CN114907339A - 4- (4-aminophenoxy) pyridin-2-amine derivatives and uses thereof - Google Patents
4- (4-aminophenoxy) pyridin-2-amine derivatives and uses thereof Download PDFInfo
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Abstract
The invention provides a novel 4- (4-aminophenoxy) pyridine-2-amine derivative which has a structure shown in a formula I, has an excellent inhibition effect on RIPK3, can be used as an inhibitor of RIPK3 to treat diseases related to programmed cell necrosis, and has important clinical value.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 4- (4-aminophenoxy) pyridine-2-amine derivative and application thereof.
Background
Apoptosis/programmed necrosis (necroptosis) is a new caspase-independent mode of programmed cell death discovered in recent years, distinct from apoptosis. It is regulated by death signals and presents the characteristics of a dead sample structure. Compared with apoptosis, apoptosis necrosis does not form apoptotic bodies, and chromatin does not agglomerate; apoptosis necrosis, in contrast to necrosis, is a controlled mode of cell death regulated by a variety of genes. After caspase inhibitor Z-VAD-FMK is added into the in vitro culture system, programmed necrosis of cells can be induced by adopting TNF, and the morphological characteristics of necrosis of the cells are cell swelling, cell rupture and cell content release, so that inflammation and immune response are caused. In addition to TNF, ligands for TLR3 and TLR4, certain bacterial, viral infections, etc. can cause apoptosis in cells.
Receptor interacting protein kinase 1(RIPK1) forms a necrotic body (neosome) with receptor interacting protein kinase 3(RIPK 3). RIPK3 will recruit further MLKL, and phosphorylated MLKL will oligomerize itself and then migrate to the cell membrane, "punching" the cell membrane, resulting in leakage of cellular contents and disruption of the ionization balance, ultimately leading to the occurrence of cell necrosis. Necrotic apoptosis can cause infiltration of a large number of inflammatory cells in the body due to the release of cellular contents, thereby inducing a severe inflammatory response. Necrotic apoptosis, as a new type of programmed cell death mode, plays an important role in the pathophysiological processes of various diseases such as ischemic injury, acute kidney injury, neurodegenerative disease, malignant tumor, viral infection, immunological disease and the like. The identification and discovery of small molecule inhibitors of necrotic apoptosis are of great importance in the clinical treatment of diseases associated with necrotic apoptosis.
Therefore, further research on a more efficient inhibitor of RIPK3 will further promote clinical treatment research on necrotic apoptosis-related diseases, and has very important value and application prospect.
Disclosure of Invention
The invention aims to provide a 4- (4-aminophenoxy) pyridine-2-amine derivative serving as a high-efficiency inhibitor of RIPK 3.
The invention provides a compound shown as a formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof:
wherein R is 1 Is selected from
R 2 、R 4 Each independently selected from hydrogen, hydroxy, methoxy, C 1-3 Alkyl, halogen;
R 3 is selected from
Wherein Ra and Ra' are independently selected from hydrogen and C 1-6 Alkyl, cycloalkyl;
R 5 is C having 1 to 3 substituents 5-10 Aryl or azaaryl; the substituents are respectively and independently selected from C 1-3 Alkyl, methoxy, trifluoromethyl, nitro or halogen;
R 6 is hydrogen, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or C substituted by 1 hydroxy 2-6 An alkyl group;
x is nitrogen, oxygen or sulfur.
Further, R 2 、R 4 Are each independently selected from hydrogen, C 1-3 Alkyl, fluoro, chloro, bromo.
Further, R 3 Is selected from-CORa, -CONRaRa'; wherein Ra is C 1-5 Alkyl or C 3-6 Cycloalkyl radical, Ra' is hydrogen or C 1-5 An alkyl group.
Further, R 5 Is p-trifluoromethylphenyl, p-methoxyphenyl or p-fluorophenyl.
Further, R 6 Is hydrogen, C 1-3 Alkyl or C substituted by 1 hydroxy 2-4 An alkyl group.
Still further, the compound is:
the invention also provides application of the compound or the isomer thereof or the pharmaceutically acceptable salt thereof in preparing a receptor-interacting protein kinase 3 inhibitor.
The invention also provides application of the compound or the isomer thereof or the pharmaceutically acceptable salt thereof in preparing medicines for treating inflammation, immune diseases, neurodegenerative diseases and/or tumors.
Further, the above-mentioned drugs are drugs for treating inflammation, immune diseases, neurodegenerative diseases and/or tumors associated with apoptosis.
The invention also provides a medicament which is a preparation prepared from the compound, or the stereoisomer or the pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
The experimental result shows that the compound has excellent inhibitory effect on RIPK3, can be used as an inhibitor of RIPK3, inhibits apoptosis, treats inflammation related to apoptosis and/or immune diseases, and/or neurodegenerative diseases and/or tumors, and has important clinical value.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C a-b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1-4 Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C 1-6 Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C 1-6 An alkoxy group.
"cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 6 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
"halogen" is fluorine, chlorine or bromine.
"heteroaryl" refers to an aromatic unsaturated cyclic group containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;
"trifluoromethyl" means: -CF 3 ；
"hydroxy" means: -OH
"para-trifluoromethylphenyl" means:
"p-methoxyphenyl" means:
"p-fluorophenyl" means:
"stereoisomers" include enantiomers and diastereomers.
