CN110563697A - preparation and application of 2-pyridine carboxamide compound - Google Patents
preparation and application of 2-pyridine carboxamide compound Download PDFInfo
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Abstract
The invention relates to 2-pyridine carboxamide derivatives shown as formula I, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, wherein a substituent R1、R2X, Y have the meaning given in the description. The invention also relates to a compound of the general formula I, which has strong FLT-3 kinase inhibition effect, and also relates to application of the compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicaments for treating diseases caused by abnormally high expression of FLT-3 kinase, in particular to application in preparing medicaments for treating and/or preventing cancers.
Description
Technical Field
The invention relates to a preparation method of a novel 2-pyridine carboxamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a pharmaceutical composition containing the compound, and application of the compound in preparing a medicament for treating and/or preventing cancers.
background
AML (acute myeloid leukemia) is a disease caused by malignant proliferation of myeloid hematopoietic progenitor cells, and its total incidence is 4.1 cases per 10 ten thousand people. Complex pathogenesis and prognostic signatures at the cytogenetic level increase the risk of treating acute myeloid leukemia.
FLT-3 (FMS-like tyrosine kinase) is a stem cell tyrosine kinase, a member of the type III receptor tyrosine kinase family. Researchers found that FLT-3 protein is highly expressed in most AML patients and greatly promoted the survival and proliferation of hematopoietic stem cells. The gene for FLT-3 protein is located on chromosome 13q12, belongs to the type III Receptor Tyrosine Kinase (RTK) family, and has high structural homology with KIT, FMS and Platelet Derived Growth Factor Receptor (PDGFR). FLT-3 plays a definite role in the growth and differentiation of hematopoietic progenitor cells. FLT-3 expression is generally restricted to CD34+In cells, the ligand is almost ubiquitous in such cells, and like other RTKs, binding of the FLT-3 receptor to the ligand results in receptor dimerization at the cell membrane, resulting in autophosphorylation, activation of a series of downstream signaling pathways such as RAS/MEK/PI3K/AKT/mTOR and STAT-5 pathways, which play multiple roles in promoting cell cycle progression, inhibiting apoptosis and promoting cell differentiation. Mutant FLT-3 generally showed higher activity and lost interaction with CD34+and is capable of activating a downstream signaling pathway in the absence of ligand binding by autophosphorylation.
Mutations in the FLT-3 gene are the most common genetic alterations in AML and are well known as important driver mutations for the development of myeloid malignancies. The most common FLT-3 mutant is an internal tandem repeat change (FLT3-ITD mutation) that affects the membrane proximal region of the receptor. The FLT3-ITD mutation is of varying length and position, and is present in approximately 23% of AML patients. Other important mutations occur in the tyrosine kinase domain (FLT3-TKD), usually at the Activation Loop (AL) residue D835, where the aspartic acid residue is replaced by a tyrosine residue to stabilize the conformation of the activation site for binding to ATP, increasing its activity. These mutations are present in about 30% of all AML patients and lead to a poorer prognosis. In view of the current situation of generally poor curative effect of FLT-3 mutant AML, the research of targeted inhibitors of FLT-3 receptor tyrosine kinase has become the focus of drug research.
in order to develop a novel high-efficiency FLT-3 receptor tyrosine kinase inhibitor, the inventor carries out further research on pyridine FLT-3 inhibitor compounds, modifies and modifies a plurality of structural sites, and synthesizes a series of 2-pyridine carboxamide derivatives with novel structures. In vitro antitumor activity screening tests show that the compounds have antitumor activity.
Disclosure of Invention
The invention relates to a 2-pyridine carboxamide compound shown as a general formula I and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
R1is methyl, dimethyl, ethyl, n-propyl, isopropyl, 4-methylmorpholinyl, cyano;
R21-4 same or different hydrogen and fluorine;
X is O, S;
Y is-Ar1-Ar2；
Ar1Is a 6-membered heteroaryl group containing 2 heteroatoms of N and 1 heteroatom of O;
Ar2is (C)6-C10) Heteroaryl group, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R3Is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkane (I) and its preparation methodBase, (C)1-C4) Alkoxy, optionally halogenated (C)1-C4) Alkyl or (C)1-C4) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group.
