CN114044769B - Beta-indolyl quinazolinone derivative and preparation method and application thereof - Google Patents

Beta-indolyl quinazolinone derivative and preparation method and application thereof Download PDF

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CN114044769B
CN114044769B CN202111414796.1A CN202111414796A CN114044769B CN 114044769 B CN114044769 B CN 114044769B CN 202111414796 A CN202111414796 A CN 202111414796A CN 114044769 B CN114044769 B CN 114044769B
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CN114044769A (en
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黄志纾
江志
赵丹丹
李江青
饶勇
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Sun Yat Sen University
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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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The application discloses a beta-indolyl quinazolinone derivative, a preparation method and application thereof. The structural formula of the beta-indoloquinazolinone derivative is shown as follows:wherein the R is 1 、R 2 Is one or more groups, the R is 1 And R is 2 Independently selected from H, C-C6 alkyl orAnd R is 1 And R is 2 Are not hydrogen at the same time; r is R 3 And R is 4 Independently selected from hydrogen, C2-C6 alkyl, cyclohexyl orAnd R is 3 And R is 4 Are not hydrogen at the same time; wherein the R is 5 Saturated heterocyclic groups of C2-12 which are substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heterocyclic ring and substituted or unsubstituted containing 1-3 hetero atoms selected from N, O and S; n is 0, 1, 2, 3, 4, 5, 6; or R is 3 And R is 4 It is also possible to link the ring by means of a C3-C10 alkyl chain having at least one heteroatom. The compound has higher anti-tumor activity and lipid-lowering effect.

Description

Beta-indolyl quinazolinone derivative and preparation method and application thereof
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a beta-indolyl quinazolinone derivative, and a preparation method and application thereof.
Background
The series of beta-indoloquinazolinone alkaloids and derivatives thereof found in Rutaceae plants (Rutaceae) are reported to have various pharmacological activities, such as anti-inflammatory, antibacterial and cytotoxic activities, and the structure of the series of beta-indoloquinazolinone alkaloids is formed by connecting the 2-position of quinazolinone with the 2-position of indole, and the natural beta-indoloquinazolinone skeleton is not easy to carry out diversified derivatization modification expansion, so that the derivatization research on the skeleton is relatively single.
For example, chinese patent CN104367575a discloses a Bouchardatine and a Bouchardatine derivative, and a preparation method and an application thereof, wherein the Bouchardatine derivative disclosed in the disclosure is a derivative obtained by modifying a substituent on a carbonyl group of a quinazolinone, and the derivative obtained by the preparation has a lipid-lowering effect, but the lipid-lowering effect of some derivatives is not obvious, and in addition, the scheme can only provide modification of the substituent on the carbonyl group of the quinazolinone, but cannot modify the substituent on other sites of the skeleton.
Therefore, there is a need to provide a series of novel β -indoloquinazolinone derivatives having high lipid lowering effect and antitumor effect.
Disclosure of Invention
The present application aims to solve at least one of the above technical problems in the prior art. To this end, the application provides a β -indoloquinazolinone derivative.
The application also provides a preparation method of the beta-indolyl quinazolinone derivative.
The application also provides application of the beta-indolyl quinazolinone derivative.
The first aspect of the application provides a beta-indoloquinazolinone derivative, which has a structural formula shown in a formula (I):
wherein the R is 1 And R is 2 Is one or more groups, the R is 1 And R is 2 Independently selected from H, C-C6 alkyl orAnd R is 1 And R is 2 Are not hydrogen at the same time;
R 3 and R is 4 Independently selected from hydrogen, C2-C6 alkyl, cyclohexyl orAnd R is 3 And R is 4 Are not hydrogen at the same time; wherein the R is 5 A substituted or unsubstituted phenyl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted C2-C12 saturated heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S; n is 0, 1, 2, 3, 4, 5 or 6;
or R is 3 And R is 4 It is also possible to link the ring by means of a C3-C10 alkyl chain having at least one heteroatom.
The application relates to one technical scheme of the technical scheme of beta-indolyl quinazolinone derivatives, which has at least the following beneficial effects:
the applicant realizes the C-N coupling amination modification method of different positions on the aromatic ring on the beta-indoloquinazolinone mother nucleus, and can meet the requirement of post-rapid C-N derivatization modification of any position of the medicine containing the skeleton; the obtained derivative is subjected to anti-tumor activity research and lipid-lowering activity evaluation, and the result shows that the substituent modification on the aromatic ring can improve the anti-tumor effect and the lipid-lowering effect.
Substituent definition and general terminology:
the "C1-C6 alkyl group" in the present application means an alkyl group having 1 to 6 total carbon atoms, and includes a straight-chain alkyl group having 1 to 6 carbon atoms and a branched-chain alkyl group having 1 to 6 carbon atoms. "C2-C6 alkyl" in the present application is also defined as the same except that the total number of carbon atoms is different.
"substituted or unsubstituted phenyl" in the context of the present application means that at least one H in the phenyl group is replaced by a corresponding group as defined herein. The "substituted or unsubstituted phenyl aromatic heterocyclic group" in the present application has a similar definition.
"a saturated heterocyclic group of C2-12 containing 1 to 3 hetero atoms selected from N, O and S, which is substituted or unsubstituted", means a heterocyclic group having 2 to 12 in total carbon atoms, the ring-forming atoms in the heterocyclic ring containing a hetero atom and having 1 to 3 hetero atoms, and the hetero atom being selected from at least one of N, O and S, the heterocyclic ring being a saturated group, and optionally at least one H in the group being substituted with a corresponding group as defined herein.
In the present application, halogen means any one or two or more of fluorine, chlorine, bromine and iodine.
According to some embodiments of the application, theSelected from-> X is bromine or H.
According to some embodiments of the application, the β -indoloquinazolinone derivative is of any of the following structural formulas:
according to some preferred embodiments of the application, the β -indoloquinazolinone derivative is of one of any of the following structural formulas:
the second aspect of the application provides a preparation method of the beta-indoloquinazolinone derivative, which comprises the following synthesis steps:
the compound OAC is combined with a pharmaceutical composition containingThe compound of the group is dissolved in an organic solvent and reacts under the conditions of alkali and lithium bis- (trimethylsilyl) amide to obtain the beta-indoloquinazolinone derivative;
the compound OAC is selected from one of the following structural formulas:
R 3 and R is 4 Independently selected from hydrogen, C2-C6 alkyl, cyclohexyl orAnd R is 3 And R is 4 Are not hydrogen at the same time; wherein the R is 5 A saturated heterocyclic group of 2 to 12 carbon atoms which is a substituted or unsubstituted phenyl group, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted C containing 1 to 3 hetero atoms selected from N, O and S; n is 0, 1, 2, 3, 4, 5 or 6;
or R is 3 And R is 4 Is connected into a ring through a C3-C10 alkyl chain, wherein the alkyl chain has at least one heteroatom.
