WO2018233553A1

WO2018233553A1 - Fused bicyclic compound and use thereof in medicine

Info

Publication number: WO2018233553A1
Application number: PCT/CN2018/091392
Authority: WO
Inventors: 潘圣强; 马发城; 张英勋; 熊绍辉; 杨新业; 王晓军; 张英俊
Original assignee: 广东东阳光药业有限公司
Priority date: 2017-06-19
Filing date: 2018-06-15
Publication date: 2018-12-27
Also published as: CN110770233B; CN110770233A

Abstract

Disclosed are a fused bicyclic compound and the use thereof in a medicine, particularly a novel fused bicyclic compound used as an ASK1 activity regulator and a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the use of the compound in the preparation of a medicine for treating a disease and/or condition regulated by ASK1. Also disclosed are a pharmaceutical composition comprising the compound and a method for treating a disease and/or condition regulated by ASK1 by using the compound or the pharmaceutical composition thereof.

Description

Fused bicyclic compounds and their application in medicine

Field of invention

The present invention relates to a fused bicyclic compound having an enzyme inhibitory activity and a pharmaceutical composition thereof, which are useful for the preparation of a medicament for treating a disease regulated by ASK1.

Background of the invention

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase (MAP3Ks) family, and MAP3Ks can activate c-Jun N. N-terminal protein kinase (JNK) and p38 MAP (mitogen-activated protein) kinase (Ichijo, H., Nishida, E., Irie, K., Dijke, PT, Saitoh, Moriguchi, T., Matsumoto , K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94).

ASK1, also known as mitogen-activated protein kinase kinase 5 (MAPKKK5, MAP3K5), contains 1375 amino acid residues, which constitutes 11 kinase subdomains and one at the N-terminus and The serine/threonine kinase region in the middle of the side molecule of the C-terminal coiled-coil region (Wang et al. J. Biol. Chem. 1996, 271, 31607-31611, Ichijo et al. Science. 1997, 275, 90-94; Tobiume Et al. Biochem. Biophys. Res. Commun. 1997, 239, 905-910). ASK1 can be activated by a variety of stimuli such as oxidative stress, reactive oxygen species, endotoxin, tumor necrosis factor-α, endoplasmic reticulum stress, and intracellular calcium concentration.

Studies have shown that ASK1 not only regulates cell death, but also plays an important role in cellular activities such as cytokine response, cell differentiation, and innate immune response. Modulating the activity of ASK1 will treat or prevent a variety of diseases, including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders. Especially in the treatment of heart and kidney diseases (including kidney disease, diabetic nephropathy and chronic kidney disease), fibrotic diseases (including pulmonary fibrosis and renal fibrosis), respiratory diseases (including chronic embolic lung damage and acute lung injury) and liver disease, ASK1 Regulators have great potential.

The data show that liver disease has now become one of the leading causes of human death. According to the duration of the disease, liver diseases are generally classified into acute and chronic liver diseases. Liver disease can be caused by infection, injury, medication, poisoning, alcohol consumption, unclean food, abnormal accumulation of normal components of the blood, autoimmunity, genetic defects or other unknown factors. Common liver diseases include chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia-reperfusion injury, and primary biliary cirrhosis Wait.

At present, humans have conducted some studies to find therapeutic agents that can effectively inhibit the expression or activity of ASK1. Small molecule compounds are used as ASK1 modulators for the prevention or treatment of autoimmune diseases, inflammation, cardiovascular diseases and neurodegenerative diseases, as disclosed in WO2009027283, WO2009123986, WO2010008843, WO2011008709, WO2011041293, WO2011097079, WO2012003387, WO2013112741, WO2014100541, WO2015095059. WO 2015187499 and WO2016049070 disclose the use of ASK1 modulators for the treatment of liver diseases. However, there is still a need for more and better ASK1 modulators in the clinic.

Summary of invention

The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as a modulator of ASK1. The invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a disease and/or condition by modulation of ASK1 activity by said compound. The present invention further describes a method of synthesizing the compound. The compounds of the invention exhibit excellent biological activity and pharmacokinetic properties.

Specifically:

In one aspect, the invention relates to a compound which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (I) a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

among them:

for

Each W ^{1 is} independently O, S or N(R ^x );

Each W ^{2 is} independently CH or N;

Each W ^{3 is} independently CH or N;

Each W ^{4 is} independently CH or N;

Each W ^{5 is} independently CH or N;

W ⁶ is C(R ^a ) or N;

W ⁷ is C(R ^b ) or N;

X is -C(=O)- or -S(O) ₂ -;

Y is -O- or -N(R ^y )-;

R ^a and R ^b are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- alkoxy} or a C _1-3 haloalkoxy;

Each R ^x and R ^{y is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl;

Each R ^{1 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _{6 a -10} aryl or 5-10 membered heteroaryl group, wherein said hydroxy, fluorenyl, amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkane , C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5 The -10 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, oxo (=O), amino, nitro, cyano Substituted by a group of a C _1-6 alkyl group, a C _1-6 haloalkyl group, and a C _1-6 alkoxy group;

Each of R ² and R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkane Oxy or C _1-4 haloalkoxy;

R ⁴ is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _{1- 4} -haloalkoxy;

R is hydrogen, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or a 5-10 membered heteroaryl group, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl are optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino Substituted by a group of a nitro group, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;

Or R, R ⁴ together with the atoms to which they are attached form a 3-8 membered heterocyclic ring, which may optionally be 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, Anthracene, oxo (=O), hydroxy, decyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy Replaced by a group;

L is a bond, -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -C(=O)-O-, -OC(=O)-, -S( O) ₂ -, -NHC(=O)NH-, -C _1-6 alkylene-, -C _1-6 alkylene-O-, -C _1-6 alkylene-NH-, -S (O) ₂ -NH-, C _6-10 arylene or 5-10 membered heteroarylene; said C _6-10 arylene and 5-10 membered heteroarylene optionally being 1, 2 or 3 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkane Substituted by a group of oxy groups;

Q is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -S(O) ₂ -C _1-6 alkyl, -C(=O)-C _1-6 alkyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclic, C _6-12 aryl or 5-10 membered heteroaryl;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3; and

r is 0, 1, 2 or 3.

In some embodiments,

for

In some embodiments, R ^a and R ^b are each independently hydrogen, hydrazine, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, Fluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, each R ^x and R ^{y are} independently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl.

In some embodiments, each R ^{1 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-8 a heterocyclic group, a C _6-10 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group , C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-8 membered heterocyclic, C _{6 The -10} aryl group and the 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino group. Substituted by a group of a nitro group, a cyano group, a C _1-3 alkyl group, a C _1-3 haloalkyl group, and a C _1-3 alkoxy group.

