CN103709162A - Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof - Google Patents
Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof Download PDFInfo
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Abstract
The invention relates to 1,3,5-tri-substituted-1H-imidazo[4,5-h]1,6-diazanaphthalene-2(3H)-one compounds shown as the general formula I, isomers thereof and pharmaceutically acceptable salts thereof, a preparation method and applications thereof, and compositions comprising the compounds. The invention also relates to applications of the compounds, the isomers thereof, the pharmaceutically acceptable salts thereof and the compositions comprising the compounds, as protein multi-target kinase inhibitors, in preparation of medicines used for treating protein kinase related disease, especially c-Met related disease, such as neoplastic disease.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to 1,3,5-tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound, its isomer and pharmacy acceptable salt, Preparation Method And The Use and the composition that comprises described compound.The composition that the invention still further relates to described compound, its isomer and pharmacy acceptable salt and contain it as many target point proteins kinase inhibitor for the preparation for the treatment of tumor disease etc. and the protein kinase purposes in the medicine of the relevant disease of c-Met particularly.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, take cell or mutant abnormality proliferation and towards periphery tissue to shift be feature, the death that the mankind cause because of malignant tumour occupy the second of all mortalities, is only second to cardiovascular and cerebrovascular diseases.The methods for the treatment of of tumour has operative treatment, radiotherapy and pharmacological agent (chemotherapy) etc., but still take to a great extent chemotherapy as main, the appearance of the targeting antineoplastic medicine thing especially designing for the key enzyme in tumour mechanism, makes chemotherapy can successfully heal the sick or extend significantly patient's life-span.
In recent years, tyrosine protein kinase (Protein tyrosine kinase, PTK), as the target of targeting antineoplastic medicine thing, has caused medicine scholar interest widely.Tyrosine protein kinase is the important factor in signal transduction process, participates in a series of cell functions, with Growth of Cells, differentiation, closely related [the Microsc Res Tech.2003Jan 1 of propagation; 60 (1): 70-75], the γ phosphate that it can catalysis ATP is transferred on the tyrosine residues of many key proteins, makes phenolic hydroxyl group phosphorylation.The expression product of many cancer genes also all has PTK activity, and the PTK activity in a lot of malignant conversioning cells is far away higher than normal cell.If therefore can suppress PTK activity, just likely block the growth of tumour cell.PTK has become noticeable antitumor drug novel targets [Curr Drug Targets.2003, Feb; 4 (2): 113-121].
The antitumour drug of target PTK has been obtained rapid progress at last decade; Gleevec, Iressa and Crizotinib are successively by U.S. FDA approval listing; fully proved that receptor tyrosine kinase is an effective antitumour drug target; and many target spots Tyrosylprotein kinase suppresses oncotherapy New Policy [European J.Cancer.2006, Jun that (multiple targeted tyrosine kinase inhibition) also becomes prospect as rich as Croesus; 42,1351-1356].Because most tumours are not to rely on a bars pathway to maintain its growth and survival, so, many target drugs can suppress the multi-step of multiple signal pathway or a bars pathway, not only have synergy, and are difficult for inducing tumor cell generation resistance.The new ideas of this molecular targeted tumor pharmacother have also obtained successful clinical evidence, if the medicine Crizotinib of the treatment advanced Non-small cell lung recently being gone on the market by FDA approval is exactly the kinase whose many target drugs of multiple protein such as while target c-Met and ALK.
Mostly the tyrosine kinase inhibitor of bibliographical information is the derivative of pyrimidine or quinazoline structure, 1H-imidazo [4 of the present invention, 5-h] 1,6-naphthyridine-2 (3H)-one compounds is the multiple kinase inhibitor of a class new texture, show c-Met, FGFR, Abl, Lck, KDR, the kinase whose inhibition activity such as IGF-1 α, ALK, and can effectively suppress related neoplasms clone as the Growth of Cells of BaF3-TPR-Met.
Patent documentation related to the present invention is listed as follows:
A series of quinoline vascular endothelial growth factor receptor inhibitors in WO98/13350, have been disclosed.Wherein also comprise 1,8-naphthyridine analog derivative, the embodiment 53:2-acetylaminohydroxyphenylarsonic acid 5-in this patent (the fluoro-5-hydroxy-4-methyl of 2-aniline)-1 for example, 8-naphthyridine.
In WO99/32450, disclose 4-hydroxyquinoline-2-carboxamide derivatives and be used for the treatment of herpesvirus infection.
In WO98/11073, disclose Bioquin-7CA's sulfonamide derivatives and be used for the treatment of herpesvirus infection.
In WO02/30931, disclosed 8-hydroxyl-1,6-naphthyridine-7-carbonyl amines compound is used for the treatment of HIV-1 virus infection.
In CN2008102000645.4, disclose 5,8-, bis-replacement-1,6-naphthyridine-7-amidocarbonylation compounds and be used for the treatment of mammary cancer, colorectal carcinoma, ovarian cancer, prostate cancer.
In CN201010615647.7, disclosed 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound is used for the treatment of mammary cancer, ovarian cancer, malignant melanoma, Skin Squamous Cell Carcinoma, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia and prostate cancer.
Summary of the invention
An object of the present invention is to provide a kind of by 1,3 shown in general formula I below, 5-tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound, its isomer and pharmacy acceptable salt,
Wherein,
R
1for hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, amino C
1-C
6alkyl, amino C
3-C
6cycloalkyl, C
1-C
6alkylamino C
1-C
6alkyl, C
1-C
6alkoxycarbonyl amido C
3-C
6cycloalkyl, C
6-C
10aryl C
1-C
6alkyl, adamantyl C
1-C
6alkyl or C
5-C
10heteroaryl C
1-C
6alkyl;
R
2for hydrogen, C
1-C
6alkyl, replaces or unsubstituted C
6-C
10aryl C
1-C
6alkyl, wherein, described substituting group has 1-2 to be also halogen ,-CN ,-CF independently of one another
3,-NO
2, hydroxyl, amino, C
1-C
6alkyl, C
1-C
6the C that alkoxyl group, halogen replace
1-C
6alkoxyl group, C
5-C
10heteroaryl C
1-C
6alkyl, C
1-C
6alkyl sulphonyl, C
6-C
10phenyl sulfonyl, adamantyl C
1-C
6alkyl or C
5-C
10heteroarylsulfonyl;
R
3for hydrogen, halogen, hydroxyl, C
1-C
6alkyl oxy, replaces or unsubstituted C
6-C
10aryloxy, wherein, described substituting group has 1-2 to be also halogen, aldehyde radical, C independently of one another
1-C
6hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, or C
5-C
10heteroaryl oxygen base;
Wherein, the heteroatoms in described heteroaryl is to be selected from one or more in N, S and O;
Preferably,
R
1for hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, amino C
1-C
6alkyl, amino C
3-C
6cycloalkyl, C
1-C
6alkylamino C
1-C
6alkyl, C
1-C
4alkoxycarbonyl amido C
3-C
6cycloalkyl, phenyl C
1-C
3alkyl, adamantyl C
1-C
3alkyl or C
5-C
10hetero-aromatic ring base C
1-C
6alkyl;
R
3for hydrogen, F, Cl, Br, hydroxyl, C
1-C
6alkyl oxy, replaces or unsubstituted phenyl oxygen base, and wherein, described substituting group has 1-2 to be also Cl, carboxaldehyde radicals, C independently of one another
1-C
3hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, or pyridyl oxygen base;
R
2for hydrogen,
wherein,
L is C
1-C
6alkyl or-SO
2-;
R
4and R
5be hydrogen, halogen ,-CN ,-CF independently of one another
3,-NO
2, hydroxyl, amino, C
1-C
3alkyl, C
1-C
6the C that alkoxyl group or fluorine replace
1-C
6alkoxyl group;
Heteroatoms in described heteroaryl is to be selected from one or more in N and O;
More preferably,
R
1for C
3-C
6cycloalkyl, amino C
3-C
6cycloalkyl, the amino C of tert-butoxycarbonyl
3-C
6cycloalkyl,
phenmethyl or 1-phenylethyl;
R
3for Br, hydroxyl, C
1-C
6alkyl oxy, replaces or unsubstituted phenyl oxygen base, and wherein, described substituting group has 1-2 to be also Cl, carboxaldehyde radicals, C independently of one another
1-C
3hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, 3-pyridyl oxygen base or 2-pyridyl oxygen base;
R
2for hydrogen,
wherein,
L is C
1-C
3alkyl or-SO
2-;
R
4and R
5be hydrogen, F, Cl ,-CN ,-CF independently of one another
3, methyl, methoxyl group or-OCF
3;
Most preferably, described compound, its isomer and pharmacy acceptable salt are following compound:
Another object of the present invention is to provide shown in a kind of above-mentioned general formula I 1,3,5-, tri-replacement-1H-imidazos [4,5-h] 1, the preparation method of 6-naphthyridine-2 (3H)-one compound, its isomer and pharmacy acceptable salt, the method is as shown in following reaction scheme:
Wherein, R
1, R
2, R
3, R
4, R
5definition same as described above, and be preferably the group shown in table; Reaction reagent and condition: (a) Virahol, refluxes; (b) thionyl chloride, refluxes; (c) sodium borohydride, tetrahydrofuran (THF), 0 ℃; (d) TsNHCH
2cOOCH
3, DEAD (diethyl azodiformate), triphenylphosphine, tetrahydrofuran (THF), 0 ℃; (e) sodium methylate, methyl alcohol, 0 ℃ ~ room temperature; (f) NBS (N-bromo-succinimide), methylene dichloride, room temperature; (g) TsCl, triethylamine, methylene dichloride; (h) R
1nH
2, tetrahydrofuran (THF), refluxes; (i) LiOH solution/methyl alcohol, or NaOH solution/THF, refluxes; (j) DPPA (diphenyl phosphate azide), triethylamine, toluene, refluxes; (k) trifluoracetic acid/methylene dichloride, room temperature; (l) R
2x, K
2cO
3, DMF, room temperature; X is Cl or Br; (m) replacement or unsubstituted phenol, described substituting group has 1-2 to be also halogen, aldehyde radical, C independently of one another
1-C
6hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, DMF, 110 ℃; (n) benzene sulfonyl chloride that does not replace or replace, described substituting group has 1-2 can be also F, Cl ,-CN ,-CF independently of one another
3, methyl, methoxyl group or-OCF
3, K
2cO
3, THF, refluxes; (o) sodium borohydride, THF, room temperature; (p) EDCI, HOAt, DIPEA, amine, methylene dichloride; Wherein amine can be piperidines, morpholine, (R)-1-styroyl amine or N methyl piperazine.
