CN114907339B - 4- (4-aminophenoxy) pyridin-2-amine derivatives and use thereof - Google Patents
4- (4-aminophenoxy) pyridin-2-amine derivatives and use thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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 inhibiting effect on RIPK3, can be used as an inhibitor of RIPK3, and has important clinical value for treating diseases related to cell programmed necrosis.
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
Cell apoptosis (necroptosis/programmed necrosis) is a new caspase-independent mode of apoptosis that has been discovered in recent years, unlike apoptosis. It is regulated by death signal and exhibits necrosis-like structure. In contrast to apoptosis, programmed necrosis of cells does not form apoptotic bodies and chromatin does not aggregate; in contrast to necrosis, apoptosis is a controlled means of cell death that is regulated by a variety of genes. After adding caspase inhibitor Z-VAD-FMK into the in vitro culture system, TNF can induce cells to produce programmed necrosis, and the morphological characteristics of the necrosis of the cells are cell swelling, rupture and release of cell contents, thereby causing inflammation and immune response. In addition to TNF, ligands for TLR3 and TLR4, certain bacterial, viral infections, etc. can cause apoptosis.
The receptor interacting protein kinase 1 (RIPK 1) and the receptor interacting protein kinase 3 (RIPK 3) form necrotic bodies (necromes). RIPK3 will recruit MLKL further, phosphorylated MLKL will oligomerize itself and migrate to the cell membrane, "punch" the cell membrane, leading to leakage of cell contents and disruption of ionization balance, ultimately leading to the occurrence of cell necrosis. Necrotic apoptosis, due to the release of cellular content, causes massive inflammatory cell infiltration in the body and thus induces severe inflammatory responses. Necrotic apoptosis, which is a new class of apoptosis, plays an important role in pathophysiological processes of various diseases such as ischemic injury, acute kidney injury, neurodegenerative diseases, malignant tumor, viral infection, immune diseases, etc. The identification and discovery of small molecule inhibitors of necrotic apoptosis is of great importance in the clinical treatment of diseases associated with necrotic apoptosis.
Therefore, further research on the more efficient inhibitor of RIPK3 will further advance the clinical treatment research on the diseases related to necrotic cell apoptosis, and has very important value and application prospect.
Disclosure of Invention
The invention aims to provide a 4- (4-aminophenoxy) pyridin-2-amine derivative which is a high-efficiency inhibitor of RIPK 3.
The invention provides a compound shown in a formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from the group consisting of
R 2 、R 4 Independently selected from hydrogen, hydroxy, methoxy, C 1-3 Alkyl, halogen;
R 3 selected from the group consisting of
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 each independently selected from C 1-3 Alkyl, methoxy, trifluoromethyl, nitro or halogen;
R 6 is hydrogen, C 1-6 Alkyl, 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 Independently selected from hydrogen, C 1-3 Alkyl, fluorine, chlorine, bromine.
Further, R 3 Selected from-CORa, -CONRaRa'; wherein Ra is C 1-5 Alkyl or C 3-6 Cycloalkyl, 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 an isomer or a pharmaceutically acceptable salt thereof in preparing a receptor interaction protein kinase 3 inhibitor.
The invention also provides application of the compound, or an isomer or a 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 cell necrosis.
The invention also provides a medicine which is a preparation prepared from the compound, or a stereoisomer or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
Experimental results show that the composition has excellent inhibition effect on RIPK3, can be used as an inhibitor of RIPK3, can inhibit cell apoptosis, can treat inflammation related to cell 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 IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or 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.
"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 of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a-b Alkyl indicates 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. For example, 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 heteroatom means a nitrogen atom, an oxygen atom, and a sulfur atom;
"trifluoromethyl" means: -CF 3 ；
"hydroxy" refers to: -OH
"Parafluoromethylphenyl" means:
"Parafethoxyphenyl" means:
"Parafluorophenyl" means:
"stereoisomers" include enantiomers and diastereomers.
The term "pharmaceutically acceptable" refers to a carrier, cargo, diluent, adjuvant, and/or salt formed in general
Chemically or physically compatible with the other components that make up a pharmaceutical dosage form, and physiologically compatible with the receptor.
The terms "salts" and "pharmaceutically acceptable salts" refer to the acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). 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 salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.
In certain embodiments, one or more compounds of the present invention may be used in combination with one another. The compounds of the invention may alternatively 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 a subject simultaneously, separately or sequentially.
