CN110642837B - Pyridine amide compound containing triazole or quinolinone structure and application thereof - Google Patents
Pyridine amide compound containing triazole or quinolinone structure and application thereof Download PDFInfo
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Abstract
The invention provides a pyridine amide compound containing a triazole or quinolinone structure and application thereof. According to the technical scheme, the pyridine amide compounds are widely researched, a plurality of structural sites are modified and reformed, and a series of pyridine amide derivatives with novel structures are synthesized. On the basis, the chemical property and the biological property of the compound are considered, and the result shows that the compound has stronger c-Met kinase inhibition effect and can play a role in treating diseases caused by abnormal high expression of c-Met kinase; based on the above beneficial findings, the present invention determines the use of the compound or its derivative for the preparation of a proliferative disease drug or a tumor drug; the experimental result shows that the compound has exact and obvious inhibition effect on tumor cells, thereby providing data support for the pharmaceutical application of the compound.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a pyridine amide compound containing a triazole or quinolinone structure and application thereof.
Background
Malignant tumors are a disease that seriously jeopardizes human health and life. Human malignancies cause mortality second to cardiovascular, ranked second. c-Met kinase is widely present in epithelial tissues and plays an important role in embryonic development and wound healing. Recent studies report that c-Met kinase exhibits abnormally high expression, mutation or activity change in tumor tissues such as lung cancer, colon cancer, liver cancer, rectal cancer, stomach cancer, kidney cancer, ovarian cancer, glioma, melanoma, breast cancer, prostate cancer and the like. The c-Met kinase can promote the proliferation of tumor cells, regulate the migration of the tumor cells, enhance the invasion capacity of the tumor cells and induce the generation of tumor new vessels.
Research shows that the interaction between c-Met and membrane receptor influences the action of signal molecules, further influences the invasion and metastasis of tumor and the generation process of new blood vessels, and thus leads to the emergence of tumor drug resistance. A large number of researches prove that the c-Met signal pathway is related to tumor drug resistance, which provides a theoretical basis for the development of multi-target kinase inhibitors. Receptor Tyrosine Kinases (RTKs) play a crucial role in signal transduction pathways and cellular processes, many of which are involved in cancer. c-Met (hepatocyte growth factor/scatter factor receptor (HGF/SF)) belongs to the RTK subfamily consisting of an extracellular α chain and a transmembrane chain linked by a disulfide bond. The presence of c-Met has been shown to include various possibilities, including being amplified or overexpressed in brain, colorectal, gastric, lung, head, neck and olfactory cancers. At present, c-Met kinase has become an important target for the research of antitumor drugs.
In the prior art, c-Met kinase inhibitors including crizotinib, voritinib and the like have been applied to a certain extent; however, the available drugs for treating diseases caused by abnormally high expression of c-Met kinase are still relatively limited, and under the circumstances, if a completely new c-Met kinase inhibitory drug can be developed, the range of the available drugs for treating part of cancers and proliferative diseases is expected to expand.
Disclosure of Invention
The invention aims to provide a pyridine amide compound containing a triazole or quinolinone structure and application thereof aiming at overcoming the technical defects in the prior art, so as to solve the technical problem that the compound does not exist in the prior art.
The invention also aims to solve the technical problem of expanding the selectable range of c-Met kinase inhibition drugs.
The invention further solves the technical problem of expanding the application range of the compound.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
the invention relates to a pyridine amide compound containing triazole or quinolinone structure shown in a general formula I, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
R 1 is methyl, ethyl, n-propyl, isopropyl, 4-methylmorpholinyl, cyclopentyl, cyclohexyl, 2-ethylthiophene, 4-methylmorpholinyl, cyano;
R 2 selected from 1 to 4 same or different hydrogen and fluorine;
x is O and S;
y is-Ar 1 -Ar 2 ；
Ar 1 Is (C) 5 -C 10 ) Heteroaryl, which heteroaryl contains 2 to 3 heteroatoms of N/O;
Ar 2 is (C) 6 -C 10 ) Heteroaryl group, ar 2 Removing Ar 1 And in addition, is also represented by R 3 Substituted aryl substitution;
R 3 is 1-2 selected from hydrogen, halogen, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Alkylthio, mono-or di (C) 1 -C 6 Alkyl) substituted amino, (C) 1 -C 6 ) Alkylamido, free, salified, esterified and amidated carboxyl, (C) 1 -C 6 ) Alkylsulfinyl, sulfonyl, (C) 1 -C 6 ) Alkanoyl, carbamoyl, mono-or di (C) 1 -C 6 Alkyl) substituted carbamoyl, (C) 1 -C 3 ) A substituent of an alkylenedioxy group.
The 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 R is 1 Is methyl, ethyl, n-propyl, 4-methylmorpholinyl, cyclopentyl, 2-ethylthiophene;
R 2 is F/H, and the substitution position is the ortho position of the carbon atom connected with X on the benzene ring;
x is O;
y is-Ar 1 -Ar 2 ；
Ar 1 Is (C) 5 -C 10 ) Heteroaryl, which heteroaryl contains 2 to 3 heteroatoms of N/O;
Ar 2 is (C) 6 -C 10 ) Heteroaryl group, ar 2 Removing Ar 1 And in addition, is also represented by R 3 Substituted aryl substitution;
R 3 is 1-2 selected from hydrogen, halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, optionally halogenated (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) Alkoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino, (C) 1 -C 4 ) Alkoxy group, (C) 1 -C 4 ) Alkyl, (C) 1 -C 6 ) Alkanoyl, carbamoyl, mono-or bis (C) 1 -C 6 Alkyl) substituted carbamoyl, (C) 1 -C 3 ) An alkylenedioxy group.
The invention preferably also relates to compounds of the general formula I as defined below and to pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein R is 1 Is methyl, ethyl, n-propyl, 4-methylmorpholinyl, cyclopentyl, 2-ethylthiophene;
R 2 is F/H, and the substitution position is the ortho position of the carbon atom connected with X on the benzene ring;
x is O;
y is
R 3 Is hydrogen, 3-methyl, 4-fluoro, 4-chloro, 4-bromo, 2-methoxy, 2-trifluoromethyl, 4-methoxy, 2-chloro-4-trifluoromethyl, 3-fluoro-4-fluoro and 4-bromo-2-fluoro.
