CN110283162B - Epidermal growth factor receptor inhibitor and application thereof - Google Patents
Epidermal growth factor receptor inhibitor and application thereof Download PDFInfo
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- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a novel epidermal growth factor receptor inhibitor and application thereof. Pyrimidines of the general formula (I), pyrido [2,3-d]The pyrimidine and quinazoline compounds and the pharmaceutically acceptable salts, prodrugs or solvates thereof are compounds which have an inhibitory effect on tumor cells which produce variation in EGFR tyrosine kinase and can be used for the treatment, combined treatment or prevention of various cancers. More particularly, the compounds have obvious treatment effect on the del19, L858R, T790M and C797S variant types of EGFR.
Description
Technical Field
The invention discloses a derivative taking pyrimidines, pyrido [2,3-d ] pyrimidines and quinazolines as parent nucleus, and pharmaceutically acceptable salt, prodrug and solvate thereof, and a preparation method and medical application thereof, and the derivative is a compound which has an inhibitory effect on tumor cells generating variation of EGFR tyrosine kinase, and can be used for treating, combining and preventing various cancers. More particularly, the compounds have obvious treatment effect on the del19, L858R, T790M and C797S variant types of EGFR.
Background
Malignant tumors, as the biggest public health problem in the world, are common diseases and frequently encountered diseases that seriously threaten human health. Research shows that EGFR has over-expression in various tumors and plays an important role in cell proliferation, so that EGFR is one of the potential antitumor drug targets. In recent years, dry-to-drug development for EGFR has achieved encouraging performance. The first generation of EGFR inhibitors Gefitinib, Erlotinib, Icotininib and the second generation of EGFR inhibitors Afatinib which take EGFR as a target have been approved for clinical treatment of non-small cell lung cancer.
EGFR (also known as ErbB1 or HER1) is part of the ErbB family of transmembrane receptor tyrosine kinases that primarily regulate signaling pathways for cell amplification and apoptosis. EGFR structurally consists of an extracellular ligand binding region, a single-chain transmembrane region, and an intracellular protein tyrosine kinase region. It is widely present on epithelial cell membranes except vascular tissues, and is overexpressed in various human malignant tumors, particularly in solid tumors such as lung cancer, gastric cancer, cervical cancer, pancreatic cancer, renal cancer, breast cancer and the like.
The representative drug of the third generation EGFR-TKI is Osimetinib (AZD-9291), the molecule can be combined with Cys-797 residue in an ATP binding site of EGFR kinase in an irreversible covalent bond mode, so that the drug resistance of the first two generations of drugs is overcome, and the EGFR-TKI has excellent inhibitory activity on L858R mutant tumor cells, exon 19 deletion tumor cells and T790M mutant tumor cells. Unlike the first and second generations, the activity of the mutant EGFR (including the T790M mutation) by the Osimetinib (AZD-9291) is much higher than that of the wild-type EGFR, and higher safety is shown. For patients, the drug reduces toxicity of skin and gastrointestinal tract caused by inhibition of wild-type EGFR, thereby having a wide clinical application prospect.
Unfortunately, clinical data show that after the patient uses the Osimetinib (AZD-9291) for a long time, a new C797S mutation is generated at the exon 20 site of the EGFR of the patient, so that the treatment effect of the drug is greatly reduced. In vitro studies show that after EGFR kinase is mutated at C797S site, drug molecules cannot form covalent bonds with EGFR kinase, so that the binding capacity of the drug molecules and EGFR kinase is reduced, the inhibitory activity of the drug is further reduced, and drug resistance is generated. How to overcome the problem of drug resistance of the Osimetinib (AZD-9291) caused by the mutation of C797S is a necessary difficulty for developing a new generation of EGFR-TKI.
Disclosure of Invention
The invention discloses a derivative taking pyrimidines, pyrido [2,3-d ] pyrimidines and quinazolines as parent nucleus and pharmaceutically acceptable salt, prodrug and solvate thereof, which is a compound having an inhibiting effect on tumor cells generating variation of EGFR tyrosine kinase and can be used for treating, combining and preventing various cancers. More particularly, the compounds have obvious treatment effect on the variant types of del19, L858R and T790M of EGFR.
The technical scheme adopted by the invention is as follows: pyrimidines, pyrido [2,3-d ] pyrimidines, quinazolines and pharmaceutically acceptable salts, prodrugs or solvates thereof having the general formula (I):
wherein the content of the first and second substances,
R1is composed of
Wherein X is selected from one of F, Cl, Br, OH or CN;
R2is composed of
Any one of the above;
R3is hydrogen or oxygen substituted C1-C6 alkyl, CD3 or F substituted C1-any one of C6 alkyl;
R4is composed of
The pyrimidine compounds, pyrido [2,3-d ] pyrimidine compounds and quinazoline compounds represented by the general formula (I) have the following structures.
A composition is prepared by taking the pyrimidine, pyrido [2,3-d ] pyrimidine and quinazoline compounds and pharmaceutically acceptable salts thereof as effective components and combining the effective components with pharmaceutically acceptable carriers.
Further, the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder and a lubricant.
Further, the composition is prepared into the dosage forms of tablets, capsules, granules, sprays or injections.
The pyrimidine, pyrido [2,3-d ] pyrimidine and quinazoline compounds and pharmaceutically acceptable salts, prodrugs or solvates thereof and the application of the composition as a protein tyrosine kinase inhibitor.
