CN110642837B - Pyridine amide compound containing triazole or quinolinone structure and application thereof - Google Patents

Abstract

The invention provides pyridine amide compounds containing a triazole or quinolinone structure and applications thereof. The technical scheme firstly carried out extensive research on pyridine amide compounds, modified and transformed multiple structural sites, and synthesized a series of novel pyridine amide derivatives. On this basis, the present invention investigates the chemical properties and biological properties of such compounds, and the results show that the compounds of the present invention have strong inhibitory effect on c-Met kinase, and can treat diseases caused by abnormally high expression of c-Met kinase. Play a therapeutic effect; based on the above beneficial findings, the present invention has determined the use of the compound or its derivatives to prepare proliferative disease drugs or tumor drugs; experimental results show that the present invention has a definite and significant inhibitory effect on tumor cells, Thereby providing data support for the pharmaceutical use of the compound.

Description

Pyridinamide compounds containing triazole or quinolinone structure and application thereof

technical field

The invention relates to the technical field of organic chemistry, in particular to pyridine amide compounds containing triazole or quinolinone structures and applications thereof.

Background technique

Malignant tumor is a disease that seriously endangers human health and life. The death rate caused by human malignant tumors ranks second only to cardiovascular diseases. c-Met kinase widely exists in epithelial tissues and plays an important role in embryonic development and wound healing. Recent studies have reported that c-Met kinase is abnormally highly expressed in tumor tissues such as lung cancer, colon cancer, liver cancer, rectal cancer, gastric cancer, renal cancer, ovarian cancer, glioma, melanoma, breast cancer, and prostate cancer. Mutation or Altered Activity. c-Met kinase can promote the proliferation of tumor cells, regulate the migration of tumor cells, enhance the invasion ability of tumor cells and induce tumor angiogenesis.

Studies have shown that the interaction between c-Met and membrane receptors affects the role of signaling molecules, further affecting tumor invasion, metastasis and angiogenesis, resulting in the emergence of tumor drug resistance. A large number of studies have confirmed that the c-Met signaling 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 critical roles 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 subfamily of RTKs consisting of an extracellular alpha chain and a transmembrane chain linked by disulfide bonds. The presence of c-Met has been demonstrated including a variety of possibilities, including brain, colorectal, gastric, lung, head, neck and olfactory cancers where it is frequently amplified or overexpressed. At present, c-Met kinase has become an important target of antitumor drug research.

In the prior art, c-Met kinase inhibitors including crizotinib and savolitinib have been used to a certain extent; however, they are currently used to treat diseases caused by abnormally high expression of c-Met kinase In this case, if a new c-Met kinase inhibitory drug can be developed, it is expected to expand the range of optional drugs for some cancers and proliferative diseases.

Contents of the invention

The present invention aims at the technical defects of the prior art, and provides pyridine amide compounds containing a triazole or quinolinone structure and applications thereof, so as to solve the technical problem that such compounds do not exist in the prior art.

Another technical problem to be solved by the present invention is how to expand the optional range of c-Met kinase inhibitory drugs.

Another technical problem to be solved by the present invention is how to expand the scope of use of the above-mentioned compounds.

To achieve the above technical purpose, the present invention adopts the following technical solutions:

The present invention relates to pyridine amide compounds containing triazole or quinolinone structure represented by general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

^R is methyl, ethyl, n-propyl, isopropyl, 4-methylmorpholinyl, cyclopentyl, cyclohexyl, 2-ethylthiophene, 4-methylmorpholinyl, cyano;

R ² is selected from 1 to 4 identical or different hydrogen and fluorine;

X is O, S;

Y is -Ar ₁ -Ar ₂ ;

Ar ₁ is a (C ₅ -C ₁₀ ) heteroaryl group, and the heteroaryl group contains 2 to 3 N/O heteroatoms;

Ar ₂ is a (C ₆ -C ₁₀ )heteroaryl group, and Ar ₂ is substituted with an aryl group substituted by R ³ in addition to being combined with Ar ₁ ;

R ³ is 1-2 selected from hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, mono or di( C ₁ -C ₆ alkyl) substituted amino, (C ₁ -C ₆ )alkylamido, free, salt-formed, esterified and amidated carboxyl, (C ₁ -C ₆ )alkylene Sulfonyl, sulfonyl, (C ₁ -C ₆ )alkylacyl, carbamoyl, mono- or di(C ₁ -C ₆ alkyl) substituted carbamoyl, (C ₁ -C ₃ )alkylenedi Oxygen substituents.

The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,

Wherein ^R is methyl, ethyl, n-propyl, 4-methylmorpholinyl, cyclopentyl, 2-ethylthiophene;

R ² is F/H, and its substituent position is the ortho position of the carbon atom connected to X on the benzene ring;

X is O;

Y is -Ar ₁ -Ar ₂ ;

Ar ₁ is a (C ₅ -C ₁₀ ) heteroaryl group, and the heteroaryl group contains 2 to 3 N/O heteroatoms;

Ar ₂ is a (C ₆ -C ₁₀ )heteroaryl group, and Ar ₂ is substituted with an aryl group substituted by R ³ in addition to being combined with Ar ₁ ;

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, amino substituted by mono or di(C ₁ -C ₆ alkyl), (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkyl, (C ₁ -C ₆ )alkylacyl, carbamoyl, carbamoyl substituted by mono- or di-(C ₁ -C ₆ alkyl), (C ₁ -C ₃ )alkylenedioxy.

