CN103923078A - 3,4-disubstituted(1H-pyrazole[3,4-b]pyridine) compound and use thereof - Google Patents

3,4-disubstituted(1H-pyrazole[3,4-b]pyridine) compound and use thereof Download PDF

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CN103923078A
CN103923078A CN201310013356.4A CN201310013356A CN103923078A CN 103923078 A CN103923078 A CN 103923078A CN 201310013356 A CN201310013356 A CN 201310013356A CN 103923078 A CN103923078 A CN 103923078A
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phenyl
pyrazoles
pyridin
isophthalic acid
urea
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李剑
陈玉龙
倪帅帅
车鹏
楼江平
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SHANGHAI HUFA CHEMICAL INDUSTRY Co Ltd
East China University of Science and Technology
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SHANGHAI HUFA CHEMICAL INDUSTRY Co Ltd
East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention mainly relates to a 3,4-disubstituted(1H-pyrazole[3,4-b]pyridine) compound and a use thereof. The 3,4-disubstituted(1H-pyrazole[3,4-b]pyridine) compound is a compound represented by the formula I or a pharmaceutically acceptable salt thereof (referring to the description or claims for details). The compound provided by the invention shows a stronger inhibitory activity on tyrosine kinase (including c-Kit, PDGFR[alpha], VEGFR2 and FGFR1) related to occurrence and development of four tumors. The compound is indicated to be used as a multi-target kinase inhibitor, and is developed into a targeted anti-tumor drug in allusion to acute granulocytic leukemia and solid tumors.

Description

3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds and uses thereof
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to 3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds and its production and use (this compounds is applied in many target spots of preparation receptor tyrosine kinase inhibitors class antitumour drug).
Background technology
Cancer (malignant tumour) is one of topmost disease of serious threat human health.In recent years, along with the development that molecular weight tumor is learned, the research of antitumor drug also transfers to from traditional cell toxicity medicament the newtype drug that acts on molecular target.
Find through research, canceration is mainly some link generation pathology molecular signal due to the regulating cell process of conducting in from cell surface to core, and the conduction of the signal of film external signal and film is the committed step in signal conductive process, most typical is exactly somatomedin and its receptors bind.Protein tyrosine kinase (protein tyrosine kinase, PTK) is the modal growth factor receptors of most tumors, can tumoricidal signal transmission by suppressing its activity, and selectivity inhibition tumor cell and normal cell be there is no to impact.
C-Kit be within 1987, find belong to III type tyrosine kinase receptor family member, be a transmembrane protein, exact expression position is mainly on cytolemma.It exists the acquired (gain-of-function of 30 several functions, GOF) mutant form, STEM CELL FACTOR (stem cell factor, SCF) acceptor, after c-Kit is combined with its acceptor SCF, can excite tyrosine residues phosphorylation, thereby realize its function, in the generation of tumour and progress, play very important regulating effect.Research shows, the generation of c-Kit acceptor and kinds of tumors, development, prognosis are closely related, in the kinds of tumors tissues such as gastrointestinal stromal tumor (gastrointestinal stromal tumor, GIST), acute myeloblastic leukemia (AML), lung cancer, all there is the unconventionality expression of c-Kit acceptor.
In addition the growth of tumour and shift and must rely on abundant nutrition supply, that organizes medium vessels is generated as that nutritive substance and oxygen enter tumor tissues, that meta-bolites is transported to histocyte is outer and established important basic condition for tumor cell migration to target organ.If without vasculogenesis, tumor tissue growth's volume of vitro culture is no more than 4mm 3, in-vivo tumour is no more than 1-2mm 3.At present, research finds that the factor relevant with tumor-blood-vessel growth has more than 30 to plant, as Thr6 PDGF BB (PDGF), vascular endothelial growth factor (VEGF), angiostatin, Endostatin, scleroproein somatomedin etc., wherein PDGF mainly stimulates tumor-blood-vessel growth by raising pericyte, and raising of pericyte is conducive to tumor vascular mature and stable and survival, plays vital effect in tumor angiogenesis process.Further research shows, the signal path of fibroblast growth factor (FGF) and acceptor FGFR composition thereof also plays a significant role in the process such as invasion and attack and transfer of tumor angiogenesis, tumour.
Therefore, develop that many target spots (c-Kit, PDGFR, VEGFR and FGFR) target tumor occurs, the medicine expection of development coherent signal path can produce good antitumous effect.
Summary of the invention
Compound involved in the present invention has brand-new 3, 4-bis-replaces (1H-pyrazoles [3, 4-b] pyridine) class formation, and choose four kinds of tumor tissues and generate closely-related receptor protein kinase and (comprise c-Kit, PDGFR-α, VEGFR-2 and FGFR-1), the kinase inhibiting activity test of carrying out, active result shows, part of compounds of the present invention all has stronger inhibition activity to four kinds of kinases, wherein especially obvious to the inhibition activity of c-Kit and PDGFR-α acceptor, lay a good foundation for further designing and developing from now on novel many target spots receptor tyrosine kinase inhibitors series antineoplastic medicament.
An object of the present invention is, provide a kind of 3,4-bis-to replace (1H-pyrazoles [3,4-b] pyridine) compounds, it is pharmaceutically acceptable salt of compound shown in formula I or its:
In formula I: R 1for C 1～C 4straight or branched alkyl or the C being replaced by hydroxyl (OH) 1～C 4straight or branched alkyl; R 2for hexa-atomic aromatic ring yl or replace hexa-atomic aromatic ring yl, X is O or S;
Wherein, the substituting group of the hexa-atomic aromatic ring yl of described replacement is selected from: C 1～C 6straight or branched alkyl, C 1～C 6straight or branched perfluoroalkyl, halogen (F, Cl, Br or I), cyano group (CN), hydroxyl (OH), nitro (NO 2), (R 3for C 1～C 4straight or branched alkyl), or (Y is that O or S, R4 are C 1～C 4straight or branched alkyl or the C being replaced by phenyl 1～C 4straight or branched alkyl) in one or two or more kinds (containing two kinds), the integer that substituent number is 1～4.
Another object of the present invention is, disclose above-mentioned 3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) a kind of purposes of compounds (compound shown in formula I or its pharmaceutically acceptable salt), be compound shown in formula I or its pharmaceutically acceptable salt (comprise c-Kit at many target spots of preparation receptor tyrosine kinase, PDGFR α, VEGFR2 and FGFR1) in inhibitor class antitumour drug application (as it is at preparation treatment acute myeloblastic leukemia (AML) and solid tumor (volume >2-3mm 3) medicine in apply).
