CN111362925B - 4-pyrimidine formamide compound, pharmaceutical composition, preparation method and application - Google Patents

4-pyrimidine formamide compound, pharmaceutical composition, preparation method and application Download PDF

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CN111362925B
CN111362925B CN202010453727.0A CN202010453727A CN111362925B CN 111362925 B CN111362925 B CN 111362925B CN 202010453727 A CN202010453727 A CN 202010453727A CN 111362925 B CN111362925 B CN 111362925B
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CN111362925A (en
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王永广
黄巧萍
万晓梦
苏小庭
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention belongs to the technical field of biological medicines, and provides a 4-pyrimidine carboxamide compound, a pharmaceutical composition, a preparation method and an application thereof, wherein the 4-pyrimidine carboxamide compound is a compound with a structure shown in formula I, a stereoisomer or a pharmaceutically acceptable salt, a hydrate, a solvate and an isotope compound thereof. The structure of the formula I is as follows:
Figure 978105DEST_PATH_IMAGE001
wherein R is1Represents methoxyethyl, 2-amino-2-oxoethyl or 2-hydroxy-2-methylpropyl, R2Represents a substituted or unsubstituted benzene ring or an aromatic heterocyclic ring. The 4-pyrimidine formamide compound can be used as an effective IDH inhibitor, and meanwhile, the pharmaceutical composition of the compound has good multiple anti-tumor pharmacological activities.

Description

4-pyrimidine formamide compound, pharmaceutical composition, preparation method and application
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a 4-pyrimidine formamide compound, a pharmaceutical composition, a preparation method and application.
Background
Cancer is one of the major diseases threatening human health, and the main treatment modalities of cancer at present include drug therapy, surgical therapy, radiation therapy, etc., wherein drug therapy is one of the most common treatment modalities. The traditional cytotoxic drugs can not distinguish tumor cells from normal cells, so that serious side effects are often caused, and the targeted drugs take the tumor cells as specific targets, can accurately act on tumors, can greatly improve the treatment level of cancers and can effectively reduce the adverse reaction rate.
The Isocitrate Dehydrogenase (IDH) family includes three members: IDH1 dependent on NADP (Nicotinamide Adenine Dinucleotide Phosphate) cytoplasm, IDH2 dependent on NADP mitochondria and IDH3 dependent on NAD mitochondria, which are rate-limiting enzymes of the tricarboxylic acid cycle by means of the accessory factor NAD+And NADP+Catalyzes the oxidative decarboxylation of isocitric acid to α -ketoglutaric acid (α -KG).
The IDH2 mutation is associated with various cancers, such as acute myelogenous leukemia and the like, and the IDH2 mutation includes R140 and R172 and the like, and these mutations occur at or near critical residues in the active site. Studies have shown that mutations in IDH2 present in cancer cells result in the enzyme's ability to catalyze the reduction of α -ketoglutarate-dependent resistance to 2-hydroxyglutarate (2-HG), and that high levels of 2-HG resulting from IDH2 mutations can promote the formation and progression of cancer. Therefore, the research of IDH 2-targeted tumor drugs draws attention, and the research and discovery of new IDH inhibitors are of great significance.
Disclosure of Invention
The researchers of the invention find that the compound with the structure shown in the formula I has better IDH inhibitory activity and very good application prospect in the aspect of preparing the medicine for treating tumors. The invention aims to provide a 4-pyrimidine formamide compound, a pharmaceutical composition, a preparation method and application.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect of the invention, there is provided a compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate, isotopic compound having the structure of formula I:
Figure 927883DEST_PATH_IMAGE001
wherein R is1Represents methoxyethyl, 2-amino-2-oxoethyl or 2-hydroxy-2-methylpropyl;
R2represents a substituted or unsubstituted benzene ring or an aromatic heterocyclic ring.
