autologous adjusting of physiology, and transgenation/rearrangement can make PTKs extremely or overexpression, thereby causes the generation of disease, therefore can use the agonist of these enzymes or antagonist to treat.
Nonreceptor tyrosine kinase (CTKs): take src gene product as representative, also have in addition Yes, Fyn, Lck, Fgr, Lyn, Fps/Fes and Ab1 etc.Except rear, both, all the other non-receptor type protein tyrosine kinase Src family molecules reasons are about the protein of 60kDa, and between them, except 80 amino acid of N-terminal form differences, other parts are all closely similar.The regulation mechanism of nonreceptor tyrosine kinase (CTKs) differs greatly, and they are by with transmembrane receptor (as hormone, cytokine and growth factor receptors), physical property effect occurring, and then the response of participation extracellular signal.In the specified phase of cell cycle, when combining with extracellular part or cell adhesion composition, these acceptors are activated.The sudden change of protein kinase, the puzzlement of signal protein are the pathology reasons that causes tumour, equally also can cause the generation of Other diseases.In some immunodeficiency symptoms, can observe the mutagenicity inactivation of non-receptor tyrosine, for example the inactivation of JAK3 causes serious severe combined immunodeficiency (Leonard WJ, Nat Rev Immunol, 2001,1:200; Leonard WJ, Int J Hematol, 2001,73:271).Bruton protein tyrosine kinase (BTK or BPK, ATK) belongs to Src family, it is the ripe necessary a kind of Tyrosylprotein kinase of B cell development, and that Btk transgenation meeting causes is congenital without Immunoglobulinemia (Cheng G, et al, Proc Natl Acad Sci USA, 1994,91:8152; Maas A, et al, J Immunol, 1999,162:6526).
Tyrosine protein kinase also has important physiological action in central nervous system, its not normal generation that also can cause corresponding disease, for example, at alzheimer's disease (Alzheimer disease, AD) relevant (the Ferguson SS of immunoreactivity of neurone spot and neuregulin-1 (neuregulin-1) and ErbB4 in patient body, Trends Neurosci, 2003,26:119; Chaudhury AR, et al, J Neuropathol Exp Neurol, 2003,62:42).RhIGF-1 (IGFs) and adjusting albumen thereof are to be secreted by cardiovascular systems, these factor dysregulations can cause developing of coronary atherosclerosis and restenosis, and the effect of IGFs is mediated by specific membranes acceptor, wherein IGF receptor type I has tyrosine kinase activity, comes across the smooth muscle cell of atherosclerotic lesions, inflammatory cell and arterial endothelial cell (Bayes-genis A, et al, Circ Res, 2000,86:125; Bayes-genis A, et al, Artherio Thromb and Vascu Biol, 2001,21:335; Che WY, et al, Circ Res, 2002,90:1222).Vascular endothelial growth factor and acceptor thereof are expressed in the various kinds of cell of rheumatoid arthritis, and be key factor in rheumatoid arthritis rationality angiogenic process (De Bandt M, et al, J Immunol, 2003,1712:4853).Jak2 is endochylema nonreceptor tyrosine kinase, and JAK2 transgenation at least causes three kinds of diseases (Spivak JL, Blood, 2002,100:4272; Thiele J, et al, Acta Haematol, 2004,111:155)---polycythemia vera (PV), idiopathic myelofibrosis (IMF), primary thrombocytosis (ET) and some other myeloproliferative diseases that is not true to type (MPD).The trans-regional sudden change of fibroblast growth factor acceptor can cause the most common heredity nanism---and osteochondrodysplasia (Shiang R, etal, Cell, 1994,78:335).In addition, numerous disease with lack tyrosine signal correction, for example non-insulin-dependent diabetes mellitus (NIDDM) and peripheral neuropathy, and transmission by wild phase induction signal can effectively improve symptom (Hunter T, Cell, 2000,100:111).For some other and blood vessel, relevant disease occurs, for example some cardiovascular disorder, stimulates vasculogenesis than suppressing more effective.
The discussion that relevant Tyrosylprotein kinase is detailed, referring to Manning G, Science, 2002,298:1912.
Serine-threonine kinase (STKs) is the kinases family of a large class specificity catalytic protein Serine and threonine residues phosphorylation, numbering: EC2.7.1.37.The same with nonreceptor tyrosine kinase, serine-threonine kinase is dominate in cell, although only have several serine-threonine receptor kinases.Serine-threonine kinase is modal cytosol kinases, be kinases in tenuigenin part rather than in cytoplasmic organoid and cytoskeleton, bring into play their function, and then affect the inside biological chemistry of cell, often as the descending reaction to Tyrosylprotein kinase event.Serine-threonine kinase can participate in signalling process simultaneously, and the latter causes DNA and synthesizes and cause subsequently the mitotic division of cell proliferation.In addition serine-threonine kinase has related to polytype cancer, as mammary cancer (Cance et al, Int.J.Cancer, 1993,55,571) etc.
To sum up, Tyrosylprotein kinase and serine-threonine kinase all comprise related to cancer with host's pathological condition.Other pathological condition relevant with protein kinase also comprises that psoriasis, liver cirrhosis, diabetes, blood vessel generation, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder are as arteriosclerosis and multiple ephrosis.
Along with molecular biological research is goed deep into, on molecular level, for cell signalling, the function of the growth regulation factor and regulation and control oncogene are the effective ways that suppresses cell proliferation and treat tumour.This approach can weaken the effect of improper signalling channel, stops the growth of tumour, also can impel death of neoplastic cells simultaneously.Find that there is so far half proto-oncogene and on encoding histone, all there is tyrosine structure, they participate in cell signalling by phosphorylation and dephosphorylation, simultaneously in tumour generating process, the Tyrosylprotein kinase of variation or overexpression can change normal cell into cancer cells, promotes growth and the mitotic division of tumour cell simultaneously.Because Tyrosylprotein kinase and serine-threonine kinase have important effect in the carinogenicity conversion process of cell, and have directly or indirectly and contact with the generation of tumour and development, the treatment that therefore tyrosine kinase inhibitor or serine-threonine kinase inhibitor is applied to tumour is particularly suitable.
7-naphthyridine derivatives has biological activity widely, at field of medicaments, has important application.In recent years, many naphthyridines micromolecular compounds have been used as kinases inhibitor, be widely used in the multiple disease relevant to aberrant kinase activity for the treatment of, if tumour, psoriasis, liver cirrhosis, diabetes, blood vessel generation, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder are as arteriosclerosis and multiple ephrosis.Wherein, 2, 7-naphthyridines compounds (WO2013033981, WO0192256, WO0242264), 1, 5-naphthyridines compounds (WO2006106046), 1, 6-naphthyridines compounds (WO2007060028, WO2010037249, WO2010088177), 2, 6-naphthyridines compounds (WO2008122614), heterocyclic fused naphthyridines compounds (WO2009148887, WO2009148916), 2, 7-naphthyridones compound (WO2008109613, WO2009097287), 1, 8-naphthyridones compounds (WO2010002779) etc. are all for Tyrosylprotein kinase and/or serine-threonine kinase inhibitor.But 2,7-naphthyridines-1(2H)-one compounds is used for the treatment of Tyrosylprotein kinase and/or the rarely seen report of serine-threonine kinase inhibitor, one class is only disclosed in WO2013033981 patent as 2 of c-Met kinase inhibitor, 7-naphthyridines-1(2H)-one compounds, this compounds has certain inhibition activity to VEGFR-2 and c-kit kinases simultaneously.
2,7-naphthyridines-1(2H)-one is the important heterocycle structure of a class, and molecular formula is C 8h 6n 2o, molecular weight is 146.1, has following chemical structure.
Therefore, need development structure type abundanter, to the active compound that has different of the kinase whose inhibition of difference, to be applied to treat various types of tumours.
Summary of the invention
The object of the invention is to development structure type abundanter, to active fused ring compound or its pharmacy acceptable salt that has different of the kinase whose inhibition of difference, to be applied to treat various types of tumours.
The present inventor is by a large amount of scientific researches, prepare fused ring compound or its pharmacy acceptable salt of the structure shown in (I) that there is formula, and find that this fused ring compound or its pharmacy acceptable salt are to VEGFR-2, it is active that c-kit and PDGFR-β show excellent inhibition, obviously be better than disclosed typical compound A in positive drug OSI-930 and WO2013033981 patent, and to c-Met kinases without obvious inhibition, in kinases spectrum, also there is obvious difference with disclosed typical compound A in WO2013033981 patent, thereby may be applied to the treatment of dissimilar tumour.
The invention provides a kind of fused ring compound or its pharmacy acceptable salt, wherein, the structural formula of this fused ring compound as shown in the formula (I),
Wherein,
M is 0 or 1; N is 0,1,2,3 or 4;
R 1be selected from hydrogen, unsubstituted C 1-C 10alkyl (can be straight or branched) and by one or more C of being selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkyl;
R 2be selected from hydrogen, halogen, unsubstituted C 1-C 10alkyl (can be straight or branched), hydroxyl, unsubstituted C 1-C 10alkoxyl group, by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10alkyl and by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkoxyl group;
A is selected from six membered heteroaryl, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring, hexa-atomic and hexa-atomic aromatic ring yl, and by one or more hydrogen, C of being selected from 1-C 4alkyl, halogen, halo C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group, C 6-C 10a kind of in the six membered heteroaryl that aryloxy, cyano group, nitro and amino substituting group replace, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring and hexa-atomic and hexa-atomic aromatic ring yl.
