CN117050085A - Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof - Google Patents

Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof Download PDF

Info

Publication number
CN117050085A
CN117050085A CN202310758070.2A CN202310758070A CN117050085A CN 117050085 A CN117050085 A CN 117050085A CN 202310758070 A CN202310758070 A CN 202310758070A CN 117050085 A CN117050085 A CN 117050085A
Authority
CN
China
Prior art keywords
compound
preparation
cancer
reaction
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310758070.2A
Other languages
Chinese (zh)
Inventor
王坚毅
董云怡
王勉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangxi University
Original Assignee
Guangxi University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangxi University filed Critical Guangxi University
Priority to CN202310758070.2A priority Critical patent/CN117050085A/en
Publication of CN117050085A publication Critical patent/CN117050085A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

Aryl-substituted 8-amino imidazopyrazines of the general formula (I) and of the general formula (II) are disclosed. In addition, the inventors have also established a process for the preparation of the corresponding compounds. The compound has the characteristics of easily available reaction raw materials, novel structure, simple preparation and the like. Experimental study shows that the compounds show excellent killing effect on the cell level against A549 tumor cells; preliminary medicine activity researches show that the target compound has quite good or even better effect than the positive control drug ibutinib, is hopeful to be developed into a novel, efficient, economic and simple related disease medicine, and has wide market application and development prospect.

Description

Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of imidazopyrazines, and particularly relates to an aryl-substituted 8-amino imidazopyrazines, and a preparation method and application thereof.
Background
Cancer is the second leading cause of death worldwide, second only to cardiovascular disease. According to World Health Organization (WHO) reports, over 70% of cancer-related deaths occur in developing countries, asia being the region with the greatest incidence of cancer and mortality. The harm of cancer is not peepable, and efforts are struggling with cancer all over the world, and efforts are made to develop new antitumor drugs, and significant progress is made.
Nitrogen-containing heterocycles are common in natural products such as nucleosides, amino acids, sugars, vitamins, alkaloids, and the like. The introduction of heterocyclic structure in medicine molecule has great effect in improving medicine selectivity and utilization, liposolubility and water solubility and molecular polarity. In the field of pharmaceutical chemistry, nitrogen heterocycles are one of the most important structural components of pharmaceuticals. Analysis of the drug database approved by the FDA in the united states shows that 59% of small molecule drugs contain nitrogen heterocycles. Imidazopyrazines are nitrogen-containing heterocyclic compounds which are involved in drug development in a variety of biological activities and important pharmacophores, and compounds containing such backbone structures have broad spectrum activities such as anti-inflammatory, anticoagulant, antitumor, and the like.
Disclosure of Invention
The invention aims to provide an aryl-substituted 8-amino imidazo pyrazine compound with strong anti-tumor activity, and a preparation method and application thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
aryl substituted 8-amino imidazopyrazines, which are compounds according to the following general formula (I) or (II) or pharmaceutically acceptable salts, solvates or hydrates or isomers thereof;
wherein,
a is any one of the following groupsB is any one of the following groups
R 1 Is any one of the following groupsR 2 is-CH 3; x is-O-, -NHCO-, CONH-.
The compound is one of the following compounds DYY to DYY:
the application of any aryl substituted 8-amino imidazo pyrazine compound in preparing medicaments for preventing or treating heterologous immune diseases, autoimmune diseases or malignant tumors.
Malignant tumors are non-small cell carcinoma, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelogenous leukemia, multiple myeloma, melanoma.
Non-small cell carcinomas are derived from the a549 cell strain.
The preparation method of the compound comprises the following steps:
the preparation method of the compound comprises the following steps:
<1> cyclizing 2-amino-3-chloropyrazine with 2-bromo-1, 1-diethoxyethane (A) to obtain imidazo [1,2-a ] pyrazine of compound (IV);
<2> bromine the compound (IV) with N-bromosuccinimide (B) to give the compound (V);
<3> preparing the compound (VI) from the compound (V) and the compound (C) by nucleophilic substitution reaction under basic conditions;
<4> preparing the compound (VII) from the compound (VI) by Suzuki coupling reaction with boric acid or boric acid ester (D) under the alkaline condition of palladium catalyst and inert gas protection;
<5> removal of the Boc protecting group of the coupled product (VII) under TFA-DCM solution to give compound (VIII);
<6> condensation or substitution reaction of piperidine or pyrrolidine (VIII) compound to give compound (IX).
The preparation method of the compound comprises the following steps:
the preparation method of the compound comprises the following steps:
<1> cyclizing 2-amino-3-chloropyrazine with 2-bromo-1, 1-diethoxyethane (A) to obtain imidazo [1,2-a ] pyrazine of compound (IV);
<2> bromine the compound (IV) with N-bromosuccinimide (B) to give the compound (V);
<3> preparing the compound (VI) from the compound (V) and the compound (C) by nucleophilic substitution reaction under basic conditions;
<4> preparing the compound (VII) from the compound (VI) by Suzuki coupling reaction with boric acid or boric acid ester (D) under the alkaline condition of palladium catalyst and inert gas protection;
<5> removal of the Boc protecting group of the coupled product (VII) under TFA-DCM solution to give compound (VIII);
<6> condensation or substitution reaction of piperidine or pyrrolidine (VIII) compound to give compound (IX).
In the step <1>, the alkali is anhydrous sodium bicarbonate, the reaction solvent is isopropanol and tetrahydrofuran, and the reaction temperature is 80 ℃;
in the step <3>, the alkali is N, N-diisopropylethylamine, the reaction solvent is N, N-dimethylformamide and N-butanol, and the reaction temperature is 120 ℃;
in the step <4>, the base is potassium carbonate, the catalyst is [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and tetrakis (triphenylphosphine) palladium, and the reaction solvent is 1, 4-dioxane: water=4:1 (volume ratio), reaction temperature 85 ℃;
in the step <5>, the volume ratio of DCM to TFA is 3:1, and the reaction temperature is room temperature;
in the step <6>, the base is N, N-diisopropylethylamine or triethylamine, and the reaction temperature is 0 ℃ to room temperature.
The inventors have reasonably designed aryl substituted 8-amino imidazopyrazines according to general formula (I) and general formula (II). In addition, the inventors have also established a process for the preparation of the corresponding compounds. The compound has the characteristics of easily available reaction raw materials, novel structure, simple preparation and the like. Experimental study shows that the compounds show excellent killing effect on the cell level against A549 tumor cells; preliminary medicine activity researches show that the target compound has quite good or even better effect than the positive control drug ibutinib, is hopeful to be developed into a novel, efficient, economic and simple related disease medicine, and has wide market application and development prospect.
Detailed Description
EXAMPLE 1 preparation of Compound (IV)
Bromoacetaldehyde diethyl acetal (3.83 ml,25.47 mmol) was added to 48% aqueous HBr (9.6 ml,84.86 mmol). The reaction mixture was heated to 70℃and refluxed for 1.5 hours. Stirring and heating were stopped and transferred to room temperature. NaHCO3 (1.95 g,23.16 mmol) was weighed and suspended in an appropriate amount of isopropanol, and added to the reaction system and stirred at room temperature for 30min. 2-amino-3-chloropyrazine (1 g,7.72 mmol) was added to the filtrate, warmed to 85℃and stirred under reflux. The reaction was completed for about 4 hours and the product was collected by filtration. The resulting solid was washed with saturated sodium bicarbonate solution and extracted with DCM, the organic phases were separated and combined to give an organic phase which was dried over anhydrous sodium sulfate. The organic phase was concentrated to give compound (IV) as a pale yellow solid (1.08 g, 91.11%).