The present invention preferably also relates to compounds of the general formula I as defined below, or racemates or optical isomers thereof, or pharmaceutically acceptable salts and/or hydrates thereof, wherein
R1Is methyl, ethyl, n-propyl, 4-methylmorpholinyl;
R2Is H, the substitution position of which is the ortho position of the carbon atom on the benzene ring to which X is connected;
X is O;
y is-Ar1-Ar2；
Ar1is a 6-membered heteroaryl group containing 2 heteroatoms of N and 1 heteroatom of O;
Ar2Is (C)6-C10) Heteroaryl group, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R3Is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, optionally halogenated (C)1-C4) Alkyl or (C)1-C4) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group.
The present invention preferably also relates to compounds of the general formula I as defined below, or racemates or optical isomers thereof, or pharmaceutically acceptable salts and/or hydrates thereof, wherein
R1Is methyl, ethyl, n-propyl, 4-methylmorpholinyl;
R2Is H, the substitution position of which is the ortho position of the carbon atom on the benzene ring to which X is connected;
X is O;
y is
R3Is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) An alkoxy group.
Very particular preference is given according to the invention to the following derivatives of the general formula I, including racemates or optical isomers thereof, and pharmaceutically acceptable salts and/or hydrates thereof, without these compounds being intended to restrict the invention in any way:
(1) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide
(2) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(3)1- (2-chlorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
(4)1- (3-fluorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
(5) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(6) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(7)1- (4-bromo-2-fluorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
(8) N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide
(9) N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(10)1- (2-chlorophenyl) -N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(11) n- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(12) n- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(13) n- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(14)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(15) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(16) n- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(17) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(18)1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(19) n- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(20) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(21) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(22) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(23)1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
(24) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxylic acid
(25) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(26) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(27)1- (3-fluorophenyl) -4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(28)1- (4-bromo-2-fluorophenyl) -4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(29) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(30) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
(31) 4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
(32)1- (3-fluorophenyl) -4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
(33)1- (4-bromo-2-fluorophenyl) -4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
(34) 4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
The 2-pyridinecarboxamide derivatives of formula I of this invention may be formed with acids into their pharmaceutically acceptable salts according to conventional methods in the art to which this invention pertains. The acid may include inorganic or organic acids, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, and the like. In addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs, according to the present invention, are derivatives of compounds of formula i which may themselves have poor or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The term "halo" as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-to 10-membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples thereof include imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
The invention also relates to the compound with the general formula I, which has strong FLT-3 inhibiting effect, and also relates to the application of the compound and the pharmaceutically acceptable salt and hydrate thereof in preparing medicaments for treating diseases caused by abnormal high expression of FLT-3 kinase, in particular to the application in preparing medicaments for treating and/or preventing cancers.
The following schemes 1-3 describe the preparation of compounds of general formula I according to the invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these equations or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these equations are as defined below or in the claims.
According to the invention, compounds of the formula I in which Y isR3As defined in the summary section, can be prepared from intermediate a and intermediate B by substitution reactions in the manner of scheme 1.
The compounds of formula I, intermediates A, according to the invention are prepared as in scheme 2, and the other substituents are as defined in the claims.
According to the invention, compounds of the formula I in which Y isintermediate B is prepared as in scheme 3, and the other substituents are as defined in the claims.
Substituents R of all intermediates in the above three routes1、R2、R3As defined in the claims.
The specific implementation mode is as follows:
The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the compounds was measured using BrukeraRx-300 and Mass Spectroscopy was measured using Agilent1100 LC/MSD; all reagents used were analytically or chemically pure.
The compounds of examples 1-34 were each prepared according to preparative general method 1 (see Table I).
Watch 1
Example 1
4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:455.16.
Example 2
4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:469.18.
Example 3
1- (2-chlorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:489.12.
example 4
1- (3-fluorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:473.15.
Example 5
4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:523.15.