Preferably, m is 1; N is 0,1 or 2;
R 1be selected from hydrogen and C 1-C 4a kind of in alkyl;
R 2be selected from hydrogen, halogen, C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group and the C being replaced by one or more halogenic substituents 1-C 4a kind of in alkoxyl group;
A is selected from furyl, pyridyl, pyrimidyl, thienopyridine base, quinazolyl, quinolyl, naphthyl, phenyl, and by one or more hydrogen, halogen and C of being selected from 1-C 4a kind of in furyl, pyridyl, pyrimidyl, thienopyridine base, quinazolyl, quinolyl, naphthyl and phenyl that the substituting group of alkyl replaces;
More preferably, A is selected from following group:
in a kind of.
Preferably, described fused ring compound is selected from:
In a kind of.
The present invention also provides a kind of described above fused ring compound of structure or method of its pharmacy acceptable salt shown in formula (I) of having of preparing, and the method comprises the following steps: at reaction solvent S 1, under alkali B, catalyzer C and ligand L exist, 2 shown in formula (II), the amino substitution compound generation linked reaction shown in 7-naphthyridones compound and formula (III);
Concrete reaction process is as follows:
Wherein, m is 0 or 1; N is 0,1,2,3 or 4;
R 1be selected from hydrogen, unsubstituted C 1-C 10alkyl (can be straight or branched) and by one or more C of being selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkyl;
R 2be selected from hydrogen, halogen, unsubstituted C 1-C 10alkyl (can be straight or branched), hydroxyl, unsubstituted C 1-C 10alkoxyl group, by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10alkyl and by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkoxyl group;
A is selected from six membered heteroaryl, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring, hexa-atomic and hexa-atomic aromatic ring yl, and by one or more hydrogen, C of being selected from 1-C 4alkyl, halogen, halo C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group, C 6-C 10a kind of in the six membered heteroaryl that aryloxy, cyano group, nitro and amino substituting group replace, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring and hexa-atomic and hexa-atomic aromatic ring yl.
Preferably, m is 1; N is 0,1 or 2;
R 1be selected from hydrogen and C 1-C 4a kind of in alkyl;
R 2be selected from hydrogen, halogen, C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group and the C being replaced by one or more halogenic substituents 1-C 4a kind of in alkoxyl group;
A is selected from furyl, pyridyl, pyrimidyl, thienopyridine base, quinazolyl, quinolyl, naphthyl, phenyl, and by one or more hydrogen, halogen and C of being selected from 1-C 4a kind of in furyl, pyridyl, pyrimidyl, thienopyridine base, quinazolyl, quinolyl, naphthyl and phenyl that the substituting group of alkyl replaces;
More preferably, A is selected from following group:
in a kind of.
According to the present invention, reaction solvent S 1can be selected from 4-dioxane and/or glycol dimethyl ether, be preferably Isosorbide-5-Nitrae-dioxane;
Preferably, alkali B is selected from one or more in sodium hydroxide, sodium hydride, sodium tert-butoxide and potassium tert.-butoxide, is preferably sodium tert-butoxide;
Preferably, catalyzer C is selected from one or more in palladium, four triphenyl phosphorus palladiums, dichloro two triphenyl phosphorus palladiums and three (dibenzalacetone) two palladiums, is preferably three (dibenzalacetone) two palladiums;
Preferably, ligand L is phosphine part, is preferably two (diphenylphosphine) propane of 1,2-and/or two diphenylphosphine-9 of 4,5-, 9-dimethyl oxa-anthracene;
Preferably, the temperature of described linked reaction is 90-115 ℃, is preferably 100-110 ℃.
According to the present invention, compound involved in the present invention (II) can be prepared with reference to the method for this area similar information report, as the pertinent literature that WO2013033981 and they quoted.
The present invention also provides a kind of pharmaceutical composition, this pharmaceutical composition contain the fused ring compound with structure shown in formula (I) described above or its pharmacy acceptable salt as activeconstituents, medicinal carrier substance and/or thinner.
According to the present invention, the consumption of described activeconstituents, medicinal carrier substance and/or thinner is concrete restriction not, selects consumption well-known to those skilled in the art.
The present invention also provides a kind of medicinal compositions, this pharmaceutical composition contain adopt the fused ring compound with structure shown in formula (I) described above prepared by method of the present invention or its pharmacy acceptable salt as activeconstituents, medicinal carrier substance and/or thinner.In addition, this pharmaceutical composition can also contain the fused ring compound with structure shown in formula (I) and pharmaceutically acceptable carrier, vehicle or the thinner described above that adopts method of the present invention to prepare.
The invention still further relates to a kind of medicinal compositions of combination, the fused ring compound with structure shown in formula (I) of the free form that comprises significant quantity or pharmaceutical acceptable salt or its pharmacy acceptable salt, one or more medicinal carrier substances and/or thinner.
The present invention also provide have structure shown in formula (I) fused ring compound or its pharmacy acceptable salt, contain described above have the fused ring compound of structure shown in formula (I) or the pharmaceutical composition of its pharmacy acceptable salt in preparation treatment through the application aspect the disease medicament of protein kinase intermediary.
According to the present invention, the described disease through protein kinase intermediary can be selected from the disease relevant to VEGFR-2, c-kit or PDGFR-β, is also that described protein kinase can be selected from one or more in VEGFR-2, c-kit and PDGFR-β.
Preferably, the described disease through protein kinase intermediary is selected from one or more in colorectal carcinoma, bladder cancer, mammary cancer, liver cancer, lung cancer, carcinoma of the pancreas, gastrointestinal cancer, leukemia, ovarian cancer, head and neck cancer, prostate cancer, kidney, nasopharyngeal carcinoma, glioblastoma, squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, melanoma, neurospongioma, genitourinary cancer and bone marrow proliferative illness.
According to the present invention, preferably, described protein kinase related disorder is selected from relevant disease or the relevant disease of serine-threonine kinase of disease, nonreceptor tyrosine kinase that receptor tyrosine kinase is relevant.
According to the present invention, preferably, described protein kinase related disorder is selected from pHGF, the disease that vascular endothelial growth factor receptor is relevant, relevant relevant relevant disease or the relevant disease of tire liver kinases of disease, IGF-1 of disease, platelet derived growth factor receptor of disease, EGF-R ELISA that STEM CELL FACTOR acceptor is relevant.
According to the present invention, preferably, described protein kinase related disorder is selected from diabetes, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder.
According to the present invention, preferably, described protein kinase related disorder (or proliferative disease) is selected from colorectal carcinoma, bladder cancer, mammary cancer, liver cancer, lung cancer, carcinoma of the pancreas, gastrointestinal cancer, leukemia, ovarian cancer, head and neck cancer, prostate cancer, kidney, nasopharyngeal carcinoma, glioblastoma, squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, melanoma, neurospongioma, genitourinary cancer or bone marrow proliferative illness.
According to the present invention, in order checking, provided by the inventionly to there is the fused ring compound of structure shown in formula (I) for the exposure level of protein kinase, to adopt the test of biochemistry level enzymic activity, the test of cell levels enzymic activity, inhibition tumor cell proliferation activity to test and determine that various fused ring compound of the present invention is to the activity of one or more PK and exposure level.The method of knowing in operation, all tests like design class in the same way for any kinases.
According to the present invention, in the test of biochemistry level enzymic activity, utilize the activity of HTRF technology for detection Tyrosylprotein kinase, HTRF is a kind of time resolved fluorescence resonance ability transfer techniques, can carry out according to known specification sheets or literature method, referring to Kolb etc., " Tyrosine kinase assays adapted to homogenous time-resolved fluorescence " .Drug Discovery Today magazine .3 volume: pp333-342.HTRF (homogeneous phase time discrimination fluorescence) is for detecting a kind of the most frequently used method of determinand in homogeneous system, this technology combines FRET (fluorescence resonance energy transfer) (FRET) and TIME RESOLVED TECHNIQUE (TR), has been widely used in the different steps of the medicament research and development based on cell experiment and biochemical test.According to the measuring principle of HTRF method, by pure enzyme together with biotinylated substrate and ATP after incubation reaction, the antibody that adds the XL-665 of avidin mark and the Eu mark of identification substrate phosphorylation, after substrate is by tyrosine phosphorylation, the antibody of Eu mark can identify this phosphorylation product, the FRET (fluorescence resonance energy transfer) (FRET) of differentiating with the XL665 formation time of avidin mark, and the substrate not being phosphorylated is due to can not times antibody recognition and cannot form FRET signal, by measure the fluorescent signal difference of 665nm and 620nm measure determinand under different concns to VEGFR-2, c-Kit, PDGFR-β, the inhibition of the Tyrosylprotein kinases such as c-Met is active.Thereby, adopt this method can measure the active function of fused ring compound of the present invention to the biochemistry level of above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.
According to the present invention, in the test of cell levels enzymic activity, enzyme-linked immunosorbent assay (ELISA) can be used for checking and measuring the existence of tyrosine kinase activity.ELISA can carry out in accordance with known methods, such as Voller etc., 1980, " enzyme-linked immunosorbent assay " (Enzyme-Linkd Immunosorbent Assay), see the < < clinical immunology handbook > > (Manual of Clinical Immunology) that Rose and Friedman write, the 2nd edition, pp359-371, AAM publishes, Washington D.C..The phosphorylation reaction of the peptide substrate of the tyrosine-kinase enzyme catalysis ATP such as VEGFR-2, c-Kit, PDGFR-β, c-Met and vitamin H mark mark, inhibitory enzyme activity will suppress this reaction.