In other embodiments, each R ^{1 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl, allyl , propenyl, propargyl, propynyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, morpholinyl, phenyl, decyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, Pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolyl, wherein said hydroxy, thiol, amino, methyl, ethyl, isopropyl, allyl, propylene , propargyl, propynyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, methylthio Base, ethylthio group, methylamino group, dimethylamino group, ethylamino group Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, decyl, pyrrolyl, pyridyl Azyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, anthracene The base and quinolyl can be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, a group of methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy and ethoxy groups Replaced.

In some embodiments, each R ² and R ^{3 are} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl Base, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, R ⁴ is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl 1,2-Difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, R is hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein said C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 The heterocyclic group, the C _6-10 aryl group and the 5-10 membered heteroaryl group are optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, oxo ( =O), amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl and 3-6 membered heterocyclic Replaced by the group.

In other embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thia An azole group, wherein the methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, allyl, ethynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl groups , cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl , imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl are optionally 1, 2, 3, 4 or 5 are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoro Methyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl Substituted by a group of propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups.

In some embodiments, R, R ⁴ and the atoms to which they are attached each form a 3-8 membered heterocyclic ring, which may optionally be 1, 2 or 3 selected from the group consisting of fluorine and chlorine. , bromine, iodine, hydrazine, oxo (=O), hydroxy, decyl, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C ₁ Substituted by a group of _-3 haloalkoxy.

In other embodiments, R, R ⁴ and the atoms to which they are attached each form a 3-6 membered heterocyclic ring, which may optionally be 1, 2 or 3 selected from fluoro, Chlorine, bromine, iodine, hydrazine, oxo (=O), hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1,2 -difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

And R. )-, -S(O) ₂ -, -NHC(=O)NH-, -C _1-3 alkylene-, -C _1-3 alkylene-O-, -C _1-3 alkylene -NH-, -S(O) ₂ -NH-, C _6-10 arylene or 5-6 membered heteroarylene; said C _6-10 arylene and 5-6 membered heteroarylene Optionally, 1, 2 or 3 are selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy Substituted with a C _1-3 haloalkoxy group.

In other embodiments, L is a bond, -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -C(=O)-O-, -OC(= O)-, -S(O) ₂ -, -NHC(=O)NH-, -C _1-3 alkylene-, -C _1-3 alkylene-O-, -C _1-3 alkylene -NH-, -S(O) ₂ -NH-, phenylene, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridylene or pyrimidinyl; said phenylene , pyridazolyl, imidazolyl, thiazolyl, oxazolyl, pyridylene and pyrimidinyl may be optionally 1, 2 or 3 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl , amino, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, Substituted by groups of ethoxy, difluoromethoxy and trifluoromethoxy.

In some embodiments, Q is hydrogen, hydrazine, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl 1,1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfonyl, ethylsulfonyl, Acetyl, propionyl, butyryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl , tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl , oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.

In some embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (II). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

In some embodiments, the compound of the invention is a compound of formula (III) or (IV), or a stereoisomer, geometric isomer of a compound of formula (III) or (IV), Tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

In one aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or (IV) of the invention, or a stereoisomer thereof, geometrically different a construct, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, Adjuvants, vehicles or combinations thereof.

In one aspect, the invention relates to a compound of formula (I), formula (II), formula (III) or (IV) or a pharmaceutical composition thereof for use in the manufacture of a medicament for the prevention, treatment or alleviation of a disease modulated by ASK1 in a patient use.

In some embodiments, the ASK1 regulated disease of the present invention is an autoimmune disease, an inflammation, a cardiovascular disease, a heart and kidney disease, a fibrotic disease, a respiratory disease, a liver disease, or a neurodegenerative disease.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), formula (II), formula (III) or (IV).

The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.

Detailed description of the invention

Definitions and general terms

The present invention will list the documents corresponding to the specific content of the determination, and the examples are accompanied by the diagrams of the structural formula and the chemical formula. The present invention is intended to cover all alternatives, modifications, and equivalents, which may be included in the field of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to those described herein, which can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or contradict the application of the present invention, including but not limited to the definition of terms, the use of terms, the techniques described, or the scope as controlled by the present application.

The invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version and Handbook of Chemicals, 75, thEd, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, therefore all The content is a fusion of references.

The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

A compound as described herein may optionally be substituted by one or more substituents, such as a compound of the formula in the invention, or a particular example, subclass, and a class of compounds encompassed by the invention, as in the examples . It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "optionally" whether preceded by the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents can be substituted at the various positions, either identically or differently. The substituents described therein may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkane. , haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH , -alkylene-C(=O)O-alkyl, -alkylene-S(=O) ₂ -alkyl, -alkylene-S(=O) ₂ -amino, -S(=O ) ₂ -alkyl, -S(=O) ₂ -amino, -S(=O) ₂ OH, -O-alkylene-C(=O)O-alkyl, -O-alkylene-S (=O) ₂ -alkyl, -O-alkylene-S(=O) ₂ -amino, -O-alkylene-S(=O) ₂ OH, -C(=O)NH ₂ ,- C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O) ₂ -alkyl, -C(=O)NHS(= O) ₂ -amino, -C(=O)NHS(=O) ₂ OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O) ₂ -alkyl, -NHS ( =O) ₂ -alkyl, -NHS(=O) ₂ -haloalkyl, -N(alkyl)S(=O) ₂ -haloalkyl, -N(alkyl)S(=O) ₂ -alkylamino , -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, -N(alkyl)C(=O)-halogen , -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O) O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH ₂ , -NHC (=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC (=O)-Amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl) S(=O) ₂ -alkyl, -C(=O)N(alkyl)S(=O) ₂ -amino, -C(=O)NH-S(=O) ₂ OH, -C(= NH)NH ₂ , -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH ₂ , -C(=O) NH-alkylene-S(=O) ₂ OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N (alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O) O-alkyl, and the like.

In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C _1-6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

The term "alkyl" as used herein, includes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or A linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH _{2 )} CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (- CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-A 2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1 -butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )) 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2, 3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl and n-octyl and so on. The term "alkyl" and its prefix "alk" are used herein to encompass both straight-chain and branched saturated carbon chains. The term "alkylene" or "alkylene" is used herein to mean a saturated divalent hydrocarbon radical derived by the elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene Base, ethylene and isopropylidene, etc.

The term "alkenyl" denotes 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or a linear or branched monovalent hydrocarbon radical of 2 to 4 carbon atoms, wherein at least one carbon - the carbon is a sp ² double bond wherein the group of alkenyl groups may be independently and optionally substituted by one or more substituents described herein, including the group having "anti""positive" or "E""Z""Positioning, specific examples of which include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), and enbutyl (-CH ₂ CH ₂ CH=CH ₂ )and many more.

The term "alkynyl" means 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or a linear or branched monovalent hydrocarbon radical of 2 to 4 carbon atoms, wherein at least one carbon The carbon is a sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described herein, specific examples including, but not limited to, ethynyl (-C≡CH) and Propargyl (-CH ₂ C≡CH).