EXAMPLE 2 preparation of Compound (V)
Compound (IV) (1 g,6.51 mmol) was weighed out, NBS (1.16 g,6.51 mmol) was dissolved in an appropriate amount of DCM, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, stirring was stopped. Washed with saturated sodium carbonate solution and extracted with DCM. The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated in vacuo to give compound (V) (1.29 g, 85.22%).
EXAMPLE 3 preparation of Compound (VI-1)
Compound (V) (1 g,4.30 mmol), 4-amino-1-Boc-piperidine (1.03 g,5.16 mmol), DIPEA (2.25 mL,12.91 mmol) were dissolved in an appropriate amount of n-butanol and stirred at 120℃for 15 hours. TLC monitored the progress of the reaction, and after completion of the reaction, cooled to room temperature and spin-dried to remove the solvent. The crude product was purified by column chromatography to give compound (VI) (1.28 g, 75.09%).
EXAMPLE 4 preparation of Compound (VI-2)
EXAMPLE 5 preparation of Compound (VI-3)
The target compounds of examples 4-5 were synthesized in a similar manner as in reference example 3.
EXAMPLE 6 preparation of Compound (F-1)
To a solution of 4-aminophenylboronic acid pinacol ester (1 g,4.56 mmol) and triethylamine (951.67 mmL,56.85 mmol) in DCM (10 mL) at 0deg.C was added dropwise 4-trifluoromethylbenzoyl chloride (750.11 mmL,5.02 mmol). After 5min, the reaction was transferred to room temperature and the mixture was stirred for 6 hours. When the reaction was complete, the reaction was quenched with water. The DCM extracts and combines the organic phases. The solvent was removed under reduced pressure. Purification by column chromatography gave compound (F-1) (1.63 g, 91.29%).
EXAMPLE 7 preparation of Compound (F-2)
The title compound of example 7 was synthesized in a similar manner as in example 6.
EXAMPLE 8 preparation of Compound (G)
4-Bromobenzoic acid (1.17 g,5.84 mmol) was weighed, 10mL of dichloromethane was added, EDCI. HCl (1.02 g,5.31 mmol) was added sequentially under ice bath conditions, DIPEA (2.35 mL,13.28 mmol) was stirred for 5min, 2-aminopyridine (500 mg,5.31 mmol) was added at 0deg.C and then allowed to react overnight at room temperature. The solvent was removed under reduced pressure, and saturated brine and ethyl acetate were added thereto for extraction. Purification by column chromatography gave compound (G) (612 mg, 41.57%) as a white solid.
EXAMPLE 9 preparation of Compound (H)
Compound (G) (500 mg,1.80 mmol), pinacol biborate (595.63 mg,2.35 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (66.01 mg, 90.21. Mu. Mol), potassium acetate (531.22 mg,5.41 mmol) were weighed out. Deoxidizing and bubbling nitrogen gas into 12ml of 1, 4-dioxane at the same time by using a syringe. The reaction mixture was stirred at 85℃for 16 hours under inert gas. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase is washed for 2-3 times by saturated sodium chloride solution and dried under reduced pressure. The crude product was purified by column chromatography (mobile phase PE: ea=10:1 to 7:1) to give compound (H) as a white solid (401.00 mg, 68.56%).
EXAMPLE 10 preparation of Compound (VIII-1)
Compound (VI-1) (0.5 g,1.26 mmol), 4-phenoxyphenylboronic acid (324.05 mg,1.51 mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (46.29 mg, 63.09. Mu. Mol), anhydrous potassium carbonate (523.12 mg,3.79 mmol) were weighed out. Deoxidizing, nitrogen bubbling was done while simultaneously injecting 1 solvent (1, 4-dioxane: water=4:1) with a syringe. The reaction mixture was heated at 85 ℃ and stirred under nitrogen for 16 hours. Cool to room temperature, open the vent valve, quench the reaction with water, add ethyl acetate and extract. The organic phases were combined and dried over anhydrous sodium sulfate. Purification by column chromatography gave compound (VII-1) (448.00 mg, 73.12%). To a solution of compound (VII-1) (500 mg,1.03 mmol) in methylene chloride (6 ml), trifluoroacetic acid (3 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, neutralized with saturated aqueous sodium hydrogencarbonate, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound (VIII-1) as a brown oil. The next reaction was carried out without purification.
EXAMPLE 11 preparation of Compound (VIII-2)
EXAMPLE 12 preparation of Compound (VIII-3)
EXAMPLE 13 preparation of Compound (VIII-4)
EXAMPLE 14 preparation of Compound (VII-5)
EXAMPLE 15 preparation of Compound (VIII-6)
EXAMPLE 16 preparation of Compound (VIII-7)
EXAMPLE 17 preparation of Compound (VIII-8)
EXAMPLE 18 preparation of Compound (VIII-9)
The target compounds of examples 11-18 were synthesized in a similar manner to that of reference example 10.
Example 19 preparation of 1- [4- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] prop-2-en-1-one (DYY-1)
Compound (VIII-1) (300 mg, 778.27. Mu. Mol) and triethylamine (162.27 mmL,1.17 mmol) were dissolved in methylene chloride. Under ice bath conditions, acryloyl chloride (63.46 mmL, 778.27. Mu. Mol) was added dropwise with stirring. After 10min of reaction at 0 ℃, the reaction was transferred to room temperature. The reaction was completed for about 1 hour, quenched with water, and extracted with ethyl acetate. Purification by column chromatography (mobile phase PE: ea=1:1) afforded DYY-1 as an off-white solid (208.00 mg, 60.81%).
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d6)δ7.72(d,J＝4.8Hz,1H),7.68(s,1H),7.65(d,J＝8.4Hz,2H),7.45(s,2H),7.34(d,J＝4.8Hz,1H),7.21(t,J＝7.4Hz,1H),7.16(d,J＝8.3Hz,2H),7.12(d,J＝8.0Hz,2H),6.86(dd,J＝16.7,10.4Hz,1H),6.12(d,J＝16.2Hz,1H),5.69(d,J＝10.5Hz,1H),4.46(d,J＝13.1Hz,1H),4.39–4.29(m,1H),4.11(d,J＝12.4Hz,1H),3.19(t,J＝13.1Hz,1H),2.80(t,J＝12.6Hz,1H),1.96(s,2H),1.61–1.53(m,2H). 13 C NMR(151MHz,DMSO-d6)δ164.64,157.40,156.54,148.99,133.34,130.76,130.67,130.03,129.24,128.96,127.60,127.46,124.47,123.79,119.64,119.41,107.87,47.56,44.77,41.27,32.52,31.52.MS(ESI+)m/z：440[M+H]+.
