CN114805350B - Benzo heterocycle-pyridone derivative, and preparation method and application thereof - Google Patents

Benzo heterocycle-pyridone derivative, and preparation method and application thereof Download PDF

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CN114805350B
CN114805350B CN202210609107.0A CN202210609107A CN114805350B CN 114805350 B CN114805350 B CN 114805350B CN 202210609107 A CN202210609107 A CN 202210609107A CN 114805350 B CN114805350 B CN 114805350B
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张力丹
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Abstract

The invention provides a benzo heterocycle-pyridone derivativeAnd a preparation method and application thereof, belonging to the pharmaceutical field. The structure of the benzoheterocycle-pyridone derivative is shown as a formula I. Experimental results show that the compound can effectively inhibit the activity of EZH2 or BRD4, and particularly the compounds 1-3 and 5 can simultaneously effectively inhibit the activity of EZH2 and BRD 4. Therefore, the compound can be used for preparing EZH2 and/or BRD4 inhibitors, and medicines for preventing and/or treating diseases related to EZH2 and/or BRD4 activity (including but not limited to follicular lymphoma, diffuse large B cell lymphoma, breast cancer, lung cancer, colorectal cancer, prostatic cancer, gastric cancer, inflammation, pancreatic cancer, cardiovascular diseases, central nervous system diseases and immunodeficiency virus infection), and has wide application prospect.

Description

Benzo heterocycle-pyridone derivative, and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a benzo heterocycle-pyridone derivative, a preparation method and application thereof.
Background
Malignant tumors are one of the diseases with highest mortality in the world, and the development mechanism thereof is always one of hot spots of biomedical research. Drosophila zeste gene enhancer homolog 2 (enhancer of zeste homolog, EZH 2) is a histone methyltransferase that regulates normal physiological functions of cells by catalyzing methylation of histone H3 lysine 27 (H3K 27) to control expression of various genes. Various human diseases (e.g., cancer, inflammation, etc.) are associated with EZH2 imbalance, and EZH2 overexpression can lead to the development and progression of cancer. Dysregulation of EZH2 exists in a variety of cancers, such as follicular lymphoma and diffuse large B-cell lymphoma, and is associated with clinically poor prognosis and efficacy. In addition, EZH2 disorders are also common in solid tumors such as breast cancer, lung cancer, colorectal cancer, prostate cancer, and gastric cancer.
GSK126 is a representative EZH2 inhibitor, and has obvious regulation effect on the over expression of EZH2 genes. Research has reported that GSK126 has better prevention and treatment effects on non-solid tumors. However, GSK126 is not ideal for solid tumors, greatly limiting its clinical studies and applications. It was found that the EZH2 inhibitor induces activated H3K27 acetylation (H3K 27 ac) which is an important cause of solid tumor resistance to EZH2 inhibitors.
Bromodomain protein 4 (bromodomain-containing protein, brd 4), another important highly proprietary target in the epigenetic family, recognizes and binds to acetylated lysine residues on histones (acetylated lysine residues, KAc) as a transcription cofactor, recruits proteins to the vicinity of promoters and enhancers, and regulates transcription processes by coupling to RNA polymerase II (RNAP II), promoting aberrant expression of oncogenes such as c-Myc, NF- κb, aurora B, PAX5, and BCL-XL, and regulating expression of downstream effector proteins involved in disease development. Various human diseases, such as cancer, inflammation, cardiovascular diseases, central Nervous System (CNS) diseases and Human Immunodeficiency Virus (HIV) infections, etc., are associated with BRD4 disorders, and it has been found that BRD4 inhibitors have better control effects on a variety of solid tumors including pancreatic cancer.
In order to improve the therapeutic effect of the medicine and expand the applicable indication range of the medicine, the development of the EZH2/BRD4 double-target inhibitor has important significance.
Disclosure of Invention
The invention aims to provide a benzo heterocycle-pyridone derivative, a preparation method and application thereof.
The invention specifically provides a compound shown as a formula I, or pharmaceutically acceptable salts, stereoisomers, solvates and deuterated compounds thereof:
x is selected from C 1-6 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, LZ; l is selected from 1-3 methylene groups, Z is selected from 3-6 membered saturated cycloalkyl and 3-6 membered saturated heterocyclic group;
y is selected from hydrogen, C 1-6 An alkyl group;
w is selected from CH or N;
R 1 selected from hydrogen, C 1-6 Alkyl, R 2 Selected from hydrogen, C 1-6 An alkyl group; or R is 1 And R is R 2 Connected into a ring;
R 3 selected from hydrogen, C 1-6 An alkyl group;
R 4 selected from hydrogen, C 1-6 An alkyl group.