The application relates to a preparation method of a beta-indolyl quinazolinone derivative, which has at least the following beneficial effects:
the method for realizing C-N coupling modification of different positions on the aromatic ring by the beta-indoloquinazolinone derivative has the advantages of mild reaction conditions, low-cost and wide raw material sources, and the prepared beta-indoloquinazolinone Pd oxidation addition product is stable and separable, and can meet the requirement of post-rapid C-N derivatization modification of any position of a medicine containing the skeleton.
According to some embodiments of the application, the base is at least one of potassium carbonate, cesium carbonate, sodium t-butoxide, sodium dihydrogen phosphate dihydrate, or sodium acetate.
According to some embodiments of the application, the organic solvent is at least one of tetrahydrofuran, toluene, or 1, 4-dioxane.
According to some embodiments of the application, the compound OAC comprisesThe molar ratio of the compound of the group to the base is 1: (1.0-3.0): (1.0-4.0).
According to some embodiments of the application, the reaction time is 1 to 3 hours.
According to some embodiments of the application, the reaction is carried out under a nitrogen atmosphere.
According to some embodiments of the application, the compound 2 is prepared by:
adding a compound IQ, (1, 5-cyclooctadiene) palladium (II) dichloride and 2-di-tert-butyl phosphino-2, 4, 6-triisopropyl biphenyl into tetrahydrofuran for reaction to obtain a compound 2;
the compound 3 is selected from one of the following structures:
wherein X is a halogen atom.
According to some embodiments of the application, the compounds IQ, (1, 5-cyclooctadiene) palladium (II) dichloride and 2-di-tert-butyl phosphino-2, 4, 6-triisopropylbiphenyl have a molar ratio of 1:1: (1.0-2.0).
According to some embodiments of the application, the compound IQ may be obtained commercially or may be prepared as follows.
As one embodiment, the compound IQ-a is prepared by the following method, and the synthetic route is as follows:
s1, dissolving a compound 4 and thionyl chloride in chloroform for reaction to obtain an intermediate I;
s2, adding o-aminobenzamide and pyridine into chloroform, then dropwise adding the intermediate I, and reacting to obtain a compound 5;
s3, reacting the compound 5 under the condition of ethanol and sodium hydroxide to obtain a compound IQ-A.
As one embodiment, the compound IQ-D is prepared by the following method, and the synthetic route is as follows:
s10, dissolving the compound 6 and thionyl chloride in chloroform for reaction to obtain an intermediate I;
s20, dissolving halogenated o-aminobenzamide and pyridine in chloroform, and adding an intermediate I for reaction to obtain a compound 7;
s30, reacting the compound 7 in acetic anhydride to obtain a compound 8, and reacting the compound 8 under the condition of ammonia water to obtain a compound IQ-D.
The third aspect of the application provides application of the beta-indoloquinazolinone derivative in preparing antitumor or lipid-lowering drugs.
Detailed Description
Technical solutions in the embodiments of the present application will be clearly and completely described below, but the embodiments of the present application are not limited thereto.
The reagents, methods and apparatus employed in the present application, unless otherwise specified, are all conventional in the art.
Example 1
Example 1 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
synthesis of Compound IQ-11:
s1, compound 4 (10.0 mmol,1.0 equiv) was dissolved in chloroform (100 mL, 0.1M) and reacted at 75deg.C for 4h with thionyl chloride (4.35 mL,60mmol,6.0 equiv); after the reaction is finished, the solvent and the redundant thionyl chloride are removed by decompression, and an intermediate I is obtained;
s2 anthranilamide (10.0 mmol,1.0 equiv), pyridine (0.83 mL,10.0mmol,1.0 equiv) were added to chloroform (60 mL), intermediate I was then added dropwise, the reaction was allowed to proceed overnight at room temperature, and the TCL monitored for completion. After the reaction is finished, filtering, washing a filter cake with chloroform, and drying to obtain a compound 5;
s3, stirring the compound 5 uniformly under the conditions of ethanol (25.0 mL) and 2M sodium hydroxide (25 mL). The reaction was carried out at 85℃for 2 hours, after the completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to about 2 with 4M diluted hydrochloric acid, whereby a large amount of solids were precipitated. Filtering, washing the filter cake with water, and vacuum drying to obtain the compound IQ-11.
Nuclear magnetic resonance data of compound IQ-11 1 H NMR(400MHz,DMSO-d6)δ12.67(s,1H),11.94(s,1H),8.16(dd,J＝7.8,1.5Hz,1H),7.90–7.83(m,1H),7.75(d,J＝8.1Hz,1H),7.73–7.67(m,2H),7.62(d,J＝8.5Hz,1H),7.52(t,J＝7.5Hz,1H),7.19(dd,J＝8.5,1.8Hz,1H). 13 CNMR(101MHz,DMSO-d6)δ161.7,148.6,146.2,138.3,134.8,131.0,127.0,126.5,126.4,126.1,123.4,123.0,121.3,116.9,114.8,105.0.HRMS(ESI-TOF):m/z calculated for C16H10N3OBr[M+H]+:340.0080,found:340.0075.
The compounds IQ-11 (3.0 mmol,1.0 equiv), (1, 5-cyclooctadiene) palladium (II) dichloride (3.0 mmol,1.0 equiv) and 2-di-tert-butyl phosphino-2, 4, 6-triisopropylbiphenyl (3.0 mmol,1.0 equiv) were added. The rubber plug is arranged on the reaction bottle plug, the nitrogen replaces the gas in the bottle, and the process is repeated for three times. Subsequently, anhydrous tetrahydrofuran was added as a solvent to the reaction flask by syringe, and the reaction was stirred at room temperature for 16 hours. After the reaction, the solvent was removed by spinning under reduced pressure, n-pentane was added to the reaction flask, and the solid was sufficiently ground with a spatula to be suspended in n-pentane as a powder, filtered, and the cake was washed with n-pentane, followed by vacuum drying to give compound 11-OAC.
Compound 11-OAC (0.2 mmol,1.0 equiv.) and cesium carbonate (0.4 mmol,2.0 equiv.) are added and the gases in the flask are replaced three times with nitrogen. Anhydrous tetrahydrofuran (2 mL) was then added with the injection and stirred well. Amination reagent(0.3 mmol,1.5 eq.) was dissolved in an appropriate amount of anhydrous tetrahydrofuran, added to the reaction system by syringe, followed by the addition of lithium bis- (trimethylsilyl) amide (0.4 mmol,2.0 eq.). After the addition, the reaction was carried out at room temperature for 2 hours, followed by adding a dichloromethane solution (2 mL) of 0.2M acetic acid to the reaction flask and stirring for 0.5 hours to quench the reaction. After the reaction was completed, DCM was added to the reaction solution for dilution, followed by filtration of the solid residue through celite, the filtrate was collected, the solvent was removed by spin-on under reduced pressure, and the objective compound 11-9 (41.0 mg,47% yield) was obtained by flash column chromatography on silica gel. 1 H NMR(500MHz,DMSO-d6)δ12.50(s,1H),11.48(s,1H),8.45(s,1H),8.14(d,J＝7.9Hz,1H),7.82(t,J＝7.7Hz,1H),7.69(d,J＝8.0Hz,1H),7.60(s,1H),7.53(d,J＝8.5Hz,1H),7.47(t,J＝7.5Hz,1H),7.29(s,1H),7.22(d,J＝8.6Hz,2H),7.15(d,J＝7.2Hz,2H),6.88(d,J＝8.7Hz,1H). 13 C NMR(126MHz,DMSO-d6)δ162.3,149.4,147.0,144.0,141.0,141.0,140.4,139.4,135.1,130.1,129.3,127.2,126.5,126.4,123.0,122.8,122.7,121.8,121.4,119.8,117.2,114.5,106.0,99.7.HRMS(ESI-TOF):m/z calculated for C 23 H 15 N 4 O 2 F 3 [M+H] + :437.1220,found:437.1212.
