Tetrahydropyrimido [1, 6-a] indole-3-ketone compound as well as preparation method, application and pharmaceutical composition of tetrahydropyrimido [1, 6-a] indole-3-ketone compound

Abstract

The invention provides an tetrahydropyrimido [1, 6-a] indole-3-ketone compound as well as a preparation method and application thereof and a pharmaceutical composition, and belongs to the technical field of pharmaceutical chemistry. In the invention, the tetrahydropyrimido [1, 6-a] indole-3-ketone compound has a structure as shown in a formula A in the specification. The tetrahydropyrimido [1, 6-a] indole-3-ketone compound provided by the invention is novel in structure, can significantly inhibit tumor cell proliferation, and can be applied to preparation of antitumor drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a tetrahydropyrimido[1,6-a]indole-3-one compound, a preparation method and application thereof, and a pharmaceutical composition. Background Art

[0002] Cancer, also known as malignant tumors, is a disease with extremely high morbidity and mortality worldwide. Its characteristics include abnormal cell proliferation, invasiveness and spread, diversity and complexity. Research in this field has shown that pyrimidine compounds and their derivatives can exert anti-tumor effects by interfering with the signaling pathways of tumor cells and promoting cell apoptosis, and can achieve specific inhibition of tumor cells. However, there are few types of pyrimidine compounds that can be used for specific inhibition of tumor cells, resulting in limited selectivity of clinical candidate drugs. Summary of the invention

[0003] The object of the present invention is to provide a tetrahydropyrimido[1,6-a]indol-3-one compound and its preparation method, application and pharmaceutical composition. The tetrahydropyrimido[1,6-a]indol-3-one compound provided by the present invention has a novel structure, can significantly inhibit tumor cell proliferation, and can be used in the preparation of anti-tumor drugs.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The present invention provides a tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof, wherein the tetrahydropyrimido[1,6-a]indol-3-one compound has a structure shown in formula A:

[0006]

[0007] In Formula A, the R 1 , R 2 , R 3 and R 4 independently selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy;

[0008] The R 5 is -H, substituted or unsubstituted alkyl, or substituted or unsubstituted benzyl;

[0009] The R 6 , R 7 and R 9 independently selected from -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, alkoxy or benzyloxy;

[0010] The R 8is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted methylenearyl, -COR 1a 、-CO2R 1a Or - SO2R 1a ; said R 1a C1~C 15 The alkyl group;

[0011] The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 In the above, the substitution refers to the replacement of one or more hydrogen atoms in the group by halogen, alkyl, -OTBS or the replacement of two hydrogen atoms in the group by replaced.

[0012] Preferably, the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The substituted or unsubstituted alkyl group includes substituted or unsubstituted C1 to C 15 alkyl;

[0013] The alkoxy group includes C1 to C4 alkoxy groups;

[0014] The substituted or unsubstituted aryl group includes substituted or unsubstituted C6 to C 15 Aryl;

[0015] The substituted or unsubstituted alkenyl group includes substituted or unsubstituted C2 to C 15 The alkenyl group;

[0016] The substituted or unsubstituted methylene aryl group includes substituted or unsubstituted C6~C 16 The methylene aromatic group.

[0017] Preferably, the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 9 The unsubstituted alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

[0018] The R 1 , R 2 , R 3 and R 4 wherein alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy;

[0019] The R 8 The unsubstituted alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopentyl or cyclohexyl, the unsubstituted alkenyl is vinyl, propenyl, butenyl, isobutenyl or allylaryl, and the unsubstituted methylenearyl is methylenethiophene, methylenephenyl, methylenebenzothienyl, methylenenaphthyl, methyleneanthryl or methylenephenanthryl.

[0020] Preferably, the R 1 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I;

[0021] The R 2 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I;

[0022] The R 3 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I

[0023] The R 4 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I;

[0024] The R 5 is benzyl, -H, -CH3, -C2H5 or -C4H 10 ;

[0025] The R 6 is -H, phenyl, -CH3 or -C2H5;

[0026] The R 7 is -H, phenyl, -CH3 or -C2H5;

[0027] The R 8 is -H, -CH3, -C2H5, n-propyl, isopropyl, n-butyl, isobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted benzyl, methylenethiophene, methylenebenzothienyl, -COR 1a 、-CO2R 1a 、-SO2R 1a ; said R1a C1~C 15 The alkyl group;

[0028] The R 9 It is -H, phenyl, -CH3 or -C2H5.

[0029] Preferably, the tetrahydropyrimido[1,6-a]indol-3-one compound includes at least one of a compound of type a, a compound of type b, a compound of type c, a compound of type d and a compound of type e;

[0030] In the a-type compound, the R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0031] In the b-type compound, the R 1 = substituted or unsubstituted C1~C 15 alkyl, halogen or alkoxy, R 2 =H, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0032] In the class C compound, the R 1 =H, R 2 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 3 =H, R4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0033] In the class d compound, the R 1 =H, R 2 =H, R 3 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0034] In the e-type compound, the R 1 =H, R 2 =H, R 3 =H, R 4 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H.

