CN111777613A - Preparation and application of pyrimidinedione indole and pyridone indole compounds - Google Patents

Preparation and application of pyrimidinedione indole and pyridone indole compounds Download PDF

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CN111777613A
CN111777613A CN201910270295.7A CN201910270295A CN111777613A CN 111777613 A CN111777613 A CN 111777613A CN 201910270295 A CN201910270295 A CN 201910270295A CN 111777613 A CN111777613 A CN 111777613A
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ethyl
indole
dihydro
pyrimido
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孙海鹰
马宗辉
傅源涛
方坤森
郭天玥
袁易南
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China Pharmaceutical University
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to compositions containing pyrimidine-2, 4-diketo [5, 4-b ]]Indole skeleton or pyridine-2-one [3, 2-d ]]The invention further relates to the medical use thereof as BET Bromo domain inhibitors.

Description

Preparation and application of pyrimidinedione indole and pyridone indole compounds
Technical Field
The present invention relates to a method for preparing a compound having a pyrimidine-2, 4-diketo [5, 4-b ] indole skeleton or a pyridine-2-keto [3, 2-d ] indole skeleton, and further relates to the medical use thereof as a BET Bromo domain inhibitor.
Background
Histone acetylation is an important histone post-transcriptional modification and also an important research content of epigenetics. BRD (Bromodomain) is a conserved protein domain capable of specifically recognizing acetylated lysine, and proteins containing BRD can promote related proteins such as chromatin remodeling factors and transcription factors to be enriched in specific gene transcription sites by combining with the acetylated lysine so as to regulate the transcription expression of genes. Currently, 61 BRDs are found in humans, and are present in 46 proteins, which are classified into 8 major families according to their functions. The BET (Bromodomain and extra-terminal) protein family is class 2 of the BRD protein family, comprising 4 members, BRDT, BRD2, BRD3 and BRD4, respectively. BET family proteins are capable of binding to acetylated lysines in histones H3 and H4 and regulating transcription of genes associated with cell cycle and cell growth by recruiting different transcription complexes. Dysfunction of BET proteins has been linked to the development of a variety of human diseases, and therefore small molecule BET inhibitors have the potential to be developed as drugs for the treatment of human diseases such as cancer, inflammation, viral infection, etc. (j.med.chem.2017, 60, 4533-4558; Future med.chem.2016, 8, 1655-1680.).
The present invention relates to compounds that bind to the Bromo domain of BET family proteins and inhibit the binding of the Bromo domain to acetylated lysine.
Disclosure of Invention
In one embodiment, the present invention discloses a compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:
Figure BSA0000181449210000011
wherein:
A1is-N or-C (R)5)-；
A2is-N or-C (R)6)-；
A3is-N-or-CH-;
A4is-N-or-CH-;
X1is O or S;
X2is O or S;
R1is an optionally substituted five-membered aromatic heterocycle, and the substituent is hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy;
R2hydrogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, alkylthio, alkylamino and halogen;
R3is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic aryl, aralkyl, heterocyclic aralkyl;
R4is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, (heterocyclyl) alkyl, (amino) alkyl, optionally substituted heterocyclyl, and carboxamide;
R5hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;
R6hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and fluorine.
Preferred compounds of formula I of the present invention are as follows:
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-1);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-2);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-3);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1-benzyl-1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-4);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-5);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-6);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-7);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-8);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-9);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-10);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-11).
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following reaction formula:
Figure BSA0000181449210000031
the method specifically comprises the following steps:
(1) step a, reacting a compound 1 with acetic anhydride to obtain a compound 2;
(2) step b, preparing a compound 3 from the compound 2 and 2-ethyl bromoacetate;
(3) in the step c, the compound 3 is deacetylated to prepare a compound 4;
(4) in the step d, the compound 4 reacts with ethyl isocyanate and then reacts with sodium methoxide to prepare a compound 5;
(5) step e, reacting the compound 5 with di-tert-butyl dicarbonate to prepare a compound 6;
(6) step f, preparing a compound 7 by using the compound 6 and different halogenated hydrocarbons;
(7) and step g, reacting the compound 7 with 3, 5-dimethylisoxazole-4-boric acid to prepare a compound I-1 to 11.
In another embodiment, the present invention discloses a compound represented by formula II, or a pharmaceutically acceptable salt thereof, having the structure:
Figure BSA0000181449210000041
wherein:
B1is-N or-C (R)10)-；
B2is-N or-C (R)11)-；
B3is-N-or-CH-;
y is O or S;
R7is an optionally substituted five membered heteroaryl;
R8hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;
R9is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl) alkyl;
R10hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;
R11hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and fluorine;
preferred compounds of formula II of the present invention are as follows:
7- (3, 5-dimethylisoxazol-4-yl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-1);
7- (3, 5-dimethylisoxazol-4-yl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-2);
7- (3, 5-dimethylisoxazol-4-yl) -1- (1-phenylethyl) -1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-3).
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following reaction formula:
Figure BSA0000181449210000051
the method specifically comprises the following steps:
(1) step h, reacting the compound 7 with tin tetrachloride and silver chloride to obtain a compound 8;
(2) step i, reacting the compound 8 with 4-methoxy benzyl chloride to obtain a compound 9;
(3) step j is that the compound 9 reacts with hydroxylamine hydrochloride and sodium ethoxide to prepare a compound 10;
(4) step k, reacting the compound 10 with aluminum trichloride to obtain a compound 11;
(5) step l, reacting the compound 11 with different halogenated hydrocarbons to obtain a compound 12;
(6) m is that the compound 12 reacts with phosphorus oxychloride and N, N-dimethylformamide to close the ring and prepare a compound 13;
(7) step n is that the compound 13 reacts with 3, 5-dimethyl isoxazole-4-boric acid to prepare a compound 14;
(8) step o is the reaction of compound 14 with trifluoroacetic acid to give compound II-1 to 3.
It is another object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt thereof and a compound of formula II or a pharmaceutically acceptable salt thereof as BET bromodomain inhibitors for the treatment of cancer.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of N- (5-bromo-2-cyanophenyl) acetamide (2-A)
Figure BSA0000181449210000061
2-amino-4-bromobenzonitrile (15.6g, 79.3mmol) was dissolved in acetic anhydride (75.0mL, 793mmol) at room temperature, heated to 100 deg.C, and stirred for 40 min. And monitoring by TLC, cooling to room temperature after the reaction is finished, adding 100mL of water, stirring for 30min, performing suction filtration, and drying a filter cake to obtain a crude product. Purification by silica gel column chromatography gave 14.2g of a white solid in 75% yield.1H NMR(300MHz，DMSO-d6)10.27(s，1H)，7.92(m，1H)，7.76(m，1H)，7.53(m，1H)，2.13(s，3H).
