CN105399686A - Pyrimidine derivative, preparation method and applications thereof - Google Patents
Pyrimidine derivative, preparation method and applications thereof Download PDFInfo
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Abstract
The present invention provides a pyrimidine derivative represented by a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and applications thereof, wherein the pyrimidine derivative represented by a formula (I), or 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 a JAK3 kinase inhibitor, and can be used for preparation of drugs for prevention 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, 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 selective JAK 3 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,
A is selected from the aromatic nucleus of 6 ~ 10 yuan or the hetero-aromatic ring of 5 ~ 10 yuan;
X is halogen;
R
1one or more independently selected from the alkoxyl group of the alkyl of hydrogen, cyano group, halogen, amino, hydroxyl, C1 ~ C6 or haloalkyl, C1 ~ C6;
R
2one or more independently selected from hydrogen or halogen;
R
3for alkyl or the substituted alkyl of hydrogen or C1 ~ C6;
N is the integer of 1 to 7;
P is the integer of 0 to 3.
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, A is selected from the aromatic nucleus of 6 ~ 10 yuan or the hetero-aromatic ring of 5 ~ 10 yuan, is preferably phenyl ring or pyridine ring.
In the present invention, X is halogen, is preferably chlorine.
In the present invention, R
1one or more independently selected from the alkoxyl group of the alkyl of hydrogen, cyano group, halogen, amino, hydroxyl, C1 ~ C6 or haloalkyl, C1 ~ C6, what be more preferably selected from the haloalkyl of hydrogen, cyano group, halogen, amino, C1 ~ C6 is one or more, R
1for time multiple, it can be identical, also can be different, is preferably different; R
1number be preferably 1 ~ 3, be more preferably 1 ~ 2.Wherein, haloalkyl is preferably the alkyl that fluorine replaces, and the number of fluoro substituents can be multiple; The carbon atom of haloalkyl is preferably 1 ~ 4, is more preferably 1 ~ 3.
In the present invention, R
2one or more independently selected from hydrogen or halogen, are preferably hydrogen or F.
In the present invention, R
3for alkyl or the substituted alkyl of hydrogen or C1 ~ C6, be preferably hydrogen or methyl.
In the present invention, n and p is the number of methylene radical, and n is the integer of 1 to 7, is preferably 2 ~ 4, is more preferably 2 or 4; P is the integer of 0 to 3.
As preferably, in formula (I), A is phenyl ring or pyridine ring; R
1one or more independently selected from hydrogen, cyano group, fluorine, amino, trifluoromethyl; R
2for hydrogen or halogen; R
3for hydrogen or methyl; N is the integer of 1 to 4; P is the integer of 0 to 2.
As preferably, in formula (I), A is phenyl ring or pyridine ring; R
1one or more independently selected from hydrogen, cyano group, fluorine, amino, trifluoromethyl; R
2for hydrogen or fluorine; R
3for hydrogen or methyl; N is the integer of 1 to 4; P is the integer of 0 to 2.
As preferably, in formula (I), A is phenyl ring; One or more independently selected from fluorine, amino, trifluoromethyl of R1; R
2for fluorine; R
3for methyl; N is 4, p is 0.
" 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 above-mentioned pyrimidine derivatives, comprising:
General formula (VI) compound and general formula (VII) compound are formed under organic solvent and catalyst action the compound that general formula is (I);
Wherein,
A is selected from the aromatic nucleus of 6 ~ 10 yuan or the hetero-aromatic ring of 5 ~ 10 yuan;
R
1one or more independently selected from the alkoxyl group of the alkyl of hydrogen, cyano group, halogen, amino, hydroxyl, C1 ~ C6 or haloalkyl, C1 ~ C6;
R
2one or more independently selected from hydrogen or halogen;
R
3for alkyl or the substituted alkyl of hydrogen or C1 ~ C6;
N is the integer of 1 to 7;
P is the integer of 0 to 3.
General formula (VI) compound and general formula (VII) compound condensation obtain the pyrimidine derivatives shown in formula (I), and reaction process is as follows:
This condensation reaction preferably with peptide condensing agent for catalyzer, as 1-ethyl-3-(3-dimethylamine propyl) carbodiimide (EDC), N, N '-dicyclohexylcarbodiimide (DCC), N, N '-phosphinylidyne diimidazole (CDI) etc.Temperature of reaction is preferably 0 ~ 60 DEG C, and the reaction times is preferably 2 ~ 72 hours.Reaction solvent for use is common solvent, as benzene, toluene, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, DMF etc.If desired, alkali can also be added as sodium hydroxide, triethylamine or pyridine.
In the present invention, general formula (VII) compound can directly commercially obtain, and general formula (VI) compound is preferably prepared in accordance with the following methods:
General formula (IV) compound and logical formula V compound are formed the compound that general formula is (VI) under the effect of organic solvent and catalyzer;
General formula (IV) compound and logical formula V compound generation substitution reaction, obtain general formula (VI) compound, reaction process is as follows:
In this substitution reaction, described catalyzer is selected from trifluoroacetic acid, hydrochloric acid or methylsulfonic acid, is preferably trifluoroacetic acid; Temperature of reaction is backflow, and the reaction times is 8-16 hour.Reacting common solvent used is Virahol, propyl carbinol etc.
General formula (IV) compound can be prepared in accordance with the following methods:
General formula (II) compound and general formula (III) compound generation substitution reaction, obtain general formula (IV) compound, reaction process is as follows:
Wherein, general formula (II) compound and general formula (III) compound are market can directly purchase available raw material, and it in the presence of base substitution reaction occurs.Temperature of reaction is backflow, and the reaction times is 8-16 hour.Reacting common solvent used is ethanol, methyl alcohol, propyl carbinol etc.Alkali is triethylamine, diisopropyl ethyl amine etc.
Logical formula V compound can be prepared in accordance with the following methods:
The condensation under diisopropyl ethyl amine exists of general formula (VIII) compound and acrylate chloride obtains general formula (IX) compound, after reduction, obtain logical formula V compound.
General formula (VIII) compound can directly commercially obtain, the condensation under diisopropyl ethyl amine exists of itself and acrylate chloride obtains general formula (IX) compound, general formula (IX) compound must logical formula V compound through iron powder reducing nitro, and reaction process is as follows:
After general formula (VI) compound and general formula (VII) compound condensation obtain the 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 of 2-(20.0g, 128.2mmol) with paraformaldehyde (16.0g, 533.3mmol) be dissolved in 500mL methyl alcohol in stirred at ambient temperature, then NaOMe (3.4g is dripped, methanol solution 100mL 63mmol), after this reaction solution at room temperature stirs 16 hours, point two deciles add NaBH
4(9.7g, 255.2mmol), stir 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) with DIPEA (23mL, 129.4mmol) be dissolved in 100mLTHF in stirred at ambient temperature, then acrylate chloride (11mL is dripped, 129.4mmol), 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 add the ethyl acetate solution 20mL of N-(the fluoro-5-nitrophenyl of 2-)-N methacrylamide (12g, 53.6mmol).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 43-(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 53-(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-d6)δ2.56(t,J＝7.1Hz,2H,CH2),3.59-3.62(m,2H,CH2),3.12(s,3H,CH3),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)。
The preparation of embodiment 6N-(5-(4-(3-(4-cyanobenzyls is amino)-3-oxopropyl is amino)-5-chloropyrimide base-2-is amino)-2-fluorophenyl)-N methacrylamide
By 3-(the chloro-2-of 5-(the fluoro-3-of 4-(N methacrylamide base) phenyl amino) pyrimidyl-4-is amino) propionic acid (200mg, 0.51mmol), 4-(amine methyl) cyanophenyl hydrochloride (110mg, 0.65mmol) be dissolved in 10mLDMF, then DIPEA (0.3mL is added, 1.7mmol), I-hydroxybenzotriazole (103mg, 0.76mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (200mg, 1.05mmol), mixture at room temperature stirs 20 hours, then uses NaHCO
3aqueous solution adjust pH is to 8-10.Solid is had to separate out, filtration obtains gray solid N-(5-(4-(3-(4-cyanobenzyls is amino)-3-oxopropyl is amino)-5-chloropyrimide base-2-is amino)-2-fluorophenyl)-N methacrylamide (220mg, 79%yield).1HNMR(DMSO-d6)δ2.54(t,J＝6.6Hz,2H,CH2),3.18(s,3H,CH3),3.64-3.66(m,2H,CH2),4.36(d,J＝5.7Hz,2H,CH2),5.60(d,J＝10.1Hz,1H,CH),6.04-6.10(m,1H,CH),6.18-6.22(m,1H,CH),7.18-7.22(m,1H,Ar-H),7.21(t,J＝10.0Hz,1H,NH),7.41(d,J＝8.0Hz,2H,Ar-H),7.71(s,1H,Ar-H),7.74(d,J＝8.1Hz,2H,Ar-H),7.85(d,J＝5.4Hz,1H,Ar-H),7.97(s,1H,miazine-H),8.52(t,J＝5.7Hz,1H,miazine-NH),9.44(s,1H,benzene-NH).LC-MS(m/z)508(M+1)。
The preparation of embodiment 73-(2-(1H-benzo [d] [1,2,3] triazole-1-oxygen base)-5-chloropyrimide base-4-is amino)-N-(2,3,6-tri-flunamine) propionic acid amide
3-(2,5-dichloro pyrimidine-4-is amino) propionic acid (0.5g, 2.1mmol) He 2,3,6-tri-flunamine (0.34g, 2.1mmol) is dissolved in 10mLDMF, add EDC (0.8g successively again, 4.2mmol), HOBt (0.35g, 2.5mmol), in room temperature for overnight.Thin up, separates out solid, filters to obtain yellow solid 3-(2-(1H-benzo [d] [1,2,3] triazole-1-oxygen base)-5-chloropyrimide base-4-amino)-N-(2,3,6-tri-flunamine) propionic acid amide (0.16g, 16%yield).LC-MS(m/z)478(M+1)。
The preparation of embodiment 8N-(5-(4-(3-(2,3,6-trifluoro-benzyl is amino)-3-oxopropyl is amino)-5-chloropyrimide base-2-is amino)-2-fluorophenyl)-N methacrylamide
By 3-(2-(1H-benzo [d] [1,2,3] triazole-1-oxygen base)-5-chloropyrimide base-4-amino)-N-(2,3,6-tri-flunamine) propionic acid amide (0.16g, 0.34mmol), N-(5-amino-2-fluorophenyl)-N methacrylamide (0.07g, 0.34mmol) and trifluoroacetic acid (40 μ L, 0.5mmol) are dissolved in 5mL Virahol.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, EA extraction, and organic phase washed with water, anhydrous sodium sulfate drying, is spin-dried for solvent and obtains crude product.Crude product chromatography column is crossed post and to be purified to obtain faint yellow look solid N-(5-(4-(3-(2,3,6-trifluoro-benzyl is amino)-3-oxopropyl amino)-5-chloropyrimide base-2-amino)-2-fluorophenyl)-N methacrylamide (72.7mg, 39.9%yield, PE:EA=1:1).1HNMR(DMSO-d6)δ2.44(t,J＝6.7Hz,2H,CH2),3.18(s,3H,CH3),3.56-3.62(m,2H,CH2),4.34(d,J＝4.8Hz,2H,CH2),5.59(d,J＝9.6Hz,1H,CH),6.02-6.09(m,1H,CH),6.17-6.21(m,1H,CH),7.06-7.11(m,2H,Ar-H),7.19(t,J＝9.3Hz,1H,NH),7.37-7.45(m,1H,Ar-H),7.72-7.73(m,1H,Ar-H),7.78-7.80(m,1H,Ar-H),7.94(s,1H,miazine-H),8.38(m,J＝4.9Hz,1H,miazine-NH),9.41(s,1H,benzene-NH).LC-MS(m/z)537(M+1)。
The preparation of embodiment 9N-(3-nitrophenyl) acrylamide
According to the method for 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 10N-(3-aminophenyl) acrylamide
According to the method for 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 113-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) propionic acid
According to method disclosed in embodiment 5, by 3-(2,5-dichloro pyrimidine base-4-is amino) propionic acid (0.23g, 1mmol) with N-(3-aminophenyl) acrylamide (0.18g, 1.1mmol) prepare gray solid 3-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) propionic acid (0.23g, 65%yield).LC-MS(m/z)362(M+1)。
The preparation of embodiment 12N-(3-(the chloro-4-of 5-(3-oxygen-3-(pyridyl-4-methyl amido) propylcarbamic) pyrimidyl-2-is amino) phenyl) acrylamide
According to method disclosed in embodiment 6, by 3-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) propionic acid (36mg0.1mmol) and 4-aminomethyl-pyridine (43mg, 0.4mmol) prepare white solid N-(3-(the chloro-4-of 5-(3-oxygen-3-(pyridyl-4-methyl amido) propylcarbamic) pyrimidyl-2-is amino) phenyl) acrylamide (26mg, 58%yield).1HNMR(DMSO-d6)δ2.58(t,J＝6.8Hz,2H,CH2),3.72-3.74(m,2H,CH2),4.31(d,J＝5.6Hz,2H,CH2),5.66(d,J＝10.2Hz,1H,CH),6.22(d,J＝16.8Hz,1H,CH),6.45-6.50(m,1H,CH),7.14(t,J＝8.2Hz,1H,Ar-H),7.16-7.20(m,1H,NH),7.22(d,J＝4.7Hz,2H,Ar-H),7.35(d,J＝8.0Hz,2H,Ar-H),7.95(s,1H,miazine-H),8.04(s,1H,Ar-H),8.46(d,J＝4.8Hz,2H,Ar-H),8.64(t,J＝5.8Hz,1H,miazine-NH),9.27(s,1H,benzene-NH),10.03(s,1H,benzene-NH).LC-MS(m/z)452(M+1)。
The preparation of embodiment 13N-(5-(the chloro-4-of 5-(3-oxygen-3-(pyridyl-4-methyl amido) propylcarbamic) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide
According to method disclosed in embodiment 6, by 3-(the chloro-2-of 5-(the fluoro-3-of 4-(N methacrylamide base) phenyl amino) pyrimidyl-4-is amino) propionic acid (30mg, 0.08mmol) with 4-aminomethyl-pyridine (13mg, 0.12mmol) prepare white solid N-(5-(the chloro-4-of 5-(3-oxygen-3-(pyridyl-4-methyl amido) propylcarbamic) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide (7mg, 16.4%yield).1HNMR(DMSO-d6)δ2.63-2.65(m,2H,CH2),3.19(s,3H,CH3),3.51-3.56(m,2H,CH2),4.39-4.41(m,2H,CH2),5.62(d,J＝3.29Hz,1H,CH),6.08-6.21(m,2H,CH),7.22-7.24(m,4H,Ar-H),7.71-7.72(m,1H,Ar-H),7.76-7.86(m,1H,Ar-H),7.91-7.98(m,1H,Ar-H),8.47(s,1H,miazine-H),8.56-8.58(m,2H,miazine-NH，NH),9.49(s,1H,benzene-NH).LC-MS(m/z)484(M+1).
The preparation of embodiment 14N-(5-(the chloro-4-of 5-(3-oxygen-3-(pyridyl-4-ethyl amido) propylcarbamic) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide
According to method disclosed in embodiment 6, by 3-(the chloro-2-of 5-(the fluoro-3-of 4-(N methacrylamide base) phenyl amino) pyrimidyl-4-is amino) propionic acid (30mg, 0.08mmol) with 4-aminoethyl pyridine (15mg, 0.12mmol) prepare white solid N-(5-(the chloro-4-of 5-(3-oxygen-3-(pyridyl-4-ethyl amido) propylcarbamic) pyrimidyl-2-is amino)-2-fluorophenyl)-N methacrylamide (5mg, 12.6%yield).1HNMR(DMSO-d6)δ2.39(t,J＝6.6Hz,2H,CH2),2.72(t,J＝7.0Hz,2H,CH2),3.18(s,3H,CH3),3.28-3.34(m,2H,CH2),3.55-3.60(m,2H,CH2),5.60(d,J＝10.4Hz,1H,CH),6.05-6.09(m,1H,CH),6.16-6.20(m,1H,CH),7.16-7.18(m,1H,NH),7.20(d,J＝5.6Hz,2H,Ar-H),7.24-7.27(m,1H,Ar-H),7.66-7.71(m,1H,Ar-H),7.84-7.86(m,1H,Ar-H),7.94(s,1H,miazine-H),7.96-7.98(m,1H,miazine-NH),8.43(d,J＝5.5Hz,2H,Ar-H),9.42(s,1H,benzene-NH).LC-MS(m/z)498(M+1)。
The preparation of embodiment 155-(2,5-dichloro pyrimidine base-4-is amino) valeric acid
According to method disclosed in embodiment 4, by 2,4,5-trichloropyrimidine (156mg, 0.85mmol) with 5-aminovaleric acid (100mg, 0.85mmol) prepare white solid 5-(2,5-dichloro pyrimidine base-4-is amino) valeric acid (200mg, 80.5%yield).LC-MS(m/z)264(M+1)。
The preparation of embodiment 165-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) valeric acid
According to method disclosed in embodiment 5, by 5-(2,5-dichloro pyrimidine base-4-is amino) valeric acid (100mg, 0.38mmol) with N-(3-aminophenyl) acrylamide (62mg, 0.38mmol) prepare white solid 5-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) valeric acid (60mg, 40.5%yield).LC-MS(m/z)390(M+1)。
The preparation of embodiment 175-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(pyridyl-4-methyl) valeramide
According to method disclosed in embodiment 6, by 5-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) valeric acid (30mg, 0.08mmol) with 4-aminomethyl-pyridine (12mg, 0.12mmol) prepare white solid 5-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(pyridyl-4-methyl) valeramide (19mg, 51.5%yield).1HNMR(DMSO-d6)δ1.55-1.60(m,4H,2×CH2),2.19-2.21(m,2H,CH2),3.42-3.44(m,2H,CH2),4.26(d,J＝5.91Hz,2H,CH2),5.69-5.72(m,1H,CH),6.21-6.25(m,1H,CH),6.42-6.49(m,1H,CH),7.09-7.28(m,5H,miazine-NH,Ar-H),7.45(d,J＝7.88Hz,1H,Ar-H),7.91(s,1H,miazine-H),8.06(s,1H,Ar-H),8.39(t,J＝5.88Hz,1H,NH),8.45(d,J＝5.84Hz,2H,Ar-H),9.19(s,1H,benzene-NH),10.04(s,1H,benzene-NH).LC-MS(m/z)480(M+1)。
The preparation of embodiment 185-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(2-aminophenyl) valeramide
According to method disclosed in embodiment 6, by 5-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) valeric acid (39mg0.1mmol) and O-Phenylene Diamine (43mg, 0.4mmol) prepare white solid 5-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(2-aminophenyl) valeramide (30mg, 62%yield).1HNMR(DMSO-d6)δ1.60-1.64(m,4H,2×CH2),2.31-2.35(m,2H,CH2),3.43-3.47(m,2H,CH2),4.80(s,2H,NH2),5.70(d,J＝9.48Hz,1H,CH),6.23(d,J＝16.84Hz,1H,CH),6.41-6.45(m,1H,CH),6.49-6.51(m,1H,Ar-H),6.69-6.71(m,1H,Ar-H),6.87-6.93(m,1H,Ar-H),7.13-7.45(m,4H,Ar-H),7.44-7.46(m,1H,miazine-NH),7.91(s,1H,miazine-H),7.99(s,1H,Ar-H),9.07(s,1H,benzene-NH),9.19(s,1H,benzene-NH),10.01(s,1H,benzene-NH).LC-MS(m/z)480(M+1)。
The preparation of embodiment 195-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(2-amino-4-fluorophenyl) valeramide
According to method disclosed in embodiment 6, by 5-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) valeric acid (39mg0.1mmol) and 4-fluorine O-Phenylene Diamine (50mg, 0.4mmol) prepare yellow solid 5-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(2-amino-4-fluorophenyl) valeramide (25mg, 50%yield).1HNMR(DMSO-d6)δ1.60-1.64(m,4H,2×CH2),2.31-2.35(m,2H,CH2),3.44-3.48(m,2H,CH2),5.13(s,2H,NH2),5.72(d,J＝9.76Hz,1H,CH),6.25(d,J＝16.64Hz,1H,CH),6.27-6.28(m,1H,Ar-H),6.43-6.50(m,2H,CH，Ar-H),7.03-7.20(m,4H,Ar-H),7.46-7.48(m,1H,miazine-NH),7.92(s,1H,miazine-H),8.02(s,1H,Ar-H),9.03(s,1H,benzene-NH),9.21(s,1H,benzene-NH),10.04(s,1H,benzene-NH).LC-MS(m/z)498(M+1)。
The preparation of embodiment 205-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(2-amino-4-trifluoromethyl) valeramide
According to method disclosed in embodiment 6, by 5-(2-(3-acrylamido phenyl amino) the chloro-pyrimidyl of-5--4-is amino) valeric acid (39mg0.1mmol) and 4-trifluoromethyl O-Phenylene Diamine (70mg, 0.4mmol) prepare black solid 5-(2-(3-acrylamide phenyl amino)-5-chloropyrimide base-4-is amino)-N-(2-amino-4-trifluoromethyl) valeramide (32mg, 69%yield).1HNMR(DMSO-d6)δ1.60-1.64(m,4H,2×CH2),3.38-3.40(m,2H,CH2),3.45-3.47(m,2H,CH2),5.63(s,2H,NH2),5.69(d,J＝10.1Hz,1H,CH),6.23(d,J＝16Hz,1H,CH),6.44-6.50(m,1H,CH),6.8(d,J＝8.4Hz,1H,Ar-H),7.14-7.15(m,1H,Ar-H),7.16(s,1H,Ar-H),7.18-7.20(m,1H,Ar-H),7.20-7.22(m,1H,Ar-H),7.45(d,J＝7.7Hz,1H,Ar-H),7.63-7.65(m,1H,miazine-NH),7.90(s,1H,miazine-H),8.02(s,1H,Ar-H),9.18(s,1H,benzene-NH),9.23(s,1H,benzene-NH),10.06(s,1H,benzene-NH).LC-MS(m/z)548(M+1).
The preparation of embodiment 21N-(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 22N-(5-amino-2-fluorophenyl) acrylamide
According to method 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 235-(2-(3-acrylamido-4-Fluorophenylamino)-5-chloropyrimide base-4-is amino) valeric acid
According to method disclosed in embodiment 5, by 5-(2,5-dichloro pyrimidine base-4-is amino) valeric acid (53mg, 0.2mmol) with N-(5-amino-2-fluorophenyl) acrylamide (40mg, 0.4mmol) prepare gray solid 5-(2-(3-acrylamido-4-Fluorophenylamino)-5-chloropyrimide base-4-is amino) valeric acid (40mg, 50%yield).LC-MS(m/z)408(M+1)。
The preparation of embodiment 245-(2-(3-acrylamide-4-Fluorophenylamino)-5-chloropyrimide base-4-is amino)-N-(2-amino-4-fluorophenyl) valeramide
According to method disclosed in embodiment 6, by 5-(2-(3-acrylamido-4-Fluorophenylamino)-5-chloropyrimide base-4-is amino) valeric acid (40mg, 0.1mmol) with 4-fluorine O-Phenylene Diamine (50mg, 0.4mmol) prepare white solid 5-(2-(3-acrylamide-4-Fluorophenylamino)-5-chloropyrimide base-4-is amino)-N-(2-amino-4-fluorophenyl) valeramide (30mg, 60%yield).1HNMR(DMSO-d6)δ1.49-1.61(m,4H,2×CH2),2.36-2.38(m,2H,CH2),3.36-3.38(m,2H,CH2),5.26(s,2H,NH2),5.73(d,J＝9.9Hz,1H,CH),6.26(d,J＝15.6Hz,2H,Ar-H),6.48(d,J＝10.6Hz,1H,CH),6.49-6.64(m,1H,CH),7.12-7.14(m,1H,Ar-H),7.15-7.16(m,1H,Ar-H),7.20-7.22(m,1H,Ar-H),7.48-7.49(m,1H,miazine-NH),7.94(s,1H,miazine-H),8.27(s,1H,Ar-H),9.24(s,1H,benzene-NH),9.30(s,1H,benzene-NH),9.95(s,1H,benzene-NH).LC-MS(m/z)516(M+1)。
Embodiment 25 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 detect the people utilizing GST to mark recombinate JAKs kinases JAK1/PV4774, JAK2/PV4210, JAK3/PV3855, TYK2/PV4790 and corresponding specific substrate Tyr6 thereof (
kinaseAssayKit-Tyrosine6Peptide, JAK1/PV4122), Tyr4 (
kinaseAssayKit-Tyrosine4Peptide, JAK2/PV3193), Tyr4 (
kinaseAssayKit-Tyrosine4Peptide, JAK3/PV3193), Tyr3 (
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 |
| 6 | 0.88 | 0.03 | 0.50 |
| 8 | 0.88 | 0 | 0.11 |
| 12 | 1.06 | 0 | 0.11 |
| 13 | 0.69 | 0 | 0.26 |
| 14 | 1.03 | 0.04 | 0.27 |
| 17 | 0.70 | 0 | 0.24 |
| 18 | 1.08 | 0 | 0.88 |
| 19 | 1.22 | 0.09 | 0.87 |
| 20 | 0.65 | 0 | 0.48 |
| 24 | 1.12 | 0.07 | 0.7 |
In table 1, the inhibit activities of embodiment compound is the inhibit activities compared with positive control.
In table 1, to JAK3, JAK2, test compounds concentration is 30nM; Detect JAK1, test compounds concentration is 300nM.
As shown in Table 1, 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) or its pharmacy acceptable salt:
Wherein,
A is selected from the aromatic nucleus of 6 ~ 10 yuan or the hetero-aromatic ring of 5 ~ 10 yuan;
X is halogen;
R
1one or more independently selected from the alkoxyl group of the alkyl of hydrogen, cyano group, halogen, amino, hydroxyl, C1 ~ C6 or haloalkyl, C1 ~ C6;
R
2one or more independently selected from hydrogen or halogen;
R
3for alkyl or the substituted alkyl of hydrogen or C1 ~ C6;
N is the integer of 1 to 7;
P is the integer of 0 to 3.
2. pyrimidine derivatives according to claim 1, is characterized in that, Ar is phenyl ring or pyridine ring.
3. pyrimidine derivatives according to claim 1, is characterized in that, R
1one or more independently selected from hydrogen, cyano group, fluorine, amino, trifluoromethyl, R
2be selected from hydrogen or fluorine, R
3be selected from hydrogen or methyl.
4. pyrimidine derivatives according to claim 1, is characterized in that, A is phenyl ring; R
1one or more independently selected from fluorine, amino, trifluoromethyl; R
2for fluorine; R
3for methyl; N is 4, p is 0.
5. pyrimidine derivatives according to claim 1, is characterized in that, has formula (1) ~ formula (10) structure:
6. a preparation method for the pyrimidine derivatives shown in formula (I), comprising:
General formula (VI) compound and general formula (VII) compound are formed under organic solvent and catalyst action the compound that general formula is (I);
Wherein,
A is selected from the aromatic nucleus of 6 ~ 10 yuan or the hetero-aromatic ring of 5 ~ 10 yuan;
R
1one or more independently selected from the alkoxyl group of the alkyl of hydrogen, cyano group, halogen, amino, hydroxyl, C1 ~ C6 or haloalkyl, C1 ~ C6;
R
2one or more independently selected from hydrogen or halogen;
R
3for alkyl or the substituted alkyl of hydrogen or C1 ~ C6;
N is the integer of 1 to 7;
P is the integer of 0 to 3.
7. preparation method according to claim 6, is characterized in that, described catalyzer is selected from 1-ethyl-3-(3-dimethylamine propyl) carbodiimide, N, N '-dicyclohexylcarbodiimide or N, N '-phosphinylidyne diimidazole.
8. preparation method according to claim 6, is characterized in that, described organic solvent is selected from benzene, toluene, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride, chloroform or DMF.
9. preparation method according to claim 6, is characterized in that, described general formula (VI) compound is prepared in accordance with the following methods:
General formula (IV) compound and logical formula V compound are formed the compound that general formula is (VI) under the effect of organic solvent and catalyzer;
10. preparation method according to claim 9, is characterized in that, described catalyzer is selected from trifluoroacetic acid, hydrochloric acid or methylsulfonic acid.
11. preparation methods according to claim 9, is characterized in that, described organic solvent is selected from Virahol or propyl carbinol.
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 11 or 12 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 11 or 12.
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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| CN111153938A (en) * | 2018-11-08 | 2020-05-15 | 香港理工大学深圳研究院 | Chiral monodentate benzimidazole-indolylphosphine ligand compound and preparation method and application thereof |
| 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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| CN111153938A (en) * | 2018-11-08 | 2020-05-15 | 香港理工大学深圳研究院 | Chiral monodentate benzimidazole-indolylphosphine ligand compound and preparation method and application thereof |
| 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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| CN105399686B (en) | 2018-05-22 |
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Address after: 518057 room 601-606, building 2, Shenzhen biological incubator, ten Nanshan District high tech Middle Road, Shenzhen, Guangdong, China Patentee after: Shenzhen microbiology Polytron Technologies Inc Address before: 518057 room 601-606, building 2, Shenzhen biological incubator, ten Nanshan District high tech Middle Road, Shenzhen, Guangdong, China Patentee before: Shenzhen Weixin Biological Science and Technology Co., Ltd. |