The method specifically comprises the steps:
(1), by compound 1 pyridine 2,3-dicarboxylic anhydride selective esterification under condition a obtains compound 2; Compound 2 chloro under condition b obtains compound 3; Compound 3 obtains compound 4 with the selective reduction under condition c of acyl chlorides form; Compound 4 is reacted and is obtained compound 5 by Mitsunobo under condition d; Compound 5 obtains 1,6-naphthyridine carbonyl acid methyl compound 6 at condition e ShiShimonoseki ring; Compound 6 reacts and obtains 5-Br-1 under condition f with N-bromo-succinimide, 6-naphthyridine carbonyl acid methyl compound 7; 8 hydroxyls of compound 7 under condition g with the synthetic route that Ts protection obtains compound 8(compound 8 see reference document WO2002030426 and WO2002030930); Compound 8 under condition h with amine (R
1nH
2) nucleophilic substitution reaction occurs obtain 8 bit amino substitution compounds 9; Compound 9 is further hydrolyzed to compound 10 under alkaline condition i; Compound 10, under condition j DPPA exists, Cutis occurs to be reset, then molecule nucleophilic substitution reaction generation 1H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one compound 11 occur; With
(2) R
1compound 11 during for the aminocyclohexyl of end Boc protection under condition k directly Deprotection can obtain compound S 1; Compound 11 is as compound S 10, the S13-S20 in general formula I as described in 3 corresponding substituting groups of introducing obtain under l condition; And/or
(3) R
1compound 11 during for the aminocyclohexyl of end Boc protection under condition l with R
2x reaction obtains compound 12; Compound 12 removes Boc and generates 1,3 of described general formula I under condition k, 5-tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound S 2-S9; And/or
(4) R
1compound 11 reflux under condition n during for the aminocyclohexyl of end Boc protection is reacted the 3-benzenesulfonyl replacement that do not replaced or replace-1H-imidazo [4 for 8 hours with the benzene sulfonyl chloride that does not replace or replace, 5-h] 1,6-naphthyridine-2 (3H)-one compound, then through 20% trifluoracetic acid/methylene dichloride, slough the compound S 11-S12 that Boc obtains described general formula I under condition k; And/or
(5) 5 1H-imidazos [4 that bromine replaces, 5-h] 1,6-naphthyridine-2 (3H)-one compound can obtain described compound S 21-S22 with replacement or unsubstituted phenol reactant under alkaline condition, by compound S 22 further under condition o in sodium borohydride reduction obtain the compound S 23 of described general formula I; And/or
(6) compound 12 is in salt of wormwood (trace water existence), and in DMF, reacting by heating can obtain the compound 13 that 5 hydroxyls replace for 12 hours, then through 20% trifluoracetic acid/methylene dichloride, sloughs Boc and obtain compound S 24; Compound 12 obtains 1 with the phenol reactant replacing under alkaline condition, 3,5-, tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound 13, compound 13 sloughs through 20% trifluoracetic acid/methylene dichloride the compound S 25-S28 that Boc obtains described general formula I; And/or
(7) 5 compounds 13 for the replacement of 4-methyl-formiate-phenyl are hydrolyzed and obtain compound 14 under alkaline condition i, compound 14, in EDCI, HOAt, DIPEA and methylene dichloride, reacts the compound that condensation obtains and in trifluoracetic acid/methylene dichloride of 20%, removes the compound S 29-S32 that Boc generates described general formula I with corresponding amine under normal temperature.
A further object of the present invention is to provide a kind of one or more composition in compound shown in general formula I, its isomer and pharmacy acceptable salt that is selected from that comprises treatment significant quantity.
The composition that an object is to provide compound shown in general formula I, its isomer and pharmacy acceptable salt and comprises it of the present invention is also being prepared as the application in the medicine of many target point proteins kinase inhibitor.
Described kinases comprises c-Met, FGFR, Abl, Lck, KDR, IGF-1 α and ALK.
Described medicine is used for the treatment of and/or prevention and the protein kinase relevant disease of c-Met particularly, as tumour etc.
By c-Met kinase activity is screened, applicant finds: the compound that above-mentioned general formula I represents has efficient inhibition active to c-Met kinases under 10 μ M.Find, the compound that general formula I represents has efficient inhibition active to BaF3-TPR-Met cell under 10 μ M simultaneously.
Therefore, the compound that general formula I represents is the signal path of target c-Met mediation effectively, can be used in the treatment of the relative diseases such as tumour that cause with the overexpression of c-Met kinases.
The pharmaceutical composition that contains the compound that general formula I represents allowing on technology of pharmaceutics can play the signal path of effective target c-Met mediation equally, can be used in the treatment of the relative diseases such as tumour that cause with the overexpression of c-Met kinases.
Accompanying drawing explanation
Fig. 1 shows the restraining effect of the compounds of this invention to a plurality of protein kinases.
Embodiment
Preparation Example:
Below in conjunction with Preparation Example, the invention will be further described, but do not limit the present invention.
The 1H-NMR spectroscopic data of compound is measured and is used Varian Mercury-300MHz or Varian Mercury-400MHz nucleus magnetic resonance, ultimate analysis to use Vario EL determinator, and fusing point is measured with Buchi-510 capillary tube technique, and temperature is not calibrated.Infrared spectra is by Bio-Rad FTS-185 determination of infrared spectroscopy; Finnigan MAT 95 mass spectrographs for mass spectrum EI-MS, ESI-MS is used Finnigan LCQ Deca mass spectrograph to measure.Specific rotation is measured by P-1030 (A012360639) automatic polarimeter.Rapid column chromatography carries out on silica gel H (10-40 μ M).Reagent purifying is with reference to Purification of laboratory Chemicals; D.D.Perrin; W.L.F.Armarego and D.R.Perrin Eds., Pergamon Press:Oxiford, 1980.
As be not specifically noted, reagent of the present invention and method etc. are reagent well known in the art and method.
Preparation Example 1 pyridine-2,3-dioctyl phthalate-2-isopropyl ester (2)
By compound 1 pyridine 2,3-dicarboxylic anhydride (48.1g, 0.32mol) is dissolved in the 2-Virahol of 100mL reflux 16 hours, then solution is cooled to-20 ℃ to obtain white solid compound 2 (44.4g, 68%).Fusing point: 140-141 ℃;
1h NMR (CDCl
3, 300MHz): δ 8.87 (d, J=4.2Hz, 1H), 8.35 (d, J=7.8Hz, 1H), 7.55 (dd, J=5.1,8.1Hz, 1H), 5.36 (septet (septet), J=6.3Hz, 1H), 1.41 (d, J=6.3Hz, 6H).
Preparation Example 2 3-hydroxymethyl-pyridine-2-isopropyl formates (4)
Compound 2 (52.7g, 0.25mol) is dissolved in to reflux to solution in the thionyl chloride of 400mL and becomes homogeneous phase, be then spin-dried for solvent.Add the anhydrous THF of 2 * 50mL and revolve steaming, remove residual thionyl chloride.Resulting red liquid is dissolved in the anhydrous THF of 400mL and is cooled to 0 ℃, add sodium borohydride (28.6g, 0.76mol) in batches, stir 4 hours at 0 ℃, by careful the pouring in frozen water of reaction soln, 3 * 200mL dichloromethane extraction, adds anhydrous Na
2sO
4dry.Column chromatography (sherwood oil: ethyl acetate=3:2) obtain yellow solid compound 4 (18.8g, 38%).
1H?NMR(CDC1
3,300MHz):δ8.69(dd,J=1.5,4.7Hz,1H),7.88(dd,J=1.5,7.7Hz,1H),7.46(dd,J=4.7,7.8Hz,1H),5.35(septet,J=6.4Hz,1H),4.81(m,2H),1.45(d,J=6.3Hz,6H);EI-MS?m/z:195(M)
+。
Preparation Example 3 3-{[methoxycarbonyl methyl-(toluene-4-alkylsulfonyl)-amino]-methyl }-pyridine-2-carboxylic acids isopropyl ester (5)
By compound 4 (1.734g, 8.89mmol), 2-tolysulfonyl glycine methyl esters (TsNHCH
2cOOCH
3) (2.163g, 8.89mmol), and triphenylphosphine (3.499g, 13.338mmol) is dissolved in the anhydrous THF of 100mL, is cooled to 0 ℃, inflated with nitrogen protection.DEAD (2.165mL, 13.338mmol) is dissolved in the anhydrous THF of 10mL, dropwise adds DEAD.Remove ice bath, stir to be spin-dried for after two hours and obtain red oily fluid cpds 5 and be directly used in the next step.