Example 2
Preparation of 1-acetyl-3-amino-6-bromo-1H-indole-2-carboxylic acid ethyl ester (3-A)
Figure BSA0000181449210000062
N- (5-bromo-2-cyanophenyl) acetamide (2-A) (13.1g, 54.6mmol) was dissolved in anhydrous tetrahydrofuran (150mL) at room temperature, cooled to 0 deg.C, and potassium tert-butoxide (9.2g, 81.9mmol) was added in portions and, after the addition, stirred at 0 deg.C for 30 min. Ethyl bromoacetate (13.7g, 81.9mmol) was added dropwise, after which time the reaction was allowed to warm to room temperature and stirred for 2 h. TLC monitoring, after completion of the reaction, water (100mL) and ethyl acetate (100mL) were added and stirred for 10 min. The organic phase was separated, the aqueous phase (100mL x 2) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography to give 13.3g of a yellow solid in 75% yield.1H NMR(300MHz，CDCl3)7.93(d，J＝1.6Hz，1H)，7.70-7.59(m，2H)，4.98(m，1H)，4.22(q，J＝7.2Hz，2H)，3.82(m，1H)，1.96(s，3H)，1.29(t，J＝7.2Hz，3H).
Example 3
Preparation of 3-amino-6-bromo-1H-indole-2-carboxylic acid ethyl ester (4-A)
Figure BSA0000181449210000063
Ethyl 1-acetyl-3-amino-6-bromo-1H-indole-2-carboxylate (3-A) (11.9g, 36.6mmol) was dissolved in a mixed solvent of ethanol (75mL) and water (75mL) at room temperature, potassium carbonate (25.3g, 183mmol) was added, and the reaction was refluxed with heating for 4 hours. TLC monitoring, after the reaction was complete, cool to room temperature, add water (100mL), stir for 30 min. The filter cake was washed with water (20mL) and dried to give 8.3g of a grey solid in 54% yield.1H NMR(300MHz，DMSO-d6)10.55(s，1H)，7.73(d，J＝8.6Hz，1H)，7.38(d，J＝1.5Hz，1H)，7.03(dd，J＝8.6，1.7Hz，1H)，5.79(s，2H)，4.30(q，J＝7.1Hz，2H)，1.33(t，J＝7.1Hz，3H).
Example 4
Preparation of 7-bromo-3-ethyl-1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (5-A)
Figure BSA0000181449210000071
Ethyl 3-amino-6-bromo-1H-indole-2-carboxylate (4-A) (5.2g, 18.5mmol) was dissolved in anhydrous toluene (60mL) at room temperature, ethyl isocyanate (4.4mL, 55.6mmol) and N, N-diisopropylethylamine (3.1mL, 18.5mmol) were added, the temperature was raised to 80 ℃ and the reaction was heated for 12H. Cooling to room temperature, filtering, washing the filter cake with toluene (20mL), and drying the filter cake to obtain an off-white solid. The resulting solid was dissolved in methanol (60mL), sodium methoxide (3.0g, 55.6mmol) was added in portions, and the reaction was stirred at room temperature for 1 h. TLC monitoring, after completion of the reaction, water (30mL) was added, stirred for 30min, filtered, the filter cake was washed with water, dried and slurried with diethyl ether (30mL) to give 4.6g of an off-white solid in 80% yield.1H NMR(300MHz，DMSO-d6)11.97(s，2H)，7.88(d，J＝8.6Hz，1H)，7.57(s，1H)，7.27(d，J＝8.6Hz，1H)，3.97(q，J＝6.9Hz，2H)，1.17(t，J＝6.9Hz，3H).
Example 5
Preparation of 7-bromo-3-ethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] indole-5-carboxylic acid tert-butyl ester (6-A)
Figure BSA0000181449210000072
Under the condition of room temperature, adding 7-bromo-3-ethyl-1, 5-dihydro-2H-pyrimido [5, 4-b)]Indole-2, 4(3H) -dione (5-A) (4.6g, 14.8mmol) was dissolved in anhydrous tetrahydrofuran (40mL), di-tert-butyl dicarbonate (3.4mL, 14.8mmol) and 4-dimethylaminopyridine (0.18g, 1.48mmol) were added, and the reaction was stirred for 12H. TLC monitoring, after completion of the reaction, water was added, stirred for 30min, filtered, the filter cake was washed with water, dried, slurried with diethyl ether (30mL), filtered and dried to give 4.4g of a white solid in 73% yield.1H NMR(300MHz，DMSO-d6)12.30(s，1H)，8.18(s，1H)，8.00(d，J＝8.3Hz，1H)，7.58(d，J＝8.3Hz，1H)，3.95(q，J＝7.0Hz，2H)，1.59(s，9H)，1.16(t，J＝6.9Hz，3H).
Example 6
Preparation of ethyl 7-bromo-3-ethyl-2, 4-dioxo-1- (1-phenylethyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] indole-tert-butyl ester-5-carboxylate (7-A-1)
Figure BSA0000181449210000081
At room temperature, 7-bromo-3-ethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-A) (94mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and (1-bromoethyl) benzene (85.1mg, 0.46mmol) were added, the temperature was raised to 82 ℃, and the reaction was heated under stirring and refluxed for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration and evaporation to remove the solvent, and purification by silica gel column chromatography to obtain 70.7mg of compound white solid with yield of 60%.1H NMR(300MHz，CDCl3)8.37(s，1H)，7.42-7.18(m，7H)，6.42(m，1H)，4.12(q，J＝7.0Hz，2H)，2.04(q，J＝7.7Hz，3H)，1.68(s，9H)，1.26(t，J＝7.0Hz，3H).
Example 7
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-1)
Figure BSA0000181449210000082
At room temperature, 7-bromo-3-ethyl-2, 4-dioxo-1- (1-phenylethyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate ethyl ester (7-A-1) (56.7mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O＝4∶1) Heating to 80 ℃ under the protection of nitrogen, and heating and stirring for reaction for 12 hours. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to give 19.0mg of an off-white solid in 40% yield.1H NMR(300MHz，CDCl3)10.60(s，1H)，7.45-7.23(m，7H)，6.88(m，1H)，6.53(m，1H)，4.23(m，2H)，2.43(s，3H)，2.30(s，3H)，2.09(d，J＝7.0Hz，3H)，1.33(t，J＝7.0Hz，3H).MS(ESI)m/z：427.9[M+H]+
Example 8
Preparation of ethyl 7-bromo-3-ethyl-2, 4-dioxo-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] indole-tert-butyl ester-5-carboxylate (7-A-2)
Figure BSA0000181449210000091
At room temperature, 7-bromo-3-ethyl-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-A) (94mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 5- (chloromethyl) -3-cyclopropyl-1-methyl-1H-pyrazole (78.5mg, 0.46mmol) were added, the temperature was raised to 82 ℃ and the reaction was refluxed with heating for 2H. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration and evaporation to remove the solvent, and purification by silica gel column chromatography to obtain 78.6mg of compound white solid with the yield of 63%.1H NMR(300MHz，CDCl3)8.42-8.35(m，1H)，7.48-7.41(m，1H)，7.39-7.32(m，1H)，5.60(s，1H)，5.44(s，2H)，4.13(q，J＝7.3Hz，2H)，3.98(s，3H)，1.80-1.72(m，1H)，1.68(s，9H)，1.29(t，J＝7.3Hz，3H)，0.83-0.74(m，2H)，0.61-0.53(m，2H).