[0035] Preferably, the tetrahydropyrimido[1,6-a]indol-3-one compound is any one of the following compounds A1 to A15:

[0036]

[0037]

[0038] The present invention provides a method for preparing the tetrahydropyrimido[1,6-a]indol-3-one compounds described in the above technical scheme, comprising the following steps:

[0039] Mixing compound 1, compound 2, a metal catalyst and an oxazoline ligand, and performing a nucleophilic addition reaction to obtain the tetrahydropyrimido[1,6-a]indol-3-one compound;

[0040] The structural formulas of the compound 1, compound 2 and oxazoline ligand are shown in Formula 1, Formula 2 and Formula 3 respectively:

[0041]

[0042] The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in Formula A.

[0043] Preferably, the metal catalyst is a copper compound;

[0044] The organic solvent comprises at least one of ethyl acetate, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,2-dichloroethane, methanol, acetone and toluene;

[0045] The temperature of the nucleophilic addition reaction is -20 to 70° C., and the time is 2 to 180 hours.

[0046] The present invention provides the use of the tetrahydropyrimido[1,6-a]indol-3-one compounds and pharmaceutically acceptable salts thereof described in the above technical solution in the preparation of anti-tumor drugs.

[0047] The present invention provides a pharmaceutical composition, comprising the tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof or a mixture thereof as described in the above technical solution.

[0048] The present invention provides a tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof, wherein the tetrahydropyrimido[1,6-a]indol-3-one compound has a structure shown in formula A. The tetrahydropyrimido[1,6-a]indol-3-one compound provided by the present invention has a novel structure, can significantly inhibit tumor cell proliferation, and can be used in the preparation of anti-tumor drugs. The examples show that the tetrahydropyrimido[1,6-a]indole-3-one compounds A1 to A15 provided by the present invention have good inhibitory effects on human erythroleukemia cells, human myeloid leukemia cells, human acute lymphocytic leukemia cells and human chronic myeloid leukemia cells. Among them, compound 10 has the strongest inhibitory effect on tumor cells HEL and HL-60, with a cell survival rate of less than 40%; compounds A1 and A14 have strong inhibitory effects on tumor cells HEL, HL-60 and CEM-C1, with a cell survival rate of less than 50%; compounds A3, A4 and A8 have obvious inhibitory effects on tumor cells HEL, HL-60 and CEM-C1, with a cell survival rate of less than 60%.

[0049] The present invention provides a method for preparing the tetrahydropyrimido[1,6-a]indol-3-one compounds. Specifically, the present invention uses commercially available and relatively cheap metal catalysts and oxazoline ligands as catalysts, uses commercially available tetrahydro-γ-carboline as a reaction substrate, and uses intramolecular 1,3 rearrangement-intermolecular nucleophilic addition reaction to efficiently and concisely synthesize tetrahydropyrimido[1,6-a]indol-3-one compounds in only one step. At the same time, the preparation method of the present invention has high reaction yield, short synthesis steps, a wide range of applicable substituents, simple operation, and good application prospects in realizing industrial production. DETAILED DESCRIPTION

[0050] The present invention provides a tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof, wherein the tetrahydropyrimido[1,6-a]indol-3-one compound has a structure shown in formula A:

[0051]

[0052] In Formula A, the R 1 , R 2 , R 3 and R 4 independently selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy;

[0053] The R 5 is -H, substituted or unsubstituted alkyl, or substituted or unsubstituted benzyl;

[0054] The R6 , R 7 and R 9 independently selected from -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, alkoxy or benzyloxy;

[0055] The R 8 is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted methylene aryl, -COR 1a 、-CO2R 1a Or - SO2R 1a ; said R 1a C1~C 15 The alkyl group;

[0056] The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 In the above, the substitution refers to the replacement of one or more hydrogen atoms in the group by halogen, alkyl, -OTBS or the replacement of two hydrogen atoms in the group by replaced.

[0057] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 1 is selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy. 1 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 1 The halogen in is preferably -F, -Cl, -Br or -I. In the present invention, the R 1 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 1 Preferred are -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I.

[0058] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 2is selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy. 2 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 2 The halogen in is preferably -F, -Cl, -Br or -I. In the present invention, the R 2 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 2 Preferred are -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I.

[0059] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 3 is selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy. 3 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 3 The halogen in is preferably -F, -Cl, -Br or -I. In the present invention, the R 3 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 3 Preferred are -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I.

[0060] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 4 is selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy. 4 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 4 The halogen in is preferably -F, -Cl, -Br or -I. In the present invention, the R 4 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 4 Preferred are -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I.

[0061] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 5 is -H, substituted or unsubstituted alkyl, or substituted or unsubstituted benzyl. 5 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 5 Preferably, benzyl, -H, -CH3, -C2H5 or -C4H 10 .

[0062] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 6 is selected from -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, alkoxy or benzyloxy. 6 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 6 The substituted or unsubstituted aryl group preferably includes substituted or unsubstituted C6 to C 15 In the present invention, the R 6The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 6 Preferred are -H, phenyl, -CH3 or -C2H5.