8-hydroxyl-1,6-naphthyridine-7-carboxylate methyl ester (6)
The compound 5 (8.89mmol) that upper step reaction is obtained is dissolved in 50mL anhydrous methanol, is cooled to 0 ℃.Slowly add sodium methylate (1.681g, 31.123mmol).Remove ice bath, stir 3 hours.Spin off solvent, add 20mL water, 20mL ethyl acetate, organic phase saturated sodium carbonate back extraction.Merge water, adjust pH to 7, maintain water pH to 7, use dichloromethane extraction 5 times.Organic phase anhydrous sodium sulfate drying, column chromatography (sherwood oil: ethyl acetate=2:1) obtain pale solid compound 6 (0.62g, two step productive rates 65%).Fusing point: 179-180 ℃;
1hNMR (CDC1
3, 300MHz): δ 11.79 (s, 1H), 9.20 (s, 1H), 8.85 (s, 1H), 8.32 (d, J=8.2Hz, 1H), 7.71 (dd, J=4.1,8.2Hz, 1H), 4.12 (s, 3H).
The Preparation Example bromo-8-of 4 5-hydroxyl-1,6-naphthyridine-7-carboxylate methyl ester (7)
Under normal temperature, NBS (30mg, 0.167mmol) is joined to the 1mLCH of compound 6 (34mg, 0.167mmol)
2cl
2in solution, stir 1 hour.Filter the dry white solid compound 7 (30mg, productive rate 85%) that obtains;
1hNMR (d
6-DMSO, 300MHz): δ 9.26 (dd, J=1.5,4.2Hz, 1H), 8.59 (dd, J=1.6,8.4Hz, 1H), 8.00 (dd, J=4.2,8.4Hz, 1H), 3.94 (s, 3H).
The bromo-8-tolysulfonyl of Preparation Example 5 methyl 5-Oxy-1,6-naphthyridine-7-carboxylicesters (8)
The 50 ℃ of stirrings in chloroform of Tosyl chloride, compound 7, triethylamine are used to saturated ammonium chloride after 5 hours successively, saturated common salt washing, dry.Column chromatography obtains white solid compound 8, productive rate: 76%.
1H?NMR(300MHz,CDCl
3):δ9.05(d,J=4.2Hz,1H),8.59(d,J=7.8Hz,1H),7.85(d,J=8.1Hz,2H),7.70(dd,J=4.2,7.8Hz,1H),7.34(d,J=8.1Hz,2H),3.83(s,3H),2.47(s,3H)。
Preparation Example 6 tertiary butyl (1r, 4r)-4-(7-(methoxy carbonic acyl radical)-5-is bromo-1, and 6-naphthyridine-8-is amino) cyclohexyl carbamate (9-1)
By compound 8, the Isosorbide-5-Nitrae-trans cyclohexanediamine of triethylamine and single Boc protection reflux 8 hours in tetrahydrofuran (THF), is spin-dried for THF, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound 9-1, productive rate: 78%.
1HNMR(300MHz,CDCl
3):δ8.95(dd,1H,J=1.5,4.2Hz),8.88(d,1H,J=7.5Hz),8.47(dd,1H,J=1.5,8.4Hz),7.64(dd,1H,J=4.2,8.4Hz),4.92(m,1H),4.42(m,1H),3.97(s,3H),3.47(m,1H),2.20(m,2H),2.05(m,2H),1.44(s,9H),1.43-1.23(m,4H);EI-MS?m/z:478(M)
+,480(M+2)
+。
Preparation Example 7
The bromo-8-of 5-((1r, 4r)-4-t-butoxycarbonyl amino hexamethylene is amino)-1,6-naphthyridine-7-carboxylic acid (10-1)
Compound 10-1 is by compound 9-1 in 1N NaOH solution/THF, and under 60 degree, 10h hydrolysis makes.Yellow-green colour solid, productive rate: 85%.Fusing point: 122-126 ℃;
1h NMR (300MHz, CDCl
3): δ 8.96 (dd, 1H, J=1.5,4.2Hz), 8.88 (d; 1H, J=7.5Hz), 8.45 (dd, 1H, J=1.5; 8.4Hz), 7.64 (dd, 1H, J=4.2,8.4Hz); 4.96 (m, 1H), 4.41 (m, 1H), 3.47 (m; 1H), 2.21 (m, 2H), 2.08 (m, 2H); 1.44 (s, 9H), 1.43-1.23 (m, 4H); EI-MS m/z:464 (M)
+, 466 (M+2)
+.
Preparation Example 8 tertiary butyls ((1r, 4r)-4-(5-Br-2-ketone-2,3-dihydro-1H-imidazo [4,5-h] 1,6-naphthyridine-1-yl)-hexanaphthene)-carboxylicesters (11-1)
By compound 10-1, triethylamine and DPPA reflux 8 hours in toluene, is spin-dried for solvent, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound 11-1, productive rate: 83%.
1H?NMR(300MHz,CDCl
3):δ9.05(d,J=3.9Hz,1H),8.58(d,J=8.7Hz,1H),7.47(dd,J=3.9,8.7Hz,1H),4.47(br?s,1H),2.19(d,J=12.3Hz,2H),1.87(d,J=11.7Hz,2H),1.48(s,9H),1.30-1.42(m,4H);
13C?NMR(100MHz,d
6-DMSO):δ154.9?152.8?139.6?137.4?133.3?121.3?119.3?115.7?77.5?48.3?32.0?28.3?28.0;MS-EI?m/z:461(M)
+,463(M+2)
+。
Preparation Example 9 1-((1r, 4r)-4-aminocyclohexane-)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S1)
Compound 11-1 removes Boc and generates compound S 1 in trifluoracetic acid/methylene dichloride of 20%.Yellow-green colour solid, productive rate: 78%.
1h NMR (300MHz, d
6-DMSO): δ 9.07 (d, J=3.0Hz, 1H), 8.56 (d, J=6.9Hz; 1H), 7.54 (dd, J=3.0,6.9Hz; 1H), 5.25 (br s, 1H), 2.85 (t; 1H), 2.66 (d, J=12Hz, 2H); 1.96 (d, J=11.1Hz, 2H), 1.74 (d; J=10.2Hz, 2H), 1.31 (m, 2H);
13c NMR (100MHz, d
6-DMSO): δ 154.1140.1 135.2 120.2 116.7 49.2 34.4 29.9; MS-ESI m/z:362 (M+H)
+; HR-ESI MSC
15h
16brN
5o
3(M+H)
+calculated value: 362.0616, measured value: 362.0620.
Preparation Example 10 1-((1r, 4r)-4-aminocyclohexane-)-3-benzyl-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S2)
1, the preparation of the tertiary butyl ((1r, 4r)-4-(3-benzyl-5-Br-2-ketone-2,3-dihydro-1H-imidazo [4,5-h] 1,6-naphthyridine-1-yl)-hexanaphthene)-carboxylicesters (12-1)
By compound 11-1, Anhydrous potassium carbonate and bromobenzyl room temperature reaction 12 hours in DMF, is spin-dried for solvent, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains the yellow solid compound tertiary butyl ((1r, 4r)-4-(3-benzyl-5-Br-2-ketone-2,3-dihydro-1H-imidazo [4,5-h] 1,6-naphthyridine-1-yl)-hexanaphthene)-carboxylicesters (12-1), productive rate: 60%.
1H?NMR(300MHz,CDCl
3):δ9.00(d,J=3.6Hz,1H),8.56(d,J=8.7Hz,1H),7.54(d,J=6.9Hz,2H),7.42(dd,J=3.6,8.7Hz,1H),7.31(m,3H),5.25(s,2H),4.45(br?s,1H),2.16(d,J=12.3Hz,2H),1.84(d,J=10.8Hz,2H),1.47(s,9H),1.26-1.40(m,4H)。
2,1-((1r, 4r)-4-aminocyclohexane-)-3-benzyl-5-Br-1-H-imidazo [4,5-h] 1, the preparation of 6-naphthyridine-2 (3H)-one (S2)
Compound 12-1 removes Boc and generates compound S 2 in trifluoracetic acid/methylene dichloride of 20%.Yellow solid, productive rate: 45%.
1H?NMR(300MHz,CD
3OD):δ9.06(d,J=3.6Hz,1H),8.68(d,J=8.4Hz,1H),7.60(m,1H),7.43(d,J=6.9Hz,2H),7.32(m,3H),5.24(s,2H),2.84(m,2H),2.21(d,J=14.7Hz,2H),2.02(d,J=8.1Hz,2H),1.59-1.72(m,2H);MS-EI?m/z:451(M)
+,453(M+2)
+。
Preparation Example 111-((1r, 4r)-4-aminocyclohexane-)-3-(the fluoro-benzyl of 4-)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S3)
Except replacing bromobenzyl with 4-fluorine bromobenzyl, the preparation method of compound S 3 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 61%.
1h NMR (300MHz, CDCl
3): δ 8.96 (d, J=3.9Hz, 1H), 8.56 (d, J=7.5Hz; 1H), 7.53 (t, J=9.0Hz, 2H), 7.42 (dd; J=3.9,7.5Hz, 1H), 6.99 (t, J=8.4Hz; 2H), 5.20 (s, 2H), 2.96 (t, 1H); 2.75 (m, 2H), 2.03 (d, J=13.2Hz, 2H); 1.87 (d, J=9.9Hz, 2H), 1.34-1.46 (m, 2H); MS-ESIm/z:470 (M+H)
+; C
22h
21brFN
5o1/4CF
3cOOH calculated value: C 54.17, H 4.29, N14.04, measured value: C 54.20, H 4.32, and N 14.03.
Preparation Example 121-((1r, 4r)-4-aminocyclohexane-)-3-(the fluoro-4-methoxy-benzyl of 3-)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S4)
Except replacing bromobenzyl with the fluoro-4-methoxyl group of 3-bromobenzyl, the preparation method of compound S 4 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 83%.