The term "pharmaceutically acceptable" refers to a carrier, cargo, diluent, excipient, and/or salt formed generally
Chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form, and physiologically compatible with the receptor.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by mixing the above compound with a certain amount of an acid or a base as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1 Synthesis of Compound A of the invention
The reaction formula is as follows:
intermediate 1
4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-amine
Adding 1-fluoro-2, 3-dimethyl-4-nitrobenzene (5g,29.56mmol), 2-amino-4-hydroxypyridine (5.2g,47.23mmol), potassium carbonate (8.6g,62.23mmol) and DMSO (100mL) into a single-neck bottle, heating to 75 ℃ under stirring, reacting for 14 hours, naturally cooling to room temperature, slowly adding ice water, separating out a brown solid, filtering, washing a filter cake to be neutral by water, and drying to obtain 5.6g of a brown solid, wherein the yield is as follows: 73.1 percent and M +1: 260.0.
Intermediate 2
(4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
Adding 4- (2, 3-dimethyl-4-nitrophenoxy) pyridine-2-amine (1.5g,19.67mmol), triethylamine (7.95g,78.67mmol) and dichloromethane (110mL) into a single-neck bottle, cooling to 0 ℃ under stirring, dropwise adding cyclopropyl formyl chloride (4.52g,43.27mmol), naturally heating to room temperature after dropwise adding, reacting for 14 hours, pouring into water, separating, extracting an aqueous phase with dichloromethane, combining extracts, drying with magnesium sulfate, filtering, evaporating a filtrate under reduced pressure to dryness to obtain a light yellow solid 5.9g, and obtaining the yield: 91.8%, M +1: 327.8.
Intermediate 3
N- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Adding N- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide (3g,9.17mmol), ethanol (45mL) and water (7mL) into a single-neck flask, heating to 60 ℃ with stirring, adding ammonium chloride (0.49g,9.17mmol) and iron powder (2.55g,45.83mmol), reacting for one hour, cooling to room temperature, filtering, evaporating the filtrate under reduced pressure, adding dichloromethane and sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane, combining the extracts, drying with magnesium sulfate, filtering, evaporating the filtrate under reduced pressure, and purifying with silica gel (EA/PET ═ 1.1) to obtain 0.8g of light yellow solid, yield: 29.6%, M +1:298.2.
Intermediate 4
2-cyano-N- (4-methoxyphenyl) acetamide
To a one-neck flask was added 4-methoxyaniline (4g,32.48mmol), 2-cyanoacetic acid (3.32g,39.03mmol), dichloromethane (80mL), diisopropylethylamine (12.6g,97.49mmol), stirred at room temperature to a clear solution, HATU (17.3g,45.50mmol) was added, stirred at room temperature for 14 hours, the reaction solution was evaporated under reduced pressure to remove the solvent and purified with silica gel (EA/PET ═ 1.1) to give 2.7g yellow solid, yield: 43.8%, M +1:191.1.
Intermediate 5
1- (4-methoxyphenyl) -4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
Adding 2-cyano-N- (4-methoxyphenyl) acetamide (0.5g,2.63mmol), acetylacetone (0.27g,2.70mmol), absolute ethyl alcohol (10mL), piperidine (0.09g,1.06mmol) into a single-neck flask, heating to 90 ℃ under stirring, reacting for 14 hours, separating out white solid, cooling to room temperature, carrying out suction filtration, leaching a filter cake with a small amount of ethanol, draining, and drying to obtain white powder 0.62g, wherein the yield is as follows: 92.8 percent and M +1: 255.2.
Intermediate 6
(E) -4- (2- (dimethylamino) vinyl) -1- (4-methoxyphenyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
1- (4-methoxyphenyl) -4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (1.5g,5.9mmol), DMF (15mL), DMF-DMA (0.92g,7.72mmol) was added to a single-neck flask, and after heating to 110 ℃ with stirring and reacting for 6 hours, the reaction mixture was evaporated under reduced pressure to remove the solvent and recrystallized from ethanol to give 0.6g of a yellow solid, yield: 32.9%, M +1: 310.2.
Intermediate 7
8-hydroxy-2- (4-methoxyphenyl) -3-methyl-2, 7-naphthyridin-1 (2H) -one
To a single-necked flask was added 80% sulfuric acid (9mL), (E) -4- (2- (dimethylamino) vinyl) -1- (4-methoxyphenyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (0.3g,0.97mmol), and the reaction was heated to 110 ℃ with stirring for 2 hours, poured into crushed ice, and a white solid precipitated, filtered and washed with water to neutrality, and dried to give 63mg of an off-white solid, yield: 23.1%, M +1: 283.2.
Intermediate 8
8-chloro-2- (4-methoxyphenyl) -3-methyl-2, 7-naphthyridin-1 (2H) -one
Adding phosphorus oxychloride (3mL) and 8-chloro-2- (4-methoxyphenyl) -3-methyl-2, 7-naphthyridin-1 (2H) -ketone (60mg,0.21mmol) into a single-mouth bottle, heating to 110 ℃ under stirring, reacting for 2 hours, pouring the reaction liquid into crushed ice, separating out white solid, filtering, washing with water to be neutral, and drying to obtain 32mg of off-white solid, wherein the yield is as follows: 47.8%, M +1:301.2.