Example 6
4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
The method comprises the following steps: preparation of 4-chloropyridinoyl chloride (2)
A150 mL round-bottom flask was charged with picolinic acid (10g,0.081mol), NaBr (0.1g,0.001mol) and 50mL of thionyl chloride sequentially for ultrasonic dissolution, and refluxed at 85 ℃ for 24 h. The reaction solution is cooled to room temperature and then concentrated, and a proper amount of toluene is added for standby application, so that light yellow liquid which is a target product is obtained, and the yield is about 97.5%.
Step two: preparation of ethyl 4-chloropicolinate (3)
30mL of dichloromethane, ethanol (16.43g,0.17mol), and triethylamine (17.17g,0.17mol) were added successively to a 100mL round bottom flask, stirred under ice bath conditions for 20min, key intermediate 2(16.43 g,0.11mol) was added dropwise, and stirred under ice bath conditions for 0.5 h. Adding the reaction solution into a proper amount of saturated salt solution, adding a proper amount of NaOH aqueous solution to adjust the pH value to 9-10, extracting with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, concentrating, adding a small amount of petroleum ether, precipitating a large amount of light yellow solids, and performing suction filtration to obtain a target product with the yield of 80%.
Step three: preparation of ethyl 4- (4-nitrophenoxy) picolinate (4)
The key intermediate 3(13.22g,0.071mol) and p-nitrophenol (3.61g,0.026mol) were added sequentially to a 150mL round bottom flask, dissolved with 40mL chlorobenzene under ultrasound, then warmed to 130 deg.C and condensed at reflux for 4 h. After the reaction liquid is cooled to room temperature, pouring the reaction liquid into 100mL of cold petroleum ether solvent, stirring for 10min at normal temperature, and pouring out the supernatant to leave viscous liquid. Dissolving the viscous liquid with appropriate amount of dichloromethane, adding appropriate amount of NaOH aqueous solution to adjust pH to 9-10, extracting with dichloromethane, mixing organic layers, drying with anhydrous sodium sulfate, concentrating, adding small amount of petroleum ether to precipitate out a large amount of pale yellow solid, and filtering to obtain the target product with a yield of 80%.
Step four: 4- (4-Nitrophenoxy) picolinic acid (5)
A100 mL round bottom flask was charged with intermediate 4(10g,0.035mol) dissolved in 20mL ethanol, 10% NaOH (22.8g,0.057mol) was added dropwise at room temperature and stirred at room temperature for 1 h. After most of the reaction liquid is dried by spinning, 250mL of saturated saline solution is added, the mixture is stirred at room temperature, concentrated hydrochloric acid is added dropwise to adjust the pH value to 2-3, a light yellow solid is separated out, and the stirring is continued for 3 hours. And (5) carrying out suction filtration to obtain a solid, and drying to obtain 7.51g of a light yellow solid with the yield of 83.2%.
Step five: preparation of 4- (4-Nitrophenoxy) picolinoyl chloride (6)
A50 mL round-bottomed flask was charged with intermediate 5(5g,0.019mol) and dissolved by sonication with 15mL thionyl chloride, then warmed to 85 ℃ and stirred for 10min, then DMF (0.073g,0.001mol) was added dropwise and stirred for 40 min. And concentrating the reaction solution, and adding a proper amount of toluene for later use. A pale yellow liquid was obtained as the desired product in about 98.0% yield.
Step six: preparation of 4-chloro-N-methylpyridinamide (7)
30mL of dichloromethane, 30% aqueous methylamine solution (5.66g,0.0377mol) and triethylamine (3.81g,0.0377mol) were added sequentially to a 100mL beaker, and after stirring for 20min under ice bath conditions, key intermediate 6 (5.24g,0.0188mol) was added dropwise, with stirring continuing under ice bath conditions for 0.5 h. Adding the reaction solution into a proper amount of saturated salt solution, adding a proper amount of NaOH aqueous solution to adjust the pH value to 9-10, extracting with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, concentrating, adding a small amount of petroleum ether, precipitating a large amount of tawny solids, and performing suction filtration to obtain a target product 7 with the yield of 85%.