1h NMR (300MHz, CDCl
3): δ 8.96 (d, J=3.9Hz, 1H), 8.55 (d, J=8.7Hz, 1H); 7.42 (dd, J=3.9,8.7Hz, 1H), 7.29 (d, J=3.9Hz; 1H), 7.26 (m, 1H), 6.90 (t, J=8.7Hz, 1H); 5.15 (s, 2H), 3.84 (s, 3H), 2.94 (t, J=11.1Hz; 1H), 2.74 (m, 2H), 2.00 (d, J=12.0Hz, 2H); 1.86 (d, J=11.1Hz, 2H), 1.31-1.43 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 153.7 153.3 150.8 147.3 147.2 139.2 138.4 137.9 134.6 129.4 129.3 124.7 120.6 120.5 116.6116.4 113.2 56.1 49.5 42.9 35.8 28.3; MS-ESIm/z:500 (M+H)
+; C
23h
23brFN
5o
23/2H
2o calculated value: C 52.38, H 4.97, and N 13.28, measured value: C 52.42, and H 4.73, and N 13.06.
Preparation Example 13 1-((1r, 4r)-4-aminocyclohexane-)-3-(3-trifluoromethyl benzyl)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S5)
Except replacing bromobenzyl with 3-trifluoromethyl bromobenzyl, the preparation method of compound S 5 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 85%.
1h NMR (300MHz, CDCl
3): δ 8.98 (d, J=2.7Hz, 1H), 8.57 (d, J=8.7Hz, 1H); 7.82 (s, 1H), 7.70 (d, J=7.5Hz, 1H); 7.53 (d, J=8.1Hz, 1H), 7.46 (m, 2H); 5.28 (s, 2H), 2.98 (t, J=10.2Hz, 1H); 2.76 (m, 2H), 2.04 (d, J=11.7Hz, 2H); 1.88 (d, J=13.8Hz, 2H), 1.36-1.48 (m, 2H); MS-EIm/z:519 (M)
+, 521 (M+2)
+; HR-EI MS C
23h
21brF
3n
5o (M)
+calculated value: 519.0882, measured value: 519.0878; C
23h
21brF
3n
5o1/6CF
3cOOH calculated value: C 51.96, H3.96, N 12.98, measured value: C 51.98, and H 3.88, and N 12.93.
Preparation Example 14 1-((1r, 4r)-4-aminocyclohexane-)-3-(4-chlorobenzyl)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S6)
Except replacing bromobenzyl with 4-chlorine bromobenzyl, the preparation method of compound s 6 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 60%.
1h NMR (300MHz, CDCl
3): δ 8.97 (d, J=3.9Hz, 1H), 8.57 (d, J=8.7Hz, 1H); 7.49 (d, J=8.4Hz, 2H), 7.44 (dd, J=3.9; 8.7Hz, 1H), 7.29 (d, J=8.4Hz, 2H); 5.20 (s, 2H), 3.00 (t, J=11.7Hz, 1H); 2.75 (m, 2H), 2.05 (d, J=13.2Hz, 2H); 1.88 (d, J=12.9Hz, 2H), 1.38-1.50 (m, 2H); MS-ESIm/z:488 (M+H)
+; HR-ESI MS C
22h
21brClN
5o (M+Na)
+calculated value: 508.0516, measured value: 508.0503; C
22h
21brClN
5o1/6CF
3cOOH calculated value: C 53.03, H 4.22, N13.85, measured value: C 53.19, H 4.25, and N 13.76.
Preparation Example 151-((1r, 4r)-4-aminocyclohexane-)-3-(2-chlorobenzyl)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S7)
Except replacing bromobenzyl with 2-chlorine bromobenzyl, the preparation method of compound S 7 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 49%.
1h NMR (300MHz, CDCl
3): δ 9.00 (d, J=2.7Hz, 1H), 8.57 (d, J=8.7Hz; 1H), 7.38-7.47 (m, 2H), 7.13-7.23 (m, 2H); 7.06 (d, J=6.0Hz, 1H), 5.39 (s, 2H); 3.03 (t, J=12.6Hz, 1H), 2.81 (m, 2H); (2.09 d, J=10.8Hz, 2H), 1.93 (d; J=10.5Hz, 2H), 1.42-1.54 (m, 2H); MS-ESIm/z:488 (M+H)
+; C
22h
21brClN
5o1/3CF
3cOOH calculated value: C 51.88, H 4.10, N13.34, measured value: C 52.10, H 4.36, and N 13.17.
Preparation Example 161-((1r, 4r)-4-aminocyclohexane-)-3-(3-trifluoro-methoxybenzyl)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S8)
Except replacing bromobenzyl with 3-trifluoromethoxy bromobenzyl, the preparation method of compound S 8 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 83%.
1h NMR (300MHz, CDCl
3): δ 8.99 (s, 1H), 8.57 (d, J=9.0Hz, 1H); 7.58 (d, J=7.8Hz, 2H), 7.43 (dd, J=9.0Hz; 1H), 7.17 (d, J=7.8Hz, 2H), 5.23 (s; 2H), 3.10 (m, 1H), 2.78 (m, 2H); (2.13 d, J=13.2Hz, 2H), 1.91 (d; J=13.5Hz, 2H), 1.47-1.59 (m, 2H);
13cNMR (100MHz, CDCl
3): δ 153.8 152.6 148.8 137.9 135.1 130.3 121.1 120.7 49.6 43.0 34.528.1; MS-EIm/z:535 (M)
+, 537 (M+2)
+; HR-EI MS C
23h
21brF
3n
5o
2(M)
+calculated value: 535.0831, measured value: 535.0837.
Preparation Example 171-((1r, 4r)-4-aminocyclohexane-)-3-(3,4-dichloro benzyl)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S9)
Except replacing outside bromobenzyl with 3,4-dichloro bromobenzyl, the preparation method of compound S 9 is identical with the preparation method of compound S 2.Yellow solid, productive rate: 71%.
1h NMR (300MHz, CDCl
3): δ 8.97 (d, J=2.7Hz, 1H), 8.56 (d, J=10.5Hz; 1H), 7.61 (s, 1H), 7.43 (dd, J=2.7; 10.5Hz, 1H), 7.38 (s, 2H), 5.17 (s; 2H), 2.97 (t, 1H), 2.74 (m, 2H); 2.03 (d, J=12.0Hz, 2H), 1.89 (d; J=16.2Hz, 2H), 1.35-1.48 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 153.8152.4138.9137.9136.4134.7132.5131.9130.5128.1120.71 20.649.442.635.528.2; MS-EIm/z:519 (M)
+, 521 (M+2)
+; HR-EI MS C
22h
20brCl
2n
5o (M)
+calculated value: 519.0228, measured value: 519.0229; C
22h
21brFN
5o1/4CF
3cOOH calculated value: C 49.16, H 3.71, and N 12.74, measured value: C 49.28, and H 3.75, and N 12.77.
Preparation Example 18 tertiary butyls ((1r, 4r)-4-(3-(3,4-dichloro benzyl)-5-Br-2-ketone-2,3-dihydro-1H-imidazo [4,5-h] 1,6-naphthyridine-1-yl)-hexanaphthene)-carboxylicesters (S10)
Except replacing outside bromobenzyl with 3,4-dichloro bromobenzyl, the preparation method of compound S 10 is identical with the preparation method of compound 12-1.Yellow solid, productive rate: 91%.
1H?NMR(300MHz,CDCl
3):δ9.02(d,J=3.9Hz,1H),8.57(d,J=9.0Hz,1H),7.62(s,1H),7.44(dd,J=3.9,9.0Hz,1H),7.38(s,2H),5.18(s,2H),4.43(br?s,1H),3.71(br?s,1H),2.88(br?s,1H),2.17(d,J=12.6Hz,2H),1.85(d,J=11.4Hz,2H),1.47(s,9H),1.21-1.40(m,4H);MS-ESIm/z:622(M+H)
+。
Preparation Example 191-((1r, 4r)-4-aminocyclohexane-)-3-(4-Methyl benzenesulfonyl oxygen base)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S11)
By compound 11-1, Anhydrous potassium carbonate and Tosyl chloride back flow reaction 12 hours in THF, is spin-dried for solvent, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound and directly in trifluoracetic acid/methylene dichloride of 20%, removes Boc generation compound S 11.Yellow-green colour solid, productive rate: 78%.
1hNMR (300MHz, CDCl
3): δ 8.99 (d, J=2.4Hz, 1H), 8.58 (d, J=8.4Hz; 1H), 8.20 (d, J=8.1Hz, 2H), 7.52 (dd; J=2.4,8.4Hz, 1H), 7.35 (d, J=7.8Hz; 1H), 2.97 (t, J=12.3Hz, 1H), 2.66 (m; 2H), 2.05 (d, J=10.5Hz, 2H), 1.83 (d; J=11.4Hz, 2H), 1.35-1.48 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 154.0 146.0 137.8 135.1 129.8 128.6 122.149.434.627.621.7; MS-ESIm/z:518 (M+H)
+; C
22h
22brFN
5o
3s1/4CF
3cOOH calculated value: C49.59, H 4.12, and N 12.85, measured value: C 49.48, and H 4.10, and N 12.84.
Preparation Example 201-((1r, 4r)-4-aminocyclohexane-)-3-(3,4-dichlorobenzene sulfonyloxy)-5-Br-1-H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one (S12)
Except Tosyl chloride being replaced with outside the benzene sulfonyl chloride of 3,4-dichloro replacement, the preparation method of compound S 12 is identical with the preparation method of compound S 11.Yellow solid, productive rate: 45%.