The present invention preferably also relates to compounds of general formula I as defined below and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

Wherein ^R is methyl, ethyl, n-propyl, 4-methylmorpholinyl, cyclopentyl, 2-ethylthiophene;

R ² is F/H, and its substituent position is the ortho position of the carbon atom connected to X on the benzene ring;

X is O;

Y is

R ³ is hydrogen, 3-methyl, 4-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 particularly preferred derivatives of the following general formula I of the present invention, including their racemates or optical isomers, and pharmaceutically acceptable salts and/or hydrates thereof, but these compounds do not imply any limitation to the present invention :

(1) N-ethyl-4-(4-(5-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)picolinylmethyl amides;

(2) N-ethyl-4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)pyridine Formamide;

(3) N-ethyl-4-(4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy) picolinamide;

(4) N-ethyl-4-(2-fluoro-4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido) Phenoxy) pyridinecarboxamide;

(5) 4-(4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-propylpyridinecarboxamide;

(6) 4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-propylpyridine Formamide;

(7) 4-(4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-propyl picolinamide;

(8) 4-(2-fluoro-4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)- N-Propylpyridinecarboxamide;

(9) 4-(4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamido)phenoxy )-N-propylpyridinecarboxamide;

(10) 4-(2-fluoro-4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamide )phenoxy)-N-propylpyridinecarboxamide;

(11) 4-(4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(2-(thiophene-2 -yl) ethyl) pyridine amide;

(12) 4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(2- (Thien-2-yl)ethyl)pyridine amide;

(13) 4-(4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(2 -(thiophen-2-yl)ethyl)pyridine amide

(14) 4-(2-fluoro-4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)- N-(2-(thiophen-2-yl)ethyl)pyridineline amide

(15) 4-(4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamido)phenoxy )-N-(2-(thiophen-2-yl)ethyl)pyridine amide

(16) 4-(2-fluoro-4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamide )phenoxy)-N-(2-(thiophen-2-yl)ethyl)pyridinoline amide

(17) 5-methyl-1-phenyl-N-(4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1H-1,2,3 -Triazole-4-carboxamide

(18) N-(3-fluoro-4-(((2-(pyrrolidin-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-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1H- 1,2,3-Triazole-4-carboxamide

(20) N-(3-fluoro-4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-methyl Base-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-propylpyridinecarboxamide

(22) 4-(4-(1-(3-chloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)phenoxy)-N-propylpyridinecarboxamide

(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-carboxamido)phenoxy base)-N-propylpyridinecarboxamide

(25) 4-(4-(1-(2-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)-2-fluorophenoxy)-N-propylpyridinecarboxamide

(26) 4-(4-(1-(3-chloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)-2-fluorophenoxy)-N-propylpyridinecarboxamide

(27) 4-(2-fluoro-4-(5-(trifluoromethyl)-1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazole-4- Carboxamido)phenoxy)-N-propylpyridinecarboxamide

(28)4-(4-(1-(3,4-difluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamido)-2 -fluorophenoxy)-N-propylpyridinecarboxamide

(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-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-5-(trifluoromethyl)-1-(2-(trifluoro Methyl)phenyl)-1H-1,2,3-triazole-4-carboxamide

(32) 1-(3,4-difluorophenyl)-N-(4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-5-(tri Fluoromethyl)-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)oxygen Base) 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)oxygen Base) phenyl) -5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide

(35) N-(3-fluoro-4-((2-(pyrrolidin-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)pyridinolamide

(38) 4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(3- Morpholinopropyl) pyridinoline amide

(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-carboxamido)phenoxy)- N-(3-Morpholinopropyl)pyridinolamide

(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-(thiophen-2-yl)ethyl)carbamoyl)pyridin-4-yl)oxy)phenyl)-1-( 4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

(46) 1-(4-bromo-2-fluorophenyl)-N-(3-fluoro-4-((2-((2-(thiophen-2-yl)ethyl)carbamoyl)pyridine- 4-yl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

According to some common methods in the field of the present invention, the pyridine amide derivatives of the general formula I of the present invention can form its pharmaceutically acceptable salts with acids. The acids may include inorganic or organic acids, the salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid, etc. Furthermore, the present invention also includes prodrugs of the compounds of the present invention. According to the invention, prodrugs are derivatives of the compounds of general formula I, which themselves may have weak activity or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) is converted into the corresponding biologically active form.

Unless otherwise indicated, the term "halo" used in the present invention refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkenyl" refers to straight-chain or branched alkenyl; "alkynyl" refers to straight-chain or branched alkynyl; "aryl" refers to the removal of one hydrogen in aromatic Atom-derived organic groups, such as phenyl, naphthyl; 5-10 membered heteroaryls include one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl can be It is monocyclic or polycyclic, and the ring system is aromatic, containing 5-10 atoms in total, such as imidazolyl, pyridyl, pyrimidyl, pyrazolyl, (1,2,3)- and (1,2,4)-Triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, Benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolinyl, etc.; 5-10 membered heterocyclic groups include one or more heteroatoms selected from N, O and S, wherein each The ring system of each heteroaryl group can be monocyclic or polycyclic, but is non-aromatic, and the ring system contains 5-10 atoms in total, and can optionally include 1 or 2 carbon-carbon double bonds or carbon-carbon triple bonds. Bonds include, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.

The present invention also relates to the compound of the general formula I having a strong inhibitory effect on c-Met kinase, and also relates to the preparation and treatment of such compounds and their pharmaceutically acceptable salts and hydrates caused by abnormally high expression of c-Met kinase. Use in medicines for diseases, especially in the preparation of medicines for treating and/or preventing cancer.

The following synthetic schemes 1-3 describe the preparation of the compounds of general formula I of the present invention. All starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the field of organic chemistry or are commercially available. All final compounds of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which methods are well known to those of ordinary skill in the art of organic chemistry. All variables used in these diagrams are as defined below or as defined in the claims.

时，R³如发明内容部分所定义，均可按在路线1.1的方法由中间体A和中间体B₁通过取代反应制得实施例1-20。According to the compound of formula I of the present invention, Y is

When ^R3 is as defined in the Summary of the Invention, Examples 1-20 can be prepared from Intermediate A and Intermediate _B1 through substitution reactions according to the method in Route 1.1.

时，R³如发明内容部分所定义，均可按在路线1.2的方法由中间体A和中间体B₂通过取代反应制得实施例21-40。According to the compound of formula I of the present invention, Y is

When ^R3 is as defined in the Summary of the Invention, Examples 21-40 can be prepared from Intermediate A and Intermediate _B2 through substitution reactions according to the method in Scheme 1.2.

时，R³如发明内容部分所定义，均可按在路线1.3的方法由中间体A和中间体B₃通过取代反应制得实施例41-46。According to the compound of formula I of the present invention, Y is

When ^R3 is as defined in the Summary of the Invention, Examples 41-46 can be prepared from Intermediate A and Intermediate _B3 through substitution reactions according to the method in Scheme 1.3.

According to the compound of formula I of the present invention, the preparation method of intermediate A is as shown in Scheme 2, and other substituents are as defined in the claims.

According to the compound of formula I of the present invention, the preparation method of intermediates _B1 and _B2 is as shown in route 3.1, and other substituents are as defined in the claims.

According to the compound of formula I of the present invention, the preparation method of intermediate _B3 is as shown in route 3.2, and other substituents are as defined in the claims.

The substituents R ¹ , R ² and R ³ of all intermediates in the above three routes are as defined in the claims.

The invention provides pyridine amide compounds containing a triazole or quinolinone structure and applications thereof. The technical scheme firstly carried out extensive research on pyridine amide compounds, modified and transformed multiple structural sites, and synthesized a series of novel pyridine amide derivatives. On this basis, the present invention investigates the chemical properties and biological properties of these compounds, and the results show that the compounds of the present invention have strong inhibitory effect on c-Met kinase, and can treat diseases caused by abnormally high expression of c-Met kinase. Play a therapeutic effect; based on the above beneficial findings, the present invention has determined the use of the compound or its derivatives to prepare proliferative disease drugs or tumor drugs; experimental results show that the present invention has a definite and significant inhibitory effect on tumor cells, Thereby providing data support for the pharmaceutical use of the compound.

Detailed ways

Specific embodiments of the present invention will be described in detail below. In order to avoid too many unnecessary details, well-known structures or functions will not be described in detail in the following embodiments. Approximate language used in the following examples is for quantitative representations, indicating that certain variations in quantities are permissible without altering essential 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.

The proton nuclear magnetic resonance spectrum of the compound was determined by BrukerARX-400, and the mass spectrum was determined by Agilent1100LC/MSD; the reagents used were analytically pure or chemically pure. According to the general preparation method of Example 1, the compounds of Examples 1-40 were prepared respectively; according to the general preparation method of Example 41, the compounds of Examples 41-46 were respectively prepared (see Table 1).

Table 1 Example 1～46 product structure list

Example 1 N-ethyl-4-(4-(5-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)picolinylmethyl Amide

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, 6.6 Hz,2H),2.59(s,3H),1.09(t,J=7.0Hz,3H).

ESI-MS m/z:442.18

Step 1: Preparation of 4-chloropyridine chloride (b)

Add picolinic acid (10g, 0.081mol), thionyl chloride (50mL) for ultrasonic dissolution and NaBr (0.1g, 0.001mol) to a 150mL round-bottom flask, gradually raise the temperature to 85°C, and reflux for 24h. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and an appropriate amount of toluene was added for use. A pale yellow liquid was obtained with a yield of about 97.5%.