According to the present invention, in the test of inhibition tumor cell proliferation activity, measure and adopt routinely blue (MTT) method of bromination tetrazole.Succinodehydrogenase in viable cell plastosome can make the bromination 3-(4 of exogenous yellow, 5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole (MTT) is reduced to the bluish voilet crystallisate Jia Za (Formazan) of insoluble, and be deposited in cell, and dead cell is without this function, purple crystal thing first Za in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument at 570nm wavelength place, can indirectly reflect viable cell quantity.Thereby first Za growing amount is directly proportional to viable count under normal conditions, can infer the number that viable cell according to OD value, understand that medicine suppresses or the ability of killer cell.This measuring method can utilize method well known in the art for measuring different fused ring compounds of the present invention or its pharmacy acceptable salt inhibition ability to one or more cancer cell multiplications, can use similar measuring method to any cancer cells.
According to the present invention, structure prepared by the present invention fused ring compound or its pharmacy acceptable salt as shown in the formula (I) has good restraining effect to multiple kinase activity, and it is to kinase whose half-inhibition concentration (IC such as VEGFR-2 and c-kit 50) generally 10 -7below mol/L.Meanwhile, the fused ring compound with formula I structure or its pharmacy acceptable salt in the embodiment of the present invention, prepared are inhibited to the propagation of kinds of tumor cells, and wherein the effect of most fused ring compound inhibition tumor cell propagation is remarkable, its IC 5010 -5below mol/L.Have this to know by inference, the present invention has the fused ring compound of formula (I) structure or the medicine that its pharmacy acceptable salt can be applicable to protein kinase related disorder in preparation treatment organism.
Detailed description of the invention
According to the present invention, unless there is phase counter-statement, the following term being used in specification sheets and claim has following implication.
According to the present invention, " alkyl " refers to saturated aliphatic hydrocarbon group.The straight or branched group that comprises 1 to 20 carbon atom.The median size alkyl that preferably contains 1 to 10 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, and when being substituted, preferred group is: halogen, C 2-C 6thiazolinyl, C 6-C 10aryl, C 5-C 10heteroaryl, halo C 1-C 10alkyl, 5 to 8 yuan of heterolipid cyclic groups, hydroxyl, C 1-C 10alkoxyl group, C 6-C 10aryloxy ,-NR 7r 8,-NR 7c (=O) R 8,-C (=O) OR 9or-OC (=O) R 9.
According to the present invention, " cycloalkyl " refers to 5 yuan/6 yuan of 3 to 8 yuan of full carbon monocycles, full carbon or 6 yuan/6 yuan thick and rings or encircles thick and ring (" thick and " ring mean that each ring in system share a pair of carbon atom adjoining with other ring in system) group more, wherein one or more rings have the electronic system connecting completely, and the example of cycloalkyl (being not limited to) is cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl is commutable and is what replace.When being substituted, substituting group is preferably one or more following groups that are selected from separately, comprising: C 1-C 10alkyl, C 6-C 10aryl, C 5-C 10heteroaryl, halogen, 5 to 8 yuan of heterolipid cyclic groups, hydroxyl, sulfydryl, C 1-C 10alkoxyl group, C 6-C 10aryloxy, C 1-C 10alkane sulfydryl, C 6-C 10aromatic thiohydroxy, cyano group, nitro ,-NR 7r 8,-NR 7c (=O) R 8,-C (=O) NR 7r 8,-C (=O) R 9,-C (=O) OR 9,-S (O) R 10,-S (O) 2r 10,-S (O) 2nR 7r 8or-OC (=O) R 9.
According to the present invention, " aryl " represents full carbon monocycle or the fused polycycle group of 6 to 14 carbon atoms, has the π-electron system of total conjugated.
" aryl " comprising:
Hexa-atomic carbon aromatic nucleus, as, benzene;
Dicyclo, wherein having a ring at least is carbon aromatic nucleus, as, naphthalene, indenes and 1,2,3,4-tetrahydroquinoline; And
Three rings, wherein having a ring at least is carbon aromatic nucleus, as, fluorenes.
For example, aryl comprises that this heterocycle comprises one or more heteroatomss that are selected from nitrogen, oxygen and sulphur containing hexa-atomic carbon aromatic nucleus a hexa-member heterocycle, and condition is that tie point is on carbon aromatic nucleus.But aryl do not comprise, also by any mode with the heterocyclic aryl of definition is not overlapping respectively below.Therefore,, in this definition, if one or more carbon aromatic nucleus and an assorted aromatic nucleus also encircle, consequent loop systems is heteroaryl, rather than aryl.The limiting examples of aryl has phenyl, naphthyl.Aryl can be that replace or unsubstituted.When being substituted, preferred group is: hydrogen, C 1-C 10alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 6-C 10aryl, C 5-C 10heteroaryl, C 6-C 10aryl C 1-C 10alkyl, C 5-C 10heteroaryl C 1-C 10alkyl, halogen, halo C 1-C 10alkyl, 5 to 8 yuan of heterolipid cyclic groups, hydroxyl, C 1-C 10alkoxyl group, C 6-C 10aryloxy, cyano group, nitro ,-NR 7r 8,-NR 7c (=O) R 8,-C (=O) R 9,-C (=O) OR 9,-C (=O) NR 7r 8,-S (O) R 10,-S (O) 2r 10,-S (O) 2nR 7r 8,-O (CH 2) nR 11or-OC (=O) R 9.
According to the present invention, " heteroaryl " represents monocycle or the fused rings group of 5 to 14 annular atomses, contains one, two, three or four ring hetero atoms that are selected from N, O or S, and all the other annular atomses are C, have in addition the π-electron system of total conjugated.
Heteroaryl refers to:
The mononuclear aromatics of 5-8 unit, containing one or more heteroatomss that are selected from N, O and S, as 1-4 heteroatoms, in some embodiments, and 1-3 heteroatoms, on ring, other atoms are carbon atoms;
The double ring arene of 8-12 unit, containing one or more heteroatomss that are selected from N, O and S, as 1-4 heteroatoms, in some embodiments, and 1-3 heteroatoms, on ring, other atoms are carbon atoms; Wherein having a ring at least is aromatic nucleus; And
The thrcylic aromatic hydrocarbon of 11-14 unit, containing one or more heteroatomss that are selected from N, O and S, as 1-4 heteroatoms, in some embodiments, and 1-3 heteroatoms, on ring, other atoms are carbon atoms; Wherein having a ring at least is aromatic nucleus.
For example, heteroaryl comprises the assorted aromatic nucleus of a 5-6 unit the cycloalkyl of a 5-6 unit.For such dicyclo the heteroaryl getting up, wherein only have a ring to contain one or more heteroatomss, connection site is on assorted aromatic nucleus.
When the sulphur atom on heteroaryl and Sauerstoffatom sum surpass 1, these heteroatomss can be not adjacent one by one.In some embodiments, sulphur atom and the Sauerstoffatom sum in heteroaryl is no more than 2.In some embodiments, sulphur atom and the Sauerstoffatom sum in heteroaryl is no more than 1.
The example of heteroaryl, include but not limited to pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzoglyoxaline, indoline, indolone, quinoline, isoquinoline 99.9, quinazoline, thienopyridine, Thienopyrimidine etc.The preferred embodiment of this type of group is thiophene, pyridine, quinoline, quinazoline, Thienopyrimidine.In heteroaryl one or all hydrogen atom can be replaced by following groups: C 1-C 10alkyl, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 6-C 10aryl, C 5-C 10heteroaryl, C 6-C 10aryl C 1-C 10alkyl, C 5-C 10heteroaryl C 1-C 10alkyl, halogen, halo C 1-C 10alkyl, 5 to 8 yuan of heterolipid cyclic groups, hydroxyl, C 1-C 10alkoxyl group, C 6-C 10aryloxy, cyano group, nitro ,-NR 7r 8,-NR 7c (=O) R 8,-C (=O) R 9,-C (=O) OR 9,-C (=O) NR 7r 8,-S (O) R 10,-S (O) 2r 10,-S (O) 2nR 7r 8,-O (CH 2) nR 11or-OC (=O) R 9.
According to the present invention, " heterolipid cyclic group " represents monocycle or thick and cyclic group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is to be selected from N, O or S (O) p(wherein p0 to 2 integer) heteroatoms, all the other annular atomses are C.These rings can have one or more pair of key, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heterolipid cyclic group has pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine for base, homopiperazine subbase etc.Heterolipid cyclic group can be that replace or unsubstituted.When being substituted, substituting group is preferably one or more, be more preferably one, two or three, and then more preferably one or two, independently selected from following group, comprising: hydrogen, hydroxyl, C 1-C 10alkyl, C 6-C 10aryl, C 5-C 10heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan of heterolipid cyclic groups ,-C (=O) R 9or-S (O) 2r 10, C wherein 1-C 10alkyl, C 6-C 10aryl, C 5-C 10heteroaryl, 3 to 8 yuan of full carbon monocyclic cycloalkyls, 5 to 8 yuan of heterolipid cyclic groups are further by one or more C that are selected from 1-C 10alkyl, C 2-C 6thiazolinyl, C 6-C 10aryl, C 5-C 10heteroaryl ,-C (=O) R 9,-C (=O) OR 9, hydroxyl, C 1-C 10alkoxyl group, C 6-C 10aryloxy ,-O (CH 2) nR 11,-OC (=O) R 10,-NR 7r 8or-NR 7c (=O) R 8substituting group replace.