Embodiment
In preferred technical scheme of the present invention, R 1for C 1～C 2alkyl or the C being replaced by hydroxyl (OH) 1～C 2alkyl;
Further preferred technical scheme is: R 1the methyl replacing for methyl or by hydroxyl (OH).
In another preferred technical scheme of the present invention, R 2for phenyl or substituted-phenyl,
The substituting group of described substituted-phenyl is selected from: C 1～C 6straight or branched alkyl, C 1～C 6straight or branched perfluoroalkyl, halogen (F, Cl, Br or I), cyano group (CN), hydroxyl (OH), nitro (NO 2), (R 3for C 1～C 4straight or branched alkyl), or (Y is O or S, R 3for C 1～C 4straight or branched alkyl or the C being replaced by phenyl 1～C 4straight or branched alkyl) in one or two or more kinds (containing two kinds), the integer that substituent number is 1～4;
Further preferred technical scheme is: R 2for substituted-phenyl, the substituting group of described substituted-phenyl is selected from: C 1～C 3straight or branched alkyl, C 1～C 3straight or branched perfluoroalkyl, halogen (F, Cl, Br or I), cyano group (CN), (R 3for C 1～C 2alkyl), or (Y is O or S, R 4for C 1～C 2alkyl or the C being replaced by phenyl 1～C 2alkyl) in one or two or more kinds (containing two kinds), the integer that substituent number is 1～3;
Further preferred technical scheme is: R 2for substituted-phenyl, the substituting group of described substituted-phenyl is selected from: methyl, ethyl, trifluoromethyl, halogen (F, Cl, Br or I), cyano group (CN), methoxyl group, methylthio group (CH 3s-), a kind of or two kinds in ethanoyl or benzyloxy, substituent number is 1 or 2;
The R that the present invention recommends 2be: o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, an ethylphenyl, adjacent fluorophenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, an iodophenyl, m-trifluoromethylphenyl, a cyano-phenyl, m-methoxyphenyl, 3; 4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl, a benzyloxy phenyl, meta-methylthio phenyl, an acetylphenyl, 5-chloro-2-methyl phenyl or the fluoro-5-aminomethyl phenyl of 2-.
In addition, the present invention also provides 3 of general formula I structure, and 4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds I a~ I cand the preparation method of intermediate II～VIII, concrete synthesis strategy is as follows respectively.
I asynthetic:
In formula, R 1afor C 1～C 4straight or branched alkyl, R 2implication with described identical above.
Specifically comprise the steps:
1) by 3-R 1a-5-amino-1H-pyrazoles, paranitrobenzaldehyde and 2,2-dimethyl-1,3-dioxane-4,6-diketone adds in round-bottomed flask, after dissolving, under its boiling temperature, heats until there is no CO with DMF 2till emitting.In solution, there is solid precipitation to separate out, add appropriate isopropanol after being cooled to room temperature.Suction filtration, solid dissolves latter ultrasonic 15 minutes with DMF, then obtains intermediate 3-R after suction filtration 1-4-(4-nitrophenyl)-4,5-dihydro-1 h-pyrazole [3,4-b] pyridine-6 (7H)-one (intermediate II).
2) intermediate II is dissolved in dioxane, adds 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone and N, two (TMS) trifluoroacetamides of O-, backflow is spent the night.After reaction finishes, reaction solution is poured in appropriate water, used saturated NaHCO 3solution furnishing alkalescence, a large amount of solids are separated out from solution.Suction filtration, filter cake dissolves with DMF, after ultrasonic 15 minutes, continues suction filtration, and with ethyl acetate filter wash cake, filter cake is dried to obtain intermediate 3-R 1a-4-(4-nitrophenyl)-1H-pyrazoles [3,4-b] pyridine-6 (7H)-one (intermediate III).
3) intermediate III is dissolved in appropriate benzene phosphinylidyne dichloro, at 110 DEG C, reacts and spend the night.After reaction finishes, system is poured in appropriate frozen water, stirs after half hour, suction filtration, is adjusted to weakly alkaline with saturated sodium bicarbonate solution after filter cake adds water and stirs.Suction filtration, filter cake is dried and is obtained the chloro-3-R of intermediate 6- 1a-4-(4-nitrophenyl)-6,7-dihydro-1 h-pyrazole [3,4-b] pyridine (intermediate compound IV)
4) zinc powder, hydrazine hydrate, tetrahydrofuran (THF) mixed with there-necked flask in, under nitrogen protection, the tetrahydrofuran solution that is dissolved with intermediate compound IV is at the uniform velocity added drop-wise in reaction system, finish rear back flow reaction 4 hours.Reaction finishes rear suction filtration, and filtrate extracts three times with tetrahydrofuran (THF), underpressure distillation extraction liquid, and resistates, through column chromatography for separation, obtains intermediate 4-(3-R 1a-1H-pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate V).
5) intermediate V is dissolved in appropriate methyl-sulphoxide, adds isocyanate ester compound (R 2-NCO), then add after triethylamine room temperature reaction 8 hours.After reaction finishes, be extracted with ethyl acetate three times, saturated common salt washing, anhydrous magnesium sulfate drying, filters, and concentrated, resistates, through column chromatography for separation, obtains compound N-R 2-N '-[4-(3-R 1a-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a).
I bsynthetic:
In formula, R 1afor C 1～C 4straight or branched alkyl, R 2implication with described identical above.
Specifically comprise the steps:
1) intermediate V is dissolved in appropriate methyl-sulphoxide, adds isosulfocyanate compound (R 2-NCS), then add after triethylamine room temperature reaction 8 hours.After reaction finishes, in system, add water, be extracted with ethyl acetate three times, saturated common salt washing, anhydrous magnesium sulfate drying, filters, and concentrated, resistates, through column chromatography for separation, obtains compound N-R 2-N '-[4-(3-R 1a-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b).
I csynthetic:
In formula, R 1afor C 1～C 4straight or branched alkyl, R 1bfor C 1～C 3straight or branched alkyl, R 1cfor the C being replaced by hydroxyl (OH) 1～C 4straight or branched alkyl, R 2implication with described identical above.