example 20 preparation of (2E) -1- [4- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] but-2-en-1-one (DYY-2)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,Chloroform-d)δ7.47(d,J＝4.8Hz,1H),7.44(s,1H),7.40(d,J＝8.3Hz,2H),7.32(t,J＝7.7Hz,2H),7.30(d,J＝4.8Hz,1H),7.10(t,J＝7.4Hz,1H),7.06(d,J＝8.3Hz,2H),7.02(d,J＝8.0Hz,2H),6.81(dd,J＝14.8,7.1Hz,1H),6.27–6.21(m,1H),4.54(d,J＝14.1Hz,1H),4.29(dq,J＝10.9,3.2Hz,1H),3.97(d,J＝13.5Hz,1H),2.90(d,J＝14.1Hz,2H),2.18–2.11(m,2H),1.49(d,J＝13.3Hz,2H),1.19(d,J＝3.7Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ164.66,157.40,156.54,149.00,140.93,133.35,130.74,130.67,130.03,129.24,129.19,127.46,124.46,123.80,122.58,119.64,119.41,114.62,107.84,47.66,28.58,24.94,18.21.MS(ESI+)m/z：454[M+H]+.
example 21 preparation of 2-methyl-1- [4- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] prop-2-en-1-one (DYY-3)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,Chloroform-d)δ7.56(d,J＝4.8Hz,1H),7.52(s,1H),7.48(d,J＝8.4Hz,2H),7.39(t,J＝7.7Hz,2H),7.36(d,J＝4.8Hz,1H),7.17(t,J＝7.4Hz,1H),7.14(d,J＝8.3Hz,2H),7.09(d,J＝8.0Hz,2H),6.13(d,J＝7.9Hz,1H),5.19(s,1H),5.07(s,1H),4.55(s,1H),4.37(dtd,J＝10.8,7.1,3.9Hz,1H),4.03(s,1H),3.26(s,1H),2.99(s,1H),2.21(dd,J＝13.3,3.9Hz,2H),1.98(s,3H),1.57(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ171.14,157.32,157.31,149.90,138.82,138.19,134.83,132.98,130.80,130.68,130.05,129.23,124.48,119.65,119.42,115.95,114.32,107.90,47.53,43.17,31.14,20.70.MS(ESI+)m/z：454[M+H]+.
EXAMPLE 22 preparation of 2-chloro-1- [4- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] ethan-1-one (DYY-4)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.72(d,J＝4.8Hz,1H),7.68(s,1H),7.68–7.63(m,2H),7.45(d,J＝7.9Hz,2H),7.33(d,J＝4.8Hz,1H),7.21(t,J＝7.4Hz,1H),7.18–7.14(m,2H),7.12(d,J＝8.1Hz,2H),4.41(d,J＝6.6Hz,2H),4.38–4.31(m,1H),4.13(d,J＝5.2Hz,1H),3.92–3.86(m,1H),3.21(d,J＝11.8Hz,1H),2.80(td,J＝12.9,2.9Hz,1H),2.00–1.91(m,2H),1.68(dd,J＝11.8,4.0Hz,1H),1.56(dd,J＝11.7,4.2Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ169.06,164.91,157.62,156.48,132.51,131.98,131.92,130.68,130.19,129.26,129.18,124.52,119.69,119.40,45.03,42.52,41.96,41.43,31.97,31.18,25.42,14.55.MS(ESI+)m/z：462[M+H]+.
EXAMPLE 23 preparation of 1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] prop-2-en-1-one (DYY-5)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d6)δ7.75(dd,J＝10.5,4.8Hz,1H),7.70(d,J＝3.1Hz,1H),7.68–7.64(m,2H),7.45(t,J＝7.8Hz,2H),7.36(d,J＝5.5Hz,1H),7.21(t,J＝7.4Hz,1H),7.16(d,J＝8.5Hz,2H),7.12(d,J＝7.9Hz,2H),6.79(ddd,J＝59.5,16.7,10.5Hz,1H),6.14–6.04(m,1H),5.66(ddd,J＝28.3,10.5,2.4Hz,1H),4.42(dd,J＝12.4,4.1Hz,1H),4.18–4.09(m,1H),3.98–3.91(m,1H),3.23(dd,J＝12.9,9.3Hz,1H),3.13–3.06(m,1H),2.94–2.83(m,1H),1.82–1.76(m,2H),1.48(s,2H). 13 C NMR(151MHz,DMSO-d6)δ157.42,156.54,149.08,148.99,133.31,130.86,130.66,130.15,130.03,129.23,129.09,128.79,127.59,127.51,124.46,123.75,119.64,119.42,108.25,49.89,47.84,46.60,46.44,45.84,42.36,30.41,30.14,25.41,25.16,23.98.MS(ESI+)m/z：440[M+H]+.
example 24 preparation of (2E) -1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] but-2-en-1-one (DYY-6)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d6)δ7.77–7.72(m,1H),7.70(d,J＝3.3Hz,1H),7.68–7.64(m,2H),7.45(t,J＝7.9Hz,2H),7.35(d,J＝8.0Hz,1H),7.21(t,J＝7.4Hz,1H),7.16(d,J＝8.3Hz,2H),7.12(d,J＝8.0Hz,2H),6.64(ddd,J＝41.9,14.9,7.8Hz,1H),6.48(dd,J＝77.6,14.9Hz,1H),4.19(s,1H),4.08(s,2H),3.28–3.25(m,1H),3.17(s,2H),2.89(t,J＝11.3Hz,1H),1.99(d,J＝7.2Hz,1H),1.84(t,J＝9.6Hz,1H),1.75(dd,J＝20.8,8.5Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.07,157.42,156.52,140.99,140.66,133.30,130.85,130.67,130.01,129.22,127.50,124.47,123.71,122.63,119.63,119.41,108.27,49.02,47.81,45.74,30.41,30.07,25.15,23.85,18.19,8.89.MS(ESI+)m/z：454[M+H]+.
example 25 preparation of 2-methyl-1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] prop-2-en-1-one (DYY-7)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.74(d,J＝4.7Hz,1H),7.70(s,1H),7.68–7.64(m,2H),7.45(t,J＝7.9Hz,2H),7.40(d,J＝8.0Hz,1H),7.33(d,J＝4.7Hz,1H),7.21(t,J＝7.4Hz,1H),7.17–7.15(m,2H),7.12(d,J＝8.0Hz,2H),5.14(d,J＝28.8Hz,1H),4.99(s,1H),4.11(s,2H),2.83(s,1H),2.00(d,J＝13.6Hz,1H),1.87(s,3H),1.79–1.76(m,2H),1.60(s,1H),1.49(s,1H),1.38(s,1H). 13 C NMR(151MHz,DMSO-d 6 )δ170.59,157.42,156.52,148.95,133.27,130.87,130.68,130.04,129.17,127.52,124.48,123.72,119.64,119.41,114.91,45.70,20.64,8.90.MS(ESI+)m/z：454[M+H]+.