Example 9
7- (3, 5-Dimethylisoxazol-4-yl) -3-ethyl-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-2)
Figure BSA0000181449210000092
Under the condition of room temperature, 7-bromo-3-ethyl-2, 4-dioxo-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b)]Indole tert-butyl-5-carboxylate ethyl ester (7-A-2) (60.0mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to give 19.4mg of an off-white solid in 38% yield.1H NMR(300MHz，CDCl3)11.20(s，1H)，7.74(d，J＝8.5Hz，1H)，7.52(s，1H)，7.08(d，J＝8.3Hz，1H)，5.70(s，1H)，5.54(s，2H)，4.27(q，J＝6.7Hz，2H)，4.03(s，3H)，2.49(s，3H)，2.36(s，3H)，1.85-1.70(m，1H)，1.37(t，J＝6.7Hz，3H)，0.85-0.72(m，2H)，0.64-0.51(m，2H).MS(ESI)m/z：458.1[M+H]+
Example 10
Preparation of N- (5-bromo-2-cyano-4-methoxyphenyl) acetamide (2-B)
Figure BSA0000181449210000101
2-amino-4-bromo-5-methoxybenzonitrile (18.0g, 79.3mmol) was dissolved in acetic anhydride (75.0mL, 793mmol) at room temperature, heated to 100 deg.C, and stirred for 40 min. And monitoring by TLC, cooling to room temperature after the reaction is finished, adding 100mL of water, stirring for 30min, performing suction filtration, and drying a filter cake to obtain a crude product. Purification by silica gel column chromatography gave 16.2g of a white solid in 76% yield.1H NMR(300MHz，DMSO-d6)10.07(s，1H)，7.81(s，1H)，7.55(s，1H)，3.90(s，3H)，2.08(s，3H).
Example 11
Preparation of 1-acetyl-3-amino-6-bromo-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (3-B)
Figure BSA0000181449210000102
N- (5-bromo-2-cyano-4-methoxyphenyl) acetamide (2-B) (14.7g, 54.6mmol) was dissolved in anhydrous tetrahydrofuran (150mL) at room temperature, and after cooling to 0 ℃ potassium tert-butoxide (9.2g, 81.9mmol) was added in portions and stirred at 0 ℃ for 30 min. Ethyl bromoacetate (13.7g, 81.9mmol) was added dropwise, after which time the reaction was allowed to warm to room temperature and stirred for 2 h. TLC monitoring, after completion of the reaction, water (100mL) and ethyl acetate (100mL) were added and stirred for 10 min. The organic phase was separated, the aqueous phase (100mL x 2) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography to give 14.2g of a yellow solid with a yield of 73%.1H NMR(300MHz，CDCl3)7.87(s，1H)，7.17(s，1H)，4.87(m，1H)，4.21-4.06(m，2H)，3.93(s，3H)，3.74(m，1H)，1.88(s，3H)，1.27-1.19(m，3H).
Example 12
Preparation of 3-amino-6-bromo-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (4-B)
Figure BSA0000181449210000111
Ethyl 1-acetyl-3-amino-6-bromo-5-methoxy-1H-indole-2-carboxylate (3-B) (13.0g, 36.6mmol) was dissolved in a mixed solvent of ethanol (75mL) and water (75mL) at room temperature, potassium carbonate (25.3g, 183mmol) was added, and the reaction was refluxed with heating for 4 hours. TLC monitoring, after the reaction was complete, cool to room temperature, add water (100mL), stir for 30 min. The filter cake was washed with water (20mL) and dried to give 6.0g of a grey solid in 52% yield.1H NMR(300MHz，DMSO-d6)10.17(s，1H)，7.48-7.40(m，2H)，5.56(s，2H)，4.29(d，J＝6.9Hz，2H)，3.82(s，3H)，1.33(t，J＝6.9Hz，3H).
Example 13
Preparation of 7-bromo-3-ethyl-8-methoxy-1, 5-dihydro-2H-pyrimido [5, 4-B ] indole-2, 4(3H) -dione (5-B)
Figure BSA0000181449210000112
Ethyl 3-amino-6-bromo-5-methoxy-1H-indole-2-carboxylate (4-B) (5.8g, 18.5mmol) was dissolved in anhydrous toluene (60mL) at room temperature, ethyl isocyanate (4.4mL, 55.6mmol) and N, N-diisopropylethylamine (3.1mL, 18.5mmol) were added, the temperature was raised to 80 ℃ and the reaction was heated for 12H. Cooling to room temperature, filtering, washing the filter cake with toluene (20mL), and drying the filter cake to obtain an off-white solid. The resulting solid was dissolved in methanol (60mL), sodium methoxide (3.0g, 55.6mmol) was added in portions, and the reaction was stirred at room temperature for 1 h. TLC monitoring, after completion of the reaction, water (30mL) was added, stirred for 30min, filtered, the filter cake was washed with water, dried and slurried with diethyl ether (30mL) to give an off-white solid 5.3g with 85% yield.1H NMR(300MHz，DMSO-d6)11.86-11.58(m，2H)，7.68-7.55(m，2H)，3.97(q，J＝7.2Hz，2H)，3.86(s，3H)，1.17(t，J＝7.2Hz，3H).
Example 14
Preparation of 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole-5-carboxylic acid tert-butyl ester (6-B)
Figure BSA0000181449210000113
Under the condition of room temperature, adding 7-bromo-3-ethyl-8-methoxy-1, 5-dihydro-2H-pyrimido [5, 4-b)]Indole-2, 4(3H) -dione (5-B) (5.0g, 14.8mmol) was dissolved in anhydrous tetrahydrofuran (40mL), di-tert-butyl dicarbonate (3.4mL, 14.8mmol) and 4-dimethylaminopyridine (0.18g, 1.48mmol) were added, and the reaction was stirred for 12H. TLC monitoring, after completion of the reaction, water was added, stirred for 30min, filtered, the filter cake was washed with water, dried, slurried with diethyl ether (30mL), filtered and dried to give 4.9g of a white solid in 75% yield.1H NMR(300MHz，DMSO-d6)12.17(s，1H)，8.20(s，1H)，7.76(s，1H)，4.00-3.84(m，5H)，1.58(s，9H)，1.16(t，J＝6.8Hz，3H).
Example 15
Preparation of ethyl 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1- (1-phenylethyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole-tert-butyl ester-5-carboxylate (7-B-1)
Figure BSA0000181449210000121
Tert-butyl 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole-5-carboxylate (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL) at room temperature, cesium carbonate (148.7mg, 0.46mmol) and (1-bromoethyl) benzene (85.1mg, 0.46mmol) were added, the temperature was raised to 82 ℃ and the reaction was refluxed for 2H with heating and stirring. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration to remove the solvent by evaporation, and purification by silica gel column chromatography to obtain 78.6mg of white solid with the yield of 63%.