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.
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
To a single vial was added 1-fluoro-2, 3-dimethyl-4-nitrobenzene (5 g,29.56 mmol), 2-amino-4-hydroxypyridine (5.2 g,47.23 mmol), potassium carbonate (8.6 g,62.23 mmol) and DMSO (100 mL), reacted for 14 hours with stirring at 75 degrees celsius, cooled naturally to room temperature, ice water was slowly added, a brown solid precipitated, filtered, the filter cake was washed with water to neutrality, dried to give 5.6g brown solid, yield: 73.1%, M+1:260.0.
Intermediate 2
(4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
To a single-necked flask, 4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-amine (1.5 g,19.67 mmol), triethylamine (7.95 g,78.67 mmol) and dichloromethane (110 mL) were added, the temperature was reduced to 0℃with stirring, cyclopropylcarboxychloride (4.52 g,43.27 mmol) was added dropwise, the mixture was allowed to spontaneously warm to room temperature for reaction for 14 hours, the mixture was poured into water, the separated liquid was extracted with dichloromethane, the combined extracts were dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give a pale yellow solid of 5.9g, yield: 91.8%, M+1:327.8.
Intermediate 3
N- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
To a single vial was added N- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide (3 g,9.17 mmol), ethanol (45 mL) and water (7 mL), warmed to 60 degrees celsius with stirring, ammonium chloride (0.49 g,9.17 mmol) and iron powder (2.55 g,45.83 mmol) were added, reacted for one hour, cooled to room temperature, filtered, the filtrate evaporated to dryness under reduced pressure, dichloromethane and sodium carbonate solution were added, the separated liquid was extracted with dichloromethane, the combined extracts dried over magnesium sulfate, filtered, the filtrate evaporated to dryness under reduced pressure and purified with silica gel (EA/pet=1.1) to give 0.8g of pale yellow solid, yield: 29.6%, M+1:298.2.
Intermediate 4
2-cyano-N- (4-methoxyphenyl) acetamide
To a single vial was added 4-methoxyaniline (4 g,32.48 mmol), 2-cyanoacetic acid (3.32 g,39.03 mmol), dichloromethane (80 mL), diisopropylethylamine (12.6 g,97.49 mmol), stirred at room temperature until clear, HATU (17.3 g,45.50 mmol) was added, stirred at room temperature for 14 hours, the solvent was distilled off under reduced pressure and purified over silica gel (EA/pet=1.1) to give 2.7g of yellow solid, yield: 43.8%, M+1:191.1.
Intermediate 5
1- (4-methoxyphenyl) -4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
To a single vial was added 2-cyano-N- (4-methoxyphenyl) acetamide (0.5 g,2.63 mmol), acetylacetone (0.27 g,2.70 mmol), absolute ethanol (10 mL), piperidine (0.09 g,1.06 mmol), and the mixture was stirred and warmed to 90℃for 14 hours, white solid was precipitated, cooled to room temperature and then suction filtered, the filter cake was rinsed with a small amount of ethanol, dried to give a white powder of 0.62g, yield: 92.8%, M+1:255.2.
Intermediate 6
(E) -4- (2- (dimethylamino) vinyl) -1- (4-methoxyphenyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
To a single vial was added 1- (4-methoxyphenyl) -4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (1.5 g,5.9 mmol), DMF (15 mL), DMF-DMA (0.92 g,7.72 mmol), and the reaction was allowed to proceed for 6 hours at 110℃with stirring, the solvent was distilled off under reduced pressure and recrystallized from ethanol to give 0.6g of 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 vial was added 80% sulfuric acid (9 mL), (E) -4- (2- (dimethylamino) vinyl) -1- (4-methoxyphenyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (0.3 g,0.97 mmol), reacted for 2 hours with stirring at 110 degrees celsius, the reaction solution was poured into crushed ice, a white solid precipitated, filtered and washed with water to neutrality, dried to give 63mg 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
Phosphorus oxychloride (3 mL) was added to a single-port flask, 8-chloro-2- (4-methoxyphenyl) -3-methyl-2, 7-naphthyridin-1 (2H) -one (60 mg,0.21 mmol) was reacted for 2 hours at 110℃with stirring, the reaction solution was poured into crushed ice, white solid was precipitated, filtered and washed with water to neutrality, and 32mg of off-white solid was obtained by drying, yield: 47.8%, M+1:301.2.