Further, the structure of the compound is shown as a formula II:
wherein X is selected from C 1-5 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, LZ; l is selected from 1-2 methylene groups, Z is selected from 3-6 membered saturated cycloalkyl and 3-6 membered saturated heterocyclic group;
y is selected from hydrogen, C 1-3 An alkyl group;
w is selected from CH or N.
Further, the structure of the compound is shown in a formula III:
wherein X is selected from C 1-5 Alkyl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclyl, LZ; l is selected from 1-2 methylene groups, Z is selected from 5-6 membered saturated cycloalkyl and 5-6 membered saturated heterocyclic group.
Further, the structure of the compound is shown as a formula IV:
wherein X is selected from C 1-5 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, LZ; l is selected from 1-2 methylene groups, Z is selected from 3-6 membered saturated cycloalkyl and 3-6 membered saturated heterocyclic group;
y is selected from hydrogen, C 1-3 An alkyl group;
w is selected from CH or N.
Further, the structure of the compound is shown as a formula V:
wherein X is selected from C 1-5 Alkyl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclyl, LZ; l is selected from 1-2 methylene groups, Z is selected from 5-6 membered saturated cycloalkyl and 5-6 membered saturated heterocyclic group.
Further, the compound is selected from:
the invention also provides a method for preparing the compound, which comprises the following steps:
(1) Carrying out hydrolysis reaction on the compound I-1 to obtain a compound I-2;
(2) Reacting the compound I-2 with a compound I-3 to obtain I-4;
(3) Reacting the compound I-4 with a compound I-5, and then deprotecting to obtain a compound shown in the formula I;
therein, X, Y, W, R 1 -R 4 As described above; t is halogen, preferably bromine; r is R 5 The amino protecting group is preferably p-toluenesulfonyl.
The invention also provides a medicine for preventing and/or treating diseases related to EZH2 and/or BRD4 activity, which is a preparation prepared by taking the compound or pharmaceutically acceptable salts, stereoisomers, solvates and deuterated compounds thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound or pharmaceutically acceptable salts, stereoisomers, solvates and deuterated compounds thereof in preparing the EZH2 and/or BRD4 inhibitor.
Further, the EZH2 and/or BRD4 inhibitor is a medicament for preventing and/or treating diseases related to EZH2 and/or BRD4 activity; preferably, the disease associated with EZH2 and/or BRD4 activity is follicular lymphoma, diffuse large B-cell lymphoma, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, inflammation, pancreatic cancer, cardiovascular disease, central nervous system disease, immunodeficiency virus infection;
more preferably, the pancreatic cancer is metastatic pancreatic cancer or orthotopic pancreatic cancer.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for terms herein apply to the terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1-6 Alkyl refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms.
Halogen is fluorine, chlorine, bromine or iodine.
"deuterated compound" refers to a compound obtained by substituting one or more hydrogen atoms in the compound with deuterium.
By "pharmaceutically acceptable" is meant that the carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
"salts" are acidic and/or basic salts formed with inorganic and/or organic acids and/or bases of a compound or stereoisomer thereof, and also include zwitterionic salts (inner salts) and also include quaternary ammonium salts, for example alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of an acid or base. These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
The pharmaceutically acceptable salt of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salt of the compound.
Experimental results show that the compound can effectively inhibit the activity of EZH2 or BRD4, and particularly the compounds 1-3 and 5 can simultaneously effectively inhibit the activity of EZH2 and BRD 4. Thus, the compounds of the present invention may be used in the preparation of EZH2 and/or BRD4 inhibitors, and in the prevention and/or treatment of diseases associated with EZH2 and/or BRD4 activity, including but not limited to follicular lymphoma, diffuse large B-cell lymphoma, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, inflammation, pancreatic cancer, cardiovascular disease, central nervous system disease, immunodeficiency virus infection.
Proliferation inhibition activity experiments on tumor cell lines further prove that the compound can effectively inhibit the activity of AsPC-1 (human metastatic pancreatic cancer cells) and BxPC-3 (human in-situ pancreatic cancer cells). Thus, the compounds of the present invention can be used for the preparation of a medicament for the prevention and/or treatment of pancreatic cancer (including metastatic pancreatic cancer or pancreatic cancer in situ).
The preparation method of the compound is simple, the raw materials are easy to obtain, the compound is suitable for industrial production, and the application prospect is wide.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The invention is further illustrated below with reference to examples. The examples are intended to be illustrative of the invention only and are not intended to be limiting in any way.
Example 1: preparation of 1- (sec-butyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 1)
Step 1 preparation of intermediate methyl-6-bromo-1-sec-butyl-1H-indole-4-carboxylic acid methyl ester
Sodium hydride (5.66 g,141.7 mmol) was placed in DMF (100 ml) of methyl 6-bromo-4-indolecarboxylate (30 g,118.1 mmol), stirred in ice for 20 min, 2-bromopentane (29.1 g,22.5 mmol) was added while maintaining the ice, the ice was removed, and the reaction was allowed to warm to room temperature overnight by TLC. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product in 40% yield.
Step 2. Preparation of intermediate 6-bromo-1H-indole-4-carboxylic acid
methyl-6-bromo-1-sec-butyl-1H-indole-4-carboxylate (2.54 g,10 mmol) as an intermediate was dissolved in ethanol (25 ml), and an aqueous solution (25 ml) of sodium hydroxide (0.6 g,15 mmol) was added thereto and stirred at 60℃for 1 hour. After the TLC detection reaction is finished, the reaction solution is concentrated, water is added, 1N hydrochloric acid is slowly used for acidification until PH=3-4, and when the solid precipitation is finished, the product is obtained through suction filtration and drying, and the yield is 88%. Step 3 preparation of intermediate 6-bromo-1-sec-butyl-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole 4-carboxamide
Under the protection of nitrogen, the intermediate 6-bromo-1H-indole-4-carboxylic acid (1.42 g,5.92 mmol) was added to 25ml DMSO, N-methylmorpholine (3.14 g,31.0 mmol) was slowly added with stirring, EDCI (2.14 g,11.2 mmol), HOAt (1.52 g,11.2 mmol) were added separately, after stirring for 10 min 3- (aminomethyl) -4, 6-dimethylpyridine-2 (1H) -one (1.43 g,7.44 mmol) was added, and the system was stirred overnight to complete the reaction. Pouring the reaction solution into ice water, precipitating a large amount of solids, carrying out suction filtration, and drying a filter cake to obtain white solids, wherein the yield is 69%.
Step 4.1- (sec-butyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide preparation
6-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1-p-toluenesulfonyl-1, 6-dihydro-7H-pyrrolo [2,3-C ] pyridin-7-one (513.6 mg,1.2 mmol), 6-bromo-1-sec-butyl-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3 yl) methyl) -1H-indole 4-carboxamide (430 mg,1 mmol), sodium carbonate (381 mg,3.6 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (40 mg,0.05 mmol) were added to a round bottom flask followed by dioxane (5 mL) and water (2 mL), nitrogen replaced three times and heated at 110℃for 4 hours under nitrogen. TLC monitored the completion of the reaction, the organic solvent was spun off under reduced pressure, then diluted with water and extracted with ethyl acetate. The ethyl acetate phase was then washed with water and saturated brine, and dried over anhydrous sodium sulfate. Removing the organic solvent under reduced pressure, stirring the solid mixture with silica gel, and purifying on a 200-300 silica gel column to obtain the intermediate product. The intermediate was placed in dioxane (5 mL) and aqueous sodium hydroxide (2 m,5 mL), heated at 90 ℃ for 2 hours, TLC monitored the reaction was complete, and after spinning off the organic solvent under reduced pressure, water was added to dilute and extracted with ethyl acetate. The ethyl acetate phase was washed with water, saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the product in 23% yield.
1 H NMR(400MHz,DMSO)δ12.13(s,1H),11.57(s,1H),8.22(t,J＝5.1Hz,1H),7.80(s,1H),7.62(s,1H),7.59(d,J＝3.1Hz,1H),7.43(s,1H),7.37(t,J＝2.4Hz,1H),6.86(d,J＝3.1Hz,1H),6.48(s,1H),5.89(s,1H),4.65-4.60(m,1H),4.39(d,J＝5.0Hz,2H),3.61(s,3H),2.25(s,3H),2.12(s,3H),1.89-1.83(m,2H),1.47(d,J＝6.6Hz,3H),0.74(t,J＝7.3Hz,3H).
Example 2: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1- (pentan-2-yl) -1H-indole-4-carboxamide (Compound 2)
The title compound was obtained in 38% yield by the preparation method of example 1 using 2-bromopentane as a starting material.
1 H NMR(400MHz,DMSO)δ12.15(s,1H),11.58(s,1H),8.22(s,1H),7.80(s,1H),7.70–7.52(m,2H),7.40(d,J＝18.0Hz,2H),6.87(d,J＝2.7Hz,1H),6.49(s,1H),5.88(s,1H),4.65(t,J＝28.7Hz,1H),4.40(d,J＝4.6Hz,2H),3.62(s,3H),2.25(s,3H),2.12(s,3H),1.98–1.69(m,2H),1.47(d,J＝6.5Hz,3H),1.36–0.96(m,2H),0.82(t,J＝7.2Hz,3H).
Example 3: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1- (pentan-3-yl) -1H-indole-4-carboxamide (Compound 3)
The preparation method of example 1 was used to obtain the objective compound in 21% yield using 3-bromopentane as a starting material.
1 H NMR(400MHz,DMSO)δ12.12(s,1H),11.54(s,1H),8.20(t,J＝5.3Hz,1H),7.80(s,1H),7.71–7.50(m,1H),7.38(dd,J＝9.6,6.9Hz,1H),6.88(d,J＝3.1Hz,1H),6.45(s,1H),5.88(s,1H),4.39(d,J＝5.0Hz,2H),3.61(s,2H),2.25(s,2H),2.11(s,2H),1.87(dd,J＝10.6,5.6Hz,3H),1.23(s,2H),0.69(t,J＝7.3Hz,3H).
Example 4: preparation of 1-cyclopentyl-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 4)
The title compound was obtained in 25% yield by the preparation method of example 1 using bromocyclopentane as a starting material.
1 H NMR(400MHz,DMSO)δ12.12(s,1H),11.54(s,1H),8.20(t,J＝5.0Hz,1H),7.80(s,1H),7.62(s,1H),7.57(d,J＝3.2Hz,1H),7.42(s,1H),7.36(t,J＝2.6Hz,1H),6.83(d,J＝3.2Hz,1H),6.50(s,1H),5.88(s,1H),5.15–4.81(m,1H),4.38(d,J＝5.0Hz,2H),3.61(s,3H),2.24(s,3H),2.18(d,J＝7.6Hz,2H),2.11(s,3H),1.95–1.61(m,6H).
Example 5: preparation of 1- (cyclohexylmethyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 5)
The title compound was obtained in 29% yield by the preparation method of example 1 using bromomethylcyclohexane as a starting material.
1 H NMR(400MHz,DMSO)δ12.12(s,1H),11.54(s,1H),8.20(t,J＝5.2Hz,1H),7.74(s,1H),7.60(s,1H),7.45(d,J＝3.1Hz,1H),7.39(s,1H),7.37(t,J＝2.7Hz,1H),6.81(d,J＝3.0Hz,1H),6.50(d,J＝22.5Hz,1H),5.88(s,1H),4.38(d,J＝5.1Hz,2H),4.09(d,J＝7.1Hz,2H),3.61(s,3H),2.24(s,3H),2.11(s,3H),1.78(d,J＝22.5Hz,1H),1.62(d,J＝19.0Hz,2H),1.50(d,J＝12.5Hz,2H),1.23(m,4H),1.17–0.91(m,6H).
Example 6: preparation of 1- (sec-butyl) -N- ((1-methyl-3-oxo-2,3,5,6,6,5,6,6,7,5-hexahydroxyquinolin-4-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 6)
Reference example 1 preparation method, wherein step 3 using 4- (aminomethyl) -1-methyl-5, 6,7, 8-four hydrogen isoquinoline-3 (2H) -ketone as raw material, obtained the target compound, yield 27%.
1 H NMR(400MHz,DMSO)δ12.11(s,1H),11.56(s,1H),8.22(t,J＝4.0Hz,1H),7.79(s,1H),7.60-7.54(m,2H),7.40(s,1H),7.36(t,J＝2.7Hz,1H),6.86(d,J＝3.2Hz,1H),6.47(t,J＝4.0Hz,1H),4.76–4.65(m,1H),4.41(d,J＝5.0Hz,2H),3.61(s,3H),2.80(s,2H),2.11(s,3H),1.92-1.80(m,4H),1.64(s,4H),1.47(d,J＝6.7Hz,3H),0.81(t,J＝7.3Hz,3H).
Example 7: preparation of N- ((1-methyl-3-oxo-2, 3,5,6,7, 8-hexahydroxyquinolin-4-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1- (pentan-2-yl) -1H-indole-4-carboxamide (Compound 7)
Reference example 1 preparation method, wherein step 1 using 2-bromo pentane as raw material, step 3 using 4- (amino methyl) -1-methyl-5, 6,7, 8-four hydrogen isoquinoline-3 (2H) -ketone as raw material, to obtain the target compound, yield 21%.
1 H NMR(400MHz,DMSO)δ12.12(s,1H),11.56(s,1H),8.22(t,J＝4.0Hz,1H),7.79(s,1H),7.60-7.54(m,2H),7.40(s,1H),7.36(t,J＝2.7Hz,1H),6.86(d,J＝3.2Hz,1H),6.47(t,J＝4.0Hz,1H),4.76–4.65(m,1H),4.41(d,J＝5.0Hz,2H),3.61(s,3H),2.80(s,2H),2.38(s,2H),2.11(s,3H),1.88-1.78(m,4H),1.64(s,4H),1.47(d,J＝6.7Hz,3H),0.82(t,J＝7.3Hz,3H).
Example 8: preparation of 1- (cyclohexylmethyl) -N- ((1-methyl-3-oxo-2, 3,5,6,7, 8-hexahydroxyquinolin-4-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 8)
Reference example 1 preparation method, wherein step 1 with bromomethyl cyclohexane as raw material, step 3 with 4- (aminomethyl) -1-methyl-5, 6,7, 8-four hydrogen isoquinoline-3 (2H) -ketone as raw material, obtained the target compound, yield 34%.
1 H NMR(400MHz,DMSO)δ12.15(s,1H),11.64(s,1H),8.25(t,J＝5.0Hz,1H),7.75(s,1H),7.63(s,1H),7.44(d,J＝3.1Hz,1H),7.40(s,1H),7.37(t,J＝2.7Hz,1H),6.83(d,J＝2.9Hz,1H),6.48(t,J＝2.1Hz,1H),4.42(d,J＝4.9Hz,2H),4.08(d,J＝7.0Hz,2H),3.61(s,3H),2.80(s,2H),2.37(s,2H),2.11(s,3H),1.80(s,1H),1.63(s,6H),1.59(s,1H),1.50(d,J＝11.8Hz,2H),1.11-1.08(m,2H),1.06–0.92(m,2H).
Example 9: preparation of 1- (sec-butyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3-methyl-6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrole [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 9)
Step 1 preparation of intermediate methyl-6-bromo-1-sec-butyl-3-aldehyde-1H-indole-4-carboxylic acid methyl ester
Phosphorus oxychloride (0.83 g,5.43 mmol) was added to anhydrous DMF (50 mL) in a reaction flask under ice bath and stirred for 30 min, methyl-6-bromo-1-sec-butyl-1H-indole-4-carboxylate (1.40 g,4.53 mmol) of the product of example 1 step 1 was dissolved in DMF (50 mL), slowly added to the reaction flask and stirring was continued at room temperature for 2.5H. After the reaction was completed, it was diluted with cold water, pH was adjusted to 8 with 2N sodium hydroxide solution, extracted with ethyl acetate, and the combined organic layer was washed with cold water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product in 99% yield.
Step 2 preparation of intermediate 6-bromo-sec-butyl-3-methyl-1H-indole-4-carboxylic acid methyl ester
methyl-6-bromo-1-sec-butyl-3-aldehyde-1H-indole-4-carboxylic acid methyl ester (1.51 g,4.46 mmol) was dissolved in DMF, p-toluenesulfonic acid monohydrate (0.11 g,0.58 mmol), p-toluenesulfonic acid hydrazide (1.08 g,5.8 mmol) were added at room temperature followed by sulfolane 12ml, followed by warming to 100℃for 1 hour. The reaction solution was cooled to room temperature, sodium cyanoborohydride was added in portions, the temperature was raised to 100℃for 2 hours, then cooled to room temperature, and stirring was continued for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with cold water, brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and chromatographed to give the product in 34% yield.
Step 3 preparation of intermediate 6-bromo-sec-butyl-3-methyl-1H-indole-4-carboxylic acid
With reference to the procedure of step 2 of example 1, hydrolysis gave the title compound in 90% yield.
Step 4 preparation of intermediate 6-bromo-1-sec-butyl-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) 3-methyl-1H-indole 4-carboxamide
Referring to the procedure of step 3 of example 1, the title compound was obtained in 73% yield.
Step 5.1- (sec-butyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3-methyl-6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide preparation
The procedure of example 1, step 4, was followed to afford the title compound in 24% yield.
1 H NMR(400MHz,DMSO)δ12.10(s,1H),11.45(s,1H),8.18(t,J＝4.9Hz,1H),7.64(s,1H),7.36(dd,J＝6.5,3.9Hz,2H),7.28(s,1H),7.17(s,1H),6.51(s,1H),5.86(s,1H),4.53(d,J＝7.0Hz,1H),4.35(d,J＝4.9Hz,2H),3.60(s,3H),2.24(s,3H),2.17(s,3H),2.10(s,3H),1.83(dd,J＝11.2,7.3Hz,2H),1.42(d,J＝6.7Hz,3H),0.74(t,J＝7.3Hz,3H).
Example 10: preparation of 1-cyclohexylmethyl-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3-methyl-6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 10)
The title compound was obtained in 27% yield by the method of example 9 using bromomethylcyclohexane as a starting material.
1 H NMR(400MHz,DMSO)δ12.10(s,1H),11.47(s,1H),8.15(s,1H),7.59(s,1H),7.35(s,2H),7.16(d,J＝9.1Hz,2H),6.51(s,2H),4.38(d,J＝4.7Hz,2H),3.99(d,J＝7.0Hz,2H),3.75–3.48(m,3H),2.35(d,J＝15.6Hz,3H),2.17(s,3H),2.09(s,3H),1.75(s,1H),1.63(s,2H),1.51(d,J＝13.1Hz,2H),1.23(m,4H),1.18–1.06(m,3H),0.98(d,J＝11.6Hz,6H).
Example 11: preparation of 1- (sec-butyl) -3-methyl-N- ((1-methyl-3-oxo-2,3,5,6,7,5,6,7,8-hexahydroxyquinolin-4-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 11)
The procedure of example 9 is followed, wherein step 4 is performed using 4- (aminomethyl) -1-methyl-5, 6,7, 8-tetrahydroisoquinolin-3 (2H) -one as a starting material, to obtain the objective compound in 20% yield.
1 H NMR(400MHz,DMSO)δ12.10(s,1H),11.48(s,1H),8.15(t,J＝4.9Hz,1H),7.65(s,1H),7.35(dd,J＝8.0,5.3Hz,2H),7.28(s,1H),7.18(s,1H),6.52(s,1H),4.53(d,J＝7.2Hz,1H),4.39(d,J＝4.8Hz,2H),3.60(s,3H),2.78(s,2H),2.37(s,2H),2.19(s,3H),2.09(s,3H),1.92–1.74(m,2H),1.63(s,4H),1.42(d,J＝6.6Hz,3H),0.74(t,J＝7.3Hz,3H).
Example 12: preparation of 1- (cyclohexylmethyl) -3-methyl-N- ((1-methyl-3-oxo-2,3,5,6,6,6,7,8-hexahydroxyquinolin-4-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indole-4-carboxamide (Compound 12)
The procedure of example 9 was followed, wherein step 1 was conducted using bromomethylcyclohexane as a starting material and step 4 was conducted using 4- (aminomethyl) -1-methyl-5, 6,7, 8-tetrahydroisoquinolin-3 (2H) -one as a starting material, to give the objective compound in 23% yield.
1 H NMR(400MHz,DMSO)δ12.10(s,1H),11.45(s,1H),8.18(t,J＝4.9Hz,1H),7.59(s,1H),7.43–7.24(m,1H),7.15(d,J＝8.0Hz,2H),6.47(d,J＝34.1Hz,1H),5.81(d,J＝40.1Hz,1H),4.35(d,J＝4.8Hz,2H),3.99(d,J＝6.9Hz,2H),3.60(s,3H),2.23(s,3H),2.17(d,J＝14.8Hz,3H),2.10(s,4H),1.21(d,J＝17.0Hz,4H),1.14(m,8H),0.98(m,3H).
Example 13: preparation of 1-cyclopentyl-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indazole-4-carboxamide (Compound 13)
Starting with cyclopentane bromide and 6-bromo-1H-indazole-4-carboxylic acid, the title compound was obtained in 26% yield by the method of example 1.
1 H NMR(400MHz,DMSO)δ12.23(s,1H),11.60(s,1H),8.56(s,1H),8.34(s,1H),7.96(s,1H),7.77(s,1H),7.54(s,1H),7.39(s,1H),6.54(s,1H),5.88(s,1H),5.26(s,1H),4.40(s,2H),3.62(s,3H),2.23(s,3H),2.12(s,3H),2.02-1.96(m,4H),1.92-1.88(m,2H),1.67-1.62(m,2H).
Example 14: preparation of 1-cyclopentyl-N- ((1-methyl-3-oxo-2, 3,5,6,7, 8-hexahydroxyquinolin-4-yl) methyl) -6- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-C ] pyridin-4-yl) -1H-indazole-4-carboxamide (Compound 14)
The method of example 1 was referred to, wherein step 1 was conducted using bromocyclopentane and 6-bromo-1H-indazole-4-carboxylic acid as starting materials, and step 3 was conducted using 4- (aminomethyl) -1-methyl-5, 6,7, 8-tetrahydroisoquinolin-3 (2H) -one as starting material, to obtain the objective compound in 32% yield.
1 H NMR(400MHz,DMSO)δ12.22(s,1H),11.59(s,1H),8.54(s,1H),8.34(s,1H),7.95(s,1H),7.75(s,1H),7.53(s,1H),7.38(s,1H),6.53(s,1H),5.26(t,J＝8.0Hz,1H),4.42(d,J＝4.4Hz,2H),3.61(s,3H),2.76(s,2H),2.37(s,2H),2.11-1.98(m,4H),2.07–1.94(m,2H),1.88(s,2H),1.70-1.64(m,2H),1.63(s,5H).
The beneficial effects of the compounds of the invention are demonstrated below by experimental examples.
Experimental example 1: in vitro enzyme inhibition assay
1. Experimental method
His-tagged EZH2 or BRD4 is cloned, expressed and purified to homogeneity. EZH2 or BRD4 binding and inhibition was assessed by detecting biotinylated H4-tetraacetyl peptide (AnaSpec, H4k5/8/12/16 (Ac), biotin-labeled) interactions with the target using the AlaphaScreen technique. BRD4 (2 nM final) is combined with peptide (15 nM final) in 50mM HEPES (pH 7.3), 10mM NaCl, 0.25mM TCEP, 0.1% (w/v) BSA and 0.005% (w/v) Brij-35 in 384-well ProxiPlate in the presence of a dilution series of compound in DMSO. After incubation for 20 minutes at room temperature at 25 degrees celsius, the alpha streptavidin donor and acceptor beads were added to a final concentration of 5 μg/mL. After 2 hours of equilibration, plates were read on an Envison instrument and IC was calculated using fitting 50 。
JQ1 (a known BET bromodomain inhibitor) was used as a positive control with GSK126 (a known selective EZH2 inhibitor).
2. Experimental results
Table 1 inhibitory Activity of Compounds against enzymes.
It can be seen that the compounds of the present invention are effective in inhibiting the activity of EZH2 or BRD4, and in particular that compounds 1-3, 5 are effective in inhibiting both EZH2 and BRD 4.
Experimental example 2: in vitro tumor cell inhibition assay
1. Experimental method
Pancreatic cancer cell lines AsPC-1 (human metastatic pancreatic cancer cells) and BxPC-3 (human in situ pancreatic cancer cells) were purchased from american standard collection for organisms (American Type Culture Collection, ATCC), RPMI1640 medium, and Fetal Bovine Serum (FBS) were purchased from the company GIBICO in the united states; penicillin and streptomycin were purchased from Dalianbao biosome; cultured cells were purchased from Corning company using plates, 96-well plates, etc.; centrifuge tubes of various sizes were purchased from BD company; MTT reagent was purchased from the Japan same-kernel chemical institute (Donjindo).
Cell culture conditions were all cultured with conventional high-glucose RPMI1640 complete medium containing 10% Fetal Bovine Serum (FBS), 100IU/mL penicillin, 100. Mu.g/mL streptomycin at 37℃with 5% CO 2 Is cultured in an incubator of (a).
In order to examine the proliferation effect of the novel compounds on cells. Cells in the logarithmic growth phase were collected, single cell suspensions were adjusted to a cell concentration of 1000 to 2000 cells/mL, and inoculated into 96-well plates at 100uL per well. Stock solutions of the compounds (10 mM/L in DMSO) were diluted to different concentrations with medium using a triple dilution method. Adding into 96-well plate at a volume of 100uL per well, with the highest concentration of 30uM and the lowest concentration of 0.1uM, setting 3 multiple wells per drug concentration, treating cells with culture medium containing 0.1% DMSO and pure culture medium as negative control, placing into cell incubator, culturing for 6 days, detecting mitochondrial dehydrogenase activity of cells with MTT, and calculating half-effective Inhibitory Concentration (IC) of new compound on tumor cells 50 μM) values (Table 1).
2. Experimental results
TABLE 2 proliferation inhibiting Activity of Compounds against tumor cell lines
Examples AsPC-1IC 50 (μM) BxPC-3(μM)
1 1.6 3.2
2 1.2 3.3
3 1.7 3.8
4 4.4 7.9
5 3.4 7.3
6 3.2 8.7
7 4.0 12.3
8 15.1 13.6
9 4.3 9.1
10 8.4 8.7
11 9.2 13.8
12 ＞20 ＞20
13 20.1 17.2
14 15.2 18.1
GSK126 10.2 13.7
JQ1 3.7 1.4
It can be seen that the compounds of the present invention are effective in inhibiting the activity of AsPC-1 (human metastatic pancreatic cancer cells) and BxPC-3 (human in situ pancreatic cancer cells).
In summary, a class of benzoheterocycle-pyridone derivatives, and a preparation method and application thereof are provided. Experimental results show that the compound can effectively inhibit the activity of EZH2 or BRD4, and particularly the compounds 1-3 and 5 can simultaneously effectively inhibit the activity of EZH2 and BRD 4. Thus, the compounds of the present invention may be used in the preparation of EZH2 and/or BRD4 inhibitors, and in the prevention and/or treatment of diseases associated with EZH2 and/or BRD4 activity, including but not limited to follicular lymphoma, diffuse large B-cell lymphoma, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, inflammation, pancreatic cancer, cardiovascular disease, central nervous system disease, immunodeficiency virus infection. Proliferation inhibition activity experiments on tumor cell lines further prove that the compound can effectively inhibit the activity of AsPC-1 (human metastatic pancreatic cancer cells) and BxPC-3 (human in-situ pancreatic cancer cells). Thus, the compounds of the present invention can be used for the preparation of a medicament for the prevention and/or treatment of pancreatic cancer (including metastatic pancreatic cancer or pancreatic cancer in situ).

Claims (9)

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown in a formula III:
wherein X is selected from C 1-5 Alkyl, LZ; l is selected from 1-2 methylene groups, and Z is selected from 5-6 membered saturated cycloalkyl.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the compound is selected from:
3. a process for preparing a compound according to any one of claims 1-2, characterized in that: the method comprises the following steps:
(1) Carrying out hydrolysis reaction on the compound I-1 to obtain a compound I-2;
(2) Reacting the compound I-2 with a compound I-3 to obtain I-4;
(3) Reacting the compound I-4 with a compound I-5, and then deprotecting to obtain a compound shown in a formula III;
wherein X is as defined in any one of claims 1-2; t is halogen; r is R 5 Is an amino protecting group.
4. A method according to claim 3, characterized in that: the T is bromine; r is R 5 Is p-toluenesulfonyl.
5. A medicament for preventing and/or treating diseases associated with EZH2 and BRD4 activity, characterized in that: a preparation prepared by adding pharmaceutically acceptable auxiliary materials into the compound or pharmaceutically acceptable salt thereof as active ingredient in any one of claims 1-2.
6. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the preparation of an EZH2 and BRD4 inhibitor.
7. Use according to claim 6, characterized in that: the EZH2 and BRD4 inhibitor is a medicament for preventing and/or treating diseases related to EZH2 and BRD4 activities.
8. Use according to claim 7, characterized in that: the diseases related to EZH2 and BRD4 activity are follicular lymphoma, diffuse large B cell lymphoma, breast cancer, lung cancer, colorectal cancer, prostatic cancer, gastric cancer, inflammation, pancreatic cancer, cardiovascular disease, central nervous system disease and immunodeficiency virus infection.
9. Use according to claim 8, characterized in that: the pancreatic cancer is metastatic pancreatic cancer or in situ pancreatic cancer.
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