Example 2
Example 2 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the synthesis of the compound IQ-2 is carried out by the following synthetic route:
s10. Compound 6 (10.0 mmol,1.0 equiv) and thionyl chloride (4.35 mL,60mmol,6.0 equiv) are dissolved in chloroform (100 mL, 0.1M); under ice bath, drop SOCl into the reaction flask 2 (4.35 mL,60mmol,6.0 equiv); after the addition, the reaction bottle is moved to 75 ℃ for reaction for 4 hours; after the reaction is finished, the solvent and the redundant thionyl chloride are removed by decompression, and an intermediate I is obtained;
s20 chlorinated anthranilamide (10.0 mmol,1.0 equiv) and pyridine (0.83 mL,10.0mmol,1.0 equiv) were dissolved in chloroform (60 mL) and intermediate I was added to the reaction, which was allowed to react overnight at room temperature, and TCL was monitored for completion. After the reaction is finished, filtering, washing a filter cake with chloroform, and drying to obtain a compound 7;
s30, reacting the compound 7 in acetic anhydride (20 mL), reacting for 2h at 120 ℃, cooling to room temperature after the reaction is finished, and separating out solids at the moment; filtering, washing a filter cake with absolute ethyl alcohol, then drying in vacuum to obtain a compound 8, reacting the compound 8 under the condition of ammonia water (20.0 mL), moving the reaction to 110 ℃ for 2h, cooling to room temperature after the reaction is finished, pouring the reaction solution into ice water, fully volatilizing excessive ammonia, and then adjusting the pH to about 2 by 4M dilute hydrochloric acid, wherein a large amount of solids are precipitated. Filtering, washing the filter cake with water, and vacuum drying to obtain the compound IQ-2. 1 H NMR(500MHz,DMSO-d 6 )δ12.68(s,1H),11.94(s,1H),8.17(dd,J＝7.9,1.5Hz,1H),7.89–7.83(m,1H),7.76(d,J＝8.1Hz,1H),7.72(s,1H),7.70(d,J＝2.0Hz,1H),7.63(d,J＝8.5Hz,1H),7.53(t,J＝6.9Hz,1H),7.20(dd,J＝8.5,1.8Hz,1H). 13 C NMR(126MHz,DMSO-d 6 )δ162.2,149.1,146.7,138.8,135.2,131.5,127.4,127.0,126.9,126.6,123.9,123.5,121.7,117.3,115.3,105.5.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OCl[M+H] + :296.0585,found:296.0586.
The compounds IQ-2 (3.0 mmol,1.0 equiv), (1, 5-cyclooctadiene) palladium (II) dichloride (3.0 mmol,1.0 equiv) and 2-di-tert-butyl phosphino-2, 4, 6-triisopropylbiphenyl (3.0 mmol,1.0 equiv) were added. The rubber plug is arranged on the reaction bottle plug, the nitrogen replaces the gas in the bottle, and the process is repeated for three times. Subsequently, anhydrous tetrahydrofuran was added as a solvent to the reaction flask by syringe, and the reaction was stirred at room temperature for 16 hours. After the reaction, the solvent was removed by spinning under reduced pressure, n-pentane was added to the reaction flask, and the solid was sufficiently ground with a spatula to be suspended in n-pentane as a powder, filtered, and the cake was washed with n-pentane, followed by vacuum drying to give compound 2-OAC.
Compound 2-OAC (0.2 mmol,1.0 equiv.) and cesium carbonate (0.4 mmol,2.0 equiv.) are added and the gases in the reaction flask are replaced three times with nitrogen. Anhydrous tetrahydrofuran (2 mL) was then added with the injection and stirred well. Amination reagent(0.3 mmol,1.5 eq.) was dissolved in an appropriate amount of anhydrous tetrahydrofuran, added to the reaction system by syringe, followed by the addition of lithium bis- (trimethylsilyl) amide (0.4 mmol,2.0 eq.). After the addition, the reaction was carried out at room temperature for 2 hours, followed by adding a dichloromethane solution (2 mL) of 0.2M acetic acid to the reaction flask and stirring for 0.5 hours to quench the reaction. After the completion of the reaction, methylene chloride was added to dilute the reaction mixture, followed by filtration of the solid residue through celite, collecting the filtrate, spin-removing the solvent under reduced pressure, and subjecting the resulting mixture to flash column chromatography on silica gel to give the objective compound 2-5 (40.9 mg,62% yield) 1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),11.69(s,1H),7.81(d,J＝8.7Hz,1H),7.61(d,J＝9.5Hz,2H),7.52(d,J＝8.2Hz,1H),7.20(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.88(t,J＝5.4Hz,1H),6.80(dd,J＝8.8,2.3Hz,1H),6.67(d,J＝2.2Hz,1H),3.03(t,J＝6.0Hz,2H),1.15–1.06(m,1H),0.51(q,J＝5.5Hz,2H),0.26(q,J＝4.8Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ161.2,154.0,150.9,146.4,137.4,130.5,127.5,126.9,123.8,121.4,119.8,113.9,112.3,109.7,104.2,104.0,46.9,10.2,3.6.HRMS(ESI-TOF):m/z calculated for C 20 H 18 N 4 O[M+H] + :331.1553,found:331.1548.
Example 3
Example 3 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the preparation of example 3 is the same as that of example 2, except that the amination reagent is
The obtained compound 2-2 (43.0 mg,60% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.29(s,1H),11.79(s,1H),7.94(d,J＝8.8Hz,1H),7.62(d,J＝7.7Hz,2H),7.53(d,J＝8.2Hz,1H),7.21(t,J＝7.7Hz,1H),7.16(d,J＝9.1Hz,1H),7.05(t,J＝7.5Hz,1H),6.99(s,1H),3.43(s,4H),2.63(s,4H),2.33(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ161.7,155.4,150.9,147.2,138.0,130.8,127.9,127.5,124.4,121.9,120.4,115.2,112.9,112.3,109.1,105.1,54.2,46.7,45.4.HRMS(ESI-TOF):m/z calculated for C 21 H 21 N 5 O[M+H] + :360.1819,found:360.1816.
Example 4
Example 4 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
example 4 the preparation was identical to example 1, except that compound 4 of example 1 had the structureThe amination reagent is as follows: />The structural formula of the prepared compound IQ-10 (1.83 g,6.2 mmol) is as follows: />Its nuclear magnetic data is 1 H NMR(400MHz,DMSO-d 6 )δ12.68(s,1H),12.03(s,1H),8.16(dd,J＝7.9,1.5Hz,1H),7.88–7.82(m,1H),7.74(d,J＝7.1Hz,1H),7.71(d,J＝2.0Hz,1H),7.65(s,1H),7.57–7.48(m,2H),7.23(dd,J＝8.8,2.1Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ161.7,148.6,146.2,136.0,134.7,131.6,128.4,127.0,126.5,126.1,124.5,124.1,121.3,120.5,114.0,104.5.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OCl[M+H] + :296.0585,found:296.0583.