A compound A:
adding intermediate 8(16mg,0.0168mmol), intermediate 3(16mg,0.0168mmol) and n-butanol (3mL) into a single-neck flask, adding p-toluenesulfonic acid (10.5mg,0.0168mmol) under stirring, heating to 110 ℃ for reaction for 2 hours, evaporating the solvent under reduced pressure, and purifying by reverse phase preparative chromatography to obtain 19mg of a white solid with yield: 63.3%, 100% (UV214), M +1: 562.2. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.77(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.35-7.26 (m,2H), 7.15-7.07 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),3.84(s,3H),2.86(s,1H),2.20(s,3H),2.05(s,3H),1.97(s,4H),0.75(d, J ═ 6.3Hz,4H).
Example 2 Synthesis of Compound B of the invention
The reaction formula is as follows:
intermediate 9
2-cyano-N- (4-fluorophenyl) acetamide
Operating as a method for the synthesis of intermediate 4 gave 4.6g of yellow solid, yield: 95.8 percent, and M +1:179.2.
Intermediate 10
1- (4-fluorophenyl) -4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
The procedure was carried out to synthesize intermediate 5, yielding 2.3g of white powder: 85.2%, M +1:243.2.
Intermediate 11
(E) -4- (2- (dimethylamino) vinyl) -1- (4-fluorophenyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
The procedure was carried out to synthesize intermediate 6, yielding 0.46g of yellow powder: 25%, M +1:298.2.
Intermediate 12
2- (4-fluorophenyl) -8-hydroxy-3-methyl-2, 7-naphthyridin-1 (2H) -one
The procedure was carried out to synthesize intermediate 7 to give 140mg of off-white solid in yield: 88.2%, M +1:271.2.
Intermediate 13
8-chloro-2- (4-fluorophenyl) -3-methyl-2, 7-naphthyridin-1 (2H) -one
Operating as a method for the synthesis of intermediate 8 gave 78mg of off-white solid in yield: 52.2%, M +1:289.2.
Compound B:
n- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2, 3-dimethylphenoxypyridin-2-yl) cyclopropanecarboxamide
Prepared by the method in example 1 starting from compound 13 and compound 3 as white solids 16mg, yield: 42.1%, 97.51% (UV214), M +1: 550.2. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.77(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.35-7.26 (m,2H), 7.15-7.07 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),2.86(s,1H),2.20(s,3H),2.05(s,3H), 1.98-1.95 (m,4H),0.74(d, J ═ 6.3Hz,4H).
Example 3 preparation of Compound C of the invention
The reaction formula is as follows:
intermediate 14
2-cyano-N- (4- (trifluoromethyl) phenyl) acetamide
The procedure used to synthesize intermediate 4 gave 1.94g of a yellow solid in yield: 68.6%, M +1:229.2 intermediate 15
4, 6-dimethyl-2-oxo-1- (4- (trifluoromethyl) phenyl) -1, 2-dihydropyridine-3-carbonitrile
The procedure was carried out to synthesize intermediate 5, yielding 2.1g of white powder: 82%, M +1:293.2.
Intermediate 16
(E) -4- (2- (dimethylamino) vinyl) -6-methyl-2-oxo-1- ((4- (trifluoromethyl) phenyl) -1, 2-dihydropyridine-3-carbonitrile
The procedure was carried out to synthesize intermediate 6, yielding 0.46g of yellow powder: 46.1 percent and M +1:348.2.
Intermediate 17
8-hydroxy-3-methyl-2- (4- (trifluoromethyl) phenyl) -2, 7-naphthyridin-1 (2H) -one
The procedure used to synthesize intermediate 7 gave 141mg of off-white solid in yield: 95.6%, M +1:321.2.
Intermediate 18
8-chloro-3-methyl-2- (4- (trifluoromethyl) phenyl) -2, 7-naphthyridin-1 (2H) -one
Operating as a method for the synthesis of intermediate 8 gave 103mg of off-white solid in yield: 75% and M +1:339.2.
Compound C:
n- (4- (2, 3-dimethyl-4- ((6-methyl-8-oxo-7- (4- (trifluoromethyl) phenyl)) -7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) phenoxy) pyridin-2-yl) cyclopropanecarboxamide
Prepared according to the procedure in example 1, using compound 18 and compound 3 as reactants, 13mg of a white solid was obtained, yield: 24.4%, 97.58% (UV254), M +1: 600.2. 1H NMR (400MHz, DMSO-d6) δ 11.49(s,1H),10.78(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.61(s,1H), 7.44-7.36 (m,2H), 7.23-7.14 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),2.86(s,1H),2.20(s,3H),2.05(s,3H), 1.99-1.96 (m,4H),0.75(d, J ═ 6.3Hz,4H).
Example 4 preparation of Compound D of the invention
The reaction formula is as follows:
intermediate 19
1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid methyl ester
To a single neck flask was added 4-fluoroaniline (0.5g,4.5mmol), 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (0.714g,4.95mmol), dichloromethane (10mL), diisopropylethylamine (1.75g,13.5mmol), stirred at room temperature to a clear solution, HATU (2.4g,6.3mmol) was added, stirred at room temperature for 14 hours, the reaction solution was evaporated under reduced pressure to remove the solvent and purified with silica gel (EA/PET ═ 1.1) to give 1.14g of a white solid, yield: 100%, M +1:238.2.