Piperazino refers to the group with following chemical structure.
Morpholino base refers to the group with following chemical structure.
Piperidino-(1-position only) refers to the group with following chemical structure.
Pyrrolidyl refers to the group with following chemical structure.
According to the present invention, " thiazolinyl " represents to have the straight or branched alkyl of one or more pair of key.Typically be C 2-c 6thiazolinyl, for example vinyl, allyl group, butenyl, butadienyl, pentenyl or hexenyl.
According to the present invention, " alkynyl " represents to have the straight or branched alkyl of one or more triple bonds.Typically be C 2-c 6alkynyl, for example ethynyl, proyl, butynyl.
According to the present invention, the unsubstituted alkyl of " alkoxyl group " expression-O-() and-the unsubstituted cycloalkyl of O().Representational example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
According to the present invention, " aryloxy " expression-O-aryl and-O-heteroaryl.Representative example includes but not limited to phenoxy group, pyridyloxy, furans oxygen base, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygen base etc. and derivative thereof.
According to the present invention, " aralkyl " represents alkyl, preferred low alkyl group as defined above, and it is replaced by aryl as above, for example-CH 2phenyl ,-(CH 2) 2phenyl ,-(CH 2) 3phenyl, CH 3cH (CH 3) CH 2phenyl and derivative thereof.
According to the present invention, " heteroaralkyl " represents alkyl, preferred low alkyl group as defined above, and it is replaced by heteroaryl as above, for example-CH 2pyridyl ,-(CH 2) 2pyrimidyl ,-(CH 2) 3imidazolyl etc. and derivative thereof.
" hydroxyl " expression-OH group.
" sulfydryl " expression-SH group.
" halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine or chlorine.
" haloalkyl " represents alkyl, preferred low alkyl group as defined above, and it is replaced by one or more identical or different halogen atoms, for example-CH 2cl ,-CF 3,-CCl 3,-CH 2cF 3,-CH 2cCl 3deng.
" trihalogenmethyl " expression-CX 3group, wherein X is halogen as defined above.
" cyano group " expression-CN group.
" amino " expression-NH 2group.
" nitro " expression-NO 2group.
According to the present invention, the meaning of so-called " optionally " refers to that the event of subsequent descriptions or situation may also may not can occur, and this description comprises that things or situation may also may not can occur, and this description comprises that two kinds of situations occur and do not occur for things or situation.
According to the present invention, in some embodiments, " by one or more groups, being replaced " refers to that the identical or different group that in the atom of appointment or group, two, three or four hydrogen atoms are selected in the group of designated scope respectively replaces.
According to the present invention, " pharmacy acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of character.This class salt comprises:
(1) with sour salify, free alkali by parent compound reacts and obtains with mineral acid or organic acid, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprise acetic acid, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) salt that is present in that acid proton in parent compound is replaced by metal ion or is generated with organic bases ligand compound, metal example is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, organic bases such as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.
" pharmaceutical composition " refers to one or more or its pharmacy acceptable salt, solvate, hydrate or prodrug and other chemical composition in the fused ring compound in the present invention, and for example pharmaceutically acceptable carrier, mixes.The object of pharmaceutical composition is to promote administration to the process of animal.
" pharmaceutical carrier " refer to organism do not cause obvious pungency and do not disturb the biological activity of given compound and the pharmaceutical composition of character in non-active ingredient, such as but not limited to calcium carbonate, calcium phosphate, various sugar (such as lactose, N.F,USP MANNITOL etc.), starch, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer or methacrylate polymer, gel, water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C or hydrogenated castor oil or many oxyethyl groups hydrogenated castor oil, sesame oil, Semen Maydis oil, peanut wet goods.
In aforesaid pharmaceutical composition, except comprising pharmaceutically acceptable carrier, can also be included in conventional assistant agent in medicine (agent), such as: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMIN, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
Embodiment
The invention provides intermediate of a kind of fused ring compound or its pharmacy acceptable salt and preparation method thereof, this fused ring compound or its pharmacy acceptable salt and preparation method thereof, and this fused ring compound or its pharmacy acceptable salt are as the application of Tyrosylprotein kinase and/or serine-threonine kinase inhibitor, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention.
Embodiment 1
The preparation of compound 1:
The chloro-2-of 8-(4-fluorophenyl)-2, the preparation of 7-naphthyridines-1 (2H)-one:
The method of reporting in reference literature WO2013033981 can be prepared the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one (2.4g).MS:[M+H] +=275.0。
2-(4-fluorophenyl)-8-phenyl amino-2, the preparation of 7-naphthyridines-1 (2H)-one:
In reaction flask, add aniline (47mg, 0.5mM), the chloro-2-of 8-(4-fluorophenyl)-2, 7-naphthyridines-1 (2H)-one (137mg, 0.5mM), three (dibenzalacetone) two palladium (92mg, 0.1mM), 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene (58mg, 0.1mM), sodium tert-butoxide (58mg, 0.12mM) He 1, 4-dioxane (15mL), take out inflated with nitrogen three times, in 106 ℃ of reactions 4 hours, point plate reacts completely, be chilled to room temperature, suction filtration, concentrated, crude product silica gel column chromatography (PE/EA10/1to3/1) obtains 2-(4-fluorophenyl)-8-phenyl amino-2, 7-naphthyridines-1 (2H)-one (108mg).
MS:[M+H] +=332.1。 1H-NMR(400M,DMSO-d6)δ11.80(s,1H),8.30(d,J=5.2Hz,1H),7.81(d,J=8.4Hz,2H),7.69(d,J=7.2Hz,1H),7.58-7.61(m,2H),7.41(t,J=8.4Hz,2H),7.34(t,J=7.6Hz,2H),7.03(t,J=7.2Hz,1H),6.95(d,J=5.2Hz,1H),6.68(d,J=7.2Hz,1H)ppm。
Embodiment 2
The preparation of compound 2:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 2,6-xylidine.
MS:[M+H] +=360.1。 1H-NMR(400M,CDCl 3)δ10.57(s,1H),8.13(d,J=5.6Hz,1H),7.42-7.45(m,2H),7.10-7.24(m,3H),6.55(d,J=5.2Hz,1H),6.41(d,J=7.2Hz,1H),2.23(s,6H)ppm。
Embodiment 3
The preparation of compound 3:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 2,6-DCA.
MS:[M+H] +=400.0。 1H-NMR(400M,CDCl 3)δ10.85(s,1H),8.19(d,J=5.2Hz,1H),7.39-7.46(m,4H),7.20-7.28(m,2H),7.15(t,J=8.0Hz,1H),6.69(d,J=5.6Hz,1H),6.45(d,J=7.2Hz,1H)ppm。
Embodiment 4
The preparation of compound 4:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 3-aminopyridine.
MS:[M+H] +=333.1。 1H-NMR(400M,DMSO-d6)δ11.81(s,1H),8.90(s,1H),8.37(d,J=8.4Hz,1H),8.33(d,J=5.2Hz,1H),8.23(d,J=4.0Hz,1H),7.72(d,J=7.2Hz,1H),7.58-7.62(m,2H),7.35-7.44(m,3H),7.02(t,J=5.2Hz,1H),6.71(d,J=7.2Hz,1H)ppm。
Embodiment 5
The preparation of compound 5:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 7-aminoisoquinoline.
MS:[M+H] +=383.1。 1H-NMR(400M,CDCl 3)δ12.00(s,1H),9.22(s,1H),8.85(s,1H),8.41(t,J=5.2Hz,2H),7.82(d,J=8.8Hz,1H),7.75(d,J=8.8Hz,1H),7.56(d,J=5.6Hz,1H),7.40-7.44(m,2H),7.23-7.30(m,3H),6.80(d,J=5.2Hz,1H),6.50(d,J=7.2Hz,1H)ppm。
Embodiment 6
The preparation of compound 6:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into benzylamine.
MS:[M+H] +=346.1。 1H-NMR(400M,DMSO-d6)δ9.60(b,1H),8.15(d,J=5.2Hz,1H),7.60(d,J=7.2Hz,1H),7.52-7.55(m,2H),7.25-7.38(m,7H),6.70(d,J=5.2Hz,1H),6.56(d,J=7.2Hz,1H),4.70(d,J=5.2Hz,2H)ppm。
Embodiment 7
The preparation of compound 7:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 4-aminomethyl-pyridine.
MS:[M+H] +=347.1。 1H-NMR(400M,CDCl 3)δ9.71(b,1H),8.50(d,J=5.2Hz,2H),8.16(d,J=5.2Hz,1H),7.36-7.39(m,2H),7.19-7.27(m,5H),6.56(d,J=5.6Hz,1H),6.40(d,J=7.2Hz,1H),4.78(d,J=5.6Hz,2H)ppm。
Embodiment 8
The preparation of compound 8:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 3-aminomethyl-pyridine.
MS:[M+H] +=347.1。 1H-NMR(400M,DMSO-d6)δ9.71(t,J=5.6Hz,1H),8.63(s,1H),8.49(d,J=4.4Hz,1H),8.19(d,J=4.2Hz,1H),7.79(d,J=7.6Hz,1H),7.64(d,J=7.2Hz,1H),7.55-7.59(m,2H),7.37-7.41(m,3H),6.75(d,J=5.2Hz,1H),6.60(d,J=7.2Hz,1H),4.77(d,J=4.4Hz,2H)ppm。
Embodiment 9
The preparation of compound 9:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 2-aminomethyl-furan.