1h NMR (300MHz, CDCl
3): δ 9.01 (d, J=4.2Hz, 1H), 8.61 (d, J=8.7Hz; 1H), 8.46 (d, J=2.1Hz, 1H), 8.18 (d; J=8.4Hz, 1H), 7.65 (d, J=8.7Hz, 1H); 7.55 (dd, J=4.2,8.7Hz, 1H), 2.94 (m; 1H), 2.64 (m, 2H), 2.03 (d, J=12.3Hz; 2H), 1.88 (m, 2H), 1.33-1.45 (m, 2H); MS-ESI m/z:572 (M+H)
+; C
21h
18brCl
2n
5o
3s2/H
2o1/10CF
3cOOH calculated value: C 43.17, H 3.23, and N 11.87, measured value: C 43.43, and H 3.52, and N 11.61.
Preparation Example 215-Br-1-cyclohexyl-3-(3,4-dichloro benzyl)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S13)
By compound 8, triethylamine and hexahydroaniline reflux 8 hours in tetrahydrofuran (THF), is spin-dried for THF, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, the compound that column chromatography obtains is directly used in the next step.
By compound obtained in the previous step, in 1N NaOH solution/THF, under 60 degree, 10h is hydrolyzed, and the compound making is directly used in the next step.
By compound obtained in the previous step, triethylamine and DPPA reflux 8 hours in toluene, is spin-dried for solvent, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, the compound that column chromatography obtains is directly used in the next step.
By compound obtained in the previous step, the bromobenzyl that Anhydrous potassium carbonate and 3,4-dichloro replace room temperature reaction 12 hours in THF, is spin-dried for solvent, adds methylene dichloride, uses successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound S 13.Productive rate 82.3%:
1h NMR (300MHz, CDCl
3): δ 8.98 (d, J=4.2Hz, 1H), 8.54 (d, J=8.7Hz; 1H), 7.62 (s, 1H), 7.42 (dd; J=4.2,8.7Hz, 1H), 7.38 (d; J=0.9Hz, 2H), 5.17 (s, 2H); 2.64 (m, 1H), 1.89 (m, 4H); 1.71 (m, 2H), 1.46 (m, 4H);
13c NMR (100MHz, CDCl
3): δ 153.7,152.5, and 139.0,138.6,137.8,136.6,134.5,132.6,131.9,130.6,130.6,128.1,120.6,42.7,31.2,29.9,26.1,25.2; MS-EI m/z 505 (M)
+; HR-EI MSC
22h
19brCl
2n
4o (M)
+calculated value: 505.2225, measured value: 505.2221.
Preparation Example 22 2-((5-Br-1-cyclohexyl-2-ketone-1H-imidazo [4,5-h] [1,6]-naphthyridine-3 (2H)-methyl) phenethyl cyanogen (S14)
Except the bromobenzyl that 3,4-dichloro is replaced replaces with outside 2-cyano-benzyl bromide, the preparation method of compound S 14 is identical with the preparation method of compound S 13.Yellow solid, productive rate 93%,
1h NMR (CDCl
3) 9.011 (d, J=4.2,1H), 8.573 (d, J=8.7,1H), 7.698 (d, J=7.5,1H), 7.468 (m, 2H), 7.365 (m, 2H), 5.497 (s, 2H), 2.628 (m, 1H), 1.898 (m, 4H), 1.721 (m, 2H), 1.433 (m, 4H).
13c NMR (CDCl
3) 153.72,152.62,139.87,139.10,138.61,137.89,134.70,133.08,133.02,129.71,127.99,120.77,120.69,117.13,111.76,55.55,41.82,29.91,26.09,25.13; MSEI m/z 461[M+1]
+.
Preparation Example 235-Br-1-cyclohexyl-3-(4-luorobenzyl)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S15)
Except the bromobenzyl that 3,4-dichloro is replaced replaces with outside 4-cyanogen bromobenzyl, the preparation method of compound S 15 is identical with the preparation method of compound S 13.Yellow solid, productive rate 89%,
1h NMR (CDCl
3) 8.979 (d, J=3.9,1H), 8.556 (d, J=8.7,1H), 7.553 (d, J=6.6,1H), 7.411 (dd, J=3.9,8.7Hz, 1H), 7.006 (d, J=6.6Hz, 2H), 5.204 (s, 2H), 2.649 (m, 1H), 1.886 (m, 4H), 1.587 (m, 2H), 1.431 (m, 4H).
13c NMR (CDCl
3) 163.57,161.13,153.58,152.65,139.23,138.49,137.81,135.58,134.35,132.40,132.37,130.66,130.58,120.47,115.55,115.33,55.37,43.04,29.92,26.11,25.17; MSEI m/z454[M+1]
+.
Preparation Example 24 1-benzyl-5-Br-3-(3,4-dichloro benzyl)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S16)
Except hexahydroaniline is replaced with benzylamine, the preparation method of compound S 16 is identical with the preparation method of compound S 13.Yellow solid, productive rate 72.3%:
1h NMR (300MHz, CDCl
3): δ 8.98 (d, J=4.2Hz, 1H), 8.52 (d, J=8.7Hz, 1H), 7.56 (m, 3H), 7.42 (dd, J=4.2,8.7Hz, 1H), 7.37 (m, 2H), 5.78 (s, 2H), 5.21 (s, 2H);
13c NMR (100MHz, CDCl
3): δ 154.1,153.1, and 138.7,138.6,137.7,137.4,136.4,135.5,134.7,132.6,132.1,130.6,130.5,128.4,128.0,127.7,121.0,120.7,115.5,46.3,42.9; MS-EI m/z 513 (M)
+; HR-EI MS C
23h
15brCl
2n
4o (M)
+calculated value: 513.2015, measured value: 513.2010.
Preparation Example 25 (S)-5-Br-3-(3,4-dichloro benzyl)-1-(1-styroyl)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S17)
Except hexahydroaniline being replaced with to (S)-1-phenylethylamine, the preparation method of compound S 17 is identical with the preparation method of compound S 13.Yellow solid, productive rate 84%,
1h NMR (CDCl
3) 8.958 (d, J=3.9,1H), 8.557 (d, J=8.4,1H), 7.584 (m; 3H), 7.425 (dd, J=3.9,8.4,1H), 7.368 (m, 2H); 7.132 (m, 1H), 5.183 (s, 2H), 2.142 (d, J=7.2,3H); MSEI m/z 528[M+1]
+.
Preparation Example 26 (R)-5-Br-3-(3,4-dichloro benzyl)-1-(1-styroyl)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S18)
Except hexahydroaniline being replaced with to (R)-1-phenylethylamine, the preparation method of compound S 18 is identical with the preparation method of compound S 13.Yellow solid, productive rate 86%,
1h NMR (CDCl
3) 8.958 (d, J=4.2,1H), 8.554 (d, J=8.7,1H), 7.584 (m; 3H), 7.423 (dd, J=4.2,8.7,1H), 7.367 (m, 2H); 7.156 (m, 1H), 5.168 (s, 2H), 2.144 (d, J=7.2,3H); MSEI m/z 528[M+1]
+.
Preparation Example 275-Br-1-cyclopropyl-3-(3,4-dichloro benzyl)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S19)
Except hexahydroaniline is replaced with cyclopropylamine, the preparation method of compound S 19 is identical with the preparation method of compound S 13.Yellow solid, productive rate 86.3%:
1h NMR (300MHz, CDCl
3): δ 9.02 (d, J=4.2Hz, 1H), 8.57 (d; J=8.4Hz, 1H), 7.64 (s, 1H); 7.45 (dd, J=4.2,8.4Hz, 1H); (7.37 d, J=1.2Hz, 2H), 5.16 (s; 2H), 3.49 (m, 1H), 1.56 (m; 2H), 1.25 (m, 2H); MS-EI m/z:464 (M)
+; HR-EI MSC
19h
13brCl
2n
4o (M)
+calculated value: 463.9645, measured value: 463.9640.
Preparation Example 28 N-((3r, 5r, 7r)-diamantane-1-methyl)-8-(((3r, 5r, 7r)-diamantane-1-methyl) amino)-5-Br-1,6-naphthyridine-7-methane amide (S20)
Except hexahydroaniline being replaced with to diamantane methylamine, 3,4-dichloro bromobenzyl replaces with outside diamantane methylene radical bromine, and the preparation method of compound S 20 is identical with the preparation method of compound S 13.Yellow solid, productive rate 76%,
1h NMR (CDCl
3) 9.016 (d, J=4.2,1H), 8.453 (d, J=8.4,1H), 8.123 (t, J=6.6; 1H), 7.621 (dd, J=4.2,8.4,1H), 3.849 (s, 2H); 3.167 (d, J=6.6,2H), 2.007 (m, 6H), 1.684 (m, 24H); MSEI m/z 562[M+1]
+.
Preparation Example 291-cyclohexyl-3-(3,4-dichloro benzyl)-5-(pyridine-3-oxygen base)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S21)
By compound S 13, Anhydrous potassium carbonate and 3-pyridone in DMF 110 ℃ reaction 6 hours, be spin-dried for solvent, add methylene dichloride, use successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound S 21.Productive rate 93%,
1h NMR (CDCl
3) 9.025 (d, J=4.2,1H), 8.696 (d, J=8.7,1H), 8.633 (d, J=8.1,2H), 7.609 (m, 1H), 7.525 (s, 1H), 7.504 (dd, J=4.2,8.4,1H), 7.392 (dd, J=4.2,8.7,1H), 7.334 (d, J=4.5,1H), 7.118 (d, J=8.1,1H), 4.899 (s, 2H), 2.667 (m, 1H), 1.894 (m, 4H), 1.758 (m, 2H), 1.447 (m, 4H).
13c NMR (CDCl
3) 154.42,154.04,152.58,150.72,144.46,142.23,140.15,136.79; 136.14,133.26,132.26,131.79,130.92,130.49,128.26,126.75; 124.65,119.23,110.48,55.11,42.62,30.01,26.11,25.15; MSEI m/z519[M+1]
+.
