CN112225729B - Pyrimidine derivative, preparation method and application thereof and pharmaceutical composition - Google Patents
Pyrimidine derivative, preparation method and application thereof and pharmaceutical composition Download PDFInfo
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Abstract
The invention relates to the technical field of chemical medicines, in particular to a pyrimidine derivative, a preparation method and application thereof and a pharmaceutical composition. The structural formula of the pyrimidine derivative is shown as follows:
wherein R is1And R1Each independently selected from any one of substituted or unsubstituted alkyl, H, and substituted or unsubstituted cycloalkyl; r2And R2Each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, halo, -NH2、‑NO2and-CN; r3、R3＇、R4And R4Each independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a pyrimidine derivative, a preparation method and application thereof and a pharmaceutical composition.
Background
Protein kinase is an important messenger of cell life activity, can catalyze and transfer gamma-phosphate group at the end of ATP to substrate, influence the structure and activity of the substrate, and transmit various intracellular and extracellular signals to make proper response to environmental stimulus. In most cases, this phosphorylation reaction occurs at a serine (ser), threonine (thr), or tyrosine (tyr) residue of a protein kinase. At least 538 protein kinases are found in humans, whereas more than 900 genes encoding proteins with kinase activity account for approximately 2.5% of the human genome. Protein kinases are involved in a wide variety of physiological regulatory processes including cell survival, proliferation, differentiation, apoptosis, metabolism, and the like. Pathological and pharmacological studies have shown that the dysfunction of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory reactions, central nervous system diseases, cardiovascular diseases and diabetes.
The study of kinase inhibitors plays an important role in the elucidation of the mechanism of action of kinases and has become an important hotspot in drug research. Kinases have been extensively studied by researchers as a very potential drug target in the last 30 years. By 4 months of 2020, FDA approved 59 small molecule inhibitors of kinases for marketing, again provoking the rise of targeted drugs for the treatment of cancer and other diseases.
PLK4 is a major regulator of centromeric replication and plays a key role in the process of centrosomal replication. Previous studies have shown that interfering RNA-mediated loss of PLK4 results in blocked centrosome replication, while over-expressed PLK4 results in amplification of the centrosome by producing an excess of centrosomes. In normal cells in the dividing phase, the expression level of PLK4 was high, whereas in normal non-dividing cells, the protein was hardly expressed. Since tumor cells are a class of cells whose proliferation/division is in an uncontrolled state, PLK4 is highly expressed in a variety of malignancies including breast, myeloma, and colorectal cancers. Further studies in tumors have shown that aberrant expression of PLK4 can result in a variation in the number of centromeres, resulting in a potential failure of chromosomes to normally partition into daughter cells during cell division, thus inducing genomic instability, one of the most prominent malignant phenotypes of tumors. Therefore, the molecule has an important role in the development and development of tumors. In addition, studies suggest that of PTEN-deficient tumor cells, tumor cells with malignant phenotype were dependent on PLK4 for survival. Suggesting a synthetic lethal effect between PLK4 and PTEN. PLK4 may therefore be a molecular target for the treatment of tumours, in particular for the treatment of PTEN-deficient tumours. Few reports have been made to date on small molecule inhibitors of PLK4, and their backbone diversity is insufficient. Therefore, a high-selectivity PLK4 small-molecule inhibitor with better drugability is searched and used for developing anti-tumor research and research on action mechanism, and needs to be carried out.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a novel pyrimidine derivative, a preparation method and application thereof and a pharmaceutical composition, wherein the novel pyrimidine derivative has an excellent inhibition effect on kinase, particularly has a remarkable inhibition effect on PLK4, and can inhibit tumor growth.
The invention is realized by the following steps:
in a first aspect, the embodiments of the present invention provide a pyrimidine derivative, which is a compound represented by | or | a, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof;
wherein R is1And R1Each independently selected from any one of substituted or unsubstituted alkyl, H, and substituted or unsubstituted cycloalkyl;
R2and R2Each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, halo, -NH2、-NO2and-CN;
R3、R3＇、R4and R4Each independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
And any one of Y-X; wherein R is5And R5Each independently selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group, and Y is-O-, -S-, NH-, -C-O-, -S-O-, and-SO2-X is any of a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl and ester group.
In a second aspect, the embodiments of the present invention further provide a method for preparing the above pyrimidine derivative, wherein the pyrimidine derivative is synthesized according to the following synthetic route;
in a third aspect, the embodiments of the present invention further provide a pharmaceutical composition, which includes the above pyrimidine derivative or the compound prepared by the above preparation method of the pyrimidine derivative;
preferably, the pharmaceutical composition comprises pharmaceutically acceptable excipients;
preferably, the pyrimidine derivative is present in the pharmaceutical composition in a form that is also a prodrug thereof.
In a fourth aspect, the embodiment of the invention also provides an application of the pyrimidine derivative in preparing a medicament for treating tumors or preparing a kinase inhibitor.
The invention has the following beneficial effects: the embodiment of the invention provides a novel pyrimidine derivative which has a good inhibition effect on protein kinase, particularly has a remarkable inhibition effect on PLK4, and can effectively treat cancers.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides a pyrimidine derivative which is a compound shown as the following formula, a tautomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein the structural formula of the pyrimidine derivative is shown as follows:
R2and R2Each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, halo, -NH2、-NO2and-CN;
R3、R3＇、R4and R4Each independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
And any one of Y-X; wherein R is5And R5Each independently selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group, and Y is-O-, -S-, NH-, C-O, S-O, and-SO2-X is any of substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, methylenearyl, methyleneheteroaryl, carbonyl and ester groups.
More preferably, R1And R1Each independently selected from the group consisting of C1-C4 substituted alkyl, C1-C4 unsubstituted alkyl and C3-C5 substituted cycloalkyl; for example, the substituted alkyl group of C1-C4 may be a trifluoromethyl group, the unsubstituted alkyl group of C1-C4 may be a methyl group, and the substituted cycloalkyl group of C3-C5 may be a cyclopropyl group or a cyclohexyl group. It is understood that other C1-C4 substituted alkyls, such as ethyl, propyl, isopropyl, and substituted ethyl, C1-C4 unsubstituted alkyls, and C3-C5 substituted cycloalkyls are within the scope of the embodiments of the present invention.
Preferably, R2And R2' respectivelyIndependently selected from C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 alkyl and C3-C8 cycloalkyl, for example, R2And R2Each independently selected from methyl, isopropyl, -CF3or-OCF3. It is understood that C1-C8 alkoxy groups such as methoxy, ethoxy, and propoxy; C1-C8 alkylamino such as methylamino, ethylamino, propylamino, etc.; C3-C8 cycloalkyl groups such as cyclohexyl, cyclopentyl and cyclopropyl; C1-C8 alkyl groups such as n-hexyl, n-pentyl, isopropyl and n-propyl are all within the scope of the embodiments of the present invention.
Preferably, X is a C1-C8 carbonyl group, a C1-C8 ester group and-CH2-R6Wherein R is6Independently any one of substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
r3 and R3' are independently selected from any one of the following groups;
wherein Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R7and R7Each independently selected from any one of halo, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and-CN; for example, R7And R7The substituted alkyl group is a trifluoromethyl group and the unsubstituted alkyl group is an isopropyl group.
Most preferably, R1 and R1' are each methyl; r3 and R3' are each independently
Further, the pyrimidine derivative is selected from any one of the following compounds:
the embodiment of the invention also provides a preparation method of the pyrimidine derivative, and the specific synthetic route is as follows:
more preferably, the reaction conditions are: (a) DMA, potassium bicarbonate, 45 ℃ or 1, 4-dioxane, water 4:1, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, potassium carbonate, 95 ℃ and a (hetero) aryl, arylboronic acid or vinyl boronic acid ester containing R4; (b) an amino pyrazole intermediate containing R2, triethylamine and toluene, wherein the temperature is 80 ℃; (c) DMF, potassium carbonate, 80 ℃ and contains R3An intermediate of (1); (d)1, 4-dioxane, water 4:1, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, potassium carbonate and a (hetero) aryl, arylboronic acid or vinylboronic acid ester containing R3 at 95 ℃.
Specifically, the synthesis steps are as follows:
the method comprises the following steps:
prepared by nucleophilic substitution reaction, 1A (1eq.) is dissolved in DMA, and R is added4Adding potassium bicarbonate (2-3eq.) into nucleophilic reagent (1.2-1.5eq.) to react at 45-60 deg.C for more than 24 hr, extracting with ethyl acetate, drying, and performing column chromatography to obtain intermediate 1B (1B has a structural formula:
). Or prepared by Suzuki coupling reaction, the compounds 1A and R4Aryl pinacol ester (1.2eq.), base(s) ((ii))2.0eq.), added to a mixed solvent of 1, 4-dioxane and water (4:1-6:1), added with a catalyst (3-8 mmol%), and N2Heating to 90-100 ℃ under protection, and reacting for 6-10h to obtain a product 1B. Examples of bases include, but are not limited to, potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate. Examples of catalysts include, but are not limited to, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium.
Step two:
dissolving 1B (1eq.) in DMF, adding base (2.0eq.) and corresponding R2Reacting the amino pyrazole intermediate at 80 ℃ for 8-12h to obtain a compound 1C (the structural formula of 1C is:
). Examples of bases include, but are not limited to, triethylamine, DIPEA, potassium carbonate, potassium phosphate, sodium carbonate, and cesium carbonate.
Step three:
prepared by nucleophilic substitution reaction, 1C (1eq.) is dissolved in DMA, and R is added3Adding potassium bicarbonate (2-3eq.) into the nucleophilic reagent (1.2-1.5eq.) to react at 80-deg.C for more than 24 hr, extracting with ethyl acetate, drying, and performing column chromatography to obtain product 1D.
Or prepared by Suzuki coupling reaction, the compounds 1C and R3Aryl pinacol ester (1.2eq.), alkali (2.0eq.), a mixed solvent of 1, 4-dioxane and water (4:1-6:1), a catalyst (3-8mmol percent) and N2Heating to 90-100 ℃ under protection, and reacting for 6-10h to obtain a product 1D (the structural formula of 1D is:
). Examples of bases include, but are not limited to, potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate. Examples of catalysts include, but are not limited to, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium.
Preferably, the first and second electrodes are formed of a metal,R1and R1Each is methyl, and R3And R3Respectively are
The pyrimidine derivative is prepared by the following synthetic route:
wherein, in the step (A),
preferably, the reaction conditions are: (a) (ii) a Solvent, alkali metal, guanidine carbonate; (b) refluxing the chlorine-containing compound; (c) solvent, alkali metal salt, 75-85 deg.C; (d) solvent, carbonate, acetylene compound and 40-55 ℃; (e) solvent, amine substance, oxime compound and 75-85 ℃; (f) solvent, carbonate, containing R275-85 deg.C; (g) solvent, containing R485-95 deg.C; (h) carbonate, solvent and reflux;
more preferably, the reaction conditions are: (a) guanidine carbonate, metallic sodium, CH3OH; (b) refluxing phosphorus oxychloride; (c) acetic anhydride, potassium acetate, 80 ℃; (d) DMA, potassium carbonate, potassium bicarbonate, bromopropyne, 45 ℃; (e) triethylamine, toluene, N-hydroxyisobutylimidochloroxime, 80 ℃; (f) DMF, potassium bicarbonate, containing R2(ii) an aminopyrazole intermediate of (i), 80 ℃; (g) DMF, 90 ℃ containing R4Intermediates such as amines, alcohols and thiols of the group or 1, 4-dioxane, water ═ 4:1, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, potassium carbonate and compounds containing R4(hetero) aryl, arylboronic acid or vinylboronic acid ester of (a); (h) potassium carbonate, methanol, reflux, overnight.
Specifically, the synthesis steps are as follows:
the method comprises the following steps:
slowly adding sodium metal (2eq.) into methanol under the protection of nitrogen, turning the reaction liquid to 80 ℃, adding guanidine carbonate (1eq.), and stirring for 0.5 h. Adding a methanol solution of dimethyl methoxymaleate (1eq.), heating under reflux for 2 hours, then stirring overnight at room temperature, filtering the reaction solution, dissolving the solid in water, acidifying with acetic acid to pH 6, collecting the remaining solid by filtration, washing with water, and drying to obtain the product compound 2.
Step two:
dissolving the compound 2(1eq.) in a proper amount of phosphorus oxychloride, adding PCl5(0.5eq.), refluxing for 16 hours, cooling, concentrating to remove part of the solvent, pouring the residue into ice water, neutralizing with NH4OH, and adding CH2Cl2And (3) drying an organic phase by anhydrous magnesium sulfate, filtering, concentrating, and performing silica gel column chromatography to obtain a compound 3.
Step three:
dissolving the compound 3 in acetic anhydride, adding potassium acetate, and reacting at 80 ℃ for 5h to obtain a compound 4.
Step four:
dissolving the compound 4(1eq.) and potassium carbonate (1.2eq.) and potassium bicarbonate (1.2eq.) in DMF, heating to 45 ℃, adding bromopropyne (1.2eq.) and reacting for 15h to obtain a compound 5.
Step five:
adding the compound 5(1eq.) and N-hydroxy isobutyl imido chloroxime (1.2eq.), adding triethylamine (2.0eq.) and reacting at 60 ℃ for 3-5h to obtain a compound 6.
Step six:
dissolving the compound 6 in DMF, adding alkali (2.0eq.) and corresponding aminopyrazole intermediate, and reacting at 80 deg.C for 8-12h to obtain compound 7.
Step seven:
method 1: the preparation method comprises the following steps of (1eq.) dissolving a compound 7 in DMF, adding excessive aliphatic cyclic amine, and reacting at 90 ℃ overnight to obtain the product.
Method 2: suzuki coupling reaction, compound 7 and aryl alcohol ester (1.2eq.), alkali (2.0eq.), and mixed solvent of 1, 4-dioxane and water (4:1-6:1) are added, catalyst (3-8mmol percent) and N are added2Heating to 90-100 ℃ under protection, and reacting for 6-10h to obtain the product. Examples of bases include, but are not limited to, potassium carbonate, phosphoric acidPotassium, sodium carbonate, cesium carbonate. Examples of catalysts include, but are not limited to, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium.
Step eight:
dissolving the product obtained in the step g in methanol, adding a base (2.0eq.) and stirring at room temperature overnight to obtain a series of compounds. Examples of bases include, but are not limited to, potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate.
The embodiment of the invention also provides a pharmaceutical composition, which comprises the pyrimidine derivatives, wherein the pharmaceutical composition comprises pharmaceutically acceptable auxiliary materials, such as an excipient, a diluent, a medium, a disintegrant and the like. The pyrimidine derivative can exist in the pharmaceutical composition in a form of a prodrug, a hydrate or a solvate, besides the directly added compound, the added tautomer or the salt. And the dosage form of the pharmaceutical composition is a pharmaceutically acceptable dosage form, including but not limited to liquid preparations, such as oral liquid preparations or intravenous injection, and the liquid preparations may contain water for injection, saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, geline solution or geline solution containing lactate, etc. The pharmaceutical composition can also be solid preparations, such as granules, tablets, freeze-dried powder, powder and the like.
The embodiment of the invention also provides an application of the pyrimidine derivative, and the application comprises the preparation of a kinase inhibitor or a medicament for treating tumors. Wherein the kinase inhibitor is a PLK4 kinase inhibitor; the tumor includes any one of breast cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, gastric cancer, renal cancer, brain cancer, liver cancer, neck cancer, thyroid cancer, melanoma, uterine cancer, ovarian cancer, central nervous system cancer, glioblastoma, myeloproliferative disease and hematological tumor. The application further improves the commercial value of the novel pyrimidine derivatives.
The term "hydrate" refers to a compound that further binds stoichiometric or non-stoichiometric water by non-covalent intermolecular forces.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- (4-methylpiperazin-1-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (numbered 8A), having the formula:
this example also provides a method for preparing the above 8A, which includes the following steps:
first step, Synthesis of intermediate 2
Methanol (80mL) was added slowly sodium metal (2.8g,120mmol) under nitrogen, the reaction turned to 80 deg.C, guanidine carbonate (5.6g,31mmol) was added, and stirring was continued for 0.5 h. A methanol solution (20mL) of dimethyl methoxymaleate (10g,62mmol) was added, the mixture was heated under reflux for 2 hours, then stirred at room temperature overnight, the reaction solution was filtered, the solid was dissolved in water, acetic acid was acidified to pH 6, and the remaining solid was collected by filtration, washed with water, and dried to obtain the product (6.8g, 70%). MS m/z (ESI): 157.1[ M + H]+。
Second step, Synthesis of intermediate 3
Compound 2(4.7g, 1eq.) was dissolved in phosphorus oxychloride (45mL), PCl was added5(3.2g, 0.5eq.) and refluxing for 16 hours, cooling, concentrating to remove some of the solvent, pouring the residue into ice water, NH4After OH neutralization, by CH2Cl2Extraction, drying of the organic phase over anhydrous magnesium sulfate, filtration, concentration and silica gel column chromatography gave compound 3(4.5g, 79%). MS m/z (ESI): 193.0[ M + H]+。
Third step, synthesis of intermediate 4
Dissolving compound 3(4g, 1eq.) in acetic anhydride (80mL), adding potassium acetate (3.9g, 2eq.), reacting at 80 deg.C for 5h, concentrating the solvent, and purifying the residue by silica gel column chromatography to obtain compound 3.2g (67 g)％)。MS m/z(ESI)：235.1[M+H]+。
Fourth step, Synthesis of intermediate 5
Dissolving compound 4(2.4g, 1eq.) and potassium carbonate (1.7g, 1.2eq.) in DMF, heating to 45 deg.C, adding bromopropyne (1.44g, 1.2eq.) for reaction for 15 hr, pouring the reaction solution into water, and adding CH2Cl2Extraction, drying of the organic phase over anhydrous magnesium sulfate, filtration, concentration and silica gel column chromatography gave compound 5(2.6g, 93%). MS m/z (ESI): 273.0[ M + H]+。
Fifth step, Synthesis of intermediate 6
30mL of toluene was added with compound 5(2.2g, 1eq.) and N-hydroxyisobutyliminochloroxime (1.2g, 1.2eq.), triethylamine (2.3mL, 2.0eq.) was added, the mixture was reacted at 60 ℃ for 3 to 5 hours, the solvent was concentrated, and the residue was purified by silica gel column chromatography to give compound 6(1.8g, 64%). MS m/z (ESI): 358.1[ M + H]+。
Sixth step, Synthesis of intermediate 7A
Compound 6(0.72g, 1eq.) was dissolved in DMF, potassium bicarbonate (0.3g, 2.0eq.) and 5-cyclopropyl-1H-pyrazol-3-amine (0.44g, 1.2eq.) were added, reaction was performed at 80 ℃ for 10H, and then the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound 7A (0.75g, 84%). To obtain the compound 7A. MS m/z (ESI): 445.2[ M + H]+. Wherein the structural formula of the intermediate 7A is as follows:
the seventh step: synthesis of the end product 8A
After compound 7A (111.3mg, 1eq.) was dissolved in DMF and added with potassium bicarbonate (50mg, 2.0eq.) and 1-methylpiperazine (0.14mL, 5eq.) to react at 80 ℃ for 8h, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was used in the next reaction without purification.
Mixing the restDissolved in methanol, 70mg of potassium carbonate was added, and the mixture was stirred at room temperature overnight, after completion of the reaction, the mixture was directly stirred and purified by silica gel column chromatography to obtain 8A (25.8mg, yield 21.0%).1H NMR(400MHz,CDCl3)δ7.46(s,1H),6.05(s,1H),5.90(s,1H),5.25(t,J＝6.3Hz,1H),4.60(d,J＝5.9Hz,2H),3.65(t,J＝4.8Hz,4H),3.58(s,3),3.01(p,J＝7.0Hz,1H),2.46(t,J＝4.9Hz,4H),2.31(s,3H),1.85(m,J＝8.7,5.0,4.3Hz,1H),1.24(s,6H),0.94-0.86(m,2H),0.71(m,J＝6.9,3.3Hz,2H).HRMS(ESI-TOF)m/z Calcd for C23H33N9O2[M+H]+:468.22830,found:468.2837。
Example 2
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- (4-morpholin-1-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (numbered 8B), having the formula:
the synthesis procedure for 8B is the same as that for 8A provided in example 1, except that: when 7A was used to synthesize 8B, 1-methylpiperazine was replaced by 1-methylmorpholine, and other conditions and intermediates were synthesized in the same manner as in example 1.
The yield of 8B synthesized from 7A was 28.4%,1H NMR(400MHz,CDCl3)δ7.47(s,1H),6.04(s,1H),5.93(s,1H),5.30(s,1H),4.60(d,J＝6.0Hz,2H),3.75(t,J＝4.7Hz,4H),3.61(d,J＝4.8Hz,4H),3.59(s,3H),3.02(p,J＝7.0Hz,1H),1.86(m,J＝8.7,5.0Hz,1H),1.26(m,6H),(d,J＝6.7Hz,6H),0.94-0.87(m,2),0.74-0.69(m,2H).HRMS(ESI-TOF)m/z Calcd for C22H30N8O3[M+H]+:455.2514,found:455.2516。
example 3
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- ((2R,6S) -2, 6-dimethylmorpholin-4-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (numbered 8C), having the formula:
the synthesis procedure for 8C is the same as that for 8A provided in example 1, except that: when 8C was synthesized using 7A, the starting material was different, 1-methylpiperazine was replaced by cis-2, 6-dimethylmorpholine, and other conditions and synthesis of intermediates were the same as in example 1.
The yield of 8C synthesized from 7A was 31.7%,1H NMR(400MHz,CDCl3)δ7.42(s,1H),6.04(s,1H),5.88(s,1H),5.36(s,1H),4.60(d,J＝6.0Hz,2),4.04(m,2H),3.70(m,2H),3.58(s,3H),3.35(m,2H),3.10–2.95(m,2H),1.86(m,1H),1.21(d,6H),0.90(m,2H),0.71(d,2H).HRMS(ESI-TOF)m/z Calcd for C24H34N8O3[M+H]+:483.2837,found:483.2831。
example 4
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- ((2R,6R) -2, 6-dimethylmorpholin-4-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (code 8D), having the formula:
the synthesis procedure for 8D is the same as that for 8A provided in example 1, except that: when 8D was synthesized using 7A, the starting material was different, 1-methylpiperazine was replaced by trans-2, 6-dimethylmorpholine, and other conditions and synthesis of intermediates were the same as in example 1.
The yield of 8D from 7A was 22.1%.1H NMR(400MHz,CDCl3)δ7.34(s,1H),6.05(s,1H),5.83(s,1H),5.37(d,J＝22.1Hz,1H),4.60(d,J＝5.9Hz,2H),4.21(d,J＝13.0Hz,2H),3.65(m,2H),3.56(s,3H),3.02(p,J＝6.9Hz,1H),2.56(m,2H),1.25(d,6H),1.20(d,J＝6.2Hz,6H),0.97–0.82(m,2H),0.76–0.57(m,2H).HRMS(ESI-TOF)m/z Calcd for C24H34N8O3[M+H]+:483.2837,found:483.2835。
Example 5
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- [ (1S,4S) -2-oxa-5-azacyclo [2.2.1] heptan-5-yl ] -N2- { [3- (propyl-2-yl) -1, 2-oxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (accession number 8E), having the formula:
the synthesis procedure for 8E was the same as that for 8A provided in example 1, except that: in the synthesis of 8E from 7A, the starting material was varied, 1-methylpiperazine was replaced by (1R,4R) -2-oxa-5-azabicyclo [2.2.1] heptane, and other conditions and the synthesis of intermediates were the same as in example 1.
The yield of 8E synthesized from 7A was 19.6%,1H NMR(400MHz,CDCl3)δ7.34(s,1H),6.05(s,1H),5.82(s,1H),5.32(s,1H),4.61(s,2H),3.85(d,J＝7.5Hz,1H),3.79(d,J＝7.5Hz,1H),3.59–3.55(m,2H),3.54(s,3H),3.06–2.98(m,1H),1.87(q,J＝9.7Hz,1H),1.69–1.55(m,1H),1.39(d,1H),1.24(d,6H),0.94-0.87(m,2H),0.75-0.70(m,2H)..HRMS(ESI-TOF)m/z Calcd for C23H30N8O3[M+H]+:467.2514,found:467.2518。
example 6
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- { 2-oxa-6-azaspiro [3.3] heptan-6-yl-N2- { [3- (propyl-2-yl) -1, 2-oxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (code 8F), having the formula:
the synthesis procedure for 8F is the same as that for 8A provided in example 1, except that: in the synthesis of 8F using 7A, the starting material was different, 1-methylpiperazine was replaced with 2-oxa-6-aza-spiro [3,3] heptane, and other conditions and synthesis of intermediates were the same as in example 1.
The yield of 8F synthesized from 7A was 28.4%,1H NMR(400MHz,Chloroform-d)δ7.37(s,1H),6.05(s,1H),5.90(s,1H),5.39(s,1H),4.82(s,4H),4.61(d,J＝5.7Hz,2H),4.25(s,4H),3.56(s,3H),3.01(p,J＝6.9Hz,1H),1.84(m,1H),1.24(s,6H),0.94-0.87(m,2H),0.74-0.64(m,2H).HRMS(ESI-TOF)m/z Calcd for C23H30N8O3[M+H]+:467.2514,found:467.2516。
example 7
This example provides a pyrimidine derivative, N4- (5-cyclopropyl-1H-pyrazol-3-yl) -5-methoxy-6- [4- (4-methylpiperazin-1-yl) phenyl ] -N2- { [3- (propyl-2-yl) -1, 2-oxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (accession number 8G), having the formula:
the synthesis procedure for 8G was the same as that for 8A provided in example 1, except that:
seventh step, Synthesis of the final product 8G
Compound 7A (111.3mg, 1eq.) and 4- (4-methylpiperazin-1-yl) phenylboronic acid pinacol ester (90mg, 1.2eq.), potassium carbonate (70mg, 2.0eq.), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (20mg) was added to a mixed solvent of 1, 4-dioxane and water (4:1-6:1), and N was added2Heating to 100 ℃ under protection, reacting for 6h, concentrating the solvent, extracting with ethyl acetate, drying the organic phase with anhydrous magnesium sulfate, filtering, concentrating, and directly using the residue in the next reaction without purification. The residue was dissolved in methanol, 70mg of potassium carbonate was added, and the mixture was stirred at room temperature overnight, after completion of the reaction, the sample was directly stirred and purified by silica gel column chromatography to obtain 8G (24.5mg, yield of this step 20.7%).
1H NMR(400MHz,CDCl3)δ8.00(d,J＝8.5Hz,2H),7.81(s,1H),6.95(d,J＝8.6Hz,2H),6.11(d,J＝10.9Hz,2H),5.48(s,1H),4.73(d,J＝6.1Hz,2H),3.50(s,3H),3.33(t,J＝5.0Hz,4H),3.02(p,J＝6.9Hz,1H),2.60(t,J＝5.1Hz,4H),2.37(s,3H),1.87(m,J＝9.0,5.2Hz,1H),1.26(d,J＝1.9Hz,6H),0.98–0.91(m,2H),0.74(d,J＝5.3Hz,2H).HRMS(ESI-TOF)m/z Calcd for C29H37N9O2[M+H]+:544.3143,found:544.3147.
Example 8
This example provides a pyrimidine derivative, N4- (5-methyl-1H-pyrazol-3-yl) -5-methoxy-6- (4-methylpiperazin-1-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (No. 8H), having the formula:
the synthesis procedure for 8H is the same as that for 8A provided in example 1, except that:
sixthly, synthesizing an intermediate 7B;
compound 6(0.72g, 1eq.) was dissolved in DMF, potassium bicarbonate (0.3g, 2.0eq.) and 5-methyl-1H-pyrazol-3-amine (0.35g, 1.2eq.) were added to react at 80 ℃ for 8H, and after the reaction liquid was poured into water, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound 7B (0.53g, 66%). MS m/z (ESI): 419.2[ M + H]+。
The seventh step: synthesis of final product 8H and the seventh step provided in example 1: the synthesis of final product 8A was identical except that intermediate 7A was replaced with 7B.
The yield of 8H synthesized by 7B is 33.6 percent,1H NMR(400MHz,CDCl3)δ7.47(s,1H),6.04(s,1H),5.93(s,1H),5.30(s,1H),4.60(d,J＝6.0Hz,2H),3.75(t,J＝4.8Hz,4H),3.61(d,J＝4.8Hz,4H),3.59(s,3H),3.02(p,J＝7.0Hz,1H),2.36(s,3H),2.27(s,3H),1.26(m,6H).HRMS(ESI-TOF)m/z Calcd for C21H31N9O2[M+H]+:442.2637,found:442.2632。
example 9
This example provides a pyrimidine derivative, N4- (5-methyl-1H-pyrazol-3-yl) -5-methoxy-6- (4-morpholin-1-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (accession number 8I), having the formula:
the synthesis procedure for 8I is the same as that for 8H provided in example 8, except that: when 8I was synthesized using 7B, 1-methylpiperazine was replaced by 1-methylmorpholine, the starting material was changed, and the other conditions and the synthesis of intermediates were the same as in example 8.
The yield of 8I synthesized from 7B was 28.4%,1H NMR(400MHz,CDCl3)δ7.46(s,1H),6.05(s,1H),5.92(s,1H),5.33(s,1H),4.61(d,J＝6.0Hz,2H),3.59(s,3H),3.25(t,J＝4.8Hz,4H),2.77(d,J＝4.8Hz,4H),3.02(p,J＝7.0Hz,1H),2.33(s,3H),1.24(m,6H).HRMS(ESI-TOF)m/z Calcd for C20H28N8O3[M+H]+:428.2284,found:428.2287。
example 10
This example provides a pyrimidine derivative, N4- (5-methyl-1H-pyrazol-3-yl) -5-methoxy-6- [4- (4-methylpiperazin-1-yl) phenyl ] -N2- { [3- (propyl-2-yl) -1, 2-oxazol-5-yl ] methyl } pyrimidine-2, 4-diamine (accession number 8J), having the formula:
the synthesis procedure for 8J is the same as that for 8G provided in example 8, except that: when 8J was synthesized using 7B, the other conditions and the synthesis of the intermediate were the same as in example 8G.
The yield of 8J synthesized from 7B was 20.1%,1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.5Hz,2H),7.79(s,1H),6.95(d,J＝8.6Hz,2H),6.08(d,J＝10.9Hz,2H),5.47(s,1H),4.72(d,J＝6.0Hz,2H),3.53(s,3H),3.43(t,J＝5.0Hz,4H),3.06(m,J＝6.9Hz,1H),2.59(t,J＝5.0Hz,4H),2.37(s,3H),1.26-1.23(d,6H).HRMS(ESI-TOF)m/z Calcd for C29H37N9O2[M+H]+:518.2986,found:518.2979。
example 11
This example provides a pyrimidine derivative, 5-methoxy-N4- (5-methyl-1H-pyrazol-3-yl) -N2- { [3- (propyl-2-yl) -1, 2-isoxazol-5-yl ] methyl } -6- [ (1E) -2- (pyridin-4-yl) vinyl ] pyrimidine-2, 4-diamine (No. 8K), having the formula:
the synthesis procedure for 8K is the same as that for 8J provided in example 10, except that: when 8K was synthesized using 7B, the starting material was varied, and the trans-4-pyridylvinylbenzeneboronic acid pinacol ester was replaced with 4- (4-methylpiperazin-1-yl) benzeneboronic acid pinacol ester, and other conditions and synthesis of intermediates were the same as in example 10.
The yield of 8K synthesized from 7B was 16.7%,1H NMR(400MHz,CDCl3)δ7.86(d,J＝16.8Hz,1H),7.71(d,J＝5.4Hz,2H),7.51(d,2H),7.46(s,1H),6.89(d,J＝16.8Hz,1H),6.05(s,1H),5.92(s,1H),5.30(s,1H),4.62(d,2H),3.59(s,3H),3.02(p,J＝7.0Hz,1H),2.36(s,3H),1.24(m,6H).HRMS(ESI-TOF)m/z Calcd for C23H26N8O2[M+H]+:447.2251,found:447.2258。
examples of the experiments
The compounds of examples 1 to 11 (0.001. mu.M, 0.01. mu.M, 0.1. mu.M, 1. mu.M and 10. mu.M) or blank solvents, respectively, were added to the reaction buffer consisting of 8mM propanesulfonate (MOPS, pH 7.0), 0.2mM ethylenediaminetetraacetic acid (EDTA), 10mM magnesium acetate and a 10. mu.M gamma.33P-ATP solution, with the protein kinase to be tested and the corresponding polypeptide substrate and incubated. After the whole reaction was carried out at room temperature for 40min, a 3% phosphate solution was added to the reaction buffer to terminate the reaction. Then, 10. mu.L of the reaction mixture was quantitatively pipetted onto a P30 filter and washed 3 times with 75mM phosphate solution and once with methanol, and the P30 filter was air-dried and scintillation counting was performed by adding scintillation fluid. The inhibitory activity of the compounds was expressed as the median inhibitory concentration IC50, and IC50 values were fitted from the inhibition ratios corresponding to each concentration gradient. The experimental results are seen in the following table:
inhibitory Activity of Compounds on mitosis-related kinases
In the table, A represents that the IC50 of the compound against the corresponding target protein is less than 10nM, B represents that the IC50 of the compound against the corresponding target protein is between 10-50nM, C represents that the IC50 of the compound against the corresponding target protein is between 50-100nM, and D represents that the IC50 of the compound against the corresponding target protein is greater than 100 nM.
The test results show that the compounds have good inhibition effect on PLK4 kinase and the like.
Mitosis-related kinase activity of some compounds
aIC of each compound50Test 2 times for each IC50Three times dilution starting from 10 μ M was set for 9 concentrations.
The results of the above tests indicate that these compounds are significantly superior to Aurora a kinase with respect to PLK4 kinase activity.
Proliferation inhibition effect of partial compounds on tumor cell lines with different states of PTEN gene
aIC of each compound50Test 2 times for each IC50Three times dilution starting from 10 μ M was set for 9 concentrations.
In conclusion, the pyrimidine derivatives provided by the embodiment of the invention have a significant inhibitory effect on PLK4 protein kinase. The PTEN deletion mutant tumor cell line is very sensitive to PTEN deletion mutant tumor cell lines such as PC-3, BT549 and the like, and has weaker activity to PTEN wild type cell lines such as MDA-MB-231, SKBR-3 and the like. Meanwhile, the invention also shows that the PTEN-resistant tumor inhibitor has unique inhibition effect on PTEN-resistant tumors.
In conclusion, the pyrimidine derivative provided by the embodiment of the invention has a good inhibition effect on protein kinase, particularly has a significant inhibition effect on PLK4, and can effectively inhibit PTEN-deficient tumors.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A pyrimidine derivative is characterized by being selected from any one of the following compounds:
2. a pharmaceutical composition comprising the pyrimidine derivative of claim 1, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient.
3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a liquid formulation.
4. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is an oral liquid formulation or an intravenous injection.
5. Use of the pyrimidine derivative according to claim 1 or the pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of tumors.
6. The use of claim 5, wherein the tumor comprises any one of breast cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, gastric cancer, renal cancer, brain cancer, liver cancer, neck cancer, thyroid cancer, melanoma, uterine cancer, ovarian cancer, central nervous system cancer, glioblastoma, myeloproliferative disorders, and hematological tumors.
7. Use of the pyrimidine derivative according to claim 1 or the pharmaceutical composition according to claim 2 for the preparation of a kinase inhibitor; wherein the kinase inhibitor is a PLK4 kinase inhibitor.
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