In a second aspect of the present invention, there is provided a method for preparing a compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate, isotopic compound having a structure as described above with formula I, comprising the steps of:
Figure 129189DEST_PATH_IMAGE002
synthesis of intermediate IV:
dissolving a compound II with a structure of a formula II, a compound III with a structure of a formula III and a first alkali in a first reaction solvent, reacting at a first preset temperature, adding water after the reaction is finished, extracting and drying by using a first organic solvent, and carrying out chromatographic separation after concentration to obtain an intermediate IV with a structure of a formula IV;
synthesis of the final product I:
and dissolving the intermediate IV, the compound with the structure of the formula V, a catalyst, a ligand and a second alkali in a second reaction solvent, reacting at a second preset temperature, quenching the reaction with water after the reaction is finished, extracting with a second organic solvent, and performing column chromatography on an organic layer to obtain a final product I with the structure of the formula I.
In one embodiment, the first base is one, two or more selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide;
the second alkali is one or two or more of cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate.
In one embodiment, the first reaction solvent is dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), Dimethylacetamide (DMA), or acetonitrile, and the first organic solvent is ethyl acetate;
the second reaction solvent is toluene, dimethyl sulfoxide, dimethylformamide or dimethylacetamide, and the second organic solvent is ethyl acetate.
In one embodiment, the catalyst is selected from bis (triphenylphosphine) palladium (II) dichloride (formula abbreviated as PdCl)2(PPh3)2) Tetrakis (triphenylphosphine) palladium (formula abbreviated as Pd (PPh))3)4) Bis (dibenzylideneacetone) palladium (molecular formula is abbreviated as Pd (dba))2) Palladium acetate (molecular formula is abbreviated as Pd (OAc))2) 1,1' - [ bis (diphenylphosphino) ferrocene]Palladium dichloride (molecular formula abbreviated as Pd (dppf))2Cl2) One, two or more;
the ligand is selected from one, two or more of triphenylphosphine, tributyl, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (SPhos) and 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (XantPhos).
In one embodiment, the first preset temperature is 20 ℃ to 100 ℃, and the second preset temperature is 80 ℃ to 120 ℃.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound thereof, as described above, and a pharmaceutically acceptable carrier or diluent.
In a fourth aspect of the present invention, there is provided a use of a substance in the manufacture of a medicament for the treatment of a tumour, the substance comprising a compound having a structure according to formula I as described above, a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound thereof;
or, the substance comprises a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound thereof, as described above, as an active ingredient;
alternatively, the substance comprises a pharmaceutical composition as described above.
In one embodiment, the tumor is selected from:
skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, fibrosarcoma.
In a fifth aspect of the present invention, there is provided a compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate, isotopic compound thereof, selected from the group consisting of compounds having the following structure:
structure of compound Name of Compound Structure of compound Name of Compound
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 25
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Figure 749745DEST_PATH_IMAGE023
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Figure 990233DEST_PATH_IMAGE024
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Figure 675293DEST_PATH_IMAGE025
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Figure 723331DEST_PATH_IMAGE027
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Figure 900552DEST_PATH_IMAGE029
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Figure 872367DEST_PATH_IMAGE031
 15 Picture 65
Figure 579292DEST_PATH_IMAGE032
 30
The invention has the following beneficial effects:
(1) the invention provides a compound with a structure shown in formula I, which can be used as an effective IDH inhibitor.
(2) The pharmaceutical composition provided by the invention has good multiple anti-tumor physical activities.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Some of the embodiments of the invention are defined as follows:
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises:
acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, or the like;
alternatively, salts are formed when the acid proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinated with an organic base; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
"pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or a physiologically acceptable salt thereof with other chemical ingredients such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
"carrier" when used herein refers to a carrier or diluent that does not significantly stimulate the organism and does not abrogate the biological activity and properties of the administered compound.
"method" refers to manners, means, techniques and procedures for accomplishing a specified task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of chemistry, pharmacy, biology, biochemistry and medicine.
The compounds of the invention may have one or more asymmetric centers and may thus be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include the individual enantiomers as well as racemic or other mixtures thereof. Methods for determining stereochemical configuration and separating stereoisomers are well known in the art (see the discussion in chapter 4 of Advanced Organic Chemistry, 4 th edition, j. March, John Wiley and Sons, New York, 1992). Thus, the present invention also encompasses any stereoisomeric form, its corresponding enantiomers (d-and l-or (+) and (-) isomers) and its diastereoisomers and mixtures thereof having the ability to inhibit IDH and is not limited to any one stereoisomeric form.