Preparation Example 304-((1-cyclohexyl-3-(3,4-dichloro benzyl)-2-ketone-2,3-dihydro-1H-imidazo [4,5-h] [1,6] naphthyridine-5-oxygen base) phenyl aldehyde (S22)
Except 3-pyridone is replaced with 4-hydroxy benzaldehyde, the preparation method of compound S 22 is identical with the preparation method of compound S 21.Yellow solid, productive rate 92%,
1h NMR (CDCl
3) 10.059 (s, 1H), 9.052 (d, J=4.2,1H), 8.6960 (d; J=8.4,1H), 8.015 (d, J=8.7,2H); 7.874 (d, J=8.4,2H), 7.380 (dd, J=4.2; 8.4,1H), 7.346 (d, J=1.8,2H); 4.919 (s, 2H), 2.670 (m, 1H), 1.899 (m; 4H), 1.720 (m, 2H), 1.571 (m, 4H); MSEI m/z 546[M+1]
+.
Preparation Example 311-cyclohexyl-3-(3,4-dichloro benzyl)-5-(4-(methylol) benzene oxo)-1H-imidazo [4,5-h] [1,6] naphthyridine-2 (3H)-one (S23)
Compound S 2250mg is dissolved in dry THF, adds the NaBH of 4eq
4, stirring reaction 6h under room temperature, adds frozen water termination reaction, after add EA extraction, saturated NH for organic layer
4cl solution washing, saturated NaCl washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, column chromatography obtains target compound S23, yellow solid, productive rate 96%,
1h NMR (CDCl
3) 9.021 (d, J=4.2,1H), 8.729 (d, J=8.4; 1H), 7.504 (d, J=8.4,2H), 7.360 (m; 2H), 7.286 (d, J=7.8,2H), 7.196 (d; J=8.1,2H), 4.880 (s, 2H), 4.798 (s; 2H), 2.625 (m, 1H), 1.885 (m, 4H); 1.752 (m, 2H), 1.496 (m, 4H); MSEI m/z 548[M+1]
+.
Preparation Example 321-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-5-hydroxyl-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S24)
By compound S 10, Anhydrous potassium carbonate in DMF 110 ℃ reaction 6 hours, be spin-dried for solvent, add methylene dichloride, use successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound, after in trifluoracetic acid/methylene dichloride of 20%, remove Boc and generate compound S 24.Yellow solid, productive rate: 56.7%.
1h NMR (300MHz, CDCl
3): δ 8.94 (d, J=2.5Hz, 1H), 8.52 (d, J=8.8Hz; 1H), 7.52 (d, J=1.9Hz, 1H), 7.41 (dd; J=8.7,4.2Hz, 1H), 7.33 – 7.26 (m, 2H); 5.09 (s, 2H), 3.31 – 3.17 (m, 1H); 2.86 – 2.62 (m, 2H), 2.29 – 2.01 (m, 2H); 1.95 – 1.79 (m, 2H), 1.72 – 1.47 (m, 2H); MS-EI m/z:457 (M)
+; HR-EI MS C
22h
21cl
2n
5o
2(M)
+calculated value: 457.1072, measured value: 457.1040.
Preparation Example 331-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-5-(3-pyridone)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S25)
By compound S 10,3-pyridone, Anhydrous potassium carbonate in DMF 110 ℃ reaction 6 hours, be spin-dried for solvent, add methylene dichloride, use successively saturated Na
2cO
3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2sO
4dry.Column chromatography obtains yellow solid compound (productive rate: 56.7%.), then in trifluoracetic acid/methylene dichloride of 20%, remove Boc and generate compound S 25.Yellow solid, productive rate 77.6%,
1h NMR (300MHz, CDCl
3): δ 9.07 (d, J=4.2Hz, 1H), 8.82 (d; J=8.6Hz, 1H), 8.57 (d, J=2.5Hz; 1H), 8.53 (d, J=4.8Hz, 1H); 7.78 (d, J=7.0Hz, 1H), 7.63 – 7.51 (m; 2H), 7.38 (d, J=8.3Hz, 1H); (7.35 d, J=1.9Hz, 1H), 7.07 (d; J=8.3Hz, 1H), 4.91 (s; 2H), 2.96 – 2.80 (m, 2H); 2.31 – 2.18 (m, 2H), 2.07 – 1.96 (m; 2H), 1.78 – 1.58 (m, 2H); MS-EI m/z:534 (M)
+; HR-EI MS C
27h
24cl
2n
6o
2(M)
+calculated value: 534.1342, measured value: 534.1356.
Preparation Example 344-((1-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-h] [1,6]-naphthyridine-5-oxo) phenyl aldehyde (S26)
Except 3-pyridone is replaced with 4-hydroxy benzaldehyde, the preparation method of compound S 26 is identical with the preparation method of compound S 25.Yellow solid, productive rate 63.4%,
1h NMR (300MHz, CDCl
3): δ 10.04 (s, 1H), 9.07 (d, J=4.3Hz; 1H), 8.80 (d, J=8.7Hz, 1H); (8.05 d, J=8.4Hz, 2H), 7.90 (s; 1H), 7.57 – 7.53 (m, 1H); 7.42 (d, J=8.8Hz, 2H); 7.37 (s, 1H), 7.13 (d; J=11.3Hz, 1H), 4.94 (s; 2H), 3.00 – 2.80 (m, 2H); 2.30 – 2.16 (m, 2H), 2.12 – 1.96 (m; 2H), 1.77 – 1.59 (m, 2H); MS-EIm/z:561 (M)
+; HR-EI MS C
29h
25cl
2n
5o
3(M)
+calculated value: 561.2353, measured value: 561.2359.
Preparation Example 351-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-5-(4-(methylol) phenoxy group)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S27)
Compound S 2650mg is dissolved in dry THF, adds the NaBH of 4eq
4, stirring reaction 6h under room temperature, adds frozen water termination reaction, after add EA extraction, saturated NH for organic layer
4cl solution washing, saturated NaCl washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, after in trifluoracetic acid/methylene dichloride of 20%, remove Boc and generate compound S 27.Column chromatography obtains yellow solid, productive rate: 72.6%.
1h NMR (300MHz, CDCl
3): δ 9.03 (d, J=4.0Hz, 1H), 8.78 (d; J=8.5Hz, 1H), 7.86 (s, 1H); 7.50 (d, J=7.8Hz, 3H), 7.42 – 7.35 (m; 1H), 7.21 (d, J=8.1Hz; 2H), 7.12 (d, J=8.2Hz; 1H), 4.88 (s, 2H); 4.70 (s, 2H), 3.03 – 2.94 (m; 1H), 2.84 – 2.75 (m, 1H); 2.11 – 2.04 (m, 2H), 1.93 – 1.88 (m; 2H), 1.55 – 1.36 (m, 4H); MS-EIm/z:563 (M)
+; HR-EIMS C
29h
27cl
2n
5o
3(M)
+calculated value: 563.1491, measured value: 563.1495.
Preparation Example 364-((1-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-h] [1,6]-naphthyridine-5-oxo)-2-chlorobenzaldehyde (S28)
Except 3-pyridone being replaced with to 2-chlorine 4-hydroxy benzaldehyde, the preparation method of compound S 28 is identical with the preparation method of compound S 25.Yellow solid, productive rate 65.5%:
1h NMR (300MHz, CDCl
3): δ 10.04 (s, 1H), 9.12-9.03 (m, 1H); 8.74 (d, J=8.5Hz, 1H), 8.15-8.05 (m; 1H), 7.24-7.20 (m, 1H), 7.92 (d; J=8.4Hz, 1H), 7.43 (d; J=8.3Hz, 2H), 7.30-7.27 (m; 1H), 7.14-7.03 (m, 1H); 4.86 (s, 2H), 4.57-4.34 (m; 2H), 3.90-3.60 (m, 2H); 3.02-2.85 (m, 2H), 2.26-2.06 (m; 2H), 1.43-1.37 (m, 2H); MS-EI m/z:595 (M)
+; HR-EI MS C
29h
24cl
3n
5o
3(M)
+calculated value: 595.1047, measured value: 595.1042.
Preparation Example 37 1-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-5-(4-(piperidines-1-carbonyl) benzene oxo)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S29)
Ether synthetic: the S10 of 0.15mmol is dissolved in dry DMF, adds the methyl p-hydroxybenzoate of 1.5eq, after add 5eq and now dry the anhydrous K of milling
2cO
3, 110 ℃ of stirring reactions, TLC follows the tracks of, and adds EA to rinse, with saturated NH after having reacted
4cl solution washing, saturated NaCl washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, the compound that column chromatography obtains is directly used in the next step.
Saponification: the compound obtained in the previous step of 1eq is dissolved in methanol aqueous solution, after add the NaOH of 4eq, stirring reaction under room temperature, TLC follows the tracks of reaction, adds EA to rinse, with saturated NH after having reacted
4cl solution washing, saturated NaCl washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, the compound that recrystallization obtains is directly used in the next step.
Acid amides synthetic: the compound obtained in the previous step of 1eq is dissolved in dry THF solution, after add the piperidines of 1.5eq, add the triethylamine of 3-5eq, the Bop of 2eq, stirring reaction under room temperature, TLC follows the tracks of, and adds EA flushing, with saturated NH after react
4cl solution washing, saturated NaCl washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure, the compound that column chromatography obtains is directly used in the next step.
Boc is protectant to be removed: the compound of Boc protection is dissolved in DCM, after add TFA, make it the concentration of last TFA greatly about 30% left and right, stirring reaction under room temperature, TLC follows the tracks of, and has reacted rear concentrating under reduced pressure, column chromatography obtains compound S 29.