Step seven: preparation of 4-chloro-N-methylpyridinamide (A)
A50 mL round bottom flask was charged with key intermediate 7(4.37g,0.016mol), activated carbon (1.92g,0.16mol) and FeCl in sequence3·6H2O (0.43g,0.0016mol) is dissolved with 20mL ethanol by ultrasound, condensed and refluxed at 90 ℃ for 0.5h, then 80% hydrazine hydrate (8.0g,0.128mol) is added dropwise, and stirring is continued for 3-4 h. And (3) carrying out suction filtration on the solution while the solution is hot, leaving filtrate, carrying out spin drying, adding a proper amount of isopropanol and petroleum ether to precipitate brown solid, and carrying out suction filtration to obtain a target product 8 with the yield of 70%.
Step eight: (E) -ethyl 2- (2- (3-methoxyphenyl) hydrazono) -3-oxobutanoate (9)
10mL of water, 40mL of ethanol and anhydrous sodium acetate were added to a 250mL three-necked flask (A flask) and sonicated to dissolve, ethyl acetoacetate (21.06g,0.162mol) was added and the mixture was stirred at room temperature for 2 h. Adding 3-methoxyaniline (10g,0.081mol) and 10mL of water into another 250mL (B bottle) three-neck bottle, mixing, stirring at room temperature, dropwise adding concentrated hydrochloric acid to adjust pH to 2-3, cooling to-5 deg.C with ice salt bath, dropwise adding 20mL of 50% sodium nitrite aqueous solution, keeping solution temperature below 0 deg.C, and stirring for 30 min. If there is a solid in the solution, a small amount of water is added to keep the diazonium salt solution clear. And (3) cooling the mixed solution in the bottle A to below 0 ℃, mechanically stirring for 10min, slowly dropping the diazonium salt solution in the bottle B, generating a large amount of yellow solid in the reaction solution, adding 100mL of saturated saline after dropping, and keeping the temperature below 0 ℃ for reacting for 2 h. Suction filtration left a yellow solid, which was washed with appropriate amount of water and dried to give 23.4g of a yellow solid in 93% yield.
Step nine: 1- (3-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid ethyl ester (10)
A100 mL round bottom flask was charged with intermediate 9(5g,0.0214mol), ethoxycarbonylmethylenetriphenylphosphonium (9.39g,0.027mol), Et2NH (0.28mL,0.0027mol) and 30mL DMSO, after ultrasonic dissolution, the temperature is raised to 85 ℃ for reaction for 4h, and the intermediate 10 is not reacted completely. The reaction solution is cooled to room temperature, poured into 500mL of water, extracted by dichloromethane, the organic layers are combined, washed with saturated saline solution for three times, dried by anhydrous sodium sulfate and dried in a rotary manner to obtain brown oily substance, and the intermediate 9 can be remained in the product. The yield was about 70%.
Step ten: 1- (3-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid (11)
A50 mL round bottom flask was charged with intermediate 10(3g,0.0116mol) dissolved in 20mL ethanol, 10% NaOH (7.0g,0.0174mol) was added dropwise at room temperature, and the mixture was stirred at 60 ℃ for 1 h. And after the solvent is completely and rotationally dried after the reaction, adding 50mL of saturated salt water, stirring at room temperature, dropwise adding concentrated hydrochloric acid to adjust the pH value to 2-3, separating out a light yellow solid, performing suction filtration, and drying to obtain 2.22g of the light yellow solid, wherein the yield is 83%.
step eleven: 1- (3-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carbonyl chloride (B)
A100 mL round-bottom flask was charged with intermediate 11(1g,0.0043mol), 10mL toluene, pyridine (0.679g,0.0086mol), and 10mL thionyl chloride, dissolved by sonication, and allowed to warm to 85 ℃ for 6 h. And cooling the reaction liquid to room temperature, and evaporating toluene and thionyl chloride under reduced pressure to obtain oily liquid acyl chloride. The yield is about 78%
Step twelve: 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide (I)
to a 50mL round bottom flask (A bottle) was added intermediate A (0.05g,0.00021mol), N-diisopropylethylamine (0.5mL,0.003mol), and 10mL of dichloromethane in succession. Intermediate B (0.2g,0.00071mol) was dissolved in 5mL dichloromethane in a 50mL round bottom flask (B bottle). And (4) dropwise adding the solution B into the solution A under an ice bath condition, slowly raising the temperature to room temperature after dropwise adding, and reacting for 0.5 h. After the reaction is finished, 5mL of 5% sodium hydroxide aqueous solution is added, the pH value is adjusted to 9-10, dichloromethane is used for extraction, organic layers are combined, anhydrous sodium sulfate is used for drying and concentrating, a small amount of petroleum ether is added, a large amount of off-white solid is separated out, and the target product is obtained through suction filtration, wherein the yield is 70%.