Example 1
6- ((2-hydroxy-2-methylpropyl) amino) -2- (3-oxo-4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 238943DEST_PATH_IMAGE033
The first step is as follows:
a mixture of compound 1a (38.2 g, 200.0 mmol), compound 1b (17.8 g, 200.0 mmol), and K2CO3(30.4g, 220.0mmol) in DMF (400 ml) and reacted at 60 ℃ for 8 hours, Thin Layer Chromatography (TLC) detection, water (300 ml) was added after the reaction was completed, extraction was performed twice with ethyl acetate (300 ml), the organic layer was dried and concentrated to give a chromatographic separationCompound 1c, 40.3g, was obtained in 82.6% yield, as an off-white solid, compound 1 c.
The second step is that:
compound 1c (2.4 g, 10.0 mmol), compound 1d (2.4 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.6g of a pale yellow solid, yield 57.5%, ESI (+) m/z = 453.2.
Example 2
2- (4- (3-aminocarbonylphenyl) -3-oxopiperazin-1-yl) -6- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-4-carboxamide
Figure 932093DEST_PATH_IMAGE034
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.3g of a pale yellow solid, yield 53.9%, ESI (+) m/z = 428.2.
Example 3
6- ((2-hydroxy-2-methylpropyl) amino) -2- (3-oxo-4- (3- (trifluoromethoxy) phenyl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 603377DEST_PATH_IMAGE035
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 3a (2.6 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 3.0g of a pale yellow solid, yield 64.2%, ESI (+) m/z = 469.2.
Example 4
6- ((2-hydroxy-2-methylpropyl) amino) -2- (4- (2-methoxypyridin-4-yl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 622148DEST_PATH_IMAGE036
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.2g of a pale yellow solid, yield 53.0%, ESI (+) m/z = 416.2.
Example 5
6- ((2-hydroxy-2-methylpropyl) amino) -2- (3-oxo-4- (2- (trifluoromethyl) pyridin-4-yl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 362571DEST_PATH_IMAGE037
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 5a (2.5 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.1g of a pale yellow solid, yield 46.4%, ESI (+) m/z = 454.2.
Example 6
2- (4- (3-cyanophenyl) -3-oxopiperazin-1-yl) -6- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-4-carboxamide
Figure 859411DEST_PATH_IMAGE038
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 6a (2.0 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.9g of a pale yellow solid with a yield of 70.9%, ESI (+) m/z = 410.2.
Example 7
2- (4- (3, 4-difluorophenyl) -3-oxopiperazin-1-yl) -6- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-4-carboxamide
Figure 775415DEST_PATH_IMAGE039
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 7a (2.1 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.8g of a pale yellow solid, yield 66.7%, ESI (+) m/z = 421.2.
Example 8
2- (4- (5-Fluoropyridin-3-yl) -3-oxopiperazin-1-yl) -6- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-4-carboxamide
Figure 574875DEST_PATH_IMAGE040
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 8a (2.0 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.5g of a pale yellow solid with a yield of 62.0%, ESI (+) m/z = 404.2.
Example 9
6- ((2-hydroxy-2-methylpropyl) amino) -2- (3-oxo-4- (pyrimidin-5-yl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 943539DEST_PATH_IMAGE041
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 9a (1.8 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 3.0g of a pale yellow solid, yield 77.7%, ESI (+) m/z = 387.2.
Example 10
2- (4- (1H-benzo [ d ] imidazol-6-yl) -3-oxopiperazin-1-yl) -6- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-4-carboxamide
Figure 103125DEST_PATH_IMAGE042
Compound 1c was synthesized according to the procedure of the first step of example 1.
Compound 1c (2.4 g, 10.0 mmol), compound 10a (2.2 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.6g of a pale yellow solid, yield 61.3%, ESI (+) m/z = 425.2.
Example 11
6- ((2-amino-2-oxoethyl) amino) -2- (3-oxo-4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 873635DEST_PATH_IMAGE043
The first step is as follows:
a mixture of compound 1a (38.2 g, 200.0 mmol), compound 11a (14.8 g, 200.0 mmol), and K2CO3(30.4g, 220.0mmol) was dissolved in DMF (400 ml) and reacted at 60 ℃ for 8 hours, the reaction was checked by TLC, after the reaction was complete, water (300 ml) was added and extracted twice with ethyl acetate (500 ml), the organic layer was dried and concentrated to give compound 11b33.5g, yield 73.1% and compound 11b as an off-white solid.
The second step is that:
compound 11b (2.3 g, 10.0 mmol), compound 1d (2.4 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.3g of a pale yellow solid, yield 52.6%, ESI (+) m/z = 438.1.
Example 12
6- ((2-amino-2-oxoethyl) amino) -2- (4- (3-aminocarbonylphenyl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 843996DEST_PATH_IMAGE044
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.7g of a pale yellow solid, yield 65.5%, ESI (+) m/z = 413.2.
Example 13
6- ((2-amino-2-oxoethyl) amino) -2- (3-oxo-4- (3- (trifluoromethoxy) phenyl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 434377DEST_PATH_IMAGE045
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 3a (2.6 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.8g of a pale yellow solid, yield 61.8%, ESI (+) m/z = 454.1.
Example 14
6- ((2-amino-2-oxoethyl) amino) -2- (4- (2-methoxypyridin-4-yl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 397654DEST_PATH_IMAGE046
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.6g of a pale yellow solid, yield 65.0%, ESI (+) m/z = 401.2.
Example 15
6- ((2-amino-2-oxoethyl) amino) -2- (3-oxo-4- (2- (trifluoromethyl) pyridin-4-yl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 288250DEST_PATH_IMAGE047
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 5a (2.5 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.2g of a pale yellow solid with a yield of 50.2%, ESI (+) m/z = 439.1.
Example 16
6- ((2-amino-2-oxoethyl) amino) -2- (4- (3-cyanophenyl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 554146DEST_PATH_IMAGE048
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 6a (2.0 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.4g of a pale yellow solid, yield 61.1%, ESI (+) m/z = 394.2.
Example 17
6- ((2-amino-2-oxoethyl) amino) -2- (4- (3, 4-difluorophenyl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 772769DEST_PATH_IMAGE049
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 7a (2.1 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.1g of a pale yellow solid, yield 51.9%, ESI (+) m/z = 406.1.
Example 18
6- ((2-amino-2-oxoethyl) amino) -2- (4- (5-fluoropyridin-3-yl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 149524DEST_PATH_IMAGE050
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 8a (2.0 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.7g of a pale yellow solid, yield 69.6%, ESI (+) m/z = 389.1.
Example 19
6- ((2-amino-2-oxoethyl) amino) -2- (3-oxo-4- (pyrimidin-5-yl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 753680DEST_PATH_IMAGE051
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 9a (1.8 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.5g of a pale yellow solid, yield 67.4%, ESI (+) m/z = 372.1.
Example 20
2- (4- (1H-benzo [ d ] imidazol-6-yl) -3-oxopiperazin-1-yl) -6- ((2-methoxyethyl) amino) pyrimidine-4-carboxamide
Figure 456057DEST_PATH_IMAGE052
Compound 11b was synthesized according to the procedure of the first step of example 11.
Compound 11b (2.3 g, 10.0 mmol), compound 10a (2.2 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.2g of a pale yellow solid, yield 52.6%, ESI (+) m/z = 410.2.
Example 21
2- (4- (3-cyanophenyl) -3-oxopiperazin-1-yl) -6- ((2-methoxyethyl) amino) pyrimidine-4-carboxamide
Figure 21031DEST_PATH_IMAGE053
The first step is as follows:
a mixture of compound 1a (38.2 g, 200.0 mmol), compound 21a (15.0 g, 200.0 mmol), and K2CO3(30.4g, 220.0mmol) was dissolved in DMF (400 ml) and reacted at 60 ℃ for 8 hours, the reaction was checked by TLC, after completion of the reaction, water (300 ml) was added, extraction was carried out twice with ethyl acetate (50 ml), the organic layer was dried and concentrated to give compound 21b30.6g, yield 66.5%, and compound 21b was an off-white solid.