1h NMR (300MHz, CDCl
3): δ 9.12 (d, J=5.5Hz, 1H), 8.87 (d; J=8.6Hz, 1H), 7.60 (d, J=8.5Hz; 3H), 7.47 (d, J=5.8Hz, 2H); 7.39 (d, J=8.0Hz, 2H), 7.20 (d; J=9.5Hz, 1H), 4.98 (s, 2H); 3.80-3.75 (m, 1H), 3.56-3.46 (m, 1H); 3.03-2.82 (m, 3H), 2.31-2.22 (m; 2H), 2.11-2.00 (m, 2H); 1.84-1.68 (m, 6H), 1.68-1.50 (m; 4H), 1.40-1.26 (m, 4H); MS-EI m/z:644 (M)
+; HR-EI MS C
34h
34cl
2n
6o
3(M)
+calculated value: 644.2069, measured value: 644.2072.
Preparation Example 38 1-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-5-(4-(morpholine-4-carbonyl) phenoxy group)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S30)
Except piperidines is replaced morpholine, the preparation method of compound S 30 is identical with the preparation method of compound S 29.Yellow solid, productive rate 92%,
1h NMR (300MHz, CDCl
3): δ 8.96 (d, J=5.7Hz, 1H), 8.61 (d; J=8.2Hz, 1H), 7.64 (s, 1H); 7.56 – 7.49 (m, 1H), 7.45 (d, J=8.3Hz; 1H), 7.40 – 7.35 (m, 1H), 5.15 (s; 2H), 4.63 (t, J=6.2Hz, 2H); 3.78 (t, J=6.3Hz, 2H), 3.69 – 3.50 (m; 4H), 3.18 (dd, J=14.6,7.3Hz; 4H), 2.19 (s, 1H), 2.12 – 2.05 (m; 2H), 1.98 – 1.94 (m, 1H), 1.32 – 1.25 (m; 4H), 1.20 – 1.11 (m, 4H); MS-EI m/z:646 (M)
+; HR-EI MS C
33h
32cl
2n
6o
4(M)
+calculated value: 646.1860, measured value: 646.1862.
Preparation Example 394-((1-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-h] [1,6]-naphthyridine-5-oxo)-N-((R)-1-styroyl) benzamide (S31)
Except piperidines being replaced with to (R)-1-phenylethylamine, the preparation method of compound S 31 is identical with the preparation method of compound S 29.Yellow solid, productive rate 82%,
1h NMR (300MHz, CDCl
3): δ 8.958 (d, J=3.9,1H), 8.557 (d, J=8.4,1H), 7.584 (m; 3H), 7.425 (dd, J=3.9,8.4,1H), 7.368 (m, 2H); 7.132 (m, 1H), 5.183 (s, 2H), 2.142 (d, J=7.2,3H); MS-EI m/z:680 (M)
+; HR-EI MS C
37h
34cl
2n
6o
3(M)
+calculated value: 680.2069, measured value: 680.2071.
Preparation Example 401-((1r, 4r)-4-aminocyclohexyl)-3-(3,4-dichloro benzyl)-5-(4-(4-methylpiperazine-1-carbonyl) phenoxy group)-1H-imidazo [4,5-h] [1,6]-naphthyridine-2 (3H)-one (S32)
Except piperidines is replaced with N methyl piperazine, the preparation method of compound S 32 is identical with the preparation method of compound S 29.Yellow solid, productive rate 92%, NMR (400MHz, ) δ 9.07 (dd, J=4.2, 1.6Hz, 1H), 8.78 (dd, J=8.5, 1.7Hz, 1H), 7.67 (d, J=8.6Hz, 2H), 7.53 (dd, J=8.5, 4.3Hz, 1H), 7.43 (d, J=4.9Hz, 1H), 7.41 (s, 1H), 7.41 – 7.38 (m, 2H), 7.14 (dd, J=8.3, 2.0Hz, 1H), 5.60 – 5.31 (m, 1H), 4.93 (s, 2H), 4.17 – 3.73 (m, 1H), 3.42 – 3.34 (m, 4H), 2.96 (s, 3H), 2.94 – 2.76 (m, 2H), 2.25 (d, J=12.0Hz, 2H), 2.03 (d, J=11.2Hz, 2H), 1.79 – 1.63 (m, 2H) .MS-EI m/z:660 (M)
+,
EXPERIMENTAL EXAMPLE 1:1,3,5-, tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound is to the kinase whose restraining effect of c-Met
Receptor tyrosine kinase c-Met molecular level enzyme is lived and is suppressed preliminary assessment experiment
(1) enzyme reaction substrate Poly (Glu, Tyr)
4:1with the PBS(10mM sodium phosphate buffer without potassium ion, 150mMNaCl, pH7.2-7.4) be diluted to 20 μ g/mL, 125 μ L/ hole coated elisa plates, put 37 ℃ of reaction 12-16 hour.Discard liquid in hole.Wash plate, with the T-PBS(in 200 μ L/ holes, contain the PBS without potassium ion of 0.1%Tween-20) wash plate three times, each 5 minutes.Dry enzyme plate 1-2 hour in 37 ℃ of baking ovens.
(2) every hole adds with reaction buffer (50mM HEPES pH 7.4,50mM MgCl
2, 0.5mM MnCl
2, 0.2mM Na
3vO
4, 1mM DTT) dilution ATP(Triphosaden) solution 50 μ L, final concentration 5 μ M.In every hole, add 1 μ L the compounds of this invention (1%DMSO dissolves, and final concentration is 10 μ M), then add the c-Met tyrosine-kinase zymoprotein of reaction buffer dilution for 50 μ L.Put 37 ℃ of shaking tables (100rpm) reaction 1 hour.Each experiment need be established without ATP control wells two holes and corresponding DMSO solvent control hole (negative control hole).Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99100 μ L/ hole (the T-PBS dilution containing BSA5mg/mL for antibody, concentration is 0.4 μ g/mL), 37 ℃ of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(4) add the anti-100 μ L/ holes of sheep anti mouse two (the T-PBS dilution containing BSA 5mg/mL for antibody, concentration is 0.5 μ g/mL) of horseradish peroxidase-labeled, 37 ℃ of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(5) add the OPD nitrite ion 100 μ L/ holes of 2mg/mL (with containing 0.03%H
2o
20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution), 25 ℃ of lucifuges reaction 1-10 minute.(need be with ultrasonic when OPD dissolves, nitrite ion needs now with the current).
(6) add 2M H
2sO
450 μ L/ hole stopped reactions, with the wavelengthtunable orifice plate microplate reader VERSAmax reading that declines, wavelength is 490nm.
(7) inhibiting rate of sample is tried to achieve by following formula:
Result is listed in table 1.
(compound is 10 for the c-Met enzyme inhibiting compound alive that clearly has that above-mentioned screening is obtained
-5the inhibiting rate >50% of M to receptor tyrosine kinase c-Met) be made into gradient concentration, carry out IC
50evaluate.By four parameter methods, calculate the IC of the horizontal arrestin Tyrosylprotein kinase of each compound molecule
50value, result is listed in table 1.
Result: research finds that a plurality of the compounds of this invention have inhibition in various degree active to c-Met kinases, part of compounds under 10 μ M concentration to c-Met kinase inhibition rate up to 80%.Pointing out compound useful effect of the present invention in c-Met kinases, is the c-Met kinase inhibitor of novel structure.Detailed data is in Table 1.In table, space represents not carry out dependence test, without related data.
Table 1 compound is to the kinase whose inhibition of c-Met
From the experimental result of table 1, can find out, compound useful effect of the present invention, in c-Met kinases, is the c-Met kinase inhibitor of novel structure.
EXPERIMENTAL EXAMPLE 2:1,3,5-, tri-replacement-1H-imidazos [4,5-h] 1, the impact of 6-naphthyridine-2 (3H)-one compound on the cell strain multiplication capacity of c-Met mediation
Inoculation is in the BaF3/TPR-Met of logarithmic phase cell (8000/ hole) in 96 well culture plates, and every hole 100 μ L add respectively the compounds of this invention of 10 μ L different concns after overnight incubation, 3 concentration are set, each multiple hole of concentration 3.After compound effects 72 hours, every hole adds 20 μ LMTT (5mg/mL), after 37 ℃ of cultivation 4hr, adds 100 μ L tri-liquid (10%SDS-5% isopropylcarbinol-0.01M HCl), and 37 ℃ are spent the night, and measure OD value under 570nm wavelength.By calculate the inhibiting rate of medicine to growth of tumour cell with following formula: inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells * 100%.Experiment repeats twice.
Result: cell proliferation has obvious restraining effect to a plurality of compounds of the present invention to BaF3-TPR-Met, shows that this compound can suppress the cell-proliferation activity by c-Met activation mediation.Concrete data are in Table 2.
The inhibiting rate % of table 2 compound to tumor cell proliferation
To BaF3-TPR-Met, cell proliferation has obvious restraining effect to a plurality of compound of the present invention, shows that this compound can suppress the cell-proliferation activity by c-Met activation mediation.
EXPERIMENTAL EXAMPLE 3: the restraining effect of 9 pairs of a plurality of protein kinases of compound S
Experimentation is shown in Millpore`s Kinaseprofile assay services.
www.millipore.com
Concrete data are shown in Fig. 1.Result: compound S 9 of the present invention shows c-Met, FGFR, Abl, Lck, KDR, the kinase whose inhibition activity such as IGF-1 α, ALK, shows that this compounds is the multiple kinase inhibitor of a class new texture.
1H-imidazo [4 of the present invention, 5-h] 1,6-naphthyridine-2 (3H)-one compound shows c-Met, FGFR, Abl, Lck, KDR, the kinase whose inhibition activity such as IGF-1 α, ALK, shows that this compounds is the multiple kinase inhibitor of a class new texture.