Intermediate 20
1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid
Adding methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate (0.5g,2.11mmol) and methanol (18mL) into a single-neck flask, stirring at room temperature until the mixture is clear, adding an aqueous solution (3mL) of sodium hydroxide (0.11g,2.74mmol), stirring at room temperature for 14 hours, evaporating the methanol from the reaction solution under reduced pressure, adjusting the pH to 3 by using 1N hydrochloric acid, precipitating a white solid, filtering, rinsing with water to be neutral, and drying to obtain 0.34g of a white solid, wherein the yield is as follows: 72.3%, M +1:224.2.
Compound D:
n- (4- ((2- (cyclopropanecarboxamido) pyridin-4-yl) oxy) -2, 3-dimethylphenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
To a single-necked flask was added intermediate 3(20mg,0.067mmol), intermediate 20(16mg,0.067mmol), dichloromethane (4mL), diisopropylethylamine (27mg,0.202mmol), stirred at room temperature to a clear solution, HATU (36mg,0.094mmol) was added, stirred at room temperature for 14 hours, the reaction solution was evaporated under reduced pressure to remove the solvent and purified by reverse phase preparative chromatography to give 4mg of a white solid, yield: 11.8%, 96.41% (UV214), M +1: 503.2. 1H NMR (400MHz, DMSO-d6) δ 12.83(s,1H),10.79(s,1H),10.61(s,1H),8.71(s,1H), 8.28-8.07 (m,2H),7.72(dd, J ═ 8.4,5.4Hz,2H),7.30(t, J ═ 8.8Hz,2H),6.96(d, J ═ 8.9Hz,1H),6.59(dd, J ═ 5.7,2.4Hz,1H),2.30(s,3H),2.07(s,3H), 2.01-1.90 (m,1H), 1.67-1.51 (m,4H), 0.76(d, J ═ 6.1Hz,4H).
EXAMPLE 5 preparation of Compound E of the invention
The reaction formula is as follows:
intermediate 21
4- (4-fluorophenyl) -3-oxobutanoic acid ethyl ester
Adding cyclopropyl (ylidene) malonate (2g,13.88mmol), dichloromethane (40mL) and triethylamine (2.8g,27.72mmol) into a single-neck bottle, stirring at room temperature until the mixture is clear, cooling to 0 ℃, dropwise adding 4-fluorobenzeneacetyl chloride (2.63g,15.24mmol), naturally heating to room temperature and stirring for 2 hours, pouring the mixture into water, extracting with dichloromethane, combining extract liquids, adding 1N hydrochloric acid, stirring, separating liquid, washing an organic phase with water until the organic phase is neutral, adding anhydrous magnesium sulfate, drying, filtering, evaporating the solvent from a filtrate under reduced pressure, adding ethanol (50mL) and p-toluenesulfonic acid (0.48g,2.78mmol), stirring and heating to reflux for 2 hours, evaporating the solvent from the filtrate under reduced pressure, dissolving the residue with dichloromethane, washing with a saturated sodium bicarbonate solution, washing with water until the organic phase is neutral, drying the organic phase with magnesium sulfate, filtering, evaporating the solvent from the filtrate under reduced pressure, purifying with silica gel (EA/PET: 1/3) to obtain 1.8g of light yellow oil, yield: 57.9%, M +1:225.2.
Intermediate 22
5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid ethyl ester
Ethyl 4- (4-fluorophenyl) -3-oxobutyrate (1g,4.46mmol), xylene (15mL), N-dimethylformamide dimethyl acetal (1.17g,9.81mmol) were added to a single-neck flask, the mixture was heated to reflux with stirring for 6 hours, the solvent was distilled off under reduced pressure, ethanol (20mL) and ammonium acetate (0.69g,8.93mmol) were added, the mixture was heated to 60 ℃ with stirring for 14 hours, the solvent was distilled off under reduced pressure, ethyl acetate and water were added, the organic phase was washed with water until neutral, dried over magnesium sulfate, filtered, the filtrate was distilled off under reduced pressure, and purified with silica gel (EA/PET ═ 1/1) to give 0.48g of a white solid, yield: 41.4%, M +1:262.1.
Intermediate 23
5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid
Adding 5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid ethyl ester (0.1g,0.383mmol) and methanol (12mL) into a single-neck flask, stirring at room temperature until the mixture is clear, adding an aqueous solution (2mL) of sodium hydroxide (0.034g,0.842mmol), stirring at 50 ℃ for 4 hours, evaporating the methanol from the reaction solution under reduced pressure, adjusting the pH to 3 with 1N hydrochloric acid to precipitate a white solid, filtering, rinsing with water to be neutral, and drying to obtain 0.063g of the white solid, wherein the yield is as follows: 70.8 percent and M +1: 234.2.
Compound E:
n- (4- ((2- (cyclopropanecarboxamido) pyridin-4-yl) oxy) -2, 3-dimethylphenyl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide
To a single-necked flask was added compound 3(52mg,0.172mmol), intermediate 23(40mg,0.172mmol), N-dimethylformamide (2mL), diisopropylethylamine (67mg,0.515mmol), stirred at room temperature to a clear solution, HATU (98mg,0.257mmol) was added, and after stirring at room temperature for 14 hours, purified by reverse phase preparative chromatography to give 37mg of a white solid, yield: 42.1%, 97.66% (UV214), M +1: 513.2. 1H NMR (400MHz, DMSO-d6) δ 12.84(s,1H),10.79(s,1H),8.63(d, J ═ 1.6Hz,1H),8.18(dd, J ═ 13.2,7.3Hz,2H),8.09(d, J ═ 1.7Hz,1H), 7.76-7.67 (m,2H),7.58(d, J ═ 2.4Hz,1H), 7.34-7.23 (m,2H),6.97(d, J ═ 8.9Hz,1H),6.59(dd, J ═ 5.7,2.4Hz,1H),2.90(s,1H),2.30(s,3H),2.07(s,3H), 2.01-1.94 (m,1H), 0.81-0.70H (m,4H), 0.81-4H).
Example 6 preparation of Compound F of the invention
The reaction formula is as follows:
intermediate 24
5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridine-3-carboxylic acid
To a single neck flask was added ethyl 5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate (0.2g,0.766mmol), N-dimethylformamide (4mL), stirred at room temperature to a clear solution, added sodium hydride (62mg,1.531mmol, 60%), stirred at room temperature for 1 hour, added iodomethane (0.218g,1.531mmol) stirred for 14 hours, and the reaction was directly purified by reverse phase preparative chromatography to give 110mg of a white solid, yield: 58.1% and M +1: 248.2.
Compound F:
n- (4- ((2- (cyclopropanecarboxamido) pyridin-4-yl) oxy) -2, 3-dimethylphenyl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridine-3-carboxamide
To a single-necked flask was added compound 3(61mg,0.202mmol), intermediate 24(50mg,0.202mmol), N-dimethylformamide (2mL), diisopropylethylamine (79mg,0.607mmol), and stirred at room temperature to a clear solution, HATU (116mg,0.303mmol) was added, and after stirring at room temperature for 14 hours, the mixture was purified by reverse phase preparative chromatography to give 46mg of a white solid, yield: 43.2%, 97.19% (UV214), M +1: 527.2. 1H NMR (400MHz, DMSO-d6) δ 12.83(s,1H),10.79(s,1H),8.69(s,1H), 8.28-8.08 (m,3H),7.73(dd, J ═ 8.4,5.4Hz,2H),7.58(s,1H),7.30(t, J ═ 8.8Hz,2H),6.98(d, J ═ 8.9Hz,1H),6.59(dd, J ═ 5.7,2.4Hz,1H),3.93(s,3H),2.30(s,3H),2.07(s,3H), 2.01-1.90 (m,1H),0.76(d, J ═ 6.1Hz,4H).
Example 7 preparation of Compound G of the invention
The reaction formula is as follows:
compound G:
n- (4- (4- (3- (2- (4- (4-fluorophenyl) acetyl) thioureido) -2, 3-dimethylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Adding potassium thiocyanate (49mg,0.5mmol) and acetone (2mL) into a single-mouth bottle, dropwise adding a 4-fluorobenzeneacetyl chloride (86mg,0.5mmol) solution in acetone (2mL) while stirring, heating to 50 ℃, reacting for 2 hours, dropwise adding an intermediate 3(148mg,0.5mmol) solution in acetone (4mL) after reacting for 2 hours, reacting for 7 hours at 50 ℃, evaporating under reduced pressure to remove acetone, and purifying by using a reverse phase preparative chromatography system to obtain 13mg of off-white solid, wherein the yield is as follows: 5.3%, 97.69% (UV214), M +1: 493.1. 1H NMR (400MHz, DMSO-d6) δ 12.94(s,1H),10.97(s,1H),10.68(s,1H),8.74(s,1H), 8.25-8.07 (m,2H),7.73(dd, J ═ 8.4,5.4Hz,2H),7.31(t, J ═ 8.8Hz,2H),6.94(d, J ═ 8.9Hz,1H),6.61(dd, J ═ 5.7,2.4Hz,1H),3.91(s,2H),2.30(s,3H),2.07(s,3H), 2.01-1.90 (m,1H),0.76(d, J ═ 6.1Hz,4H).
Example 8 Synthesis of Compound B2 of the invention
The reaction formula is as follows:
intermediate 25
N- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) acetamide
The procedure was carried out to synthesize intermediate 2 to give 3.8g of yellow solid, yield: 93.6%, M +1:302.2.
Intermediate 26
N- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) acetamide
The procedure was carried out to synthesize intermediate 3, yielding 2.9g of white powder: 86.6 percent and M +1:272.2.
Compound B2:
n- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2, 3-dimethylphenoxypyridin-2-yl) acetamide
Prepared in the method of example 1 starting from compound 13 and compound 26 to give 13mg of a white solid in yield: 37.8%, 98.01% (UV214), M +1: 524.2. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.77(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.29-7.22 (m,2H), 7.18-7.00 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),2.20(s,3H),2.05(s,3H),2.01(s,3H),1.98(s,3H).
Example 9 Synthesis of Compound B3 of the invention
The reaction formula is as follows:
intermediate 27
N- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) isobutyramide
The procedure was carried out to synthesize intermediate 2 to give 3.8g of yellow solid, yield: 94.5%, M +1:330.2.
Intermediate 28
N- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) isobutyramide
The procedure was carried out to synthesize intermediate 3, yielding 2.9g of white powder: 81.7% and M +1:300.2.
Compound B3:
n- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2, 3-dimethylphenoxypyridin-2-yl) isobutyramide
Prepared by the method in example 1 starting from compound 13 and compound 26 as white solids 13mg, yield: 41.1%, 97.02% (UV214), M +1: 552.3. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.77(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.29-7.22 (m,2H), 7.18-7.00 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),2.20(s,3H),2.05(s,4H),2.01(s,3H),1.09(s,6H).
EXAMPLE 10 Synthesis of Compound B4 of the present invention
The reaction formula is as follows:
intermediate 29
1- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) -3-methylurea
Adding 4- (2, 3-dimethyl-4-nitrophenoxy) pyridine-2-amine (0.5g,1.93mmol), dichloromethane (10mL), triethylamine (0.59g,5.79mmol), stirring, adding p-nitrophenyl chloroformate (0.47g,2.31mmol), stirring at room temperature for 14 hours, evaporating the solvent under reduced pressure, adding toluene (10mL), triethylamine (0.59g,5.79mmol), methylamine hydrochloride (0.39g,5.79mmol), stirring, heating to 80 ℃, sealing, reacting for 14 hours, evaporating the solvent under reduced pressure, and purifying the residue by medium-pressure reverse-phase preparative chromatography to obtain 0.18g of white solid
Yield: 29.5%, M +1:317.2.
Intermediate 30
1- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) -3-methylurea
The procedure was carried out to synthesize intermediate 3, yielding 0.11g of white powder: 64.2%, M +1:287.2.
Compound B4:
1- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2, 3-dimethylphenoxy) pyridin-2-yl) -3-methylurea
Prepared by the method in example 1 starting from compound 13 and compound 30 to give 9mg of a white solid in yield: 20.8%, 96.4% (UV214), M +1: 539.3. 1H NMR (400MHz, DMSO-d6) δ 11.51(s,1H),10.77(s,1H),8.22(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.29-7.22 (m,2H), 7.18-7.00 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),2.67(s,3H),2.20(s,3H),2.05(s,3H),2.01(s,3H).
Example 11 Synthesis of Compound B5 of the present invention
The reaction formula is as follows:
intermediate 31
1-cyclopropyl-3- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) urea
Operating as a method for the synthesis of intermediate 29 gave 0.21g of white solid, yield: 21.6%, M +1:343.2.
Intermediate 32
1- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) -3-cyclopropylurea
The procedure was carried out to synthesize intermediate 3, yielding 0.15g of white powder: 71.4% and M +1:313.2.
Compound B5:
1-cyclopropyl-3- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2, 3-dimethylphenoxy) pyridin-2-yl) urea
14mg of a white solid was prepared starting from compound 13 and compound 26 in the procedure of example 1, yield: 33.7%, 95.71% (UV214), M +1: 565.3. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.77(s,1H),8.31(d, J ═ 8.9Hz,1H),8.19(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.29-7.22 (m,2H), 7.18-7.00 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),2.82(m,1H),2.20(s,3H),2.05(s,3H),2.01(s,3H),0.77(d, J ═ 6.8Hz,4H).
EXAMPLE 12 Synthesis of Compound B6 of the invention
The reaction formula is as follows:
intermediate 33
3- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) -1, 1-dimethylurea
Operating as a method for the synthesis of intermediate 29 gave 0.18g of white solid, yield: 27.9%, M +1:331.2.
Intermediate 34
3- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) -1, 1-dimethylurea
The procedure was carried out to synthesize intermediate 3, yielding 0.11g of white powder: 75.7%, M +1:301.2.
Compound B6:
3- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2, 3-dimethylphenoxy) pyridin-2-yl) -1, 1-dimethylurea
Prepared by the method in example 1 starting from compound 13 and compound 34 to give 15mg of a white solid in yield: 31.6%, 97.04% (UV214), M +1: 553.3. 1H NMR (400MHz, DMSO-d6) δ 11.58(s,1H),10.79(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.63(s,1H), 7.31-7.25 (m,2H), 7.21-7.04 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.79(d, J ═ 5.4Hz,1H),6.59(s,2H),3.26(s,6H),2.20(s,3H),2.05(s,3H),2.01(s,3H).
Example 13 Synthesis of Compound B7 of the invention
The reaction formula is as follows:
intermediate 35
4- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-amine
The procedure was carried out to synthesize intermediate 1 to give 1.2g of yellow solid, yield: 71.2 percent and M +1:264.1.
Intermediate 36
N- (4- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 2 to give 1.4g of white powder, yield: 81.5%, M +1:332.1.
Intermediate 37
N- (4- (4-amino-2-fluoro-3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 3, yielding 0.7g of white powder: 54.7% and M +1:302.2.
Compound B7:
n- (4- (2-fluoro-4- ((7- (4-fluorophenyl) -6-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Prepared by the method in example 1 starting from compound 13 and compound 37 to give 9mg of a white solid in yield: 32.3%, 97.21% (UV214), M +1: 554.2. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.77(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.35-7.26 (m,2H), 7.15-7.07 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.76(m,1H),6.59(m,2H),2.86(s,1H),2.20(s,3H),2.05(s,3H),1.97(m,1H),0.75(d, J ═ 6.3Hz,4H).
Example 14 Synthesis of Compound B8 of the present invention
The reaction formula is as follows:
intermediate body 38
5- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-amine
The procedure was carried out to synthesize intermediate 1 to give 1.7g of yellow solid, yield: 79.2%, M +1:246.1.
Intermediate 39
N- (4- (3-methyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 2 to give 1.4g of white powder, yield: 82.7%, M +1:314.2.
Intermediate 40
N- (4- (4-amino-3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 3 to give 0.82g of white powder, yield: 53.8%, M +1:284.2.