MS:[M+H] +=336.1。 1H-NMR(400M,CDCl 3)δ9.49(b,1H),8.22(d,J=5.2Hz,2H),7.32-7.37(m,3H),7.17-7.21(m,3H),6.53(d,J=5.6Hz,1H),6.37(d,J=7.2Hz,1H),6.27(d,J=8.4Hz,2H),4.74(d,J=5.2Hz,2H)ppm。
Embodiment 10
The preparation of compound 10:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 1-naphthalene methylamine.
MS:[M+H] +=396.1。 1H-NMR(400M,DMSO-d6)δ9.60(t,J=5.0Hz,1H),8.19(d,J=5.2Hz,1H),8.11(d,J=7.6Hz,1H),7.95(d,J=6.4Hz,1H),7.85(d,J=8.0Hz,1H),7.49-7.56(m,7H),7.31(t,J=8.8Hz,2H),6.71(d,J=5.6Hz,1H),6.55(d,J=7.2Hz,1H),5.16(d,J=5.2Hz,2H)ppm。
Embodiment 11
The preparation of compound 11:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, changes aniline into 4-aminomethyl quinoline.
MS:[M+H] +=397.1。 1H-NMR(400M,CDCl 3)δ9.80(b,1H),8.81(d,J=4.4Hz,1H),8.19(d,J=5.2Hz,1H),8.11(d,J=8.0Hz,2H),7.71(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.43(d,J=4.4Hz,1H),7.35-7.39(m,2H),7.17-7.24(m,3H),6.58(d,J=5.2Hz,1H),6.42(d,J=7.2Hz,1H),5.29(d,J=6.4Hz,2H)ppm。
Embodiment 12
The preparation of compound 12:
The chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the preparation of 7-naphthyridines-1 (2H)-one:
The method of reporting in reference literature WO2013033981 can be prepared the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2,7-naphthyridines-1 (2H)-one (160mg).MS:[M+H] +=289.1。
2-(4-fluorophenyl)-3-methyl-8-(pyridin-3-yl is amino)-2, the preparation of 7-naphthyridines-1 (2H)-one:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-(4-fluorophenyl of 8-into)-3-methyl-2,7-naphthyridines-1 (2H)-one, changes aniline into 3-aminopyridine.
MS:[M+H] +=347.1。 1H-NMR(400M,DMSO-d6)δ11.73(s,1H),8.87(s,1H),8.36(d,J=8.4Hz,1H),8.27(d,J=5.6Hz,1H),8.19(d,J=4.4Hz,1H),7.32-7.50(m,5H),6.90(d,J=5.6Hz,1H),6.65(s,1H),1.98(s,3H)ppm。
Embodiment 13
The preparation of compound 13:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl-pyridine.
MS:[M+H] +=361.1。 1H-NMR(400M,DMSO-d6)δ9.59(t,J=5.6Hz,1H),8.46(d,J=5.2Hz,2H),8.04(d,J=5.2Hz,1H),7.38-7.45(m,4H),7.28(d,J=5.2Hz,2H),6.59(d,J=5.6Hz,1H),6.49(s,1H),4.70(d,J=6.0Hz,2H),1.94(s,3H)ppm。
Embodiment 14
The preparation of compound 14:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminomethyl-pyridine.
MS:[M+H] +=361.1。 1H-NMR(400M,DMSO-d6)δ9.53(t,J=5.6Hz,1H),8.55(s,1H),8.42(d,J=4.4Hz,1H),8.08(d,J=5.6Hz,1H),7.72(d,J=7.6Hz,1H),7.30-7.41(m,5H),6.58(d,J=5.6Hz,1H),6.48(s,1H),4.68(d,J=6.0Hz,2H),1.93(s,3H)ppm。
Embodiment 15
The preparation of compound 15:
In employing and embodiment 1, prepare 2-(4-fluorophenyl)-8-phenyl amino-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl quinoline.
MS:[M+H] +=411.2。 1H-NMR(400M,DMSO-d6)δ9.65(t,J=5.6Hz,1H),8.79(d,J=4.0Hz,1H),8.21(d,J=8.0Hz,1H),8.05(d,J=6.0Hz,2H),7.78(t,J=7.6Hz,1H),7.64(t,J=8.0Hz,1H),7.34-7.45(m,5H),6.60(d,J=5.6Hz,1H),6.51(s,1H),5.21(d,J=6.0Hz,2H),1.95(s,3H)ppm。
Embodiment 16
The preparation of compound 16:
Phenyl-2,8-chloro-3-methyl-2, the preparation of 7-naphthyridines-1 (2H)-one:
The method of reporting in reference literature WO2013033981 can be prepared phenyl-2,8-chloro-3-methyl-2,7-naphthyridines-1 (2H)-one, and difference is, changes starting raw material 2-cyano group-N-(4-fluorophenyl) ethanamide into 2-cyano group-phenyl acetanilide,Phenacetylaniline.
MS:[M+H] +=271.1。 1H-NMR(400M,CDCl 3)δ8.55(d,J=5.6Hz,1H),7.46-7.56(m,2H),7.20-7.24(m,4H),6.34(s,1H),2.03(s,3H)ppm。
3-methyl-2 phenyl-8-(pyridin-3-yl is amino)-2, the preparation of 7-naphthyridines-1 (2H)-one:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes phenyl-2,8-chloro-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminopyridine.
MS:[M+H] +=329.1。 1H-NMR(400M,DMSO-d6)δ11.76(s,1H),8.87(s,1H),8.36(d,J=8.0Hz,1H),8.26(d,J=5.2Hz,1H),8.19(d,J=4.0Hz,1H),7.50-7.63(m,3H),7.31-7.41(m,2H),6.89(d,J=5.6Hz,1H),6.64(s,1H),1.97(s,3H)ppm。
Embodiment 17
The preparation of compound 17:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes phenyl-2,8-chloro-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl-pyridine.
MS:[M+H] +=343.2。 1H-NMR(400M,DMSO-d6)δ9.61(t,J=6.0Hz,1H),8.46(d,J=4.0Hz,2H),8.04(d,J=5.2Hz,1H),7.47-7.57(m,3H),7.35(d,J=7.6Hz,2H),7.28(d,J=4.8Hz,2H),6.59(d,J=5.2Hz,1H),6.49(s,1H),4.70(d,J=6.0Hz,2H),1.93(s,3H)ppm。
Embodiment 18
The preparation of compound 18:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes phenyl-2,8-chloro-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminomethyl-pyridine.
MS:[M+H] +=343.2。 1H-NMR(400M,DMSO-d6)δ9.55(t,J=5.6Hz,1H),8.55(s,1H),8.42(d,J=4.4Hz,1H),8.08(d,J=4.8Hz,1H),7.72(d,J=7.6Hz,1H),7.31-7.54(m,6H),6.59(d,J=5.6Hz,1H),6.48(s,1H),4.68(d,J=6.0Hz,2H),1.92(s,3H)ppm。
Embodiment 19
The preparation of compound 19:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes phenyl-2,8-chloro-3-methyl-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl quinoline.
MS:[M+H] +=393.5。 1H-NMR(400M,DMSO-d6)δ9.67(t,J=5.6Hz,1H),8.79(d,J=4.0Hz,1H),8.21(d,J=8.0Hz,1H),8.05(d,J=6.0Hz,2H),7.78(t,J=7.6Hz,1H),7.64(t,J=8.0Hz,1H),7.46-7.56(m,3H),7.33-7.38(m,3H),6.60(d,J=5.2Hz,1H),6.51(s,1H),5.21(d,J=5.6Hz,2H),1.94(s,3H)ppm。
Embodiment 20
The preparation of compound 20:
The chloro-2-of 8-(4-chloro-phenyl-)-3-methyl-2, the preparation of 7-naphthyridines-1 (2H)-one:
The method of reporting in reference literature WO2013033981 can be prepared the chloro-2-of 8-(4-chloro-phenyl-)-3-methyl-2,7-naphthyridines-1 (2H)-one, difference is, changes starting raw material 2-cyano group-N-(4-fluorophenyl) ethanamide into 2-cyano group-N-(4-chloro-phenyl-) ethanamide.
MS:[M+H] +=305.0。 1H-NMR(400M,CDCl 3)δ8.39(d,J=5.2Hz,1H),7.52(d,J=8.8Hz,2H),7.16-7.22(m,3H),6.37(s,1H),2.04(s,3H)ppm。
2-(4-chloro-phenyl-)-3-methyl-8-(pyridin-3-yl is amino)-2, the preparation of 7-naphthyridines-1 (2H)-one:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-chloro-phenyl-)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminopyridine.
MS:[M+H] +=363.1。 1H-NMR(400M,DMSO-d6)δ11.58(s,1H),8.86(s,1H),8.40(d,J=8.4Hz,1H),8.25(d,J=5.6Hz,2H),7.22-7.30(m,5H),6.90(d,J=5.6Hz,1H),6.36(s,1H),2.03(s,3H)ppm。
Embodiment 21
The preparation of compound 21:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-chloro-phenyl-)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl-pyridine.
MS:[M+H] +=377.1。 1H-NMR(400M,DMSO-d6)δ9.55(t,J=5.6Hz,1H),8.46(d,J=4.0Hz,2H),8.04(d,J=5.6Hz,1H),7.61(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),7.28(d,J=5.2Hz,2H),6.59(d,J=5.3Hz,1H),6.50(s,1H),4.70(d,J=6.0Hz,2H),1.94(s,3H)ppm。
Embodiment 22
The preparation of compound 22:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-chloro-phenyl-)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminomethyl-pyridine.