[0063] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 7 is selected from -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, alkoxy or benzyloxy. 7 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 7 The substituted or unsubstituted aryl group preferably includes substituted or unsubstituted C6 to C 15 In the present invention, the R 7 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 7 Preferred are -H, phenyl, -CH3 or -C2H5.

[0064] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 8 is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted methylenearyl, -COR 1a 、-CO2R 1a Or - SO2R 1a ; said R 1a C1~C 15 In the present invention, the R 8 The unsubstituted alkyl group preferably includes substituted or unsubstituted C1-C 15 The unsubstituted alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopentyl or cyclohexyl; the substituted alkyl is preferably C1-C1 substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the unsubstituted alkenyl group preferably includes substituted or unsubstituted C2 to C 15The unsubstituted methylene aryl is preferably a methylene thiophene, a methylene phenyl, a methylene benzothiophene, a methylene naphthyl, a methylene anthracenyl or a methylene phenanthryl. 8 Preferred are -H, -CH3, -C2H5, n-propyl, isopropyl, n-butyl, isobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted benzyl, methylenethiophene, methylenebenzothienyl, -COR 1a 、-CO2R 1a 、-SO2R 1a ; said R 1a C1~C 15 of alkyl.

[0065] In the tetrahydropyrimido[1,6-a]indol-3-one compounds of the present invention, the R 9 is selected from -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, alkoxy or benzyloxy. 9 The substituted or unsubstituted alkyl group preferably includes substituted or unsubstituted C1 to C 15 The unsubstituted alkyl is preferably an unsubstituted C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the substituted alkyl is preferably a C1-C4 alkyl substituted by one or more halogens or -OTBS. 15 Alkyl, more preferably In the present invention, the R 9 The substituted or unsubstituted aryl group preferably includes substituted or unsubstituted C6 to C 15 In the present invention, the R 9 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 9 Preferred are -H, phenyl, -CH3 or -C2H5.

[0066] In the present invention, the tetrahydropyrimido[1,6-a]indol-3-one compound preferably includes at least one of a compound of type a, a compound of type b, a compound of type c, a compound of type d and a compound of type e;

[0067] In the a-type compound, the R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8=H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0068] In the b-type compound, the R 1 = substituted or unsubstituted C1~C 15 alkyl, halogen or alkoxy, R 2 =H, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0069] In the class C compound, the R 1 =H, R 2 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0070] In the class d compound, the R 1 =H, R 2 =H, R 3 = substituted or unsubstituted C1~C 15alkyl, halogen, alkoxy or benzyloxy, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H;

[0071] In the e-type compound, the R 1 =H, R 2 =H, R 3 =H, R 4 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H.

[0072] In the present invention, the tetrahydropyrimido[1,6-a]indol-3-one compound is preferably any one of the following compounds A1 to A15:

[0073]

[0074] The present invention also provides a method for preparing the tetrahydropyrimido[1,6-a]indol-3-one compound described in the above technical solution, comprising the following steps:

[0075] Mixing compound 1, compound 2, a metal catalyst and an oxazoline ligand, and performing a nucleophilic addition reaction to obtain the tetrahydropyrimido[1,6-a]indol-3-one compound;

[0076] The structural formulas of the compound 1, compound 2 and oxazoline ligand are shown in Formula 1, Formula 2 and Formula 3 respectively:

[0077]

[0078] The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in Formula A.

[0079] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0080] In the present invention, the metal catalyst is preferably a copper compound; the copper compound preferably includes at least one of copper trifluoromethanesulfonate, copper bromide, copper acetate, cuprous bromide, copper perchlorate, cuprous trifluoromethanesulfonate and cuprous trifluoromethanesulfonate toluene complex, more preferably copper bromide and copper acetate. In an embodiment of the present invention, the metal catalyst is a mixture of copper bromide and copper acetate, wherein the molar ratio of copper bromide to copper acetate is 1:1. In the present invention, the molar ratio of the metal catalyst to compound 1 is preferably 0.01 to 0.2:1, more preferably 0.1 to 0.2:1; the molar ratio of the oxazoline ligand to compound 1 is preferably 0.01 to 0.15:1, more preferably 0.1 to 0.15:1; the molar amount of compound 1 is preferably one or more times the molar amount of compound 2. The organic solvent of the present invention preferably includes at least one of ethyl acetate, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,2-dichloroethane, methanol, ethanol, acetone and toluene, and more preferably methanol, ethanol or 1,4-dioxane. In the present invention, the temperature of the nucleophilic addition reaction is preferably -20 to 70°C, more preferably 25 to 30°C; the time is preferably 2 to 180h, more preferably 3 to 72h, specifically 5h, 6h, 7h, 8h, 9h, 11h or 12h). The present invention preferably tracks the progress of the nucleophilic addition reaction by thin layer chromatography until the reaction ends. After the nucleophilic addition reaction ends, the present invention preferably purifies the obtained product system by column chromatography to obtain the tetrahydropyrimido[1,6-a]indol-3-one compound. In an embodiment of the present invention, the eluent used for column chromatography purification is an ethyl acetate-petroleum ether mixed reagent, and the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed reagent is 1:5 to 10.

[0081] The present invention also provides the use of the tetrahydropyrimido[1,6-a]indol-3-one compounds and pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs.