EXAMPLE 26 preparation of 2-chloro-1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) hexahydropyridin-1-yl ] ethan-1-one (DYY-8)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d6)δ7.75(dd,J＝11.0,4.7Hz,1H),7.71(d,J＝8.8Hz,1H),7.66(d,J＝8.4Hz,2H),7.45(t,J＝7.8Hz,2H),7.37(dd,J＝13.4,6.5Hz,1H),7.21(t,J＝7.4Hz,1H),7.16(d,J＝8.3Hz,2H),7.12(d,J＝8.0Hz,2H),4.43–4.30(m,1H),4.18(s,2H),3.96(d,J＝13.2Hz,1H),3.75(d,J＝13.8Hz,1H),3.22–3.14(m,1H),2.96–2.84(m,1H),2.00(q,J＝14.2,10.6Hz,1H),1.78(s,1H),1.35–1.23(m,1H),1.08(dt,J＝23.7,7.1Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ130.81,130.68,130.06,124.48,119.64,119.42,45.69,45.68,42.16,8.82.MS(ESI+)m/z：462[M+H]+.
example 27 preparation of 1- (4- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) prop-2-en-1-one (DYY-9)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d6)δ7.66(d,J＝4.7Hz,1H),7.62(s,1H),7.56(d,J＝8.3Hz,2H),7.42(d,J＝8.2Hz,1H),7.32(d,J＝4.7Hz,1H),7.12(d,J＝8.3Hz,2H),6.86(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,2.6Hz,1H),5.69(dd,J＝10.4,2.5Hz,1H),4.46(d,J＝13.2Hz,1H),4.33(dq,J＝10.9,3.3Hz,1H),4.11(d,J＝13.7Hz,1H),3.83(s,3H),3.19(t,J＝12.9Hz,1H),2.79(td,J＝13.0,2.8Hz,1H),1.96(d,J＝12.1Hz,2H),1.56(dtd,J＝24.0,12.1,8.0Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ164.66,159.77,148.97,133.15,130.34,129.69,129.10,128.95,127.87,127.61,121.05,115.20,107.80,55.77,47.54,45.78,44.77,32.53,31.53,8.92.MS(ESI+)m/z：378[M+H]+.
example 28 preparation of (2E) -1- (4- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) but-2-en-1-one (DYY-10)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.71(d,J＝4.7Hz,1H),7.67(s,1H),7.63–7.59(m,2H),7.47(d,J＝8.3Hz,1H),7.37(d,J＝4.7Hz,1H),7.20–7.15(m,2H),6.73(dt,J＝13.7,6.9Hz,1H),6.61(dd,J＝14.9,1.9Hz,1H),4.51(d,J＝13.1Hz,1H),4.40–4.33(m,1H),4.17(d,J＝13.8Hz,1H),3.88(s,3H),3.21(dd,J＝17.3,7.9Hz,1H),2.80(t,J＝12.8Hz,1H),1.99(d,J＝13.0Hz,2H),1.90(dd,J＝6.8,1.6Hz,3H),1.63–1.56(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ164.66,159.77,148.98,140.92,133.16,130.34,129.70,129.09,127.87,123.78,122.59,121.08,115.20,107.78,55.76,47.65,18.21.MS(ESI+)m/z：392[M+H]+.
example 29 preparation of 1- (4- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) -2-methylpropan-2-en-1-one (DYY-11)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.70(d,J＝4.7Hz,1H),7.66(s,1H),7.60(d,J＝8.7Hz,2H),7.41(d,J＝8.2Hz,1H),7.36(d,J＝4.7Hz,1H),7.19–7.10(m,2H),5.23–5.18(m,1H),5.03–5.00(m,1H),4.42–4.35(m,2H),3.87(s,3H),3.22(s,2H),2.84(s,1H),2.00–1.97(m,2H),1.93–1.90(m,3H),1.63(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.26,159.77,148.95,141.11,133.17,130.36,129.69,129.08,127.87,121.07,115.19,114.71,107.81,55.75,47.52,20.68.MS(ESI+)m/z：392[M+H]+.
example 30 preparation of 2-chloro-1- (4- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) ethan-1-one (DYY-12)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.66(d,J＝4.7Hz,1H),7.62(s,1H),7.56(d,J＝8.2Hz,2H),7.43(d,J＝8.1Hz,1H),7.32(d,J＝4.7Hz,1H),7.12(d,J＝8.1Hz,2H),4.44–4.38(m,2H),4.36–4.29(m,1H),3.91–3.87(m,1H),3.83(s,3H),3.24–3.15(m,1H),2.80(td,J＝12.9,2.9Hz,1H),1.99–1.91(m,2H),1.68(qd,J＝12.2,4.2Hz,1H),1.55(qd,J＝12.4,4.4Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ164.90,159.77,148.96,130.33,129.70,129.07,127.90,121.04,115.21,107.85,55.78,47.32,45.73,45.71,45.09,42.53,41.48,32.11,31.32,8.85.MS(ESI+)m/z：400[M+H]+.
example 31 preparation of 1- (3- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) prop-2-en-1-one (DYY-13)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d6)δ7.66(d,J＝4.8Hz,1H),7.62(s,1H),7.56(d,J＝8.0Hz,2H),7.42(d,J＝8.6Hz,1H),7.32(d,J＝4.8Hz,1H),7.13(s,2H),6.87(dd,J＝16.6,10.6Hz,1H),6.12(d,J＝15.9Hz,1H),5.69(d,J＝10.4Hz,1H),4.46(d,J＝13.2Hz,1H),4.35–4.30(m,1H),4.12(d,J＝11.1Hz,1H),3.84(s,3H),2.80(t,J＝13.5Hz,1H),2.65(d,J＝8.5Hz,1H),1.96(s,2H),1.84(q,J＝10.7,6.3Hz,1H),1.56(td,J＝14.2,13.3,6.1Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ164.67,159.78,153.49,131.33,130.32,130.06,129.67,129.10,128.93,127.91,127.86,127.62,121.97,115.23,115.20,107.79,104.87,60.22,55.80,55.77,49.00,47.53,45.71,21.21,14.53,9.01.MS(ESI+)m/z：378[M+H]+.
example 32 preparation of (2E) -1- (3- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) but-2-en-1-one (DYY-14)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.70(d,J＝10.7Hz,1H),7.66(s,1H),7.57(d,J＝8.2Hz,2H),7.35(d,J＝4.5Hz,1H),7.31(d,J＝5.0Hz,1H),7.13(d,J＝8.3Hz,2H),6.71–6.57(m,1H),6.48(dd,J＝73.7,15.0Hz,1H),4.40(d,J＝12.9Hz,1H),4.08(s,2H),3.94(d,J＝13.7Hz,1H),3.83(s,3H),3.27(d,J＝11.3Hz,1H),2.88(s,1H),1.99(s,1H),1.84(s,1H),1.79–1.71(m,3H),1.46(s,1H). 13 C NMR(151MHz,DMSO-d 6 )δ165.04,159.84,133.01,130.50,129.72,128.09,122.65,120.90,115.22,108.27,55.77,49.66,46.80,45.83,30.10,25.14,23.87,18.20,8.89.MS(ESI+)m/z：392[M+H]+.