MS:[M+H] +=377.1。 1H-NMR(400M,DMSO-d6)δ9.50(t,J=5.6Hz,1H),8.55(s,1H),8.43(d,J=4.4Hz,1H),8.09(d,J=5.6Hz,1H),7.72(d,J=8.0Hz,1H),7.60(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.32(t,J=4.8Hz,1H),6.59(d,J=5.2Hz,1H),6.49(s,1H),4.68(d,J=5.6Hz,2H),1.93(s,3H)ppm。
Embodiment 23
The preparation of compound 23:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-chloro-phenyl-)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl quinoline.
MS:[M+H] +=427.1。 1H-NMR(400M,DMSO-d6)δ9.62(t,J=5.6Hz,1H),8.79(d,J=4.4Hz,1H),8.21(d,J=8.4Hz,1H),8.03-8.06(m,2H),7.78(t,J=8.0Hz,1H),7.59-7.67(m,3H),7.42(d,J=8.4Hz,2H),7.37(d,J=4.0Hz,1H),6.61(d,J=5.2Hz,1H),6.51(s,1H),5.21(d,J=6.0Hz,2H),1.95(s,3H)ppm。
Embodiment 24
The preparation of compound 24:
The chloro-2-of 8-(4-Trifluoromethoxyphen-l)-3-methyl-2, the preparation of 7-naphthyridines-1 (2H)-one:
The method of reporting in reference literature WO2013033981 can be prepared the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-3-methyl-2,7-naphthyridines-1 (2H)-one, difference is, changes starting raw material 2-cyano group-N-(4-fluorophenyl) ethanamide into 2-cyano group-N-(4-Trifluoromethoxyphen-l) ethanamide.
MS:[M+H] +=355.0。 1H-NMR(400M,CDCl 3)δ8.41(d,J=5.2Hz,1H),7.38(d,J=8.8Hz,2H),7.21-7.29(m,3H),6.38(s,1H),2.05(s,3H)ppm。
2-(4-Trifluoromethoxyphen-l)-3-methyl-8-(pyridin-3-yl is amino)-2, the preparation of 7-naphthyridines-1 (2H)-one:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminopyridine.
MS:[M+H] +=413.1。 1H-NMR(400M,DMSO-d6)δ11.68(s,1H),8.87(s,1H),8.36(d,J=8.4Hz,1H),8.27(d,J=5.2Hz,1H),8.19(d,J=4.0Hz,1H),7.59(m,4H),7.34(d,J=8.4Hz,1H),6.89(d,J=5.6Hz,1H),6.66(s,1H),1.98(s,3H)ppm。
Embodiment 25
The preparation of compound 25:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 1-naphthalene methylamine.
MS:[M+H] +=476.2。 1H-NMR(400M,DMSO-d6)δ9.44(t,J=5.6Hz,1H),8.15(d,J=5.2Hz,1H),8.09(d,J=8.8Hz,1H),7.94(d,J=8.4Hz,1H),7.84(d,J=8.0Hz,1H),7.42-7.54(m,8H),6.60(d,J=5.2Hz,1H),6.51(s,1H),5.12(d,J=5.2Hz,2H),1.92(s,3H)ppm。
Embodiment 26
The preparation of compound 26:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl-pyridine.
MS:[M+H] +=427.1。 1H-NMR(400M,DMSO-d6)δ9.57(t,J=6.0Hz,1H),8.46(d,J=5.2Hz,2H),8.05(d,J=7.6Hz,1H),7.54(b,4H),7.28(d,J=5.2Hz,2H),6.59(d,J=5.2Hz,1H),6.51(s,1H),4.70(d,J=6.0Hz,2H),1.95(s,3H)ppm。
Embodiment 27
The preparation of compound 27:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 2-aminomethyl-furan.
MS:[M+H] +=416.1。 1H-NMR(400M,DMSO-d6)δ9.33(t,J=5.2Hz,1H),8.12(d,J=5.6Hz,1H),7.50-7.56(m,5H),6.60(d,J=5.2Hz,1H),6.51(s,1H),6.37(s,1H),6.28(s,1H),4.64(d,J=5.6Hz,2H),1.93(s,3H)ppm。
Embodiment 28
The preparation of compound 28:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 3-aminomethyl-pyridine.
MS:[M+H] +=427.1。 1H-NMR(400M,DMSO-d6)δ9.51(t,J=5.2Hz,1H),8.55(s,1H),8.43(d,J=4.0Hz,1H),8.09(d,J=5.2Hz,1H),7.72(d,J=7.6Hz,1H),7.53-7.59(m,4H),7.32(d,J=5.2Hz,1H),6.59(d,J=5.2Hz,1H),6.50(s,1H),4.68(d,J=5.6Hz,2H),1.94(s,3H)ppm。
Embodiment 29
The preparation of compound 29:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-of 8-(4-Trifluoromethoxyphen-l)-2 into, 7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl quinoline.
MS:[M+H] +=477.2。 1H-NMR(400M,DMSO-d6)δ9.63(t,J=6.0Hz,1H),8.81(d,J=4.4Hz,1H),8.22(d,J=8.0Hz,1H),8.06(d,J=8.8Hz,2H),7.79(t,J=7.2Hz,1H),7.67(t,J=7.6Hz,1H),7.55-7.58(m,4H),7.37(d,J=4.0Hz,2H),6.63(d,J=5.6Hz,1H),6.54(s,1H),5.23(d,J=5.6Hz,2H),1.97(s,3H)ppm。
Embodiment 30
The preparation of compound 30:
The chloro-2-of 8-(2,4 difluorobenzene base)-3-methyl-2, the preparation of 7-naphthyridines-1 (2H)-one:
The method of reporting in reference literature WO2013033981 can be prepared the chloro-2-(2 of 8-, 4-difluorophenyl)-3-methyl-2,7-naphthyridines-1 (2H)-one, difference is, change starting raw material 2-cyano group-N-(4-fluorophenyl) ethanamide into 2-cyano group-N-(2,4 difluorobenzene base) ethanamide.
MS:[M+H] +=307.0。 1H-NMR(400M,CDCl 3)δ8.42(d,J=5.6Hz,1H),7.23-7.29(m,2H),7.02-7.08(m,2H),6.39(s,1H),2.05(s,3H)ppm。
2-(2,4 difluorobenzene base)-3-methyl-8-(pyridin-3-yl is amino)-2, the preparation of 7-naphthyridines-1 (2H)-one:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-(2 of 8-into, 4-difluorophenyl)-2,7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl-pyridine.
MS:[M+H] +=378.4。 1H-NMR(400M,DMSO-d6)δ9.52(b,1H),8.49(b,2H),8.13(d,J=4.2Hz,1H),7.40(m,2H),7.07(m,3H),6.50(d,J=4.2Hz,1H),6.31(s,1H),5.23(m,2H),2.03(s,3H)ppm。
Embodiment 31
The preparation of compound 31:
In employing and embodiment 1, prepare the chloro-2-of 8-(4-fluorophenyl)-3-methyl-2, the identical method of 7-naphthyridines-1 (2H)-one, difference is, by the chloro-2-of 8-(4-fluorophenyl)-2,7-naphthyridines-1 (2H)-one changes the chloro-2-(2 of 8-into, 4-difluorophenyl)-2,7-naphthyridines-1 (2H)-one, changes aniline into 4-aminomethyl quinoline.
MS:[M+H] +=429.1。 1H-NMR(400M,DMSO-d6)δ9.54(t,J=6.0Hz,1H),8.79(d,J=4.4Hz,1H),8.21(d,J=8.4Hz,1H),8.09(d,J=5.6Hz,1H),7.78(t,J=8.0Hz,1H),7.61-7.66(m,2H),7.58(t,J=7.2Hz,1H),7.36(d,J=4.4Hz,1H),7.30(d,J=7.2Hz,2H),6.63(d,J=5.6Hz,1H),6.56(s,1H),5.23(d,J=5.6Hz,2H),1.99(s,3H)ppm。
Embodiment 32
External biochemistry level arrestin kinases (PK) activity experiment:
Materials and methods: c-Kit, VEGFR-2, PDGFR-β and c-Met kinases, derive from Invitrogen; HTRFKinEASE; TK kit(Cisbio company); 384 orifice plates (Greiner company); ATP(sigma company), MgCl 2(sigma company); The multi-functional microplate reader of PHERAstar FS (BMG company); Low speed centrifuge (StaiteXiang yi company); Thermostat container (Binder company).The high-activity compound A of the positive drug of choosing for reporting in the OSI-930 in clinical study and WO2013033981, structure is as follows:
Compound dissolution and preservation: depending on solvability, with DMSO, test-compound is configured to the mother liquor of 0.5-10mmol/L ,-20 ℃ of preservations after packing;
The preparation of compound working fluid: before test, the compound of packing is taken out from refrigerator, be diluted to 50 * desired concn with pure DMSO; Then with deionized water by diluted chemical compound to 4 * desired concn;
The preparation of 1.33 * Enzymatic buffer: 5 * Enzymatic buffer is derived to HTRF kit) with deionized water be diluted to 1.33 *, and add the corresponding composition of 1.33 * final concentration: 1.33mmol/L DTT and 1.33mmol/L MgCl2;
The preparation of kinases working fluid: with 1.33 * Enzymatic buffer by kinase dilution to 2 * required final concentration 0.2ng/ μ L;
The preparation of substrate working fluid: substrate-biotin(is derived to HTRF kit with 1.33 * Enzymatic buffer) and ATP(10mM) dilution is the mixed solution of 4 * required final concentration;
The preparation of testing liquid: with HTRF detection buffer, the Streptavidin-XL665 of 16.67 μ mol/L is diluted to 4 * required final concentration, then mixes (all deriving from HTRF kit) with isopyknic Antibody-Cryptate.