Compound 10-1 (20.7 mg,30% yield) was obtained 1 H NMR(500MHz,DMSO-d 6 )δ12.53(s,1H),11.56(s,1H),8.14(dd,J＝7.9,1.5Hz,1H),7.86–7.81(m,1H),7.72(d,J＝8.1Hz,1H),7.55(d,J＝2.2Hz,1H),7.49(t,J＝7.5Hz,1H),7.42(d,J＝8.9Hz,1H),7.07(dd,J＝8.9,2.3Hz,1H),7.04(s,1H),3.83–3.73(m,4H),3.15–3.01(m,4H). 13 C NMR(126MHz,DMSO-d 6 )δ161.8,148.8,146.6,145.9,134.7,133.2,129.9,129.6,127.9,126.8,126.1,121.0,117.7,112.8,106.1,104.7,66.4,50.8.HRMS(ESI-TOF):m/z calculated for C 20 H 18 N4O 2 [M+H] + :347.1503,found:347.1519.
Example 5
Example 5 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method is as follows:
example 5 the preparation was identical to example 1, except that compound 4 of example 1 had the structureThe amination reagent is as follows: />The structural formula of the prepared compound IQ-12 (1.53 g,52% yield) is as follows: />Its nuclear magnetic data is 1 H NMR(400MHz,DMSO-d 6 )δ12.64(s,1H),11.70(s,1H),8.16(d,J＝7.7Hz,1H),7.86(t,J＝7.5Hz,1H),7.78(d,J＝8.1Hz,1H),7.66(d,J＝7.8Hz,2H),7.52(t,J＝7.4Hz,1H),7.35(d,J＝7.5Hz,1H),7.11(t,J＝7.8Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ161.7,148.7,145.9,134.8,134.4,131.7,129.2,127.3,126.6,126.0,123.7,121.3,121.1,120.7,116.4,106.8.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OCl[M+H] + :296.0585,found:296.0598.
The obtained compound 12-1 (35.2 mg,51% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.66(s,1H),11.03(s,1H),8.15(d,J＝7.9Hz,1H),7.83(t,J＝7.5Hz,1H),7.76(d,J＝8.1Hz,1H),7.58(d,J＝2.3Hz,1H),7.49(t,J＝7.5Hz,1H),7.35(d,J＝7.8Hz,1H),7.04(t,J＝7.7Hz,1H),6.86(d,J＝7.3Hz,1H),3.97–3.85(m,4H),3.07(t,J＝4.4Hz,4H). 13 CNMR(126MHz,DMSO-d 6 )δ162.3,149.4,146.9,139.3,135.1,131.9,130.5,129.2,127.7,126.7,126.4,121.5,121.4,116.8,112.6,107.5,67.0,51.9.HRMS(ESI-TOF):m/zcalculated for C 20 H 18 N 4 O 2 [M+H] + :347.1503,found:347.1498.
Example 6
Example 6 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method is as follows:
the preparation of example 6 is identical to that of example 1, except that the structure of Compound 4 in example 1Is thatThe amination reagent is as follows: />/>
The structural formula of the prepared compound IQ-9 (2.21 g,65% yield) is as follows:its nuclear magnetic data is 1 H NMR(500MHz,DMSO-d 6 )δ12.70(s,1H),12.17(s,1H),8.16(dd,J＝8.0,1.5Hz,1H),7.88–7.83(m,1H),7.75(d,J＝8.0Hz,2H),7.55(d,J＝8.2Hz,1H),7.54–7.50(m,1H),7.30(d,J＝7.5Hz,1H),7.16(t,J＝7.9Hz,1H). 13 C NMR(126MHz,DMSO-d 6 )δ162.0,148.5,146.5,137.9,134.6,131.1,128.2,126.8,126.4,126.1,125.0,122.6,121.3,114.5,112.0,104.7.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OBr[M+H] + :340.0080,found:340.0077.
The obtained compound 9-1 (27.0 mg,39% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.51(s,1H),11.76(s,1H),8.15(d,J＝7.9Hz,1H),7.83(d,J＝7.3Hz,2H),7.72(d,J＝8.2Hz,1H),7.54–7.45(m,1H),7.18–7.06(m,2H),6.47(d,J＝7.2Hz,1H),3.92–3.82(m,4H),3.23–3.13(m,4H). 13 C NMR(126MHz,DMSO-d 6 )δ162.3,149.3,147.0,146.6,139.6,135.2,128.7,127.3,126.6,126.5,125.4,121.5,121.2,107.0,106.2,105.0,67.0,51.7.HRMS(ESI-TOF):m/z calculated for C 20 H 18 N4O 2 [M+H] + :347.1503,found:347.1491.
Example 7
Example 7 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
preparation of example 7The process is the same as in example 2, except that in example 2Quilt is covered withInstead, the amination reagent is: />
The structural formula of the prepared compound IQ-1 (1.61 g,65% yield) isIts nuclear magnetic data is 1 H NMR(500MHz,DMSO-d 6 )δ12.80(s,1H),11.54(s,1H),8.10(d,J＝8.0Hz,1H),7.98(d,J＝7.9Hz,1H),7.71(s,1H),7.65(dd,J＝16.0,8.2Hz,2H),7.46(t,J＝7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.08(t,J＝7.5Hz,1H). 13 C NMR(126MHz,DMSO-d 6 )δ161.9,147.6,145.8,138.3,135.2,131.0,130.2,127.9,126.9,125.6,124.8,123.3,122.1,120.6,113.2,106.3.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OCl[M+H] + :296.0585,found:296.0582.
The prepared compound 1-1 (27.6 mg,40% yield) has a nuclear magnetic data of 1 H NMR(400MHz,DMSO-d 6 )δ12.52(s,1H),11.21(s,1H),7.75(d,J＝7.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.59(d,J＝8.8Hz,2H),7.39(t,J＝7.8Hz,1H),7.29(d,J＝7.7Hz,1H),7.25(t,J＝7.6Hz,1H),7.08(t,J＝7.5Hz,1H),3.94(t,J＝4.5Hz,4H),3.31(t,J＝4.7Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ162.1,148.0,144.0,141.6,137.5,130.5,127.5,126.6,124.0,122.4,121.6,121.5,120.1,118.4,112.6,105.1,66.2,51.8.HRMS(ESI-TOF):m/z calculated for C 20 H 18 N 4 O 2 [M+H] + :347.1503,found:347.1493.