Claims (10)
1. one kind by 1,3 shown in general formula I below, 5-tri-replacement-1H-imidazos [4,5-h] 1, and 6-naphthyridine-2 (3H)-one compound, its isomer and pharmacy acceptable salt,
Wherein,
R
1for hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, amino C
1-C
6alkyl, amino C
3-C
6cycloalkyl, C
1-C
6alkylamino C
1-C
6alkyl, C
1-C
6alkoxycarbonyl amido C
3-C
6cycloalkyl, C
6-C
10aryl C
1-C
6alkyl, adamantyl C
1-C
6alkyl or C
5-C
10heteroaryl C
1-C
6alkyl;
R
2for hydrogen, C
1-C
6alkyl, replaces or unsubstituted C
6-C
10aryl C
1-C
6alkyl, wherein, described substituting group has 1-2 to be also halogen ,-CN ,-CF independently of one another
3,-NO
2, hydroxyl, amino, C
1-C
6alkyl, C
1-C
6the C that alkoxyl group, halogen replace
1-C
6alkoxyl group, C
5-C
10heteroaryl C
1-C
6alkyl, C
1-C
6alkyl sulphonyl, C
6-C
10phenyl sulfonyl, adamantyl C
1-C
6alkyl or C
5-C
10heteroarylsulfonyl;
R
3for hydrogen, halogen, hydroxyl, C
1-C
6alkyl oxy, replaces or unsubstituted C
6-C
10aryloxy, wherein, described substituting group has 1-2 to be also halogen, aldehyde radical, C independently of one another
1-C
6hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, or C
5-C
10heteroaryl oxygen base;
Wherein, the heteroatoms in described heteroaryl is to be selected from one or more in N, S and O.
2. compound according to claim 1, its isomer and pharmacy acceptable salt, wherein,
R
1for hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, amino C
1-C
6alkyl, amino C
3-C
6cycloalkyl, C
1-C
6alkylamino C
1-C
6alkyl, C
1-C
4alkoxycarbonyl amido C
3-C
6cycloalkyl, phenyl C
1-C
3alkyl, adamantyl C
1-C
3alkyl or C
5-C
10hetero-aromatic ring base C
1-C
6alkyl;
R
3for hydrogen, F, Cl, Br, hydroxyl, C
1-C
6alkyl oxy, replaces or unsubstituted phenyl oxygen base, and wherein, described substituting group has 1-2 to be also Cl, carboxaldehyde radicals, C independently of one another
1-C
3hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, or pyridyl oxygen base;
R
2for hydrogen,
wherein,
L is C
1-C
6alkyl or-SO
2-;
R
4and R
5be hydrogen, halogen ,-CN ,-CF independently of one another
3,-NO
2, hydroxyl, amino, C
1-C
3alkyl, C
1-C
6the C that alkoxyl group or fluorine replace
1-C
6alkoxyl group;
Heteroatoms in described heteroaryl is to be selected from one or more in N and O.
3. compound according to claim 2, its isomer and pharmacy acceptable salt, wherein,
R
1for C
3-C
6cycloalkyl, amino C
3-C
6cycloalkyl, the amino C of tert-butoxycarbonyl
3-C
6cycloalkyl,
phenmethyl or 1-phenylethyl;
R
3for Br, hydroxyl, C
1-C
6alkyl oxy, replaces or unsubstituted phenyl oxygen base, and wherein, described substituting group has 1-2 to be also Cl, carboxaldehyde radicals, C independently of one another
1-C
3hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, 3-pyridyl oxygen base or 2-pyridyl oxygen base;
R
2for hydrogen,
wherein,
L is C
1-C
3alkyl or-SO
2-;
R
4and R
5be hydrogen, F, Cl ,-CN ,-CF independently of one another
3, methyl, methoxyl group or-OCF
3.
4. compound according to claim 3, its isomer and pharmacy acceptable salt, it is following compound:
5. one kind comprises being selected from according to one or more the composition in the compound described in any one in claim 1 to 4, its isomer and pharmacy acceptable salt for the treatment of significant quantity.
According to the compound described in any one in claim 1 to 4, its isomer and pharmacy acceptable salt and the composition that comprises it in preparation as the application in the medicine of many target point proteins kinase inhibitor.
7. application according to claim 6, wherein, described kinases comprises c-Met, FGFR, Abl, Lck, KDR, IGF-1 α and ALK.
8. according to the application described in claim 6 or 7, wherein, the disease that described medicine is used for the treatment of and/or prevention is relevant with protein kinase.
9. application according to claim 8, wherein, described disease is tumour.
10. a preparation method for the compound as described in any one in claim 1 to 4, the method is as shown in following reaction scheme:
Wherein, R
1, R
2, R
3, R
4, R
5definition identical with described in any one in claim 1 to 4 respectively; Reaction reagent and condition: (a) Virahol, refluxes; (b) thionyl chloride, refluxes; (c) sodium borohydride, tetrahydrofuran (THF), 0 ℃; (d) TsNHCH
2cOOCH
3, DEAD, triphenylphosphine, tetrahydrofuran (THF), 0 ℃; (e) sodium methylate, methyl alcohol, 0 ℃ ~ room temperature; (NBS, methylene dichloride, room temperature; (g) TsCl, triethylamine, methylene dichloride; (h) R
1nH
2, tetrahydrofuran (THF), refluxes; (i) LiOH solution/methyl alcohol, or NaOH solution/THF, refluxes; (j) DPPA, triethylamine, toluene, refluxes; (k) trifluoracetic acid/methylene dichloride, room temperature; (l) R
2x, K
2cO
3, DMF, room temperature; X is Cl or Br; (m) replacement or unsubstituted phenol, described substituting group has 1-2 to be also halogen, aldehyde radical, C independently of one another
1-C
6hydroxyalkyl, 1-hexahydropyridine base carbonyl, N-morpholinyl carbonyl, (R)-1-styroyl aminocarboxyl or 4-methylpiperazine-1-yl-carbonyl, DMF, 110 ℃; (n) benzene sulfonyl chloride that does not replace or replace, described substituting group has 1-2 can be also F, Cl ,-CN ,-CF independently of one another
3, methyl, methoxyl group or-OCF
3, K
2cO
3, THF, refluxes; (o) sodium borohydride, THF, room temperature; (p) EDCI, HOAt, DIPEA, amine, methylene dichloride; Wherein amine can be piperidines, morpholine, (R)-1-styroyl amine or N methyl piperazine.
The method specifically comprises the steps:
(1), by compound 1 pyridine 2,3-dicarboxylic anhydride selective esterification under condition a obtains compound 2; Compound 2 chloro under condition b obtains compound 3; Compound 3 obtains compound 4 with the selective reduction under condition c of acyl chlorides form; Compound 4 is reacted and is obtained compound 5 by Mitsunobo under condition d; Compound 5 obtains 1,6-naphthyridine carbonyl acid methyl compound 6 at condition e ShiShimonoseki ring; Compound 6 reacts and obtains 5-Br-1 under condition f with N-bromo-succinimide, 6-naphthyridine carbonyl acid methyl compound 7; 8 hydroxyls of compound 7 obtain compound 8 with Ts protection under condition g; Compound 8 under condition h with R
1nH
2there is nucleophilic substitution reaction and obtain 8 bit amino substitution compounds 9; Compound 9 is further hydrolyzed to compound 10 under alkaline condition i; Compound 10, under condition j DPPA exists, Cutis occurs to be reset, then molecule nucleophilic substitution reaction generation 1H-imidazo [4,5-h] 1,6-naphthyridine-2 (3H)-one compound 11 occur; With
(2) R
1compound 11 during for the aminocyclohexyl of end Boc protection under condition k directly Deprotection can obtain compound S 1; Compound 11 is as compound S 10, the S13-S20 in general formula I as described in 3 corresponding substituting groups of introducing obtain under l condition; And/or
(3) R
1compound 11 during for the aminocyclohexyl of end Boc protection under condition l with R
2x reaction obtains compound 12; Compound 12 removes Boc and generates 1,3 of described general formula I under condition k, 5-tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound S 2-S9; And/or
(4) R
1compound 11 reflux under condition n during for the aminocyclohexyl of end Boc protection is reacted the 3-benzenesulfonyl replacement that do not replaced or replace-1H-imidazo [4 for 8 hours with the benzene sulfonyl chloride that does not replace or replace, 5-h] 1,6-naphthyridine-2 (3H)-one compound, then through 20% trifluoracetic acid/methylene dichloride, slough the compound S 11-S12 that Boc obtains described general formula I under condition k; And/or
(5) 5 1H-imidazos [4 that bromine replaces, 5-h] 1,6-naphthyridine-2 (3H)-one compound can obtain described compound S 21-S22 with replacement or unsubstituted phenol reactant under alkaline condition, by compound S 22 further under condition o in sodium borohydride reduction obtain the compound S 23 of described general formula I; And/or
(6) compound 12 is at salt of wormwood, and in DMF, reacting by heating can obtain the compound 13 that 5 hydroxyls replace for 12 hours, then through 20% trifluoracetic acid/methylene dichloride, sloughs Boc and obtain compound S 24; Compound 12 obtains 1 with the phenol reactant replacing under alkaline condition, 3,5-, tri-replacement-1H-imidazos [4,5-h] 1,6-naphthyridine-2 (3H)-one compound 13, compound 13 sloughs through 20% trifluoracetic acid/methylene dichloride the compound S 25-S28 that Boc obtains described general formula I; And/or
(7) 5 compounds 13 for the replacement of 4-methyl-formiate-phenyl are hydrolyzed and obtain compound 14 under alkaline condition i, compound 14, in EDCI, HOAt, DIPEA and methylene dichloride, reacts the compound that condensation obtains and in trifluoracetic acid/methylene dichloride of 20%, removes the compound S 29-S32 that Boc generates described general formula I with corresponding amine under normal temperature.
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