Example 16
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-3)
Figure BSA0000181449210000122
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1- (1-phenylethyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate ethyl ester (7-B-1) (110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. Monitored by TLC, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure and purified by silica gel column chromatography to give an off-white solid in 38% yield.1H NMR(300MHz，CDCl3)10.89(s，1H)，7.49-7.27(m，5H)，6.78(s，1H)，6.52(s，1H)，4.31(d，J＝6.0Hz，2H)，4.14(q，J＝6.0Hz，1H)，3.40(s，3H)，2.32(s，3H)，2.17(s，3H)，2.08(d，J＝3.0Hz，3H)，1.39(t，J＝6.0Hz，3H).MS(ESI)m/z：458.1[M+H]+
Example 17
Preparation of 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1-benzyl-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole-5-carboxylic acid tert-butyl ester (7-B-2)
Figure BSA0000181449210000131
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and bromobenzyl (78.7mg, 0.46mmol) were added, the temperature was raised to 82 ℃ and the reaction was heated under reflux for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration and evaporation to remove the solvent, and purification by silica gel column chromatography to obtain 80.2mg of white solid with the yield of 66%.1H NMR(400MHz，CDCl3)8.39(s，1H)，7.38-7.32(m，2H)，7.30-7.22(m，3H)，6.88(s，1H)，5.63(s，2H)，4.21(q，J＝7.0Hz，2H)，3.57(s，3H)，1.67(s，9H)，1.33(t，J＝7.0Hz，3H).
Example 18
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1-benzyl-1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-4)
Figure BSA0000181449210000132
Under the condition of room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1-benzyl-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (7-B-2) (58.5mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (VDME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure, and purification by silica gel column chromatography gave 16.2mg of an off-white solid in 33% yield.1H NMR(400MHz，CDCl3)10.92(s，1H)，7.39-7.25(m，6H)，7.00(s，1H)，5.68(s，2H)，4.31(q，J＝7.0Hz，2H)，3.57(s，3H)，2.31(s，3H)，2.16(s，3H)，1.39(t，J＝7.0Hz，3H).MS(ESI)m/z：444.1[M+H]+
Example 19
Preparation of 7-bromo-3-ethyl-1- (3-fluorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole tert-butyl ester-5-carboxylic acid ethyl ester (7-B-3)
Figure BSA0000181449210000141
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 3-fluorobenzyl bromide (87mg, 0.46mmol) were added, the temperature was raised to 82 ℃ and the reaction was refluxed with heating under stirring for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration and evaporation to remove the solvent, and purification by silica gel column chromatography to obtain 80.4mg of white solid with the yield of 64%.1H NMR(300MHz，DMSO-d6)8.21(s，1H)，7.47-7.37(m，1H)，7.34-7.18(m，2H)，7.16-7.03(m，2H)，5.67(s，2H)，4.04(q，J＝6.9Hz，2H)，3.64(s，3H)，1.60(s，9H)，1.22(t，J＝6.9Hz，3H).
Example 20
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-5)
Figure BSA0000181449210000142
Under the condition of room temperature, the water-soluble organic silicon,reacting 7-bromo-3-ethyl-1- (3-fluorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ]]Indole tert-butyl-5-carboxylate ethyl ester (7-B-3) (60.4mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18.0mg of an off-white solid in 35% yield.1H NMR(400MHz，CDCl3)10.84(s，1H)，7.38-7.31(m，2H)，7.17-7.13(m，1H)，7.04-6.94(m，3H)，5.67(s，2H)，4.30(q，J＝7.0Hz，2H)，3.58(s，3H)，2.31(s，3H)，2.17(s，3H)，1.39(t，J＝7.0Hz，3H).MS(ESI)m/z：462.1[M+H]+
Example 21
Preparation of 7-bromo-3-ethyl-1- (4-fluorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole tert-butyl ester-5-carboxylic acid ethyl ester (7-B-4)
Figure BSA0000181449210000151
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 4-fluorobenzyl bromide (87mg, 0.46mmol) were added, the temperature was raised to 82 ℃ and the reaction was refluxed with heating under stirring for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration and evaporation to remove the solvent, and purification by silica gel column chromatography to obtain 82.9mg of white solid with the yield of 66%.1H NMR(300MHz，DMSO-d6)8.21(s，1H)，7.46-7.37(m，2H)，7.24-7.16(m，2H)，7.10(s，1H)，5.64(s，2H)，4.05(q，J＝6.6Hz，2H)，3.66(s，3H)，1.59(s，9H)，1.22(t，J＝6.9Hz，3H).
Example 22
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-6)
Figure BSA0000181449210000152
At room temperature, 7-bromo-3-ethyl-1- (4-fluorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate ethyl ester (7-B-4) (60.4mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. Monitored by TLC, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give 19.0mg of an off-white solid in 37% yield.1H NMR(400MHz，CDCl3)10.90(s，1H)，7.36-7.29(m，3H)，7.09-7.03(m，2H)，7.00(s，1H)，5.63(s，2H)，4.29(q，J＝7.0Hz，2H)，3.61(s，3H)，2.32(s，3H)，2.17(s，3H)，1.38(t，J＝7.0Hz，3H).MS(ESI)m/z：462.1[M+H]+
Example 23
Preparation of 7-bromo-3-ethyl-1- (3-chlorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole tert-butyl ester-5-carboxylic acid ethyl ester (7-B-5)
Figure BSA0000181449210000161
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 3-chlorobenzyl bromide (94.5mg, 0.46mmol) were added, the temperature was raised to 82 deg.C, and the reaction was heated under reflux for 2 h. Monitoring by TLC, cooling to room temperature after the reaction is finished, performing suction filtration, and concentrating under reduced pressureThe solvent was removed by distillation and the residue was purified by silica gel column chromatography to give 81.6mg of a white solid in a yield of 63%.1H NMR(400MHz，CDCl3)8.26(s，1H)，7.22-7.13(m，3H)，7.07-7.01(m，1H)，6.71(s，1H)，5.48(s，2H)，4.11(q，J＝6.8Hz，2H)，3.52(s，3H)，1.59(s，9H)，1.25(t，J＝6.8Hz，3H).
Example 24
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-7)
Figure BSA0000181449210000162
Under the condition of room temperature, 7-bromo-3-ethyl-1- (3-chlorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate ethyl ester (7-B-5) (62.2mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure, and purification was performed by silica gel column chromatography to obtain 19.0mg of an off-white solid in a yield of 36%.1H NMR(400MHz，CDCl3)10.99(s，1H)，7.36-7.21(m，5H)，6.97(s，1H)，5.65(s，2H)，4.31(q，J＝7.0Hz，2H)，3.61(s，3H)，2.32(s，3H)，2.17(s，3H)，1.39(t，J＝7.0Hz，3H).MS(ESI)m/z：478.1[M+H]+
Example 25
Preparation of 7-bromo-3-ethyl-1- (4-chlorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole tert-butyl ester-5-carboxylic acid ethyl ester (7-B-6)
Figure BSA0000181449210000171
At room temperatureThen, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ]]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 4-chlorobenzyl bromide (94.5mg, 0.46mmol) were added, the temperature was raised to 82 deg.C, and the reaction was heated under reflux for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration and evaporation to remove the solvent, and purification by silica gel column chromatography to obtain 84.1mg of white solid with the yield of 65%.1H NMR(400MHz，CDCl3)8.37(s，1H)，7.32(d，J＝8.4Hz，2H)，7.20(d，J＝8.4Hz，2H)，6.81(s，1H)，5.57(s，2H)，4.19(q，J＝6.9Hz，2H)，3.61(s，3H)，1.67(s，9H)，1.32(t，J＝6.8Hz，3H).
Example 26
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-8)
Figure BSA0000181449210000172
Under the condition of room temperature, 7-bromo-3-ethyl-1- (4-chlorobenzyl) -8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate ethyl ester (7-B-6) (62.2mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18.6mg of an off-white solid in 35% yield.1H NMR(400MHz，CDCl3)11.04(s，1H)，7.36-7.26(m，5H)，6.97(s，1H)，5.63(s，2H)，4.30(q，J＝7.0Hz，2H)，3.61(s，3H)，2.32(s，3H)，2.18(s，3H)，1.38(t，J＝7.0Hz，3H).MS(ESI)m/z：478.1[M+H]+
Example 27
Preparation of 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1- (3-methylbenzyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole tert-butyl ester-5-carboxylic acid ethyl ester (7-B-7)
Figure BSA0000181449210000181
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 3-methylbenzyl bromide (85.1mg, 0.46mmol) were added, the temperature was raised to 82 deg.C, and the reaction was heated under reflux for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration to remove the solvent by evaporation, and purification by silica gel column chromatography to obtain 77.4mg of white solid with the yield of 62%.1H NMR(300MHz，CDCl3)8.36(s，1H)，7.15-7.10(m，4H)，6.90(s，1H)，5.57(s，2H)，4.20(q，J＝7.0Hz，2H)，3.60(s，3H)，2.30(s，3H)，1.67(s，9H)，1.33(t，J＝7.0Hz，3H).
Example 28
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-9)
Figure BSA0000181449210000191
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1- (3-methylbenzyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate ethyl ester (7-B-7) (60.0mg, 110.6. mu. mol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after the reaction is completed, cooling to room temperature, concentrating under reduced pressure to remove the solvent, purifying by silica gel column chromatography to obtain ashWhite solid 16.2mg, yield 32%.1H NMR(400MHz，CDCl3)10.53(s，1H)，7.28-7.21(m，2H)，7.16-7.06(m，3H)，7.04(s，1H)，5.63(s，2H)，4.29(q，J＝7.0Hz，2H)，3.58(s，3H)，2.34-2.27(m，6H)，2.15(s，3H)，1.38(t，J＝7.0Hz，3H).MS(ESI)m/z：458.2[M+H]+
Example 29
Preparation of ethyl 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1- (3-methylbenzyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole-tert-butyl ester-5-carboxylate (7-B-8)
Figure BSA0000181449210000192
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 4-methylbenzyl bromide (85.1mg, 0.46mmol) were added, the temperature was raised to 82 deg.C, and the reaction was heated under reflux for 2 h. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration to remove the solvent by evaporation, and purification by silica gel column chromatography to obtain 79.8mg of white solid with the yield of 64%.1H NMR(300MHz，CDCl3)7.81(s，1H)，7.41(s，1H)，7.21(d，J＝8.4，2H)，7.09(d，J＝8.4，2H)，5.15(s，2H)，4.28(q，J＝7.2Hz，2H)，3.70(s，3H)，2.32(s，3H)，1.53(s，9H)，1.22(t，J＝7.2Hz，3H).
Example 30
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-10)
Figure BSA0000181449210000201
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1- (3-methylbenzyl) -1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole tert-butyl-5-carboxylate (7-B-8) (60.0mg, 110.6. mu. mol),3, 5-Dimethylisoxazole-4-boronic acid (23.4mg, 165.9. mu. mol), cesium carbonate (72.1mg, 221.2. mu. mol) and palladium tetratriphenylphosphine (12.8mg, 11.1. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to give 15.4mg of an off-white solid in 30% yield.1H NMR(400MHz，CDCl3)10.33(s，1H)，7.27-7.20(m，3H)，7.16(d，J＝8.0Hz，2H)，7.05(s，1H)，5.62(s，2H)，4.28(q，J＝7.0Hz，2H)，3.60(s，3H)，2.34-2.28(m，6H)，2.16(s，3H)，1.37(t，J＝7.0Hz，3H).MS(ESI)m/z：458.2[M+H]+
Example 31
Preparation of ethyl 7-bromo-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3-tert-butyl, 4-tetrahydro-5H-pyrimido [5, 4-B ] indole-5-carboxylate (7-B-9)
Figure BSA0000181449210000202
At room temperature, 7-bromo-3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3, 4-tetrahydro-5H-pyrimido [5, 4-b ] is reacted]Indole-5-carboxylic acid tert-butyl ester (6-B) (100mg, 0.23mmol) was dissolved in acetonitrile (5mL), cesium carbonate (148.7mg, 0.46mmol) and 5- (chloromethyl) -3-cyclopropyl-1-methyl-1H-pyrazole (78.5mg, 0.46mmol) were added, the temperature was raised to 82 ℃ and the reaction was refluxed with heating for 2H. TLC monitoring, after the reaction is completed, cooling to room temperature, suction filtering, reduced pressure concentration to remove the solvent by evaporation, and purification by silica gel column chromatography to obtain 82.9mg of white solid with the yield of 63%.1H NMR(300MHz，CDCl3)8.39(s，1H)，6.79(s，1H)，5.64(s，1H)，5.44(s，2H)，4.14(q，J＝6.9Hz，2H)，3.98(s，3H)，3.71(s，3H)，1.81-1.72(m，1H)，1.67(s，9H)，1.29(t，J＝6.9Hz，3H)，0.83-0.74(m，2H)，0.59-0.50(m，2H).
Example 32
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-11)
Figure BSA0000181449210000211
Under the condition of room temperature, 7-bromo-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -3-ethyl-8-methoxy-2, 4-dioxo-1, 2, 3-tert-butyl, 4-tetrahydro-5H-pyrimido [5, 4-b)]Indole-5-carboxylic acid ethyl ester (7-B-9) (63.9mg, 110.6 μmol), 3, 5-dimethylisoxazole-4-boronic acid (23.4mg, 165.9 μmol), cesium carbonate (72.1mg, 221.2 μmol) and palladium tetratriphenylphosphine (12.8mg, 11.1 μmol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4mL) and water (1mL) (VDME: VH2O ═ 4: 1), nitrogen protected, warmed to 80 ℃, and stirred under heating for 12 h. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to give 20.9mg of an off-white solid in 38% yield.1H NMR(300MHz，CDCl3)11.30(s，1H)，8.39(s，1H)，6.79(s，1H)，5.64(s，1H)，5.44(s，2H)，4.14(q，J＝6.9Hz，2H)，3.98(s，3H)，3.67(s，3H)，2.19(s，3H)，2.35(s，3H)，1.81-1.72(m，1H)，1.29(t，J＝6.9Hz，3H)，0.83-0.74(m，2H)，0.59-0.50(m，2H).MS(ESI)m/z：488.2[M+H]+
Example 33
Preparation of 1- (6-bromo-1H-indol-3-yl) ethan-1-one (8)
Figure BSA0000181449210000212
6-bromoindole (7) (15.0g, 76.5mmol) was dissolved in anhydrous toluene (150mL) at room temperature, cooled to 0 deg.C, acetyl chloride (10.9mL, 153.0mmol) was added, and stirred at 0 deg.C for 15 min. Then, a solution of tin tetrachloride (17.9mL, 153.0mmol) in toluene (75mL) was added and the reaction was stirred at 0 ℃ for 2 h. TLC monitoring, after completion of the reaction, 8% sodium bicarbonate solution (75mL) was added dropwise, followed by ethyl acetate (150mL) and stirred at room temperature for 10 min. Separating the organic layer fromThe aqueous layer was extracted with ethyl acetate (150mL × 2), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered under suction, and the solvent was evaporated off by concentration under reduced pressure to give a brown solid. Recrystallization from acetone gave 11.3g of a grey solid in 62% yield.1H NMR(400MHz，DMSO-d6)12.02(s，1H)，8.33(d，J＝3.1Hz，1H)，8.11(d，J＝8.5Hz，1H)，7.66(d，J＝1.6Hz，1H)，7.32(dd，J＝8.5，1.8Hz，1H)，2.46(s，3H).
Example 34
Preparation of 1- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) ethan-1-one (9)
Figure BSA0000181449210000221
1- (6-bromo-1H-indol-3-yl) ethan-1-one (8) (10.0g, 42.0mmol) was dissolved in dry DMF (100mL) at room temperature, 60% sodium hydride (1.85g, 46.2mmol) was added, stirring was carried out at room temperature for 30min, 4-methoxybenzyl chloride (8.5mL, 63.0mmol) was added dropwise, and after the addition, the reaction was stirred for 2H. TLC monitoring, after the reaction is completed, adding water, separating out solid and stirring for 30 min. The filter cake was filtered off with suction and dried to give 9.6g of an off-white solid in 64% yield.1H NMR(300MHz，CDCl3)8.26(m，1H)，7.65(s，1H)，7.47(m，1H)，7.38(m，1H)，7.11(d，J＝6.0Hz，2H)，6.89(d，J＝6.0Hz，2H)，5.21(s，2H)，3.80(s，3H)，2.48(s，3H).
Example 35
Preparation of 1- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) ethan-1-one oxime (10)
Figure BSA0000181449210000222
1- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) ethan-1-one (9) (5.7g, 15.1mmol) was dissolved in a mixed solvent of ethanol (20mL) and water (15mL) at room temperature, sodium acetate (3.3g, 47.7mmol) and hydroxylamine hydrochloride (3.3g, 39.8mmol) were added, and the reaction was stirred under reflux for 2.5H. Monitoring by TLC, cooling to room temperature after the reaction is finished, and slowly reacting the reaction liquidPouring into ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying the filter cake to obtain 5.5g of white solid with the yield of 92.6%.1H NMR(300MHz，DMSO-d6)10.64(s，1H)，8.09(d，J＝6.0Hz，1H)，7.86(s，1H)，7.72(s，1H)，7.22(d，J＝7.1Hz，3H)，6.88(d，J＝7.1Hz，2H)，5.34(s，2H)，3.70(s，3H)，2.17(s，3H).
Example 36
Preparation of N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) acetamide (11)
Figure BSA0000181449210000231
1- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) ethan-1-one oxime (10) (5.0g, 13.4mmol) was dissolved in acetonitrile (30mL) at room temperature, and a solution of aluminum trichloride (0.36g, 2.7mmol) in acetonitrile (10mL) was added dropwise, followed by heating and stirring for reflux reaction for 2H. TLC, after completion of the reaction, was cooled to room temperature, water (50mL) was added, followed by extraction with ethyl acetate (50mL x 3), and the organic phases were combined. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give a pale yellow solid 4.3g, yield 86%.1H NMR(300MHz，CDCl3)7.80(s，1H)，7.64(s，1H)，7.38(m，2H)，7.14(s，1H)，7.01(d，J＝8.3Hz，2H)，6.79(d，J＝8.3Hz，2H)，5.05(s，2H)，3.75(s，3H)，2.18(s，3H).
Example 37
Preparation of N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) -N-phenylacetamide (12-A)
Figure BSA0000181449210000232
N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) acetamide (11) (0.2g, 0.54mmol) was dissolved in toluene (4mL) at room temperature, iodobenzene (0.13g, 0.64mmol), brominated ketone (12mg, 53.6. mu. mol), cesium carbonate (0.35g, 1.1mmol) and N, N-dimethylethylenediamine (0.012. mu.L, 0.11mmol) were added, nitrogen was used as a blanket, the temperature was raised to 130 ℃, and then the mixture was heated to room temperatureThe reaction was stirred hot for 24 h. TLC monitoring, after the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 0.12g of a white solid with a yield of 50%.1H NMR(300MHz，CDCl3)7.39(s，1H)，7.30-7.20(m，5H)，7.18-7.08(m，2H)，7.04(s，1H)，6.97(d，J＝8.6Hz，2H)，6.76(d，J＝8.6Hz，2H)，5.07(s，2H)，3.69(s，3H)，2.00(s，3H).
Example 38
Preparation of 7-bromo-5- (4-methoxybenzyl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (13-A)
Figure BSA0000181449210000241
The compound N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) -N-phenylacetamide (12-A) (0.1g, 0.22mmol) was dissolved in DMF (2.0mL) at room temperature, cooled to 0 deg.C, and a cooled solution of POCl3(0.1mL, 1.1mmol) in DMF (1.0mL) was added dropwise, after which the reaction was stirred at 0 deg.C for 3H. The reaction was cooled to room temperature and poured into ice water (10.0mL), and then heated under stirring and refluxed for 12 h. TLC, after completion of the reaction, was cooled to room temperature, a yellow solid precipitated, filtered, the filter cake was washed with water (10.0mL), dried and purified by column chromatography to give 64.0mg of a yellow solid in 63% yield.1H NMR(300MHz，CDCl3)7.71-7.62(m，4H)，7.56-7.45(m，3H)，7.11-7.05(d，J＝8.7Hz，2H)，6.96-6.84(m，3H)，6.79-6.73(m，1H)，6.02-5.97(m，1H)，5.40(s，2H)，3.81(s，3H).
Example 39
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -5- (4-methoxybenzyl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (14-a)
Figure BSA0000181449210000242
Under the condition of room temperature, 7-bromo-5- (4-methoxybenzyl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b)]Indol-2-one (13-A) (50.0mg, 0.11mmol), 3,5-Dimethylisoxazole-4-boronic acid (23.0mg, 0.16mmol), cesium carbonate (71.0mg, 0.22mmol) and palladium tetratriphenylphosphine (12.6mg, 10.9. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4.0mL) and water (1.0mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. Monitored by TLC, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure, and purified by silica gel column chromatography to give 32.0mg of a yellow solid in 63% yield.
Example 40
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-1)
Figure BSA0000181449210000251
Under the condition of room temperature, 7- (3, 5-dimethyl isoxazol-4-yl) -5- (4-methoxybenzyl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b)]Indol-2-one (14-A) (100mg, 0.21mmol) was dissolved in trifluoroacetic acid (2mL), and a catalytic amount of anisole (2.3mg, 0.02. mu. mol) was added thereto, and the mixture was heated under stirring and reflux for 12 hours under nitrogen protection. TLC monitoring, after the reaction is completed, concentrating under reduced pressure to remove trifluoroacetic acid. Purification by column chromatography gave 36.0mg of a pale yellow solid in 48% yield.1H NMR(300MHz，CD3OD)8.06-8.00(m，1H)，7.75-7.67(m，3H)，7.53-7.45(m，2H)，7.42-7.37(m，1H)，6.79-6.69(m，2H)，6.19-6.14(m，1H)，2.38(s，3H)，2.22(s，3H).MS(ESI)m/z：355.1[M+H]+
EXAMPLE 41
Preparation of N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) -N-benzylacetamide (12-B)
Figure BSA0000181449210000252
N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) acetamide (11) (0.2g, 0.54mmol) was dissolved in acetonitrile (5.0mL) at room temperature, cesium carbonate (0.35g, 1.1mmol) was added, benzyl bromide (0.13mL, 1.1mmol) was added, and the mixture was heatedThe reaction was stirred and refluxed for 2 h. TLC monitoring, after the reaction was completed, suction filtration, vacuum concentration under reduced pressure to remove the solvent by evaporation, and purification by column chromatography gave 0.15g of a white solid in 62% yield.1H NMR(300MHz，DMSO-d6)7.74(s，1H)，7.39(s，1H)，7.27-7.20(m，4H)，7.20-7.11(m，3H)，7.04(d，J＝8.6Hz，2H)，6.85(d，J＝8.6Hz，2H)，5.28(s，2H)，4.82(s，2H)，3.71(s，3H)，1.84(s，3H).
Example 42
Preparation of 7-bromo-5- (4-methoxybenzyl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-B ] indol-2-one (13-B)
Figure BSA0000181449210000261
The compound N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) -N-benzylacetamide (12-B) (0.1g, 0.22mmol) was dissolved in DMF (2.0mL) at room temperature, cooled to 0 deg.C, and a cooled solution of POCl3(0.1mL, 1.1mmol) in DMF (1.0mL) was added dropwise, after which the reaction was stirred at 0 deg.C for 3H. The reaction was cooled to room temperature and poured into ice water (10.0mL), and then heated under stirring and refluxed for 12 h. TLC, after completion of the reaction, cooled to room temperature, a yellow solid precipitated, filtered, the filter cake was washed with water (10.0mL), dried and purified by column chromatography to give 69mg of yellow solid in 66% yield.1H NMR(300MHz，DMSO-d6)8.17(d，J＝9.6Hz，1H)，7.99(s，1H)，7.67(d，J＝8.6Hz，1H)，7.29(d，J＝7.1Hz，2H)，7.24-7.07(m，6H)，6.87(d，J＝8.1Hz，1H)，6.67(d，J＝9.5Hz，2H)，5.73(s，2H)，5.61(s，2H)，3.69(s，3H).
Example 43
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -5- (4-methoxybenzyl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-B ] indol-2-one (14-B)
Figure BSA0000181449210000262
Under the condition of room temperature, 7-bromo-5- (4-methoxybenzyl)-1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b]Indol-2-one (13-B) (52.0mg, 0.11mmol), 3, 5-dimethylisoxazole-4-boronic acid (23.0mg, 0.16mmol), cesium carbonate (71.0mg, 0.22mmol) and palladium tetratriphenylphosphine (12.6mg, 10.9 μmol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4.0mL) and water (1.0mL) (VDME: VH2O ═ 4: 1), heated to 80 ℃ under nitrogen protection, and stirred for 12 h. Monitored by TLC, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure, and purified by silica gel column chromatography to give 35.0mg of a yellow solid in 65% yield.1H NMR(300MHz，CDCl3)7.83-7.77(m，1H)，7.75-7.70(m，1H)，7.35-7.23(m，5H)，7.20-7.15(m，1H)，7.09-7.03(m，2H)，6.96-6.90(m，1H)，6.87-6.76(m，3H)，5.86(s，2H)，5.42(s，2H)，3.77(s，3H)，2.33(s，3H)，2.19(s，3H).
Example 44
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-2)
Figure BSA0000181449210000271
Under the condition of room temperature, 7- (3, 5-dimethyl isoxazol-4-yl) -5- (4-methoxybenzyl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b)]Indol-2-one (14-B) (103mg, 0.21mmol) was dissolved in trifluoroacetic acid (2mL), and a catalytic amount of anisole (2.3mg, 0.02. mu. mol) was added thereto, followed by stirring and refluxing under nitrogen for 12 hours. TLC monitoring, after the reaction is completed, concentrating under reduced pressure to remove trifluoroacetic acid. Purification by column chromatography gave 36.0mg of a pale yellow solid in 46% yield.1H NMR(300MHz，CD3OD)7.87(d，J＝9.3Hz，1H)，7.71(d，J＝8.6Hz，1H)，7.31(s，1H)，7.23-7.02(m，5H)，6.86(dd，J＝8.6，1.3Hz，1H)，6.65(d，J＝9.3Hz，1H)，5.79(s，2H)，2.29(s，3H)，2.14(s，3H).MS(ESI)m/z：369.1[M+H]+
Example 45
Preparation of N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) -N- (1-phenylethyl) acetamide (12-C)
Figure BSA0000181449210000272
N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) acetamide (11) (0.2g, 0.54mmol) was dissolved in acetonitrile (5.0mL) at room temperature, cesium carbonate (0.35g, 1.1mmol) was added, followed by (1-bromoethyl) benzene (0.15mL, 1.1mmol), and the reaction was stirred under reflux for 2H. TLC monitoring, after the reaction is completed, suction filtration, vacuum concentration and evaporation are carried out to remove the solvent, and the product is purified by column chromatography to obtain 0.15g of white solid with the yield of 58%.
Example 46
Preparation of 7-bromo-5- (4-methoxybenzyl) -1- (1-phenylethyl) -1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (13-C)
Figure BSA0000181449210000281
The compound N- (6-bromo-1- (4-methoxybenzyl) -1H-indol-3-yl) -N- (1-phenylethyl) acetamide (12-C) (0.1g, 0.22mmol) was dissolved in DMF (2.0mL) at room temperature, cooled to 0 deg.C, and a cooled solution of POCl3(0.1mL, 1.1mmol) in DMF (1.0mL) was added dropwise and the reaction was stirred at 0 deg.C for 3H after addition. The reaction was cooled to room temperature and poured into ice water (10.0mL), and then heated under stirring and refluxed for 12 h. TLC monitoring, after the reaction was complete, the temperature was reduced to room temperature, a yellow solid precipitated, which was filtered, the filter cake was washed with water (10.0mL), dried, and purified by column chromatography to give 64mg of a yellow solid in 60% yield.1H NMR(300MHz，CDCl3)7.66-7.60(m，1H)，7.55-7.50(m，1H)，7.37-7.18(m，7H)，7.10-7.00(m，3H)，6.92-6.83(m，2H)，6.78-6.68(m，1H)，5.39(s，2H)，3.80(s，3H)，2.08(d，J＝6.7Hz，3H).
Example 47
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -5- (4-methoxybenzyl) -1- (1-phenylethyl) -1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (14-C)
Figure BSA0000181449210000282
Under the condition of room temperature, 7-bromo-5- (4-methoxybenzyl) -1- (1-phenethyl) -1, 5-dihydro-2H-pyrido [3, 2-b)]Indol-2-one (13-C) (52.0mg, 0.11mmol), 3, 5-dimethylisoxazole-4-boronic acid (23.0mg, 0.16mmol), cesium carbonate (71.0mg, 0.22mmol) and palladium tetratriphenylphosphine (12.6mg, 10.9. mu. mol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (4.0mL) and water (1.0mL) (V)DME∶VH2O4: 1), heating to 80 ℃ under the protection of nitrogen, heating and stirring for reaction for 12 h. Monitored by TLC, after completion of the reaction, the temperature was lowered to room temperature, the solvent was evaporated by concentration under reduced pressure, and the product was purified by silica gel column chromatography to give 36.0mg of a yellow solid in 67% yield.1H NMR(300MHz，CDCl3)7.75-7.66(m，2H)，7.38-7.31(m，4H)，7.29-7.27(m，2H)，7.22-7.16(m，1H)，7.12-7.06(m，2H)，6.90-6.83(m，3H)，6.80-6.70(m，1H)，5.44(s，2H)，3.80(s，3H)，2.35(s，3H)，2.22(s，3H)，2.13(d，J＝6.8Hz，3H).
Example 48
Preparation of 7- (3, 5-dimethylisoxazol-4-yl) -1- (1-phenylethyl) -1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-3)
Figure BSA0000181449210000291
Under the condition of room temperature, 7- (3, 5-dimethyl isoxazol-4-yl) -5- (4-methoxybenzyl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b)]Indol-2-one (14-B) (1010.mg, 0.21mmol) was dissolved in trifluoroacetic acid (2mL), and a catalytic amount of anisole (2.3mg, 0.02. mu. mol) was added thereto, and the mixture was stirred under reflux with heating under nitrogen for 12 hours. TLC monitoring, after the reaction is completed, concentrating under reduced pressure to remove trifluoroacetic acid. Purification by column chromatography gave 33.0mg of a pale yellow solid in 43% yield.1HNMR(300MHz，CDCl3)9.56(s，1H)，7.67-7.61(m，1H)，7.42-7.06(m，8H)，6.90-6.60(m，2H)，2.38(s，3H)，2.25(s，3H)，2.16-2.06(m，3H).MS(ESI)m/z：383.1[M+H]+
Example 49
Ki and inhibition of MV4 of the compounds of formula I and formula II as BET bromopain inhibitors in combination with BRD4-BD 1; 11 activity of cell growth was determined by reference to literature methods (J.Med.chem.2017, 60, 3887-3901; J.Med.chem.2015, 58, 4927-4939; J.Med.chem.2018, 61, 6110-6120).
Figure BSA0000181449210000292

Claims (7)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FSA0000181449200000011
wherein:
A1is-N or-C (R)5)-；
A2is-N or-C (R)6)-；
A3is-N-or-CH-;
A4is-N-or-CH-;
X1is O or S;
X2is O or S;
R1is an optionally substituted five membered heteroaryl;
R2hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;
R3is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl) alkyl;
R4is hydrogen, amino, optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, heteroalkyl, (heterocyclyl) alkyl, (amino) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and carboxamide;
R5hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;
R6is hydrogen, hydroxy, alkyl, haloalkyl,Alkoxy, alkylthio, amino and fluoro.
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-1);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole-2, 4(3H) -dione (I-2);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (1-phenylethyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-3);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1-benzyl-1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-4);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-5);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-fluorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-6);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-7);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-chlorobenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-8);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (3-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-9);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- (4-methylbenzyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-10);
7- (3, 5-dimethylisoxazol-4-yl) -3-ethyl-8-methoxy-1- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) methyl) -1, 5-dihydro-2H-pyrimido [5, 4-b ] indole 2, 4(3H) -dione (I-11).
3. A process for the preparation of a compound of formula I according to claim 1, of the formula:
Figure FSA0000181449200000021
the method specifically comprises the following steps:
(1) step a, reacting a compound 1 with acetic anhydride to obtain a compound 2;
(2) step b, preparing a compound 3 from the compound 2 and 2-ethyl bromoacetate;
(3) in the step c, the compound 3 is deacetylated to prepare a compound 4;
(4) in the step d, the compound 4 reacts with ethyl isocyanate and then reacts with sodium methoxide to prepare a compound 5;
(5) step e, reacting the compound 5 with di-tert-butyl dicarbonate to prepare a compound 6;
(6) step f, preparing a compound 7 by using the compound 6 and different halogenated hydrocarbons;
(7) and step g, reacting the compound 7 with 3, 5-dimethylisoxazole-4-boric acid to prepare a compound I-1 to 11.
4. A compound of formula (II) or a pharmaceutically acceptable salt thereof:
Figure FSA0000181449200000031
wherein:
B1is-N or-C (R)10)-；
B2is-N or-C (R)11)-；
B3is-N-or-CH-;
y is O or S;
R7is an optionally substituted five membered heteroaryl;
R8is hydrogen, hydroxy, alkyl, haloAlkyl, alkoxy, alkylthio, amino and halogen;
R9is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl) alkyl
R10Hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and halogen;
R11hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino and fluorine.
5. The compound of formula II according to claim 4, wherein the compound is selected from:
7- (3, 5-dimethylisoxazol-4-yl) -1-phenyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-1);
7- (3, 5-dimethylisoxazol-4-yl) -1-benzyl-1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-2);
7- (3, 5-dimethylisoxazol-4-yl) -1- (1-phenylethyl) -1, 5-dihydro-2H-pyrido [3, 2-b ] indol-2-one (II-3).
6. The process for the preparation of the compound of formula II according to claim 4, of the formula:
Figure FSA0000181449200000041
the method specifically comprises the following steps:
(1) step h, reacting the compound 7 with tin tetrachloride and silver chloride to obtain a compound 8;
(2) step i, reacting the compound 8 with 4-methoxy benzyl chloride to obtain a compound 9;
(3) step j is that the compound 9 reacts with hydroxylamine hydrochloride and sodium ethoxide to prepare a compound 10;
(4) step k, reacting the compound 10 with aluminum trichloride to obtain a compound 11;
(5) step l, reacting the compound 11 with different halogenated hydrocarbons to obtain a compound 12;
(6) m is that the compound 12 reacts with phosphorus oxychloride and N, N-dimethylformamide to close the ring and prepare a compound 13;
(7) step n is that the compound 13 reacts with 3, 5-dimethylisoxazole-4-boric acid to prepare a compound 14;
(8) step o is the reaction of compound 14 with trifluoroacetic acid to give compound II-1 to 3.
7. Use of a compound of formula I according to any one of claims 1 or a pharmaceutically acceptable salt thereof and a compound of formula II according to any one of claims 2 or a pharmaceutically acceptable salt thereof as BET bromodomain inhibitors for the treatment of cancer.
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