Step 2: Preparation of ethyl 4-chloropicolinate (c)

Add dichloromethane (30mL), ethanol (16.43g, 0.17mol) and triethylamine (17.17g, 0.17mol) to a 100mL round-bottomed flask successively, stir for 20min under ice-bath conditions, and add intermediate b (16.43 g, 0.11mol), and kept stirring for 0.5h. Add the reaction liquid to an appropriate amount of saturated saline, then add 10% NaOH aqueous solution to adjust the pH to 9-10, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, add a small amount of petroleum ether, there is a large amount of solid Precipitate, filter with suction, and dry to obtain 25.2 g of a light yellow solid with a yield of 80.2%.

Step 3: Preparation of ethyl 4-(4-nitrophenoxy)picolinate (d)

Intermediate c (13.22g, 0.071mol) and p-nitrophenol (3.61g, 0.026mol) were dissolved in a 150mL round bottom flask with chlorobenzene (40mL), ultrasonically dissolved, heated to 130°C, condensed and refluxed for 4h. The reaction solution was cooled to room temperature, poured into cold petroleum ether (100 mL) and stirred at room temperature for 10 min, and the supernatant was discarded to leave a viscous liquid. Dissolve the viscous liquid with an appropriate amount of dichloromethane, add an appropriate amount of NaOH aqueous solution to adjust the pH to 9-10, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, add a small amount of petroleum ether, a large amount of light yellow The solid was precipitated, filtered by suction, and dried to obtain 16.35 g of a light yellow solid with a yield of 80.0%.

Step 4: 4-(4-nitrophenoxy)picolinic acid (e)

Add intermediate d (10g, 0.035mol) and ethanol (20mL) to a 100mL round bottom flask successively, ultrasonically dissolve, add 10% NaOH (22.8g, 0.057mol) dropwise at room temperature, and stir for 0.5h. Most of the solvent was distilled off the reaction solution under reduced pressure, and saturated brine (250 mL) was added, stirred at room temperature, and concentrated hydrochloric acid was added to adjust the pH value to 2-3, a light yellow solid precipitated out, and the stirring was continued for 12 h. Suction filtration and drying gave 7.51 g of light yellow solid with a yield of 83.2%.

Step 5: Preparation of 4-(4-nitrophenoxy)picolinate chloride (f)

Add intermediate e (5g, 0.019mol) and thionyl chloride (15mL) to a 50mL round-bottomed flask successively, ultrasonically dissolve, heat up to 90°C and stir for 10min, add DMF (0.073g, 0.001mol) dropwise, and continue stirring for 30min . The reaction solution was concentrated, and an appropriate amount of toluene was added for use. A light yellow liquid was obtained with a yield of about 98.0%.

Step 6: Preparation of 4-chloro-N-ethylpyridine amide (g)

Add dichloromethane (30mL), triethylamine (3.81g, 0.0377mol) and 30% ethylamine aqueous solution (5.66g, 0.0377mol) to a 100mL beaker successively, stir in an ice bath for 20min, and add intermediate f (5.24 g, 0.0188mol), and kept stirring for 1h. Add the reaction solution to an appropriate amount of saturated saline, then add 10% NaOH aqueous solution to adjust the pH to 9-10, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and add a small amount of petroleum ether to precipitate a large amount of solids. Suction filtration and drying yielded 9.18 g of a yellow-brown solid with a yield of 84.9%.

Step 7: Preparation of 4-chloro-N-methylpicolinamide (A)

The intermediate g (4.37g, 0.016mol), ethanol (20mL), FeCl ₃ 6H ₂ O (0.43g, 0.0016mol) and activated carbon (1.92g, 0.16mol) were successively added to a 50mL round bottom flask, ultrasonically dissolved, The temperature was raised to 90° C., condensed and refluxed for 0.5 h, and 80% hydrazine hydrate (8.0 g, 0.128 mol) was added dropwise, and the stirring was continued for 3-4 h. The solution was suction filtered while it was hot, the filtrate was retained, spin-dried, and a proper amount of isopropanol and petroleum ether were added to form a solid, which was filtered by suction and dried to obtain 2.88 g of a brown solid with a yield of 70.1%.

Step 8: Preparation of ethyl 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylate (i)

Phenylboronic acid (5g, 0.04mol), DMSO (50mL), Cu(OAc) ₂ (9g, 0.05mol) and piperidine (4.25g, 0.05mol) were successively added to a 100mL round bottom flask, heated to 85 ℃ reaction 6h, until the reaction is complete. After the reaction solution was cooled to room temperature, it was poured into water (500 mL), then an appropriate amount of NaOH solution was added to mix, extracted with dichloromethane solution, the organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain Yellow oil. The yield is about 82.0%.

Step 9: Preparation of 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (J)

Add intermediate i (3g, 0.0112mol) and 1,4 dioxane (25mL) successively to a 50mL round bottom flask, add 10% NaOH (7.7g, 0.0194mol) dropwise at room temperature, heat up to 60°C and stir until the reaction is complete. After spin-drying the reaction solvent, add 100mL saturated saline, stir at room temperature, add concentrated hydrochloric acid dropwise to adjust the pH value to 2-3, solid precipitates, filter with suction, and dry to obtain 1.90g of light yellow solid with a yield of 85.1 %.