Example 8
Example 8 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the preparation method of example 8 is the same as that of example 2, except that the amination reagents are different, and the amination reagents are:
the prepared compound 2-1 (40.1 mg,58% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.44(s,1H),11.44(s,1H),8.12(d,J＝7.9Hz,1H),7.82(t,J＝7.6Hz,1H),7.70(d,J＝8.2Hz,1H),7.55(s,1H),7.51–7.44(m,2H),6.92(s,1H),6.89(dd,J＝8.8,1.9Hz,1H),3.85–3.71(m,4H),3.17–3.08(m,4H). 13 C NMR(101MHz,DMSO-d 6 )δ161.3,155.4,150.4,146.8,137.5,130.3,127.5,127.0,123.9,121.5,119.9,114.5,112.4,112.1,108.4,104.6,65.9,47.1.HRMS(ESI-TOF):m/z calculated for C 20 H 18 N 4 O 2 [M+H] + :347.1503,found:347.1491.
Example 9
Example 9 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the preparation of example 9 was identical to that of example 2, except that in example 2Quilt (S)>Instead, the amination reagent is: />
The structural formula of the prepared compound IQ-4 (1.47 g,50% yield) isIts nuclear magnetic data is 1 H NMR(400MHz,DMSO-d 6 )δ12.60(s,1H),11.79(s,1H),7.75(t,J＝7.9Hz,1H),7.69(d,J＝1.4Hz,1H),7.68–7.62(m,2H),7.53(dd,J＝8.2,1.0Hz,1H),7.49(dd,J＝7.8,1.3Hz,1H),7.24(ddd,J＝8.2,6.9,1.2Hz,1H),7.07(ddd,J＝8.0,6.9,1.0Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ160.0,151.3,147.2,137.7,134.4,132.7,129.4,128.6,127.4,126.5,124.3,121.6,120.0,118.0,112.4,105.5.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OCl[M+H] + :296.0585,found:296.0598.
Compound 4-1 (27.7 mg,40% yield) was prepared with nuclear magnetic data of: 1 H NMR(400MHz,DMSO-d 6 )δ11.83(s,1H),7.75(d,J＝8.1Hz,1H),7.60(t,J＝7.8Hz,1H),7.54(d,J＝8.2Hz,1H),7.45(d,J＝8.0Hz,1H),7.24(t,J＝7.3Hz,1H),7.09(t,J＝7.2Hz,1H),7.03(d,J＝7.4Hz,1H),3.99(s,2H),3.76(s,4H),3.08(s,2H). 13 C NMR(126MHz,DMSO-d 6 )δ164.2,151.9,148.4,144.7,137.1,134.1,129.5,129.4,128.1,125.0,124.2,120.8,120.1,119.0,113.4,113.4,66.6,52.7,51.7.
example 10
Example 10 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the preparation of example 10 is the same as that of example 1, except that the structure of compound 4 in example 1 isThe amination reagent is as follows: />
Compound 11-4 (40.3 mg,56% yield) was obtained with a nuclear magnetic resonance data of 1 H NMR(500MHz,DMSO-d 6 )δ12.33(s,1H),11.16(s,1H),8.11(d,J＝7.8Hz,1H),7.80(t,J＝7.7Hz,1H),7.66(d,J＝8.1Hz,1H),7.49(s,1H),7.43(t,J＝7.5Hz,1H),7.30(d,J＝8.7Hz,1H),6.57(d,J＝7.1Hz,2H),5.69(t,J＝5.8Hz,1H),4.04(p,J＝6.4Hz,1H),3.81(q,J＝7.2Hz,1H),3.66(q,J＝7.3Hz,1H),3.10(t,J＝5.9Hz,2H),2.00(ddd,J＝19.6,10.9,4.8Hz,1H),1.86(qp,J＝13.2,7.0Hz,2H),1.63(dp,J＝14.5,7.4,6.9Hz,1H). 13 C NMR(126MHz,DMSO-d 6 )δ162.3,149.7,147.6,147.2,140.6,135.0,130.1,127.1,126.5,125.9,122.3,121.2,119.8,111.8,106.6,91.5,77.4,67.6,48.3,29.6,25.7.HRMS(ESI-TOF):m/zcalculated for C 21 H 20 N 4 O 2 [M+H] + :361.1659,found:361.1659.
Example 11
Example 11 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method is as follows:
the preparation of example 11 is identical to that of example 10, with the difference that the amination reagent is:the prepared compound 11-7 (33.0 mg,50% yield) has a nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.32(s,1H),11.15(s,1H),8.11(d,J＝7.8Hz,1H),7.80(t,J＝7.7Hz,1H),7.66(d,J＝8.2Hz,1H),7.49(s,1H),7.43(t,J＝7.6Hz,1H),7.30(d,J＝8.5Hz,1H),6.59–6.48(m,2H),5.77(t,J＝6.2Hz,1H),2.92(t,J＝5.6Hz,2H),1.27–1.22(m,1H),0.50(d,J＝7.7Hz,2H),0.26(d,J＝4.9Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ162.3,149.7,147.8,147.2,140.6,135.0,127.0,127.0,126.5,125.9,122.3,121.2,119.7,111.9,106.6,91.4,48.3,11.0,4.1.HRMS(ESI-TOF):m/z calculated for C 20 H 18 N 4 O[M+H] + :331.1553,found:331.1549.
Example 12
Example 12 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method is as follows:
the procedure for the preparation of example 12 is the same as in example 10, except that the amination reagent is:
the prepared compound 11-8 (22.9 mg,30% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.47(s,1H),11.44(s,1H),8.27(s,1H),8.13(d,J＝7.9Hz,1H),7.82(t,J＝7.6Hz,1H),7.69(d,J＝8.1Hz,1H),7.58(s,1H),7.53–7.44(m,2H),7.32(s,1H),7.14(t,J＝8.4Hz,1H),6.85(d,J＝8.6Hz,1H),6.69(d,J＝8.0Hz,2H),6.40(d,J＝7.9Hz,1H),3.73(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ162.3,160.7,149.5,147.0,145.6,140.9,139.5,135.1,130.3,129.0,127.2,126.5,126.3,122.6,122.5,121.4,114.6,109.5,106.0,105.3,102.3,98.8,55.3.HRMS(ESI-TOF):m/z calculated for C 23 H 18 N4O 2 [M+H] + :383.1503,found:383.1489.
Example 13
Example 13 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the procedure for the preparation of example 13 is identical to that of example 10, except that the amination reagent is:
the prepared chemicalCompound 11-10 (30.0 mg,42% yield) with nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.29(s,1H),11.06(s,1H),8.10(dd,J＝7.9,1.5Hz,1H),7.82–7.76(m,1H),7.64(d,J＝8.1Hz,1H),7.47(d,J＝2.1Hz,1H),7.42(t,J＝7.5Hz,1H),7.28(d,J＝8.6Hz,1H),6.55(s,1H),6.51(dd,J＝8.6,2.0Hz,1H),5.49(d,J＝7.8Hz,1H),3.18(s,1H),2.03–1.96(m,2H),1.75(dt,J＝12.2,3.0Hz,2H),1.40–1.32(m,2H),1.22–1.12(m,4H). 13 C NMR(126MHz,DMSO-d 6 )δ161.8,149.2,146.7,146.2,140.2,134.5,126.6,126.4,126.0,125.4,121.9,120.7,119.1,111.5,106.1,91.4,51.1,32.5,25.7,24.7.HRMS(ESI-TOF):m/z calculated for C 22 H 22 N 4 O[M+H] + :359.1866,found:359.1855.