ESI-MSm/z:539.14；1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),9.01(s,1H), 8.95(d,J＝4.1Hz,1H),8.66(d,J＝5.1Hz,1H),8.13(d,J＝10.7Hz,1H),8.03(d,J＝ 7.0Hz,1H),7.87(d,J＝7.0Hz,2H),7.82(d,J＝7.6Hz,2H),7.70(d,J＝8.6Hz,1H), 7.60(d,J＝8.7Hz,1H),7.55(s,1H),7.34(s,1H),2.92(s,3H),2.23(s,3H),1.35(s, 3H).
Example 7
1- (4-bromo-2-fluorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:551.06；1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.93(d,J＝ 4.7Hz,1H),8.65(d,J＝5.5Hz,1H),8.10(d,J＝6.7Hz,1H),7.96(s,1H),7.94(s,1H), 7.92(s,1H),7.80(d,J＝8.6Hz,1H),7.74(d,J＝8.1Hz,1H),7.57(d,J＝9.0Hz,1H), 7.50(s,1H),7.32(d,J＝2.3Hz,1H),7.21(s,1H),2.61(s,3H),1.40(s,3H).
Example 8
n- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:473.15.
example 9
N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:487.17.
Example 10
1- (2-chlorophenyl) -N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:507.11.
Example 11
N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:491.14.
example 12
N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:541.14.
example 13
N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:557.13.
Example 14
1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:569.05.
Example 15
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:483.19.
Example 16
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:483.19.
Example 17
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:487.17.
example 18
1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:565.08；1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.14(s,1H), 8.93(s,1H),8.62(d,J＝5.5Hz,1H),7.94(d,J＝8.8Hz,2H),7.81(d,J＝8.1Hz,1H), 7.75(d,J＝8.5Hz,1H),7.48(d,J＝6.3Hz,1H),7.34(d,J＝8.8Hz,2H),7.27(d,J＝ 3.0Hz,1H),7.20(s,1H),3.40–3.37(m,2H),2.51(s,3H),1.19(t,J＝7.1Hz,3H).
Example 19
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:553.16；1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.28(s,1H), 8.94(s,1H),8.61(d,J＝5.5Hz,1H),7.94(d,J＝8.9Hz,2H),7.76(d,J＝7.9Hz,1H), 7.70(d,J＝7.3Hz,2H),7.48(d,J＝2.2Hz,1H),7.34(d,J＝8.8Hz,2H),7.27(d,J＝ 2.4Hz,1H),7.20(s,1H),3.37(dd,J＝13.4,6.7Hz,2H),2.52(s,3H),1.19(t,J＝7.1Hz, 3H).
Example 20
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:501.18；1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.84(t,J＝5.8 Hz,1H),8.52(d,J＝5.5Hz,1H),7.84(d,J＝8.2Hz,2H),7.44(s,1H),7.41(s,2H), 7.38(d,J＝12.4Hz,2H),7.24(d,J＝8.5Hz,2H),7.17(d,J＝3.7Hz,1H),7.07(s,1H), 3.32–3.26(m,2H),2.42(s,3H),2.14(s,3H),1.10(t,J＝7.0Hz,3H).
example 21
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:501.18；1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.96(s,1H), 8.65(s,1H),7.99(s,1H),7.97(s,1H),7.72(d,J＝8.1Hz,2H),7.51(d,J＝2.0Hz,1H), 7.45(d,J＝8.0Hz,2H),7.37(d,J＝8.8Hz,2H),7.30(d,J＝2.9Hz,1H),7.17(s,1H), 3.40(dd,J＝13.2,6.7Hz,2H),2.63(s,3H),2.52(s,3H),1.22(t,J＝7.1Hz,3H).