1) intermediate V and 4-lutidine are dissolved in tetrahydrofuran (THF), at 0 DEG C, drip the mixing solutions of tert-Butyl dicarbonate and tetrahydrofuran (THF), after adding, at room temperature react 1 hour.Reaction finishes rear suction filtration, filtrate decompression distillation, and resistates, through column chromatography for separation, obtains intermediate VI;
2) intermediate VI is dissolved in appropriate tetracol phenixin, adds N-bromo-succinimide and benzoyl peroxide, back flow reaction 20 hours under nitrogen environment.Reaction finishes rear suction filtration, carries out column chromatography for separation and obtain intermediate VII after filtrate is concentrated;
3) intermediate VII is dissolved in to the mixing solutions of dioxane and water, back flow reaction 10 hours, reaction finishes rear system underpressure distillation, and resistates, through column chromatography for separation, obtains intermediate VIII;
4) intermediate VIII is dissolved in appropriate methyl-sulphoxide, adds isocyanate ester compound (R 2-NCO), then add after triethylamine room temperature reaction 8 hours.After reaction finishes, separate out solid to adding water in system, suction filtration, the mixed solvent recrystallization of ethyl acetate and sherwood oil for filter cake, obtains Compound I c.
According to above-mentioned preparation method's instruction, those of ordinary skill in the art, without creative work, can obtain all compounds that formula I comprises.
In following embodiment, will further illustrate the present invention.These embodiment are only for the present invention is described, but the protection domain not limiting the present invention in any way.All parameters in embodiment and remaining explanation, unless otherwise indicated, be all taking quality (gram) as unit.
Embodiment 1
3-methyl-4-(4-nitrophenyl)-4, the preparation of 5-dihydro-1 h-pyrazole [3,4-b] pyridine-6 (7H)-one (intermediate II)
By 4.85 grams of 3-methyl-5-amino-1H-pyrazoles, 7.55 grams of paranitrobenzaldehydes and 7.2 gram 2,2-dimethyl-1,3-dioxane-4,6-diketone drops in 100 milliliters of round-bottomed flasks, with the N of 20 milliliters, after dinethylformamide dissolves, at 110 DEG C, reacting by heating is to there is no CO 2till emitting.React and in solution, have solid precipitation to separate out after 30 minutes, be cooled to the isopropanol that adds 50 milliliters after room temperature.Suction filtration, solid is used ultrasonic 15 minutes of DMF, finishes rear continuation suction filtration, obtains title compound, 9.8 grams of white solids (intermediate II), yield 72% after solid drying.
1H-NMR(400MHz,DMSO-d 6)δ:11.92(s,1H),10.41(s,1H),8.20(d,J=8.7Hz,2H),7.45(d,J=8.7Hz,2H),4.37(t,J=6.3Hz,1H),2.88(dd,J=15.9,7.3Hz,1H),2.58(dd,J=16.0,5.6Hz,1H),1.86(s,3H).
Embodiment 2
The preparation of 3-methyl-4-(4-nitrophenyl)-1H-pyrazoles [3,4-b] pyridine-6 (7H)-one (intermediate III)
14.9 grams of intermediate II are put in 250 ml flasks, added 100 milliliters of dioxane to dissolve, then add 66 milliliters of N, two (TMS) trifluoroacetamides of O-, then add 15 gram 2,3-bis-chloro-5,6-dicyano-Isosorbide-5-Nitrae-benzoquinones, backflow is spent the night.After reaction finishes, reaction solution poured in suitable quantity of water and use saturated NaHCO 3solution furnishing alkalescence, solid is separated out from solution.Suction filtration, filter cake is successively with DMF and ethyl acetate washing, at 40 DEG C of filter cakes, dries to obtain 11.3 grams of faint yellow solids (intermediate III), yield 76%.
1H-NMR(400MHz,DMSO-d 6)δ:13.00(s,1H),11.78(s,1H),8.33(d,J=8.6Hz,2H),7.80(d,J=8.6Hz,2H),6.00(s,1H),2.01(s,3H).
Embodiment 3
The chloro-3-methyl-4-of 6-(4-nitrophenyl)-6, the preparation of 7-dihydro-1 h-pyrazole [3,4-b] pyridine (intermediate compound IV)
5 grams of intermediate III are dropped in 100 ml flasks, add 15 milliliters of benzene phosphinylidyne dichloros to dissolve, at 110 DEG C, react and spend the night.After reaction finishes, the system for the treatment of is cooling to be poured in appropriate frozen water, stirs 1 hour, has a large amount of solids to separate out.Suction filtration, secondary suction filtration after saturated sodium bicarbonate solution furnishing weakly alkaline for filter cake with a large amount of water wash filter cakes, is dried to obtain 3.1 grams of lark solids (intermediate compound IV) at 40 DEG C, and yield is 58%.
1H-NMR(400MHz,DMSO-d 6)δ:13.71(s,1H),8.39(d,J=8.7Hz,2H),7.90(d,J=8.7Hz,2H),7.25(s,1H),2.16(s,3H).
Embodiment 4
The preparation of 4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate V)
By 25 grams of zinc powders, 70 milliliter of one hydrazine hydrate, 10 milliliters of tetrahydrofuran (THF)s mixed with 250 milliliters of there-necked flasks in, under nitrogen protection, 70 milliliters of tetrahydrofuran solutions that are dissolved with 7 grams of intermediate compound IV are at the uniform velocity added drop-wise in reaction system, finish rear back flow reaction 4 hours.Reaction finishes rear suction filtration, and filtrate extracts three times with tetrahydrofuran (THF), underpressure distillation extraction liquid, and eluent for resistates (tetrahydrofuran (THF): methylene dichloride=1:3, v/v), through column chromatography for separation, obtains 3.1 grams of white solids (intermediate V), and yield is 57%.
1H-NMR(400MHz,DMSO-d 6)δ:13.20(s,1H),8.38(d,J=4.7Hz,1H),7.24(d,J=7.7Hz,2H),6.93(d,J=4.7Hz,1H),6.69(d,J=7.7Hz,2H),5.45(s,2H),2.27(s,3H).
Embodiment 5
The preparation of 4-(4-(two (tertbutyloxycarbonyl) amino) phenyl)-3-methyl isophthalic acid-tertbutyloxycarbonyl-pyrazoles [3,4-b] pyridine (intermediate VI)
1 gram of intermediate V and 96 milligrams of 4-lutidine are dissolved in 10 milliliters of tetrahydrofuran (THF)s, at 0 DEG C, drip the mixing solutions that is mixed with 9 milliliters of tert-Butyl dicarbonates and 10 milliliters of tetrahydrofuran (THF)s, after adding, at room temperature react 1 hour.Reaction finishes rear suction filtration, filtrate decompression distillation, and eluent for resistates (ethyl acetate: sherwood oil=1:6, v/v), through column chromatography for separation, obtains 130 milligrams of clear crystals (intermediate VI), and yield is 6%.
1H-NMR(400MHz,CDCl 3)δ:8.66(d,J=4.4Hz,1H),7.34(d,J=7.9Hz,2H),7.22(d,J=7.8Hz,2H),7.11(d,J=4.3Hz,1H),2.14(s,3H),1.67(s,9H),1.38(s,18H).
Embodiment 6
The preparation of 4-(4-(two (tertbutyloxycarbonyl) amino) phenyl)-3-brooethyl-1-tertbutyloxycarbonyl-pyrazoles [3,4-b] pyridine (intermediate VII)
640 milligrams of intermediate VI are dissolved in 10 milliliters of tetracol phenixin, add 239 milligrams of N-bromo-succinimides and 89 milligrams of benzoyl peroxides, back flow reaction 20 hours under nitrogen environment.Reaction finishes rear suction filtration, carries out column chromatography for separation obtain 360 milligrams of clear crystals (intermediate VII) after filtrate is concentrated with eluent (ethyl acetate: sherwood oil=1:6, v/v).Yield is 49%.
1H-NMR(400MHz,CDCl 3)δ:8.70(d,J=4.7Hz,1H),7.44(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),7.16(d,J=4.7Hz,1H),4.35(s,2H),1.67(s,9H),1.39(s,18H).
Embodiment 7
The preparation of 4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate VIII)
430 milligrams of intermediate VII are dissolved in to the mixing solutions of 4 milliliters of dioxane and 2 ml waters, backflow is spent the night, reaction finishes rear system underpressure distillation, (the methyl alcohol: methylene dichloride=1:30 of eluent for resistates, v/v) column chromatography for separation, obtain 40 milligrams of white solids (intermediate VIII), yield is 23%.
1HNMR(400MHz,MeOD)δ:8.33(d,J=4.8Hz,1H),7.33(d,J=8.4Hz,2H),6.98(d,J=4.8Hz,1H),6.74(d,J=8.4Hz,2H),4.58(s,2H).
Embodiment 8
N-(3-bromophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-1) preparation
80 milligrams of 4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate V) is dissolved in 1 milliliter of dimethyl sulfoxide (DMSO), adds 54 microlitre 3-bromobenzene isocyanic ester and 15 microlitre triethylamines, room temperature reaction spends the night.After reaction finishes, in system, add appropriate water, be extracted with ethyl acetate three times, saturated common salt washing, anhydrous magnesium sulfate drying, filters, and concentrated, resistates is through column chromatography for separation (methyl alcohol: methylene dichloride=1:30, v/v), obtain title compound, 130 milligrams of white solids, yield is 86%.
1HNMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.19(s,2H),8.47(d,J=4.3Hz,1H),7.89(s,1H),7.65(d,J=8.0Hz,2H),7.51(d,J=7.9Hz,2H),7.36(d,J=7.8Hz,1H),7.26(t,J=7.9Hz,1H),7.17(d,J=7.6Hz,1H),7.03(d,J=4.2Hz,1H),2.25(s,3H).MS(EI)m/z421.0[M] +。
Embodiment 9
N-(3-ethylphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-2) preparation
Except 3-brooethyl phenylisocyanate is replaced to 3-ethylbenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 63 milligrams of white solids, and yield is 48%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.07(s,1H),8.86(s,1H),8.47(d,J=4.6Hz,1H),7.65(d,J=8.5Hz,2H),7.50(d,J=8.5Hz,2H),7.36(s,1H),7.30(d,J=8.0Hz,1H),7.20(t,J=7.8Hz,1H),7.03(d,J=4.6Hz,1H),6.84(d,J=7.4Hz,1H),2.59(q,J=7.5Hz,2H),2.26(s,3H),1.19(s,3H);MS(EI)m/z371.1[M] +。
Embodiment 10
N-(3-trifluoromethyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-3) preparation
Except 3-ethylbenzene isocyanic ester is replaced to 3-trifluoromethyl phenylisocyanate, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 120 milligrams of white solids, yield 82%.
1H-NMR(400MHz,DMSO-d 6)δ:13.35(s,1H),9.41(d,J=50.8Hz,2H),8.47(d,J=4.7Hz,1H),8.06(s,1H),7.65(dd,J=16.5,8.5Hz,3H),7.53(dd,J=13.4,8.3Hz,3H),7.33(d,J=7.6Hz,1H),7.03(d,J=4.7Hz,1H),2.25(s,3H);MS(EI)m/z411.1[M] +。
Embodiment 11
N-(o-methyl-phenyl-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-4) preparation
Except 3-trifluoromethyl phenylisocyanate is replaced to o-methyl-benzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 57 milligrams of white solids, yield 45%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.54(s,1H),8.47(d,J=4.7Hz,1H),8.20(s,1H),7.85(d,J=8.0Hz,1H),7.67(d,J=8.6Hz,2H),7.50(d,J=8.6Hz,2H),7.18(dd,J=15.0,7.5Hz,2H),7.03(d,J=4.7Hz,1H),6.97(dd,J=10.6,4.1Hz,1H),2.27(d,J=11.0Hz,6H);MS(EI)m/z357.1[M] +。
Embodiment 12
N-(aminomethyl phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-5) preparation
Except o-methyl-benzene isocyanic ester is replaced to a methylbenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 66 milligrams of white solids, yield 52%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.16(s,1H),8.92(s,1H),8.47(d,J=4.6Hz,1H),7.65(d,J=8.5Hz,2H),7.49(d,J=8.4Hz,2H),7.34(s,1H),7.29(d,J=7.9Hz,1H),7.18(t,J=7.7Hz,1H),7.03(d,J=4.6Hz,1H),6.81(d,J=7.2Hz,1H),2.28(d,J=13.5Hz,6H);MS(EI)m/z357.1[M] +。
Embodiment 13
N-(fluorophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-6) preparation
Between inciting somebody to action, methylbenzene isocyanic ester replaces to 3-fluorobenzene isocyanic ester, and all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 84 milligrams of white solids, yield 65%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.26(d,J=11.4Hz,2H),8.47(d,J=4.7Hz,1H),7.66(d,J=8.6Hz,2H),7.60–7.46(m,3H),7.32(dd,J=15.2,8.1Hz,1H),7.22–7.11(m,1H),7.03(d,J=4.7Hz,1H),6.80(td,J=8.4,2.0Hz,1H),2.26(s,3H);MS(EI)m/z361.1[M] +。
Embodiment 14
N-(p-methylphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-7) preparation
Except 3-fluorobenzene isocyanic ester is replaced to aromatic isocyanatcs, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 32 milligrams of white solids, yield 25%.