Compound a:
to a single vial was added intermediate 8 (16 mg,0.0168 mmol), intermediate 3 (16 mg,0.0168 mmol) and n-butanol (3 mL), p-toluenesulfonic acid (10.5 mg,0.0168 mmol) was added with stirring, the temperature was raised to 110℃for 2 hours, and after evaporation of the solvent under reduced pressure, 19mg of white solid was purified by reverse phase preparative chromatography, yield: 63.3%,100% (UV 214), M+1:562.2.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.77 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.35-7.26 (m, 2H), 7.15-7.07 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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=6.3 Hz, 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 procedure for the synthesis of intermediate 4 gave 4.6g of yellow solid, yield: 95.8%, M+1:179.2.
Intermediate 10
1- (4-fluorophenyl) -4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile
Operating as a synthetic intermediate 5, 2.3g of white powder was obtained in yield: 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
Operating as a synthetic intermediate 6 gave 0.46g of yellow powder, yield: 25%, M+1:298.2.
Intermediate 12
2- (4-fluorophenyl) -8-hydroxy-3-methyl-2, 7-naphthyridin-1 (2H) -one
Operating as a synthetic intermediate 7 gave 140mg of an off-white solid, 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 synthetic intermediate 8 gave 78mg of an off-white solid, 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-dimethylphenoxy pyridin-2-yl) cyclopropanecarboxamide
Starting from compound 13 and compound 3, the method of example 1 gave 16mg of a white solid, yield: 42.1%,97.51% (UV 214), M+1:550.2.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.77 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.35-7.26 (m, 2H), 7.15-7.07 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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=6.3 Hz, 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
Operating as a synthesis for intermediate 4, 1.94g yellow solid, yield: 68.6%, M+1:229.2. Intermediate 15
4, 6-dimethyl-2-oxo-1- (4- (trifluoromethyl) phenyl) -1, 2-dihydropyridine-3-carbonitrile
Operating as a synthetic intermediate 5 gave 2.1g of white powder, yield: 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
Operating as a synthetic intermediate 6 gave 0.46g of yellow powder, yield: 46.1%, M+1:348.2.
Intermediate 17
8-hydroxy-3-methyl-2- (4- (trifluoromethyl) phenyl) -2, 7-naphthyridin-1 (2H) -one
Operating as a synthetic intermediate 7 gave 141mg of an off-white solid, 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 synthesizing intermediate 8 gave 103mg of an off-white solid, yield: 75%, 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
Following the procedure in example 1, starting from compound 18 and compound 3, 13mg of a white solid was prepared, yield: 24.4%,97.58% (UV 254), M+1:600.2.1H NMR (400 MHz, DMSO-d 6) δ11.49 (s, 1H), 10.78 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.61 (s, 1H), 7.44-7.36 (m, 2H), 7.23-7.14 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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=6.3 Hz, 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-necked flask was added 4-fluoroaniline (0.5 g,4.5 mmol), 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (0.514 g,4.95 mmol), dichloromethane (10 mL), diisopropylethylamine (1.75 g,13.5 mmol), stirred at room temperature until clear, HATU (2.4 g,6.3 mmol) was added, stirred at room temperature for 14 hours, and after the solvent was distilled off under reduced pressure, purified on 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
To a single port flask was added methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate (0.5 g,2.11 mmol), methanol (18 mL), stirred at room temperature to dissolve, aqueous sodium hydroxide (0.11 g,2.74 mmol) solution (3 mL) was added, stirred at room temperature for 14 hours, methanol was distilled off under reduced pressure, pH was adjusted to 3 with 1N hydrochloric acid, white solid precipitated, filtered and rinsed with water to neutrality, dried to give 0.34g of white solid, yield: 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 vial was added intermediate 3 (20 mg,0.067 mmol), intermediate 20 (16 mg,0.067 mmol), dichloromethane (4 mL), diisopropylethylamine (27 mg,0.202 mmol), stirred at room temperature until clear, HATU (36 mg,0.094 mmol) was added, stirred at room temperature for 14 h, the solvent was distilled off under reduced pressure and purified by reverse phase preparative chromatography to give 4mg of a white solid, yield: 11.8%,96.41% (UV 214), M+1:503.2.1H NMR (400 MHz, DMSO-d 6) delta 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=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 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=6.1 Hz, 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