Further, the protein tyrosine kinase inhibitor is an epidermal growth factor receptor inhibitor.
The pyrimidine, pyrido [2,3-d ] pyrimidine and quinazoline compounds, pharmaceutically acceptable salts, prodrugs or solvates thereof and application of the composition in preparing medicines for treating diseases related to epidermal growth factor receptor overexpression.
Further, the diseases related to the overexpression of the epidermal growth factor receptor are selected from renal cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and glioma.
The invention has the beneficial effects that: the derivative taking pyrimidines, pyrido [2,3-d ] pyrimidines and quinazolines as a parent nucleus prepared by the invention is a compound with an inhibiting effect on tumor cells generating variation of EGFR tyrosine kinase, and can be used for treating, jointly treating or preventing various cancers. More particularly, the compounds have obvious treatment effect on the variant types of del19, L858R and T790M of EGFR.
Detailed Description
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic schemes describe the preparation of the pyrimidine derivatives, pyrido [2,3-d ] pyrimidine derivatives and quinazoline derivatives of the general formula (I).
All starting materials are prepared by the means described in the synthetic schemes below, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final derivatives of the invention are prepared by, or by analogy with, the methods described in the synthetic schemes below and are well known to those of ordinary skill in the art of organic chemistry. All variables used in the synthetic routes described below are as defined below or as defined in the claims.
The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the compounds was measured using Bruker ARX-400 or ARX-600 and Mass Spectroscopy was measured using Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
The synthetic route is as follows:
fragment one: synthesized by the following method2The functional groups are shown as groups in the claims:
fragment two: synthesized by the following method5Are the corresponding basic groups.
Fragment three: the target compound is prepared by adopting the following synthesis method.
EXAMPLE 1 preparation of Compound 4
1. Synthesis of intermediate e
Dissolving d (10g, 1.0eq) in acetonitrile (30mL), dropwise adding BOC anhydride (14g, 1.2eq) at 25 ℃, then raising the temperature to 60 ℃, reacting for 10 hours, rotationally evaporating part of solvent, cooling, crystallizing, filtering to obtain a filter cake, and washing the filter cake with acetonitrile solvent to obtain a pure intermediate e. And adding BOC anhydride (8g) into the obtained filtrate to continue the reaction, cooling and crystallizing for the second time after 10 hours, and repeating the operation for 5 times to obtain an intermediate e, wherein 14g of a light yellow solid is obtained, and the yield is 91%.
LC-MS(ESI):m/z 287.10(M+H)+
2. Synthesis of intermediate f
Intermediate e (8.4g, 1eq), pyrrole (2.9g, 1.5eq), sodium hydroxide (2.3g, 2eq) were added to a 100mL eggplant-shaped flask, DMSO (15mL) was added, the reaction time was 4h at 40 ℃ and the reaction was checked by TLC to be complete. And adding water into an eggplant-shaped bottle to separate out insoluble substances, filtering, and washing a filter cake with water to obtain an intermediate f, wherein the red solid is 3.6g, and the yield is 36.8%.
LC-MS(ESI):m/z 334.13(M+H)+
3. Synthesis of intermediate g
The intermediate f (18.29g, 10eq) is dissolved in 1, 4-dioxane, then ferric trichloride (4.45g, 3.0eq) containing six crystal water, activated carbon (400mg, 6eq) and 80% hydrazine hydrate (82g, 300eq) are added, the reaction is carried out for 5h at 110 ℃, and the completion of the reaction is detected by TLC point plates. Then filtered through celite, the aqueous phase extracted with ethyl acetate and spun dry under reduced pressure to give g of intermediate, 15g with 90% yield.
LC-MS(ESI):m/z 304.16(M+H)+
4. Synthesis of intermediate h
Intermediate g (1g, 1eq) was dissolved in tetrahydrofuran (4mL) and N, N-diisopropylethylamine (0.802 g, 2.5eq) and acryloyl chloride (0.4g, 2.0eq) were added and reacted at 25 ℃ for 6 h. The reaction was complete by TLC. Excess sodium bicarbonate was added to the reaction solution to quench acryloyl chloride, extracted, washed three times with ethyl acetate, the organic phases were combined, and the intermediate h was spin-dried under reduced pressure with a yield of 1.1g of 93.4%.
LC-MS(ESI):m/z 358.17(M+H)+
5. Synthesis of intermediate i-4
The compound morpholine solution (588mg, 1.5eq), glacial acetic acid (10mL) with 40% formaldehyde content (270mg, 1.5eq) were added to an eggplant type bottle in sequence, stirred at normal temperature for 1h, then the intermediate h (2g, 1.0eq) was added to the eggplant type bottle, stirred at normal temperature, and the reaction was detected to be complete by TLC. And then, evaporating part of the solvent in a rotary manner, adding 100mL of tap water, and filtering to obtain a filter cake, namely the intermediate i-4.
LC-MS(ESI):m/z 457.2(M+H)+
6. Synthesis of intermediate j-4
Intermediate i-4(0.4g, 1.0eq) was dissolved in dichloromethane solution, then trifluoroacetic acid (1.5g, 15eq) was added for 3h and the reaction was complete by TLC. Then sodium bicarbonate is added into the reaction liquid to adjust the pH value to 10, extraction is carried out, ethyl acetate is used for washing for 3 times, organic phases are combined, decompression and spin drying are carried out, column chromatography separation is carried out, and the intermediate j-4 of the product is obtained, wherein the yield of 0.18g is 57%.
LC-MS(ESI):m/z 357.2(M+H)+
7. Synthesis of intermediate c-1
The compound a (5g, 1.0eq), b-1(5g, 0.9eq) and aluminum trichloride (5g, 1.0eq) were added to a 100mL eggplant-shaped flask, reacted at 80 deg.C, the reaction was complete by TLC, then ice water was added, stirred for 5min, filtered with suction, and the cake was rinsed with 50mL water. Column chromatography separation to obtain intermediate c-1, 7g with yield 75.3%
LC-MS(ESI):m/z 244.1(M+H)+
8. Synthesis of Compound 4
C-1(35mg, 1.5eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (48mg, 2eq) and j-4(50 mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Adding sodium bicarbonate into the reaction solution to adjust the pH value to 10, extracting, washing twice by dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 4, wherein the yield of 20mg is 24.7%.
LC-MS(ESI):m/z 564.2(M+H)+
1H NMR(600MHz,CDCl3)δ9.47(s,1H),8.96(s,1H),8.76(s,1H),8.42(d,J＝5.2Hz,1H), 8.10(d,J＝6.9Hz,1H),7.83(s,1H),7.40(d,J＝7.3Hz,1H),7.33–7.27(m,3H),7.24(d,J＝5.1 Hz,1H),6.74(s,2H),6.27(dd,J＝39.6,20.2Hz,4H),5.68(d,J＝10.2Hz,1H),3.97(s,3H),3.89 (s,3H),3.66(d,J＝17.6Hz,4H),3.28(d,J＝13.9Hz,1H),3.16(d,J＝13.8Hz,1H),2.67(s,2H), 2.33(s,2H).
EXAMPLE 2 preparation of Compound 5
1. Synthesis of intermediate i-5
Diethylamine solution (0.306g, 1.5eq), 40% formaldehyde content (0.315g, 1.5eq), and glacial acetic acid (10mL) were added sequentially to the eggplant type bottle, stirred at room temperature for 1 hour, then intermediate h (1g, 1eq) was added to the eggplant type bottle, stirred at room temperature, and the reaction was detected by TLC. Then, part of the solvent is removed by rotary evaporation, 100mL of tap water is added, and a filter cake is obtained by filtration, namely the product intermediate i-5, 0.6g, and the yield is 48.5%.
LC-MS(ESI):m/z 443.26(M+H)+
2. Synthesis of intermediate j-5
Intermediate i-5(600mg, 1eq) was dissolved in dichloromethane solution, followed by trifluoroacetic acid (2320mg, 15eq) for 3h, and the reaction was complete as detected by TLC. Adding sodium bicarbonate into the reaction solution to adjust the pH value to 10, extracting, washing with ethyl acetate for 3 times, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain a product intermediate j-5, wherein the yield of 400mg is 86%.
LC-MS(ESI):m/z 344.2(M+H)+
3. Synthesis of Compound 5
C-1(94mg, 1.5eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (110mg, 2eq) and j-5 (110mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Adding sodium bicarbonate into the reaction solution, adjusting the pH value to 10, extracting, washing twice with dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 5, wherein the yield of 100mg is 62.5%.
LC-MS(ESI):m/z 550.29(M+H)+
1H NMR(600MHz,Chloroform-d)δ10.26(s,1H),9.29(s,1H),8.76(s,1H),8.41(d,J＝5.3 Hz,1H),8.09(d,J＝6.9Hz,1H),7.78(s,1H),7.41–7.38(m,1H),7.28(ddd,J＝6.9,4.7,1.5Hz, 2H),7.23(d,J＝5.3Hz,1H),6.70(d,J＝8.7Hz,2H),6.31(dd,J＝16.9,1.7Hz,1H),6.22(d,J＝ 4.8Hz,2H),6.10(dd,J＝17.0,10.3Hz,1H),5.62(dd,J＝10.1,1.7Hz,1H),3.97(s,3H),3.87(s, 3H),3.40–3.26(m,2H),2.73(dd,J＝13.4,7.1Hz,2H),2.57(dd,J＝13.4,7.0Hz,2H),0.96(t,J ＝7.0Hz,6H).
EXAMPLE 3 preparation of Compound 6
1. Synthesis of intermediate i-6
4-methylpyridine solution (0.4g, 1.5eq), glacial acetic acid (10mL) with 40% formaldehyde content (0.54g, 2eq) were added to an eggplant type bottle in sequence, stirred at room temperature for 1 hour, then intermediate h (1.2g, 1eq) was added to the eggplant type bottle, stirred at room temperature, and the reaction was detected by TLC to be complete. Then, part of the solvent is removed by rotary evaporation, 100mL of tap water is added, and a filter cake is filtered to obtain a product intermediate i-6, 0.73g, with the yield of 46%.
LC-MS(ESI):m/z 469.26(M+H)+
2. Synthesis of intermediate j-6
Intermediate i-6(570mg, 1eq) was dissolved in dichloromethane solution, then trifluoroacetic acid (2080mg, 15eq) was added for 3h, and the reaction was complete by TLC. Adding sodium bicarbonate into the reaction solution to adjust the pH value to 10, extracting, washing 3 times with ethyl acetate, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain a product intermediate j-6, wherein the yield of 125mg is 28%.
LC-MS(ESI):m/z 369.2(M+H)+
3. Synthesis of Compound 6
C-1(48mg, 1.2eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (56mg, 2eq) and j-6 (60mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Adding sodium bicarbonate into the reaction solution, adjusting the pH value to 10, extracting, washing twice with dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 6, wherein the yield of 30mg is 48%.
LC-MS(ESI):m/z 576.3(M+H)+
1H NMR(600MHz,CDCl3)δ9.39(s,1H),8.73(s,1H),8.41(d,J＝5.2Hz,1H),8.10(d,J＝ 6.9Hz,1H),7.83(s,1H),7.40(d,J＝7.4Hz,1H),7.31–7.27(m,2H),7.24(d,J＝5.2Hz,2H), 6.72(d,J＝32.0Hz,2H),6.26(dt,J＝17.2,13.5Hz,4H),5.66(d,J＝9.8Hz,1H),3.96(s,3H), 3.88(s,3H),3.32(s,2H),2.03–1.64(m,8H),1.41(s,1H),0.91(d,J＝5.6Hz,3H).
EXAMPLE 4 preparation of Compound 7
1. Synthesis of intermediate c-2
Compound a (432mg, 1.1eq), b-2(600mg, 1.1eq), and aluminum trichloride (382.4mg, 1eq) were added to a 50mL eggplant-shaped flask, reacted at 80 deg.C, the reaction was complete by TLC, ice water was added, the mixture was stirred for 5min, filtered with suction, and the cake was rinsed with 50mL of water. Column chromatography separation to obtain intermediate c-2 with a yield of 400mg 46%.
LC-MS(ESI):m/z 295.07(M+H)+
2. Synthesis of Compound 7
C-2(50mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (53mg, 2eq) and j-4(50 mg, 1.1eq) were added thereto, nitrogen gas was introduced, reaction was carried out at 60 ℃ and completion of the reaction was detected by TLC. Adding sodium bicarbonate into the reaction solution, adjusting the pH value to 10, extracting, washing twice with dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 7, wherein the yield of 30mg is 30%.
LC-MS(ESI):m/z 615.2(M+H)+
1H NMR(600MHz,CDCl3)δ9.49(s,1H),9.18(s,1H),9.04(d,J＝2.3Hz,1H),8.56(d,J＝ 6.9Hz,1H),8.22(s,1H),7.89(s,1H),7.45(d,J＝8.2Hz,1H),7.35(t,J＝7.5Hz,1H),7.26(s, 1H),7.26–7.22(m,2H),6.75(d,J＝10.8Hz,2H),6.32–6.15(m,4H),5.67(d,J＝10.2Hz,1H), 3.99(s,3H),3.90(s,3H),3.69(d,J＝27.1Hz,4H),3.29(d,J＝12.9Hz,1H),3.16(d,J＝13.3Hz, 1H),2.69(s,2H),2.36(s,2H).
EXAMPLE 5 preparation of Compound 8
1. Synthesis of Compound 8
C-2(94mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (100mg, 2eq) and j-5 (100mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Adding sodium bicarbonate into the reaction solution, adjusting the pH value to 10, extracting, washing twice with dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 8, wherein the yield of 30mg is 17%.
LC-MS(ESI):m/z 601.3(M+H)+
1H NMR(600MHz,DMSO)δ10.19(s,1H),8.99(s,1H),8.84–8.71(m,2H),8.53(s,1H), 8.35(s,2H),7.62(d,J＝8.2Hz,1H),7.44(s,1H),7.30(dt,J＝38.8,7.2Hz,3H),6.89(s,1H), 6.57(s,1H),6.28(d,J＝41.4Hz,2H),6.10(d,J＝17.0Hz,1H),5.72(s,1H),4.00(d,J＝23.6Hz, 6H),3.08(s,2H),2.96(s,2H),1.27–0.79(m,8H).
EXAMPLE 6 preparation of Compound 9
1. Synthesis of intermediate i-9
Piperazine mesylate (1.5eq), 40% formaldehyde (270mg, 1.5eq) glacial acetic acid (10mL) were added sequentially to an eggplant type bottle and stirred at room temperature for 1 hour, then intermediate h (2g, 1eq) was added to the eggplant type bottle and stirred at room temperature, and the reaction was detected by TLC. And (4) evaporating part of the solvent, adding 100mL of tap water, and filtering a filter cake to obtain a product intermediate i-9.
LC-MS(ESI):m/z 534.2(M+H)+
2. Synthesis of intermediate j-9
Intermediate i-9(500mg, 1eq) was dissolved in dichloromethane solution, then trifluoroacetic acid (1600mg, 15eq) was added for 3h and the reaction was complete by TLC. Adding sodium bicarbonate into the reaction solution to adjust the pH value to 10, extracting, washing with ethyl acetate for 3 times, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain a product intermediate j-9, wherein the yield of 160mg is 40%.
LC-MS(ESI):m/z 434.18(M+H)+
3. Synthesis of Compound 9
C-2(60mg, 1.2eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (48mg, 2eq) and j-9 (60mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and was detected by TLC to be complete. Adding sodium bicarbonate into the reaction solution, adjusting the pH value to 10, extracting, washing twice with dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 9, wherein the yield of 15mg is 15%.
LC-MS(ESI):m/z 692.3(M+H)+
1H NMR(600MHz,DMSO)δ9.36(s,1H),8.96(d,J＝2.5Hz,1H),8.76–8.68(m,2H), 8.53(s,1H),8.35–8.29(m,2H),7.61(d,J＝8.1Hz,1H),7.41(dd,J＝8.0,4.3Hz,1H),7.33(t,J ＝7.5Hz,1H),7.26(t,J＝7.3Hz,1H),7.14(s,1H),6.75(s,1H),6.29(dd,J＝17.0,10.3Hz,1H), 6.13(s,2H),6.10(d,J＝17.5Hz,1H),5.68(d,J＝10.5Hz,1H),3.97(s,3H),3.93(d,J＝9.8Hz, 3H),3.04(s,4H),2.85(s,2H),2.42(s,4H),1.23(s,3H).
EXAMPLE 7 preparation of Compound 10
1. Synthesis of intermediate j-10
Intermediate h (1000mg, 1eq) was dissolved in dichloromethane solution, then trifluoroacetic acid (4790mg, 15eq) was added for 3h and the reaction was complete by TLC. Then adding sodium bicarbonate into the reaction liquid to adjust the pH value to 10, washing the reaction liquid for 3 times by ethyl acetate, extracting, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain a product intermediate j-10, wherein the yield of 800mg is 90%.
LC-MS(ESI):m/z 258.1M+H)+
2. Synthesis of Compound 10
C-1(113mg, 1.2eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (140mg, 2eq) and j-10 (100mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and was detected by TLC to be complete. Adding sodium bicarbonate into the reaction solution, adjusting the pH value to 10, extracting, washing twice with dichloromethane, combining organic phases, performing reduced pressure spin drying, and performing column chromatography separation to obtain the compound 10, wherein the yield of 50mg is 23%.
LC-MS(ESI):m/z 465.2M+H)+
1H NMR(600MHz,DMSO)δ9.16(s,1H),8.46(d,J＝8.0Hz,1H),8.39(d,J＝5.4Hz,1H), 8.36(s,1H),8.33(s,1H),8.08(s,1H),7.54(d,J＝8.2Hz,1H),7.30(d,J＝5.4Hz,1H),7.27(t,J ＝7.2Hz,1H),7.19(t,J＝7.3Hz,1H),7.15(s,1H),6.74(s,1H),6.09(t,J＝3.1Hz,1H),5.97(d,J ＝1.4Hz,1H),3.97(s,3H),3.89(s,3H),3.09(dt,J＝15.5,9.8Hz,1H),2.79(dd,J＝15.2,9.6Hz, 1H),2.67(dt,J＝12.7,9.7Hz,1H),2.26(t,J＝11.2Hz,1H).
EXAMPLE 8 preparation of Compound 11
1. Synthesis of intermediate c-3
The compound a (1000mg, 1eq), b-3(1370mg, 1.1eq), and aluminum trichloride (1000mg, 1eq) were added to a 50mL eggplant-shaped flask, reacted at 80 deg.C, the reaction was detected by TLC to be complete, then ice water was added, stirred for 5min, filtered with suction, and the cake was washed with 50mL of water. Column chromatography separation to obtain intermediate c-3 with 400mg yield of 18%.
LC-MS(ESI):m/z 294.1(M+H)+
2. Synthesis of Compound 11
C-3(94mg, 1.2eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (100mg, 2eq) and j-5 (100mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Sodium bicarbonate was added to the reaction mixture, pH was adjusted to 10, dichloromethane was washed twice, the organic phases were combined, spin-dried under reduced pressure, and column chromatography was performed to obtain compound 11 in a yield of 30mg of 17%.
LC-MS(ESI):m/z 600.3M+H)+
1H NMR(600MHz,DMSO)δ10.19(s,1H),8.99(s,2H),8.84–8.71(m,2H),8.53(s,1H), 8.35(s,2H),7.62(d,J＝8.2Hz,1H),7.44(s,1H),7.30(dt,J＝38.8,7.2Hz,3H),6.89(s,1H), 6.57(s,1H),6.28(d,J＝41.4Hz,2H),6.10(d,J＝17.0Hz,1H),5.72(s,1H),4.24(dd,J＝214.8, 34.7Hz,2H),4.00(d,J＝23.6Hz,6H),3.08(s,2H),2.96(s,1H),1.20(d,J＝34.6Hz,3H),0.92– 0.84(m,3H).
EXAMPLE 9 preparation of Compound 12
1. Synthesis of intermediate i-12
Dimethylamine solution (0.315g, 1.5eq), glacial acetic acid (10mL) with 40% formaldehyde content (0.315g, 1.5eq) were added to the eggplant type bottle in sequence, stirred at room temperature for 1 hour, then intermediate h (1000mg, 1eq) was added to the eggplant type bottle, stirred at room temperature, and the reaction was detected by TLC to be complete. Then, part of the solvent is removed by rotary evaporation, 100mL of tap water is added, and a filter cake is filtered to obtain a product intermediate i-12.
LC-MS(ESI):m/z 415.2(M+H)+
2. Synthesis of intermediate j-12
Intermediate i-12(500mg, 1eq) was dissolved in dichloromethane and trifluoroacetic acid (2060mg, 15eq) was added for 3h, and the reaction was complete as checked by TLC. Then adding sodium bicarbonate into the reaction liquid to adjust the pH value to 10, extracting, washing 3 times by ethyl acetate, combining organic phases, carrying out decompression spin-drying, and carrying out column chromatography separation to obtain a product intermediate j-12, wherein the recovery rate of 200mg is 52%.
LC-MS(ESI):m/z 315.2(M+H)+
3. Synthesis of Compound 12
C-3(102mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (109mg, 2eq) and j-12 (100mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Then adding sodium bicarbonate to adjust the pH value to 10, extracting, washing twice by dichloromethane, combining organic phases, carrying out reduced pressure spin-drying, and carrying out column chromatography separation to obtain the compound 12, wherein the recovery rate of 30mg is 17%.
LC-MS(ESI):m/z 572.27M+H)+
1H NMR(600MHz,DMSO)δ10.79(s,1H),9.00(s,1H),8.36(d,J＝8.2Hz,1H),8.29(s, 1H),8.23(d,J＝7.9Hz,1H),8.19(s,1H),7.83(t,J＝7.6Hz,1H),7.68(d,J＝8.4Hz,1H),7.60(d, J＝8.2Hz,1H),7.43(t,J＝7.5Hz,1H),7.31(t,J＝7.6Hz,1H),7.24(t,J＝7.4Hz,1H),7.03(s, 1H),6.80(s,1H),6.15(t,J＝17.7Hz,4H),5.73–5.64(m,1H),3.97(s,3H),3.95(d,J＝11.6Hz, 3H),2.49–2.14(m,6H),1.23(s,2H).
EXAMPLE 10 preparation of Compound 13
1. Synthesis of Compound 13
After c-1(60mg, 1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (48mg, 2eq) and j-9(40 mg, 1.2eq) were added thereto, and the reaction was purged with nitrogen at 60 ℃ and checked by TLC to be complete. Then adding sodium bicarbonate to adjust the pH value to 10, extracting, washing twice by dichloromethane, combining organic phases, carrying out reduced pressure spin-drying, and carrying out column chromatography separation to obtain the compound 13, wherein the recovery rate of 22mg is 35%.
LC-MS(ESI):m/z 641.26M+H)+
1H NMR(600MHz,CDCl3)δ9.63(s,1H),8.80(s,1H),8.43(d,J＝4.6Hz,1H),8.11(s,1H), 7.99(s,1H),7.85(s,1H),7.40(d,J＝7.0Hz,1H),7.29(dd,J＝13.9,7.0Hz,3H),6.75(d,J＝8.0 Hz,2H),6.29(s,1H),6.25(s,2H),6.11–6.02(m,1H),5.67(d,J＝10.4Hz,1H),3.96(s,3H), 3.90(s,3H),3.11(d,J＝23.2Hz,4H),2.69(s,4H),2.37(s,2H),1.26(d,J＝10.5Hz,3H).
EXAMPLE 11 preparation of Compound 14
1. Synthesis of Compound 14
C-1(85mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (109mg, 2eq) and j-12 (100mg, 1eq) were added thereto, nitrogen gas was introduced, reaction was carried out at 60 ℃ and completion of the reaction was detected by TLC. Then adding sodium bicarbonate to adjust the pH value to 10, extracting, washing twice by dichloromethane, combining organic phases, carrying out reduced pressure spin-drying, and carrying out column chromatography separation to obtain a product 14, wherein the recovery rate of 30mg is 18%.
LC-MS(ESI):m/z 522.25(M+H)+
1H NMR(600MHz,DMSO)δ11.02(s,1H),8.80(s,1H),8.49(s,1H),8.40(d,J＝5.3Hz, 1H),8.35(d,J＝7.5Hz,1H),8.02(s,1H),7.54(d,J＝8.1Hz,1H),7.32(d,J＝5.3Hz,1H),7.26(t, J＝7.5Hz,1H),7.20(t,J＝7.4Hz,1H),6.96(s,1H),6.79(s,1H),6.17(s,2H),6.14(d,J＝5.5Hz, 2H),5.72–5.66(m,1H),3.90(s,3H),3.90(s,3H),2.24(s,6H),1.23(s,2H).
EXAMPLE 12 preparation of Compound 15
1. Synthesis of intermediate i-15
The pyrrolidine solution (1g, 1.5eq) and glacial acetic acid (10mL) with 40% formaldehyde content (0.315g, 1.5eq) were added to an eggplant-shaped bottle in sequence and stirred at normal temperature for 1 hour, and then the intermediate h (1g, 1eq) was added to the eggplant-shaped bottle and stirred at normal temperature, and the reaction was detected to be complete by TLC. And (4) evaporating part of the solvent, adding 100mL of tap water, and filtering a filter cake to obtain a product intermediate i-15.
LC-MS(ESI):m/z 441.24(M+H)+
2. Synthesis of intermediate j-15
Intermediate i-15(600mg, 1eq) was dissolved in dichloromethane solution, followed by trifluoroacetic acid (2330mg, 15eq) for 3h with TLC check complete. Then sodium bicarbonate is added into the reaction liquid to adjust the pH value to 10, ethyl acetate is used for washing for 3 times, organic phases are combined, decompression and spin-drying are carried out, and column chromatography separation is carried out to obtain a product intermediate j-15 with the yield of 86 percent and the product intermediate j-15 with the yield of 400 mg.
LC-MS(ESI):m/z 341.19(M+H)+
3. Synthesis of Compound 15
C-1(100mg, 1.5eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (128mg, 2eq) and j-15 (127mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and was detected by TLC to be complete. Then adding sodium bicarbonate to adjust the pH value to 10, washing twice by dichloromethane, combining organic phases, carrying out reduced pressure spin-drying, and carrying out column chromatography separation to obtain the compound 15 with 30mg yield of 19%.
LC-MS(ESI):m/z 548.27(M+H)+
1H NMR(600MHz,DMSO)δ10.65(d,J＝51.5Hz,1H),8.80(d,J＝19.4Hz,1H),8.47(d,J ＝24.1Hz,1H),8.40(d,J＝5.3Hz,1H),8.35(t,J＝8.2Hz,1H),8.02(s,1H),7.54(d,J＝8.2Hz, 1H),7.32(t,J＝7.1Hz,1H),7.26(t,J＝7.5Hz,1H),7.19(t,J＝7.4Hz,1H),7.02(s,1H),6.75(s, 1H),6.17(s,1H),6.15(d,J＝2.6Hz,1H),6.14–6.10(m,2H),5.70(dd,J＝7.7,4.3Hz,1H),3.90 (s,6H),3.37(s,2H),2.52(d,J＝15.8Hz,4H),1.76(s,4H).
EXAMPLE 13 preparation of Compound 16
1. Synthesis of Compound 16
C-2(102mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (109mg, 2eq) and j-12 (90mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and was detected by TLC to be complete. Then sodium bicarbonate is added to adjust the pH value to 10, dichloromethane is used for washing twice, organic phases are combined, decompression and spin-drying are carried out, and column chromatography separation is carried out to obtain 16, 30mg and 19% yield.
LC-MS(ESI):m/z 573.26(M+H)+
1H NMR(600MHz,DMSO)δ10.98(s,1H),8.97(dd,J＝4.2,1.8Hz,1H),8.77(s,1H),8.73 (dd,J＝8.2,1.7Hz,1H),8.52(s,1H),8.34(s,1H),8.30(d,J＝7.2Hz,1H),7.61(t,J＝6.4Hz, 1H),7.41(dd,J＝8.1,4.3Hz,1H),7.33(dd,J＝9.0,5.3Hz,1H),7.26(q,J＝7.4Hz,1H),7.03(s, 1H),6.79(s,1H),6.16(d,J＝3.1Hz,2H),6.13(d,J＝8.4Hz,2H),5.69(dd,J＝8.5,3.5Hz,1H), 3.97(s,3H),3.92(s,3H),2.23(s,6H),1.23(s,2H).
EXAMPLE 14 preparation of Compound 17
1. Synthesis of Compound 17
C-3(137mg, 1.2eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (134mg, 2eq) and j-10 (100mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and was detected by TLC to be complete. Then sodium bicarbonate is added to adjust the pH value to 10, dichloromethane is used for washing twice, organic phases are combined, decompression and spin-drying are carried out, and column chromatography separation is carried out to obtain the compound 17 with the yield of 30mg and 15%.
LC-MS(ESI):m/z 515.26(M+H)+
1H NMR(600MHz,DMSO)δ10.79(s,1H),9.00(s,1H),8.36(d,J＝8.2Hz,1H),8.29(s, 1H),8.23(d,J＝7.9Hz,1H),8.19(s,1H),7.83(t,J＝7.6Hz,1H),7.68(d,J＝8.4Hz,1H),7.60(d, J＝8.2Hz,1H),7.43(t,J＝7.5Hz,1H),7.31(t,J＝7.6Hz,1H),7.24(t,J＝7.4Hz,1H),7.03(s, 1H),6.80(s,1H),6.15(t,J＝17.7Hz,4H),5.73–5.64(m,1H),3.97(s,3H),3.95(d,J＝11.6Hz, 3H),2.49–2.14(m,6H),1.23(s,2H).
EXAMPLE 15 preparation of Compound 18
1. Synthesis of Compound 18
C-3(95mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (101mg, 2eq) and j-15 (100mg, 1eq) were added thereto, nitrogen gas was introduced, and the reaction was carried out at 60 ℃ and checked by TLC to be complete. Then adding sodium bicarbonate to adjust the pH value to 10, washing twice by dichloromethane, combining organic phases, carrying out reduced pressure spin-drying, and carrying out column chromatography separation to obtain the compound 18 with the yield of 30mg being 18%.
LC-MS(ESI):m/z 598.26(M+H)+
1H NMR(600MHz,DMSO)δ10.47(s,1H),8.97(s,1H),8.36(d,J＝8.2Hz,1H),8.29(s, 1H),8.24(d,J＝7.9Hz,1H),8.19(s,1H),7.84(t,J＝7.5Hz,1H),7.69(d,J＝7.9Hz,1H),7.60(d, J＝8.2Hz,1H),7.43(t,J＝7.4Hz,1H),7.31(t,J＝7.5Hz,1H),7.23(t,J＝7.4Hz,1H),7.07(s, 1H),6.77(s,1H),6.15(d,J＝21.1Hz,4H),5.73–5.66(m,1H),3.97(s,3H),3.94(s,3H),2.50(s, 4H),1.83(d,J＝64.7Hz,4H),1.23(s,2H).
EXAMPLE 16 preparation of Compound 19
1. Synthesis of Compound 19
C-2(95mg, 1.1eq) was dissolved in 5mL of isopropanol, p-toluenesulfonic acid (101.3mg, 2eq) and j-15 (100mg, 1eq) were added thereto, nitrogen gas was introduced, reaction was carried out at 60 ℃ and completion of the reaction was detected by TLC. Then adding sodium bicarbonate to adjust the pH value to 10, washing twice by dichloromethane, combining organic phases, carrying out reduced pressure spin-drying, and carrying out column chromatography separation to obtain a compound 19, wherein the recovery rate of 30mg is 17%.
LC-MS(ESI):m/z 599.26(M+H)+
1H NMR(600MHz,DMSO)δ10.74(d,J＝88.1Hz,1H),8.98(d,J＝2.5Hz,1H),8.75(d,J ＝6.6Hz,2H),8.51(s,1H),8.35(s,1H),8.32(d,J＝7.2Hz,1H),7.61(t,J＝7.3Hz,1H),7.43(dd, J＝8.0,4.2Hz,1H),7.38–7.31(m,1H),7.27(d,J＝7.1Hz,1H),6.78(s,1H),6.59(s,1H),6.31 (s,1H),6.13(t,J＝28.0Hz,3H),5.68(d,J＝10.9Hz,1H),3.97(d,J＝9.2Hz,6H),2.51(s,4H), 1.87(d,J＝45.3Hz,4H),1.27–1.12(m,2H).
EXAMPLE 17 Compound 4-19 in vitro cell proliferation inhibition assay
1. The compounds 4 to 19 provided in examples 1 to 16 were used as test samples, and showed excellent antitumor effects.
(1) Half maximal Inhibitory Concentration (IC) of Compounds 4 to 19 against tumor cells50) The determination method comprises the following steps:
collecting logarithmic phase H1975, A549 cells, preparing cell suspension with RPMI1640 culture medium, inoculating the cells to 96-well cell culture plate at 37 deg.C and 5% CO at 100 μ L/well2Culturing in an incubator for 24 hours;
processing cells by the compound according to 6 concentration gradients, wherein each cell is 100 mu L; a solvent control group and a blank control group were added, each group was provided with 3 multiple wells (the original culture medium was discarded before administration, and then the medicinal liquid was added), and the temperature was controlled at 37 deg.C and 5% CO2Culturing in an incubator for 48 hours;
thirdly, observing the cell state under an inverted microscope, adding 20 mu L of MTT solution into each hole, and continuously incubating for 4 hours;
fourthly, centrifuging for 10min at room temperature of 1000rpm, carefully discarding the supernatant, airing in a superclean bench, adding DMSO to dissolve the formazan, and dissolving the formazan in 150 mu L/hole.
Fifthly, shaking the mixture on a decoloring shaking table for 5min to fully dissolve the purple crystals; and standing for 10min, measuring the OD value of each hole at 490nm wavelength of an enzyme-labeling instrument, recording the result, and calculating the survival rate of each concentration treatment group.
Survival rate was OD490 drug treated/OD 490 vehicle control; inhibition rate 1-survival rate
(2) Experimental data were analyzed using SPSS statistical software.
2. The results of the inhibition of H1975 and A549 activities of the compounds are shown in Table 1 by taking AZD9291 as a positive control result.
Table 1 results of in vitro bioactivity test of compounds
Claims (9)
1. Pyrimidines, pyrido [2,3-d ] pyrimidines, quinazolines and pharmaceutically acceptable salts thereof of formula (I):
wherein the content of the first and second substances,
R1is composed of
Wherein X is selected from one of F, Cl, Br, OH or CN;
R2is composed of
Any one of the above;
R3is any one of hydrogen, CD3 or C1-C6 alkyl substituted by F;
R4comprises the following steps:
2. a pyrimidine, pyrido [2,3-d ] pyrimidine, quinazoline compound and pharmaceutically acceptable salts thereof, characterized by the following structural formula:
3. a composition comprising the pyrimidine, pyrido [2,3-d ] pyrimidine, quinazoline compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof as an active ingredient, in combination with a pharmaceutically acceptable carrier.
4. The composition of claim 3, wherein the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder, and a lubricant.
5. The composition of claim 3, wherein the composition is formulated into a tablet, capsule, granule, spray or injection.
6. Use of a pyrimidine, pyrido [2,3-d ] pyrimidine, quinazoline compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, and a composition according to claim 3 or 4 or 5 for the manufacture of a protein tyrosine kinase inhibitor medicament.
7. The use according to claim 6, wherein the protein tyrosine kinase inhibitor is an epidermal growth factor receptor inhibitor.
8. Use of the pyrimidines, pyrido [2,3-d ] pyrimidines and quinazolines compounds of claim 1 or 2 and pharmaceutically acceptable salts thereof and the compositions of claim 3 or 4 or 5 for the manufacture of a medicament for the treatment of diseases associated with epidermal growth factor receptor overexpression.
9. The use according to claim 8, wherein the diseases associated with the overexpression of the EGF are selected from renal cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and glioma.
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