1H-NMR(400MHz,DMSO-d 6)δ:13.33(s,1H),9.30(s,1H),9.05(s,1H),8.47(d,J=4.7Hz,1H),7.64(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),7.38(d,J=8.4Hz,1H),7.10(d,J=8.2Hz,2H),7.03(d,J=4.7Hz,1H),2.26(s,6H);MS(EI)m/z357.1[M] +。
Embodiment 15
N-(the fluoro-5-aminomethyl phenyl of 2-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-8) preparation
Except aromatic isocyanatcs being replaced to the fluoro-5-aminomethyl phenyl of 2-isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 82 milligrams of white solids, yield 62%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.41(s,1H),8.64(s,1H),8.47(d,J=4.7Hz,1H),8.09–7.94(m,1H),7.65(d,J=8.6Hz,2H),7.51(d,J=8.5Hz,2H),7.12(dd,J=11.3,8.4Hz,1H),7.03(d,J=4.7Hz,1H),6.82(s,1H),2.27(d,J=13.8Hz,6H);MS(EI)m/z375.1[M] +。
Embodiment 16
N-(2-fluorophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-9) preparation
Except fluoro-2-5-methylbenzene isocyanic ester is replaced to 2-fluorobenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 90 milligrams of white solids, yield 70%.
1H-NMR(400MHz,DMSO-d 6)δ:13.35(s,1H),9.85(s,1H),8.91(s,1H),8.47(d,J=4.7Hz,1H),8.16(td,J=8.2,1.5Hz,2H),7.67(d,J=8.6Hz,2H),7.51(d,J=8.6Hz,1H),7.25(ddd,J=11.5,8.2,1.3Hz,1H),7.16(t,J=7.7Hz,1H),7.04(d,J=4.6Hz,1H),2.25(s,3H);MS(EI)m/z361.1[M] +。
Embodiment 17
N-(3-chloro-phenyl-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-10) preparation
Except 2-fluorobenzene isocyanic ester is replaced to 3-chlorobenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 112 milligrams of white solids, yield 84%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.56(d,J=7.9Hz,2H),8.47(d,J=4.7Hz,1H),7.75(d,J=0.9Hz,1H),7.66(d,J=8.6Hz,1H),7.51(d,J=8.6Hz,2H),7.33(d,J=1.0Hz,2H),7.17-6.89(m,2H),2.25(s,3H);MS(EI)m/z377.1[M] +。
Embodiment 18
N-(3-cyano-phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-11) preparation
Except 3-chlorobenzene isocyanic ester is replaced to 3-cyano group phenylisocyanate, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 70 milligrams of white solids, yield 53%.
1H-NMR(400MHz,DMSO-d 6)δ:13.35(s,1H),9.54(d,J=37.3Hz,2H),8.47(d,J=4.7Hz,1H),8.02(s,1H),7.72(d,J=8.1Hz,1H),7.66(d,J=8.5Hz,1H),7.58-7.48(m,2H),7.44(d,J=7.6Hz,1H),7.04(d,J=4.7Hz,1H),2.25(s,3H);MS(EI)m/z368.1[M] +。
Embodiment 19
N-(2,5-Dimethoxyphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (I a-12) preparation
Except 3-cyano group phenylisocyanate is replaced to outside 2,5-dimethoxy phenylisocyanate, all the other desired raw materials, reagent and preparation method, with embodiment 8, obtain title compound, 20 milligrams of white solids, yield 14%.
1H-NMR(400MHz,DMSO-d 6)δ:13.34(s,1H),9.61(s,1H),8.47(d,J=4.7Hz,1H),8.36(s,1H),7.90(d,J=3.0Hz,1H),7.65(d,J=8.6Hz,2H),7.51(d,J=8.6Hz,2H),7.03(d,J=4.7Hz,1H),6.95(d,J=8.9Hz,1H),6.52(dd,J=8.9,3.0Hz,1H),3.85(s,3H),3.71(s,3H),2.26(s,3H);MS(EI)m/z403.1[M] +。
Embodiment 20
N-(3-bromophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-1) preparation
50 milligrams of 4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate V) is dissolved in 1 milliliter of dimethyl sulfoxide (DMSO), adds 39 microlitre 3-bromobenzene lsothiocyanates and 10 microlitre triethylamines, room temperature reaction spends the night.After reaction finishes, in system, add appropriate water, be extracted with ethyl acetate three times, saturated common salt washing, anhydrous magnesium sulfate drying, filters, and concentrated, resistates is through column chromatography for separation (methyl alcohol: methylene dichloride=1:20, v/v), obtain title compound, 58 milligrams of faint yellow solids, yield is 60%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),10.17(s,1H),10.06(s,1H),8.49(d,J=4.7Hz,1H),7.83(s,1H),7.67(d,J=8.5Hz,2H),7.54(d,J=8.5Hz,2H),7.46(d,J=6.7Hz,1H),7.32(s,2H),7.05(d,J=4.7Hz,1H),2.23(s,3H);MS(ESI)m/z438.0[M+1] +。
Embodiment 21
N-(3-iodophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-2) preparation
Except 3-bromobenzene lsothiocyanates is replaced to 3-iodobenzene lsothiocyanates, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 72 milligrams of faint yellow solids, yield 67%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),10.15(s,1H),10.01(s,1H),8.49(d,J=4.7Hz,1H),7.95(s,1H),7.67(d,J=8.5Hz,2H),7.54(d,J=8.5Hz,2H),7.49(dd,J=8.0,1.6Hz,2H),7.14(t,J=8.0Hz,1H),7.04(d,J=4.7Hz,1H),2.24(s,3H);MS(ESI)m/z486.0[M+1] +。
Embodiment 22
N-(3-fluorophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-3) preparation
Except 3-iodobenzene lsothiocyanates is replaced to 3-fluorobenzene lsothiocyanates, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 43 milligrams of faint yellow solids, yield 51%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),10.13(d,J=16.0Hz,2H),8.49(d,J=4.7Hz,1H),7.69(d,J=8.5Hz,2H),7.54(d,J=8.5Hz,3H),7.38(dd,J=15.0,8.1Hz,1H),7.28(d,J=8.9Hz,1H),7.05(d,J=4.7Hz,1H),6.96(td,J=8.4,2.3Hz,1H),2.24(s,3H);MS(ESI)m/z378.1[M+1] +。
Embodiment 23
N-(3-benzyloxy phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-4) preparation
Except 3-fluorobenzene lsothiocyanates is replaced to 3-benzyloxy PhNCS, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 79 milligrams of faint yellow solids, yield 77%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),9.99(d,J=17.2Hz,2H),8.48(d,J=4.7Hz,1H),7.69(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),7.46(d,J=7.1Hz,2H),7.39(t,J=7.4Hz,2H),7.34(d,J=7.1Hz,1H),7.30–7.21(m,2H),7.05(t,J=6.1Hz,2H),6.80(dd,J=8.2,2.2Hz,1H),5.09(s,2H),2.29–2.16(m,3H);MS(ESI)m/z466.1[M+1] +。
Embodiment 24
N-(3,4-Dimethoxyphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-5) preparation
Except 3-benzyloxy PhNCS is replaced to outside 3,4-dimethoxy PhNCS, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 56 milligrams of faint yellow solids, yield 60%.