Compound B8:
n- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Prepared in the method of example 1 starting from compound 13 and compound 40 to give 21mg of a white solid in yield: 37.1%, 96.02% (UV214), M +1: 536.2. 1H NMR (400MHz, DMSO-d6) δ 11.46(s,1H),10.77(s,1H),8.23(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.35-7.26 (m,2H), 7.15-7.07 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.76(s,1H),6.62(s,1H),6.59(s,2H),2.85(s,1H),2.21(s,3H),2.05(s,3H),1.97(m,1H),0.74(d, J ═ 6.3Hz,4H).
Example 15 Synthesis of Compound B9 of the invention
The reaction formula is as follows:
intermediate 41
4- (2-methyl-4-nitrophenoxy) pyridin-2-amine
The procedure was carried out to synthesize intermediate 1 to give 1.42g of yellow solid, yield: 71.4% and M +1:246.1.
Intermediate body 42
N- (4- (2-methyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 2 to give 1.27g of white powder, yield: 88.9%, M +1:314.2.
Intermediate 43
N- (4- (4-amino-2-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 3, yielding 0.51g of white powder: 51.7%, M +1:284.2.
Compound B9:
n- (4- (4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Prepared in the method of example 1 starting from compound 13 and compound 43 as white solids 17mg, yield: 34.15%, 97.82% (UV214), M +1: 536.2. 1H NMR (400MHz, DMSO-d6) δ 11.46(s,1H),10.77(s,1H),8.22(d, J ═ 8.9Hz,1H),8.15(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.35-7.26 (m,2H), 7.15-7.07 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.82(s,1H),6.62(s,1H),6.59(s,2H),2.85(s,1H),2.21(s,3H),1.96(m,4H),0.74(d, J ═ 6.3Hz,4H).
EXAMPLE 16 Synthesis of Compound B10 of the present invention
The reaction formula is as follows:
intermediate 44
4- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-amine
The procedure was carried out as for the synthesis of intermediate 1 to give 1.36g of yellow solid, yield: 67.4%, M +1:264.1.
Intermediate 45
N- (4- (3-fluoro-2-methyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 2 in 1.12g of white powder, yield: 83.4%, M +1:332.1.
Intermediate 46
N- (4- (4-amino-3-fluoro-2-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 3, yielding 0.65g of white powder: 41.3%, M +1:302.2.
Compound B10:
n- (4- (3-fluoro-4- ((7- (4-fluorophenyl) -6-methyl-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -2-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Prepared in the method of example 1 starting from compound 13 and compound 46 to give 11mg of a white solid in yield: 25.1%, 95.61% (UV214), M +1: 554.2. 1H NMR (400MHz, DMSO-d6) δ 11.47(s,1H),10.78(s,1H),8.23(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.61(s,1H), 7.35-7.24 (m,2H), 7.15-7.06 (m,2H),6.95(m,1H),6.76(m,1H),6.59(m,2H),2.86(s,1H),2.20(s,3H),1.95(m,4H),0.75(d, J ═ 6.3Hz,4H).
Example 17 Synthesis of Compound B11 of the invention
The reaction formula is as follows:
intermediate 47
6- (2-chloro-3-methyl-4-nitrophenyl) pyridin-2-amine
The procedure was carried out as for the synthesis of intermediate 1 to give 1.32g of yellow solid, yield: 68.5%, M +1:280.1.
Intermediate 48
N- (4- (2-chloro-3-methyl-4-nitrophenyl) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 2 to give 1.24g of white powder, yield: 89.2 percent and M +1:348.1.
Intermediate 49
N- (4- (4-amino-2-chloro-3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
The procedure was carried out to synthesize intermediate 3 to give 0.78g of white powder, yield: 42.1%, M +1:318.1.
Compound B11:
n- (4- (2-chloro-4- ((7- (4-fluorophenyl) -6-8-oxo-7, 8-dihydro-2, 7-naphthyridin-1-yl) amino) -3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Prepared in the method of example 1 starting from compound 13 and compound 49 as white solids 7mg, yield: 28.3%, 97.69% (UV214), M +1: 570.2. 1H NMR (400MHz, DMSO-d6) δ 11.42(s,1H),10.77(s,1H),8.24(d, J ═ 8.9Hz,1H),8.17(d, J ═ 5.4Hz,1H),7.60(s,1H), 7.35-7.26 (m,2H), 7.15-7.07 (m,2H),6.95(d, J ═ 8.8Hz,1H),6.78(s,1H),6.48(m,2H),2.86(s,1H),2.20(s,3H),2.05(s,3H),1.97(m,1H),0.76(d, J ═ 6.3Hz,4H).
EXAMPLE 18 Synthesis of Compound F2 of the invention
The reaction formula is as follows:
intermediate 50
5- (4-fluorophenyl) -1- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid
Operating in the procedure for the synthesis of intermediate 24 gave 0.32g of white solid, yield: 41.2%, M +1:278.1.
Compound F2:
n- (4- ((2- (cyclopropanecarboxamido) pyridin-4-yl) oxy) -2, 3-dimethylphenyl) -5- (4-fluorophenyl) -1- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide
Prepared by the method in example 6 starting from compound 3 and compound 50 as white solid 11mg, yield: 21.7%, 95.01% (UV214), M +1: 557.2. 1H NMR (400MHz, DMSO-d6) δ 12.83(s,1H),10.79(s,1H),8.69(s,1H), 8.28-8.08 (m,3H),7.73(dd, J ═ 8.4,5.4Hz,2H),7.56(s,1H),7.30(t, J ═ 8.8Hz,2H),6.98(d, J ═ 8.9Hz,1H),6.59(dd, J ═ 5.7,2.4Hz,1H),4.91(s,1H),3.77(m,2H),3.51(m,2H),2.30(s,3H),2.07(s,3H), 2.01-1.90 (m,1H),0.76(d, J ═ 6.1, 4H).
The beneficial effects of the compounds of the present invention are illustrated by the following experimental examples:
experimental example 1 protective apoptosis test of Compound of the present invention
1) Experimental Material
DMEM medium was purchased from Gibco, penicillin and streptomycin from Hyclone, TNF α from Peprotech, Smac mimetic and Z-VAD-FMK from Selleck, CCK8 from Medchem Express.
2) Experimental methods
HT-29 cells (colon cancer cells) were cultured in DMEM + 10% FBS + cyan/streptomycin medium. In the experiment, HT-29 cells in logarithmic growth phase were collected at a specific number per well (adherent cells are typically 8X 10) 3 cells/well) were seeded in 96-well plates at 37 ℃ with 5% CO 2 The cell culture chamber of (1) was cultured overnight. The following day, the test compound was diluted with the medium to the corresponding concentration and added to the corresponding well of a 96-well plate, 3 duplicate wells per sample, while setting the solvent control group and the medium-only blank control group, the dosed cells were induced with the combination of TNF α/Smac mimetic/Z-VAD-FMK for 24h, 10. mu.l of CCK8 solution was added to each well and incubated in the cell incubator for 1-3h, followed by measuring absorbance at 495nm with the microplate reader and calculating the necrosis protection rate of the drug against the cells according to the following formula: protective rate of cell necrosis [ [ (X-C) 0 )/(C-C 0 )]×100％
Wherein, C, C 0 And X represents the average absorbance values of the solvent control group, the blank control group, and the drug-treated group, respectively. Finally, Graphpad Prism 5.0 software is used for fitting a cell survival rate curve and calculating the EC of the compound to be tested for inhibiting the programmed cell necrosis 50 The value is obtained.
Results of the experiment
The results are shown in Table 2, where +++ represents EC 50 <0.1. mu.M, + represents 1. mu.M>EC 50 ≧ 0.1 μ M, + represents EC 50 ≧1μM。
TABLE 2 inhibitory Activity of the compounds of the present invention on RIPK3 kinase and on apoptosis
| Compound numbering | HT-29(EC 50 ) |
| A | ++ |
| B | +++ |
| C | ++ |
| D | ++ |
| E | + |
| F | + |
| G | + |
| B2 | +++ |
| B3 | +++ |
| B4 | +++ |
| B5 | +++ |
| B6 | +++ |
| B7 | +++ |
| B8 | +++ |
| B9 | +++ |
| B10 | +++ |
| B11 | +++ |
| F2 | + |
In conclusion, the invention provides a novel compound which has an excellent inhibitory effect on RIPK3, can be used as an inhibitor of RIPK3, inhibits apoptosis, treats inflammation related to apoptosis, and/or immune diseases, and/or neurodegenerative diseases, and/or tumors, and has important clinical value.
Claims (10)
1. A compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof:
wherein R is 1 Is selected from
R 2 、R 4 Each independently selected from hydrogen, hydroxy, methoxy, C 1-3 Alkyl, halogen;
R 3 is selected from
Wherein Ra and Ra' are independently selected from hydrogen and C 1-6 Alkyl, cycloalkyl;
R 5 is C having 1 to 3 substituents 5-10 Aryl or azaaryl; the substituents are respectively and independently selected from C 1-3 Alkyl, methoxy, trifluoromethyl, nitro or halogen;
R 6 is hydrogen, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or C substituted by 1 hydroxy 2-6 An alkyl group;
x is nitrogen, oxygen or sulfur.
2. The compound of claim 1, wherein R is 2 、R 4 Are each independently selected from hydrogen, C 1-3 Alkyl, fluoro, chloro, bromo.
3. The compound of claim 1, wherein R is 3 Is selected from-CORa, -CONRaRa'; wherein Ra is C 1-5 Alkyl or C 3-6 Cycloalkyl radical, Ra' is hydrogen or C 1-5 An alkyl group.
4. The compound of claim 1, wherein R is 5 Is p-trifluoromethylphenyl, p-methoxyphenyl or p-fluorophenyl.
5. The compound of claim 1, wherein R is 6 Is hydrogen, C 1-3 Alkyl or C substituted by 1 hydroxy 2-4 An alkyl group.
6. A compound according to any one of claims 1 to 5, wherein the compound is:
7. use of a compound according to any one of claims 1 to 6, or an isomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a receptor-interacting protein kinase 3 inhibitor.
8. Use of a compound according to any one of claims 1 to 6, or an isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of inflammation, immune diseases, neurodegenerative diseases and/or tumors.
9. The use according to claim 8, wherein the medicament is a medicament for the treatment of inflammation associated with apoptosis, immune diseases, neurodegenerative diseases and/or tumors.
10. A pharmaceutical preparation comprising the compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
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| CN110041253A (en) * | 2018-01-17 | 2019-07-23 | 上海翰森生物医药科技有限公司 | Pyridines N- oxidized derivatives and its preparation method and application |
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| CN110041253A (en) * | 2018-01-17 | 2019-07-23 | 上海翰森生物医药科技有限公司 | Pyridines N- oxidized derivatives and its preparation method and application |
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