[0082] The present invention also provides a pharmaceutical composition, comprising the tetrahydropyrimido[1,6-a]indol-3-one compound or its pharmaceutically acceptable salt or mixture thereof according to the above technical solution. In the present invention, the pharmaceutically acceptable salt of the tetrahydropyrimido[1,6-a]indol-3-one compound preferably comprises the hydrochloride and / or trifluoromethanesulfonate of the tetrahydropyrimido[1,6-a]indol-3-one compound.

[0083] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0084] The structural formulas of the substrates 1a to 14a used in the examples are shown below:

[0085]

[0086] The reaction formula for preparing compounds A1 to A15 is as follows:

[0087]

[0088] Example 1

[0089] Substrate 1a (0.20 mmol), copper bromide (0.02 mmol), copper acetate (0.02 mmol) and oxazoline ligand L1 (0.024 mmol) were added to a reaction tube, and 4 mL of methanol was added. The resulting mixture was stirred and reacted in air at 30°C. The reaction was tracked by thin layer chromatography (TLC) until substrate 1a disappeared, and the reaction was stopped (the reaction duration was 48 h at this time). The resulting product system was purified by column chromatography using an ethyl acetate-petroleum ether mixed reagent as the eluent (the volume ratio of ethyl acetate to petroleum ether was 1:5-10) to obtain compound A1 (30.3 mg as a light yellow solid, with a yield of 47%).

[0090]

[0091] The H NMR spectrum of compound A1 ( 1 H NMR), carbon nuclear magnetic resonance spectroscopy ( 13 C NMR) and high resolution mass spectrometry (HRMS) data are as follows: 1HNMR(600MHz,Chloroform-d)δ7.62(d,J=7.6Hz,1H),7.51-7.48(m,1H),7.20(d,J =7.9Hz,2H),7.15(d,J=7.8Hz,2H),6.82(t,J=7.5Hz,1H),6.68(d,J=8.3Hz,1H),4. 43(dd,J=12.2,1.6Hz,1H),3.65(d,J=12.3Hz,1H),3.60(d,J=13.2Hz,1H),3.45(d, J=13.2Hz,1H),3.14(s,3H),2.86-2.77(m,2H),2.36(s,3H),1.88-1.81(m,2H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.6,159.3,137.9,137.0,134.4,129.1,128.6,125.1, 119.4,118.8,109.9,90.4,60.5,58.0,51.3,48.0,29.5,21.1ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 23 N2O2323.1760; Found 323.1742.

[0092] Example 2

[0093] Substrate 1a in Example 1 was replaced by 2a, and other conditions were the same as in Example 1 to prepare compound A2 (69.6 mg of light yellow solid, yield: 95%).

[0094]

[0095] Compound A2 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.63(d,J=7.1Hz,1H),7.56-7.51(m,1H),6.87-6.77(m,3H),6.35(d,J=3.4Hz,1H),4.54(d,J=12.4Hz ,1H),3.78(d,J=12.3Hz,1H),3.72(d,J=14.6Hz,1H),3.60(d,J=14.6Hz,1H),3.16(s,3H),2.90-2.85(m,2H),1.92-1.82(m,2H)ppm.13 C NMR (150MHz, Chloroform-d) δ200.3, 159.0, 154.2, 141.5 (q, J = 42.8Hz), 138.1, 125.2, 121.6, 119.5, 119.2, 119. 0(q,J=267.0Hz),112.5(q,J=2.9Hz),109.6,109.4,90.0,60.3,51.4,50.3,47.8,29.2ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 18 F3N2O3367.1270; Found 367.1260.

[0096] Example 3

[0097] Substrate 1a in Example 1 was replaced by 3a, and other conditions were the same as in Example 1 to prepare compound A3 (52.7 mg of light yellow solid, yield: 66%).

[0098]

[0099] Compound A3 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.86(d,J=2.0Hz,1H),7.76(d,J=8.5Hz,1H),7.63(d,J=7.3Hz,1H),7.47-7.44(m,1H),7.34(s,1H),7.31(dd,J=8.6,2.1 Hz,1H),6.83(t,J=7.4Hz,1H),6.62(d,J=8.3Hz,1H),4.49(d,J=12.4Hz,1H ),3.81-3.72(m,3H),3.16(s,3H),2.90-2.86(m,2H),1.88-1.84(m,2H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.4,159.2,139.6,138.8,138.0,130.3,126.3,125.1,125.0,1 23.7,122.5,119.4,118.9,109.7,90.4,60.4,52.0,51.4,47.9,29.2ppm.HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H19 ClN2O2SNa421.0753; Found 421.0732.

[0100] Example 4

[0101] Substrate 1a in Example 1 was replaced by 4a, and other conditions were the same as in Example 1 to prepare compound A4 (light yellow solid 36.0 mg, yield 60%).