Example 22
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:505.16；1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.94(s,1H), 8.63(s,1H),7.97(d,J＝8.8Hz,2H),7.81(d,J＝10.2Hz,1H),7.74(d,J＝7.9Hz,1H), 7.69(d,J＝7.7Hz,1H),7.50(d,J＝2.3Hz,1H),7.44(d,J＝7.9Hz,1H),7.36(d,J＝ 8.8Hz,2H),7.29(d,J＝2.5Hz,1H),7.19(s,1H),3.38(dd,J＝13.3,6.5Hz,2H),2.52 (s,3H),1.20(t,J＝7.1Hz,3H).
Example 23
1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:583.07.
example 24
N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:571.15.
Example 25
4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:497.21.
Example 26
4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:497.21.
Example 27
1- (3-fluorophenyl) -4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:501.18.
example 28
1- (4-bromo-2-fluorophenyl) -4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:579.09；1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.98(d,J＝ 5.9Hz,1H),8.69(d,J＝5.6Hz,1H),8.07(d,J＝12.8Hz,1H),7.99(d,J＝9.6Hz,1H), 7.82(s,1H),7.80(d,J＝2.6Hz,2H),7.75(d,J＝9.0Hz,1H),7.60(d,J＝8.9Hz,1H), 7.52(s,1H),7.37(d,J＝2.5Hz,1H),7.25(s,1H),3.41–3.33(m,2H),2.64(s,3H), 1.64(dt,J＝14.4,7.1Hz,2H),0.98(t,J＝7.4Hz,3H).
Example 29
4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:567.17.
Example 30
4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:551.18.
Example 31
4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:582.26.
example 32
1- (3-fluorophenyl) -4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:586.62.
Example 33
1- (4-bromo-2-fluorophenyl) -4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:664.14.
Example 34
4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MSm/z:636.23.
In vitro antitumor cell Activity
The pyridine pyridazine derivative containing the formula I performs in-vitro activity screening for inhibiting human cervical cancer cell Hela, colon cancer cell HT-29, breast cancer cell MCF-7, lung adenocarcinoma cell A549 and leukemia cell MV 4-11.
(1) After the cells were thawed and passaged 3-5 times for stabilization, they were digested from the bottom of the flask with 1mL trypsin solution (0.25%) for about 30s, and the medium was added to stop the digestion and transferred to a centrifuge tube. Centrifuging the centrifuge tube at 1000r/min for 3min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. In the 96-well plate, 180. mu.L of the cell suspension was added to the blank A1 well except that 180. mu.L of the medium was added to the blank A1 well. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 20. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample to 2 mg/mL of the liquid, and then the sample was diluted to 20,4,0.8,0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) the drug-carrying culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 20 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 3.5h, the MTT solution is discarded, and 180 mu L of dimethyl sulfoxide is added. Oscillating on a magnetic oscillator to ensure that the living cells react with MTT reaction product Afully dissolving, and placing into an enzyme-linked immunosorbent assay device to determine the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the compounds on inhibiting the activities of cervical cancer cell Hela, colon cancer cell HT-29, breast cancer cell MCF-7, lung adenocarcinoma cell A549 and leukemia cell MV4-11 (see table II).
FLT-3 enzyme Activity assay
The assay used to measure FLT-3 kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows:
The example compound, 50pMc-Met (His-tagged recombinant human FLT-3, expressed by baculovirus and 5. mu. MATP in assay buffer (25mM OPS, pH7.4,5mM MgCl.) was plated on 0.25mg/mL PGT at room temperature2,0.5raMMnCl2100 μ M sodium orthovanadate, 0.01% TritonX-100,1mM DTT, and finally a DMSO concentration of 1% (v/v)) for 20 minutes. The reaction mixture was removed by washing and the phosphorylated polymer substrate was detected with 0.2. mu.g/mL of a phosphotyrosine-specific monoclonal antibody (PY20) conjugated with horseradish peroxidase (HRP). After the color development was stopped by adding 1M phosphoric acid, the color of the developed substrate (TMB) was quantified spectrophotometrically at 450 nm. Inhibition data of the example compounds on FLT-3 kinase (see table two).
Watch two
From the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, which is equivalent to or superior to the anti-tumor drug cisplatin on the market.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (8)
1. A compound of formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein
R1is methyl, dimethyl, ethyl, n-propyl, isopropyl, 4-methylmorpholinyl, cyano;
R21-4 same or different hydrogen and fluorine;
X is O, S;
y is-Ar1-Ar2；
Ar1Is a 6-membered heteroaryl group, which heteroaryl group contains 2 heteroatoms of N and 1 heteroatom of O;
Ar2Is (C)6-C10) Heteroaryl group, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R3Is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, optionally halogenated (C)1-C4) Alkyl or (C)1-C4) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group.
2. A compound of general formula i according to claim 1, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein
R1Is methyl, ethyl, n-propyl, 4-methylmorpholinyl;
R2Is H, the substitution position of which is the ortho position of the carbon atom on the benzene ring to which X is connected;
x is O;
R3Is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, optionally halogenated (C)1-C4) Alkyl or (C)1-C4) Alkoxy, mono-or di (C)1-C4Alkyl) substituted amino, (C)1-C4) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C4) Alkylsulfinyl, sulfonyl, (C)1-C4) Alkanoyl, carbamoyl, mono-or di (C)1-C4Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group.
3. A compound of formula i according to claim 1, wherein Y is Y, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof
R3Is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) An alkoxy group.
4. A compound of the following general formula I:
(1) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide;
(2) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(3)1- (2-chlorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(4)1- (3-fluorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(5) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(6) 4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(7)1- (4-bromo-2-fluorophenyl) -4-methyl-N- (4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(8) n- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide;
(9) N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(10)1- (2-chlorophenyl) -N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(11) N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(12) N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(13) n- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(14)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(15) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(16) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(17) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(18)1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(19) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(20) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(21) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(22) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(23)1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(24) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carbonyl;
(25) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (o-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(26) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(27)1- (3-fluorophenyl) -4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(28)1- (4-bromo-2-fluorophenyl) -4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(29) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (3- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(30) 4-methyl-6-oxo-N- (4- ((2- (propylamino) pyridin-4-yl) oxy) phenyl) -1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
(31) 4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
(32)1- (3-fluorophenyl) -4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(33)1- (4-bromo-2-fluorophenyl) -4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
(34) 4-methyl-N- (4- ((2- ((3-morpholino) carbamoyl) pyridin-4-yl) oxy) phenyl) -6-oxo-1- (3- (trifluoromethyl) phenyl) -1, 6-dihydropyridazine-3-carboxamide.
5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient, in combination with a pharmaceutically acceptable excipient.
6. The use of a compound of any one of claims 1 to 4, and pharmaceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition according to claim 4, for the preparation of a medicament for the treatment and/or prevention of a proliferative disease.
7. use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
8. use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment and/or prophylaxis of advanced solid tumors, bladder cancer, non-small cell lung cancer, breast cancer, renal cancer.
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| CN111303121A (en) * | 2020-04-20 | 2020-06-19 | 辽宁大学 | 4-phenoxypyridine compound containing quinoxalinone and application thereof |
| CN111533735A (en) * | 2020-05-08 | 2020-08-14 | 张建蒙 | Oxo-dihydropyridazine thiazole derivative and application thereof in antitumor drugs |
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Cited By (4)
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| CN110642837A (en) * | 2019-11-07 | 2020-01-03 | 江西科技师范大学 | Pyridine amide compound containing triazole or quinolinone structure and application thereof |
| CN111303121A (en) * | 2020-04-20 | 2020-06-19 | 辽宁大学 | 4-phenoxypyridine compound containing quinoxalinone and application thereof |
| CN111533735A (en) * | 2020-05-08 | 2020-08-14 | 张建蒙 | Oxo-dihydropyridazine thiazole derivative and application thereof in antitumor drugs |
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