1H-NMR(400MHz,DMSO-d 6)δ:13.35(s,1H),9.81(d,J=5.6Hz,2H),8.48(d,J=4.7Hz,1H),7.67(d,J=8.5Hz,2H),7.51(d,J=8.5Hz,2H),7.12(s,1H),7.04(d,J=4.7Hz,1H),6.94(s,2H),3.75(d,J=3.5Hz,6H),2.23(s,3H);MS(ESI)m/z420.1[M+1] +。
Embodiment 25
N-(3-p-methoxy-phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-6) preparation
Except 3,4-dimethoxy PhNCS is replaced to outside 3-anisole lsothiocyanates, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 60 milligrams of faint yellow solids, yield 69%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),9.99(d,J=17.7Hz,2H),8.49(d,J=4.7Hz,1H),7.69(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),7.25(t,J=8.1Hz,1H),7.19(t,J=2.1Hz,1H),7.107.00(m,2H),6.73(dd,J=8.2,2.4Hz,1H),3.75(s,3H),2.24(s,3H);MS(ESI)m/z390.1[M+1] +。
Embodiment 26
N-(3-trifluoromethyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-7) preparation
Except 3-anisole lsothiocyanates is replaced to 3-trifluoromethyl PhNCS, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 61 milligrams of faint yellow solids, yield 64%.
1H-NMR(400MHz,DMSO-d 6)δ:13.37(s,1H),10.25(s,1H),10.18(s,1H),8.50(dd,J=9.1,4.7Hz,1H),7.97(s,1H),7.78(d,J=8.2Hz,1H),7.68(d,J=8.5Hz,2H),7.63–7.52(m,3H),7.48(d,J=7.8Hz,1H),7.05(d,J=4.7Hz,1H),2.24(s,3H);MS(ESI)m/z428.1[M+1] +。
Embodiment 27
N-(3-acetylphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-8) preparation
Except 3-trifluoromethyl PhNCS is replaced to 3-acetylbenzene lsothiocyanates, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 50 milligrams of faint yellow solids, yield 56%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),10.13(d,J=15.6Hz,2H),8.49(d,J=4.7Hz,1H),8.08(s,1H),7.81–7.65(m,4H),7.61–7.45(m,3H),7.05(d,J=4.7Hz,1H),2.58(s,3H),2.23(s,3H);MS(ESI)m/z424.1[M+23] +。
Embodiment 28
N-(5-chloro-2-methyl phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-9) preparation
Except 3-acetylbenzene lsothiocyanates is replaced to 5-chloro-2-methyl PhNCS, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 55 milligrams of faint yellow solids, yield 61%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),10.07(s,1H),9.55(s,1H),8.49(d,J=4.7Hz,1H),7.71(d,J=8.5Hz,2H),7.54(d,J=8.4Hz,2H),7.41(d,J=1.9Hz,1H),7.26(dt,J=8.2,5.1Hz,2H),7.04(d,J=4.7Hz,1H),2.25(d,J=6.5Hz,6H);MS(ESI)m/z408.1[M+1] +。
Embodiment 29
N-(3-chloro-phenyl-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-10) preparation
Except 5-chloro-2-methyl PhNCS is replaced to 3-chlorobenzene lsothiocyanates, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 63 milligrams of faint yellow solids, yield 71%.
1H-NMR(400MHz,DMSO-d 6)δ:13.36(s,1H),10.17(s,1H),10.08(s,1H),8.49(d,J=4.7Hz,1H),7.69(dd,J=9.4,5.2Hz,3H),7.54(d,J=8.5Hz,2H),7.46–7.32(m,2H),7.19(d,J=7.8Hz,1H),7.05(d,J=4.7Hz,1H),2.24(s,3H);MS(ESI)m/z394.0[M+1] +。
Embodiment 30
N-(3-cyano-phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-11) preparation
Except 3-chlorobenzene lsothiocyanates is replaced to 3-cyano group PhNCS, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 44 milligrams of faint yellow solids, yield 51%.
1H-NMR(400MHz,DMSO-d 6)δ:13.37(s,1H),10.27(s,1H),10.17(s,1H),8.49(d,J=4.7Hz,1H),8.02(s,1H),7.80(d,J=8.0Hz,1H),7.68(d,J=8.5Hz,2H),7.64-7.50(m,4H),7.05(d,J=4.7Hz,1H),2.23(s,3H);MS(ESI)m/z385.1[M+1] +。
Embodiment 31
N-(3-methylthio group phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide (I b-12) preparation
Except 3-cyano group PhNCS is replaced to 3-methylthio phenyl lsothiocyanates, all the other desired raw materials, reagent and preparation method, with embodiment 20, obtain title compound, 22 milligrams of faint yellow solids, yield 24%.
1H-NMR(400MHz,DMSO-d 6)δ:13.37(s,1H),10.07(s,1H),9.98(s,1H),8.49(d,J=4.7Hz,1H),7.69(d,J=8.5Hz,2H),7.54(d,J=8.5Hz,2H),7.47(s,1H),7.28(d,J=7.0Hz,2H),7.05(d,J=4.4Hz,2H),2.47(s,3H),2.24(s,3H);MS(ESI)m/z4.1[M+1] +。
Embodiment 32
N-(3-ethylphenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-1) preparation
12 milligrams of intermediate VIII are dissolved in 1 milliliter of methyl-sulphoxide, add 8 microlitre 3-ethylbenzene isocyanic ester, then after adding 3 microlitre triethylamines, room temperature reaction spend the night.After reaction finishes, separate out solid to adding water in system, suction filtration, mixed solvent (ethyl acetate: sherwood oil=1:3, v/v) recrystallization of ethyl acetate and sherwood oil for filter cake, obtains title compound, 6 milligrams of white solids, yield is 34%.
1H?NMR(400MHz,MeOD)δ:8.40(d,J=4.8Hz,1H),8.33(d,J=4.8Hz,1H),7.33(d,J=8.4Hz,2H),7.22(s,1H),7.19–7.08(m,2H),7.05(d,J=4.8Hz,1H),6.98(d,J=4.8Hz,1H),6.80(d,J=7.3Hz,1H),6.75(d,J=8.4Hz,2H),4.58(s,2H),2.54(q,J=7.6Hz,2H),1.15(t,J=7.6Hz,3H);MS(ESI)m/z410.1[M+23] +。
Embodiment 33
N-(3-trifluoromethyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-2) preparation
Except 3-ethylbenzene isocyanic ester is replaced to 3-trifluoromethyl phenylisocyanate, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 10 milligrams of white solids, yield 51%.
1H-NMR(400MHz,DMSO-d 6)δ:13.65(s,1H),9.33(s,1H),9.21(s,1H),8.56(d,J=4.7Hz,1H),8.12(s,1H),7.84-7.64(m,5H),7.60(t,J=7.9Hz,1H),7.39(d,J=7.5Hz,1H),7.15(d,J=4.7Hz,1H),4.56(d,J=5.3Hz,2H);MS(ESI)m/z428.1[M+1] +。
Embodiment 34
N-(3-bromophenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-3) preparation
Except 3-trifluoromethyl phenylisocyanate is replaced to 3-bromobenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 13 milligrams of white solids, yield 65%.
1H-NMR(400MHz,DMSO-d 6)δ:13.58(s,1H),9.04(d,J=5.9Hz,2H),8.49(d,J=4.7Hz,1H),7.89(s,1H),7.64(q,J=8.8Hz,4H),7.35(d,J=8.6Hz,1H),7.26(t,J=8.0Hz,1H),7.17(d,J=7.8Hz,1H),7.09(d,J=4.7Hz,1H),4.50(d,J=5.3Hz,2H);MS(ESI)m/z438.0[M+1] +。
Embodiment 35
N-(the fluoro-5-aminomethyl phenyl of 2-)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-4) preparation
Except 3-bromobenzene isocyanic ester being replaced to the fluoro-5 methylbenzene isocyanic ester of 2-, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 9 milligrams of white solids, yield 50%.
1H-NMR(400MHz,DMSO-d 6)δ:13.58(s,1H),9.33(s,1H),8.62(s,1H),8.50(d,J=4.7Hz,1H),8.01(d,J=6.1Hz,1H),7.64(dd,J=18.0,8.7Hz,4H),7.09(d,J=4.7Hz,2H),6.82(s,1H),4.50(d,J=4.1Hz,2H);MS(ESI)m/z414.1[M+23] +。
Embodiment 36
N-(3-aminomethyl phenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-5) preparation
Except fluoro-2-5 methylbenzene isocyanic ester are replaced to 3-methylbenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 10 milligrams of white solids, yield 59%.
1H?NMR(400MHz,MeOD)δ:8.52(d,J=4.7Hz,1H),8.45(d,J=4.9Hz,1H),7.46(d,J=8.4Hz,2H),7.31(s,1H),7.27(d,J=8.2Hz,1H),7.19(dd,J=16.4,6.2Hz,2H),7.10(d,J=4.9Hz,1H),6.88(t,J=9.5Hz,3H),4.70(s,2H),2.36(s,3H);MS(ESI)m/z396.1[M+23] +。
Embodiment 37
N-(3-fluorophenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-6) preparation
Except 3-methylbenzene isocyanic ester is replaced to 3-fluorobenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 7 milligrams of white solids, yield 41%.
1H-NMR(400MHz,DMSO-d 6)δ:13.58(s,1H),9.05(d,J=11.4Hz,2H),8.49(d,J=4.7Hz,1H),7.64(q,J=8.7Hz,4H),7.53(d,J=11.9Hz,1H),7.32(dd,J=15.2,8.0Hz,1H),7.17(s,1H),7.09(d,J=4.7Hz,1H),6.80(td,J=8.5,2.4Hz,1H),4.50(d,J=5.4Hz,2H);MS(ESI)m/z400.1[M+23] +。
Embodiment 38
N-(3-chloro-phenyl-)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-7) preparation
Except 3-fluorobenzene isocyanic ester is replaced to 3-chlorobenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 6 milligrams of white solids, yield 33%.
1H-NMR(400MHz,DMSO-d 6)δ:13.57(s,1H),9.11(s,2H),8.49(d,J=4.7Hz,1H),7.75(s,1H),7.64(q,J=8.9Hz,4H),7.32(d,J=5.0Hz,2H),7.08(d,J=4.7Hz,1H),7.06–7.01(m,1H),4.50(d,J=5.4Hz,2H);MS(ESI)m/z416.0[M+23] +。
Embodiment 39
N-(p-methylphenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-8) preparation
Except 3-chlorobenzene isocyanic ester is replaced to aromatic isocyanatcs, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 4 milligrams of white solids, yield 24%.
1H-NMR(400MHz,DMSO-d 6)δ:13.57(s,1H),8.86(s,1H),8.66(s,1H),8.49(d,J=4.7Hz,1H),7.63(q,J=8.7Hz,4H),7.37(d,J=8.3Hz,2H),7.15–7.04(m,3H),4.50(d,J=5.3Hz,2H),2.25(s,3H);MS(ESI)m/z396.1[M+23] +。
Embodiment 40
N-(o-methyl-phenyl-)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-9) preparation
Except aromatic isocyanatcs being replaced to o-methyl-benzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 4 milligrams of white solids, yield 24%.
1HNMR(400MHz,MeOD)δ:8.40(d,J=4.8Hz,1H),7.59-7.50(m,4H),7.08(dd,J=21.1,6.3Hz,4H),6.98-6.92(m,1H),4.56(s,2H),2.23(s,3H);MS(ESI)m/z396.1[M+23] +。
Embodiment 41
N-(adjacent fluorophenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (Compound I c-10) preparation
Except o-methyl-benzene isocyanic ester is replaced to adjacent fluorobenzene isocyanic ester, all the other desired raw materials, reagent and preparation method, with embodiment 32, obtain title compound, 4 milligrams of white solids, yield 23%.