Enzyme reaction step: the kinases working fluid to adding 4 μ L μ l in each hole of low volume 384 microwell plates adds 1.33 * Enzymatic buffer of 4 μ L as negative control (Negative) simultaneously; The compound working fluid that adds 2 μ l to hole, as pulverised compound concentration, contrast (is positive control, Positive) to the 8%DMSO aqueous solution that simultaneously adds 2 μ L; In 25 ℃ (or 30 ℃), hatch 5-10min; Xiang Kongzhong adds 2 μ L substrate working fluids to start enzyme reaction, in 25 ℃ of (or 30 ℃) oscillatory reaction 15-60min.
HTRF reagent detecting step: the testing liquid termination reaction that adds 8 μ L to hole; 25 ℃ of reaction 1h;
Reading of HTRF signal: adopt PHERAstar FS reading detection signal, instrument arranges as follows:
Optic?module Integration?delay(lag?time)50μs、Integration?time400μs、Number?of?flashes200
The raw data of reading for every hole, ratio=665nm/620nm;
The calculating of inhibiting rate:
IC 50the calculating of value: the logarithm of compound concentration of take is X-coordinate, inhibiting rate is ordinate zou, in GraphPad Prism5, matching nonlinear curve: log (inhibitor) vs.response--Variable slope, obtains the enzyme testing compound concentration IC of inhibiting rate while being 50% that live 50.
Experimental result: c-kit kinase activity half-inhibition concentration (IC 50nM)
The invention provides the half-inhibition concentration (IC of the fused ring compound of structure as shown in formula I to c-kit kinase activity 50) in Table 1:
Table 1
++++represent IC 50<50nM; +++ represent IC 50< scope is 50-500nM; ++ represent IC 50scope is 500-5000nM; + expression IC 50scope is >5000nM;-represent not test
Half-inhibition concentration (the IC of compound to VEGFR-2 kinase activity 50) in Table 2.
Table 2
++++represent IC 50<50nM; +++ represent IC 50< scope is 50-500nM; ++ represent IC 50scope is 500-5000nM; + expression IC 50scope is >5000nM;-represent not test
Half-inhibition concentration (the IC of compound to PDGFR-beta kinase activity 50) in Table 3.
Table 3
++++represent IC 50<50nM:+++ represents IC 50< scope is 50-500nM; ++ represent IC 50scope is 500-5000nM; + expression IC 50scope is >5000nM;-represent not test
Half-inhibition concentration (the IC of compound to c-Met kinase activity 50) in Table 4.
Table 4
++++represent IC 50<50nM; +++ represent IC 50< scope is 50-500nM; ++ represent IC 50scope is 500-5000nM; + expression IC 50scope is >5000nM;-represent not test
Experimental result: part fused ring compound of the present invention is all better than positive drug OSI-930 and compd A to the inhibition activity of c-kit, VEGFR-2 and PDGFR-beta kinase biochemistry level, c-Met is suppressed to active without obvious, demonstrate certain kinases selectivity, and there is obvious difference with the kinases spectrum of compd A, be likely applied to the treatment of different knurl kinds.
Embodiment 33
The measuring method (mtt assay) of compound inhibition tumor cell propagation provided by the invention:
Reagent and instrument:
RPMI1640 substratum (RPMI1640+12% calf serum+HEPES3.5g/L+NaHCO 32.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);
RPMI1640 substratum (RPMI1640+12% foetal calf serum+HEPES3.5g/L+NaHCO α 32.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);
DMEM in high glucose substratum (DMEM+10% calf serum+HEPES3.5g/L+NaHCO 32.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);
DMEM in high glucose substratum (DMEM+12% foetal calf serum+HEPES3.5g/L+NaHCO 32.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);
MC COYS5-A substratum (DMEM+12% foetal calf serum+HEPES3.5g/L+NaHCO 32.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);
Trypsinase; MTT(U.S. Amresco company product); Microplate reader (TECAN infinite M200)
People's gastric adenocarcinoma cells strain (BGC); Non-small cell lung carcinoma (A549); Human leukemia cell line (K562); Human pancreas cancer cell strain (PANC-1); Human small cell lung carcinoma (NCI-H446); RPMI1640 substratum containing 12% calf serum for listed JEG-3, in 37 ℃, 5%CO 2incubator in cultivate;
Human pancreas cancer cell strain (BXPC-3); Human bladder cancer cell's strain (T24); The RPMI1640 substratum of 12% foetal calf serum for listed JEG-3, in 37 ℃, 5%CO 2incubator in cultivate;
Human hepatoma cell strain (HEPG2); Human breast cancer cell strain (MCF-7); The DMEM in high glucose substratum of 12% calf serum for listed JEG-3, in 37 ℃, 5%CO 2incubator in cultivate;
Human colon adenocarcinoma cell's strain (CACO-2), with the DMEM in high glucose substratum of 12% foetal calf serum, in 37 ℃, 5%CO 2incubator in cultivate;
Human colon cancer cell strain (HT29); Human colon cancer cell strain (HCT116); Human oophoroma cell line (SK-OV-3); The MC COYS5-A substratum of 12% foetal calf serum for listed JEG-3, in 37 ℃, 5%CO 2incubator in cultivate.
Inoculation: get in exponential phase of growth, one bottle, cell in good condition, adds appropriate tryptic digestive juice, digestion comes off attached cell, with containing RPMI1640(or DMEM or the 5A of 12% calf serum) nutrient solution is made into cell suspension, counting, and cell density adjustment is diluted to 1.67 * 10 4/ mL obtained cell suspension is inoculated on 96 orifice plates, 180 μ L/ holes (containing tumour cell 3000/ hole).
Cultivate: culture plate is proceeded to constant temperature CO 2in incubator, at 37 ℃, 5%CO 2and under saturated humidity condition, cultivate 24 hours.
Primary dcreening operation: testing compound is first mixed with 0.1M concentration with DMSO, remakes 3 extent of dilution, and for primary dcreening operation, concentration is followed successively by 10 -5mol/L, 10 -6mol/L and 10 -7mol/L.Add testing compound, 20 μ L/ holes, cultivate 72 hours.Establish 3 parallel holes for every group, and repeat 3 times, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth, get mean value three times.
Dyeing: MTT is added in 96 orifice plates (attached cell), and 20 μ L/ holes, are placed in incubator and hatch 4 hours, inhales and abandons supernatant liquor in hole, adds DMSO100 μ L/ hole, on horizontalization plate shaking table, shakes 5 minutes.MTT is added to (suspension cell) in 96 orifice plates, and 20 μ L/ holes, are placed in incubator and hatch 4 hours, then add 20%SDS50 μ L/ hole, are placed in incubator and spend the night.
Measure: it is 570nm that microplate reader is set wavelength, and reference wavelength is 630nm, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth, to judge the anti-tumor activity of tested medicine.
Multiple sieve: be 10 in primary dcreening operation concentration -5during mol/L, the compound of 3 cell inhibitory rate>=50%, for multiple sieve, remakes 10 extent of dilution by 0.1mol/L, and concentration is followed successively by 10 -5mol/L, 0.5 * 10 -5mol/L, 10 -6mol/L, 0.8 * 10 -6mol/L, 0.6 * 10 -6mol/L, 0.4 * 10 -6mol/L, 0.2 * 10 -6mol/L, 10 -7mol/L, 0.8 * 10 -7mol/L and 0.4 * 10 -7mol/L.Add test-compound, 20 μ L/ holes, cultivate 48 hours.Establish 3 parallel holes for same every group, and repeat 3 times, and according to prescreening method, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth.
Inhibitory rate of cell growth and IC 50calculating:
Simultaneously, according to the growth inhibition ratio of each concentration, adopt the logarithm of this fused ring compound concentration with Logit linear regression, obtain the testing compound concentration IC when suppressing growth rate and being 50% 50, get mean value three times.
Test-results: in the embodiment of the present invention 1 to 31, the fused ring compound with formula (I) structure of preparation is inhibited to the propagation of kinds of tumor cells, statistical analysis, effect is (P<0.05) significantly, its IC 50all 10 -6below mol/L.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (9)

1. fused ring compound or its pharmacy acceptable salt, is characterized in that, the structural formula of this fused ring compound as shown in the formula (I),
Wherein,
M is 0 or 1; N is 0,1,2,3 or 4;
R 1be selected from hydrogen, unsubstituted C 1-C 10alkyl and by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkyl;
R 2be selected from hydrogen, halogen, unsubstituted C 1-C 10alkyl, hydroxyl, unsubstituted C 1-C 10alkoxyl group, by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10alkyl and by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkoxyl group;
A is selected from six membered heteroaryl, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring, hexa-atomic and hexa-atomic aromatic ring yl, and by one or more hydrogen, C of being selected from 1-C 4alkyl, halogen, halo C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group, C 6-C 10a kind of in the six membered heteroaryl that aryloxy, cyano group, nitro and amino substituting group replace, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring and hexa-atomic and hexa-atomic aromatic ring yl.