Very particular preference is given according to the invention to the derivatives of the following 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) N-ethyl-4- (4- (5- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide;
(2) N-ethyl-4- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) pyridinecarboxamide;
(3) N-ethyl-4- (4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) picolinamide;
(4) N-ethyl-4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) picolinamide;
(5) 4- (4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N-propylpicolinamide;
(6) 4- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N-propylpicolinamide;
(7) 4- (4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N-propylpicolinamide;
(8) 4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide;
(9) 4- (4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) -N-propylpicolinamide;
(10) 4- (2-fluoro-4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) -N-propylpicolinamide;
(11) 4- (4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thiophen-2-yl) ethyl) pyridinamide;
(12) 4- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N- (2- (thiophen-2-yl) ethyl) pyridinamide;
(13) 4- (4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thiophen-2-yl) ethyl) pyridinamide
(14) 4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thiophen-2-yl) ethyl) pyridinamide
(15) 4- (4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
(16) 4- (2-fluoro-4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
(17) 5-methyl-1-phenyl-N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
(18) N- (3-fluoro-4- (((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide
(19) 1- (4-fluorophenyl) -5-methyl-N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
(20) N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide
(21) 4- (4- (1- (2-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
(22) 4- (4- (1- (3-chloro-4- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
(23) N-propyl-4- (4- (5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide
(24) 4- (4- (1- (3, 4-difluorophenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) -N-propylpicolinamide
(25) 4- (4- (1- (2-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) -2-fluorophenoxy) -N-propylpicolinamide
(26) 4- (4- (1- (3-chloro-4- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) -2-fluorophenoxy) -N-propylpicolinamide
(27) 4- (2-fluoro-4- (5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
(28) 4- (4- (1- (3, 4-difluorophenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide) -2-fluorophenoxy) -N-propylpicolinamide
(29) 3- (2-chloro-5- (trifluoromethyl) phenyl) -N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -4- (trifluoromethyl) -3H-pyrazole-5-carboxamide
(30) 1- (3-chloro-4- (trifluoromethyl) phenyl) -N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
(31) N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
(32) 1- (3, 4-difluorophenyl) -N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
(33) 3- (2-chloro-5- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -4- (trifluoromethyl) -3H-pyrazole-5-carboxamide
(34) 1- (3-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
(35) N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
(36) 1- (3, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
(37) 4- (4- (4-methyl-3- (2- (trifluoromethoxy) phenyl) -3H-pyrazole-5-carboxamido) phenoxy) -N- (3-morpholinopropyl) pyridinamide
(38) 4- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (3-morpholinopropyl) pyridinamide
(39) N- (3-fluoro-4 ((2- (((3-morpholinopropyl) amino) methyl) pyridin-4-yl) oxy) phenyl) -4-methyl-3- (2- (trifluoromethoxy) phenyl) -3H-pyrazole-5-carboxamide
(40) 4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (3-morpholinopropyl) pyridinamide
(41) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide
(42) 1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
(43) N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
(44) 1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
(45) N- (3-fluoro-4- ((2- ((2- (thien-2-yl) ethyl) carbamoyl) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-oxy-1, 4-dihydroquinoline-3-carboxamide
(46) 1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((2- ((2- (thien-2-yl) ethyl) carbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
The picolinamide derivatives of formula I of the present invention may be used with acids to form pharmaceutically acceptable salts thereof according to conventional methods in the art to which the present 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 a group 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 there may be mentioned, for example, 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; the 5-to 10-membered heterocyclic group includes those containing one or more hetero atoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, and the ring system contains a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double bonds or carbon-carbon triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
The invention also relates to a compound with a general formula I, which has a strong effect of inhibiting c-Met kinase, and also relates to application of the compound and pharmaceutically acceptable salts and hydrates thereof in preparing medicines for treating diseases caused by abnormal high expression of c-Met kinase, in particular to application in preparing medicines 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 schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these diagrams are as defined below or in the claims.
According to the invention, compounds of the formula I in which Y is
When R is 3 As defined in the summary of the invention, each can be prepared according to the method of scheme 1.1 from intermediate A and intermediate B 1 Examples 1-20 were prepared by substitution reactions.
According to the invention, compounds of the formula I in which Y is
When R is 3 As defined in the summary of the invention, each can be prepared according to the method of scheme 1.2 from intermediate A and intermediate B 2 Examples 21-40 were prepared by substitution reactions.
According to the invention, compounds of the formula I in which Y is
When R is 3 As defined in the summary of the invention, each can be prepared according to the method of scheme 1.3 from intermediate A and intermediate B 3 Examples 41-46 were prepared by substitution reactions.
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.
The compounds of formula I according to the invention, intermediates B 1 And B 2 The process is as in scheme 3.1, and the other substituents are as defined in the claims.
The compounds of formula I according to the invention, intermediates B 3 The process is as in scheme 3.2, and the other substituents are as defined in the claims.
Substituents R of all intermediates in the above three routes 1 、R 2 、R 3 As defined in the claims.
The invention provides a pyridine amide compound containing a triazole or quinolinone structure and application thereof. According to the technical scheme, the pyridine amide compounds are widely researched, a plurality of structural sites are modified and reformed, and a series of pyridine amide derivatives with novel structures are synthesized. On the basis, the chemical property and the biological property of the compound are considered, and the result shows that the compound has stronger c-Met kinase inhibition effect and can play a role in treating diseases caused by abnormal high expression of c-Met kinase; based on the above beneficial findings, the present invention determines the use of the compound or its derivative for the preparation of a proliferative disease drug or a tumor drug; the experimental result shows that the compound has exact and obvious inhibition effect on tumor cells, thereby providing data support for the pharmaceutical application of the compound.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. Well-known structures or functions may not be described in detail in the following embodiments in order to avoid unnecessarily obscuring the details. Approximating language, as used herein in the following examples, may be applied to identify quantitative representations that could permissibly vary in number without resulting in a change in the basic function. Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
NMR of the compounds was measured using BrukeraRx-400 and Mass Spectroscopy was measured using Agilent1100 LC/MSD; all reagents used were analytically or chemically pure. The compounds of examples 1-40 were prepared according to the general procedure for preparation of example 1; the general procedure for the preparation of example 41 was followed to prepare the compounds of examples 41-46, respectively (see Table I).