The second step is that:
compound 21b (2.3 g, 10.0 mmol), compound 6a (2.0 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.8g of a pale yellow solid with a yield of 63.9%, ESI (+) m/z = 396.2.
Example 22
2- (4- (3, 4-difluorophenyl) -3-oxopiperazin-1-yl) -6- ((2-methoxyethyl) amino) pyrimidine-4-carboxamide
Figure 76843DEST_PATH_IMAGE054
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 7a (2.1 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.2g of a pale yellow solid, yield 54.2%, ESI (+) m/z = 407.2.
Example 23
2- (4- (5-Fluoropyridin-3-yl) -3-oxopiperazin-1-yl) -6- ((2-methoxyethyl) amino) pyrimidine-4-carboxamide
Figure 942030DEST_PATH_IMAGE055
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 8a (2.0 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.5g of a pale yellow solid with a yield of 64.3%, ESI (+) m/z = 390.2.
Example 24
6- ((2-methoxyethyl) amino) -2- (3-oxo-4- (pyrimidin-5-yl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 674363DEST_PATH_IMAGE056
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 9a (2.4 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.4g of a pale yellow solid, yield 64.5%, ESI (+) m/z = 373.2.
Example 25
2- (4- (1H-benzo [ d ] imidazol-6-yl) -3-oxopiperazin-1-yl) -6- ((2-methoxyethyl) amino) pyrimidine-4-carboxamide
Figure 461053DEST_PATH_IMAGE057
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 10a (2.2 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.7g of a pale yellow solid, yield 65.9%, ESI (+) m/z = 411.2.
Example 26
6- ((2-methoxyethyl) amino) -2- (3-oxo-4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 710769DEST_PATH_IMAGE058
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 1d (2.4 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 3.0g of a pale yellow solid, yield 68.5%, ESI (+) m/z = 439.2.
Example 27
2- (4- (3-aminocarbonylphenyl) -3-oxopiperazin-1-yl) -6- ((2-methoxyethyl) amino) pyrimidine-4-carboxamide
Figure 57829DEST_PATH_IMAGE059
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 2a (2.2 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.6g of a pale yellow solid, yield 63.0%, ESI (+) m/z = 414.2.
Example 28
6- ((2-methoxyethyl) amino) -2- (3-oxo-4- (3- (trifluoromethoxy) phenyl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 836429DEST_PATH_IMAGE060
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 3a (2.6 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.5g of a pale yellow solid, yield 55.1%, ESI (+) m/z = 455.2.
Example 29
6- ((2-methoxyethyl) amino) -2- (4- (2-methoxypyridin-4-yl) -3-oxopiperazin-1-yl) pyrimidine-4-carboxamide
Figure 235049DEST_PATH_IMAGE061
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 4a (2.1 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.4g of a pale yellow solid, yield 59.9%, ESI (+) m/z = 402.2.
Example 30
6- ((2-methoxyethyl) amino) -2- (3-oxo-4- (2- (trifluoromethyl) pyridin-4-yl) piperazin-1-yl) pyrimidine-4-carboxamide
Figure 22877DEST_PATH_IMAGE062
Compound 21b was synthesized according to the procedure of the first step of example 21.
Compound 21b (2.3 g, 10.0 mmol), compound 5a (2.5 g, 10.0 mmol), palladium acetate (122 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), cesium carbonate (3.9 g, 12.0 mmol) were dissolved in DMF (50 ml), and then the reaction was stirred at 100 ℃ for 8 hours, followed by TLC detection, after completion of the reaction, quenching with water (40 ml), followed by two extractions with ethyl acetate (50 ml), and column chromatography of the organic layer gave 2.8g of a pale yellow solid, yield 63.9%, ESI (+) m/z = 440.2.