Step 10: Preparation of 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carbonyl chloride (B ₁ )

Add dichloromethane (20mL), intermediate J (1.90g, 0.009mol) and oxalyl chloride (1.143g, 0.009mol) to a 50mL round-bottomed flask successively, sonicate at room temperature for 30s, and distill off dichloromethane under reduced pressure to obtain an oily Liquid, about 90.0% yield.

Step 11: N-ethyl-4-(4-(5-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)pyridine Formamide Preparation (1)

Intermediate A (0.21 g, 0.0008 mol) and sodium bicarbonate (0.34 g, 0.004 mol) and dichloromethane (20 mL) were added to a 50 mL round bottom flask. Intermediate B ₁ (0.18g, 0.0008mol) was dissolved in dichloromethane (10mL) and added dropwise to the above dichloromethane solution at 0°C. After the addition was complete, it was slowly raised to room temperature and reacted for 30min. After completion of the reaction, filter with suction and collect the filtrate. The filtrate was transferred to a 50 mL separatory funnel, then dichloromethane (10 mL) was added, washed three times with aqueous sodium carbonate solution (25 mL), the organic layer was collected, dichloromethane was distilled off under reduced pressure to obtain 0.25 g of light yellow solid powder, and The rate is 70.0%.

According to the method of Example 1, the compounds of Examples 1-40 were respectively prepared.

Example 2 N-ethyl-4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)pyridine Formamide

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 3 N-ethyl-4-(4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy) picolinamide

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 4 N-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-(4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-propylpyridinecarboxamide

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 4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-propylpyridine Formamide

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-(4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-propyl picolinamide

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 4-(2-fluoro-4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)- N-Propylpyridinecarboxamide

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-(4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamido)phenoxy )-N-Propylpyridinecarboxamide

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 4-(2-fluoro-4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamide )phenoxy)-N-propylpyridinecarboxamide

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-(4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(2-(thiophene-2 -yl)ethyl)pyridine 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 4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(2- (Thien-2-yl)ethyl)pyridineline amide

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-(4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(2 -(thiophen-2-yl)ethyl)pyridine amide

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 4-(2-fluoro-4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)- N-(2-(thiophen-2-yl)ethyl)pyridineline amide

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-(4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamido)phenoxy )-N-(2-(thiophen-2-yl)ethyl)pyridine amide

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 4-(2-fluoro-4-(5-methyl-1-(2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamide )phenoxy)-N-(2-(thiophen-2-yl)ethyl)pyridinoline amide

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 5-methyl-1-phenyl-N-(4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1H-1,2,3 -Triazole-4-carboxamide

ESI-MS m/z:468.19

Example 18 N-(3-fluoro-4-(((2-(pyrrolidin-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-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1H- 1,2,3-Triazole-4-carboxamide

ESI-MS m/z:486.18

Example 20 N-(3-fluoro-4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-5-methanol Base-1H-1,2,3-triazole-4-carboxamide

ESI-MS m/z:504.17

Example 21 4-(4-(1-(2-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)phenoxy)-N-propylpyridinecarboxamide

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-(4-(1-(3-chloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)phenoxy)-N-propylpyridinecarboxamide

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 23 N-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-(4-(1-(3,4-difluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamido)phenoxy base)-N-propylpyridinecarboxamide

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-(4-(1-(2-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)-2-fluorophenoxy)-N-propylpyridinecarboxamide

ESI-MS m/z:630.10

Example 26 4-(4-(1-(3-chloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4- Carboxamido)-2-fluorophenoxy)-N-propylpyridinecarboxamide

ESI-MS m/z:630.10

Example 27 4-(2-fluoro-4-(5-(trifluoromethyl)-1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazole-4- Carboxamido)phenoxy)-N-propylpyridinecarboxamide

ESI-MS m/z:596.14

Example 28 4-(4-(1-(3,4-difluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamido)-2 -fluorophenoxy)-N-propylpyridinecarboxamide

ESI-MS m/z:564.13

Example 29 3-(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 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

ESI-MS m/z:624.11

Example 31 N-(4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-5-(trifluoromethyl)-1-(2-(trifluoromethyl) Methyl)phenyl)-1H-1,2,3-triazole-4-carboxamide

ESI-MS m/z:590.15

Example 32 1-(3,4-difluorophenyl)-N-(4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-5-(tri Fluoromethyl)-1H-1,2,3-triazole-4-carboxamide

ESI-MS m/z:558.14

Example 33 3-(2-Chloro-5-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy Base) phenyl)-4-(trifluoromethyl)-3H-pyrazole-5-carboxamide

ESI-MS m/z:641.11

Example 34 1-(3-Chloro-4-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((2-(pyrrolidin-1-carbonyl)pyridin-4-yl)oxy Base) phenyl) -5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide

ESI-MS m/z:642.10

Example 35 N-(3-fluoro-4-((2-(pyrrolidin-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 1-(3,4-difluorophenyl)-N-(3-fluoro-4-((2-(pyrrolidin-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-(4-methyl-3-(2-(trifluoromethoxy)phenyl)-3H-pyrazole-5-carboxamido)phenoxy)-N-(3 -morpholinopropyl)pyridinolamide

ESI-MS m/z:624.62

Example 38 4-(2-fluoro-4-(5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)-N-(3- Morpholinopropyl) pyridinoline amide

ESI-MS m/z:559.23

Example 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

ESI-MS m/z:628.24

Example 40 4-(2-fluoro-4-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamido)phenoxy)- N-(3-Morpholinopropyl)pyridinolamide

ESI-MS m/z:577.22

Example 41 N-(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

Step 1: Preparation of 4-chloropyridine chloride (b)

Picolinic acid (10 g, 0.081 mol), thionyl chloride (50 mL) and NaBr (0.1 g, 0.001 mol) were successively added into a 150 mL round bottom flask for ultrasonic dissolution, and refluxed at 85° C. for 24 h. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and an appropriate amount of toluene was added for use. A pale yellow liquid was obtained with a yield of about 97.5%.

Step 2: Preparation of ethyl 4-chloropicolinate (c)

Add dichloromethane (30mL), ethanol (16.43g, 0.17mol) and triethylamine (17.17g, 0.17mol) to a 100mL round bottom flask successively, stir for 20min under ice-bath conditions, then add intermediate b (16.43 g, 0.11mol), and continued to stir for 0.5h under ice bath conditions. Add the reaction solution to an appropriate amount of saturated saline, then add an appropriate amount of NaOH aqueous solution to adjust the pH to 9-10, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, add a small amount of petroleum ether, there is a large amount of solid Precipitate, filter with suction, and dry to obtain 25.2 g of a light yellow solid with a yield of 80.2%.

Step 3: 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-bottomed flask successively, dissolved in chlorobenzene (40mL) by ultrasound, then heated to 130°C to condense and reflux 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 10 min, and the supernatant was poured off to leave a viscous liquid. Dissolve the viscous liquid with an appropriate amount of dichloromethane, then add an appropriate amount of NaOH aqueous solution to adjust the pH to 9-10, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, add a small amount of petroleum ether, there is a large amount of A light yellow solid was precipitated, filtered by suction, and dried to obtain 16.35 g of a light yellow solid with a yield of 80.0%.

Step 4: 4-(4-nitrophenoxy)picolinic acid (e)

Intermediate d (10 g, 0.035 mol) and ethanol (20 mL) were added to a 100 mL round bottom flask, dissolved by sonication, 10% NaOH (22.8 g, 0.057 mol) was added dropwise at room temperature, and stirred at room temperature for 1 h. The reaction solution was distilled off under reduced pressure to remove most of the solvent, then saturated brine (250 mL) was added, stirred at room temperature, concentrated hydrochloric acid was added dropwise to adjust the pH value to 2-3, a light yellow solid precipitated, and the stirring was continued for 3 h. Suction filtration and drying gave 7.51 g of light yellow solid with a yield of 83.2%.

Step 5: Preparation of 4-(4-nitrophenoxy)picolinate chloride (f)

Add intermediate e (5g, 0.019mol) into a 50mL round-bottomed flask, dissolve it ultrasonically with thionyl chloride (15mL), heat up to 90°C, stir for 10min, add DMF (0.073g, 0.001mol) dropwise, and continue stirring for 40min . The reaction solution was concentrated, and an appropriate amount of toluene was added for use. A light yellow liquid was obtained with a yield of about 98.0%.

Step 6: Preparation of 4-chloro-N-ethylpyridine amide (g)

Add dichloromethane (30mL), 30% ethylamine solution (5.66g, 0.0377mol) and triethylamine (3.81g, 0.0377mol) successively in a 100mL beaker, stir for 20min under ice-bath conditions, then add intermediate f dropwise (5.24g, 0.0188mol), stirring was continued for 0.5h. Add the reaction solution to an appropriate amount of saturated saline, then add an appropriate amount of NaOH aqueous solution to adjust the pH to 9-10, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, add a small amount of petroleum ether, and a large amount of solids precipitate out , filtered with suction, and dried to obtain 9.18 g of a yellow-brown solid, with a yield of 84.9%.

Step 7: Preparation of 4-chloro-N-methylpicolinamide (A)

Add intermediate g (4.37g, 0.016mol), activated carbon (1.92g, 0.16mol) and FeCl ₃ ·6H ₂ O (0.43g, 0.0016mol) to a 50mL round bottom flask successively, and dissolve it ultrasonically with ethanol (20mL) for 90 After reflux at ℃ for 0.5 h, hydrazine hydrate (8.0 g, 0.128 mol) with a concentration of 80% was added dropwise, and the stirring was continued for 3-4 h. The solution was suction filtered while it was hot, the filtrate was retained, spin-dried, and a proper amount of isopropanol and petroleum ether were added to form a solid, which was filtered by suction and dried to obtain 2.88 g of a brown solid with a yield of 70.1%.