[0102]

[0103] Compound A4 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.61(dd,J=7.6,0.8Hz,1H),7.55-7.50(m,1H),6.90(d,J=8 .3Hz,1H),6.81(t,J=7.5Hz,1H),4.63(d,J=12.1Hz,1H),3.82(d,J=12.1Hz,1H),3.16(s, 3H),2.90-2.83(m,2H),2.37-2.31(m,1H),1.93-1.87(m,3H),1.83-1.79(m,2H),1.73-1. 68(m,1H),1.65-1.61(m,1H),1.36-1.29(m,1H),1.26-1.18(m,3H),1.17-1.11(m,1H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.8,159.4,138.0,125.2,119.7,118.8,109.7,90.7, 60.3,58.0,51.3,44.4,30.4,23.0,28.9,26.1,25.6,25.5ppm.HRMS(ESI)m / z:[M+Na] + Calcd for C 18 H 24 N2O2Na323.1735; Found 323.1717.

[0104] Example 5

[0105] Substrate 1a in Example 1 was replaced by 5a, and other conditions were the same as in Example 1 to prepare compound A5 (light yellow solid 19.5 mg, yield 34%).

[0106]

[0107] Compound A5 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=7.3Hz,1H),7.54-7.51(m,1H),6.89( d,J=8.3Hz,1H),6.82(t,J=7.5Hz,1H),5.25-5.22(m,1H),4.55(dd,J=12.1,1. 8Hz,1H),3.61(d,J=12.2Hz,1H),3.16(s,3H),3.00(d,J=6.7Hz,2H),2.87-2. 83(m,1H),2.70-2.65(m,1H),1.90-1.86(m,1H),1.78(s,3H),1.63(s,3H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.6,159.2,138.1,136.4,125.1,120.1,119.5,118 .9,109.7,90.3,60.8,51.7,51.4,47.8,29.6,25.9,18.1ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 23 N2O2287.1760; Found 287.1743.

[0108] Example 6

[0109] Substrate 1a in Example 1 was replaced by 6a, and other conditions were the same as in Example 1 to prepare compound A6 (light yellow solid 23.4 mg, yield 43%).

[0110]

[0111] Compound A6 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1H NMR(600MHz,Chloroform-d)δ7.62(d,J=7.2Hz,1H),7.56-7.52(m,1H),6.93(d,J=8.3Hz,1H) ,6.83(t,J=7.5Hz,1H),5.84-5.76(m,1H),5.10(dd,J=17.1,1.7Hz,1H),5.04(d,J=10.1Hz,1H ),4.58(dd,J=12.3,1.7Hz,1H),3.72(d,J=12.2Hz,1H),3.16(s,3H),2.88-2.84(m,1H),2.78 -2.73(m,1H),2.51-2.46(m,2H),2.32-2.27(m,2H),1.88-1.84(m,1H),1.81-1.76(m,1H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.5,159.2,138.0,136.0,125.2,119.4,118.8, 116.0,109.6,90.2,60.9,53.2,51.3,47.8,31.7,29.2ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 21 N2O2273.1603; Found 273.1588.

[0112] Example 7

[0113] Substrate 1a in Example 1 was replaced by 7a, and other conditions were the same as in Example 1 to prepare compound A7 (light yellow solid 31.3 mg, yield 42%).

[0114]

[0115] Compound A7 1 H NMR, 13 The data of C NMR and HRMS are as follows: (600 MHz, Chloroform-d) δ 7.70 (d, J = 7.9 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.29-7.26 (m, 3H), 4.63 (dd, J = 13.7, 2.1 Hz, 1H), 4.29-4.22 (m, 1H), 2.97-2.89 (m, 1H), 2.81 (d, J = 12.8 Hz, 1H), 2.61-2.53 (m, 1H), 2.39 (s, 3H), 2.18 (d, J = 13.1 Hz, 1H) ppm.13 C NMR(150MHz,Chloroform-d)δ181.9,154.0,143.6,134.9,134.2,130.4,129.6,127.4,126 .3,123.4,121.1,86.9,60.4,55.8,52.7,47.8,29.9,21.4,14.1ppm.HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 20 N2O4SNa395.1041; Found 395.1018.

[0116] Example 8

[0117] Substrate 1a in Example 1 was replaced by 8a, and other conditions were the same as in Example 1 to prepare compound A8 (brown oil 37.4 mg, yield 58%).

[0118]

[0119] Compound A8 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.44(s,1H),7.38-7.29(m,6H),6.61(d,J=8.4Hz,1H),4.41(d,J=12.2Hz,1H),3 .69-3.62(m,2H),3.49(d,J=13.3Hz,1H),3.16(s,3H),2.87-2.78(m,2H),2.31(s,3H),1.90-1.81(m,2H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.7,157.8,139.2,137.7,128.7,128.4,128.4,127.4, 124.6,119.5,109.8,90.6,60.8,58.3,51.4,48.2,29.6,20.5ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 23 N2O2323.1760; Found 323.1744.

[0120] Example 9

[0121] Substrate 1a (0.20 mmol), copper bromide (0.02 mmol), copper acetate (0.02 mmol) and oxazoline ligand L1 (0.24 mmol) were added to a reaction tube, and 4 mL of ethanol was added. The resulting mixture was stirred and reacted in air at 30°C. The reaction was tracked by TLC until substrate 1a disappeared, and the reaction was stopped (the reaction duration was 36 h at this time). The resulting product system was purified by column chromatography using an ethyl acetate-petroleum ether mixed reagent as the eluent (the volume ratio of ethyl acetate to petroleum ether was 1:5-10) to obtain compound A9 (48.4 mg as a light yellow solid, with a yield of 58%).

[0122]

[0123] Compound A9 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=7.6Hz,1H),7.47(t,J=7.7Hz,1H),7.37- 7.27(m,5H),6.81(t,J=7.4Hz,1H),6.64(d,J=8.3Hz,1H),4.41(d,J=12.2Hz,1H), 3.71-3.62(m,2H),3.48(d,J=13.3Hz,1H),3.40-3.32(m,1H),3.33-3.25(m,1H),2 .89-2.80(m,2H),1.91-1.85(m,1H),1.86-1.79(m,1H),1.20(t,J=7.0Hz,3H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.8,159.0,137.8,137.6,128.7,128.4,127.4,125.1, 119.3,118.7,109.7,90.1,60.5,59.5,58.2,48.1,29.7,15.3ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 23 N2O2323.1760; Found 323.1743.

[0124] Example 10

[0125] Substrate 1a in Example 1 was replaced by 9a, and other conditions were the same as in Example 1 to prepare compound A10 (light yellow solid 43.1 mg, yield 67%).

[0126]

[0127] Compound A10 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.5(d,J=7.8Hz,1H),7.4-7.3(m,5H),6.6(d,J=7.8Hz,1H),6.4(s,1H),5.3(s,1H),4.4(d, J=12.3Hz,1H),3.6(t,J=12.6Hz,2H),3.5(d,J=13.3Hz,1H),3.1(s,3H),2.9-2.8(m,2H),2.3(s,3H),1.9-1.8(m,2H)ppm. 13 C NMR(150MHz,Chloroform-d)δ199.8,159.6,149.7,137.6,128.8,128.3,127.4,124.9,120.5, 117.2,110.1,90.6,60.3,58.1,53.4,51.3,48.1,45.8,29.5,22.7ppm.HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 22 N2O2Na345.1579; Found345.1567.

[0128] Embodiment 11

[0129] Substrate 10a (0.20 mmol), copper bromide (0.02 mmol), copper acetate (0.02 mmol) and oxazoline ligand L1 (0.024 mmol) were added to a reaction tube, and then 4 mL of 1,4-dioxane and 0.14 mL of water were added. The resulting mixture was stirred and reacted in air at 30°C. The reaction was tracked by TLC until the substrate 11a disappeared and the reaction was stopped (the reaction duration was 46 h at this time). The resulting product system was purified by column chromatography using an ethyl acetate-petroleum ether mixed reagent as the eluent (the volume ratio of ethyl acetate to petroleum ether was 1:5-10) to obtain compound A11 (brown oil 37.5 mg, yield 60%).

[0130]

[0131] Compound A11 1 H NMR, 13 The data of C NMR and HRMS are as follows:1 H NMR(600MHz,Chloroform-d)δ7.37-7.31(m,2H),7.31-7.28(m,3H),7.24-7.18(m,2H),6.56-6.50(m,1H),4.31(d,J=12 .2Hz,1H),3.78(d,J=12.4Hz,1H),3.63(d,J=13.3Hz,1H),3.48-3.37(m,2H),2.89-2.79(m,2H),1.86-1.80(m,2H)ppm. 13 CNMR(150MHz,Chloroform-d)δ201.4(d,J=3.1Hz).,156.2(d,J=240.6Hz),155.2,137.3,128.7,128.5,127.5,125.7(d,J=2 5.3Hz), 118.6 (d, J = 7.3Hz), 111.0 (d, J = 7.4Hz), 110.5 (d, J = 22.6Hz), 86.8, 60.8, 58.3, 47.8, 29.6ppm. HRMS (ESI) m / z: [M+H] + Calcd for C 18 H 18 FN2O2313.1352; Found 313.1315.

[0132] Example 12

[0133] Substrate 10a in Example 11 was replaced by 11a, and other conditions were the same as in Example 11 to prepare compound A12 (light yellow solid 39.1 mg, yield 48%).

[0134]

[0135] Compound A12 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1H NMR(600MHz,Chloroform-d)δ7.62(d,J=7.5Hz,1H),7.54-7.49(m,1H),7.41-7.3 7(m,2H),7.37-7.31(m,2H),7.30-7.24(m,3H),6.86-6.79(m,2H),6.54(d,J=15. 8Hz,1H),6.28-6.20(m,1H),4.56(dd,J=12.4,1.6Hz,1H),3.90(d,J=12.4Hz,1H) ,3.28-3.22(m,1H),3.22-3.15(m,1H),2.99-2.88(m,2H),1.88-1.82(m,2H)ppm. 13 C NMR(150MHz,Chloroform-d)δ201.3,158.4,138.2,136.5,133.6,128.7,127.8,126.4,1 25.7,125.5,119.3,118.2,109.6,86.0,60.6,56.2,47.6,29.4ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 21 N2O2321.1603; Found 321.1586.

[0136] Example 13

[0137] Substrate 10a in Example 11 was replaced by 12a, and other conditions were the same as in Example 11 to prepare compound A13 (light yellow solid 33.1 mg, yield 51%).

[0138]

[0139] Compound A13 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δδ7.55(d,J=7.8Hz,1H),7.40(q,J=7.4Hz,1H),7.32-7.23(m,2H),7.17-7.01(m,3H),6. 84-6.66(m,2H),5.46-5.21(m,1H),3.97-3.82(m,1H),3.80-3.50(m,3H),2.45-2.29(m,1H),1.98-1.83(m,1H).ppm. 13CNMR(150MHz,Chloroform-d)δ200.2,199.7,160.2,160.1,153.1,151.0,137.6,129.3,125.4,124.8,124.7,121.6, 121.6,120.2,120.0,119.5,119.3,112.7,71.86,70.9,55.7,55.345.7,45.5,36.1,35.5.ppm.HRMS(ESI)m / z:[M+Na] + Calcd for C 18 H 16 N2O4Na 347.1008; Found 347.0993.

[0140] Embodiment 14

[0141] Substrate 10a in Example 11 was replaced by 13a, and other conditions were the same as in Example 11 to prepare compound A14 (brown oil 35.9 mg, yield 59%).

[0142]

[0143] Compound A14 1 HNMR, 13 The data of C NMR and HRMS are as follows: 1 HNMR(600MHz,Chloroform-d)δ7.55(d,J=9.1Hz,1H),7.41(t,J=7.7Hz,1H),6.82(d,J=8.1Hz,1H),6.78(t,J=7.4Hz,1H),5.28 (d,J=98.9Hz,1H),3.77-3.64(m,1H),3.55(d,J=11.4Hz,1H),3.52-3.34(m,2H),2.34-2.25(m,1H),1.40(d,J=22.5Hz,9H)ppm. 13 C NMR(150MHz,Chloroform-d)δ200.4,200.0,160.1,154.3,137.6,124.7,120.3,119.2,11 2.6,79.9,72.2,71.2,55.7,54.9,45.1,45.0,36.1,35.5,28.4ppm.HRMS(ESI)m / z:[M+Na] + Calcd for C 16 H 20 N2O4Na327.1321; Found327.1301.

[0144] Embodiment 15

[0145] Substrate 10a in Example 11 was replaced by 14a, and other conditions were the same as in Example 1 to prepare compound A15 (fluorescent yellow solid 51.9 mg, yield 79%).

[0146]

[0147] Compound A15 1 H NMR, 13 The data of C NMR and HRMS are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.62(d,J=7.1Hz,1H),7.52-7.47(m,1H),7.48-7.4 4(m,1H),7.39-7.35(m,1H),7.27-7.20(m,3H),6.84(t,J=7.1Hz,1H),6.69(d,J= 8.3Hz,1H),4.45(d,J=13.9Hz,1H),3.96(d,J=12.2Hz,1H),3.73(d,J=14.4Hz,1H ),3.64(d,J=14.3Hz,1H),2.97-2.86(m,2H),2.81(s,1H),1.89-1.84(m,2H)ppm. 13 C NMR(150MHz,Chloroform-d)δ201.4,158.5,138.0,134.2,130.2,129.6,128.5,126. 8,125.7,119.3,118.3,109.6,86.1,61.0,54.7,47.6,29.9ppm.HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 18 ClN2O 329.1057; Found 329.1046.

[0148] Test Example 1

[0149] In order to further verify the beneficial effects of the compounds synthesized in the present invention, the tumor cell proliferation inhibition activity of the compounds A1 to A15 synthesized in Examples 1 to 15 was tested using the MTT method. The specific test method is as follows:

[0150] Human erythroleukemia cells (HEL), human myeloid leukemia cells (HL-60), human acute lymphoblastic leukemia cells (CEM-C1) and human chronic myeloid leukemia cells (K562) in the logarithmic growth phase were digested with trypsin (mass fraction of 0.25%) to prepare single cell suspensions and counted. The cell concentration was adjusted to 4×103 / mL, and the single cell suspension was inoculated into a 96-well plate (200 μL per well). The labeled wells were placed in an incubator and cultured overnight until the cells were completely attached. Compound A1 was added to the well plate containing the single cell suspension at a concentration of 20 μmol / L, and the culture was continued for 48 hours. Under light-proof conditions, 20 μL of freshly prepared MTT solution (concentration of 5 mg / mL) was added to the well plate and cultured for 4 hours. Take out the plate, centrifuge and discard the supernatant, add 150 μL of DMSO to each well, and place the plate on a horizontal shaker to shake until the crystalline formazan is completely dissolved. Use an ELISA reader to detect the absorbance OD value at 490 nm, and the inhibition rate can be calculated based on the OD value. Replace compound A1 with A2 to A15 respectively, repeat the above test, and the results are shown in Table 1.

[0151] Table 1 Antitumor activity data of compounds A1-A15 at a concentration of 20 μmol / L

[0152]

[0153] The anti-tumor biological activity test showed that tetrahydropyrimido[1,6-a]indole-3-one compounds A1 to A15 had obvious inhibitory effects on tumor cells HEL, HL-60, CEM-C1 and K562; among them, compound A10 had the strongest inhibitory effect on tumor cells HEL and HL-60, with a cell survival rate below 40%; compounds A1 and A14 had strong inhibitory effects on tumor cells HEL, HL-60 and CEM-C1, with a cell survival rate below 50%; compounds A3, A4 and A8 had obvious inhibitory effects on tumor cells HEL, HL-60 and CEM-C1, with a cell survival rate below 60%.