Example 14
Example 14 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the procedure for the preparation of example 14 is identical to that of example 10, except that the amination reagent is:
the prepared compound 11-13 (40.4 mg,54% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.32(s,1H),11.12(s,1H),8.10(d,J＝7.9Hz,1H),7.79(t,J＝7.6Hz,1H),7.65(d,J＝8.1Hz,1H),7.49(s,1H),7.42(t,J＝7.5Hz,1H),7.29(d,J＝8.5Hz,1H),6.53(d,J＝10.4Hz,2H),5.79(t,J＝5.6Hz,1H),3.88(dd,J＝11.5,4.1Hz,2H),3.29(t,J＝11.8Hz,2H),2.93(t,J＝6.0Hz,2H),1.91–1.79(m,1H),1.71(d,J＝12.6Hz,2H),1.28(dd,J＝12.2,4.5Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ161.9,149.2,147.4,146.7,140.2,134.6,126.6,126.5,126.0,125.4,121.9,120.7,119.2,111.3,106.1,90.9,66.9,49.5,34.1,30.9.HRMS(ESI-TOF):m/z calculated for C 22 H 22 N 4 O 2 [M+H] + :375.1816,found:375.1806.
Example 15
Example 15 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method is as follows:
the preparation of example 15 is identical to that of example 10, with the difference that the amination reagent is:
the prepared compound 11-14 (38.1 mg,60% yield) has a nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.32(s,1H),11.11(s,1H),8.10(d,J＝7.9Hz,1H),7.79(t,J＝7.7Hz,1H),7.65(d,J＝8.2Hz,1H),7.48(s,1H),7.42(t,J＝7.5Hz,1H),7.29(d,J＝8.6Hz,1H),6.53(s,1H),6.49(d,J＝8.7Hz,1H),5.48(s,1H),3.53(s,1H),1.17(d,J＝6.3Hz,6H). 13 CNMR(126MHz,DMSO-d 6 )δ162.3,149.7,147.2,146.8,140.7,135.0,127.0,127.0,126.5,125.9,122.4,121.2,119.6,112.1,106.6,92.0,43.9,22.9.HRMS(ESI-TOF):m/z calculated for C 19 H 18 N 4 O[M+H] + :319.1553,found:319.1553.
Example 16
Example 16 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the procedure for the preparation of example 16 is the same as in example 2, except that the amination reagent is
The obtained compound 2-3 (41.5 mg,60% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.08(s,1H),11.71(s,1H),7.80(d,J＝8.7Hz,1H),7.61(d,J＝8.7Hz,2H),7.52(d,J＝8.3Hz,1H),7.20(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.79(dd,J＝9.8,7.5Hz,2H),6.64(s,1H),3.13(q,J＝6.7Hz,2H),1.79–1.64(m,J＝6.8Hz,1H),1.51(q,J＝7.2Hz,2H),0.93(d,J＝6.6Hz,6H). 13 C NMR(126MHz,DMSO-d 6 )δ161.7,154.5,151.4,146.9,137.9,131.0,128.0,127.4,124.2,121.8,120.3,114.3,112.8,110.0,104.8,104.3,41.1,37.7,25.9,22.9.HRMS(ESI-TOF):m/z calculated for C 21 H 22 N 4 O[M+H] + :347.1866,found:347.1855.
Example 17
Example 17 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
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the preparation of example 17 is the same as that of example 2, except that the amination reagent is
The obtained compound 2-9 (49.6 mg,65% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.27(s,1H),11.73(s,1H),8.91(s,1H),7.99(d,J＝8.7Hz,1H),7.71–7.59(m,2H),7.52(d,J＝8.2Hz,1H),7.29(d,J＝8.5Hz,2H),7.21(t,J＝7.7Hz,1H),7.11(d,J＝8.5Hz,1H),7.05(t,J＝7.5Hz,1H),6.88(d,J＝8.0Hz,1H),6.81(s,1H),6.64(d,J＝8.2Hz,1H),3.77(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ161.6,160.6,151.2,150.3,147.3,142.9,138.0,130.7,130.7,128.0,124.4,121.9,120.4,116.4,113.0,112.8,108.4,108.0,106.4,105.1,55.5.H RMS(ESI-TOF):m/z calculated for C 23 H 18 N 4 O 2 [M+H] + :383.1503,found:383.1501.
Example 18
Example 18 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the procedure for the preparation of example 18 is the same as in example 2, except that the amination reagent is
The obtained compound 2-17 (44.6 mg,60% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.12(s,1H),11.66(s,1H),7.85(d,J＝8.7Hz,1H),7.64–7.58(m,2H),7.51(d,J＝8.2Hz,1H),7.40(d,J＝5.0Hz,1H),7.37(t,J＝5.9Hz,1H),7.20(t,J＝7.4Hz,1H),7.09(d,J＝3.5Hz,1H),7.04(t,J＝7.5Hz,1H),7.01(dd,J＝5.0,3.5Hz,1H),6.86(dd,J＝8.7,2.3Hz,1H),6.70(d,J＝2.2Hz,1H),4.61(d,J＝5.8Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ161.3,153.4,150.8,146.5,143.2,137.5,130.4,129.6,127.5,127.0,124.8,124.7,123.8,121.4,119.9,114.3,112.4,110.5,104.8,104.4,41.6.HRMS(ESI-TOF):m/z calculated for C 21 H 16 N 4 OS[M+H] + :373.1118,found:373.1126.
Example 19
Example 19 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the preparation of example 19 is the same as that of example 6, except that the amination reagent is
The obtained compound 9-2 (43.5 mg,54% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.45(s,1H),11.53(s,1H),8.13(d,J＝7.9Hz,1H),7.82(t,J＝7.6Hz,1H),7.69(d,J＝6.4Hz,2H),7.47(t,J＝7.6Hz,1H),7.36(d,J＝4.7Hz,1H),7.08–6.96(m,3H),6.79(d,J＝8.1Hz,1H),6.16(d,J＝7.5Hz,1H),5.67(t,J＝5.6Hz,1H),3.48(q,J＝6.7Hz,2H),3.18(t,J＝7.1Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ161.8,149.1,146.7,142.2,142.1,138.7,134.6,127.3,127.0,126.7,126.0,126.0,125.8,125.2,124.0,120.9,117.3,103.8,101.0,98.3,44.8,29.0.
Example 20
Example 20 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the preparation of example 19 is the same as that of example 5, except that the amination reagent is
The obtained compound 12-2 (40.0 mg,52% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.56(s,1H),11.52(s,1H),8.16(d,J＝7.9Hz,1H),7.84(t,J＝7.6Hz,1H),7.77(d,J＝8.2Hz,1H),7.62(s,1H),7.49(t,J＝7.5Hz,1H),7.35(d,J＝5.0Hz,1H),6.98(d,J＝5.5Hz,2H),6.90(d,J＝3.3Hz,2H),6.41–6.31(m,2H),3.49(q,J＝6.6Hz,2H),3.21(t,J＝7.0Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ161.8,148.8,146.7,142.1,134.8,134.7,128.8,128.0,127.2,127.0,126.8,126.1,126.1,125.3,123.9,121.5,121.1,109.3,105.7,102.0,44.7,28.9.