Step 8: Preparation of 3-(2-chlorophenyl)-3-oxopropionic acid methyl ester (l)

In a 250mL round-bottomed flask, 1-(2-chlorophenyl)ethan-1-one (5g, 0.032mol), dimethyl carbonate (3.4g, 0.038mol), toluene (100mL) and sodium carbonate (6.7 g, 0.064mol), after ultrasonic dissolution, the temperature was raised to 120°C until the reaction was complete. After cooling the reaction solution to room temperature, it was poured into 500 mL of petroleum ether, and stirred to obtain an oily substance. The oil was dissolved in dichloromethane, added an appropriate amount of NaOH solution and mixed, then extracted with dichloromethane, the organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow oil. The yield is about 81.0%.

Step 9: Preparation of (Z)-2-(2-chlorobenzoyl)-3-(dimethylamino)methyl acrylate (m)

Intermediate 1 (5 g, 0.024 mol) was added into a 50 mL round-bottom flask and dissolved in DMA-DMF (25 mL). After ultrasonic dissolution, the temperature was raised to 120° C. until the reaction was complete. Spin to dry the solvent as much as possible, add 100 mL of ethyl acetate solution to dissolve, extract with a large amount of saturated saline and ethyl acetate mixture, combine the organic layers, spin to dry, recrystallize, and filter with suction to obtain 4.60 g of a light yellow solid with a yield of 73 %.

Step 10: Preparation of (Z)-2-(2-chlorobenzoyl)-3-(phenylamino)methyl acrylate (n)

Add intermediate m (4g, 0.015mol) in a 100mL round-bottomed flask and dissolve it in nitrogen methylpyrrolidone (50mL). After ultrasonic dissolution, warm to 100°C. After stirring for 0.5 hours, add aniline (1.7g, 0.018mol) and continue stirring until the reaction is complete. After the reaction solution was cooled to room temperature, it was dissolved in 150 mL of dichloromethane solution, and dilute hydrochloric acid was added to adjust the pH to 2-3, and then extracted with dichloromethane. The organic layers were combined, spin-dried, recrystallized, filtered with suction, and dried to obtain 3.12 g of a light yellow solid with a yield of 66.1%.

Step eleven: Preparation of methyl 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylate (o)

Intermediate n (3g, 0.010mol), nitrogen methylpyrrolidone (50mL) and potassium carbonate (2.2g, 0.016mol) were successively added into a 100mL round-bottomed flask, heated to 150°C and stirred until the reaction was complete after ultrasonic dissolution. After the reaction solution was cooled to room temperature, it was dissolved with dichloromethane (150 mL), and diluted hydrochloric acid solution was added to adjust the pH of the solution to 5-6, and then extracted with dichloromethane. The organic layers were combined, spin-dried, recrystallized, filtered with suction, and dried to obtain 2.40 g of a light yellow solid with a yield of 86.0%.

Step 12: Preparation of 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (p)

Add intermediate o (3g, 0.011mol) to a 100mL round bottom flask, dissolve it in 1,4-dioxane (25mL), add absolute ethanol (35mL) for ultrasonic dissolution, raise the temperature to 60°C, and add 10% NaOH dropwise (5.2g, 0.013mol), stirring was continued for 0.5h. The reaction solvent was distilled off under reduced pressure, an appropriate amount of saturated saline was added to dissolve the solid, stirred at room temperature, concentrated hydrochloric acid was added dropwise to adjust the pH value to 2-3, a light yellow solid was precipitated, suction filtered, and dried to obtain 2.53 g of a light yellow solid. Yield 89.9%.

Step 13: Preparation of 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carbonyl chloride (B ₃ )

Add intermediate p (0.5g, 0.0019mol), dichloromethane (20mL) and oxalyl chloride (0.254g, 0.0020mol) to a 50mL round-bottomed flask successively, ultrasonically dissolve, remove dichloromethane by distillation under reduced pressure, and obtain an oily liquid 0.05g, the yield is about 90.0%.

Step Fourteen: N-(4-((2-(ethylcarbamoyl)pyridin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline - Preparation of 3-carboxamide (41)

Add intermediate A (0.63g, 0.0018mol), sodium bicarbonate (0.42g, 0.05mol) and methylene chloride (20mL) successively in a 50mL round bottom flask, intermediate B ₃ (0.5g, 0.0018mol) Dissolve in an appropriate amount of dichloromethane, add dropwise to the above dichloromethane solution while maintaining the temperature at 0°C, slowly rise to room temperature, and react for 20 minutes. After the reaction is completed, filter with suction and keep the filtrate. The filtrate was transferred to a separatory funnel (250 mL), then dichloromethane (50 mL) was added, washed three times with an appropriate amount of sodium carbonate aqueous solution, the organic layer was collected, dichloromethane was distilled off under reduced pressure to obtain 0.90 g of light yellow solid powder, and The rate is 85.3%.

According to the method of Example 41, the compounds of Examples 41-46 were respectively prepared.

Example 42 1-(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=7.5 Hz,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 43 N-(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 45 N-(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-(thiophen-2-yl)ethyl)carbamoyl)pyridine- 4-yl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

ESI-MS m/z:700.06

In vitro anti-tumor cell activity

The pyridine amide-containing derivatives according to the above formula I of the present invention have inhibited breast cancer cell MCF-7 in vitro, and human cervical cancer cell Hela, colon cancer cell HT-29 and lung adenocarcinoma with high expression of c-Met kinase Cell A549 Activity Screening.

(1) After the cells were recovered and passaged for 3-5 times, they were digested with 1 mL of trypsin solution (0.25%) for about 30 seconds from the bottom of the culture bottle, and culture medium was added to stop the digestion, and transferred into a centrifuge tube. Centrifuge the centrifuge tube at 1000r/min for 3min, discard the supernatant, add 5mL of culture medium, pipette and mix the cells, draw 10μL of the cell suspension and add it to a cell counting plate for counting, and adjust the cell concentration to 10 ⁴ cells/well. In the 96-well plate, 180 μL of cell suspension was added to well A1, which was a blank well and only 180 μL of medium was added without adding cells. The 96-well plate was placed in an incubator for 24 h.

(2) Dissolve the test sample with 20 μL dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into a 2 mg/mL drug solution, and then dilute the sample to 20, 4, 0.8, 0.16, 0.032 μg/mL.

Each concentration was added to 3 wells, and the growth of cells in the surrounding two rows and two columns was greatly affected by the environment, and only used as blank cell wells. The 96-well plate was placed in an incubator for 72 h.

(3) Discard the drug-carrying culture medium in the 96-well plate, wash the cells twice with phosphate buffer solution (PBS), add 20 μL of MTT (tetrazolium) (0.5 mg/mL) into each well and put it in the incubator After 3.5 h, the MTT solution was discarded, and 180 μL of dimethyl sulfoxide was added. Vibrate on a magnetic oscillator to fully dissolve the formazan, the product of the reaction between the surviving cells and MTT, and put it into a microplate reader to determine the result. The IC ₅₀ value of the drug can be calculated by the Bliss method.

The results of compounds inhibiting the activity of cervical cancer cell Hela, colon cancer cell HT-29, breast cancer cell MCF-7 and lung adenocarcinoma cell A549 are shown in Table II.

Table 2 IC ₅₀ values of tumor cells in each experimental group

Select the better embodiment 37, embodiment 38, embodiment 39 and embodiment 40 in embodiment 1-46 to carry out c-Met kinase activity test, the result shows that when its concentration is 0.625 μ M, c-Met kinase The inhibition rates were 17.2%, 4.3%, 23.8% and 36.0%, respectively.

It can be clearly seen from the above test results that the compound of general formula I to be protected by the present invention has good antitumor activity in vitro, which is equivalent to or better than the antitumor drug cisplatin already on the market.

While this invention has been described in terms of specific embodiments, it is apparent that modifications and equivalents will be apparent to those skilled in the art, and these are intended to be encompassed within the scope of this invention.

Application Example 1: Injection

Take 10 g of the compound of Example 5, according to the conventional method of pharmacy, carry out activated carbon adsorption, filter through a 0.65 μm microporous membrane, fill it into a nitrogen tank to make a water injection preparation, each bottle is filled with 2 mL, and a total of 100 bottles are filled.

Application Example 2: Capsules

With 10 g of the compound of Example 6, mix 20 g of auxiliary materials according to the requirements of pharmaceutical capsules, and then fill them into hollow capsules, each weighing 300 mg.

Application Example 3: Tablet

Take 10 g of the compound of Example 9, add 20 g of excipients and mix uniformly according to the general tableting method of pharmacy, and then compress it into 100 tablets, each weighing 300 mg.

Application Example 4: Suppositories

Take 10 g of the compound of Example 10, grind it finely and add an appropriate amount of glycerin, grind it evenly, add melted glycerin gelatin, grind it evenly, pour it into a model coated with lubricant, and make 50 suppositories.

Application Example 5: Aerosol

Take 10 g of the compound of Example 37, dissolve it with an appropriate amount of propylene glycol, add distilled water and other materials, and make a 500 mL clear solution.

Application Example 6: Ointment

Take 10g of the compound of Example 38, pulverize it and grind it with 500g of petroleum base such as petroleum jelly.

Application Example 7: Membrane

Take 10 g of the compound of Example 39, stir and expand polyvinyl alcohol, medicinal glycerin, water, etc., heat to dissolve, filter through an 80-mesh screen, then add the compound of Example 25 into the filtrate, stir and dissolve, and apply 100 pieces of membranes.

Application example 8: Dropping pills

With 10g of the compound of Example 40, heated, melted and mixed with 50g of substrates such as gelatin, and then dropped into low-temperature liquid paraffin, a total of 1000 dropping pills were prepared.

Application Example 9: Liniment for external use

Take 10 g of the compound of Example 40, mix and grind it with 2.5 g of auxiliary materials such as emulsifiers according to conventional pharmaceutical methods, and then add distilled water to 200 mL.

The embodiments of the present invention have been described in detail above, but the content is only a preferred embodiment of the present invention, and is not intended to limit the present invention. All modifications, equivalent replacements and improvements made within the application scope of the present invention shall be included in the protection scope of the present invention.

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.