1H-NMR(400MHz,DMSO-d 6)δ:13.58(s,1H),9.31(s,1H),8.66(s,1H),8.50(d,J=4.7Hz,1H),8.18(t,J=8.0Hz,1H),7.64(dd,J=18.8,8.6Hz,4H),7.32-7.22(m,1H),7.17(t,J=7.6Hz,1H),7.09(d,J=4.7Hz,1H),7.06-6.97(m,1H),4.50(d,J=5.6Hz,2H);MS(ESI)m/z400.1[M+23] +。
The structure of embodiment 8～41 prepared compounds is in table 1:
Table 1
Continued 1
Embodiment 42
Compound of the present invention suppresses experiment and the active result of four kinds of receptor tyrosine kinases
To synthesize 3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, chooses 4 kinds of tyrosine receptor kinases (comprising c-Kit, PDGFR α, VEGFR2 and FGFR1), the inhibition active testing carrying out.Activity data is as shown in table 1, has found that altogether 10 the compounds of this invention have very strong inhibition activity, half effective inhibition concentration IC to c-Kit 50<1 μ M, wherein 4 the compounds of this invention have extraordinary inhibition active to c-Kit, half effective inhibition concentration IC 50<10nM; Find that altogether 27 the compounds of this invention have stronger inhibition activity, half effective inhibition concentration IC to PDGFR α 50<1 μ M, wherein 7 the compounds of this invention have very strong inhibition activity, half effective inhibition concentration IC to PDGFR α 50<0.1 μ M; Find that altogether 27 the compounds of this invention have certain inhibition activity to VEGFR2, half effective inhibition concentration 1 μ M<IC 50<10 μ M.Refer to table 2(3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds to four kinds of kinase whose inhibition activity data (IC 50, nM))
In table 2, c-Kit represents III type tyrosine kinase acceptor, and PDGFRa represents platelet derived growth factor receptor, and VEGFR2 represents VEGF R2, and FGFR1 represents fibroblast growth factor acceptor 1.The positive contrast medicine of Linifanib, is the antitumor drug candidate that Abbott of the U.S. releases, current in clinical three phase conceptual phases.The positive contrast medicine of Staurosporine is a kind of natural product class microbiotic, usually used as tool compound.
Table 2.
Continued 2
Continued 2
As can be seen from Table 2, of the present invention have 3 of a general structure I, 4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds major part has stronger c-Kit and PDGFR α suppresses active and certain VEGFR2 and FGFR1 inhibition activity, wherein indivedual the compounds of this invention are particularly evident to the inhibition activity of c-Kit, illustrate that compound of the present invention is the inhibitor class antitumour drug of many target spots receptor tyrosine kinase.
Provided by the invention 3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds molecular structure is comparatively simple, preparation technology is succinct, production cost is low, suppress all to demonstrate stronger inhibition activity in experiment with the closely-related receptor tyrosine kinase of tumorigenesis at four kinds, be therefore expected to be developed to many target spots, the anti-tumor drugs targeting for acute myeloblastic leukemia and solid tumor.

Claims (10)

1. one kind 3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, and it is pharmaceutically acceptable salt of compound shown in formula I or its:
In formula I: R 1for C 1～C 4straight or branched alkyl or the C being replaced by hydroxyl 1～C 4straight or branched alkyl; R 2for hexa-atomic aromatic ring yl or replace hexa-atomic aromatic ring yl, X is O or S;
The substituting group of the hexa-atomic aromatic ring yl of described replacement is selected from: C 1～C 6straight or branched alkyl, C 1～C 6straight or branched perfluoroalkyl, halogen, cyano group, hydroxyl, nitro, or in one or two or more kinds, the integer that substituent number is 1～4;
Wherein, R 3for C 1～C 4straight or branched alkyl, Y is O or S, R 4for C 1～C 4straight or branched alkyl or the C being replaced by phenyl 1～C 4straight or branched alkyl.
2. as claimed in claim 13,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, wherein R 1for C 1～C 2alkyl or the C being replaced by hydroxyl 1～C 2alkyl.
3. as claimed in claim 23,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, wherein R 1the methyl replacing for methyl or by hydroxyl.
4. as claimed in claim 13,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, wherein R 2for phenyl or substituted-phenyl;
The substituting group of described substituted-phenyl is selected from: C 1～C 6straight or branched alkyl, C 1～C 6straight or branched perfluoroalkyl, halogen, cyano group, hydroxyl, nitro, or in one or two or more kinds, the integer that substituent number is 1～4;
Wherein, R 3for C 1～C 4straight or branched alkyl, Y is O or S, R 4for C 1～C 4straight or branched alkyl or the C being replaced by phenyl 1～C 4straight or branched alkyl.
5. as claimed in claim 43,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, wherein R 2for substituted-phenyl;
The substituting group of described substituted-phenyl is selected from: C 1～C 3straight or branched alkyl, C 1～C 3straight or branched perfluoroalkyl, halogen, cyano group, or in one or two or more kinds, the integer that substituent number is 1～3;
Wherein, R 3for C 1～C 2alkyl, Y is O or S, R 4for C 1～C 2alkyl or the C being replaced by phenyl 1～C 2alkyl.
6. as claimed in claim 53,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, wherein R 2for substituted-phenyl;
The substituting group of described substituted-phenyl is selected from: methyl, and ethyl, trifluoromethyl, halogen, cyano group, methoxyl group, methylthio group, a kind of or two kinds in ethanoyl or benzyloxy, substituent number is 1 or 2.
7. as claimed in claim 63,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, wherein R 2be: o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, an ethylphenyl, adjacent fluorophenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, an iodophenyl, m-trifluoromethylphenyl, a cyano-phenyl, m-methoxyphenyl, 3; 4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl, a benzyloxy phenyl, meta-methylthio phenyl, an acetylphenyl, 5-chloro-2-methyl phenyl or the fluoro-5-aminomethyl phenyl of 2-.
As described in claim 3 or 73,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds, it is characterized in that, described 3,4-bis-replaces (1H-pyrazoles [3,4-b] pyridine) compounds: N-(3-bromophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-ethylphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-trifluoromethyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(o-methyl-phenyl-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(aminomethyl phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(fluorophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(p-methylphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(the fluoro-5-aminomethyl phenyl of 2-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(2-fluorophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-chloro-phenyl-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-cyano-phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(2,5-Dimethoxyphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-bromophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-iodophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-fluorophenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-benzyloxy phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3,4-Dimethoxyphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-p-methoxy-phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-trifluoromethyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-acetylphenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(5-chloro-2-methyl phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-chloro-phenyl-)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-cyano-phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-methylthio group phenyl)-N '-[4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] thiocarbamide; N-(3-ethylphenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-trifluoromethyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-bromophenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(fluoro-5 aminomethyl phenyls of 2-)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-aminomethyl phenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-fluorophenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(3-chloro-phenyl-)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(p-methylphenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; N-(o-methyl-phenyl-)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea; Or N-(adjacent fluorophenyl)-N '-[4-(3-methylol-1H-pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea.
As described in any one in claim 1～8 3,4-bis-replaces the application of (1H-pyrazoles [3,4-b] pyridine) compounds in preparation many target spots receptor tyrosine kinase inhibitors series antineoplastic medicament.
10. application as claimed in claim 9, is characterized in that, wherein said many target spots receptor tyrosine kinase comprises c-Kit, PDGFR α, VEGFR2 and FGFR1.
CN201310013356.4A 2013-01-15 2013-01-15 3,4-disubstituted(1H-pyrazole[3,4-b]pyridine) compound and use thereof Pending CN103923078A (en)

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