To a single port flask were added isopropyl malonate (2 g,13.88 mmol), methylene chloride (40 mL), triethylamine (2.8 g,27.72 mmol), stirred at room temperature to dissolve, cooled to 0 degrees celsius, 4-fluorobenzene acetyl chloride (2.63 g,15.24 mmol) was added dropwise, stirred naturally to room temperature for 2 hours, poured into water, extracted with methylene chloride, the extracts were added with 1N hydrochloric acid and stirred, separated, the organic phase was washed with water to neutrality, dried with anhydrous magnesium sulfate, filtered, the filtrate was distilled off solvent under reduced pressure, ethanol (50 mL) and p-toluene sulfonic acid (0.48 g,2.78 mmol) were added, stirred and warmed to reflux for 2 hours, the solvent was distilled off under reduced pressure, the residue was dissolved with methylene chloride, washed with saturated sodium bicarbonate solution, then washed with water to neutrality, the organic phase was dried with magnesium sulfate, filtered, the filtrate was purified with silica gel (EA/pet=1/3) under reduced pressure to give 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
To a single port flask was added ethyl 4- (4-fluorophenyl) -3-oxobutanoate (1 g,4.46 mmol), xylene (15 mL), N-dimethylformamide dimethyl acetal (1.17 g,9.81 mmol), stirred and warmed to reflux for 6 hours, ethanol (20 mL) and ammonium acetate (0.69 g,8.93 mmol) were added after evaporation of the solvent under reduced pressure, stirred and warmed to 60 degrees celsius for 14 hours, ethyl acetate and water were added after evaporation of the solvent under reduced pressure, the liquid was separated, the organic phase was washed with water until neutral with magnesium sulfate and dried, filtered, and the filtrate was purified with silica gel (EA/pet=1/1) after evaporation of the solvent under reduced pressure 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
To a single vial was added ethyl 5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate (0.1 g,0.383 mmol), methanol (12 mL), stirred at room temperature to dissolve, aqueous sodium hydroxide (0.034 g,0.842 mmol) was added (2 mL), stirred at 50 ℃ for 4 hours, the reaction was distilled off under reduced pressure to give methanol, 1N hydrochloric acid was used to adjust pH to 3, white solid was precipitated, filtered and rinsed with water to neutrality, dried to give 0.063g of white solid, yield: 70.8%, 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 vial was added compound 3 (52 mg,0.172 mmol), intermediate 23 (40 mg,0.172 mmol), N, N-dimethylformamide (2 mL), diisopropylethylamine (67 mg,0.515 mmol), stirred at room temperature until clear, HATU (98 mg,0.257 mmol) was added, stirred at room temperature for 14 hours and then purified by reverse phase preparative chromatography to give 37mg of a white solid, yield: 42.1%,97.66% (UV 214), M+1:513.2.1H NMR (400 MHz, DMSO-d 6) delta 12.84 (s, 1H), 10.79 (s, 1H), 8.63 (d, J=1.6 Hz, 1H), 8.18 (dd, J=13.2, 7.3Hz, 2H), 8.09 (d, J=1.7 Hz, 1H), 7.76-7.67 (m, 2H), 7.58 (d, J=2.4 Hz, 1H), 7.34-7.23 (m, 2H), 6.97 (d, J=8.9 Hz, 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), 0.81-0.70 (m, 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 vial was added ethyl 5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate (0.2 g,0.766 mmol), N, N-dimethylformamide (4 mL), stirred at room temperature until clear, sodium hydride (62 mg,1.531mmol, 60%) was added, stirred at room temperature for 1 hour, methyl iodide (0.218 g,1.531 mmol) was added and stirred for 14 hours, and the reaction mixture was purified directly using a reverse phase preparative chromatography system to give 110mg of a white solid, yield: 58.1%, 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 vial was added compound 3 (61 mg,0.202 mmol), intermediate 24 (50 mg,0.202 mmol), N, N-dimethylformamide (2 mL), diisopropylethylamine (79 mg,0.607 mmol), stirred at room temperature until clear, HATU (116 mg,0.303 mmol) was added, stirred at room temperature for 14 hours and then purified by reverse phase preparative chromatography to give 46mg of a white solid, yield: 43.2%,97.19% (UV 214), M+1:527.2.1H NMR (400 MHz, DMSO-d 6) delta 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=8.8 Hz, 2H), 6.98 (d, J=8.9 Hz, 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=6.1 Hz, 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
To a single-port flask was added potassium thiocyanate (49 mg,0.5 mmol), acetone (2 mL), a solution of 4-fluorobenzene acetyl chloride (86 mg,0.5 mmol) in acetone (2 mL) was added dropwise under stirring, the mixture was stirred and heated to 50℃for 2 hours, an intermediate 3 (148 mg,0.5 mmol) in acetone (4 mL) was added dropwise, the mixture was reacted at 50℃for 7 hours, and after evaporation of the acetone under reduced pressure, 13mg of off-white solid was purified by a reversed phase preparative chromatography system, yield: 5.3%,97.69% (UV 214), M+1:493.1.1H NMR (400 MHz, DMSO-d 6) delta 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=8.8 Hz, 2H), 6.94 (d, J=8.9 Hz, 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=6.1 Hz, 4H).
EXAMPLE 8 Synthesis of Compound B2 of the present invention
The reaction formula is as follows:
intermediate 25
N- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) acetamide
Operating as a procedure for the synthesis of intermediate 2, 3.8g of a yellow solid, yield: 93.6%, M+1:302.2.
Intermediate 26
N- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) acetamide
Operating as a synthesis for intermediate 3, 2.9g of white powder was obtained in yield: 86.6%, 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-dimethylphenoxy pyridin-2-yl) acetamide
Starting with compound 13 and compound 26, the method of example 1 gave 13mg of a white solid, yield: 37.8%,98.01% (UV 214), M+1:524.2.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.77 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.29-7.22 (m, 2H), 7.18-7.00 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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 present invention
The reaction formula is as follows:
intermediate 27
N- (4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-yl) isobutyramide
Operating as a procedure for the synthesis of intermediate 2, 3.8g of a yellow solid, yield: 94.5%, M+1:330.2.
Intermediate 28
N- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) isobutyramide
Operating as a synthesis for intermediate 3, 2.9g of white powder was obtained in yield: 81.7%, 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-dimethylphenoxy pyridin-2-yl) isobutyramide
Starting with compound 13 and compound 26, the method of example 1 gave 13mg of a white solid, yield: 41.1%,97.02% (UV 214), M+1:552.3.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.77 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.29-7.22 (m, 2H), 7.18-7.00 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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
To a single port was added 4- (2, 3-dimethyl-4-nitrophenoxy) pyridin-2-amine (0.5 g,1.93 mmol), methylene chloride (10 mL), triethylamine (0.59 g,5.79 mmol), p-nitrophenyl chloroformate (0.47 g,2.31 mmol) was added with stirring, stirred at room temperature for 14 hours, the solvent was distilled off under reduced pressure, toluene (10 mL), triethylamine (0.59 g,5.79 mmol), methylamine hydrochloride (0.39 g,5.79 mmol) was added, the reaction was closed with stirring at a temperature of 80℃for 14 hours, and after the solvent was distilled off under reduced pressure, the residue was purified by medium pressure reverse phase preparative chromatography to give 0.18g of a white solid
Yield: 29.5%, M+1:317.2.
Intermediate 30
1- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) -3-methylurea
Operating as a synthesis for intermediate 3, 0.11g of white powder was obtained in yield: 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
Starting with compound 13 and compound 30, 9mg of a white solid was prepared according to the method in example 1, yield: 20.8%,96.4% (UV 214), M+1:539.3.1H NMR (400 MHz, DMSO-d 6) δ11.51 (s, 1H), 10.77 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.29-7.22 (m, 2H), 7.18-7.00 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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 synthetic intermediate 29, 0.21g of a white solid was obtained in yield: 21.6%, M+1:343.2.
Intermediate 32
1- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) -3-cyclopropylurea
Operating as a synthesis for intermediate 3, 0.15g of white powder was obtained in yield: 71.4%, 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
Starting with compound 13 and compound 26, 14mg of a white solid was prepared according to the method in example 1, yield: 33.7%,95.71% (UV 214), M+1:565.3.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.77 (s, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.19 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.29-7.22 (m, 2H), 7.18-7.00 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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=6.8 Hz, 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 synthetic intermediate 29, 0.18g of a white solid was obtained in yield: 27.9%, M+1:331.2.
Intermediate 34
3- (4- (4-amino-2, 3-dimethylphenoxy) pyridin-2-yl) -1, 1-dimethylurea
Operating as a synthesis for intermediate 3, 0.11g of white powder was obtained in yield: 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
Starting with compound 13 and compound 34, the method of example 1 gave 15mg of a white solid, yield: 31.6%,97.04% (UV 214), M+1:553.3.1H NMR (400 MHz, DMSO-d 6) δ11.58 (s, 1H), 10.79 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.63 (s, 1H), 7.31-7.25 (m, 2H), 7.21-7.04 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.79 (d, J=5.4 Hz, 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 present invention
The reaction formula is as follows:
intermediate 35
4- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-amine
Operating as a procedure for the synthesis of intermediate 1 gave 1.2g of yellow solid, yield: 71.2%, M+1:264.1.
Intermediate 36
N- (4- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthesis for intermediate 2, 1.4g of white powder was obtained in yield: 81.5%, M+1:332.1.
Intermediate 37
N- (4- (4-amino-2-fluoro-3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthetic intermediate 3 gave 0.7g of white powder, yield: 54.7%, 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
Starting with compound 13 and compound 37, 9mg of a white solid was prepared according to the method in example 1, yield: 32.3%,97.21% (UV 214), M+1:554.2.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.77 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.35-7.26 (m, 2H), 7.15-7.07 (m, 2H), 6.95 (d, J=8.8 Hz, 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=6.3 Hz, 4H).
EXAMPLE 14 Synthesis of Compound B8 of the invention
The reaction formula is as follows:
intermediate 38
5- (2-fluoro-3-methyl-4-nitrophenyl) pyridin-2-amine
Operating as a procedure for the synthesis of intermediate 1 gave 1.7g of yellow solid, yield: 79.2%, M+1:246.1.
Intermediate 39
N- (4- (3-methyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthesis for intermediate 2, 1.4g of white powder was obtained in yield: 82.7%, M+1:314.2.
Intermediate 40
N- (4- (4-amino-3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthetic intermediate 3 gave 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
Starting with compound 13 and compound 40, the method of example 1 gave 21mg of a white solid, yield: 37.1%,96.02% (UV 214), M+1:536.2.1H NMR (400 MHz, DMSO-d 6) δ11.46 (s, 1H), 10.77 (s, 1H), 8.23 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.35-7.26 (m, 2H), 7.15-7.07 (m, 2H), 6.95 (d, J=8.8 Hz, 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=6.3 Hz, 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
Operating as a synthesis for intermediate 1 gave 1.42g yellow solid, yield: 71.4%, M+1:246.1.
Intermediate 42
N- (4- (2-methyl-4-nitrophenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthesis for intermediate 2, 1.27g of white powder was obtained in yield: 88.9%, M+1:314.2.
Intermediate 43
N- (4- (4-amino-2-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthesis for intermediate 3, 0.51g of white powder was obtained in yield: 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
17mg of a white solid was prepared in the same manner as in example 1 starting from compound 13 and compound 43, yield: 34.15%,97.82% (UV 214), M+1:536.2.1H NMR (400 MHz, DMSO-d 6) δ11.46 (s, 1H), 10.77 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.15 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.35-7.26 (m, 2H), 7.15-7.07 (m, 2H), 6.95 (d, J=8.8 Hz, 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=6.3 Hz, 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
Operating as a synthesis for intermediate 1 gave 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
Operating as a synthesis for intermediate 2, 1.12g of white powder was obtained in yield: 83.4%, M+1:332.1.
Intermediate 46
N- (4- (4-amino-3-fluoro-2-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthesis for intermediate 3 gave 0.65g of white powder, yield: 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
Starting with compound 13 and compound 46, the method of example 1 gave 11mg of a white solid, yield: 25.1%,95.61% (UV 214), M+1:554.2.1H NMR (400 MHz, DMSO-d 6) δ11.47 (s, 1H), 10.78 (s, 1H), 8.23 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 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=6.3 Hz, 4H).
EXAMPLE 17 Synthesis of Compound B11 of the present invention
The reaction formula is as follows:
intermediate 47
6- (2-chloro-3-methyl-4-nitrophenyl) pyridin-2-amine
Operating as a procedure for the synthesis of intermediate 1 gave 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
Operating as a synthesis for intermediate 2 gave 1.24g of white powder, yield: 89.2%, M+1:348.1.
Intermediate 49
N- (4- (4-amino-2-chloro-3-methylphenoxy) pyridin-2-yl) cyclopropanecarboxamide
Operating as a synthetic intermediate 3, 0.78g of white powder was obtained in 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
Starting from compound 13 and compound 49, the method of example 1 gave 7mg of a white solid, yield: 28.3%,97.69% (UV 214), M+1:570.2.1H NMR (400 MHz, DMSO-d 6) δ11.42 (s, 1H), 10.77 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 7.35-7.26 (m, 2H), 7.15-7.07 (m, 2H), 6.95 (d, J=8.8 Hz, 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=6.3 Hz, 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 as a synthetic intermediate 24 gave 0.32g of a white solid, yield: 41.2%, M+1:278.1.
Compound F2:
n- (4- ((2- (cyclopropanecarboxamide) pyridin-4-yl) oxy) -2, 3-dimethylphenyl) -5- (4-fluorophenyl) -1- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide
Starting from compound 3 and compound 50, the method of example 6 gave 11mg of a white solid, yield: 21.7%,95.01% (UV 214), M+1:557.2.1H NMR (400 MHz, DMSO-d 6) delta 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=8.8 Hz, 2H), 6.98 (d, J=8.9 Hz, 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 Hz, 4H).
The beneficial effects of the compounds of the invention are illustrated by the following experimental examples:
experimental example 1 Compound of the invention protection cell apoptosis experiments
1) Experimental materials
DMEM medium was purchased from Gibco, blue and streptomycin from Hyclone, TNF alpha from Peprotech, smac and Z-VAD-FMK from Selleck, CCK8 from Medchem Express.
2) Experimental method
HT-29 cells (colon carcinoma)Cells) were cultured with dmem+10% fbs+green/streptomycin medium. In the experiment, HT-29 cells in logarithmic growth phase were collected at a specific number per well (adherent cells were generally 8X 10 3 cells/well) were inoculated in 96-well plates at 37℃with 5% CO 2 Is cultured overnight in a cell incubator. The following day, the test compounds were diluted with medium to the corresponding concentrations and added to the corresponding wells of 96-well plates, 3 multiplex wells per sample, simultaneously solvent control and medium-only blank control were set, the dosed cells were induced for 24h with tnfα/Smac mimic/Z-VAD-FMK combination, 10 μl CCK8 solution was added per well and incubated in the cell incubator for 1-3h, followed by detection of absorbance at 495nm wavelength with an enzyme-labeled instrument, and the necrotic protection rate of the drug on the cells was calculated according to the following formula: cell necrosis protection ratio = [ (X-C) 0 )/(C-C 0 )]×100％
Therein, 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, the cell viability curve was fitted using Graphpad Prism 5.0 software and EC of the test compound to inhibit apoptosis was calculated 50 Values.
Experimental results
The results are shown in Table 1, wherein, the liquid crystal display device comprises a liquid crystal display device, ++ + represents EC 50 <0.1. Mu.M, ++represents 1. Mu.M>EC 50 ∈ 0.1. Mu.M, + represents EC 50 ≧1μM。
TABLE 1 inhibition of RIPK3 kinase and inhibition of cellular apoptosis activity by the compounds of the invention
| Numbering of compounds | HT-29(EC 50 ) |
| A | ++ |
| B | +++ |
| C | ++ |
| D | ++ |
| E | + |
| F | + |
| G | + |
| B2 | +++ |
| B3 | +++ |
| B4 | +++ |
| B5 | +++ |
| B6 | +++ |
| B7 | +++ |
| B8 | +++ |
| B9 | +++ |
| B10 | +++ |
| B11 | +++ |
| F2 | + |
In summary, the present invention provides a novel compound having an excellent inhibitory effect on RIPK3, being useful as an inhibitor of RIPK3, inhibiting apoptosis, treating inflammation associated with apoptosis, and/or immune disorders, and/or neurodegenerative disorders, and/or tumors, and having important clinical value.
Claims (3)
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:
2. use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammation, immune disorders, neurodegenerative disorders and/or tumors associated with apoptosis.
3. A medicament, which is a preparation prepared from the compound of claim 1, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294681A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application therefore |
| 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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294681A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application therefore |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| "Synthesis, Crystal Structure and Biological Activity of 8-((4-((2,3-diaminopyridin-4-yl)oxy)-3-fluorophenyl)-amino)-2-(4-fluorophenyl)- 3-methyl-2,7-naphthyridin-1(2H)-one";ZHUO Lin-Sheng et al;《Chinese J. Struct. Chem.》;第33卷;第859-864页 * |
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