Example 31
IDH2 inhibitory Activity assay
The buffer (50 mM Tris-HCl pH7.5, 40. mu.M isocitrate, 20. mu.M NADP)+、2mM MnCl2And 100nM recombinant IDH2 wild-type protein) were placed in sample wells, 1. mu.L each of the compounds diluted to different concentrations was added to the sample wells, absorbance was measured by fluorescence spectroscopy, and IC was calculated50The results are shown in the following table.
A＜50nM，50 nM≤B≤500 nM，500 nM＜C
Examples IC50（IDH2） Examples IC50（IDH2）
Compound 1 B Compound 16 B
Compound 2 B Compound 17 B
Compound 3 C Compound 18 A
Compound 4 A Compound 19 A
Compound 5 A Compound 20 C
Compound 6 A Compound 21 B
Compound 7 C Compound 22 A
Compound 8 C Compound 23 C
Compound 9 B Compound 24 A
Compound 10 B Compound 25 B
Compound 11 A Compound 26 C
Compound 12 B Compound 27 B
Compound 13 A Compound 28 B
Compound 14 C Compound 29 A
Compound 15 A Compound 30 C
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (10)

1. A compound, stereoisomer or pharmaceutically acceptable salt, isotopic compound having the structure of formula I:
Figure FDA0002596943720000011
wherein R is1Represents methoxyethyl, 2-amino-2-oxoethyl or 2-hydroxy-2-methylpropyl;
R2represents a benzene ring or an aromatic heterocycle.
2. A process for the preparation of a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, isotope thereof, according to claim 1, comprising the steps of:
Figure FDA0002596943720000012
synthesis of intermediate IV:
dissolving a compound II with a structure of a formula II, a compound III with a structure of a formula III and a first alkali in a first reaction solvent, reacting at a first preset temperature, adding water after the reaction is finished, extracting and drying by using a first organic solvent, and carrying out chromatographic separation after concentration to obtain an intermediate IV with a structure of a formula IV;
synthesis of the final product I:
and dissolving the intermediate IV, the compound with the structure of the formula V, a catalyst, a ligand and a second alkali in a second reaction solvent, reacting at a second preset temperature, quenching the reaction with water after the reaction is finished, extracting with a second organic solvent, and performing column chromatography on an organic layer to obtain a final product I with the structure of the formula I.
3. The method according to claim 2, wherein the first base is one, two or more selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide;
the second alkali is one or two or more of cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate.
4. The method according to claim 2, wherein the first reaction solvent is dimethyl sulfoxide, dimethylformamide, dimethylacetamide, or acetonitrile, and the first organic solvent is ethyl acetate;
the second reaction solvent is toluene, dimethyl sulfoxide, dimethylformamide or dimethylacetamide, and the second organic solvent is ethyl acetate.
5. The process according to claim 2, wherein the catalyst is one, two or more selected from the group consisting of bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, palladium acetate, 1' - [ bis (diphenylphosphino) ferrocene ] palladium dichloride;
the ligand is selected from one, two or more of triphenylphosphine, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.
6. The method of claim 2, wherein the first predetermined temperature is 20 ℃ to 100 ℃ and the second predetermined temperature is 80 ℃ to 120 ℃.
7. A pharmaceutical composition comprising a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, isotopic compound of claim 1, and a pharmaceutically acceptable carrier or diluent.
8. Use of a substance comprising a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, an isotopic compound of claim 1, in the manufacture of a medicament for the treatment of a tumour;
or,
a pharmaceutical composition comprising a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, an isotopic compound of claim 1 as an active ingredient;
or,
the substance comprising the pharmaceutical composition of claim 7.
9. The use of claim 8, wherein the tumor is selected from the group consisting of:
skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, renal parenchymal cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, fibrosarcoma.
10. A compound, stereoisomer or a pharmaceutically acceptable salt, isotope thereof, selected from compounds having the following structure:
Figure FDA0002596943720000031
Figure FDA0002596943720000041
Figure FDA0002596943720000051
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