TABLE A list of product structures for examples 1-46
Example 1N-Ethyl-4- (4- (5- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide
1 H NMR(400MHz,DMSO-d 6 )δ10.75(s,1H),8.83(s,1H),8.51(d,J＝5.3Hz,1H),8.03(s,1H),8.01(s,1H),7.63(s,5H),7.41(s,1H),7.23(d,J＝8.5Hz,2H),7.17(d,J＝3.0Hz,1H),3.28(dd,J＝13.3,6.6Hz,2H),2.59(s,3H),1.09(t,J＝7.0Hz,3H).
ESI-MS m/z:442.18
The method comprises the following steps: preparation of 4-chloropyridinoyl chloride (b)
Picolinic acid (10 g, 0.081mol), thionyl chloride (50 mL) were added successively for ultrasonic dissolution and NaBr (0.1 g, 0.001mol) to a 150mL round bottom flask, gradually warmed to 85 ℃ and refluxed for 24h. After the reaction liquid is cooled to room temperature, the solvent is removed by reduced pressure distillation, and a proper amount of toluene is added for standby. A yellowish liquid is obtained in a yield of about 97.5%.
Step two: preparation of ethyl 4-chloropicolinate (c)
Dichloromethane (30 mL), ethanol (16.43g, 0.17mol) and triethylamine (17.17g, 0.17mol) were added successively to a 100mL round bottom flask, stirred for 20min under ice bath, intermediate b (16.43g, 0.11mol) was added dropwise, and stirring continued for 0.5h. Adding the reaction solution into a proper amount of saturated saline solution, adding 10% NaOH aqueous solution to adjust the pH 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 solid, filtering, and drying to obtain light yellow solid 25.2g with a yield of 80.2%.
Step three: preparation of ethyl 4- (4-nitrophenoxy) picolinate (d)
Intermediate c (13.22g, 0.071mol) and p-nitrophenol (3.61g, 0.026mol) were dissolved in chlorobenzene (40 mL) in a 150mL round-bottom flask, sonicated, warmed to 130 deg.C and condensed at reflux for 4h. The reaction was cooled to room temperature, poured into cold petroleum ether (100 mL) and stirred at room temperature for 10min, and the supernatant was discarded to leave a 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, vacuum filtering, and oven drying to obtain pale yellow solid 16.35g with a yield of 80.0%.
Step four: 4- (4-Nitrophenoxy) picolinic acid (e)
Add intermediate d (10g, 0.035 mol) and ethanol (20 mL) successively to a 100mL round-bottomed flask, ultrasonically dissolve, add 10% NaOH (22.8g, 0.057mol) dropwise at room temperature, and stir for 0.5h. Distilling the reaction solution under reduced pressure to remove most of the solvent, adding saturated saline (250 mL), stirring at room temperature, adding concentrated hydrochloric acid to adjust pH to 2-3, precipitating pale yellow solid, and continuously stirring for 12h. Suction filtration and drying are carried out, thus obtaining 7.51g of light yellow solid with the yield of 83.2 percent.
Step five: preparation of 4- (4-Nitrophenoxy) picolinoyl chloride (f)
Add intermediate e (5g, 0.019mol) followed by thionyl chloride (15 mL) to a 50mL round-bottomed flask, dissolve with ultrasound, warm to 90 ℃ and stir for 10min, add DMF (0.073g, 0.001mol) dropwise, stir for 30min. And concentrating the reaction solution, and adding a proper amount of toluene for later use. A yellowish liquid was obtained with a yield of about 98.0%.
Step six: preparation (g) of 4-chloro-N-ethylpyridinamide
Dichloromethane (30 mL), triethylamine (3.81g, 0.0377mol) and 30% aqueous solution of ethylamine (5.66g, 0.0377mol) were added successively to a 100mL beaker, stirred in an ice bath for 20min, intermediate f (5.24g, 0.0188mol) was added dropwise and stirring continued for 1h. Adding the reaction solution into a proper amount of saturated saline solution, adding 10% 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 to separate out a large amount of solid, performing suction filtration, and drying to obtain a yellow brown solid 9.18g, wherein the yield is 84.9%.
Step seven: preparation of 4-chloro-N-methylpyridinamide (A)
Intermediate g (4.37g, 0.016 mol), ethanol (20 mL) and FeCl were added sequentially 3 ·6H 2 O (0.43g, 0.0016 mol) and activated carbon (1.92g, 0.16mol) were put into a 50mL round-bottomed flask, dissolved by ultrasound, warmed to 90 ℃ and condensed under reflux for 0.5h, 80% hydrazine hydrate (8.0 g, 0.128mol) was added dropwise, and stirred for 3-4h. 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, separating out solids, carrying out suction filtration, and drying to obtain 2.88g of brown solids, wherein the yield is 70.1%.
Step eight: preparation of ethyl 5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxylate (i)
To a 100mL round-bottomed flask were added phenylboronic acid (5g, 0.04mol), DMSO (50 mL), cu (OAc) 2 (9g, 0.05mol) and piperidine (4.25g, 0.05mol), and after ultrasonic dissolution, heating to 85 ℃ for reaction for 6 hours until the reaction is complete. The reaction solution was cooled to room temperature, poured into water (500 mL), followed by addition of an appropriate amount of NaOH solution, mixing, extraction with a dichloromethane solution, combination of organic layers, and addition of saturated brineWashed for three times, dried by anhydrous sodium sulfate and spin-dried to obtain yellow oily matter. The yield was about 82.0%.
Step nine: preparation of 5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxylic acid (J)
Intermediate i (3 g, 0.0112mol) and 1,4 dioxane (25 mL) were added successively to a 50mL round bottom flask, 10% NaOH (7.7 g, 0.0194mol) was added dropwise at room temperature, and the mixture was heated to 60 ℃ and stirred until the reaction was complete. And (3) spin-drying the reaction spin solvent, adding 100mL of saturated saline solution, stirring at room temperature, dropwise adding concentrated hydrochloric acid to adjust the pH value to 2-3, separating out solids, performing suction filtration, and drying to obtain 1.90g of light yellow solids, wherein the yield is 85.1%.
Step ten: preparation of 5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carbonyl chloride (B) 1 )
Dichloromethane (20 mL), intermediate J (1.90g, 0.009mol) and oxalyl chloride (1.143g, 0.009mol) were added successively to a 50mL round-bottomed flask, and the dichloromethane was distilled off under reduced pressure at room temperature for 30s to give an oily liquid with a yield of about 90.0%.
Step eleven: preparation of N-ethyl-4- (4- (5- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide (1)
Intermediate A (0.21g, 0.0008mol) and sodium bicarbonate (0.34g, 0.004mol) and dichloromethane (20 mL) were charged to a 50mL round bottom flask. Intermediate B 1 (0.18g, 0.0008mol) was dissolved in methylene chloride (10 mL), and the resulting solution was added dropwise to the methylene chloride solution at 0 ℃ and allowed to slowly warm to room temperature after completion of the addition, followed by reaction for 30min. After the reaction is finished, carrying out suction filtration, and collecting filtrate. The filtrate was transferred to a 50mL separatory funnel, and dichloromethane (10 mL) was added thereto, and the mixture was washed three times with an aqueous solution of sodium carbonate (25 mL), and the organic layer was collected and dichloromethane was distilled off under reduced pressure to obtain 0.25g of a pale yellow solid powder with a yield of 70.0%.
The compounds of examples 1 to 40 were prepared according to the procedure of example 1.
Example 2N-Ethyl-4- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide
1 H NMR(400MHz,DMSO-d 6 )δ10.96(s,1H),8.86(s,1H),8.55(d,J＝5.1Hz,1H),8.10(d,J＝12.9Hz,1H),7.85(d,J＝8.4Hz,1H),7.67(s,5H),7.47-7.40(m,2H),7.23(d,J＝3.3Hz,1H),3.31-3.27(m,2H),2.59(s,3H),1.09(t,J＝6.8Hz,3H).
ESI-MS m/z:460.17
Example 3N-Ethyl-4- (4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide
1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),8.84(s,1H),8.52(d,J＝5.5Hz,1H),8.04(s,1H),8.02(s,1H),7.78(d,J＝4.8Hz,1H),7.76(d,J＝4.7Hz,1H),7.53(d,J＝8.6Hz,2H),7.42(d,J＝1.9Hz,1H),7.24(d,J＝8.8Hz,2H),7.19(d,J＝2.3Hz,1H),3.29(dd,J＝13.5,6.7Hz,2H),2.59(s,3H),1.10(t,J＝7.1Hz,3H).
ESI-MS m/z:460.17
Example 4N-Ethyl-4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide
ESI-MS m/z:478.16
Example 5- (4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.75(s,1H),8.82(s,1H),8.52(d,J＝5.5Hz,1H),8.03(s,1H),8.01(s,1H),7.67(s,2H),7.64(d,J＝6.4Hz,2H),7.43(s,1H),7.23(d,J＝8.4Hz,2H),7.18(d,J＝4.5Hz,1H),3.22(dd,J＝12.8,6.3Hz,2H),2.59(s,3H),1.50(dt,J＝14.1,7.0Hz,2H),0.84(t,J＝7.2Hz,3H).
ESI-MS m/z:456.19
Example 6- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.96(s,1H),8.83(s,1H),8.54(d,J＝5.4Hz,1H),8.11(d,J＝13.2Hz,1H),7.86(d,J＝8.7Hz,1H),7.67(d,J＝2.6Hz,5H),7.48-7.39(m,2H),7.23(d,J＝4.7Hz,1H),3.23(dd,J＝12.9,6.3Hz,2H),2.59(s,3H),1.57-1.4I7(m,2H),0.84(t,J＝7.3Hz,3H).
ESI-MS m/z:474.18
Example 7- (4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H),8.71(s,1H),8.40(d,J＝5.6Hz,1H),7.91(s,1H),7.89(s,1H),7.65(d,J＝4.8Hz,1H),7.63(d,J＝4.6Hz,1H),7.39(t,J＝8.7Hz,2H),7.31(d,J＝2.1Hz,1H),7.11(d,J＝8.8Hz,2H),7.06(d,J＝3.1Hz,1H),3.10(dd,J＝13.3,6.6Hz,2H),2.46(s,3H),1.38(dt,J＝14.2,7.1Hz,2H),0.72(t,J＝7.3Hz,3H).
ESI-MS m/z:474.18
Example 8- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.95(s,1H),8.82(s,1H),8.54(d,J＝5.1Hz,1H),8.10(d,J＝12.7Hz,1H),7.86(d,J＝8.6Hz,1H),7.76(s,2H),7.51(t,J＝8.4Hz,2H),7.44(d,J＝12.9Hz,2H),7.22(d,J＝2.5Hz,1H),3.22(d,J＝6.0Hz,2H),2.58(s,3H),1.51(dd,J＝13.9,6.9Hz,2H),0.84(t,J＝7.2Hz,3H).
ESI-MS m/z:492.17
Example 9- (4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.81(s,1H),8.81(s,1H),8.52(d,J＝5.3Hz,1H),8.03(s,1H),8.01(s,1H),7.88(d,J＝7.7Hz,1H),7.84(d,J＝7.6Hz,1H),7.78(d,J＝7.7Hz,1H),7.72(t,J＝7.2Hz,1H),7.42(s,1H),7.23(d,J＝8.6Hz,2H),7.18(d,J＝0.8Hz,1H),3.22(d,J＝6.2Hz,2H),2.46(s,3H),1.51(dd,J＝14.0,7.0Hz,2H),0.84(t,J＝7.2Hz,3H).
ESI-MS m/z:540.17
Example 10- (2-fluoro-4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.99(s,1H),8.82(s,1H),8.55(d,J＝5.6Hz,1H),8.10(d,J＝13.2Hz,1H),7.88(d,J＝7.5Hz,1H),7.85(d,J＝8.0Hz,2H),7.79(d,J＝8.4Hz,1H),7.73(t,J＝7.5Hz,1H),7.46(d,J＝9.0Hz,1H),7.41(d,J＝2.5Hz,1H),7.23(dd,J＝5.5,2.6Hz,1H),3.26-3.20(m,2H),2.46(s,3H),1.58-1.47(m,2H),0.85(t,J＝7.4Hz,3H).
ESI-MS m/z:558.16
Example 11- (4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinoline amide
1 H NMR(400MHz,DMSO-d 6 )δ10.80(s,1H),9.00(s,1H),8.56(s,1H),8.09(s,2H),7.70(s,6H),7.49(s,1H),7.35(s,1H),7.27(s,1H),7.21(s,1H),6.95(d,J＝13.6Hz,2H),3.59(s,2H),3.11(s,2H),2.64(s,3H).
ESI-MS m/z:524.16
Example 12- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.97(s,1H),8.98(t,J＝5.9Hz,1H),8.55(d,J＝5.6Hz,1H),8.11(d,J＝13.2Hz,1H),7.86(d,J＝8.8Hz,1H),7.67(d,J＝2.3Hz,5H),7.48-7.41(m,2H),7.32(d,J＝4.9Hz,1H),7.24(d,J＝3.0Hz,1H),6.96-6.91(m,1H),6.89(d,J＝2.6Hz,1H),3.54(dd,J＝13.4,6.8Hz,2H),3.06(t,J＝7.1Hz,2H),2.59(s,3H).
ESI-MS m/z:542.15
Example 13- (4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),8.95(s,1H),8.52(d,J＝5.3Hz,1H),7.84(d,J＝8.1Hz,3H),7.69(t,J＝7.9Hz,1H),7.64(d,J＝7.8Hz,1H),7.39(s,1H),7.32(d,J＝4.7Hz,1H),7.24(d,J＝8.4Hz,2H),7.17(d,J＝3.2Hz,1H),7.10(s,1H),6.93(d,J＝4.0Hz,1H),6.89(s,1H),3.53(dd,J＝12.7,6.3Hz,2H),3.05(t,J＝6.8Hz,2H),2.41(s,3H).
ESI-MS m/z:542.15
Example 14- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.99(s,1H),9.00(t,J＝5.7Hz,1H),8.57(d,J＝5.6Hz,1H),8.13(d,J＝13.2Hz,1H),7.88(d,J＝8.8Hz,1H),7.79(d,J＝4.8Hz,1H),7.77(d,J＝4.8Hz,1H),7.54(t,J＝8.7Hz,2H),7.47(d,J＝9.1Hz,1H),7.43(d,J＝2.1Hz,1H),7.34(d,J＝4.6Hz,1H),7.26(d,J＝2.4Hz,1H),6.98-6.94(m,1H),6.91(s,1H),3.55(dd,J＝13.3,6.8Hz,2H),3.08(t,J＝7.1Hz,2H),2.60(s,3H).
ESI-MS m/z:560.14
Example 15- (4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.82(s,1H),8.96(s,1H),8.53(s,1H),8.03(d,J＝7.6Hz,2H),7.88(s,2H),7.79(s,1H),7.72(s,1H),7.43(s,1H),7.32(s,1H),7.24(d,J＝7.6Hz,2H),7.18(s,1H),6.91(d,J＝16.3Hz,2H),3.55(s,2H),3.07(s,2H),2.46(s,3H).
ESI-MS m/z:608.15
Example 16- (2-fluoro-4- (5-methyl-1- (2- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N- (2- (thien-2-yl) ethyl) pyridinamide
1 H NMR(400MHz,DMSO-d 6 )δ10.98(s,1H),8.94(s,1H),8.55(d,J＝5.3Hz,1H),8.10(d,J＝13.2Hz,1H),7.88(d,J＝6.4Hz,2H),7.84(d,J＝7.0Hz,1H),7.78(d,J＝8.1Hz,1H),7.72(t,J＝7.4Hz,1H),7.44(t,J＝8.8Hz,2H),7.31(d,J＝4.1Hz,1H),7.23(d,J＝2.3Hz,1H),6.96-6.92(m,1H),6.90(s,1H),3.55(d,J＝6.2Hz,2H),3.07(t,J＝6.9Hz,2H),2.47(s,3H).
ESI-MS m/z:626.14
Example 17-methyl-1-phenyl-N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:468.19
Example 18N- (3-fluoro-4- (((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamide
ESI-MS m/z:486.18
Example 19 1- (4-fluorophenyl) -5-methyl-N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:486.18
Example 20N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide
ESI-MS m/z:504.17
Example 21- (4- (1- (2-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ11.30(s,1H),8.81(s,1H),8.65(s,1H),8.53(d,J＝4.9Hz,1H),8.21(d,J＝8.0Hz,1H),8.15(d,J＝7.9Hz,1H),8.00(d,J＝8.4Hz,2H),7.42(s,1H),7.27(d,J＝8.5Hz,2H),7.19(d,J＝2.1Hz,1H),3.22(dd,J＝12.2,6.0Hz,2H),1.52(dq,J＝13.9,7.1Hz,2H),0.84(t,J＝7.1Hz,3H).
ESI-MS m/z:612.11
Example 22- (4- (1- (3-chloro-4- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ11.21(s,1H),8.81(s,1H),8.53(d,J＝5.3Hz,1H),8.44(s,1H),8.17(d,J＝8.1Hz,1H),8.10(d,J＝8.4Hz,1H),7.99(d,J＝8.7Hz,2H),7.41(s,1H),7.27(d,J＝8.6Hz,2H),7.19(d,J＝2.9Hz,1H),3.22(dd,J＝12.8,6.2Hz,2H),1.52(dq,J＝14.8,7.4Hz,2H),0.84(t,J＝7.3Hz,3H).
ESI-MS m/z:612.11
Example 23N-propyl-4- (4- (5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) pyridinecarboxamide
1 H NMR(400MHz,DMSO-d 6 )δ11.26(s,1H),8.80(s,1H),8.53(d,J＝5.2Hz,1H),8.15-8.09(m,2H),8.05(d,J＝7.2Hz,1H),8.00(d,J＝7.7Hz,3H),7.43(s,1H),7.27(d,J＝8.5Hz,2H),7.18(d,J＝2.7Hz,1H),3.23(dd,J＝12.4,6.0Hz,2H),1.57-1.47(m,2H),0.84(t,J＝7.3Hz,3H).
ESI-MS m/z:578.15
Example 24- (4- (1- (3, 4-difluorophenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
1 H NMR(400MHz,DMSO-d 6 )δ11.21(s,1H),8.80(s,1H),8.52(d,J＝4.9Hz,1H),8.12(s,1H),7.98(d,J＝6.9Hz,2H),7.81(d,J＝8.9Hz,1H),7.74(s,1H),7.41(s,1H),7.27(d,J＝6.9Hz,2H),7.20(d,J＝2.3Hz,1H),3.26-3.19(m,2H),1.52(dd,J＝13.7,6.8Hz,2H),0.84(t,J＝7.1Hz,3H).
ESI-MS m/z:546.14
Example 25- (4- (1- (2-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) -2-fluorophenoxy) -N-propylpicolinamide
ESI-MS m/z:630.10
Example 26- (4- (1- (3-chloro-4- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) -2-fluorophenoxy) -N-propylpicolinamide
ESI-MS m/z:630.10
Example 27- (2-fluoro-4- (5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamido) phenoxy) -N-propylpicolinamide
ESI-MS m/z:596.14
Example 28- (4- (1- (3, 4-difluorophenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamido) -2-fluorophenoxy) -N-propylpicolinamide
ESI-MS m/z:564.13
Example 29- (2-chloro-5- (trifluoromethyl) phenyl) -N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -4- (trifluoromethyl) -3H-pyrazole-5-carboxamide
ESI-MS m/z:623.12
Example 30- (3-chloro-4- (trifluoromethyl) phenyl) -N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:624.11
Example 31N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:590.15
Example 32- (3, 4-difluorophenyl) -N- (4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:558.14
Example 33- (2-chloro-5- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -4- (trifluoromethyl) -3H-pyrazole-5-carboxamide
ESI-MS m/z:641.11
Example 34- (3-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:642.10
Example 35N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1- (2- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:608.14
Example 36- (3, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (pyrrolidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS m/z:576.13
Example 37- (4- (4-methyl-3- (2- (trifluoromethoxy) phenyl) -3H-pyrazole-5-carboxamido) phenoxy) -N- (3-morpholinopropyl) pyridinamide
ESI-MS m/z:624.62
Example 38- (2-fluoro-4- (5-methyl-1-phenyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N- (3-morpholinopropyl) pyridinamide
ESI-MS m/z:559.23
Example 39N- (3-fluoro-4 ((2- (((3-morpholinopropyl) amino) methyl) pyridin-4-yl) oxy) phenyl) -4-methyl-3- (2- (trifluoromethoxy) phenyl) -3H-pyrazole-5-carboxamide
ESI-MS m/z:628.24
Example 40- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamido) phenoxy) -N- (3-morpholinopropyl) pyridinamide
ESI-MS m/z:577.22
Example 41N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide
1 H NMR(400MHz,DMSO-d 6 )δ12.47(s,1H),8.82(s,1H),8.74(s,1H),8.52(d,J＝5.7Hz,1H),8.47(d,J＝4.0Hz,1H),7.90(d,J＝0.8Hz,1H),7.88(d,J＝0.8Hz,1H),7.81-7.78(m,1H),7.73-7.72(m,2H),7.71-7.70(m,2H),7.62(d,J＝6.6Hz,2H),7.41(s,1H),7.31(s,1H),7.27(d,J＝0.6Hz,1H),7.19(d,J＝1.3Hz,1H),7.12(d,J＝9.0Hz,1H),3.22(dd,J＝6.4,5.2Hz,2H),1.21-1.17(m,3H).
ESI-MS m/z:586.17
The method comprises the following steps: preparation of 4-chloropyridinoyl chloride (b)
A150 mL round bottom flask was charged with picolinic acid (10g, 0.081mol), thionyl chloride (50 mL) successively for ultrasonic dissolution and NaBr (0.1g, 0.001mol), and refluxed at 85 ℃ for 24 hours. After the reaction liquid is cooled to room temperature, the solvent is removed by reduced pressure distillation, and a proper amount of toluene is added for standby. A yellowish liquid is obtained in a yield of about 97.5%.
Step two: preparation of ethyl 4-chloropicolinate (c)
Dichloromethane (30 mL), ethanol (16.43g, 0.17mol) and triethylamine (17.17g, 0.17mol) were added successively to a 100mL round bottom flask, stirred for 20min under ice bath, then intermediate b (16.43g, 0.11mol) was added dropwise, and stirring under ice bath was continued for 0.5h. 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 to separate out a large amount of solids, performing suction filtration, and drying to obtain 25.2g of light yellow solids, wherein the yield is 80.2%.
Step three: preparation of ethyl 4- (4-nitrophenoxy) picolinate (d)
Intermediate c (13.22g, 0.071mol) and p-nitrophenol (3.61g, 0.026mol) were added to a 150mL round bottom flask, dissolved with chlorobenzene (40 mL) followed by sonication, and the temperature was raised to 130 deg.C and reflux condensed for 4h. After the reaction solution was cooled to room temperature, the reaction solution was poured into cold petroleum ether (100 mL) and stirred at room temperature for 10min, and the supernatant was poured off to leave a viscous liquid. Dissolving the viscous liquid with a proper amount of dichloromethane, 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 to separate out a large amount of light yellow solid, performing suction filtration, and drying to obtain 16.35g of light yellow solid, wherein the yield is 80.0%.
Step four: 4- (4-Nitrophenoxy) picolinic acid (e)
Intermediate d (10g, 0.035 mol) and ethanol (20 mL) were added to a 100mL round-bottomed flask, and dissolved by sonication, 10% NaOH (22.8g, 0.057mol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. Distilling the reaction solution under reduced pressure to remove most of the solvent, adding saturated saline (250 mL), stirring at room temperature, dropwise adding concentrated hydrochloric acid to adjust the pH value to 2-3, precipitating a light yellow solid, and continuously stirring for 3h. Suction filtration and drying are carried out, thus obtaining 7.51g of light yellow solid with the yield of 83.2 percent.
Step five: preparation of 4- (4-Nitrophenoxy) picolinoyl chloride (f)
A50 mL round-bottom flask was charged with intermediate e (5g, 0.019mol) dissolved with thionyl chloride (15 mL) by sonication, then warmed to 90 ℃, stirred for 10min, then added DMF (0.073g, 0.001mol) dropwise, and stirred for 40min. And concentrating the reaction solution, and adding a proper amount of toluene for later use. A yellowish liquid was obtained with a yield of about 98.0%.
Step six: preparation (g) of 4-chloro-N-ethylpyridinamide
Dichloromethane (30 mL), 30% aqueous ethylammonium (5.66g, 0.0377mol), and triethylamine (3.81g, 0.0377mol) were added sequentially to a 100mL beaker, and after stirring for 20min in an ice bath, intermediate f (5.24g, 0.0188mol) was added dropwise with continued stirring for 0.5h. 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 to separate out a large amount of solid, performing suction filtration, and drying to obtain a tawny solid 9.18g, wherein the yield is 84.9%.
Step seven: preparation of 4-chloro-N-methylpyridinamide (A)
A50 mL round bottom flask was charged with intermediate g (4.37g, 0.016 mol), activated carbon (1.92g, 0.16mol) and FeCl in sequence 3 ·6H 2 O (0.43g, 0.0016 mol) was dissolved ultrasonically in ethanol (20 mL) and condensed back at 90 deg.CAfter 0.5h, 80% hydrazine hydrate (8.0 g, 0.128mol) was added dropwise, and stirring was continued for 3-4h. 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, separating out solids, carrying out suction filtration, and drying to obtain 2.88g of brown solids, wherein the yield is 70.1%.
Step eight: preparation of methyl 3- (2-chlorophenyl) -3-oxopropanoate (l)
1- (2-chlorophenyl) ethan-1-one (5g, 0.032mol), dimethyl carbonate (3.4g, 0.038mol), toluene (100 mL) and sodium carbonate (6.7g, 0.064mol) were added in this order to a 250mL round-bottomed flask, and after ultrasonic dissolution, the temperature was raised to 120 ℃ until the reaction was complete. The reaction solution was cooled to room temperature, poured into 500mL of petroleum ether, and stirred to obtain an oil. Dissolving the oily substance with dichloromethane, adding appropriate amount of NaOH solution, mixing, extracting with dichloromethane, mixing organic layers, washing with saturated saline solution for three times, drying with anhydrous sodium sulfate, and spin drying to obtain yellow oily substance. The yield was about 81.0%.
Step nine: preparation of methyl (Z) -2- (2-chlorobenzoyl) -3- (dimethylamino) acrylate (m)
A50 mL round bottom flask was charged with intermediate l (5 g, 0.024mol) dissolved in DMA-DMF (25 mL), sonicated to dissolve and then warmed to 120 ℃ until the reaction was complete. After the solvent is dried by spinning as much as possible, 100mL of ethyl acetate solution is added for dissolving, a large amount of mixed solution of saturated saline and ethyl acetate is used for extraction, organic layers are combined, and the mixture is dried by spinning, recrystallized and filtered by suction, so that 4.60g of light yellow solid is obtained, and the yield is 73%.
Step ten: preparation of methyl (Z) -2- (2-chlorobenzoyl) -3- (phenylamino) acrylate (n)
A100 mL round bottom flask was charged with intermediate m (4 g, 0.015mol) dissolved in N-methylpyrrolidone (50 mL), the temperature was raised to 100 ℃ after ultrasonic dissolution, and after stirring for 0.5 hour, aniline (1.7g, 0.018mol) was added and stirring was continued until the reaction was complete. After the reaction liquid is cooled to room temperature, dissolving the reaction liquid by using 150mL of dichloromethane solution, adding dilute hydrochloric acid to adjust the pH value to 2-3, and extracting by using dichloromethane. And combining organic layers, spin-drying, recrystallizing, performing suction filtration and drying to obtain 3.12g of light yellow solid with the yield of 66.1%.
Step eleven: preparation of methyl 4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxylate (o)
A100 mL round-bottom flask was charged with intermediate n (3 g, 0.010mol), N-methylpyrrolidone (50 mL), and potassium carbonate (2.2g, 0.016 mol) in this order, dissolved by sonication, then warmed to 150 ℃ and stirred until the reaction was complete. The reaction solution was cooled to room temperature, dissolved in dichloromethane (150 mL), adjusted to pH 5-6 by the addition of dilute hydrochloric acid solution, and extracted with dichloromethane. And combining organic layers, spin-drying, recrystallizing, performing suction filtration and drying to obtain 2.40g of light yellow solid with the yield of 86.0%.
Step twelve: preparation of 4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxylic acid (p)
A100 mL round-bottomed flask was charged with intermediate o (3g, 0.011mol) dissolved in 1,4 dioxane (25 mL), and absolute ethanol (35 mL) was added for ultrasonic dissolution, and heated to 60 ℃ to drop 10% NaOH (5.2g, 0.013mol), and stirring was continued for 0.5h. Distilling under reduced pressure to remove reaction solvent, adding appropriate amount of saturated salt solution to dissolve solid, stirring at normal temperature, dropwise adding concentrated hydrochloric acid to adjust pH to 2-3, separating out light yellow solid, filtering, and oven drying to obtain light yellow solid 2.53g, with yield of 89.9%.
Step thirteen: preparation of 4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carbonyl chloride (B) 3 )
A50 mL round-bottomed flask was charged with intermediate p (0.5g, 0.0019mol), dichloromethane (20 mL) and oxalyl chloride (0.254g, 0.0020mol) in this order, ultrasonically dissolved, and dichloromethane was distilled off under reduced pressure to obtain 0.05g of an oily liquid with a yield of about 90.0%.
Fourteen steps: preparation of N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide (41)
To a 50mL round bottom flask was added intermediate A (0.63g, 0.0018 mol), sodium bicarbonate (0.42g, 0.05mol) and dichloromethane (20 mL) sequentially 3 (0.5g, 0.0018mol) was dissolved in an appropriate amount of methylene chloride, and the resulting solution was added dropwise to the methylene chloride solution while maintaining the temperature at 0 ℃ and slowly warmed to room temperature, followed by reaction for 20min. After the reaction is finished, filtering and keeping filtrate. Transferring the filtrate to a separating funnel (250 mL), adding dichloromethane (50 mL), washing with appropriate amount of sodium carbonate aqueous solution for three times, collecting organic layer, and distilling under reduced pressure to remove dichloromethane to obtain light yellow solid0.90g of powder, yield 85.3%.
The compounds of examples 41 to 46 were prepared according to the procedure of example 41.
Example 42- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
1 H NMR(400MHz,DMSO-d 6 )δ12.32(s,1H),8.89(s,1H),8.84(s,1H),8.55-8.50(m,1H),8.46(d,J＝7.5Hz,1H),8.03(d,J＝7.0Hz,1H),7.88(d,J＝6.1Hz,3H),7.78(d,J＝4.3Hz,2H),7.66-7.61(m,1H),7.42(s,1H),7.25(s,1H),7.24(d,J＝1.4Hz,1H),7.17(d,J＝2.4Hz,2H),3.28(dd,J＝4.9,3.0Hz,2H),1.08(t,J＝9.5Hz,3H).
ESI-MS m/z:604.16
Example 43N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
1 H NMR(400MHz,DMSO-d 6 )δ12.58(s,1H),8.86(s,1H),8.74(s,1H),8.54(d,J＝4.5Hz,1H),8.46(d,J＝7.4Hz,1H),8.07(d,J＝13.1Hz,1H),7.85-7.80(m,2H),7.77(d,J＝6.3Hz,1H),7.63(d,J＝7.3Hz,1H),7.57(d,J＝5.6Hz,2H),7.53(d,J＝5.2Hz,1H),7.46(d,J＝7.7Hz,1H),7.42(s,1H),7.24(s,1H),7.11(d,J＝8.7Hz,1H),3.28(dd,J＝7.9,5.8Hz,2H),1.18-1.05(m,3H).
ESI-MS m/z:682.07
Example 44 1- (4-bromo-2-fluorophenyl) -N- (4- ((2- (ethylcarbamoyl) pyridin-4-yl) oxy) -3-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
1 H NMR(400MHz,DMSO-d 6 )δ12.44(s,1H),8.91(s,1H),8.87(d,J＝5.1Hz,1H),8.54(d,J＝4.8Hz,1H),8.46(d,J＝7.7Hz,1H),8.08(s,1H),8.03(d,J＝10.3Hz,1H),7.90-7.85(m,1H),7.81(d,J＝1.5Hz,1H),7.79(s,1H),7.65-7.61(m,1H),7.57(d,J＝7.2Hz,1H),7.45(d,J＝9.2Hz,1H),7.43(s,1H),7.23(d,J＝4.7Hz,1H),7.17(d,J＝8.4Hz,1H),3.27(dd,J＝14.5,8.3Hz,2H),1.09(t,J＝6.9Hz,3H).
ESI-MS m/z:604.16
Example 45N- (3-fluoro-4- ((2- ((2- (thiophen-2-yl) ethyl) carbamoyl) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
ESI-MS m/z:622.15
Example 46 1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((2- ((2- (thien-2-yl) ethyl) carbamoyl) pyridin-4-yl) oxy) phenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide
ESI-MS m/z:700.06
In vitro antitumor cell Activity
The pyridine amide derivatives containing the formula I of the invention are subjected to activity screening of human cervical cancer cell Hela, colon cancer cell HT-29 and lung adenocarcinoma cell A549 for inhibiting high expression of breast cancer cell MCF-7 and c-Met kinase in vitro.
(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 10 4 Per well. In the 96-well plate, 180. Mu.L of cell suspension was added to the wells except that the A1-well was blank and 180. Mu.L of medium was added without adding cells. The 96-well plate was placed in an incubator for 24h.
(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 into 2mg/mL liquid medicine, 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 72h.
(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) (0.5 mg/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. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. By BDetermination of drug IC by the loss method 50 The value is obtained.
The results of the activity of the compound in inhibiting the cervical cancer cell Hela, the colon cancer cell HT-29, the breast cancer cell MCF-7 and the lung adenocarcinoma cell A549 are shown in the table II.
TABLE II IC of tumor cells in each experimental group 50 Value of
Examples 37, 38, 39 and 40, which are superior in cytotoxic activity in examples 1 to 46, were selected and subjected to the c-Met kinase activity test, and the results showed that the inhibition rates of c-Met kinase were 17.2%, 4.3%, 23.8% and 36.0% at a concentration of 0.625. Mu.M, respectively.
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 present invention.
Application example 1: injection preparation
10g of the compound obtained in example 5 was adsorbed by activated carbon in accordance with a conventional pharmaceutical procedure, filtered through a 0.65 μm microporous membrane, and then filled in nitrogen gas bottles to prepare 2mL of each of water-injection preparations, each of which was filled in 100 bottles.
Application example 2: capsule preparation
10g of the compound of the embodiment 6 is mixed with 20g of auxiliary materials according to the requirements of pharmaceutical capsules, and then the mixture is filled into hollow capsules, wherein each capsule weighs 300mg.
Application example 3: tablet formulation
10g of the compound obtained in example 9 was mixed with 20g of an adjuvant by a usual tableting method in pharmacy, and the mixture was compressed into 100 tablets each weighing 300mg.
Application example 4: suppository
10g of the compound of example 10 is ground into powder and added with a proper amount of glycerin, after being ground uniformly, the mixture is added with melted glycerin gelatin, ground uniformly and poured into a mold coated with a lubricant to prepare 50 suppositories.
Application example 5: aerosol formulation
10g of the compound of example 37 was dissolved in an appropriate amount of propylene glycol, and then 500mL of a clear solution was prepared by adding distilled water and other additives.
Application example 6: ointment formulation
Prepared by grinding 10g of the compound of example 38, and then uniformly grinding the ground compound with 500g of oil-based substances such as vaseline.
Application example 7: film agent
10g of the compound obtained in example 39 was dissolved by heating after swelling with stirring polyvinyl alcohol, medicinal glycerin, water, etc., and filtered through a 80-mesh screen, and the compound obtained in example 25 was dissolved by adding it to the filtrate by stirring, and 100 films were formed on a film coating machine.
Application example 8: drop pills
10g of the compound prepared in the embodiment 40 and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then the mixture is dropped into low-temperature liquid paraffin to prepare 1000 pills.
Application example 9: external liniment
10g of the compound in example 40 was mixed with 2.5g of an emulsifier and other adjuvants according to a conventional pharmaceutical method, and the mixture was ground, and then distilled water was added thereto to make 200 mL.
The embodiments of the present invention have been described in detail, but the description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention. Any modification, equivalent replacement, and improvement made within the scope of the present application shall be included in the protection scope of the present application.
Claims (4)
1. A compound according to any one of the following 37), 39), 40), 45):
37 4- (4- (4-methyl-3- (2- (trifluoromethoxy) phenyl) -3H-pyrazole-5-carboxamido) phenoxy) -N- (3-morpholinopropyl) pyridinamide;
39 N- (3-fluoro-4 ((2- (((3-morpholinopropyl) amino) methyl) pyridin-4-yl) oxy) phenyl) -4-methyl-3- (2- (trifluoromethoxy) phenyl) -3H-pyrazole-5-carboxamide;
40 4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-1H-1, 2, 3-triazole-4-carboxamide) phenoxy) -N- (3-morpholinopropyl) pyridinamide;
45 N- (3-fluoro-4- ((2- ((2- (thien-2-yl) ethyl) carbamoyl) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide.
2. A pharmaceutical composition characterized in that it comprises a compound according to claim 1.
3. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of cancer.
4. The use according to claim 3, wherein the cancer is lung cancer, liver cancer, stomach cancer, colon cancer or breast cancer.
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