[0154] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof, wherein the tetrahydropyrimido[1,6-a]indol-3-one compound has a structure shown in formula A: In Formula A, the R 1 , R 2 , R 3 and R 4 independently selected from -H, substituted or unsubstituted alkyl, halogen, alkoxy or benzyloxy; The R 5 is -H, substituted or unsubstituted alkyl, or substituted or unsubstituted benzyl; The R 6 , R 7 and R 9 independently selected from -H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, alkoxy or benzyloxy; The R 8 is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted methylenearyl, -COR 1a 、-CO2R 1a Or - SO2R 1a ; said R 1a C1~C 15 The alkyl group; The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 In the above, the substitution means that one or more hydrogen atoms in the group are replaced by halogen, alkyl, -OTBS or two hydrogen atoms in the group are replaced by replaced.

2. The tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The substituted or unsubstituted alkyl group includes substituted or unsubstituted C1 to C 15 alkyl; The alkoxy group includes C1 to C4 alkoxy groups; The substituted or unsubstituted aryl group includes substituted or unsubstituted C6 to C 15 Aryl; The substituted or unsubstituted alkenyl group includes substituted or unsubstituted C2 to C 15 The alkenyl group; The substituted or unsubstituted methylene aryl group includes substituted or unsubstituted C6~C 16 The methylene aromatic group.

3. The tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 9 The unsubstituted alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; The R 1 , R 2 , R 3 and R 4 wherein alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; The R 8 The unsubstituted alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopentyl or cyclohexyl, the unsubstituted alkenyl is vinyl, propenyl, butenyl, isobutenyl or allylaryl, and the unsubstituted methylenearyl is methylenethiophene, methylenephenyl, methylenebenzothienyl, methylenenaphthyl, methyleneanthryl or methylenephenanthryl.

4. The tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof according to claim 1 or 3, characterized in that: The R 1 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I; The R 2 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I; The R 3 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I The R 4 is -H, -CH3, -C2H5, -OCH3, -CH2OTBS, -F, -Cl, -Br or -I; The R 5 is benzyl, -H, -CH3, -C2H5 or -C4H 10 ; The R 6 is -H, phenyl, -CH3 or -C2H5; The R 7 is -H, phenyl, -CH3 or -C2H5; The R 8 is -H, -CH3, -C2H5, n-propyl, isopropyl, n-butyl, isobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted benzyl, methylenethiophene, methylenebenzothienyl, -COR 1a 、-CO2R 1a 、-SO2R 1a ; said R 1a C1~C 15 The alkyl group; The R 9 It is -H, phenyl, -CH3 or -C2H5.

5. The tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The tetrahydropyrimido[1,6-a]indol-3-one compound includes at least one of a compound of type a, a compound of type b, a compound of type c, a compound of type d and a compound of type e; In the a-type compound, the R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H; In the b-type compound, the R 1 = substituted or unsubstituted C1~C 15 alkyl, halogen or alkoxy, R 2 =H, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H; In the class C compound, the R 1 =H, R 2 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 3 =H, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H; In the class d compound, the R 1 =H, R 2 =H, R 3 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 4 =H, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H; In the e-type compound, the R 1 =H, R 2 =H, R 3 =H, R 4 = substituted or unsubstituted C1~C 15 alkyl, halogen, alkoxy or benzyloxy, R 5 =H, R 6 =H, R 7 =H, R 8 =H, substituted or unsubstituted C1~C 15 Alkyl, methylene aryl, -COR 1a 、-CO2R 1a 、-SO2R 1a , substituted or unsubstituted benzyl; R 1a C1~C 15 The alkyl group, R 9 =H.

6. The tetrahydropyrimido[1,6-a]indol-3-one compound or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: The tetrahydropyrimido[1,6-a]indol-3-one compound is any one of the following compounds A1 to A15:

7. A method for preparing the tetrahydropyrimido[1,6-a]indol-3-one compound according to any one of claims 1 to 6, comprising the following steps: Mixing compound 1, compound 2, a metal catalyst and an oxazoline ligand, and performing a nucleophilic addition reaction to obtain the tetrahydropyrimido[1,6-a]indol-3-one compound; The structural formulas of the compound 1, compound 2 and oxazoline ligand are shown in Formula 1, Formula 2 and Formula 3 respectively: The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in Formula A.

8. The preparation method according to claim 7, characterized in that: The metal catalyst is a copper compound; The organic solvent comprises at least one of ethyl acetate, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,2-dichloroethane, methanol, acetone and toluene; The temperature of the nucleophilic addition reaction is -20 to 70° C., and the time is 2 to 180 hours.

9. Use of the tetrahydropyrimido[1,6-a]indol-3-one compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of an anti-tumor drug.

10. A pharmaceutical composition comprising the tetrahydropyrimido[1,6-a]indol-3-one compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a mixture thereof.

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