example 33 preparation of 1- (3- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) -2-methylpropan-2-en-1-one (DYY-15)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.68(d,J＝4.7Hz,1H),7.64(s,1H),7.60–7.55(m,2H),7.37(d,J＝8.0Hz,1H),7.32(d,J＝4.7Hz,1H),7.12(d,J＝8.7Hz,2H),5.14(d,J＝25.2Hz,1H),5.00(s,1H),4.12(s,2H),3.84(s,3H),3.08(d,J＝44.0Hz,1H),2.84(s,1H),2.00(dq,J＝15.1,5.5,4.7Hz,2H),1.88(s,3H),1.79(s,2H),1.49(d,J＝12.5Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ170.56,159.80,148.96,133.10,130.46,129.70,129.03,127.93,121.03,115.20,114.89,108.14,55.76,30.50,25.41,20.66,18.40.MS(ESI+)m/z：392[M+H]+.
example 34 preparation of 2-chloro-1- (3- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } hexahydropyridin-1-yl) ethan-1-one (DYY-16)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.72(dd,J＝16.3,4.9Hz,1H),7.67–7.62(m,1H),7.58(dd,J＝8.7,2.4Hz,2H),7.33(dd,J＝14.6,5.0Hz,1H),7.22(d,J＝7.9Hz,1H),7.14–7.11(m,2H),4.28(s,2H),3.99–3.93(m,1H),3.84(s,3H),3.75(d,J＝13.5Hz,1H),3.23–3.15(m,1H),3.11–3.02(m,0H),2.90(t,J＝11.2Hz,1H),1.84–1.74(m,2H),1.59(q,J＝12.5,12.0Hz,1H),1.48–1.41(m,1H). 13 C NMR(151MHz,DMSO-d 6 )δ169.05,131.43,130.03,115.60,115.32,115.29,115.25,55.98,55.83,42.67,25.42.MS(ESI+)m/z：400[M+H]+.
example 35 preparation of 1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) tetrahydro-1H-pyrrol-1-yl ] prop-2-en-1-one (DYY-17)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.75(d,J＝4.6Hz,1H),7.69(s,1H),7.65(d,J＝8.1Hz,2H),7.44(t,J＝7.7Hz,2H),7.36(d,J＝4.8Hz,1H),7.20(d,J＝6.9Hz,1H),7.15(d,J＝8.4Hz,2H),7.11(d,J＝8.0Hz,2H),6.57(ddd,J＝28.5,16.8,10.3Hz,1H),6.13(dt,J＝19.6,9.6Hz,1H),5.65(dd,J＝16.8,10.4Hz,1H),4.70(dq,J＝41.5,6.5Hz,1H),3.92(t,J＝8.5Hz,1H),3.83–3.71(m,1H),3.68–3.61(m,1H),2.29–2.23(m,1H),2.20–2.10(m,2H). 13 CNMR(151MHz,DMSO-d 6 )δ167.45,163.93,163.90,157.42,156.53,149.44,149.36,133.40,133.38,131.07,130.86,130.83,130.64,130.18,130.01,129.75,129.13,127.48,127.10,126.97,124.44,123.74,123.72,119.63,119.40,108.29,51.39,51.05,50.92,49.28,45.02,44.44,31.34,29.65,18.54,18.01.MS(ESI+)m/z：426[M+H]+.
example 36 preparation of (2E) -1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) tetrahydro-1H-pyrrol-1-yl ] but-2-en-1-one (DYY-18)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d6)δ7.76(s,1H),7.70(s,1H),7.66(d,J＝8.2Hz,2H),7.45(t,J＝7.8Hz,2H),7.36(s,1H),7.21(d,J＝7.7Hz,1H),7.16(d,J＝8.2Hz,2H),7.12(d,J＝8.0Hz,2H),6.73–6.64(m,1H),6.27(dd,J＝28.7,15.0Hz,1H),4.77–4.55(m,1H),3.90(t,J＝8.6Hz,1H),3.80–3.68(m,1H),3.61(d,J＝8.2Hz,1H),2.30–2.22(m,1H),2.21–2.07(m,2H),1.87–1.81(m,3H). 13 C NMR(151MHz,DMSO-d 6 )δ164.15,157.43,156.54,149.45,149.40,144.73,140.16,140.06,133.38,130.89,130.84,130.71,130.66,130.04,129.15,127.48,124.47,124.21,123.80,123.74,119.78,119.64,119.41,118.19,108.32,108.29,51.39,50.94,50.91,49.29,44.92,44.31,31.34,29.62,18.12,18.07,18.02.MS(ESI+)m/z：440[M+H]+.
example 37 preparation of 2-methyl-1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) tetrahydro-1H-pyrrol-1-yl ] prop-2-en-1-one (DYY-19)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.84–7.79(m,1H),7.75(s,1H),7.72–7.63(m,2H),7.45(t,J＝7.7Hz,2H),7.36(s,1H),7.20(s,1H),7.16(s,2H),7.12(d,J＝8.4Hz,2H),5.26(d,J＝10.8Hz,1H),5.15(d,J＝18.8Hz,1H),4.74–4.60(m,1H),3.85(t,J＝9.0Hz,1H),3.72(q,J＝10.7Hz,1H),3.60–3.54(m,2H),2.21–2.09(m,2H),1.85(d,J＝13.8Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.88,167.57,157.42,156.51,149.41,149.37,144.71,141.78,141.53,133.38,133.35,130.81,130.62,129.99,129.13,127.48,125.38,124.43,123.81,123.70,123.68,119.61,119.38,116.57,116.42,108.26,53.52,50.85,49.41,47.02,44.24,31.61,29.72,20.21,18.54,17.99.MS(ESI+)m/z：440[M+H]+.
EXAMPLE 38 preparation of 2-chloro-1- [3- ({ 3- [4- (phenyloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-yl } amino) tetrahydro-1H-pyrrol-1-yl ] ethan-1-one (DYY-20)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.77(d,J＝4.9Hz,1H),7.71(s,1H),7.66(d,J＝8.3Hz,2H),7.45(t,J＝7.8Hz,2H),7.36(d,J＝4.6Hz,1H),7.21(t,J＝7.4Hz,1H),7.16(d,J＝8.4Hz,2H),7.12(d,J＝7.9Hz,2H),4.70(dq,J＝41.3,6.0Hz,1H),4.34(d,J＝2.8Hz,1H),4.32(d,J＝3.6Hz,1H),4.28(s,1H),3.84(dd,J＝10.5,6.3Hz,1H),3.71(dd,J＝12.1,6.3Hz,1H),3.58(dd,J＝10.5,5.7Hz,1H),2.22(ddt,J＝39.8,13.8,6.9Hz,1H),2.17–2.10(m,1H). 13 CNMR(151MHz,DMSO-d 6 )δ169.07,164.82,164.80,157.56,156.48,148.84,144.76,133.14,131.88,130.97,130.80,130.67,130.13,130.11,127.91,125.03,124.50,123.77,123.44,120.19,119.67,119.40,119.19,108.56,51.43,51.35,51.19,49.53,44.89,44.74,43.38,43.06,41.96,31.43,29.61,18.02.MS(ESI+)m/z：448[M+H]+
example 39 preparation of N- [4- (8- { [1- (1-oxyprop-2-enyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) phenyl ] -4- (trifluoromethyl) benzamide (DYY-21)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H),8.19(d,J＝8.1Hz,2H),7.99(d,J＝8.7Hz,2H),7.95(d,J＝8.2Hz,2H),7.77(d,J＝4.8Hz,1H),7.72(s,1H),7.69–7.65(m,2H),7.35(d,J＝4.7Hz,1H),4.47(d,J＝13.1Hz,1H),4.33(dt,J＝7.8,3.8Hz,1H),4.12(d,J＝13.9Hz,1H),3.24–3.15(m,1H),2.80(td,J＝12.9,2.8Hz,1H),1.96(d,J＝9.2Hz,2H),1.57(ddd,J＝19.5,11.6,4.2Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.04,164.66,149.01,139.34,139.07,133.37,132.05,131.84,130.76,130.56,129.26,129.13,128.95,128.51,127.78,127.61,125.95,125.92,125.90,125.29,124.34,123.49,121.36,107.97,60.23,47.57,44.77,41.27,32.52,31.52,21.22,14.54.MS(ESI+)m/z：535[M+H]+.
EXAMPLE 40 preparation of N- {4- [8- ({ 1- [ (2E) -1-oxybut-2-enyl ] hexahydropyridin-4-yl } amino) imidazo [1,2-a ] pyrazin-3-yl ] phenyl } -4- (trifluoromethyl) benzamide (DYY-22)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H),8.19(d,J＝8.1Hz,2H),8.01–7.97(m,2H),7.95(d,J＝8.1Hz,2H),7.77(d,J＝4.7Hz,1H),7.71(s,1H),7.67(d,J＝8.6Hz,2H),7.46(d,J＝8.2Hz,1H),7.35(d,J＝4.8Hz,1H),6.74–6.64(m,1H),6.60–6.53(m,1H),4.46(d,J＝13.0Hz,1H),4.37–4.27(m,1H),4.12(d,J＝12.7Hz,1H),3.20–3.12(m,1H),2.75(t,J＝10.6Hz,1H),1.96(d,J＝12.0Hz,2H),1.85(dd,J＝6.7,1.6Hz,3H),1.55(q,J＝11.3,10.5Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.03,164.68,149.02,140.94,139.35,139.07,133.39,132.05,131.84,130.75,129.27,129.14,128.50,127.78,125.95,125.92,125.90,125.87,125.30,124.35,123.49,122.58,121.35,107.95,47.67,44.66,41.19,32.58,31.59,25.41,18.21.MS(ESI+)m/z：549[M+H]+.
EXAMPLE 41 preparation of N- [4- (8- { [1- (2-methyl-1-oxyprop-2-enyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) phenyl ] -4- (trifluoromethyl) benzamide (DYY-23)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H),8.21–8.16(m,2H),8.01–7.97(m,2H),7.95(d,J＝8.1Hz,2H),7.77(d,J＝4.7Hz,1H),7.72(s,1H),7.69–7.65(m,2H),7.41(d,J＝8.2Hz,1H),7.35(d,J＝4.7Hz,1H),5.18(p,J＝1.6Hz,1H),4.98(t,J＝1.3Hz,1H),4.39–4.29(m,2H),3.91(s,1H),3.19–3.15(m,1H),2.80(s,1H),1.95(d,J＝9.7Hz,2H),1.88(t,J＝1.4Hz,3H),1.59(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.27,165.02,148.99,141.10,139.35,139.07,133.38,132.05,131.84,130.79,129.25,129.13,128.50,127.79,125.94,125.92,125.89,125.87,125.29,124.34,123.49,121.34,114.72,107.99,47.55,25.41,20.69.MS(ESI+)m/z：549[M+H]+.
EXAMPLE 42 preparation of N- [4- (8- { [1- (2-chloroacetyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) phenyl ] -4- (trifluoromethyl) benzamide (DYY-24)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.69(s,1H),8.19(d,J＝8.0Hz,2H),7.99(d,J＝8.3Hz,2H),7.95(d,J＝8.1Hz,2H),7.77(d,J＝4.8Hz,1H),7.72(s,1H),7.67(d,J＝8.2Hz,2H),7.49(d,J＝8.3Hz,1H),7.35(d,J＝4.8Hz,1H),4.42(d,J＝4.9Hz,2H),4.34(s,1H),3.90(d,J＝13.6Hz,1H),3.21(t,J＝12.9Hz,1H),2.81(t,J＝12.4Hz,1H),1.96(t,J＝14.7Hz,2H),1.83(d,J＝8.5Hz,1H),1.68(dd,J＝12.1,3.9Hz,1H),1.56(dd,J＝11.9,4.2Hz,1H). 13 CNMR(151MHz,DMSO-d 6 )δ168.74,165.05,164.91,148.79,144.76,139.41,139.04,137.19,133.31,132.05,131.84,130.86,129.23,129.14,128.53,125.91,125.88,125.86,125.46,125.29,124.22,123.77,123.48,121.37,108.11,66.81,47.50,45.08,42.50,41.47,32.07,31.28,25.40,18.53,18.02.MS(ESI+)m/z：557[M+H]+.
EXAMPLE 43 preparation of N- [4- (8- { [1- (1-oxyprop-2-enyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) phenyl ] benzamide (DYY-25)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ10.53(s,1H),8.01(s,1H),8.00(s,1H),7.77(d,J＝4.7Hz,1H),7.70(s,1H),7.66(s,1H),7.64(s,1H),7.62(s,1H),7.61(s,1H),7.57(s,1H),7.56(s,1H),7.55(s,1H),7.45(d,J＝8.2Hz,1H),7.35(d,J＝4.7Hz,1H),6.86(dd,J＝16.6,10.5Hz,1H),6.12(dd,J＝16.7,2.5Hz,1H),5.69(dd,J＝10.4,2.5Hz,1H),4.47(d,J＝13.2Hz,1H),4.34(dq,J＝7.8,4.2Hz,1H),4.19(d,J＝13.1Hz,1H),3.92(d,J＝14.9Hz,1H),3.19(q,J＝12.2Hz,1H),2.80(td,J＝13.3,12.8,3.3Hz,1H),1.97(s,1H),1.74(s,1H),1.57(dqd,J＝23.8,12.0,4.0Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ169.36,166.27,166.21,164.69,164.65,153.47,149.01,140.25,139.79,135.24,133.33,132.17,131.64,130.68,129.23,128.96,128.88,128.80,128.60,128.43,128.25,128.23,127.87,127.61,123.91,122.08,121.28,121.23,107.98,47.57,46.09,46.05,35.07,32.53,31.52,28.57,25.43.MS(ESI+)m/z：467[M+H]+.
EXAMPLE 44 preparation of N- {4- [8- ({ 1- [ (2E) -1-oxybut-2-enyl ] hexahydropyridin-4-yl } amino) imidazo [1,2-a ] pyrazin-3-yl ] phenyl } benzamide (DYY-26)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.62(s,1H),8.02(dd,J＝8.4,6.9Hz,4H),7.81(d,J＝5.0Hz,1H),7.78(s,1H),7.65(d,J＝8.6Hz,2H),7.60(t,J＝7.3Hz,1H),7.54(t,J＝7.5Hz,2H),7.36(d,J＝5.0Hz,1H),4.48(d,J＝12.7Hz,1H),4.30(s,1H),4.14(d,J＝13.6Hz,1H),2.73(t,J＝12.5Hz,1H),1.98(d,J＝14.7Hz,2H),1.84(dd,J＝6.8,1.6Hz,3H),1.57(t,J＝13.9Hz,2H),1.30(t,J＝7.3Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ159.02,141.03,139.98,135.21,133.02,132.20,131.12,128.89,128.58,128.19,123.55,122.53,121.25,108.39,74.00,48.22,46.09,25.38,18.18,8.95.MS(ESI+)m/z：481[M+H]+.
EXAMPLE 45 preparation of N- [4- (8- { [1- (2-methyl-1-oxyprop-2-enyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) phenyl ] benzamide (DYY-27)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.48(s,1H),7.99(d,J＝7.8Hz,4H),7.76(d,J＝4.8Hz,1H),7.70(s,1H),7.65(d,J＝8.5Hz,2H),7.61(d,J＝7.3Hz,1H),7.56(t,J＝7.5Hz,2H),7.40(d,J＝8.2Hz,1H),7.34(d,J＝4.8Hz,1H),5.17(s,1H),4.98(s,1H),4.38–4.30(m,2H),3.90(s,1H),3.18(s,1H),2.80(s,1H),1.97–1.93(m,2H),1.87(s,3H),1.58(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.82,170.29,167.49,166.21,148.94,144.72,141.09,139.75,135.26,133.33,132.17,131.13,130.72,129.97,129.13,128.89,128.44,128.18,127.90,123.92,123.79,121.24,114.73,108.01,74.01,60.22,49.06,47.56,46.04,32.35,31.50,25.40,21.21,20.67,18.01,14.53.MS(ESI+)m/z：481[M+H]+.
EXAMPLE 46 preparation of N- [4- (8- { [1- (2-chloroacetyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) phenyl ] benzamide (DYY-28)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.51(s,1H),8.00(t,J＝8.1Hz,4H),7.81(d,J＝5.0Hz,1H),7.79(s,1H),7.66(d,J＝8.2Hz,2H),7.61(d,J＝7.3Hz,1H),7.56(t,J＝7.4Hz,3H),7.35(d,J＝5.1Hz,1H),4.42(d,J＝8.8Hz,2H),4.42–4.35(m,1H),4.28(s,1H),3.92(d,J＝13.5Hz,1H),3.25–3.15(m,1H),2.83–2.74(m,1H),1.98–1.93(m,2H),1.71(qd,J＝12.3,4.2Hz,1H),1.59(qd,J＝12.3,4.2Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ170.84,169.05,167.48,166.28,164.99,144.75,140.28,135.17,132.51,132.24,128.91,128.81,128.21,123.77,122.94,121.25,109.06,74.01,60.23,46.05,44.90,42.51,41.96,41.31,31.74,30.96,25.40,24.93,21.22,18.02,14.53,8.97.MS(ESI+)m/z：489[M+H]+.
example 47 preparation of 4- (8- { [1- (1-oxyprop-2-enyl) hexahydropyridin-4-yl ] amino } imidazo [1,2-a ] pyrazin-3-yl) -N- (pyridin-2-yl) benzamide (DYY-29)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.51(s,1H),8.00(t,J＝8.1Hz,4H),7.81(d,J＝5.0Hz,1H),7.79(s,1H),7.66(d,J＝8.2Hz,2H),7.61(d,J＝7.3Hz,1H),7.56(t,J＝7.4Hz,3H),7.35(d,J＝5.1Hz,1H),4.42(d,J＝8.8Hz,2H),4.42–4.35(m,1H),4.28(s,1H),3.92(d,J＝13.5Hz,1H),3.25–3.15(m,1H),2.83–2.74(m,1H),1.98–1.93(m,2H),1.71(qd,J＝12.3,4.2Hz,1H),1.59(qd,J＝12.3,4.2Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ170.84,169.05,167.48,166.28,164.99,144.75,140.28,135.17,132.51,132.24,128.91,128.81,128.21,123.77,122.94,121.25,109.06,74.01,60.23,46.05,44.90,42.51,41.96,41.31,31.74,30.96,25.40,24.93,21.22,18.02,14.53,8.97.MS(ESI+)m/z：489[M+H]+.
example 48 preparation of 1- (3- { [3- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-yl ] amino } tetrahydro-1H-pyrrol-1-yl) prop-2-en-1-one (DYY-30)
The spectrum data of the target compound after detection analysis are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.70(d,J＝4.8Hz,1H),7.64(s,1H),7.57(d,J＝8.4Hz,3H),7.35(d,J＝4.8Hz,1H),7.12(d,J＝8.3Hz,2H),6.58(ddd,J＝30.1,16.8,10.2Hz,1H),6.14(dd,J＝17.5,5.9Hz,1H),5.66(dd,J＝16.9,10.5Hz,1H),4.74(q,J＝6.2Hz,1H),4.65(q,J＝6.2Hz,1H),3.93(dd,J＝10.4,6.5Hz,1H),3.83(s,3H),3.80–3.71(m,1H),3.64(dd,J＝10.5,5.9Hz,1H),2.14(ddt,J＝29.2,12.7,6.4Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ163.94,163.90,159.80,149.44,149.37,130.43,130.23,129.80,129.71,129.01,127.93,127.10,126.97,121.03,115.21,108.28,55.76,51.38,51.03,50.88,49.25,46.15,45.02,44.44,31.33,29.65,24.94.MS(ESI+)m/z：364[M+H]+.
the title compounds of examples 20-48 were synthesized in a similar manner as in reference example 19.
EXAMPLE 48 cell level Activity test
10% of Australian foetal calf serum and 5% of diabody (penicillin plus streptomycin) were added to DMEM medium and A549 cells (human lung cancer cell line) were cultured at 37℃with 5% CO 2 In an incubator. Tumor cells in the logarithmic growth phase were seeded in 96-well plates. Wherein a549 cells were seeded with 2500 cells per well. MTT experiments were performed in 2 duplicate wells per group. The compound to be tested is prepared into mother liquor with concentration of 10mM by using DMSO, a proper amount of mother liquor is taken and diluted to 10 mu M by using a culture medium, a blank control is used when the cell-free hole is read, the cell-free hole is used as a compound blank hole, and Ibutenib (INB) is used as a positive control drug. Co-culturing with A549 cells for 48h after the medicine is added; after 10. Mu.L of 5. Mu.g/ml MTT solution was added to each well, incubated at 37℃for 4 hours, the MTT solution was discarded and DMSO was added150. Mu.L/well. Mixing by shaking, testing the absorbance of each hole at 490nm by using an enzyme-labeled instrument, and calculating the cell inhibition rate.
Survival= (OD Experimental group -OD Blank group )/(OD Control group -OD Blank group )×100％
Inhibition rate = (1-survival rate) ×100%
The above experiment was repeated 3 times, and the Blies method calculated the IC50 values of compounds DYY-23, DYY-24, DYY-27, DYY-28 with good inhibition.
The proliferation inhibition of the compounds of the present invention on a549 is shown in table 1.
TABLE 1 inhibition of A549 cell proliferation by target compounds
The IC50 of the compounds of the invention against a549 cells is shown in table 2.
IC50 (mu mol/L) of the compounds of Table 2 against A549 cells
Experimental data show that most of the aryl-substituted 8-amino imidazopyrazines compounds synthesized by the invention have good anti-tumor activity, and under the condition that ibutinib is taken as a reference drug and is administrated with a synthesized target compound, the inhibition rate of the compounds is compared, and DYY-23, DYY-24, DYY-27 and DYY-28 in the compounds have stronger inhibition effect on tumor cells and have high-efficiency anti-tumor inhibition activity.

Claims (10)

1. Aryl substituted 8-amino imidazopyrazines, characterized in that they are compounds according to the following general formula (I) or (II) or pharmaceutically acceptable salts, solvates or hydrates or isomers thereof;
wherein,
a is any one of the following groups
B is any one of the following groups
R 1 Is any one of the following groups
R 2 is-CH 3; x is-O-, -NHCO-, CONH-.
2. A compound according to claim 1, characterized by one of the following compounds DYY-DYY:
3. use of an aryl-substituted 8-amino imidazopyrazines according to any one of claims 1 or 2 in the manufacture of a medicament for the prophylaxis or treatment of a heterologous immune disease, an autoimmune disease or a malignancy.
4. A use according to claim 3, characterized in that: the malignant tumor is non-small cell cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelogenous leukemia, multiple myeloma, and melanoma.
5. The use according to claim 4, characterized in that: the non-small cell carcinoma is derived from an a549 cell strain.
6. A process for the preparation of a compound according to claim 1, characterized in that the preparation of the compound of formula (I) is carried out according to the following reaction scheme:
7. the method for producing a compound according to claim 6, characterized by comprising the steps of:
<1> cyclizing 2-amino-3-chloropyrazine with 2-bromo-1, 1-diethoxyethane (A) to obtain imidazo [1,2-a ] pyrazine of compound (IV);
<2> bromine the compound (IV) with N-bromosuccinimide (B) to give the compound (V);
<3> preparing the compound (VI) from the compound (V) and the compound (C) by nucleophilic substitution reaction under basic conditions;
<4> preparing the compound (VII) from the compound (VI) by Suzuki coupling reaction with boric acid or boric acid ester (D) under the alkaline condition of palladium catalyst and inert gas protection;
<5> removal of the Boc protecting group of the coupled product (VII) under TFA-DCM solution to give compound (VIII);
<6> condensation or substitution reaction of piperidine or pyrrolidine (VIII) compound to give compound (IX).
8. A process for the preparation of a compound according to claim 1, characterized in that the preparation of the compound of formula (II) is carried out according to the following reaction scheme:
9. a process for the preparation of a compound according to claim 8, characterized by comprising the steps of:
<1> cyclizing 2-amino-3-chloropyrazine with 2-bromo-1, 1-diethoxyethane (A) to obtain imidazo [1,2-a ] pyrazine of compound (IV);
<2> bromine the compound (IV) with N-bromosuccinimide (B) to give the compound (V);
<3> preparing the compound (VI) from the compound (V) and the compound (C) by nucleophilic substitution reaction under basic conditions;
<4> preparing the compound (VII) from the compound (VI) by Suzuki coupling reaction with boric acid or boric acid ester (D) under the alkaline condition of palladium catalyst and inert gas protection;
<5> removal of the Boc protecting group of the coupled product (VII) under TFA-DCM solution to give compound (VIII);
<6> condensation or substitution reaction of piperidine or pyrrolidine (VIII) compound to give compound (IX).
10. A process for the preparation of a compound according to claim 7 or 9, characterized in that:
in the step <1>, the alkali is anhydrous sodium bicarbonate, the reaction solvent is isopropanol and tetrahydrofuran, and the reaction temperature is 80 ℃;
in the step <3>, the alkali is N, N-diisopropylethylamine, the reaction solvent is N, N-dimethylformamide and N-butanol, and the reaction temperature is 120 ℃;
in the step <4>, the base is potassium carbonate, the catalyst is [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and tetrakis (triphenylphosphine) palladium, and the reaction solvent is 1, 4-dioxane: water=4:1 (volume ratio), reaction temperature 85 ℃;
in the step <5>, the volume ratio of DCM to TFA is 3:1, and the reaction temperature is room temperature;
in the step <6>, the base is N, N-diisopropylethylamine or triethylamine, and the reaction temperature is 0 ℃ to room temperature.
CN202310758070.2A 2023-06-26 2023-06-26 Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof Pending CN117050085A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310758070.2A CN117050085A (en) 2023-06-26 2023-06-26 Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310758070.2A CN117050085A (en) 2023-06-26 2023-06-26 Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN117050085A true CN117050085A (en) 2023-11-14

Family

ID=88666994

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310758070.2A Pending CN117050085A (en) 2023-06-26 2023-06-26 Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN117050085A (en)

Similar Documents

Publication Publication Date Title
CN109983016B (en) Pyrimido [5,4-b ] indolizine or pyrimido [5,4-b ] pyridine compound, preparation method and application thereof
CN107383004B (en) 2-amino imidazopyridine derivative and preparation and application thereof
JP2015518011A (en) Pyrrolo [2,1-f] [1,2,4] triazine derivatives and their antitumor applications
CN112047950B (en) Imidazo pyrazine derivative and synthetic method and application thereof
CN106459060A (en) Fused triazole derivatives as phosphodiesterase 10A inhibitors
CN112250688B (en) 7-azabenzofuran derivatives and application thereof in antitumor drugs
CN103922992B (en) A kind of antitumour activity indolone derivatives, preparation method and use
CN110804059B (en) Carbamate compound, pharmaceutical composition and application thereof
CN117050085A (en) Aryl substituted 8-amino imidazo pyrazine compound, and preparation method and application thereof
CN112174958B (en) Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof
CN107739381B (en) Curcumenol derivative and application thereof in preparation of antitumor drugs
CN112250682B (en) Aromatic heterocycle modified naphthalimide derivative and preparation method and application thereof
CN103910643A (en) Anti-cancer activity ketone derivative as well as synthetic method and application thereof
CN110256405B (en) 5-alkyl-N-substituted aryl pyridone derivative and preparation method and application thereof
CN111269215B (en) Nitrogen-containing heterocyclic organic compound and preparation method and application thereof
CN117412973A (en) Nitrogen-containing fused heteroaromatic bicyclic compounds as USP1 inhibitors and uses thereof
CN110511226B (en) Compound or salt or solvate thereof, application thereof and pharmaceutical composition
CN111247143B (en) Pyridoquinazoline derivatives useful as inhibitors of protein kinases
CN113880836B (en) 1,5, 8-trisubstituted gamma-carboline derivative and preparation method and application thereof
CN110903341B (en) Progesterone-pyrazine amide compound, preparation method and anticancer application thereof
Kökösi et al. Nitrogen bridgehead compounds. Part 19. Synthesis of polymethylenepyrimidin‐4‐ones
CN114213396B (en) Indole-2-ketone compound and preparation method and application thereof
CN115093397B (en) Compound for treating tumor, synthesis method and application
CN111892595B (en) Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit
CN115141204B (en) Naphthalene [1,2-b ] furan-4, 5-dione derivative, preparation and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination