CN105481778A - Pyrimidine derivative, preparation method and applications thereof - Google Patents
Pyrimidine derivative, preparation method and applications thereof Download PDFInfo
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- QIKIAJNORQVISB-UHFFFAOYSA-N C=CC(Nc1cc(N)ccc1F)=O Chemical compound C=CC(Nc1cc(N)ccc1F)=O QIKIAJNORQVISB-UHFFFAOYSA-N 0.000 description 1
- ZFGNAUDLKKAVJC-UHFFFAOYSA-N CN(C(C=C)=O)c1cc(N)ccc1F Chemical compound CN(C(C=C)=O)c1cc(N)ccc1F ZFGNAUDLKKAVJC-UHFFFAOYSA-N 0.000 description 1
- YYPOZCINWYSEJS-UHFFFAOYSA-N N#CCCCCCNc1nc(Cl)ncc1Cl Chemical compound N#CCCCCCNc1nc(Cl)ncc1Cl YYPOZCINWYSEJS-UHFFFAOYSA-N 0.000 description 1
- 0 O=C(c1ccccc11)N(*2=C*C2)C1=O Chemical compound O=C(c1ccccc11)N(*2=C*C2)C1=O 0.000 description 1
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Abstract
The present invention provides a pyrimidine derivative represented by a formula (I), or a pharmaceutically acceptable salt, a preparation method and applications thereof. According to the present invention, the pyrimidine derivative represented by the formula (I), or the pharmaceutically acceptable salt thereof has JAK kinase inhibition activity, particularly provides selective and high inhibition activity on JAK3 kinase, can be used for preparation of JAK3 kinase inhibitors, and can be used for preparation of drugs for preventing or treatment of diseases associated with abnormal JAK3 kinase activity so as to prevent or treat diseases associated with abnormal JAK3 kinase activity. The formula (I) is defined in the specification.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, be specifically related to a kind of pyrimidine derivatives, its preparation method and application thereof.
Background technology
2002, the people such as Manning determined human kinase group and comprise 518 kinds of protein kinase genes, and wherein the generation of 218 kinds of enzyme genes and human diseases develops closely related (ManningG., etal.2002, Science, 298:1912-1934).In the medicine found at present, be that the medicine of action target spot accounts for 20% more than with enzyme, particularly target protein kinase has special value in clinical application.
Protein kinase is that a class intracellular messenger relies on, catalysis specific protein phosphorylation the enzyme of settling signal transmittance process, mainly comprises tyrosine protein kinase, as JAKs, Src, Abl, EGFR, FGFR, PDGFR etc.; Serine/threonine protein kitase, as PKC, MAPK, Rho kinases etc.; Dual specificity protein kinases, as MAPKK etc. and phosphatidyl inositol kinase, as PI3K.Protein kinase phosphorylation/dephosphorylation process can regulate the regulate several biological processes of different cell, as (ShchemelininI. such as metabolism, cytodifferentiation, cell survival, apoptosis, orga-nogenesis, vasculogenesis, immunne responses, etal.2006, FoliaBiol., 52:81-100).
JAKs (Januskinase), comprises four known member JAK3, JAK1, TYK2, JAK2, is the Ge little family in endochylema in non-receptor tyrosine protein kinase superfamily.JAK3 is distributed in marrow and lymphsystem, and rear three is then distributed widely in Various Tissues cell.After different cytokines is in conjunction with cell surface receptor, the JAKs of activated receptor coupling, and then make receptor phosphorylation, this is endochylema signal transduction and activating transcription factor stat protein (SignalTransducersandActivatorsofTranscription, STAT1 ~ 4, STAT5a, STAT5b, STAT6) recruitment site is provided, JAKs phosphorylation stat protein, regulate gene expression in nucleus is transferred to after the latter's dimerization, this approach and JAK/STAT signal path (O ' SheaJ.J., etal.2013, N.Engl.J.Med., 368:161-170).
JAK/STAT signal path is a signal transduction pathway stimulated by cytokine profiles and growth factor receptors, these factors comprise interleukin class (IL-2 ~ 7, IL-9, IL-10, IL-15, IL-21), interferons (IFN-α, IFN-β, IFN-γ), erythropoietin (EPO), granulocyte and giant cells G CFS (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO) etc., it is participating in the propagation of immunocyte and hemopoietic stem cell, play a crucial role in immunoregulatory biological procedures (GhoreschiK., etal.2009, Immunol.Rev., 228:273-287).Isoacceptor can not activate the jak kinase of different subtype, thus realizes the biological function of differentiation.
JAK3 by with the γ in the cytokine receptor complex such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 altogether chain (γ c) combine, regulate cell signaling.JAK3 or γ c sudden change all can cause severe combined immunodeficiency (SCID) (VillaA., etal.1996, Blood, 88:817-823).The active Novel presentation of JAK3 is that T cell and NK cell reduce in a large number, B cell afunction, has a strong impact on the natural biological function of immunity system etc.Based on its functional characteristics and special tissue distribution, JAK3 becomes the drug target for immunity system relative disease very attractive, its inhibitor is at rheumatoid arthritis (RA), Crohn's disease, systemic lupus erythematous, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), psoriatic, anaphylactic disease, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other etc. the treatment/prevention aspect of disease there is important clinical value (PapageorgiouA.C., etal.2004, TrendsPharm.Sci., 2004, 25:558-562).
JAK1 can combine (ScottJ.R., etal.1998, Cell, 93:373-383) with the IL-6 in IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, gp130 family and containing other acceptor etc. of γ c.JAK1 gene knockout experiment on mouse model shows that this enzyme plays keying action (KisselevaT., etal.2002, Gene, 285:1-24) in the biological effect regulating above-mentioned cytokine profiles acceptor.JAK1 is the novel target spot of the disease areas such as immunity, inflammation and cancer.JAK1 inhibitor can be used for treatment/prevention of autoimmune diseases, inflammation and tumour (HornakovaT., etal.2010, Blood, 115:3287-3295), as leukemia, lymphoma, melanoma, sacroiliitis, psoriatic, Crohn's disease, lupus erythematosus, acquired immune deficiency syndrome (AIDS), Behcet's disease (HouS., etal.2013, Hum.Genet., 132:1049-1058) etc., but be not limited to this.
TYK2 is first member in JAK family, and it can by the multiple receptor activation such as IFNs, IL-10, IL-6, IL-12, IL-23, IL-27.In mouse, TYK2 afunction can cause the signal path generation defect of cytokine profiles acceptor, and then causes virus infection, antibacterial immunity function reduction add (KisselevaT., the etal.2002 such as the possibility of pulmonary infection, Gene, 285:1-24).In addition, the research of LarnerA.C. group shows that TYK2 can contribute to suppressing growth and the transfer (ZhangQ., etal.2011, J.InterferonCytokineRes., 31:671-677) of mammary cancer; This seminar have recently been reported TYK2 can assist the fat achievement in research regulated in mouse and human body by the differentiation of brown adipose tissue (BAT); it can protect body to avoid obesity; even can reverse obesity (DereckaM.; etal.2012; CellMetab.; 2012,16:814-824).This is perhaps for fat cancer patients treatment provides new chance.
JAK2 is comprising in the multiple receptor signal regulate processes such as EPO, GH, PRL, IL-3, IFN-γ play a significant role (KisselevaT., etal.2002, Gene, 285:1-24; LevyD.E., etal.2002, Nat.Rev.Mol.CellBiol., 3:651-662; O ' SheaJ.J., etal.2002, Cell, 109 (suppl.): S121-S131).The animal dead (SchindlerC., etal.2007, J.Biol.Chem., 282:20059-20063) that JAK2 can cause anaemia to cause is knocked out in mouse model; A base mutation JAK2V617F on JAK2 gene in human body, closely related (the GhoreschiK. of generation of polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myelocytic leukemia (CML) etc. in itself and myeloproliferative disease, etal.2009, Immunol.Rev., 228:273-287).Therefore, JAK2 has become the definite action target spot of the treatment/prevention of such disease.
In November, 2012, the pan-JAKs inhibitor X eljanz (Tofacitinib) of Pfizer company has obtained FDA approval and has been used for the treatment of RA.In October, 2013, the said firm discloses Xeljanz and is used for the treatment of psoriatic III clinical data, and the double blind trial of contrast Enbrel (Etanercept), this medicine meets Noninferior solution design studies result.But Xeljanz has and comprises side effects such as causing red corpuscle and quantity of leucocyte decline, cholesterol levels rising, and this perhaps has high JAK2 inhibit activities relevant (ZakM., etal.2012, J.Med.Chem., 55:6176-6193) to it.Therefore, sight is focused on the research of selectivity JAK inhibitor with in discovery, such as selective JAK 3 restrainer or selectivity JAK1 inhibitor etc. by the scientist of the mechanisms such as Ge great drugmaker.
Now existing multiple choices JAK inhibitor is in different clinical investigation phase, comprise selective JAK 3 restrainer VX-509, selectivity JAK1 inhibitor GLPG0634 (FeistE., etal.2013, Rheumatology, 52:1352-1357) with INCB39110 (http://www.incyte.com/research/pipeline) etc., be used for the treatment of the immunity system relative diseases such as RA, Crohn's disease, psoriatic, myelofibrosis.In addition, the Patents of the selective depressant of multiple different types of structure is disclosed: 1) selective JAK 3 restrainer, as pyrrolo-[1, 2-b] pyridazine (WO2012125887), pyrazolo [3, 4-d] pyrimidine (WO2011048082, WO2011134861, WO2012022681), diaminopyrimidine (WO2011029807, WO2012015972), pyrrolo-[2, 3-b] pyridine (JP2012012332), diamino-pyridine-3-carboxamide (WO2010061971, US20120108566), pyrrolo-[2, 3-b] pyrazine (WO2011144584, WO2011144585) etc., 2) selectivity JAK1 inhibitor, as tricyclic compounds (WO2011086053), the pyrazoles replaced and pyroles (WO2010135650, WO2011112662), anilino phthalazines class (WO2012037132) etc.In addition, the Patents having selectivity JAK2 inhibitor, selectivity TYK2 inhibitor and have two kinds of hypotype (JAK3/1, JAK1/2 etc.) inhibitor simultaneously is also in the news, does not repeat them here.
Summary of the invention
An object of the present invention is to provide a kind of pyrimidine derivatives, and it has JAK3 kinase inhibiting activity;
Two of object of the present invention is the preparation method providing a kind of pyrimidine derivatives;
Three of object of the present invention is to provide the application of pyrimidine derivatives in preparation JAK3 kinase inhibitor.
Four of object of the present invention is to provide pyrimidine derivatives to treat the application in the medicine of the disease relevant to JAK3 abnormal kinase in preparation.
The invention provides the pyrimidine derivatives shown in formula (I) or its pharmacy acceptable salt:
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or haloalkyl;
R
2be selected from hydrogen, hydroxyl, carboxyl, cyano group, phenyl, 5 ~ 6 yuan of heteroaryls, C
1-6alkyl or haloalkyl, C
1-6alkoxyl group;
R
3be selected from hydrogen, halogen, cyano group, C
1-6one or more of alkyl or haloalkyl;
R
4for hydrogen, C
1-6alkyl or haloalkyl;
X is NH or O;
N is the integer of 1 to 7.
The present invention also comprises the enantiomer, diastereomer, hydrate, solvate etc. of compound shown in formula (I), preferably includes steric isomer or hydrate.
In the present invention, X is NH or O, is preferably NH.
In the present invention, R
1for halogen, C
1-6alkyl or haloalkyl, be preferably halogen, be more preferably chlorine.
In the present invention, R
2be selected from hydrogen, hydroxyl, carboxyl, cyano group, phenyl, 5 ~ 6 yuan of heteroaryls, C
1-6alkyl or haloalkyl, C
1-6alkoxyl group, is preferably selected from the substituting group shown in hydrogen, hydroxyl, carboxyl, cyano group, phenyl, pyridyl, morpholinyl or formula (a);
In the present invention, R
3be selected from hydrogen, halogen, cyano group, C
1-6one or more of alkyl or haloalkyl, are preferably halogen, are more preferably fluorine; R
3be preferably 4 bit substituents.
In the present invention, R
4for hydrogen, C
1-6alkyl or haloalkyl, be preferably hydrogen or methyl.
In the present invention, n is the number of methylene radical, is the integer of 1 to 7, is preferably the integer of 2 to 7, is more preferably 2,5 or 7.
As preferably, in formula (I), R
1for halogen; R
2for the substituting group shown in hydrogen, hydroxyl, carboxyl, cyano group, phenyl, pyridyl, morpholinyl or formula (a); R
3for hydrogen or fluorine; R
4for hydrogen or methyl; X is NH or O; N is the integer of 1 to 7;
As preferably, in formula (I), R
1for chlorine; R
2for the substituting group shown in hydroxyl, carboxyl, cyano group, pyridyl, morpholinyl or formula (a); R
3for fluorine; R
4for methyl; X is NH or O; N is the integer of 1 to 7.
As preferably, in formula (I), R
1for chlorine; R
2for the substituting group shown in hydroxyl, carboxyl, cyano group or formula (a); R
3for fluorine; R
4for methyl; X is NH; N is 5.
" halogen " of the present invention is fluorine, chlorine, bromine, iodine;
" alkyl " of the present invention, comprise straight chain, side chain or cyclic alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
Present invention also offers the preparation method of the pyrimidine derivatives shown in a kind of formula (I), comprising:
Shown in formula (IV), shown in compound and formula (V), compound forms pyrimidine derivatives shown in formula (I) under organic solvent and catalyst action;
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or haloalkyl;
R
2be selected from hydrogen, hydroxyl, carboxyl, cyano group, phenyl, 5 ~ 6 yuan of heteroaryls, C
1-6alkyl or haloalkyl, C
1-6alkoxyl group;
R
3be selected from hydrogen, halogen, cyano group, C
1-6one or more of alkyl or haloalkyl;
R
4for hydrogen, C
1-6alkyl or haloalkyl;
X is NH or O;
N is the integer of 1 to 7.
Compound shown in compound shown in formula (IV) and formula (V) reacts pyrimidine derivatives shown in production (I), and reaction process is as follows:
Shown in formula (IV), shown in compound and formula (V), compound generation substitution reaction obtains pyrimidine derivatives shown in formula (I), and temperature of reaction is backflow, and the reaction times is 8-16 hour.Reacting organic solvent used is common solvent, is preferably the alcohol of C1 ~ C6, is more preferably Virahol, propyl carbinol etc.Reaction used catalyst is acid, is preferably trifluoroacetic acid, hydrochloric acid, methylsulfonic acid etc.
In the present invention, general formula (IV) compound is preferably prepared in accordance with the following methods:
General formula (III) compound and general formula (II) compound form the compound that general formula is (IV) under the effect of organic solvent and alkali, and reaction process is as follows:
In above-mentioned reaction process, general formula (III) compound and general formula (II) compound all can directly commercially obtain, the temperature that general formula (III) compound and general formula (II) compound react is for reflux, and the reaction times is 8-16 hour.Reaction solvent for use is common solvent, is preferably the alcohol of C1 ~ C6, is more preferably ethanol, methyl alcohol, propyl carbinol etc.Reacting alkali used is the organic bases such as triethylamine, diisopropyl ethyl amine.
In the present invention, general formula (III) compound also can be prepared in accordance with the following methods:
There is substitution reaction and obtain formula (X) compound in formula (VIII) compound and formula (IX) compound, obtain general formula (III) compound after hydrolysis, reaction process is as follows under diisopropyl ethyl amine exists:
Formula (VIII) compound and formula (IX) compound all can directly commercially obtain, there is substitution reaction and obtain formula (X) compound in it, formula (X) compound obtains general formula (III) compound after being hydrolyzed under hydrazine hydrate effect under diisopropyl ethyl amine exists.
In the present invention, compound shown in formula (V) is preferably prepared in accordance with the following methods:
The condensation under diisopropyl ethyl amine exists of general formula (VI) compound and acrylate chloride obtains general formula (VII) compound, and after reduction, obtain logical formula V compound, reaction process is as follows:
General formula (VI) compound can directly commercially obtain, the condensation under diisopropyl ethyl amine exists of itself and acrylate chloride obtains general formula (VII) compound, and general formula (VII) compound obtains logical formula V compound through iron powder reducing nitro.
After shown in formula (IV), shown in compound and formula (V), compound generation substitution reaction obtains pyrimidine derivatives shown in formula (I), common separation method can be adopted to carry out purifying, as extraction, recrystallization, column chromatography etc., the present invention there is no particular restriction to this.
Specifically, the pyrimidine derivatives shown in formula (I) can be following compound:
Table 1 particular compound of the present invention
The present invention also provides a kind of pharmaceutical preparation, comprises pyrimidine derivatives described in technique scheme or its pharmacy acceptable salt and pharmaceutically acceptable auxiliary material.
Described pharmaceutically acceptable auxiliary material comprises carrier, thinner, weighting agent, disintegrating agent etc., can according to the corresponding auxiliary material of dosage form selection, comprise " pharmaceutical excipient handbook " (American Pharmaceutical Association, in October, 1986) listed by carrier filler, but be not limited to these carrier fillers.
Described medicine can be directly the formulations well known to those skilled in the art such as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection or paste, and the present invention is not particularly limited its working method.In preparation, the content as the compound of the general formula (I) of active ingredient is preferably 0.5 ~ 70wt%, and better content is 1 ~ 20wt%.The formulation specification of described preparation is preferably 0.0001 ~ 200mg.
Pyrimidine derivatives shown in formula (I) or its pharmacy acceptable salt have jak kinase inhibit activities, especially to JAK3 kinases, there is optionally inhibit activities, may be used for preparing selective JAK 3 kinase inhibitor, for the preparation of prevention or the medicine for the treatment of the disease relevant to JAK3 abnormal kinase, thus prevent or treat the disease relevant to JAK3 abnormal kinase, such as autoimmune disorder, diseases associated with inflammation, cancer, myeloproliferative disease, bone-resorbing disease or organ-graft refection's disease etc., especially rheumatoid arthritis, Crohn's disease, systemic lupus erythematous, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), psoriatic, anaphylactic disease, asthma, chronic obstructive pulmonary disease, leukemia or lymphoma.
Pyrimidine derivatives shown in formula of the present invention (I) or its pharmacy acceptable salt, can carry out medication by oral or injection system to Mammals (comprising people) clinically, wherein especially best with oral way.Dosage is 0.0001 ~ 200mg/kg body weight every day, and better dosage is 0.01 ~ 100mg/kg body weight every day, and best dosage is 0.1 ~ 50mg/kg body weight every day, simultaneously, optimal dose is depending on individuality, and when usually starting, dosage is less, then increases consumption gradually.
Experimental result shows, pyrimidine derivatives provided by the invention has higher inhibit activities to JAK3 kinases, and to JAK2 kinases and JAK1 kinase inhibitory activity not remarkable.
Based on foregoing, selective JAK 3 restrainer disclosed herein is used for the treatment of/prevents the immunity system relative diseases such as RA, psoriatic, Crohn's disease, systemic lupus erythematous, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), anaphylactic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymphoma, but is not limited to this.Meanwhile, expect that the clinical efficacy of these diseases can reach by the pharmaceutical composition etc. of these compounds or its activeconstituents in safe treatment window to maximize and other object.
Accompanying drawing explanation
Fig. 1 is embodiment of the present invention kinase activity Cleaning Principle schematic diagram.
Embodiment
Illustrate content of the present invention further below in conjunction with example, but protection scope of the present invention is not limited only to these examples.Per-cent of the present invention, except indicating especially, is all weight percentage.Numerical range described in specification sheets, as measure unit, reaction conditions, compound physical state or per-cent, is all to provide undoubted desk reference.Those skilled in the art, when putting into practice this patent, are used in outside this scope or are different from the temperature, concentration, quantity, carbonatoms etc. of single numerical value, still can obtain expected result.
The preparation of embodiment 12-fluoro-N-methyl-5-nitro aniline
The fluoro-5-N-methyl-p-nitroaniline (20.0g, 128.2mmol) of 2-and paraformaldehyde (16.0g, 533.3mmol) are dissolved in 500mL methyl alcohol in stirred at ambient temperature.Then the methanol solution 100mL of NaOMe (3.4g, 63mmol) is dripped.After this reaction solution at room temperature stirs 16 hours, point two deciles add NaBH
4(9.7g, 255.2mmol), stirs 15 minutes.LCMS follows the tracks of reaction.Pour in the aqueous solution of the KOH of 1M after reaction terminates, stir and separate out solid.Filter to obtain yellow solid 2-fluoro-N-methyl-5-nitro aniline (19.0g, 87%yield).LC-MS(m/z)171(M+1)。
The preparation of embodiment 2N-(the fluoro-5-nitrophenyl of 2-)-N methacrylamide
2-fluoro-N-methyl-5-nitro aniline (11.0g, 64.7mmol) and DIPEA (23mL, 129.4mmol) is dissolved in 100mLTHF in stirred at ambient temperature.Then acrylate chloride (11mL, 129.4mmol) is dripped.This reaction solution evaporates most of solvent after at room temperature stirring 1 hour, add 100mL diluted ethyl acetate, saturated common salt water washing, dry, filter, underpressure distillation obtains yellow oil N-(the fluoro-5-nitrophenyl of 2-)-N methacrylamide (12.0g, 83%yield).LC-MS(m/z)225(M+1)。
The preparation of embodiment 3N-(5-amino-2-fluorophenyl)-N methacrylamide
Iron powder (20.0g, 357mmol) and NH
4cl (20.0g, 374mmol) be dissolved in 200mL water be heated to 80 DEG C stir half an hour.Then the ethyl acetate solution 20mL of N-(the fluoro-5-nitrophenyl of 2-)-N methacrylamide (12g, 53.6mmol) is added.This reaction solution stirs after 1 hour and adds NaHCO at 80 DEG C
3aqueous solution alkali tune, filter iron mud, filtrate is extracted with ethyl acetate, and merges organic pressure of subtracting each other and distills to obtain brown oil N-(5-amino-2-fluorophenyl)-N methacrylamide (5.6g, 54%yield).LC-MS(m/z)195(M+1)。
The preparation of embodiment 46-(2,5-dichloro pyrimidine-4-base is amino) own nitrile
2,4,5-trichloropyrimidine (81mg, 0.45mmol), ACN (50mg, 0.45mmol) and triethylamine (2mL, 14mmol) are dissolved in 5mL ethanol.This reaction solution is heated to 70 DEG C and stirs reaction end after 4 hours.Washed with diethylether is used after solvent evaporated.Filter to obtain white solid 6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (100mg, 86.7%yield).LC-MS(m/z)259(M+1).
The preparation of embodiment 5N-(5-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide
6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (200mg, 0.77mmol), N-(5-amino-2-fluorophenyl)-N methacrylamide (150mg, 0.77mmol) be dissolved in 10mL Virahol with trifluoroacetic acid (20uL, 1.4mmol).This reaction solution is heated to 90 DEG C and stirs reaction end after 24 hours.Reaction solution pours NaHCO into
3in the aqueous solution, separate out solid.Leave standstill, filter.Crude product is dissolved in ethyl acetate ultrasonic, filters to obtain white solid N-(5-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide (97mg, 30.2%yield).
1HNMR(DMSO-d
6)δ1.36-1.40(m,2H,CH
2),1.51-1.59(m,4H,2×CH
2),2.48(t,J＝7.46Hz,2H,CH
2),3.19(s,3H,CH
3),3.34-3.39(m,2H,CH
2),5.62(d,1H,J＝9.93Hz,CH),6.04-6.11(m,1H,CH),6.18-6.23(m,1H,CH),7.25-7.30(m,2H,Ar-H,miazine-NH),7.60(t,J＝5.16Hz,1H,Ar-H),7.91(s,1H,miazine-H),7.94-7.98(m,1H,Ar-H),9.45(s,1H,benzene-NH).LC-MS(m/z)417(M+1).
The preparation of embodiment 6N-(3-nitrophenyl) acrylamide
According to method disclosed in embodiment 2, by 3-N-methyl-p-nitroaniline (5.0g, 36.2mmol) prepare yellow solid N-(3-nitrophenyl) acrylamide (4.3g, 62.3%yield) with acrylate chloride (6mL, 73.3mmol).LC-MS(m/z)193(M+1)。
The preparation of embodiment 7N-(3-aminophenyl) acrylamide
According to method disclosed in embodiment 3, prepare brown solid N-(3-aminophenyl) acrylamide (2.4g, 71.1%yield) by N-(3-nitrophenyl) acrylamide (4.0g, 20.8mmol).LC-MS(m/z)163(M+1)。
The preparation of embodiment 86-(2,5-dichloro pyrimidine-4-base is amino) own nitrile
According to method disclosed in embodiment 4, by 2,4,5-trichloropyrimidine (81mg, 0.45mmol) with ACN (50mg, 0.45mmol) prepare white solid 6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (100mg, 86.7%yield).LC-MS(m/z)259(M+1)。
The preparation of embodiment 9N-(3-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino) phenyl) acrylamide
According to method disclosed in embodiment 5, by 6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (50mg, 0.19mmol) with N-(3-aminophenyl) acrylamide (33mg, 0.20mmol) prepare white solid N-(3-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino) phenyl) acrylamide (22mg, 29.7%yield).
1HNMR(DMSO-d
6)δ1.36-1.41(m,2H,CH
2),1.52-1.60(m,4H,2×CH
2),2.45(t,J＝7.1Hz,2H,CH
2),3.42-3.45(m,2H,CH
2),5.71-5.74(m,1H,CH),6.21-6.26(m,1H,CH),6.42-6.49(m,1H,CH),7.14(d,J＝7.2Hz,1H,Ar-H),7.15-7.16(m,1H,Ar-H),7.16-7.18(m,1H,miazine-NH),7.42(d,J＝7.2Hz,1H,Ar-H),8.02(s,1H,Ar-H),7.91(s,1H,miazine-H),9.18(s,1H,benzene-NH),10.01(s,1H,benzene-NH).LC-MS(m/z)385(M+1)。
The preparation of embodiment 104-fluoro-N-methyl-3-nitro aniline
According to method disclosed in embodiment 1, by the fluoro-3-N-methyl-p-nitroaniline of 4-(500mg, 3.20mmol) prepare yellow solid 4-fluoro-N-methyl-3-nitro aniline (300mg, 54.7%yield) with paraformaldehyde (500mg, 13.1mmol).LC-MS(m/z)171(M+1)。
The preparation of embodiment 11N-(the fluoro-3-nitrophenyl of 4-)-N methacrylamide
According to method disclosed in embodiment 2, by 4-fluoro-N-methyl-3-nitro aniline (300mg, 1.76mmol) with acrylate chloride (320mg, 3.56mmol) prepare yellow solid N-(the fluoro-3-nitrophenyl of 4-)-N methacrylamide (300mg, 76.5%yield).LC-MS(m/z)225(M+1)。
The preparation of embodiment 12N-(3-amino-4-fluorophenyl)-N methacrylamide
According to method disclosed in embodiment 3, by N-(the fluoro-3-nitrophenyl of 4-)-N methacrylamide (300mg, 1.34mmol) prepare brown solid N-(3-amino-4-fluorophenyl)-N methacrylamide (200mg, 77.0%yield).LC-MS(m/z)195(M+1)。
The preparation of embodiment 13N-(3-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino)-4-fluorophenyl)-N methacrylamide
According to method disclosed in embodiment 5, by 6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (45mg, 0.17mmol) with N-(3-amino-4-fluorophenyl)-N methacrylamide (45mg, 0.23mmol) prepare white solid N-(3-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino)-4-fluorophenyl)-N methacrylamide (4.5mg, 6.25%yield).
1HNMR(DMSO-d
6)δ1.32-1.35(m,2H,CH
2),1.48-1.56(m,4H,2×CH
2),2.46(t,J＝7.1Hz,2H,CH
2),3.23(s,3H,CH
3),3.29-3.33(m,2H,CH
2),5.57-5.60(m,1H,CH),6.08-6.19(m,2H,CH),6.94-6.97(m,1H,Ar-H),7.26-7.30(m,2H,Ar-H,miazine-NH),7.94(s,1H,miazine-H),7.98-8.01(m,1H,Ar-H),8.71(s,1H,benzene-NH).LC-MS(m/z)417(M+1)。
The preparation of embodiment 14N-(the fluoro-5-nitrophenyl of 2-) acrylamide
According to method disclosed in embodiment 2, by the fluoro-5-N-methyl-p-nitroaniline of 2-(0.3g, 2.0mmol) prepare yellow solid N-(the fluoro-5-nitrophenyl of 2-) acrylamide (0.3g, 71.4%yield) with acrylate chloride (0.27g, 3mmol).LC-MS(m/z)211(M+1)。
The preparation of embodiment 15N-(5-amino-2-fluorophenyl) acrylamide
According to step disclosed in embodiment 3, by N-(the fluoro-5-nitrophenyl of 2-) acrylamide (0.25g, 4.7mmol) prepare brown solid N-(5-amino-2-fluorophenyl) acrylamide (0.1g, 46.7%yield).LC-MS(m/z)181(M+1)。
The preparation of embodiment 16N-(5-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino)-2-fluorophenyl) acrylamide
According to method disclosed in embodiment 5, by 6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (52mg, 0.2mmol) with N-(5-amino-2-fluorophenyl) acrylamide (36mg, 0.2mmol) prepare faint yellow solid N-(5-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino)-2-fluorophenyl) acrylamide (20mg, 25%yield).
1HNMR(DMSO-d
6)δ1.37-1.41(m,2H,CH
2),1.52-1.59(m,4H,2×CH
2),2.46(t,J＝6.9Hz,2H,CH
2),3.39-3.43(m,2H,CH
2),5.77(d,J＝10.29Hz,1H,CH),6.28(d,J＝16.76Hz,1H,CH),6.56-6.63(m,1H,CH),7.12-7.18(m,2H,Ar-H,miazine-NH),7.44(t,J＝4.9Hz,1H,Ar-H),7.91(s,1H,miazine-H),8.35(d,J＝5.16Hz,1H,Ar-H),9.25(s,1H,benzene-NH),9.86(s,1H,benzene-NH).LC-MS(m/z)403(M+1)。
The preparation of embodiment 17N-methyl-3-nitro aniline
According to method disclosed in embodiment 1, prepare yellow solid N-methyl-3-nitro aniline (300mg, 54.5%yield) by 3-N-methyl-p-nitroaniline (500mg, 3.62mmol) and paraformaldehyde (540mg, 14.2mmol).LC-MS(m/z)153(M+1)。
The preparation of embodiment 18N-methyl-N-(3-nitrophenyl) acrylamide
According to method disclosed in embodiment 2, by N-methyl-3-nitro aniline (250mg, 1.64mmol) with acrylate chloride (4444.93mg, mmol) yellow solid N-methyl-N-(3-nitrophenyl) acrylamide (250mg, 73.7%yield) is prepared.LC-MS(m/z)207(M+1)。
The preparation of embodiment 19N-(3-aminophenyl)-N methacrylamide
According to method disclosed in embodiment 3, by N-methyl-N-(3-nitrophenyl) acrylamide (250mg, 1.21mmol) prepare brown solid N-(3-aminophenyl)-N methacrylamide (190mg, 78.5%yield).LC-MS(m/z)177(M+1)。
The preparation of embodiment 20N-(3-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino) phenyl)-N methacrylamide
According to method disclosed in embodiment 5, by 6-(2,5-dichloro pyrimidine-4-base is amino) own nitrile (40mg, 0.15mmol) with N-(3-aminophenyl)-N methacrylamide (40mg, 0.23mmol) prepare white solid N-(3-(the chloro-4-of 5-(5-itrile group amylamine) pyrimidine-2--amino) phenyl)-N methacrylamide (40mg, 64.9%yield).
1HNMR(DMSO-d
6)δ1.34-1.40(m,2H,CH
2),1.51-1.61(m,4H,2×CH
2),2.47(t,J＝7.1Hz,2H,CH
2),3.23(s,3H,CH
3),3.35-3.40(m,2H,CH
2),5.55-5.58(m,1H,CH),6.11-6.14(m,1H,CH),6.15-6.18(m,1H,miazine-NH),6.79-6.81(m,1H,CH),7.27(d,J＝5.6Hz,1H,Ar-H),7.31(t,J＝8.0Hz,1H,Ar-H),7.58(d,J＝8.3Hz,1H,Ar-H),7.86(s,1H,Ar-H),7.94(s,1H,miazine-H),9.4(s,1H,benzene-NH).LC-MS(m/z)399(M+1)。
The preparation of the chloro-N-heptyl-pyrimidine base of embodiment 212,5-bis--4-amine
According to method disclosed in embodiment 4, by 2,4,5-trichloropyrimidine (92mg, 0.05mmol) and positive heptyl amice (57.5mg, 0.05mmol) prepare white solid 2,5-bis-chloro-N-heptyl-pyrimidine base-4-amine (130mg, 98%yield).LC-MS(m/z)262(M+1)。
The preparation of embodiment 22N-(3-(the chloro-4-of 5-(heptyl amice base) pyrimidine-2--amino) phenyl) acrylamide
According to method disclosed in embodiment 5, by 2,5-bis-chloro-N-heptyl-pyrimidine base-4-amine (0.26g, 1mmol) with N-(3-aminophenyl) acrylamide (0.18g, 1.1mmol) prepare gray solid N-(3-(the chloro-4-of 5-(heptyl amice base) pyrimidine-2--amino) phenyl) acrylamide (15mg, 38%yield).LC-MS(m/z)388(M+1)。
The preparation of embodiment 235-(2,5-dichloro pyrimidine-4-base is amino) amyl group-1-alcohol
According to method disclosed in embodiment 4, by 2,4,5-trichloropyrimidine (900mg, 4.92mmol) with 5-amino-1-amylalcohol (500mg, 4.90mmol) prepare white solid 5-(2,5-dichloro pyrimidine-4-base is amino) amyl group-1-alcohol (600mg, 49.0%yield).LC-MS(m/z)250(M+1)。
The preparation of embodiment 24N-(3-(the chloro-4-of 5-(5-hydroxyl amylamine base) pyrimidine-2--amino) phenyl) acrylamide
According to method disclosed in embodiment 5, by 5-(2,5-dichloro pyrimidine-4-base is amino) amyl group-1-alcohol (300mg, 1.20mmol) with N-(3-aminophenyl) acrylamide (230mg, 1.42mmol) prepare white solid N-(3-(the chloro-4-of 5-(5-hydroxyl amylamine base) pyrimidine-2--amino) phenyl) acrylamide (300mg, 66.7%yield).
1HNMR(DMSO-d
6)δ1.28-1.35(m,2H,CH
2),1.40-1.46(m,2H,CH
2),1.53-1.60(m,2H,CH
2),3.36-3.44(m,4H,CH
2),4.35(t,J＝4.96Hz,1H,OH),5.71-5.74(m,1H,CH),6.22-6.26(m,1H,CH),6.43-6.50(m,1H,CH),7.12-7.23(m,3H,Ar-H,miazine-NH),7.46(d,J＝7.76Hz,1H,Ar-H),7.91(s,1H,miazine-H),8.00(s,1H,Ar-H),9.20(s,1H,benzene-NH),10.02(s,1H,benzene-NH).LC-MS(m/z)376(M+1)。
The preparation of embodiment 25N-(5-(the chloro-4-of 5-(5-hydroxyl amylamine base) pyrimidine-2--amino)-2-fluorophenyl) acrylamide
According to method disclosed in embodiment 5, by 5-(2,5-dichloro pyrimidine-4-base is amino) amyl group-1-alcohol (25mg, and N-(5-amino-2-fluorophenyl) acrylamide (20mg 7.60.1mmol), 9.14mmol) prepare gray solid N-(5-(the chloro-4-of 5-(5-hydroxyl amylamine base) pyrimidine-2--amino)-2-fluorophenyl) acrylamide (18mg, 49%yield).
1HNMR(DMSO-d
6)δ1.31-1.34(m,2H,CH
2),1.39-1.46(m,2H,CH
2),1.52-1.59(m,2H,CH
2),3.37-3.43(m,4H,CH
2),4.35(t,J＝4.8Hz,1H,OH),5.75-5.78(m,1H,CH),6.25-6.29(m,1H,CH),6.55-6.62(m,1H,CH),7.11-7.20(m,2H,Ar-H,miazine-NH),7.46-7.48(m,1H,Ar-H),7.91(s,1H,miazine-H),8.32(d,J＝5.1Hz,1H,Ar-H),9.24(s,1H,benzene-NH),9.85(s,1H,benzene-NH).LC-MS(m/z)394(M+1)。
The preparation of embodiment 26N-(5-(the chloro-4-of 5-(5-hydroxyl amylamine base) pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide
According to method disclosed in embodiment 5, by 5-(2,5-dichloro pyrimidine-4-base is amino) amyl group-1-alcohol (115mg, 0.46mmol) with N-(5-amino-2-fluorophenyl)-N methacrylamide (100mg, 0.52mmol) prepare white solid N-(5-(the chloro-4-of 5-(5-hydroxyl amylamine base) pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide (120mg, 55.8%yield).
1HNMR(DMSO-d
6)δ1.29-1.54(m,6H,3×CH
2),3.19(s,3H,CH
3),3.31-3.33(m,4H,2×CH
2),4.33-4.34(m,1H,OH),5.59-5.60(m,1H,CH),6.01-6.07(m,1H,CH),6.16-6.20(m,1H,CH),7.23-7.27(m,2H,Ar-H,miazine-NH),7.60-7.62(m,1H,Ar-H),7.92(s,1H,miazine-H),7.92-7.93(m,1H,Ar-H),9.42(s,1H,benzene-NH).LC-MS(m/z)408(M+1)。
The preparation of embodiment 27N-(5-(thiomorpholine-1,1-dioxide-4-base)-amyl group) phthalic imidine
N-(5-bromine amyl group) phthalic imidine (1.2g, 4mmol) with thiomorpholine-1,1-dioxide (1.08g, 80mmol) and DIPEA (2ml, 11mmol) add in 10mLi-PrOH, stir and be warming up to 105 DEG C of reactions 16 hours.LCMS follows the tracks of reaction.Reaction terminates rear concentrated, adds 50ml water, ultrasonic, filters to obtain white solid N-(5-(thiomorpholine-1,1-dioxide-4-base)-amyl group) phthalic imidine (1.0g, 97%yield).LC-MS(m/z)351(M+1)。
The preparation of embodiment 285-(thiomorpholine-1,1-dioxide-4-base)-amylamine
N-(5-(thiomorpholine-1,1-dioxide-4-base)-amyl group) phthalic imidine (0.7g, 2mmol) is dissolved in 10mL dehydrated alcohol, then adds hydrazine hydrate (2mL, 4mmol).This reaction solution stirs after 16 hours and cools at 95 DEG C, solid is had to separate out, in filtrate, 10ml concentrated hydrochloric acid is added after filtering solids, solid is had to separate out, after filtering solids, filtrate concentrates, and period has solid to separate out, and after filtering solids, filtrate continuation concentrates evaporate to dryness and obtains yellow oil 5-(thiomorpholine-1,1-dioxide-4-base)-amylamine (0.34g, 77%yield).LC-MS(m/z)221(M+1)。
The preparation of embodiment 29N-(2,5-dichloro pyrimidine base-4-base)-5-(thiomorpholine-1,1-dioxide-4-base)-amylamine
2,4,5-trichloropyrimidine (0.28g, 1.55mmol), 5-(thiomorpholine-1,1-dioxide-4-base)-amylamine (0.34g, 1.55mmol) and triethylamine (2mL, 14mmol) are dissolved in 10mL ethanol.This reaction solution is heated to 70 DEG C and stirs reaction end after 4 hours.Washed with diethylether is used after solvent evaporated.Filter to obtain yellow solid N-(2,5-dichloro pyrimidine base-4-base)-5-(thiomorpholine-1,1-dioxide-4-base)-amylamine (0.56g, 98%yield).LC-MS(m/z)368(M+1)。
The preparation of embodiment 30N-(5-(the chloro-4-of 5-(5-(thiomorpholine-1,1-dioxide-4-base)-pentyl amino)-pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide
N-(2,5-dichloro pyrimidine base-4-base)-5-(thiomorpholine-1,1-dioxide-4-base)-amylamine (0.36g, 1mmol), N-(5-amino-2-fluorophenyl)-N methacrylamide (0.19g, 1mmol) be dissolved in 10mL Virahol with trifluoroacetic acid (0.5mL, 3.5mmol).This reaction solution is heated to 90 DEG C and stirs reaction end after 24 hours.Reaction solution pours NaHCO into
3in the aqueous solution, separate out solid.Leave standstill, filter.Crude product is dissolved in ethyl acetate ultrasonic, crude product PE:EA=1:1 crosses chromatography column and obtains white solid N-(5-(the chloro-4-of 5-(5-(thiomorpholine-1,1-dioxide-4-base)-pentyl amino)-pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide (0.11g, 21%yield).
1HNMR(DMSO-d
6)δ1.21-1.27(m,2H,CH
2),1.36-1.42(m,2H,CH
2),1.52-1.57(m,2H,CH
2),2.41(t,J＝7.1Hz,2H,CH
2),2.82-2.84(m,4H,2×CH
2),3.02-3.04(m,4H,2×CH
2),3.19(s,3H,CH
3),3.36-3.38(m,2H,CH
2),5.61(d,J＝10.08Hz,1H,CH),6.03-6.10(m,1H,CH),6.17-6.22(m,1H,CH),7.24-7.28(m,2H,Ar-H,miazine-NH),7.58-7.60(m,1H,Ar-H),7.94(s,1H,miazine-H),7.79(d,J＝5.56Hz,1H,Ar-H),9.44(s,1H,benzene-NH).LC-MS(m/z)526(M+1)。
The preparation of embodiment 313-(2,5-dichloro pyrimidine base-4-is amino)-1-propyl alcohol
Be dissolved in 10mL ethanol by 2,4,5-trichloropyrimidine (0.36g, 2mmol), 3-amino-1-propyl alcohol (150mg, 2mmol) and triethylamine (0.4g, 4mmol), this reaction solution is heated to 75 DEG C and stirs reaction end after 3 hours.With washed with diethylether after solvent evaporated, filter to obtain white solid 3-(2,5-dichloro pyrimidine base-4-is amino)-1-propyl alcohol (0.4g, 75%yield).LC-MS(m/z)222(M+1)。
The preparation of embodiment 32N-(5-(the chloro-4-of 5-(3-hydroxypropylamino) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide
By 3-(2,5-dichloro pyrimidine base-4-is amino) propyl alcohol (0.33g, 1.4mmol), N-(5-amino-2-fluorophenyl)-N methacrylamide (0.3g, 1.5mmol) be dissolved in 10mL Virahol with trifluoroacetic acid (40 μ L, 0.5mmol).This reaction solution is heated to 95 DEG C and stirs after 4 hours, and cooling, adds NaHCO
3the aqueous solution adjusts PH to 6-7, has solid to separate out.Filtration obtains solid ethyl alcohol recrystallization and obtains pale solid N-(5-(the chloro-4-of 5-(3-hydroxypropylamino) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide (400mg, 71%yield).LC-MS(m/z)380(M+1)。
The preparation of embodiment 33N-(5-(4-(3-bromopropyl is amino)-5-chloropyrimide base-2-is amino)-2-fluorophenyl)-N methacrylamide
By N-(5-(the chloro-4-of 5-(3-hydroxypropylamino) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide (0.28g, 0.74mmol) be dissolved in the dried chloroform of 10mL, phosphorus tribromide (0.2g, 0.74mmol) is slowly dripped at 0 DEG C.After this reaction solution stirring at room temperature 1h, with a small amount of cancellation reaction of water, suction filtration, filter cake use water rinses several times, dry, obtain dark red solid crude product N-(5-(4-(3-bromopropyl is amino)-5-chloropyrimide base-2-is amino)-2-fluorophenyl)-N methacrylamide (40mg, 12.2%yield).LC-MS(m/z)443(M+1)。
The preparation of embodiment 34N-(5-(the chloro-4-of 5-(3-(thiomorpholine-1,1-dioxide-4-base)-propylcarbamic)-pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide
By N-(5-(4-(3-bromopropyl is amino)-5-chloropyrimide base-2-is amino)-2-fluorophenyl)-N methacrylamide (40mg, 0.09mmol), 1,1,-dioxy thiomorpholine (27mg, 0.18mmol) be dissolved in 5mLEtOH, then DIPEA (26mg, 0.18mmol) is added.Mixture return stirring 4 hours.Be spin-dried for by reaction solution solvent, EA dissolves again, and organic phase brine It 3 times, organic phase anhydrous sodium sulfate drying, is spin-dried for solvent and obtains crude product.Crude product purified by silica gel chromatography is crossed post purification and is obtained faint yellow solid N-(5-(the chloro-4-of 5-(3-(thiomorpholine-1,1-dioxide-4-base)-propylcarbamic)-pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide (5mg, 11%yield, DCM:MeOH=25:1).
1HNMR(DMSO-d
6)δ1.02-1.04(m,2H,CH
2),2.04-2.05(m,2H,CH
2),3.48(s,3H,CH
3),3.75-3.78(m,10H,5×CH
2),5.64-5.66(m,1H,CH),6.08-6.11(m,1H,CH),6.21-6.25(m,1H,CH),7.43-7.45(m,1H,Ar-H),7.60-7.61(m,1H,Ar-H),7.71-7.72(m,1H,Ar-H),8.23(s,1H,miazine-H),8.55(s,1H,miazine-NH),10.66(s,1H,benzene-NH).LC-MS(m/z)497(M+1)。
The preparation of the chloro-N-of embodiment 352,5-bis-(3-morpholine base propyl group) pyrimidyl-4-amine
According to method disclosed in embodiment 29, by 2,4,5-trichloropyrimidine (183mg, 1mmol) with 3-morpholine-1-propylamine (144mg, 1mmol) prepare the chloro-N-of faint yellow solid 2,5-bis-(3-morpholine base propyl group) pyrimidyl-4-amine (1.73g, 95%yield).LC-MS(m/z)291(M+1)。
The preparation of embodiment 36N-(5-(the chloro-4-of 5-(morpholinyl propylcarbamic) pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide
According to method disclosed in embodiment 30, by 2, the chloro-N-of 5-bis-(3-morpholine base propyl group) pyrimidyl-4-amine (29mg, 0.1mmol) with N-(5-amino-2-fluorophenyl)-N methacrylamide (22mg, 0.11mmol) prepare gray solid N-(5-(the chloro-4-of 5-(morpholinyl propylcarbamic) pyrimidine-2--amino)-2-fluorophenyl)-N methacrylamide (30mg, 67%yield).
1HNMR(DMSO-d
6)δ1.70-1.73(m,2H,CH
2),2.32-2.34(m,6H,CH
2,2×CH
2),3.19(s,3H,CH
3),3.55-3.57(m,4H,2×CH
2),5.62(d,J＝9.34Hz,1H,CH),6.04-6.11(m,1H,CH),6.17-6.22(m,1H,CH),7.27(t,1H,J＝9.37Hz,miazine-NH),7.36-7.42(m,1H,Ar-H),7.58-7.60(m,1H,Ar-H),7.91(s,1H,miazine-H),7.95-7.98(m,1H,Ar-H),9.45(s,1H,benzene-NH).LC-MS(m/z)449(M+1)。
The preparation of the chloro-5-methyl of embodiment 372--4-(4-(pyridin-4-yl) butoxy) pyrimidine
4-(4-pyridyl)-n-butyl alcohol hydrochloride (50mg; 0.27mmol) be dissolved in 3mLDMF; ice bath is cooled to 0 DEG C; then hydrogen sodium (20mg, 0.83mmol) is added, nitrogen protection; react after 10 minutes; add the chloro-5-methylpyrimidine (56mg, 0.34mmol) of 2,4-bis-.This reaction solution at room temperature stirs reaction after 4 hours to be terminated.Add water cancellation, dilute hydrochloric acid adjusts PH4-5, extraction into ethyl acetate, washing, aqueous phase sodium bicarbonate adjusts PH8-10, extraction into ethyl acetate, washing, organic phase is dry, concentrates and obtains the chloro-5-methyl of white solid 2--4-(4-(pyridin-4-yl) butoxy) pyrimidine (34mg, 56.7%yield).LC-MS(m/z)278(M+1).
The preparation of embodiment 38N-(3-(5-methyl-4-(4-(pyridin-4-yl) butoxy) pyrimidine-2--amino) phenyl) acrylamide
According to method disclosed in embodiment 5, by the chloro-5-methyl of 2--4-(4-(pyridin-4-yl) butoxy) pyrimidine (34mg, 0.12mmol) with N-(3-aminophenyl) acrylamide (22mg, 0.14mmol) prepare white solid N-(3-(5-methyl-4-(4-(pyridin-4-yl) butoxy) pyrimidine-2--amino) phenyl) acrylamide (9mg, 18.4%yield).
1HNMR(DMSO-d
6)δ1.64-1.68(m,2H,CH
2),1.72-1.76(m,2H,CH
2),1.98(s,3H,CH
3),2.64-2.66(m,2H,CH
2),4.41-4.43(m,2H,CH
2),5.68(d,J＝10.0Hz,1H,CH),6.20(d,J＝16.8Hz,1H,CH),6.41-6.48(m,1H,CH),7.16(d,J＝3.7Hz,2H,pyridine-H),7.22(d,J＝3.7Hz,2H,pyridine-H),7.31(d,J＝3.2Hz,1H,Ar-H),8.03(s,1H,Ar-H),8.24(s,1H,miazine-H)),8.42-8.46(m,2H,Ar-H),9.31(s,1H,benzene-NH),10.02(s,1H,benzene-NH).LC-MS(m/z)404(M+1)。
The preparation of embodiment 393-(2,5-dichloro pyrimidine base-4-is amino) propionic acid
Be dissolved in 25mL ethanol by 2,4,5-trichloropyrimidine (1.0g, 5.6mmol), L-Ala (500mg, 5.6mmol) and triethylamine (0.2mL, 1.4mmol), this reaction solution is heated to 75 DEG C and stirs reaction end after 3 hours.With washed with diethylether after solvent evaporated, filter to obtain white solid 3-(2,5-dichloro pyrimidine base-4-is amino) propionic acid (1.1g, 83%yield).LC-MS(m/z)236(M+1)。
The preparation of embodiment 403-(the chloro-2-of 5-(the fluoro-3-of 4-(N methacrylamide base) phenyl amino) pyrimidyl-4-is amino) propionic acid
3-(2,5-dichloro pyrimidine base-4-is amino) propionic acid (1.1g, 4.7mmol), N-(5-amino-2-fluorophenyl)-N methacrylamide (1.0g, 5.2mmol) be dissolved in 16mL water and 4mL Virahol with trifluoroacetic acid (0.5mL, 3.5mmol).This reaction solution is heated to 95 DEG C of stirrings and adds NaHCO after 4 hours
3the aqueous solution adjusts PH to 6-7, has solid to separate out.Filtration obtains solid ethyl alcohol recrystallization and obtains gray solid 3-(the chloro-2-of 5-(the fluoro-3-of 4-(N methacrylamide base) phenyl amino) pyrimidyl-4-is amino) propionic acid (350mg, 18%yield).
1HNMR(DMSO-d
6)δ2.56(t,J＝7.1Hz,2H,CH
2),3.59-3.62(m,2H,CH
2),3.12(s,3H,CH
3),5.61(d,J＝10.2Hz,1H,CH),6.03-6.09(m,1H,CH),6.16-6.21(m,1H,CH),7.21(s,1H,Ar-H),7.24-7.28(m,1H,Ar-H),7.71(t,J＝3.4Hz,1H,miazine-NH),7.79-7.82(m,1H,Ar-H),7.99(s,1H,miazine-H),9.47(s,1H,benzene-NH),12.30(s,1H,COOH).LC-MS(m/z)394(M+1)。
Embodiment 41 the enzyme activity detects
Experiment cardinal principle
The ultimate principle of external zymetology Activity determination utilizes fluorescently-labeled specific substrate, under zymogenesis, carry out phosphorylation, and phosphorylated substrate can produce strong and weak different fluorescent signals (445nm and 520nm) with phosphorylated substrate at different wave length.When adding different test compounds, it is presented as the degree of substrate phosphorylation to the suppression of kinase activity, thus shows different fluorescent signals, and with this computerized compound to kinase whose inhibit activities.As shown in Figure 1, Fig. 1 is embodiment of the present invention kinase activity Cleaning Principle schematic diagram to basic Cleaning Principle.
Zymetology inhibit activities detects the people utilizing GST to mark and to recombinate JAKs kinases JAK1/PV4774, JAK2/PV4210, JAK3/PV3855, TYK2/PV4790 and corresponding specific substrate Tyr6 (Z'-thereof
kinaseAssayKit-Tyrosine6Peptide, JAK1/PV4122), Tyr4 (Z'-
kinaseAssayKit-Tyrosine4Peptide, JAK2/PV3193), Tyr4 (Z'-
kinaseAssayKit-Tyrosine4Peptide, JAK3/PV3193), Tyr3 (Z'-
kinaseAssayKit-Tyrosine4Peptide, TYK2/PV3192).Detection reagent is developer A (DevelopmentreagentA, PV3297).Above-mentioned all material is all bought from Invitrogen company.
Experiment main process
The flow process that experimentation requires according to detection reagent working instructions is carried out (Invitrogen).Flow process is as follows:
(1) Preparatory work of experiment: prepare kinase reaction damping fluid (working fluid) as requested, (detect JAK1, JAK2, compound maximum concentration is 10 μMs with kinase reaction damping fluid, test compounds to be diluted to different concns gradient; Detect JAK3, compound maximum concentration is 1 μM).
(2) zymetology reaction system 10 μ L, comprises 2.5 μ L test compounds, 5 μ L kinase reaction damping fluids and 2.5 μ LATP solution (test kit provides), after mixing, and room temperature reaction 1h.
(3) detection reaction is provided with control reaction simultaneously, comprises the positive control not adding 0 of test compounds and suppress contrast, do not add the 0 phosphorylation contrast of ATP and interpolation phosphorylated substrate.All detections adopt multiple hole.
(4), after zymetology reaction terminates, the color reaction damping fluid that 5 μ L prepare in advance is added, room temperature reaction 1h.Add 5 μ L stop buffer termination reactions subsequently.
(5) use fluorescence detector (AscentFluoroskanFLreader, ThermoLabsystems) to detect the fluorescent signal in every hole, excitation wavelength is 400nm, and the emission wavelength of detection is respectively 445nm and 520nm.The ratio of substrate phosphorylation is with reference to fluorescence signal intensity C445/F520.
(6) the zymetology inhibiting rate calculation formula of test compounds: inhibiting rate (%)=1-detect aperture substrate phosphorylation/0 suppresses control wells phosphoric acid rate.
The positive control chosen is CP690550, and structural formula is as follows:
According to above-mentioned experimental technique, carry out external zymetology Activity determination to compound of Formula I of the present invention, experimental result is in table 2, and table 2 provides compound to jak kinase vitro inhibition Activity Results for the embodiment of the present invention.
Table 2 compound of Formula I of the present invention is to jak kinase vitro inhibition Activity Results
| Embodiment | JAK3 | JAK2 | JAK1 |
| CP-690550 | 1 | 1 | 1 |
| 5 | 1.01 | 0 | 0.17 |
| 9 | 0.89 | 0.15 | 0.77 |
| 13 | 0.83 | - | - |
| 16 | 0.99 | 0.23 | 0.69 |
| 20 | 0.98 | 0.09 | 0.54 |
| 22 | 0.78 | - | 0.10 |
| 24 | 0.89 | 0 | 0.88 |
| 25 | 1.18 | 0.11 | 0.76 |
| 26 | 0.93 | 0 | 0.36 |
| 30 | 0.79 | 0.14 | 0.27 |
| 34 | 0.57 | 0.06 | 0.36 |
| 36 | 1.88 | 0 | 0.60 |
| 38 | 0.57 | 0 | 0 |
| 40 | 0.59 | - | 0.23 |
In table 2, the inhibit activities of embodiment compound is the inhibit activities compared with positive control.
In table 2, to JAK3, JAK2, test compounds concentration is 30nM; Detect JAK1, test compounds concentration is 300nM.
As shown in Table 2, compared with full inhibitor C P-690550, compound provided by the invention has selective inhibitory to jak kinase, comparatively remarkable to JAK3 kinase inhibitory activity, and remarkable to JAK2 kinases and JAK1 kinase inhibiting activity, can selective JAK 3 kinases inhibitor be used as.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (17)
1. the pyrimidine derivatives shown in formula (I) and pharmacy acceptable salt thereof:
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or haloalkyl;
R
2be selected from hydrogen, hydroxyl, carboxyl, cyano group, phenyl, 5 ~ 6 yuan of heteroaryls, C
1-6alkyl or haloalkyl, C
1-6alkoxyl group;
R
3be selected from hydrogen, halogen, cyano group, C
1-6one or more of alkyl or haloalkyl;
R
4for hydrogen, C
1-6alkyl or haloalkyl;
X is NH or O;
N is the integer of 1 to 7.
2. pyrimidine derivatives according to claim 1, is characterized in that, R
1for halogen; R
2be selected from the substituting group shown in hydrogen, hydroxyl, carboxyl, cyano group, phenyl, pyridyl, morpholinyl or formula (a);
R
3for hydrogen or fluorine;
R
4for hydrogen or methyl;
X is NH or O;
N is the integer of 1 to 7.
3. pyrimidine derivatives according to claim 1, is characterized in that, has formula (I-a) structure:
Wherein, R
2be selected from the substituting group shown in hydroxyl, carboxyl, cyano group, pyridyl, morpholinyl or formula (a);
N is the integer of 1 to 7.
4. pyrimidine derivatives according to claim 1, is characterized in that, has formula (I-b) structure:
Wherein, R
2be selected from the substituting group shown in hydroxyl, carboxyl, cyano group or formula (a).
5. pyrimidine derivatives according to claim 1, is characterized in that, has formula (1) ~ (14) structure:
6. a preparation method for the pyrimidine derivatives shown in formula (I), comprising:
Shown in formula (IV), shown in compound and formula (V), compound forms pyrimidine derivatives shown in formula (I) under organic solvent and catalyst action;
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or haloalkyl;
R
2be selected from hydrogen, hydroxyl, carboxyl, cyano group, phenyl, 5 ~ 6 yuan of heteroaryls, C
1-6alkyl or haloalkyl, C
1-6alkoxyl group;
R
3be selected from hydrogen, halogen, cyano group, C
1-6one or more of alkyl or haloalkyl;
R
4for hydrogen, C
1-6alkyl or haloalkyl;
X is NH or O;
N is the integer of 1 to 7.
7. preparation method according to claim 6, is characterized in that, described catalyzer is selected from trifluoroacetic acid, hydrochloric acid or methylsulfonic acid.
8. preparation method according to claim 6, is characterized in that, described organic solvent is selected from the alcohol of C1 ~ C6.
9. preparation method according to claim 6, is characterized in that, shown in described formula (IV), compound is prepared in accordance with the following methods:
Compound shown in formula (III) and compound shown in formula (II) form the compound that general formula is (IV) under the effect of organic solvent and alkali;
10. preparation method according to claim 9, is characterized in that, described organic solvent is selected from ethanol, methyl alcohol or propyl carbinol.
11. preparation methods according to claim 9, is characterized in that, described alkali is selected from triethylamine or diisopropyl ethyl amine.
12. 1 kinds of pharmaceutical preparations, comprise pyrimidine derivatives described in Claims 1 to 5 any one or its pharmacy acceptable salt and pharmaceutically acceptable auxiliary material.
13. pharmaceutical preparations according to claim 12, is characterized in that, described preparation is tablet, capsule, pulvis, syrup, liquor, suspension agent, injection or paste.
Pyrimidine derivatives described in 14. Claims 1 to 5 any one or its pharmacy acceptable salt or the application of the pharmaceutical preparation described in claim 12 or 13 in preparation JAK3 kinase inhibitor.
The application in the medicine of preparation prevention or the treatment disease relevant to JAK3 abnormal kinase of pyrimidine derivatives described in 15. Claims 1 to 5 any one or its pharmacy acceptable salt or the pharmaceutical preparation described in claim 12 or 13.
16. application according to claim 15, is characterized in that, described disease is autoimmune disorder, diseases associated with inflammation, cancer, myeloproliferative disease, bone-resorbing disease or organ-graft refection's disease.
17. application according to claim 16, it is characterized in that, described disease is rheumatoid arthritis, Crohn's disease, systemic lupus erythematous, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), psoriatic, anaphylactic disease, asthma, chronic obstructive pulmonary disease, leukemia or lymphoma.
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| CN111728974A (en) * | 2019-03-25 | 2020-10-02 | 深圳微芯生物科技股份有限公司 | Seoroni for treatment of small cell lung cancer |
| WO2021088975A1 (en) * | 2019-11-08 | 2021-05-14 | 深圳微芯生物科技股份有限公司 | Use of compound in preventing or treating graft versus host disease |
| WO2021179959A1 (en) * | 2020-03-09 | 2021-09-16 | 深圳微芯生物科技股份有限公司 | Pharmaceutical composition comprising jak3/jak1/tbk1 inhibitor and methotrexate and use thereof |
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| WO2021179959A1 (en) * | 2020-03-09 | 2021-09-16 | 深圳微芯生物科技股份有限公司 | Pharmaceutical composition comprising jak3/jak1/tbk1 inhibitor and methotrexate and use thereof |
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