2. fused ring compound according to claim 1 or its pharmacy acceptable salt,
Wherein,
M is 1; N is 0,1 or 2;
R 1be selected from hydrogen and C 1-C 4a kind of in alkyl;
R 2be selected from hydrogen, halogen, C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group and the C being replaced by one or more halogenic substituents 1-C 4a kind of in alkoxyl group;
A is selected from furyl, pyridyl, pyrimidyl, thienopyridine base, quinazolyl, quinolyl, naphthyl, phenyl, and by one or more hydrogen, halogen and C of being selected from 1-C 4a kind of in furyl, pyridyl, pyrimidyl, thienopyridine base, quinazolyl, quinolyl, naphthyl and phenyl that the substituting group of alkyl replaces;
Preferably, A is selected from following group:
in a kind of.
3. fused ring compound according to claim 1 or its pharmacy acceptable salt, wherein, described fused ring compound is selected from:
In a kind of.
4. a method of preparing fused ring compound claimed in claim 1 or its pharmacy acceptable salt, the method comprises the following steps: at reaction solvent S 1, under alkali B, catalyzer C and ligand L exist, 2 shown in formula (II), the amino substitution compound generation linked reaction shown in 7-naphthyridones compound and formula (III);
Wherein,
M is 0 or 1; N is 0,1,2,3 or 4;
R 1be selected from hydrogen, unsubstituted C 1-C 10alkyl and by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkyl;
R 2be selected from hydrogen, halogen, unsubstituted C 1-C 10alkyl, hydroxyl, unsubstituted C 1-C 10alkoxyl group, by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10alkyl and by one or more C that are selected from 1-C 10alkyl, C 1-C 10the C that the substituting group of alkoxyl group and halogen replaces 1-C 10a kind of in alkoxyl group;
A is selected from six membered heteroaryl, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring, hexa-atomic and hexa-atomic aromatic ring yl, and by one or more hydrogen, C of being selected from 1-C 4alkyl, halogen, halo C 1-C 4alkyl, hydroxyl, C 1-C 4alkoxyl group, C 6-C 10a kind of in the six membered heteroaryl that aryloxy, cyano group, nitro and amino substituting group replace, five yuan six membered heteroaryl, hexa-atomic and six membered heteroaryl, hexa-atomic aromatic ring and hexa-atomic and hexa-atomic aromatic ring yl.
5. method according to claim 4, wherein, reaction solvent S 1be selected from 4-dioxane and/or glycol dimethyl ether, be preferably Isosorbide-5-Nitrae-dioxane;
Preferably, alkali B is selected from one or more in sodium hydroxide, sodium hydride, sodium tert-butoxide and potassium tert.-butoxide, is preferably sodium tert-butoxide;
Preferably, catalyzer C is selected from one or more in palladium, four triphenyl phosphorus palladiums, dichloro two triphenyl phosphorus palladiums and three (dibenzalacetone) two palladiums, is preferably three (dibenzalacetone) two palladiums;
Preferably, ligand L is phosphine part, is preferably two (diphenylphosphine) propane of 1,2-and/or two diphenylphosphine-9 of 4,5-, 9-dimethyl oxa-anthracene;
Preferably, the temperature of described linked reaction is 90-115 ℃, is preferably 100-110 ℃.
6. a pharmaceutical composition, this pharmaceutical composition contain the fused ring compound described in any one in claims 1 to 3 or its pharmacy acceptable salt as activeconstituents, medicinal carrier substance and/or thinner.
7. in claim 1-3, the fused ring compound described in any one or its pharmacy acceptable salt, pharmaceutical composition claimed in claim 6 are being prepared treatment through the application aspect the medicine of the disease of protein kinase intermediary.
8. application according to claim 7, wherein, the described disease through protein kinase intermediary is selected from the disease relevant to VEGFR-2, c-kit or PDGFR-β.
9. application according to claim 8, wherein, the described disease through protein kinase intermediary is selected from one or more in colorectal carcinoma, bladder cancer, mammary cancer, liver cancer, lung cancer, carcinoma of the pancreas, gastrointestinal cancer, leukemia, ovarian cancer, head and neck cancer, prostate cancer, kidney, nasopharyngeal carcinoma, glioblastoma, squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, melanoma, neurospongioma, genitourinary cancer and bone marrow proliferative illness.
CN201410027270.1A 2014-01-13 2014-01-13 One class fused ring compound or its pharmaceutically acceptable salt and its preparation method and application Active CN104151311B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410027270.1A CN104151311B (en) 2014-01-13 2014-01-13 One class fused ring compound or its pharmaceutically acceptable salt and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410027270.1A CN104151311B (en) 2014-01-13 2014-01-13 One class fused ring compound or its pharmaceutically acceptable salt and its preparation method and application

Publications (2)

Publication Number Publication Date
CN104151311A true CN104151311A (en) 2014-11-19
CN104151311B CN104151311B (en) 2017-01-04

Family

ID=51876969

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410027270.1A Active CN104151311B (en) 2014-01-13 2014-01-13 One class fused ring compound or its pharmaceutically acceptable salt and its preparation method and application

Country Status (1)

Country Link
CN (1) CN104151311B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016204429A1 (en) * 2015-06-18 2016-12-22 한국화학연구원 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
US10526337B2 (en) 2015-06-18 2020-01-07 Korea Research Institute Of Chemical Technology Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing same as active ingredient
WO2020063860A1 (en) * 2018-09-28 2020-04-02 Fochon Pharmaceuticals, Ltd. Naphthyridinone and pyridopyrimidinone compounds useful as kinases inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102317284A (en) * 2008-12-16 2012-01-11 西特里斯药业公司 Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
CN102548992A (en) * 2009-07-30 2012-07-04 Irm责任有限公司 2, 7 -naphthyridin- 1 -one derivatives as syk kinase inhibitors
CN102977125A (en) * 2011-09-06 2013-03-20 江苏先声药物研究有限公司 2,7-naphthyridine derivative, and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102317284A (en) * 2008-12-16 2012-01-11 西特里斯药业公司 Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
CN102548992A (en) * 2009-07-30 2012-07-04 Irm责任有限公司 2, 7 -naphthyridin- 1 -one derivatives as syk kinase inhibitors
CN102977125A (en) * 2011-09-06 2013-03-20 江苏先声药物研究有限公司 2,7-naphthyridine derivative, and preparation method and application thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016204429A1 (en) * 2015-06-18 2016-12-22 한국화학연구원 Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient
US10526337B2 (en) 2015-06-18 2020-01-07 Korea Research Institute Of Chemical Technology Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing same as active ingredient
RU2719367C2 (en) * 2015-06-18 2020-04-17 Корея Рисерч Инститьют Оф Кемикал Текнолоджи Heteroaryl derivative or a pharmaceutically acceptable salt thereof, a method for production thereof and a pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing said active substance
WO2020063860A1 (en) * 2018-09-28 2020-04-02 Fochon Pharmaceuticals, Ltd. Naphthyridinone and pyridopyrimidinone compounds useful as kinases inhibitors
CN112771042A (en) * 2018-09-28 2021-05-07 重庆复创医药研究有限公司 Nalidinone and pyridylpyrimidinone compounds as protein kinase inhibitors

Also Published As

Publication number Publication date
CN104151311B (en) 2017-01-04

Similar Documents

Publication Publication Date Title
Hamby et al. Structure− activity relationships for a novel series of pyrido [2, 3-d] pyrimidine tyrosine kinase inhibitors
CN105452223B (en) As Raf kinases and/or the fused tricyclic carbamide compounds of Raf kinases dimer inhibitor
Ishikawa et al. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo [3, 2-d] pyrimidine scaffold
CN105008351B (en) Cdc7 inhibitor
CN103183674B (en) One class fused heterocyclic derivative and its application
US10364247B2 (en) Preparation and use of novel protein kinase inhibitors
KR20140048968A (en) Inhibitors of bruton&#39;s tyrosine kinase
JP5993010B2 (en) Pyrimido-pyridazinone compounds and uses thereof
TW200825081A (en) Compositions and methods for modulating C-KIT and PDGFR receptors
WO2013170671A1 (en) Pteridine ketone derivative and applications thereof as egfr, blk, and flt3 inhibitor
KR20190140966A (en) Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compound
CN102558147B (en) Compound, and preparation method and application thereof
CN113480543B (en) 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and synthetic method and application thereof
CN108290899A (en) A kind of substituted Pyrrolopyrimidine compounds and its application
CN104151311A (en) Fused ring compound or pharmaceutically acceptable salt thereof as well as preparation method and application of fused ring compound
Salerno et al. Investigation of new 2-aryl substituted benzothiopyrano [4, 3-d] pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2
CN104250252B (en) Pyrazolo [1,5 a] pyrimidines and preparation method thereof and medical usage
Cao et al. The design and preliminary structure–activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes
US10745360B2 (en) Quinoxaline compounds, method for preparing the same and use thereof
TW201738227A (en) Fused ring compound and preparation method, application and intermediate compound thereof
WO2021129561A1 (en) Cyano-substituted pyridine and cyano-substituted pyrimidine compound and preparation method therefor and application thereof
CN102146074B (en) Preparation method of pyrrole derivative and application thereof
CN108727355A (en) A kind of carboxamides derivatives, preparation method and its application in antitumor drug
CN110041336A (en) Pyrimidinones and its composition obtained
WO2014017802A1 (en) Fused ring compound containing furan or salt thereof and pharmaceutical composition comprising same

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant