CN108503593B - 2-aminopyrimidine compounds and application thereof - Google Patents
2-aminopyrimidine compounds and application thereof Download PDFInfo
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- CN108503593B CN108503593B CN201710113487.8A CN201710113487A CN108503593B CN 108503593 B CN108503593 B CN 108503593B CN 201710113487 A CN201710113487 A CN 201710113487A CN 108503593 B CN108503593 B CN 108503593B
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention relates to a 2-aminopyrimidine compound with a structure shown in a formula I, and pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof, belonging to the technical field of chemical medicines. The compounds can inhibit the kinase activity of FGFR4 protein with high selectivity, but do not inhibit the kinase activity of other FGFR family members (FGFR1, FGFR2 and FGFR 3). Can effectively inhibit the growth of tumor cells caused by the abnormal FGFR4 signal pathway, and can be used for preventing and treating transitional proliferative diseases such as tumors caused by the abnormal FGFR4 signal pathway in human and other mammals.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a 2-aminopyrimidine compound and application thereof.
Background
Fibroblast Growth Factor Receptors (FGFRs) belong to the Receptor Tyrosine Kinase Superfamily (RTKs), which includes four subtypes (FGFR1, FGFR2, FGFR3 and FGFR 4). Each subtype has the common structural characteristics of RTKs: an extracellular region to which a ligand binds, a transmembrane region, and an intracellular region comprising a kinase domain. The FGFRs family has 18 human ligands, which are widely distributed in various tissues of the human body and selectively bind to receptors, and co-receptors (HSPG or KLB) enhance the binding of the receptors to the corresponding ligands. Upon specific binding of the ligand to the receptor, FGFR dimerization is induced, which in turn is autophosphorylated, causing its domain to transition from an inactive state to an active state. The activated FGFR phosphorylates downstream target proteins, activates related signal pathways such as Mitogen Activated Protein Kinase (MAPK), phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) and the like, and finally stimulates the proliferation and differentiation of cells and inhibits the apoptosis. The FGFRs signal channel abnormality has a close relation with the occurrence and development of various tumors, and FGFRs small molecule inhibitors aiming at related tumors are in different research stages.
FGFR4 is distributed primarily in liver, lung, lymph and breast tissues, and FGF19 is a specific human ligand. Co-receptors (KLBs) are capable of enhancing the binding of FGF19 to FGFR 4. The FGF19-FGFR4 signal channel plays an important role in controlling bile acid homeostasis and maintaining biological functions such as sugar and protein metabolism. FGF19 and FGFR4 are frequently reported to mutate, amplify and overexpress tumor tissues. For example: FGF19 gene amplification is considered to be a driver for a partial liver cancer (Sawey, Chanrion et al.2011); FGFR4 overexpression and mutations have also been reported to be associated with breast cancer (Roidl, Foo et al.2010, tieng, Tan et al.2016). In addition, aberrant FGF9-FGFR4 signaling pathways are involved in mediating chemotherapy resistance (Roidl, Berger et al 2009). Can effectively inhibit the generation and development of tumors and the synergistic effect with chemotherapeutic drugs through gene silencing or monoclonal antibody interference (Haq andAhn 2015, Tiong, Tan et al.2016). The results of these studies indicate that FGFR4 can be a potential therapeutic target for related tumors. For example: liver cancer, breast cancer, lung cancer, melanoma, prostate cancer, pancreatic cancer, cholangiocarcinoma and the like are all cancers caused by abnormal FGF19-FGFR4 signaling pathway.
At present, although many small molecule inhibitors of FGFRs are under clinical study, their selectivity is poor, and side effects caused by off-target are frequently reported in clinic. Therefore, the development of a highly selective FGFR4 small molecule inhibitor is still very necessary.
Disclosure of Invention
Based on the 2-aminopyrimidine compound, the invention provides a 2-aminopyrimidine compound which can be used for high-selectivity targeted inhibition of the activity of FGFR4 protein kinase.
The specific technical scheme is as follows:
2-aminopyrimidines having the structure of formula (I) or pharmaceutically acceptable salts thereof or stereoisomers or prodrug molecules thereof:
wherein:
R1，R2，R3，R4each independently selected from: h, halogen, C1-C6 alkyl, C1-C6 alkoxy;
R6，R7selected from halogens; or R6，R7One of which is selected from hydrogen or halogen and the other is selected from halogen substituted C1-C2 alkyl;
R8selected from H or C1-C6 alkyl.
In some of these embodiments, R6，R7Selected from halogens.
In some of these embodiments, R6，R7Each independently selected from Cl or F.
In some of these embodiments, R1，R2，R3，R4Any two of which are selected from halogens and the other two are selected from C1-C6 alkoxy groups.
In some of these embodiments, R1，R2，R3，R4Any two of which are selected from Cl or F and the other two are selected from methoxy.
In one of themIn some embodiments, R1，R2，R3，R4Any two of which are selected from Cl or F, the other two are selected from methoxy; r6，R7Each independently selected from Cl or F; r8Is selected from H.
2-aminopyrimidine compounds with the structure of formula (I) or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof,
the 2-aminopyrimidine compound is selected from the following compounds:
n- (3, 5-dichloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (3-chloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) -5-fluorophenyl) acrylamide,
N- (3-chloro-2- ((5- ((2, 6-dichloro-3, 5-dimethoxy) oxy) pyrimidin-2-yl) amino-5-trifluoromethylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-ethylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-fluorophenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-methoxyphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-ethoxyphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-isopropoxyphenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2, 6-dichloro-3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2, 6-dichlorobenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chloro-3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chloro-5-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chlorobenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- (benzyloxy) pyrimidin-2-yl) -amino) -3-chloro-phenyl) acrylamide,
N- (3-chloro-2- ((5- (1- (2, 6-dichloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- (1- (2-chloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- (1- (3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-6-methylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-4-methylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-3, 5-difluorophenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-4- (4-methylpiperidin-1-yl) phenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-3- (trifluoromethyl) phenyl) acrylamide.
The invention also provides application of the 2-aminopyrimidine compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof.
The specific technical scheme is as follows:
the 2-aminopyrimidine compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof is applied to preparation of drugs for treating or preventing hyperproliferative diseases caused by abnormal FGFR4 signal path.
In some of these embodiments, the hyperproliferative disease is a tumor.
In some of these embodiments, the tumor comprises breast cancer, liver cancer, stomach cancer, prostate cancer, rhabdomyosarcoma, melanoma.
The 2-aminopyrimidines can also be used in combination with currently used or currently under development estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, and EGF antibodies are co-administered to increase their clinical effectiveness.
The invention also provides a pharmaceutical composition for treating or preventing hyperproliferative diseases.
The specific technical scheme is as follows:
a pharmaceutical composition for treating or preventing hyperproliferative diseases comprises the 2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof serving as active ingredients and pharmaceutically acceptable carriers. The compositions may be prepared according to conventional methods of manufacture in the pharmaceutical arts, e.g., by mixing the active ingredient with one or more carriers and then formulating the same into the desired dosage form.
In some of these embodiments, the hyperproliferative disease is a tumor.
In some of these embodiments, the tumor comprises breast cancer, liver cancer, stomach cancer, prostate cancer, rhabdomyosarcoma, melanoma.
The 2-aminopyrimidine compound has the following beneficial effects:
the 2-aminopyrimidine compounds are a series of novel compounds, and can inhibit the kinase activity of FGFR4 protein with high selectivity, but not inhibit the kinase activity of other FGFR family members (FGFR1, FGFR2 and FGFR 3). Can effectively inhibit the growth of tumor cells caused by the abnormal FGFR4 signal pathway, and can be used for preventing and treating transitional proliferative diseases such as tumors caused by the abnormal FGFR4 signal pathway in human and other mammals.
The 2-aminopyrimidine compound of the invention is R on a benzene ring6,R7When the compounds are all halogen, the activity is higher, and the selectivity to FGFR4 protein kinase is good.
Drawings
FIG. 1 shows the results of experiments in which the compounds prepared in example 1 inhibited the phosphorylation of downstream target proteins (FRS2, ERK1/2 and Akt).
Detailed Description
In the compounds of the present invention, when any variable (e.g., R1, R2, etc.) occurs more than one time in any constituent, its definition in each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
The terms "alkyl" and "alkylene" as used herein are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
Unless otherwise defined, alkyl and alkoxy substituents may be unsubstituted or substituted. For example, (C1-C6) alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, e.g., morpholinyl, piperidinyl, and the like.
As understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.
The compounds (I) of the present invention are in free form and include pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are sodium salts of 2-aminopyrimidines. The term "free form" refers to a compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous acid solution, such as dilute aqueous HCl, dilute aqueous phosphoric acid, dilute acetic acid, and dilute aqueous sulfuric acid. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such base and acid salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. Salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-monobenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. For example, conventional non-toxic salts include salts derived from inorganic bases including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, in "Pharmaceutical Salts," J.pharm.Sci.' 1977: 66: 1-19, the preparation of the pharmaceutically acceptable salts described above, as well as other typical pharmaceutically acceptable salts, is described in more detail.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention
EXAMPLE 1 Synthesis of N- (3, 5-dichloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide
The synthetic route is as follows:
step 1.2 Synthesis of chloro-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidine
In a 250ml flask were added 2, 6-dichloro-3, 5-dimethoxybenzyl bromide (6.3g,21mmol), 2-chloro-5-hydroxypyrimidine (2.61g,20mmol), tetra-tert-butylammonium iodide (1.48g,4mmol), K2CO3(5.53g,40mmol) and 80ml DMF at 60 ℃ for 2 h. Pouring the reaction solution into ice, stirring for 1h, performing suction filtration by using a Buchner funnel, washing a filter cake for multiple times, and performing vacuum drying at 50 ℃ to obtain 6.31g of solid, wherein the yield is as follows: 90.25 percent.1H NMR(400MHz,DMSO-d6):δ(ppm)8.68(s,2H),7.02(s,1H),5.42(s,2H),3.95(s,6H).
Step 2. Synthesis of N- (2-chloro-4-fluorophenyl) acetamide
In a 100ml flask was added acetic anhydride (20ml) and 2-chloro-4-fluoro-aniline (4.22g,29mmol) in that order and reacted at 100 ℃ for 1 h. After the reaction, the reaction solution was poured into water, extracted 3 times with ethyl acetate, and the organic phases were combined. Washing the organic phase with saturated sodium bicarbonate water solution and saturated salt water in sequence, drying the organic phase with anhydrous sodium sulfate, concentrating, and obtaining the target compound after column chromatography, wherein the target compound is 2.801g, and the yield is as follows: 43.29 percent.1H NMR(400MHz,DMSO-d6):δ(ppm)9.55(s,1H),7.65(dd,J＝8.9,5.9Hz,1H),7.48(dd,J＝8.6,2.8Hz,1H),7.20(td,J＝8.6,2.9Hz,1H),2.03(d,J＝34.3Hz,3H).
N- (2-chloro-4-fluorophenyl) acetamide (2.801g, 14.944mmol), acetic acid (2.9ml) and concentrated sulfuric acid (9.8ml) were added successively to a 50ml flask at 0 ℃ followed by slow dropwise addition of a mixture of fuming nitric acid (1.31ml) and acetic acid (0.327 ml). After reacting for 1.5h at 0 ℃, pouring the reaction solution into ice, stirring until the ice is dissolved, filtering, and washing a filter cake with water. 2.58g of solid are obtained, yield: 74.39 percent.1H NMR(400MHz,DMSO-d6):δ(ppm)10.19(s,1H),7.99(dd,J＝19.3,7.4Hz,2H),2.05(s,3H).
Step 4.2 Synthesis of chloro-4-fluoro-6-nitroaniline
A100 ml flask was charged with N- (2-chloro-4-fluoro-6-nitrophenyl) acetamide (2.58g,11.11mmol) and 30ml of concentrated hydrochloric acid, and reacted at 120 ℃ for 1.25 hours. Concentrating under reduced pressure, dissolving with ethyl acetate, washing the organic phase with saturated sodium bicarbonate, concentrating, and performing column chromatography to obtain 1.904g of solid, wherein the yield is as follows: 90.0 percent.1H NMR(400MHz,DMSO-d6):δ(ppm)7.88(s,1H),7.86(s,1H),7.21(s,2H).
Step 5.3 Synthesis of chloro-5-fluoro-1, 2-phenylenediamine
2-chloro-4-fluoro-6-nitroaniline (1.904g, 9.991mmol), ammonium chloride (3.21g), reduced iron powder (2.234g), methanol (70ml) and water (30ml) were charged in this order in a 250ml flask, and the reaction system was reacted at 75 ℃ for 3 hours. Filtering with diatomaceous earth, washing with methanol, concentrating under reduced pressure, dissolving the residue with ethyl acetate, washing with water, concentrating, and performing column chromatography to obtain 1.376g of solid, yield: 85.77 percent.1H NMR(400MHz,DMSO-d6):δ(ppm)6.36(dd,J＝8.7,2.9Hz,1H),6.32(dd,J＝10.8,2.9Hz,1H),5.18(s,2H),4.47(s,2H).
Step 6. Synthesis of t-butyl (2-amino-3-chloro-5-fluorophenyl) carbamate
Di-tert-butyl dicarbonate (1.97ml) was added dropwise to a mixture of 3-chloro-5-fluoro-1, 2-phenylenediamine (1.376g, 8.5716mmol), triethylamine (1.3ml) and tetrahydrofuran (10ml) in a water bath, and the mixture was reacted at room temperature for 12 hours. Adding ethyl acetate, mixing with water, separating liquid, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography to obtain 1.087g of solid, wherein the yield is as follows: 48.67 percent.1H NMR(400MHz,DMSO)δ8.65(s,1H),7.28(dd,J＝10.8,2.7Hz,1H),6.99(dd,J＝8.3,2.9Hz,1H),4.96(s,2H),1.47(s,9H).
Step 7 Synthesis of tert-butyl (3-chloro-2 ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) -5-fluorophenyl) carbamate
In a 100ml flask were added 2-chloro-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidine (1.0488g, 3mmol), tert-butyl (2-amino-3-chloro-5-fluorophenyl) carbamate (0.8603g, 3.3mmol), Na in that order2CO3(1.272g)，Pd2(dba)3(0.412g), DavePhos (0.3542g) and 2-methyl-2-butanol (30ml) were reacted at 100 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, filtered through celite, and the filtrate was concentrated. Column chromatography gave 0.644g solid, yield: 37.41 percent.1H NMR(400MHz,DMSO)δ8.46(s,1H),8.36(s,1H),8.24(s,2H),7.72(dd,J＝8.0,2.7Hz,1H),7.16(dd,J＝8.2,2.7Hz,1H),7.00(s,1H),5.24(s,2H),3.94(s,6H),1.45(s,9H).
Step 8.6-chloro-N1Synthesis of- (5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -4-fluorobenzene-1, 2-diamine
Trifluoroacetic acid (9ml) was added dropwise to a solution of tert-butyl (3-chloro-2 ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) -5-fluorophenyl) carbamate (0.644g,1.223mmol) in dichloromethane (20ml) and reacted at room temperature for 12 h. Spin-drying with dichloromethaneThe residue was dissolved in an alkane and the organic phase was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase is concentrated and column chromatographed to give 0.423g of a solid, yield: 79.55 percent.1H NMR(400MHz,DMSO)δ8.20(s,2H),8.13(s,1H),6.99(s,1H),6.47(m,2H),5.43(s,2H),5.22(s,2H),3.94(s,6H)。
Step 9 Synthesis of N- (3, 5-dichloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide
In a 50ml flask were added 6-chloro-N1- (5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -4-fluorobenzene-1, 2-diamine (0.423g, 0.8929mmol), N, N-diisopropylethylamine (0.24ml) and dry dichloromethane (7ml) in that order. Acryloyl chloride (87. mu.L) was added dropwise to the reaction flask at 0 ℃ and reacted at 0 ℃ for 2 h. After the reaction, the organic phase was washed with water and saturated brine in this order and separated. The organic phase is concentrated and the column chromatography gives 0.35g of solid, yield: 74.27 percent.1H NMR(400MHz,DMSO)δ9.62(s,1H),8.34(s,1H),8.24(s,2H),8.02(dd,J＝11.1,2.8Hz,1H),7.25(dd,J＝8.2,2.9Hz,1H),7.00(s,1H),6.65(dd,J＝16.9,10.2Hz,1H),6.25(dd,J＝17.0,1.5Hz,1H),5.76(dd,J＝10.4,1.6Hz，1H),5.24(s,2H),3.94(s,6H).HRMS(ESI)C22H18Cl3FN4O4[M+H]+:527.04544.
EXAMPLE 2 Synthesis of N- (3-chloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) -5-fluorophenyl) acrylamide
The synthetic route is as follows:
step 1. Synthesis of tert-butyl- (2-amino-3, 5-dichlorophenyl) -carbamate
Di-tert-butyl dicarbonate (0.46ml,10mmol) was added dropwise to 3, 5-dichloro-1, 2-phenylenediamine (1.7703g, 10mmol), triethylamine (1.5ml) and tetrahydro-l in a water bathAfter the completion of the dropwise addition to a mixture of furan (12ml), the mixed system was reacted at room temperature for 12 hours. Adding ethyl acetate, mixing with water, separating liquid, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography to obtain 1.1967g of solid, wherein the yield is as follows: 43.2 percent.1H NMR(400MHz,DMSO)δ8.64(s,1H),7.39(d,J＝1.5Hz,1H),7.13(d,J＝2.4Hz,1H),5.24(s,2H),1.47(s,9H)。
Step 2 Synthesis of tert-butyl (3, 5-dichloro-2 ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) carbamate
2-chloro-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidine (1.0488g, 3 mmol; Synthesis reference example 1.), tert-butyl (2-amino-3, 5-dichlorophenyl) carbamate (0.9142g, 3.3mmol), Na2CO3(1.272g)，Pd2(dba)3(0.412g), DavePhos (0.3542g) and 2-methyl-2-butanol (30ml) were reacted at 100 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, filtered through celite, and the filtrate was concentrated. Column chromatography gave 0.6689g of solid, yield: 37.78 percent.1H NMR(400MHz,DMSO)δ8.54(s,1H),8.45(s,1H),8.25(s,2H),7.90(d,J＝2.3Hz,1H),7.33(d,J＝2.4Hz,1H),7.00(s,1H),5.24(s,2H),3.94(s,6H),1.44(s,9H)。
Step 3.4, 6-dichloro-N1Synthesis of- (5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) benzene-1, 2-diamine
Trifluoroacetic acid (9ml) was added dropwise to a solution of tert-butyl (3-chloro-2 ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) -5-fluorophenyl) carbamate (0.6689g,1.334mmol) in dichloromethane (20ml) and reacted at room temperature for 12 h. Spin-dry, dissolve the residue with dichloromethane and wash the organic phase successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was concentrated and column chromatographed to give 0.436g of solid, yield: 78.48 percent.1H NMR(400MHz,DMSO)δ8.22(s,1H),8.20(s,2H),6.99(s,1H),6.71(d,J＝2.3Hz,1H),6.66(d,J＝2.3Hz,1H),5.43(brs,2H),5.23(s,2H),3.94(s,6H)。
Step 4 Synthesis of N- (3, 5-dichloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide
4, 6-dichloro-N was added in sequence to a 50ml flask1- (5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) benzene-1, 2-diamine (0.098g, 0.2mmol), N, N-diisopropylethylamine (52. mu.L) and dry dichloromethane (2.5 ml). Acryloyl chloride (19 μ L) was added dropwise to the reaction flask at 0 ℃ and reacted at 0 ℃ for 2 h. After the reaction, the organic phase was washed with water and saturated brine in this order and separated. The organic phase was concentrated and column chromatographed to give 0.0845g of a solid, yield: 78.46 percent.1H NMR(400MHz,DMSO)δ9.66(s,1H),8.46(s,1H),8.25(s,2H),8.18(d,J＝2.4Hz,1H),7.43(d,J＝2.4Hz,1H),7.00(s,1H),6.63(dd,J＝17.0,10.2Hz,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.76(dd,J＝10.4,2Hz,1H),5.25(s,2H),3.94(s,6H)。HRMS(ESI)C22H18Cl4N4O4[M+H]+：545.01328.
EXAMPLE 3 Synthesis of N- (3-chloro-2- ((5- ((2, 6-dichloro-3, 5-dimethoxy) oxy) pyrimidin-2-yl) amino-5-trifluoromethylphenyl) acrylamide
And (3) characterization of a final product:1H NMR(500MHz,DMSO-d6):δ(ppm)9.81(s,1H),8.72(s,1H),8.43(s,1H),8.27(s,2H),7.67(s,1H),7.00(s,1H),6.62(dd,J＝17.0,10.2Hz,1H),6.27(d,J＝17.0Hz,1H),5.78(d,J＝10.4Hz,1H),5.25(s,2H),3.94(s,6H).HRMS(ESI)C23H18Cl3F3N4O4[M+H]+:579.03984.
the synthesis method is referred to example 2.
EXAMPLE 4 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide
The synthetic route is as follows:
step 1. same as step 1 in example 2.
Step 2. in a 100ml flask, 2-chloro-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidine (1.0 eq; Synthesis reference example 1.), tert-butyl (2-amino-phenyl) carbamate (1.1eq), Cs2CO3(2.0eq)，Pd2(dba)3(0.1eq), Xantphos (0.2eq) and 2-methyl-2-butanol (10ml/mmol) were reacted at 100 ℃ for 12 h. And (3) concentrating the reaction solution under reduced pressure, dissolving the residue with dichloromethane, performing suction filtration on the solution with diatomite, concentrating the filtrate, and performing column chromatography to obtain a target product.
Step 4. the same as step 4 in example 2.
And (3) characterization of a final product:1H NMR(400MHz,DMSO-d6):δ(ppm)9.83(s,1H),8.44(s,1H),8.31(s,2H),7.80(d,J＝7.1Hz,1H),7.51(d,J＝7.6Hz,1H),7.23–7.12(m,1H),7.06(td,J＝7.8,1.4Hz,1H),7.00(s,1H),6.50(dd,J＝17.0,10.1Hz,1H),6.27(dd,J＝17.0,1.9Hz,1H),5.77(dd,J＝10.2,1.8Hz,1H),5.28(s,2H),3.94(s,6H).HRMS(ESI)C22H20Cl2N4O4[M+H]+:475.09299.
EXAMPLE 5 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-ethylphenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.39(s,1H),8.18(s,2H),8.07(s,1H),7.69(d,J＝7.8Hz,1H),7.20(t,J＝7.8Hz,1H),7.13–7.04(m,1H),6.99(s,1H),6.49(dd,J＝17.0,10.2Hz,1H),6.19(dd,J＝17.0,1.9Hz,1H),5.68(dd,J＝10.2,1.9Hz,1H),3.93(s,6H),2.49(q,J＝7.5Hz,2H),1.05(t,J＝7.5Hz,3H).HRMS(ESI)C24H24Cl2N4O4[M+H]+:503.12469.
synthesis method referring to example 4, 3-ethyl-o-phenylenediamine (prepared as follows) was used in place of o-phenylenediamine in step 1.
a.N- (4-bromo-2-ethyl-6-nitrophenyl) -2, 2, 2-trifluoroacetamide was synthesized by slowly adding trifluoroacetic anhydride (20.85ml,150mmol,10.0eq) dropwise to 4-bromo-2-ethylaniline (3.0g,15mmol,1.0eq) at 2 deg.C followed by 1.8ml of anhydrous 2-methyltetrahydrofuran, moving the flask to room temperature, and adding ammonium nitrate (1.56g,19.5mmol,1.3eq) in portions to the flask and monitoring the reaction system temperature, if necessary using an ice bath to control the reaction temperature below 40 deg.C. After 40 minutes of reaction, crushed ice was slowly added to the reaction solution and stirred. The aqueous phase was extracted with ethyl acetate, the organic phase was concentrated, and column chromatography gave 1.046g of a solid with a yield of 20.44%.1H NMR(500MHz,DMSO-d6):δ(ppm)11.54(s,1H),8.16(d,J＝2.2Hz,1H),8.00(d,J＝2.2Hz,1H),2.64(q,J＝7.5Hz,2H),1.13(t,J＝7.5Hz,3H).
b, synthesizing 4-bromo-2-ethyl-6-nitroaniline: 6M aqueous NaOH (1.5ml,0.5ml/mmol) was added to a solution of N- (4-bromo-2-ethyl-6-nitrophenyl) -2, 2, 2-trifluoroacetamide (1.0232g,3mmol,1.0eq) in 1, 4-dioxane (3.6ml,1.2ml/mmol) and the reaction refluxed for two days. Cooling, adding water, extracting with ethyl acetate, concentrating the organic phase, and column chromatography to obtain 0.703g solid with 95.61% yield.1H NMR(500MHz,DMSO-d6):δ(ppm)8.00(d,J＝2.2Hz,1H),7.44(s,1H),7.32(s,2H),2.60(q,J＝7.3Hz,2H),1.15(t,J＝7.4Hz,3H).
Preparation of 3-Ethyl-o-phenylenediamine 4-bromo-2-ethyl-6-nitroaniline (0.703g,2.8683mmol,1.0eq), MeOH/THF (4:1volume/volume 35ml), 10% Pd/C (0.050g) and KOH (0.177g,3.1551mmol,1.1eq) were added in that order in a 100-flask. The air in the reaction system is replaced by argon, then the argon is replaced by hydrogen, and the reaction is carried out for 12 hours at room temperature under a hydrogen balloon. Suction filtration is carried out on kieselguhr, an organic phase is concentrated, and column chromatography is carried out to obtain 0.365g of solid, wherein the yield is 76.30 percent.1H NMR(500MHz,DMSO-d6):δ(ppm)6.41(dd,J＝7.3,1.4Hz,1H),6.33(m,2H),4.25(s,4H),2.43(q,J＝7.5Hz,2H),1.10(t,J＝7.5Hz,3H).
EXAMPLE 6 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-fluorophenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.70(s,1H),8.25(s,2H),8.23(s,1H),7.71(d,J＝8.3Hz,1H),7.23(td,J＝8.3,6.1Hz,1H),7.03(dd,J＝13.5,4.9Hz,1H),7.00(s,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.75(dd,J＝10.2,1.9Hz,1H),5.25(s,2H),3.94(s,6H).HRMS(ESI)C22H19Cl2FN4O4[M+H]+:493.08402.
the synthesis method is referred to example 4.
EXAMPLE 7 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-methoxyphenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.42(s,1H),8.17(s,2H),7.80(s,1H),7.52(d,J＝8.1Hz,1H),7.18(t,J＝8.3Hz,1H),6.98(s,1H),6.89–6.79(m,1H),6.53(dd,J＝17.0,10.2Hz,1H),6.21(dd,J＝17.0,1.9Hz,1H),5.70(dd,J＝10.2,1.9Hz,1H),5.23(s,2H),3.94(d,J＝8.0Hz,6H),3.67(s,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.33,157.33,155.69,154.37,146.35,146.22,135.53,132.39,131.95,126.76,125.94,120.62,114.74,107.96,99.11,67.15,56.76,55.62.HRMS(ESI)C23H22Cl2N4O5[M+H]+:505.10433.
the synthetic route is as follows:
step 1. is the same as step 2 in example 4.
Step 2.0 ℃ 5- ((2, 6-dichloro) was added sequentially to a 50ml flask-3, 5-Dimethoxybenzyl) oxy-N- (2-methoxy-6-nitrophenyl) pyrimidin-2-amine (0.4144g,0.8611mmol,1.0eq), NiCl2·6H2O (0.3070g,1.2965mmol,1.5eq) and MeOH/DCM (1:4, vol/vol, 7ml) were then added in portions to the NaBH4(0.0831g,2.1527mmol,2.5eq), remove the ice bath and react at room temperature for 1.5 h. Suction filtration, concentration of filtrate, column chromatography to obtain 0.1930g of solid, yield 49.65%.1H NMR(400MHz,DMSO-d6):δ(ppm)8.14(s,2H),7.66(s,1H),6.99(s,1H),6.89(t,J＝8.1Hz,1H),6.35(d,J＝7.4Hz,1H),6.22(d,J＝7.6Hz,1H),5.22(s,2H),4.71(s,2H),3.95(d,J＝7.7Hz,6H),3.60(s,3H).
EXAMPLE 8 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-ethoxyphenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.46(s,1H),8.18(s,2H),7.74(s,1H),7.49(d,J＝8.1Hz,1H),7.14(t,J＝8.2Hz,1H),6.99(s,1H),6.81(d,J＝7.7Hz,1H),6.55(dd,J＝16.9,10.2Hz,1H),6.22(dd,J＝17.0,1.9Hz,1H),5.71(dd,J＝10.2,1.8Hz,1H),3.98–3.82(m,8H),1.05(t,J＝6.9Hz,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.31,157.40,154.83,154.36,146.39,146.16,135.28,132.42,131.95,126.75,125.69,121.05,114.69,109.03,99.07,67.27,63.53,56.74,14.43.HRMS(ESI)C24H24Cl2N4O5[M+H]+:519.12003.
the synthesis method is referred to example 7.
EXAMPLE 9 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-isopropoxyphenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.43(s,1H),8.17(s,2H),7.67(s,1H),7.50(d,J＝8.1Hz,1H),7.13(t,J＝8.2Hz,1H),6.98(s,1H),6.80(d,J＝7.9Hz,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.22(dd,J＝17.0,1.8Hz,1H),5.70(dd,J＝10.2,1.8Hz,1H),5.24(s,2H),4.49-4.44(m,1H),3.93(s,6H),1.04(d,J＝6.0Hz,6H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.28,157.58,154.35,153.73,146.38,146.24,135.70,132.43,132.00,126.69,125.66,121.68,114.68,114.35,110.14,99.03,69.75,67.35,56.72,21.68.HRMS(ESI)C25H26Cl2N4O5[M+H]+:533.13497.
the synthesis method is referred to example 7.
EXAMPLE 10 Synthesis of N- (3-chloro-2- ((5- ((2-chloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.59(s,1H),8.30(s,1H),8.22(s,2H),7.92(d,J＝7.3Hz,1H),7.32–7.15(m,2H),6.76(d,J＝2.6Hz,1H),6.72(d,J＝2.6Hz,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,1.7Hz,1H),5.73(dd,J＝10.2,1.6Hz,1H),5.10(s,2H),3.86(s,3H),3.78(s,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,158.79,156.52,155.56,146.43,146.08,137.00,135.53,133.03,131.65,129.23,127.24,126.77,125.26,121.52,112.22,106.53,99.66,68.82,56.30,55.57.HRMS(ESI)C22H20Cl2N4O4[M+H]+:475.09355.
the synthetic route is as follows:
step 1. same as step 1 in example 1.
Step 2. same as step 2 in example 4.
Step 4. same as step 4 in example 4.
Example 11 Synthesis of N- (3-chloro-2- ((5- ((2, 6-dichloro-3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.61(s,1H),8.35(s,1H),8.25(s,2H),7.93(dd,J＝7.7,1.7Hz,1H),7.51(d,J＝9.0Hz,1H),7.35–7.20(m,3H),6.58(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.73(dd,J＝10.2,1.9Hz,1H),5.23(s,2H),3.89(s,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,156.71,154.04,146.66,146.19,137.02,133.07,132.05,131.66,129.20,128.56,127.24,126.80,126.33,125.25,124.21,121.51,114.33,67.02,56.64.HRMS(ESI)C21H17Cl3N4O3[M+H]+:479.04415.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
Example 12 Synthesis of N- (3-chloro-2- ((5- ((2, 6-dichlorobenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.62(s,1H),8.36(s,1H),8.27(s,2H),7.94(d,J＝7.7Hz,1H),7.56(d,J＝7.8Hz,2H),7.47(dd,J＝8.7,7.4Hz,1H),7.34–7.17(m,2H),6.58(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,1.1Hz,1H),5.74(dd,J＝10.2,1.8Hz,1H),5.25(s,2H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,156.74,146.63,146.23,137.03,136.03,133.07,131.70,131.66,131.30,129.19,128.77,127.25,126.81,125.25,121.52,66.74.HRMS(ESI)calcd for C20H15Cl3N4O2[M+H]+:449.03334；found 449.03365.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
Example 13 Synthesis of N- (3-chloro-2- ((5- ((2-chloro-3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.60(s,1H),8.30(s,1H),8.22(s,2H),7.92(d,J＝7.5Hz,1H),7.34(t,J＝8.0Hz,1H),7.29-7.24(m,2H),7.16(m,2H),6.56(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,1.7Hz,1H),5.73(dd,J＝10.2,1.6Hz,1H),5.14(s,2H),3.87(s,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,156.50,154.79,146.47,146.01,136.98,135.23,133.04,131.65,129.24,127.69,127.24,126.76,125.26,121.59,121.52,120.71,112.56,68.74,56.23.HRMS(ESI)calcd for C21H18Cl2N4O3[M+H]+:445.08287；found 445.08328.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
Example 14 Synthesis of N- (3-chloro-2- ((5- ((2-chloro-5-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.59(s,1H),8.31(s,1H),8.24(s,2H),7.92(d,J＝7.7Hz,1H),7.40(d,J＝8.8Hz,1H),7.32–7.19(m,2H),7.17(d,J＝3.0Hz,1H),6.97(dd,J＝8.8,3.1Hz,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,1.7Hz,1H),5.73(dd,J＝10.2,1.7Hz,1H),5.10(s,2H),3.76(s,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.59,158.20,156.56,146.43,146.11,137.02,134.84,133.05,131.65,130.19,129.24,127.24,126.77,125.26,123.79,121.52,115.99,115.29,68.72,55.50.HRMS(ESI)calcd for C21H18Cl2N4O3[M+H]+:445.08287；found445.08328.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
EXAMPLE 15 Synthesis of N- (3-chloro-2- ((5- ((3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.60(s,1H),8.26(s,1H),8.19(s,2H),7.92(d,J＝6.9Hz,1H),7.35–7.16(m,2H),6.64–6.49(m,3H),6.45(s,1H),6.23(dd,J＝17.0,1.8Hz,1H),5.72(dd,J＝10.2,1.7Hz,1H),5.03(s,2H),3.73(s,6H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,160.53,156.32,146.40,145.90,138.88,136.98,133.03,131.65,129.28,127.24,126.74,125.25,121.49,105.60,99.69,70.62,55.18.HRMS(ESI)calcd for C22H21ClN4O4[M+H]+:441.13241；found441.13218.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
Example 16 Synthesis of N- (3-chloro-2- ((5- ((2-chlorobenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.60(s,1H),8.31(s,1H),8.24(s,2H),7.92(dd,J＝7.6,1.7Hz,1H),7.67–7.56(m,1H),7.56–7.46(m,1H),7.46–7.33(m,2H),7.32–7.17(m,2H),6.56(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.82–5.61(m,1H),5.15(s,2H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,156.53,146.47,146.05,136.99,133.87,133.05,132.82,131.64,130.51,130.11,129.41,129.24,127.33,127.24,126.77,125.26,121.52,68.69.HRMS(ESI)calcd for C20H16Cl2N4O2[M+H]+:415.07231；found 415.07259.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
Example 17 Synthesis of N- (3-chloro-2- ((5- ((3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.60(s,1H),8.27(s,1H),8.20(s,2H),7.92(d,J＝7.4Hz,1H),7.31-7.23(m,3H),6.99(s,2H),6.90(dd,J＝8.1,1.7Hz,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,1.7Hz,1H),5.72(dd,J＝10.2,1.7Hz,1H),5.07(s,2H),3.75(s,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.58,159.34,156.32,146.46,145.90,138.12,136.99,133.05,131.66,129.56,129.30,127.25,126.74,125.27,121.51,119.92,113.53,113.30.HRMS(ESI)calcd for C21H19ClN4O3[M+H]+:411.12184；found 411.12159.
synthetic method referring to example 10, only step 3 employed the synthetic method of step 3 of example 4.
Example 18 Synthesis of N- (3-chloro-2- ((5- (benzyloxy) pyrimidin-2-yl) -amino) -3-chloro-phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.59(s,1H),8.25(s,1H),8.20(s,2H),7.92(d,J＝7.5Hz,1H),7.43(d,J＝7.4Hz,2H),7.39(t,J＝7.3Hz,2H),7.34(t,J＝7.0Hz,1H),7.26(dt,J＝15.9,7.9Hz,2H),6.55(dd,J＝16.9,10.2Hz,1H),6.23(d,J＝17.0Hz,1H),5.72(d,J＝10.2Hz,1H),5.09(s,2H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,156.31,146.49,145.87,136.98,136.54,133.04,131.65,129.29,128.42,128.03,127.89,127.24,126.73,125.26,121.50,70.76.HRMS(ESI)calcd for C20H17ClN4O2[M+H]+:381.11128；found 381.11107..
the synthetic route is the same as that of example 10, and only step 3 adopts the synthetic method of step 3 of example 4.
EXAMPLE 19 Synthesis of N- (3-chloro-2- ((5- (1- (2, 6-dichloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.55(s,1H),8.28(s,1H),7.94(s,2H),7.89(dd,J＝7.2,1.9Hz,1H),7.29–7.13(m,2H),6.86(s,1H),6.52(dd,J＝17.0,10.2Hz,1H),6.20(dd,J＝17.0,1.8Hz,1H),6.01(q,J＝6.5Hz,1H),5.69(dd,J＝10.2,1.7Hz,1H),3.89(s,6H),1.69(d,J＝6.6Hz,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.55,156.37,154.57,145.95,144.99,136.91,135.38,132.83,131.63,129.08,127.10,126.69,125.23,121.55,112.39,98.08,74.02,56.63.HRMS(ESI)calcd for C23H21Cl3N4O4[M+H]+:523.07012；found 523.06996.
the synthetic route is as follows:
step 1.1 Synthesis of 1- (2, 6-dichloro-3, 5-dimethoxyphenyl) ethan-1-ol
Under ice bath, a tetrahydrofuran solution of methylmagnesium bromide (1.3ml,1.5eq,1M) was slowly added dropwise to an argon-protected anhydrous tetrahydrofuran (1.5ml) solution of 2, 6-dichloro-3, 5-dimethoxybenzaldehyde (0.2077g,0.8838mmol,1.0eq), and after the addition was complete, the ice bath was removed and stirred at room temperature for 2 h. Saturated aqueous ammonium chloride solution was added dropwise to the reaction solution to quench the reaction, followed by extraction with ethyl acetate and concentration of the organic phase. Column chromatography gave 0.171g of the desired product in 77.08% yield.1H NMR(400MHz,DMSO-d6):δ(ppm)6.82(s,1H),5.50(qd,J＝6.8,4.8Hz,1H),5.24(d,J＝4.7Hz,1H),3.90(d,J＝7.1Hz,6H),1.44(d,J＝6.8Hz,3H).
Step 2.2 Synthesis of 2-chloro-5- (1- (2, 6-dichloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidine
Diisopropyl azodicarboxylate (0.8298g,4.104mmol,6.0eq) was added dropwise to a solution of triphenylphosphine (1.0765g,4.104mmol,6.0eq) in anhydrous tetrahydrofuran (13.5ml) while cooling on ice. After 15 minutes of reaction under ice bath, a solution of 1- (2, 6-dichloro-3, 5-dimethoxyphenyl) ethan-1-ol (0.171g,0.6840mmol,1.0eq) in tetrahydrofuran (3.67ml,5.36ml/mmol) was added dropwise to a reaction flask followed by the addition of 2-chloro-5-hydroxypyrimidine (0.3571g,2.736mmol,4.0 eq). The ice bath was removed and the reaction was carried out at room temperature for 12 h. 1M NaOH (2.8ml) aqueous solution and water (6ml) were added to the reaction flask, and extraction was performed with ethyl acetate, the organic phase was concentrated, and column chromatography was performed to obtain 0.1271g of the objective product, yield: 51.12%.1H NMR(400MHz,DMSO-d6):δ(ppm)8.29(s,2H),6.89(s,1H),6.25(q,J＝6.6Hz,1H),3.89(s,6H),1.74(d,J＝6.6Hz,3H).
Step 4. same as step 3 of example 4.
Step 5. same as step 4 of example 4.
EXAMPLE 20 Synthesis of N- (3-chloro-2- ((5- (1- (2-chloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.54(s,1H),8.27(s,1H),8.00(s,2H),7.90(d,J＝6.6Hz,1H),7.29–7.17(m,2H),6.62(dd,J＝10.5,2.5Hz,2H),6.52(dd,J＝17.0,10.2Hz,1H),6.20(dd,J＝17.0,1.6Hz,1H),5.69((dd,J＝10.0,5.0Hz,1H),5.61(q,J＝6.0Hz,1H),3.84(s,3H),3.74(s,3H),1.54(d,J＝6.2Hz,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.55,159.27,156.36,155.49,146.52,145.25,140.90,136.95,132.90,131.64,129.12,127.13,126.72,125.22,121.52,110.72,102.97,99.14,73.89,56.26,55.49,21.95.HRMS(ESI)calcd for C23H22Cl2N4O4[M+H]+:489.10909；found489.10933.
the synthesis method refers to example 19, except for step 4, refer to step 3 of example 10.
EXAMPLE 21 Synthesis of N- (3-chloro-2- ((5- (1- (3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide
And (3) product characterization:1H NMR(500MHz,DMSO-d6):δ(ppm)9.55(s,1H),8.21(s,1H),8.07(s,2H),7.90(d,J＝7.5Hz,1H),7.37–7.14(m,2H),6.62–6.45(m,3H),6.39(d,J＝2.1Hz,1H),6.21(dd,J＝17.0,1.7Hz,1H),5.70(dd,J＝10.2,1.7Hz,1H),5.31(q,J＝6.2Hz,1H),3.71(s,6H),1.52(d,J＝6.3Hz,3H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,160.64,156.17,146.77,145.52,144.60,136.95,132.97,131.66,129.26,127.15,126.67,125.23,121.50,103.96,99.27,76.73,55.13,23.68.HRMS(ESI)calcd for C23H23ClN4O4[M+H]+:455.14806；found 455.14786.
the synthesis method refers to example 19, except for step 4, refer to step 3 of example 10.
EXAMPLE 22 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-6-methylphenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.57(s,1H),8.33(s,2H),8.00(s,1H),7.84(d,J＝8.0Hz,1H),7.16(t,J＝7.9Hz,1H),7.00(s,1H),6.95(d,J＝7.4Hz,1H),6.51(dd,J＝17.1,10.2Hz,1H),6.26(dd,J＝17.1,1.8Hz,1H),5.78(dd,J＝10.2,1.8Hz,1H),5.29(s,2H),3.94(s,6H),2.18(s,3H).13C NMR(500MHz,DMSO-d6):δ(ppm)163.81,155.39,154.39,146.83,146.30,136.07,135.07,132.26,131.12,126.88,126.43,126.41,124.05,119.06,114.74,99.17,67.12,56.77,18.29.HRMS(ESI)calcd for C23H22Cl2N4O4[M+H]+:489.10909；found 489.10929.
the synthesis method is referred to example 4.
EXAMPLE 23 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-4-methylphenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.77(s,1H),8.37(s,1H),8.32(s,2H),7.63(s,1H),7.35(d,J＝8.1Hz,1H),7.00(s,1H),6.88(d,J＝8.1Hz,1H),6.48(dd,J＝17.0,10.1Hz,1H),6.25(dd,J＝17.0,1.8Hz,1H),5.81–5.70(m,1H),3.94(s,6H),2.28(s,3H).13C NMR(500MHz,DMSO-d6):δ(ppm)163.70,155.75,154.39,146.80,146.31,134.53,133.09,132.30,131.50,126.86,126.56,124.56,123.60,123.32,114.76,99.15,67.12,56.77,20.81.HRMS(ESI)calcd for C23H22Cl2N4O4[M+H]+:489.10909；found 489.10929.
the synthesis method is referred to example 4.
EXAMPLE 24 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-3, 5-difluorophenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.63(s,1H),8.56(s,1H),8.46(s,2H),7.97(d,J＝11.5Hz,1H),7.01(s,1H),6.93(t,J＝10.0Hz,1H),6.49(dd,J＝10.0,7.0Hz,1H),6.25(d,J＝17.0Hz,1H),6.25(d,J＝17.0Hz,1H),5.33(s,2H),3.95(s,6H).
the synthesis method is referred to example 1.
EXAMPLE 25 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-4- (4-methylpiperidin-1-yl) phenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.68(s,1H),8.33(s,1H),8.31(s,2H),7.45(s,1H),7.24(d,J＝8.8Hz,1H),7.00(s,1H),6.66(d,J＝8.4Hz,1H),6.45(dd,J＝16.8,6.0Hz,1H),6.23(d,J＝8.8Hz,1H),5.73(d,J＝10.0Hz,1H),5.8(s,2H),3.94(s,6H),3.10(t,4H),2.45(t,4H),1.99(s,3H).
synthesis method referring to example 7, 2-methoxy-6-nitroaniline in step 1 was replaced with 5- (4-methylpiperazin-1-yl) 2-nitroaniline.
EXAMPLE 26 Synthesis of N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-3- (trifluoromethyl) phenyl) acrylamide
And (3) product characterization:1H NMR(400MHz,DMSO-d6):δ(ppm)9.45(s,1H),8.23(d,J＝7.6Hz,1H),8.19(s,2H),8.09(s,1H),7.51(dt,J＝15.8,7.1Hz,2H),6.99(s,1H),6.50(dd,J＝17.0,10.2Hz,1H),6.19(dd,J＝17.0,1.8Hz,1H),5.70(dd,J＝10.2,1.8Hz,1H),5.22(s,2H),3.95(d,J＝14.2Hz,6H).13C NMR(125MHz,DMSO-d6):δ(ppm)163.57,157.49,154.38,146.67,146.08,138.11,132.29,131.53,129.81,128.59,128.36,127.27,127.10,124.66,122.49,122.26,114.74,99.16,66.95,56.76.HRMS(ESI)calcd for C23H19Cl2F3N4O4[M+H]+:543.08082；found 543.08068.
the synthesis method is referred to example 1.
Experimental example 1 in vitro detection of kinase Activity and tumor cell proliferation inhibitory Activity
Detection method
1. Kinase activity assay
Kinase activity assays were performed using the Z' -LYTETM kit from Invitrogen, usa, following the technical instructions. The specific operation is as follows: the drug was diluted in a gradient (3-fold dilution from 10. mu.M/L) and FGFRs kinase (about 0.1-0.01. mu.M/mL) was added with a baseThe substance (about 50. mu.M to 800. mu.M) was added to a 25. mu.l reaction system and the phosphorylation reaction was carried out for 2 hours; then adding the phosphorylated polypeptide with the fluorescent label and an antibody for recognizing the phosphorylated polypeptide into the reaction system, balancing for about 4-24 hours, and then detecting on a microplate reader. The FP value (fluorescence polarization value) of the drug is subjected to Graphpad Prism 5.0 fitting analysis to obtain the IC of the screened drug50. Half maximal Inhibitory Concentration (IC) of each compound against FGFRs kinase50) The values are described in table 1.
2. Detection of tumor cell proliferation inhibitory Activity
Inhibition of cell proliferation in vitro was detected using CCK8 assay: MDA-MB-453 (breast cancer cell line), MDA-MB 231 (breast cancer cell line) and MCF-7 (breast cancer cell line) were stored in corresponding growth media and passaged at least two times before resuscitative use. The appropriate number of cells in the logarithmic growth phase were seeded in 96-well plates in a volume of 100. mu.L per well and then cultured overnight in a 37 ℃ incubator containing 5% CO 2. In addition, the test compound was dissolved in DMSO to prepare a 10mM/L stock solution, and then the test compound was diluted to 1X 10 with the medium-5M/L to 1X 10-10Between M/L, 100. mu.L of compound solutions of different concentrations were added to the corresponding 96-well plates. Cell controls and blank controls were set. After 72 hours of co-incubation, 10. mu.L of CCK-8 reagent was added, incubation continued in the incubator for 1 to 3 hours, and after 10 minutes of shaking, OD450 was read using a Synergy TMHT (Bio Tek) microplate reader. Finally, the data were processed with GraphPad Prism version 5.0 and the IC was fitted using a non-linear regression model50Values (table 2).
Second, experimental results
The results of the experiment are shown in tables 1 and 2:
TABLE 1 kinase Activity test results (units: nM/L) for the compounds prepared in examples 1-26
TABLE 2 test results of inhibition of tumor cell proliferation by the compounds prepared in example 1 and example 2
The BGJ398 is a positive control drug and is an FGFR4 selective small molecule inhibitor.
The compounds in tables 1 and 2 were selected from the compounds prepared in examples 1 to 26, respectively, and are indicated by the numbers of the examples in the tables.
The above biological test results show that: the 2-aminopyrimidines can selectively inhibit the kinase activity of FGFR4, but not inhibit the kinase activity of other members of FGFR family (FGFR1, FGFR2 and FGFR 3). When R is on the phenyl ring6,R7All of them are halogen (e.g., the compounds prepared in examples 1, 2 and 24), the activity is higher, and the selectivity is good. On cells, 2-aminopyridines also show selectivity: the compounds prepared in example 1 and example 2 strongly inhibited MDA-MB-453 cell proliferation with abnormal FGF19-FGFR4 signaling pathway, while having less effect on cell proliferation of MDA-MB-231 and MCF-7 with low FGFR4 expression. The compounds can be used for the targeted treatment of tumors caused by the abnormal FGF19-FGFR4 signaling pathway.
EXAMPLE 2 protein immunoblotting test (Western blot)
MDA-MB-453 cells were seeded into a 6-cm cell well plate, and 24 hours later, the medium was changed, the compound prepared in example 1 was added at the corresponding concentration, and 1% DMSO was used as a control. After 2 hours incubation, the well plates were washed twice with pre-cooled PBS and the residual PBS was removed completely, followed by addition of 400. mu.L of 1 × cell lysis buffer (prepared according to the CST manual). After incubation on ice for 5 minutes, cells were scraped off and immediately sonicated. Centrifugation was carried out at 14,000 rpm at 4 ℃ to obtain a supernatant, the protein was denatured by boiling, and the supernatant was stored at-70 ℃ to be assayed. If necessary, 20. mu.L of the protein sample was applied to SDS-PAGE gel and separated by electrophoresis. The gels were transferred to PVDF membrane (Milipore) and then the PVDF membrane was blocked by dipping in a solution of 5% bovine serum albumin and TBST for 1 hour. After incubating the membrane with primary antibodies [ antibodies FGFR4, phor-FGFR 4(Y642), phor-FRS 2, ERK, phor-ERK (t202/Y204), Akt, phor-Akt (Thr308), GAPDH ] for 2 hours at room temperature, the membrane was washed three times with TBST for 10 minutes each. Then, a 2000-fold dilution of horseradish peroxidase (HRP, sigma) labeled rabbit secondary antibody with 5% BSA/TBST was added and incubated again for 1 hour at room temperature. Rinse three times with TBST for 10 minutes each. Finally, development was performed by enhancing cheminescence (thermo) (the result is shown in fig. 1).
FIG. 1 shows that compound 1 dose-dependently inhibits the phosphorylation of downstream target proteins (FRS2, ERK1/2, and Akt).
Combining the data in table 1, table 2 and fig. 1, we can see that the compound prepared by the present invention shows strong in vitro biological activity (at kinase and cellular level) and can be used as candidate molecule for targeting treatment of relevant tumors.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. 2-aminopyrimidines having the structure of formula (i):
wherein:
R1，R2，R3，R4each independently selected from: h, halogen, C1-C6 alkyl, C1-C6 alkoxy;
R6，R7selected from halogens; or R6，R7One of which is selected from hydrogen or halogen and the other is selected from halogen substituted C1-C2 alkyl;
R8selected from H or C1-C6 alkyl.
2. A2-aminopyrimidine according to claim 1 wherein R is selected from the group consisting of6，R7Selected from halogens.
3. A2-aminopyrimidine according to claim 2 wherein R is selected from the group consisting of6，R7Each independently selected from Cl or F.
4. A2-aminopyrimidine according to claim 1 wherein R is selected from the group consisting of1，R2，R3，R4Any two of which are selected from halogens and the other two are selected from C1-C6 alkoxy groups.
5. A2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 4 wherein R is1，R2，R3，R4Any two of which are selected from Cl or F and the other two are selected from methoxy.
6. 2-aminopyrimidines according to claim 1Or a pharmaceutically acceptable salt thereof, wherein R is1，R2，R3，R4Any two of which are selected from Cl or F, the other two are selected from methoxy; r6，R7Each independently selected from Cl or F; r8Is selected from H.
7. 2-aminopyrimidine compounds with a structure shown in a formula (I) or pharmaceutically acceptable salts thereof,
the 2-aminopyrimidine compound is characterized by being selected from the following compounds:
n- (3, 5-dichloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (3-chloro-2- ((-5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) -5-fluorophenyl) acrylamide,
N- (3-chloro-2- ((5- ((2, 6-dichloro-3, 5-dimethoxy) oxy) pyrimidin-2-yl) amino-5-trifluoromethylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-ethylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-fluorophenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-methoxyphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-ethoxyphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) -3-isopropoxyphenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2, 6-dichloro-3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2, 6-dichlorobenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chloro-3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chloro-5-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((2-chlorobenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- ((3-methoxybenzyl) oxy) pyrimidin-2-yl) -amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- (benzyloxy) pyrimidin-2-yl) -amino) -3-chloro-phenyl) acrylamide,
N- (3-chloro-2- ((5- (1- (2, 6-dichloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- (1- (2-chloro-3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (3-chloro-2- ((5- (1- (3, 5-dimethoxyphenyl) ethoxy) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-6-methylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-4-methylphenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-3, 5-difluorophenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-4- (4-methylpiperidin-1-yl) phenyl) acrylamide,
N- (2- ((5- ((2, 6-dichloro-3, 5-dimethoxybenzyl) oxy) pyrimidin-2-yl) amino-3- (trifluoromethyl) phenyl) acrylamide.
8. Use of a 2-aminopyrimidine compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of hyperproliferative diseases caused by abnormalities of the FGFR4 signalling pathway.
9. The use according to claim 8, wherein the hyperproliferative disease is a tumor, wherein the tumor is breast cancer, liver cancer, stomach cancer, prostate cancer, rhabdomyosarcoma, melanoma.
10. A pharmaceutical composition for treating or preventing hyperproliferative disorders, comprising a 2-aminopyrimidine compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
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