Example 21
Example 21 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method comprises the following steps:
the preparation method of example 21 is the same as that of example 2, except that the amination reagents are different, and the amination reagents are:
the prepared compound 2-18 (35.2 mg,50% yield) has nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.13(s,1H),11.68(s,1H),7.86(d,J＝8.7Hz,1H),7.65–7.59(m,3H),7.53(d,J＝8.4Hz,1H),7.20(q,J＝6.9,6.0Hz,2H),7.05(t,J＝7.5Hz,1H),6.87(d,J＝8.8Hz,1H),6.76(s,1H),6.42(s,1H),6.34(d,J＝3.1Hz,1H),4.41(d,J＝5.8Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ161.3,153.5,152.4,150.8,146.5,142.3,137.5,130.4,127.5,127.0,123.8,121.4,119.9,114.1,112.4,110.5,110.4,107.1,104.7,104.4,27.5.
Example 22
Example 22 provides a beta-indoloquinazolinone derivative, which has the following structural formula, and the preparation method is as follows:
the preparation method of example 22 is the same as that of example 2, except that the amination reagents are different, and the amination reagents are:
compound 2-10 (38.5 mg,50% yield) was prepared with a nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.12(s,1H),11.69(s,1H),7.85(d,J＝8.7Hz,1H),7.62(d,J＝8.0Hz,2H),7.53(d,J＝8.3Hz,1H),7.36(d,J＝4.5Hz,1H),7.21(t,J＝7.7Hz,1H),7.05(t,J＝7.5Hz,1H),6.98(d,J＝4.7Hz,2H),6.88(t,J＝5.8Hz,1H),6.80(d,J＝8.2Hz,1H),6.71(s,1H),3.45(q,J＝6.0Hz,2H),3.18(d,J＝3.5Hz,1H),3.13(t,J＝7.2Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ161.7,154.0,151.4,147.0,142.0,137.9,130.9,130.1,128.0,127.6,127.5,125.8,124.5,124.3,121.9,120.3,112.8,110.5,104.8,104.6,104.6,44.5,29.1.
Example 23
Example 23 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the procedure for the preparation of example 23 is the same as in example 10, except that the amination reagent is:
the prepared compound 11-11 (38.1 mg,55% yield) has a nuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.33(s,1H),11.19(s,1H),8.10(d,J＝7.8Hz,1H),7.78(t,J＝7.7Hz,1H),7.65(d,J＝8.2Hz,1H),7.49(s,1H),7.42(t,J＝7.5Hz,1H),7.29(d,J＝8.7Hz,1H),6.52(d,J＝7.7Hz,2H),5.69(s,1H),3.03(t,J＝7.5Hz,2H),1.72(dp,J＝13.5,6.7Hz,1H),1.49(q,J＝7.1Hz,2H),0.93(d,J＝6.6Hz,6H). 13 C NMR(126MHz,DMSO-d 6 )δ162.3,149.7,147.8,147.2,140.7,135.0,127.0,126.9,126.5,125.9,122.3,121.1,119.6,111.9,106.7,91.2,41.8,38.0,25.9,23.0.HRMS(ESI-TOF):m/z calculated for C 21 H 22 N 4 O[M+H] + :347.1866,found:347.1862.
Example 24
Example 24 provides a β -indoloquinazolinone derivative having the following structural formula, and the preparation method is as follows:
the procedure for the preparation of example 24 was identical to that of example 2, except that in example 2Quilt is covered withInstead, the amination reagent is: />The structural formula of the prepared compound IQ-3 isNuclear magnetic data of 1 H NMR(500MHz,DMSO-d 6 )δ12.77(s,1H),11.81(s,1H),8.08(d,J＝2.4Hz,1H),7.86(dd,J＝8.7,2.6Hz,1H),7.74(d,J＝8.7Hz,1H),7.68(d,J＝2.1Hz,1H),7.65(d,J＝8.1Hz,1H),7.54(d,J＝8.3Hz,1H),7.24(t,J＝7.6Hz,1H),7.07(t,J＝7.5Hz,1H). 13 C NMR(126MHz,DMSO-d 6 )δ160.9,147.5,147.0,137.7,134.8,130.4,129.8,129.1,127.4,125.1,124.2,122.4,121.6,120.0,112.4,105.4.HRMS(ESI-TOF):m/z calculated for C 16 H 10 N 3 OCl[M+H] + :296.0585,found:296.0592.
The nuclear magnetic data of M3-1 (24.5 mg,34% yield) obtained was 1 H NMR(500MHz,DMSO-d 6 )δ12.43(s,1H),11.49(s,1H),7.62(d,J＝8.0Hz,1H),7.56(d,J＝10.9Hz,2H),7.47(s,1H),7.33(s,1H),7.22(t,J＝7.8Hz,1H),7.05(t,J＝7.5Hz,1H),3.78(d,J＝4.6Hz,4H),3.23(d,J＝3.1Hz,4H),2.69(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ162.1,148.8,142.5,140.5,137.4,136.6,130.7,129.6,123.8,123.7,121.7,121.3,119.8,112.2,106.0,103.6,66.0,48.2,17.5.HRMS(ESI-TOF):m/z calculated for C 21 H 20 N 4 O 2 [M+H] + :361.1659,found:361.1663.
Comparative example 1
The compound of comparative example 1 is
The synthesis method is as follows: 2-indolecarboxylic acid (10 mmol,1.61g,1.0 equiv) was added to the reaction flask, and 50ml of chloroform was added thereto and stirred well; under ice bath, adding 4.5ml of thionyl chloride; after the addition, the reaction was carried out at 75℃for 4 hours. After the reaction is finished, the solvent and the redundant thionyl chloride are removed by decompression, and the acyl chloride solid is obtained. Anthranilamide (10 mmol,1.36g,1.0 equiv) was added to a reaction flask, 50ml chloroform was added to dissolve, then 0.8ml pyridine was added to mix well, and the mixture was cooled to 0 ℃ in an ice bath; the acid chloride solid was dissolved in 20ml of chloroform and slowly added dropwise to the mixed system, and the reaction was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, and the cake was washed with chloroform and dried in vacuo. The dried cake was white, and was added to a reaction flask, 25ml of 2M sodium hydroxide solution was added, and 20ml of ethanol was added, and the mixture was stirred at 85℃for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to about 2 with 4M hydrochloric acid, whereby a large amount of solids was precipitated. Filtering, cleaning the filter cake with a large amount of clear water, and vacuum drying to obtain the compound IQ.
Antitumor and lipid lowering activity assay
The antitumor activity detection method comprises the following steps:
1. screening:
HCT116, 5000 cells/well in logarithmic growth phase, was inoculated uniformly into 96-well plates, and treated with drug (10 μm and 50 μm) for 24 hours after standing in a cell culture incubator for 24 hours. The cells were then fixed in-20℃refrigerator overnight with-20℃pre-chilled 70% ethanol. Adding 10 mug/mL Propidium Iodide (PI) for dyeing for 4 hours at room temperature, detecting by adopting a full-automatic cell group high content screening analysis system, and calculating to obtain the inhibition rate, wherein the data are shown in Table 1.
Inhibition = 100% - (value (compound)/value (Ctrl)) ×100%
2、IC 50 Detection of
HCT116, 5000 cells/well in logarithmic growth phase, was inoculated uniformly into 96-well plates, and after standing in a cell culture incubator for 24 hours, 3gj, 3gn and comparative example 1 administration (0.1, 1,5, 10, 25 and 50 μm) treatments were performed for 24 hours. The cells were then fixed in-20℃refrigerator overnight with-20℃pre-chilled 70% ethanol. Adding 10 mug/mL Propidium Iodide (PI) for dyeing for 4 hours at room temperature, detecting by adopting a full-automatic cell group high content screening analysis system, and finally obtaining the IC by nonlinear regression fitting by using GraphPad Prism 8.0.1 50 . IC with 3gj 50 The value was 1.7. Mu.M; 3gn IC 50 The value was 12.5. Mu.M; IC of comparative example 1 50 A value of greater than50μM。
Table 1 anti-tumor inhibition rates of examples and comparative example 1
The lipid-lowering activity test steps are as follows:
3T3-L1 preadipocytes in logarithmic growth phase, 5.0X104 cells/well, were inoculated into 48 well plate uniformly, and the cell incubator was left to stand for culture with medium replacement every two days. After the cells grew to be nearly 80% confluent, the culture solution was changed, and the culture was continued for 2 days until the cells were completely confluent (Day 0), the DMEM complete medium containing differentiation-inducing solution I (DMEM medium containing 10% fbs and 1% diabody) was changed, and 5% CO at 37 °c 2 Stationary culture for 3 days (Day 3). After 3 days, the culture was continued for 3 days by changing the complete DMEM medium containing differentiation-inducing liquid II (Day 6). For the drug intervention group (compounds prepared in examples and comparative examples), the compounds were diluted to a certain concentration in DMEM complete medium containing differentiation-inducing solution, and added together at Day0 and Day 3. The blank control group and the differentiated control group were respectively added with an equal volume of DMSO solution. At Day6, oil red O staining and quantitative analysis were performed.
(1) Preparation of differentiation inducing liquid
Differentiation-inducing liquid I: DMEM complete medium containing 500 μ M M3-isobutyl-1-methyl-xanthine, 1 μ M dexamethasone, 5 μg/mL insulin; differentiation-inducing liquid II: DMEM complete medium containing 5. Mu.g/mL insulin.
(2) Oil red O staining and quantification
When the cells were induced to differentiate to Day6, the medium was discarded, and 4% paraformaldehyde fixed solution was fixed at room temperature for 60min. After removing the fixative and rinsing the cells with isopropanol, the working solution was stained with oil red O (0.5% stock solution of oil red O isopropanol: ddH) 2 O=3:2) at room temperature for 30min. Discarding the dyeing liquid, and rinsing with deionized water for 2-3 times. Subsequently, 100. Mu.L of 60% isopropyl alcohol was washed for 10min, and extracted with 100. Mu.L of pure isopropyl alcohol for 30min. 80 μl of the extract was placed in 96-well plates and subjected to detection of absorbance at 510nm and calculation of inhibition rate, the results are shown in Table 2：
Inhibition = 100% - (OD (Compound) -OD (UND) )/(OD (Ctrl) -OD (UND) )×100％
Table 2 data of lipid lowering inhibition rate of examples
It is to be understood that the above examples of the present application are provided by way of illustration only and not by way of limitation of the embodiments of the present application. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the application are desired to be protected by the following claims.

Claims (4)

1. The beta-indolyl quinazolinone derivative is characterized in that the structural formula of the beta-indolyl quinazolinone derivative is shown as a formula (I):
wherein the R is 1 And R is 2 Independently selected from H orAnd R is 1 And R is 2 Are not hydrogen at the same time;
R 3 and R is 4 Independently selected from hydrogen, C2-C6 alkyl, cyclohexyl, x is bromine or H; and R is 3 And R is 4 Are not hydrogen at the same time;
or R is 3 And R is 4 Is connected into a ring through a C3-C10 alkyl chain, wherein the alkyl chain has at least one heteroatom.
2. A β -indoloquinazolinone derivative, characterized in that said β -indoloquinazolinone derivative is of any of the following structural formulas:
3. the β -indoloquinazolinone derivative of claim 2, wherein said β -indoloquinazolinone derivative is of any of the following structural formulas:
4. use of a β -indoloquinazolinone derivative according to any one of claims 1 to 3 for the preparation of an anti-tumor or lipid lowering drug; the tumor is colon cancer.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1398032A1 (en) * 2002-09-10 2004-03-17 PheneX Pharmaceuticals AG 4-Oxo-quinazolines as LXR nuclear receptor binding compounds
CN101460490A (en) * 2006-04-07 2009-06-17 奥克兰联合服务有限公司 Substituted ring fused azines and their use in cancer therapy
CN104367575A (en) * 2014-12-04 2015-02-25 中山大学 Bouchardatine, Bouchardatine derivative and preparation methods and applications of Bouchardatine and Bouchardatine derivative
CN104447702A (en) * 2014-12-04 2015-03-25 中山大学 Amidogen substituted Bouchardatine derivative as well as preparation method and application thereof
CN107721982A (en) * 2017-10-16 2018-02-23 中山大学 A kind of antiobesity compounds and its preparation method and application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2870140B8 (en) * 2012-07-09 2016-09-28 Lupin Limited Tetrahydroquinazolinone derivatives as parp inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1398032A1 (en) * 2002-09-10 2004-03-17 PheneX Pharmaceuticals AG 4-Oxo-quinazolines as LXR nuclear receptor binding compounds
CN101460490A (en) * 2006-04-07 2009-06-17 奥克兰联合服务有限公司 Substituted ring fused azines and their use in cancer therapy
CN104367575A (en) * 2014-12-04 2015-02-25 中山大学 Bouchardatine, Bouchardatine derivative and preparation methods and applications of Bouchardatine and Bouchardatine derivative
CN104447702A (en) * 2014-12-04 2015-03-25 中山大学 Amidogen substituted Bouchardatine derivative as well as preparation method and application thereof
CN107721982A (en) * 2017-10-16 2018-02-23 中山大学 A kind of antiobesity compounds and its preparation method and application

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
2-(2-indolyl-)-4(3H)-quinazolines derivates as new inhibitors of AChE: design, synthesis, biological evaluation and molecular modelling;Li, Zeng et al.;《Journal of Enzyme Inhibition and Medicinal Chemistry》;第28卷(第3期);第583-592页 *
Palladium oxidative addition complex-enabled synthesis of amino-substituted indolyl-4(3H)-quinazolinones and their antitumor activity evaluation;Jiang, Zhi et al.;《Organic & Biomolecular Chemistry》;第20卷(第3期);第553-557页 *
降脂活性分子bouchardatine及其类似物的合成;高琳等;《中国药物化学杂志》;第26卷(第5期);第380-385页 *

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