The term "heteroatom" denotes one or more of O, S, N, P and Si, including the form of any of the oxidation states of C, N, S and P; the form of primary, secondary, tertiary and quaternary ammonium salts; a form in which a hydrogen in a nitrogen atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted NR) in the pyrrolidinyl group; or -CH ₂ - in the heterocyclic ring is oxidized to form a form of -C(=O)-.

The term "halogen" means F, Cl, Br or I.

The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.

The term "alkoxy" or "alkyloxy" as used in the present invention relates to an alkyl group, as defined herein, attached to the other part of the compound molecule through an oxygen atom. In some embodiments, the alkoxy group is a C _1-4 alkoxy group; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy group may be independently unsubstituted or substituted by one or more substituents described herein.

The term "alkylthio" or "alkylthio" as used in the present invention relates to an alkyl group, as defined herein, attached to other moieties of the compound molecule through a sulfur atom. In some embodiments, the alkylthio group is a C _1-6 alkylthio group; in other embodiments, the alkylthio group is a C _1-3 alkylthio group, examples of which include, but are not limited to, A Alkylthio group, ethylthio group, n-propylthio group, isopropylthio group and the like. And the alkylthio group may be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkoxyalkyl" as used in the present invention means that the alkyl group may be substituted by one or more alkoxy groups having the meanings as described herein. In some embodiments, the alkoxyalkyl group is a C _1-6 alkoxy C _1-6 alkyl group. In other embodiments, the alkoxyalkyl group is a C _1-3 alkoxy C _1-3 alkyl group. The "alkoxyalkyl" group may be independently and optionally substituted with one or more substituents described herein.

The terms "haloalkyl", "haloalkenyl" and "haloalkyloxy" denote the case where an alkyl, alkenyl or alkyloxy group may be substituted by one or more halogen atoms. In some embodiments, the haloalkyl group is a halo C _1-6 alkyl group. In other embodiments, the haloalkyl group is a halo C _1-3 alkyl group. In some embodiments, the haloalkyloxy or haloalkoxy group is a halo _C1-6 alkyloxy group or a halogenated _C1-6 alkoxy group. In other embodiments, the haloalkyloxy or haloalkoxy group is a halo C _1-3 alkyloxy group or a halogenated C _1-3 alkoxy group. Such examples include, but are not limited to, trifluoromethyl, difluoromethyl, 2-chloro-vinyl, 2,2-difluoroethyl, difluoromethoxy, trifluoromethoxy, and the like. The "haloalkyl", "haloalkenyl" and "haloalkyloxy" groups may be independently and optionally substituted by one or more substituents described herein.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is a C _1-6 alkylamino group or a (C _1-6 alkyl) amino group. In other embodiments, the alkylamino group is a C _1-3 alkylamino group or a (C _1-3 alkyl)amino group. Such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino, and the like. The alkylamino group can be optionally substituted with one or more substituents described herein.

The term "cycloalkyl" or "cycloalkane" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 3 to 12 carbon atoms, but never containing an aromatic ring. In one embodiment, the cycloalkyl group contains from 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains from 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains from 3 to 6 carbon atom. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkyloxy" denotes that a cycloalkyl group is attached to the other part of the compound molecule through an oxygen atom, wherein the cycloalkyl group has the meaning as described herein.

The term "cycloalkylalkyl" denotes the attachment of a cycloalkyl group to another moiety of the compound molecule through an alkyl group, wherein the cycloalkyl and alkyl groups have the meanings as described herein.

The term "carbocycle" or "carbocyclyl" denotes a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon radical containing from 3 to 12 carbon atoms. Carbon bicyclic groups include spirocarbon bicyclic groups and fused carbon bicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. In one embodiment, the carbocyclic group contains 4-8 carbon atoms; in yet another embodiment, the carbocyclic group contains 4-6 carbon atoms. Examples of the carbocyclic group further include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl group- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Base, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, excluding aromatic rings, wherein At least one ring atom is a hetero atom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3-10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3-8 ring atoms; In one embodiment, "heterocyclyl" or "heterocycle" contains 5-8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3-6 ring atoms; In one embodiment, "heterocyclyl" or "heterocycle" contains 5-6 ring atoms; unless otherwise stated, heterocyclyl can be carbyl or nitro, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl, thiecycloheptyl, oxazepine

Base, diaza

Base

And 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl group and pyrimidindione group. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group. The heterocyclyl group can be optionally substituted with one or more substituents described herein.

The term "heterocyclylalkyl" means that the heterocyclyl is attached to the other part of the compound molecule through an alkyl group, wherein the heterocyclyl and alkyl groups have the meanings as described herein.

The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic Each of the rings contains a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.

The term "arylalkyl" denotes an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meanings as described herein, such examples include, but are not limited to, Benzyl and phenethyl.

The term "heteroaryl" denotes a monocyclic, bicyclic and tricyclic ring system having 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one of the ring systems is an aromatic ring, and At least one ring system comprises one or more heteroatoms, wherein each ring comprises a ring of 5-7 atoms and one or more attachment points are attached to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.

Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl (eg, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (eg N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (eg 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (eg 5-tetrazolyl), Triazolyl, thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5- Thiodidiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, anthracene Base (eg 2-indenyl), fluorenyl, quinolyl (eg 2-quinolyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinoline Base, 1,3-benzodioxanyl, porphyrinyl, isoquinolinyl (eg 1-isoquinolinyl, 3- Quinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, Imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,[1,2,4]triazolo[1,5-a Pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

As described herein, a ring system formed by a substituent attached to a central ring represents that the substituent can be substituted at any substitutable position on the ring. For example, the formula (a) represents that the substituent R ^o may be mono- or polysubstituted at any position on the E ring which may be substituted, as shown in the formulae (b) to (h).

In addition, it should be noted that, unless otherwise explicitly indicated, the descriptions used herein are "individually..." and "individually", "... and ... are independently" and "... and ... respectively, independently "Alternatively, it should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and can also be expressed in the same group, the same symbol. The specific options expressed between them do not affect each other.

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational): for example, R, S containing an asymmetric center Configuration, (Z), (E) isomer of double bond, and conformational isomer of (Z), (E). Thus, a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers, geometric isomers or conformational isomers thereof, is within the scope of the invention.

Unless otherwise indicated, the structural formulae and compounds described herein include all isomeric forms (eg, enantiomeric, diastereomeric, geometric or conformational), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Compounds of pharmaceutically acceptable salts and prodrugs are also within the scope of the invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

"metabolite" means a product obtained by metabolism of a specific compound of the present invention or a pharmaceutically acceptable salt, analog or derivative thereof, which exhibits in vivo or in vitro with formula (I) A similar activity of the compound of formula (II), formula (III) or (IV). Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such products may be obtained by oxidative, reducing, hydrolyzing, amidating, deamidating, esterifying, defatting, or enzymatic cleavage of the administered compound. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.

The use of definitions and conventions of stereochemistry in the present invention is generally referred to the following documents: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric centers or chiral centers, and thus different stereoisomers are present. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. portion. Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the molecular chiral center. The prefix d, l or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their stereostructures are different. A particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lack optical activity.

The term "tautomer" or "tautomeric form" means that the isomers of the structure of different energies can be converted into each other by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. The valence (valence) tautomer includes the interconversion of recombination bond electrons.

"Pharmaceutically acceptable salt" as used herein means an organic salt and an inorganic salt of a compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates. Organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates; or by other methods described in the literature, such as ion exchange These salts are obtained. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, heavy sulfuric acid Salt, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, antibutene Diacid salt, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, milk Acid salt, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectic acid Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valeric acid Salt and so on. Salts obtained by a suitable base include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal which can form a salt includes sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C _{1 -8} sulfonate and aromatic sulfonate.

The "hydrate" of the present invention means that the solvent molecule is an association formed by water.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

The "ester" of the present invention means that the compound of the formula (I), the formula (II), the formula (III) or (IV) having a hydroxyl group forms an in vivo hydrolysable ester. Such esters are, for example, pharmaceutically acceptable esters which are hydrolyzed in a human or animal body to yield the parent alcohol. The group of the in vivo hydrolysable ester of the compound of formula (I), formula (II), formula (III) or (IV) containing a hydroxyl group includes, but is not limited to, a phosphate group, an acetoxymethoxy group, 2,2- Dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylamino Formyl and the like.

The "nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), for example in an inert solvent such as dichloromethane, to give the amine compound with m-chloroperoxybenzoic acid (MCPBA). )reaction.

The term "prodrug" as used herein, denotes a compound which is converted in vivo to a compound of formula (I), formula (II), formula (III) or (IV). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C _1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.

The term "protecting group" or "Pg" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "protecting group of an amino group" refers to a substituent which is attached to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc), and the like. Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group. Suitable protecting groups include methyl, methoxymethyl, acetyl and silyl groups, and the like. . "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, and nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "therapeutically effective amount" as used herein refers to an amount of a compound of formula (I), formula (II), formula (III) or (IV) sufficient to achieve said effect. Thus, a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) or (IV) for use in the treatment of a disease modulated by ASK1 will be an amount sufficient to treat a disease modulated by ASK1.

The term "heart and kidney disease" as used herein refers to a kidney function-related disease which can be caused or aggravated by cardiovascular problems such as hypertension. Hypertension is widely believed to be a major cause of kidney disease.

The term "respiratory disease" as used herein refers to a disease comprising chronic embolic pulmonary obstruction and idiopathic pulmonary fibrosis.

The term "nonalcoholic fatty liver disease (NAFLD)" as used herein is a metabolic disease associated with insulin resistance, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH), fatty liver fibrosis and Cirrhosis of the liver.

The term "liver fibrosis" as used herein includes liver fibrosis for any reason including, but not limited to, viral-induced liver fibrosis such as liver fibrosis caused by hepatitis B and hepatitis C; due to alcohol (alcoholicity) Hepatic fibrosis caused by liver disease), drug compounds, oxidative stress, cancer radiotherapy or exposure to industrial chemicals; and such as primary biliary cirrhosis, fatty liver, obesity, nonalcoholic steatohepatitis, cystic fibrosis, Liver fibrosis caused by diseases such as hemochromatosis and autoimmune hepatitis.

The term "ASK1 modulator" as used herein refers to a substance that binds to ASK1 and modulates its activity.

The terms "a", "an", "the" and "the" are used in the context of the invention (especially in the context of the claims), unless otherwise indicated herein. Similar terms may be interpreted to include both singular and plural.

Description of the compounds of the invention

The present invention provides a compound or a pharmaceutical composition thereof, which is useful as a modulator of ASK1. The invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a disease and/or condition by modulating ASK1 activity with said compound. The invention further describes a method of synthesizing the compound. The compounds of the invention exhibit improved biological activity and pharmacokinetic properties.

The present invention relates to a compound which is a compound represented by the formula (I), or a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate of a compound represented by the formula (I). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,

among them:

for

Each W ^{1 is} independently O, S or N(R ^x );

Each W ^{2 is} independently CH or N;

Each W ^{3 is} independently CH or N;

Each W ^{4 is} independently CH or N;

Each W ^{5 is} independently CH or N;

W ⁶ is C(R ^a ) or N;

W ⁷ is C(R ^b ) or N;

X is -C(=O)- or -S(O) ₂ -;

Y is -O- or -N(R ^y )-;

R ^a is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy;

R ^b is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy;

Each R ^{x is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl;

R ^y is hydrogen, hydrazine, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl;

Each R ^{2 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy;

Each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3; and

r is 0, 1, 2 or 3.

In some embodiments,

for

Wherein R ^x has the meaning as described in the present invention.

In some embodiments, R ^a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoro Methyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, R ^b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoro Methyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, each R ^{x is} independently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. .

In some embodiments, R ^y is hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, each R ^{2 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, tri Fluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, tri Fluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

Wherein Q, L, W ¹ , W ³ , W ⁶ , W ⁷ , R, R ¹ , R ² , R ³ , R ⁴ , m, n and r have the meanings indicated in the present invention.

In another aspect, the invention comprises a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a solvate, a hydrate, a metabolite, or a compound of one of the following compounds or one of the following: An ester, a pharmaceutically acceptable salt or a prodrug thereof, but is in no way limited to:

In one aspect, the invention relates to a pharmaceutical composition comprising a stereoisomer, geometric isomer of a compound of formula (I), formula (II), formula (III) or (IV) of the invention , tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles thereof Things, or any combination of them.

In one aspect, the invention relates to a compound of formula (I), formula (II), formula (III) or (IV) or a pharmaceutical composition thereof for use in the manufacture of a medicament for the prevention, treatment or amelioration of a disease modulated by ASK1 in a patient the use of.

In some of these embodiments, the cardiovascular diseases of the present invention include diabetes, diabetic nephropathy, and other diabetic complications.

In some of these embodiments, the fibrotic diseases of the invention include pulmonary and renal fibrosis.

In some of these embodiments, the respiratory diseases of the present invention include chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, and acute lung injury.

In some embodiments, the liver disease of the present invention includes chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia-re Perfusion injury and primary biliary cirrhosis.

One aspect of the invention relates to a method of preventing, treating or ameliorating a disease modulated by ASK1 in a patient comprising administering to the patient a pharmaceutically acceptable effective amount of a compound of the invention.

Pharmaceutical compositions, formulations, administrations and compounds of the compounds of the invention and uses of the pharmaceutical compositions

In another aspect, the pharmaceutical composition of the present invention comprises a compound of formula (I), formula (II), formula (III) or (IV), a compound of the invention and a pharmaceutically acceptable carrier, Agent or excipient. The amount of the compound in the compositions of the present invention is effective to detectably reduce or alleviate ASK1-mediated diseases in a patient.

The compounds of the invention exist in free form or, as appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other agent that can be administered, directly or indirectly, depending on the needs of the patient. An adduct or derivative, a compound described in other aspects of the invention, a metabolite thereof or a residue thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent or other liquid. Excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, are suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999 Marcel Dekker, New York, incorporating the contents of the literature, indicates that different carriers are useful in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to any conventional carrier medium that is incompatible with the compounds of the invention, such as any undesirable biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a detrimental manner, The use is also within the scope of the invention.

The compound of the present invention can be uniformly incorporated in the mixture as an active ingredient together with a pharmaceutical carrier according to a conventional pharmaceutical compounding technique. Depending on the form of preparation desired for administration, such as oral or parenteral (including intravenous), the carrier can take a wide variety of forms. When preparing a composition for oral dosage forms, any conventional pharmaceutical medium may be used, for example, water, ethylene glycol, oil, alcohol, fragrance, antiseptic when used in the preparation of oral liquid preparations such as suspensions, elixirs and solutions. Agents, colorants, and the like; or in the preparation of oral solid preparations such as powders, hard capsules, soft capsules and tablets, for example, starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, A disintegrating agent or the like, wherein a solid oral preparation is more preferable than a liquid medicine.

Because tablets and capsules are easy to take, they represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets can be coated with standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1% active compound. Of course, the percentage of active compound in these compositions can be varied, and the percentage can conveniently be between about 2% and about 60% by weight. The active compound can be administered intranasally, for example, in the form of droplets or sprays.

The tablets, pills, capsules and the like may also comprise: a binder (such as gum tragacanth, acacia, corn starch or gelatin); an excipient (such as dicalcium phosphate); a disintegrating agent (such as corn starch, Potato starch, alginic acid); a lubricant (such as magnesium stearate); and a sweetener (such as sucrose, lactose or saccharin). When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

A wide variety of other materials may be present as coatings or to modify the shape of the dosage unit. For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl or propylparaben as a preservative, a dye and a flavoring such as cherry or orange.

Also included within the scope of the invention are ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like.

The compounds of the invention may also be administered parenterally. A solution or suspension of these active substances can be prepared by suitably mixing with a surfactant such as hydroxypropylcellulose in water. Dispersing agents can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under the usual conditions of storage and use.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. In all cases, the form of the drug must be sterile and must be in the form of an easily injectable fluid. It must be stable under the conditions of manufacture and storage and must be preserved under the conditions of contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable method of administration can be used to provide an effective amount of a compound of the invention to a mammal, especially a human. For example, oral, transrectal, topical, parenteral, transocular, transpulmonary, nasal, and the like can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, emulsions, ointments, aerosols, and the like. Preferably, the compounds of the invention are administered orally.

The therapeutically effective dose of a compound, pharmaceutical composition or combination thereof of the invention will depend on the species, weight, age and individual condition of the individual, the disorder or disease to be treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.

When treating or preventing a condition modulated by ASK1 as indicated by a compound of the invention, when administered in a daily dose of from about 0.1 mg to about 100 mg per kilogram of animal body weight, preferably in a single daily dose, or from 2 to 6 times per day A substantially satisfactory effect is obtained when a compound of the present invention is administered in divided doses or in a continuous release form. For most large mammals, the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. For a 70 kg adult, the total daily dose is generally from 7 mg to about 350 mg. This dosage method can be adjusted to provide optimal therapeutic results.

The compound, composition or pharmaceutically acceptable salt thereof or hydrate thereof according to the invention can be effectively used for preventing, treating, treating or alleviating a disease regulated by ASK1 in a patient, in particular, effective treatment for diabetes, diabetic nephropathy, other diabetic complications, Chronic kidney disease, lung and renal fibrosis, chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, acute lung injury, chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver Nonalcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and other hepatitis.

General synthetic method

In general, the compounds of the invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I), formula (II), formula (III) or (IV). . The following reaction schemes and examples are provided to further illustrate the contents of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. The general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.

The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.

The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The nuclear magnetic resonance spectrum is tested under the conditions of room temperature, Bruker 400MHz or 600MHz nuclear magnetic instrument, using CDC1 ₃ , d ⁶ -DMSO, CD ₃ OD or d ⁶ -acetone as solvent (reported in ppm). TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), q (quartet, quadruple peak), dt (doublet of triplets), tt (triplet of triplets), dddd (doublet) Of doublet of doublet of doublets, qd (quartet of doublets), ddd (doublet of doublet of doublets), td (triplet of doublets), Dq(doublet of quartets, double quadruple), ddt (doublet of doublet of triplets), tdd (triplet of doublet of doublets), dtd (doublet of triplet of doublets, double three Double peak). Coupling constant, expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data was measured with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS spectrometer, G1329A autosampler and G1315B DAD detector applied For analysis, the ESI source was applied to an LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data was measured with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30 °C) Agilent 6120 Series LC-MS spectrometer, G1329A autosampler and G1315D DAD detector for analysis The ESI source was applied to an LC-MS spectrometer.

Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 μm. The injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B). The gradient elution conditions are shown in Table 1:

Table 1: Gradient elution conditions for mobile phases of low resolution mass spectrometry

Compound purity was evaluated by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, size 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min 5-95% (0.1% formic acid in acetonitrile) (0.1% aqueous formic acid), the column temperature was kept at 40 °C.

The following abbreviations are used throughout the invention:

CDCl ₃ deuterated chloroform

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d ₆ deuterated dimethyl sulfoxide

CD ₃ OD deuterated methanol

MeOH methanol

THF tetrahydrofuran

DCM dichloromethane

EtOAc, EA ethyl acetate

PE petroleum ether

Pd/C, Pd-C palladium/carbon

g g

Mg mg

H ₂ O water

M mole per liter

Mol Moore

Mm mmol

mL ml

μL microliter

A typical synthetic procedure for the preparation of the compounds disclosed herein is shown in the synthetic scheme below. Unless otherwise stated,

Q, L, R, R ¹ , R ² , R ³ , R ⁴ , W ⁶ , W ⁷ , m, n and r have the meanings as described in the present invention.

Synthetic scheme

Synthetic scheme 1

The compound (Ia) can be obtained by a condensation reaction of the compound (1a) and the compound (1b). In the condensation reaction, the reaction raw material is in a condensing agent (for example, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3) -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc.) and a base (for example, N,N-diisopropylethylamine, N-methylmorpholine) in the presence of a solvent reaction. The reaction is preferably carried out in a solvent inert to the reaction, and the solvent used includes, but is not limited to, N,N-dimethylformamide and the like.

Synthetic scheme 2

Wherein, L ^o is a halogen.

Compound (2b) can be obtained by reacting compound (2a) with ethyl bromoacetate;

Compound (2c) can be obtained by coupling reaction of compound (2b) with an amino group protected by a protecting group;

The compound (2d) can be obtained by removing the amino group protecting group from the compound (2c), and the hydrolysis reaction can be carried out by referring to "Protective Groups in Organic Synthesis";

Compound (2e) can be obtained by subjecting compound (2d) to a substitution reaction with an α-haloacyl compound;

Compound (2e) is reacted with potassium thiocyanate to form a compound (2f), and compound (2f) is further decarboxylated to obtain a compound (2g);

The compound (2g) was finally hydrolyzed to give a carboxylic acid compound (2h).

The invention is further described in the following examples, which should not be construed as limiting the scope of the invention.

Detailed ways

Example

Example 1: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)benzofuran-2-carboxamide

First step ethyl 4-bromobenzofuran-2-carboxylate

2-Bromo-6-hydroxybenzaldehyde (10.00 g, 49.75 mmol) and potassium carbonate (17.2 g, 125 mmol) were dissolved in anhydrous N,N-dimethylformamide (50 mL), and bromine was slowly added dropwise at room temperature. Ethyl acetate (8.3 mL, 75 mmol) was added and the mixture was warmed to 130 ° C and stirred for 2.5 h. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. The organic layer was washed with EtOAc EtOAc m. The residue was purified by EtOAc EtOAcqqqqqq

MS (ESI, pos.) m/z: 268.9 [M + 1] ⁺ ;

Step 2 4-((tert-Butoxycarbonyl)amino)benzofuran-2-carboxylic acid ethyl ester

Ethyl 4-bromobenzofuran-2-carboxylate (6.00 g, 22.3 mmol), tert-butyl carbamate (3.15 g, 26.9 mmol), palladium acetate (0.50 g, 2.2 mmol), 4 under nitrogen ,5-bisdiphenylphosphino-9,9-dimethyloxaxanthene (2.60 g, 4.5 mmol), cesium carbonate (18.1 g, 55.5 mmol) dissolved in anhydrous 1,4-dioxane (120 mL) In the reaction, the temperature was raised to 110 ° C to react overnight. After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj

MS (ESI, neg.ion) m/z: 304.1 [M-1] ^- ;

The third step is 4-aminobenzofuran-2-carboxylic acid ethyl ester

Ethyl 4-((tert-butoxycarbonyl)amino)benzofuran-2-carboxylate (5.25 g, 17.2 mmol) was dissolved in dichloromethane (200 mL), trifluoroacetic acid (30 mL) 1 hour. After removing most of the solvent by distillation under reduced pressure, the residue was evaporated to dryness eluted eluted eluted eluted eluted eluted eluted Dry over sodium sulfate, filter, and concentrate EtOAc. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 206.1 [M + 1] ⁺ ;

The fourth step 4-((2-cyclopropyl-2-oxoethyl)amino)benzofuran-2-carboxylic acid ethyl ester

Ethyl 4-aminobenzofuran-2-carboxylate (3.40 g, 16.6 mmol), potassium carbonate (2.80 g, 20.3 mmol) and potassium iodide (3.00 g, 18.1 mmol) were dissolved in anhydrous N. In dimethylformamide (15 mL), hydrazine-bromocyclopropaneethyl ketone (2.00 mL, 20.5 mmol) was slowly added dropwise, and the mixture was warmed to 60 ° C and stirred overnight. Saturated brine (20 mL), EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAcqqqqqqq

MS (ESI, pos.) m/z: 288.2 [M+1] ⁺ ;

Step 5 4-(4-Cyclopropyl-2-indolyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester

Add thiocyanate to a solution of ethyl 4-((2-cyclopropyl-2-oxoethyl)amino)benzofuran-2-carboxylate (4.10 g, 14.3 mmol) in glacial acetic acid (15 mL) Potassium (2.80 g, 28.8 mmol) was stirred and heated to 110 ° C for 5 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. (petroleum ether/ethyl acetate (v/v) = 5/1)

MS (ESI, pos.) m/z: 329.0 [M + 1] ⁺ ;

Step 6 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester

Ethyl 4-(4-cyclopropyl-2-indolyl-1H-imidazol-1-yl)benzofuran-2-carboxylate (3.80 g, 11.6 mmol) was dissolved in water (10 mL) and EtOAc (EtOAc) In the mixed solvent, hydrogen peroxide (3.50 mL, 30 mass%) was added dropwise at room temperature, and the mixture was heated to 50 ° C for 5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) Dry with sodium sulfate. Filtration, and the solvent was evaporated to dryness crystals crystals crystalssssssssssssssssssssss

MS (ESI, pos.) m/z: 297.2 [M+1] ⁺ ;

Step 7 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Ethyl 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylate (1.00 g, 3.37 mmol) was dissolved in tetrahydrofuran (30 mL). An aqueous solution of 17 mmol) was reacted overnight at room temperature. The solvent was evaporated under reduced pressure, diluted with water (15 mL), and evaporated, evaporated, evaporated, evaporated, evaporated. The title compound (440 mg, 48.6%)

MS (ESI, pos.) m/z: 269.1 [M + 1] ⁺ ;

Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (120 mg, 0.45 mmol) and 6-(2-isopropyl-1,2,4-triazole 3-yl)pyridin-2-amine (100 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole) was added at 0 °C. N,N,N',N'-tetramethyluronium hexafluorophosphate (0.26 g, 0.67 mmol) and N,N-diisopropylethylamine (0.5 mL) were stirred at room temperature overnight. The mixture was washed with brine (20 mL×3) After filtration, the solvent was evaporated.jjjjjjjjjjj

MS (ESI, pos.) m/z: 454.3 [M + 1] ⁺ ;

1H NMR (400MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.99 ( d, J = 8.1 Hz, 1H), 7.81 (d, J = 4.1 Hz, 2H), 7.64-7.60 (m, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.15 (s, 1H), 5.64-5.50 (m, 1H), 2.04-1.93 (m, 1H), 1.64 (s, 6H), 1.00 - 0.93 (m, 2H), 0.93 - 0.88 (m, 2H).

Example 2: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

Benzofuran-2-carboxylic acid (800 mg, 4.9 mmol), 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine under nitrogen (500 mg, 2.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.9 g, 5.0 mmol), N, N A mixture of dimethylformamide (30 mL) and N,N-diisopropylethylamine (1.3 mL) was warmed to 50 ° C and stirred for 8 h. The residue was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

MS (ESI, pos.) m/z: 348.5 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.43 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 0.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 5.63 - 5.54 (m, 1H), 1.63 (d, J = 6.7 Hz, 6H).

Example 3: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)benzofuran-2-carboxamide

First step 6-bromobenzofuran-2-carboxylic acid ethyl ester

4-Bromo-2-hydroxy-benzaldehyde (5.0 g, 25 mmol) and potassium carbonate (8.6 g, 62 mmol) were dissolved in N,N-dimethylformamide (80 mL). Ethyl acetate (4 mL), EtOAc (EtOAc)EtOAc.

Second step 6-((tert-Butoxycarbonyl)amino)benzofuran-2-carboxylic acid ethyl ester

Ethyl 6-bromobenzofuran-2-carboxylate (6.0 g, 22 mmol), tert-butyl carbamate (3.1 g, 26 mmol), cesium carbonate (18 g, 55 mmol), palladium acetate (0.25 g, Heating to 110 ° C in a mixed system of 1.1 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (0.65 g, 1.1 mmol) and 1,4-dioxane (80 mL) Stir overnight. The reaction was quenched with aq. EtOAc EtOAc (EtOAc (EtOAc) concentrate. The residue was purified by EtOAc EtOAcjjjjjjj

The third step is 6-aminobenzofuran-2-carboxylic acid ethyl ester

Trifluoroacetic acid (3 mL) was added to a solution of ethyl 6-((tert-butoxycarbonyl)amino)benzofuran-2-carboxylate (5.0 g, 16 mmol) in dichloromethane (3 mL). Stir overnight. The solvent was evaporated under reduced pressure. The mixture was evaporated. Filtration and EtOAc (EtOAc)

MS (ESI, pos.) m/z: 206.1 [M + 1] ⁺ ;

The fourth step 6-formamide benzofuran-2-carboxylic acid ethyl ester

Formic acid (2.8 mL, 74 mmol) was slowly added dropwise to acetic anhydride (6.9 mL, 73 mmol). After the dropwise addition, the temperature was raised to 65 ° C, stirred for 2 h, then cooled to room temperature, and the reaction mixture was slowly added dropwise to an ice bath. A solution of ethyl 6-aminobenzofuran-2-carboxylate (3.0 g, 15 mmol) in tetrahydrofuran (15 mL) was evaporated. Most of the solvent was evaporated under reduced pressure. EtOAc EtOAc m. Filtration and EtOAc (EtOAc)

MS (ESI, pos.) m/z: 234.1 [M+H] ⁺

Step 5 6-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylic acid ethyl ester

A-bromocyclopropanedione (2.7 mL, 28 mmol) was slowly added dropwise to ethyl 6-carboxamide benzofuran-2-carboxylate (3.0 g, 13 mmol), potassium iodide (230 mg, 1.4 mmol) and phosphoric acid at room temperature. Potassium (8.7 g, 41 mmol) in EtOAc (EtOAc) The reaction mixture was diluted with water (50 mL), and evaporated, evaporated, evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 316.0 [M+1] ⁺ ;

Step 6 6-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester

Ethyl 6-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylate (3.0 g, 9.5 mmol) was dissolved in EtOAc (50 mL) Ammonium acetate (3.7 g, 48 mmol) was added, the mixture was warmed to 120 ° C and stirred under reflux overnight. It was naturally cooled to room temperature, and a large amount of solvent was evaporated under reduced pressure. The reaction mixture was diluted with water (20 mL), EtOAc (EtOAc m. Concentrate under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 297.0 [M+1] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.77 (d, J = 8.6Hz, 2H), 7.60-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.08 (d, J = 1.0Hz, 1H), 4.51-4.45 (m, 2H), 1.98-1.90 (m, 1H), 1.46 (t, J = 7.1 Hz, 3H), 0.95-0.90 (m, 2H), 0.89-0.84 (m, 2H) ;

Step 7 6-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Ethyl 6-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylate (2.0 g, 6.7 mmol) was dissolved in a mixture of tetrahydrofuran (30 mL) and methanol (15 mL). Then sodium hydroxide (10 mL, 5 mol/L) was added and stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure, and the aqueous solution was adjusted to pH = 4 with dilute hydrochloric acid. Filtration and filtration of EtOAc EtOAc EtOAc. MS (ESI, pos.) m/z: 269.0 [M+H] ⁺

Step 8 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide

6-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (350 mg, 1.3 mmol), 6-(4-isopropyl-1,2,4- under N2. Triazol-3-yl)pyridin-2-amine (200 mg, 1.0 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro A mixed system of phosphoric acid ester (0.8 g, 2 mmol,), N,N-dimethylformamide (30 mL) and N,N-diisopropylethylamine (1 mL) was warmed to 50 ° C and stirred overnight. The title compound (30 mg, 6.7%)

MS (ESI, pos.) m/z: 454.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.50-8.39 (m, 2H), 8.07 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H) , 7.83 (d, J = 5.4 Hz, 2H), 7.73 (s, 1H), 7.62 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H), 5.64 - 5.51 ( m, 1H), 1.98-1.92 (m, 1H), 1.62 (d, J = 6.5 Hz, 6H), 0.98 - 0.91 (m, 2H), 0.90 - 0.85 (m, 2H).

Example 4: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)benzofuran-2-carboxamide

First step ethyl 5-bromobenzofuran-2-carboxylate

5-Bromo-2-hydroxy-benzaldehyde (5.0 g, 25 mmol) and potassium carbonate (3.8 g, 27 mmol) were dissolved in N,N-dimethylformamide (30 mL), and bromine was slowly added dropwise with stirring at room temperature. Ethyl acetate (4 mL) was added dropwise, and the mixture was warmed to <RTI ID=0.0></RTI> </RTI> <RTIgt; After filtration, the filter cake was evaporated to dryness crystallite

Second step 5-((tert-Butoxycarbonyl)amino)benzofuran-2-carboxylic acid ethyl ester

Ethyl 5-bromobenzofuran-2-carboxylate (3.8 g, 14 mmol), tert-butyl carbamate (2.0 g, 17 mmol), cesium carbonate (12 g, 36.8 mmol), palladium acetate (0.32 g) , 1.4mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (0.82g, 1.4mmol) and 1,4-dioxane (80mL) mixed system heated to 110 Stir at °C overnight. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The obtained residue was purified /jjjjjjjjjj

The third step is 5-aminobenzofuran-2-carboxylic acid ethyl ester

A 100 mL one-necked flask was taken and ethyl 5-((tert-butoxycarbonyl)amino)benzofuran-2-carboxylate (2.3 g, 7.5 mmol) was dissolved in dichloromethane (50 mL) and then trifluoroacetic acid was added. 2 mL), heated to 50 ° C, condensed reflux and stirred overnight. The raw material was completely reacted by TLC and the reaction was stopped. A large amount of the solvent was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) . The organic phase was evaporated to dryness crystals crystals

MS (ESI, pos.) m/z: 206.1 [M + 1] ⁺ ;

Step 4 5-Carboxamide benzofuran-2-carboxylic acid ethyl ester

Formic acid (2.0 mL, 53 mmol) was slowly added dropwise to acetic anhydride (5.0 mL, 50 mmol). After the dropwise addition, the temperature was raised to 65 ° C, stirred for 2 h, then cooled to room temperature, and the reaction solution was slowly added dropwise to the solution under ice bath. Ethyl 5-aminobenzofuran-2-carboxylate (1.2 g, 5.8 mmol) in tetrahydrofuran (20 mL) was evaporated. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. Compound (1.2 g, 88%).

MS (ESI, pos.) m/z: 234.1 [M+H] ⁺

Step 5 5-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylic acid ethyl ester

A-bromocyclopropaneethyl ketone (1.0 mL, 10 mmol) was slowly added dropwise to ethyl 5-formamide benzofuran-2-carboxylate (1.2 g, 5.1 mmol), potassium iodide (90 mg, 0.54 mmol) and A solution of potassium phosphate (3.3 g, 16 mmol) in N,N-dimethylformamide (40 mL). The reaction mixture was diluted with water (50 mL), EtOAc (EtOAc m. The title compound (580 mg, 36%).

MS (ESI, pos.) m/z: 316.0 [M+1] ⁺ ;

Step 6 5-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester

Add acetic acid to a solution of ethyl 5-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylate (550 mg, 1.7 mmol) in EtOAc (30 mL) Ammonium (1.3 g, 17 mmol), and the reaction mixture was warmed to 120 ° C and stirred overnight. It was naturally cooled to room temperature, and a large amount of solvent was evaporated under reduced pressure. The mixture was diluted with water (20 mL), EtOAc (EtOAc m. Filter and concentrate under reduced pressure. The residue was purified by mjjjjlililililililililililililili

MS (ESI, pos.) m/z: 297.1 [M + 1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.74 (d, J = 1.2Hz, 1H), 7.68-7.66 (m, 2H), 7.57 (d, J = 0.7Hz, 1H), 7.47-7.45 (m, 1H), 7.04 (d, J = 1.1 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.98-1.89 (m, 1H), 1.46 (t, J = 7.1 Hz, 3H), 0.96- 0.89 (m, 2H), 0.89-0.82 (m, 2H);

Step 7 5-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Ethyl 5-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylate (280 mg, 0.9 mmol) was dissolved in tetrahydrofuran (20 mL) and methanol (10 mL) Sodium hydroxide (5 mL, 5 mol/L) was added and stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure, and the aqueous solution was adjusted to pH = 4 with dilute hydrochloric acid. The aqueous layer was evaporated to dryness.

MS (ESI, pos.) m/z: 269.2 [M+H] ⁺

Step 8 5-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride

5-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (240 mg, 0.89 mmol) was dissolved in dry dichloromethane (20 mL) Oxalyl chloride (1 mL) and N,N-dimethylformamide (0.05 mL) were slowly added dropwise and stirred at room temperature for 3 h. The reaction was quenched and EtOAc (EtOAc m.

The ninth step 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (250 mg, 0.87 mmol) was dissolved in dichloromethane (30 mL) then 6-(4-isopropyl 4-H-1,2,4-Triazol-3-yl)pyridin-2-amine (180 mg, 0.89 mmol) and 4-dimethylaminopyridine (17 mg, 0.14 mmol) were stirred at room temperature overnight. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc)EtOAc. The title compound (100 mg, 25.3%).

MS (ESI, pos.) m/z: 454.3 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ11.05 (s, 1H), 9.48 (s, 1H), 8.93 (s, 1H), 8.26 (d, J = 2.1Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.12 - 8.02 (m, 4H), 7.93 - 7.85 (m, 2H), 5.74 - 5.66 (m, 1H), 2.07 - 2.00 (m, 1H), 1.47 (d, J = 6.7 Hz, 6H), 1.09-1.02 (m, 2H), 0.90-0.83 (m, 2H).

Example 5: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(3-methanesulfonylpropoxy Benzofuran-2-carboxamide

First step 4-(3-(Methanesulfonyl)propoxy)benzofuran-2-carboxylic acid methyl ester

Methyl 4-hydroxybenzofuran-2-carboxylate (400 mg, 2.1 mmol), p-toluenesulfonic acid-3-methanesulfonylpropyl ester (0.75 g, 2.5 mmol) and potassium carbonate (0.6 g, 4 mmol) were dissolved. In N,N-dimethylformamide (30 mL), it was warmed to 90 ° C, stirred overnight, then cooled to room temperature, diluted with water (30 mL), ethyl acetate (50 mL×2), and organic phase, organic phase The extract was washed with saturated brine (30 mL? The obtained residue was purified by mjjjjlilililililililililili

MS (ESI, pos.) m/z: 313.1 [M+H] ⁺

Step 2 4-(3-(Methanesulfonyl)propoxy)benzofuran-2-carboxylic acid

Methyl 4-(3-(methylsulfonyl)propoxy)benzofuran-2-carboxylate (650 mg, 2.1 mmol) was dissolved in tetrahydrofuran (20 mL) and methanol (10 mL). (5 mL, 5 mol/L), stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure. EtOAc (EtOAc m.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.38 (t, J = 8.2 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.9 Hz) , 1H), 4.51 (t, J = 6.0 Hz, 2H), 3.35 (t, J = 7.4 Hz, 2H), 3.03 (s, 3H), 2.57-2.51 (m, 2H);

The third step 4-(3-(methylsulfonyl)propoxy)benzofuran-2-carbonyl chloride

4-(3-(Methanesulfonyl)propoxy)benzofuran-2-carboxylic acid (200 mg, 0.67 mmol) was dissolved in anhydrous dichloromethane (20 mL). Oxalyl chloride (1 mL, 12 mmol) and N,N-dimethylformamide (0.05 mL) were added and stirred at room temperature for 3 h. The reaction was quenched and EtOAc (EtOAc m.

Fourth step N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(3-methanesulfonylpropoxy) Benzofuran-2-carboxamide

4-(3-(Methanesulfonyl)propoxy)benzofuran-2-carbonyl chloride (200 mg, 0.65 mmol) was dissolved in dichloromethane (30 mL), and 6-(4-isopropyl-4H -1,2,4-Triazol-3-yl)pyridin-2-amine (120 mg, 0.6 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The reaction was quenched with aq. EtOAc (EtOAc (EtOAc) concentrate. The residue was purified with EtOAc EtOAcjjjjjjjj

MS (ESI, pos.) m/z: 484.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.79 (s, 1H), 8.55 (d, J = 8.4Hz, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 7.9 Hz) , 1H), 5.13-5.01 (m, 1H), 4.51 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H), 2.73 (s, 3H), 2.53-2.46 (m, 2H), 1.52 (d, J = 6.7 Hz, 6H).

Example 6: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(2-methoxyethoxy) Benzofuran-2-carboxamide

First step 4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid methyl ester

A solution of sodium methoxide (3 mL, 16 mmol, 30%) in methanol was dissolved in methanol (30 mL), and then a solution of 1,3-cyclohexanedione (1.9 g, 17 mmol) in methanol (30 mL) and dissolved in 3 A solution of ethyl bromopyruvate (2.7 mL, 17 mmol, 78%) in MeOH (15 mL). The solvent was evaporated under reduced pressure, diluted with water (50 mL), and then evaporated to EtOAc (EtOAc) (EtOAc (EtOAc) The solvent was evaporated under reduced pressure. EtOAc m. m. Stop the reaction. The solvent was evaporated under reduced pressure, diluted with water (30 mL), EtOAc (EtOAc) (EtOAc (EtOAc) The aqueous sodium sulfate was dried, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 195.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.90 (s, 1H), 3.88 (s, 3H), 2.92 (t, J = 6.3Hz, 2H), 2.60-2.55 (m, 2H), 2.23-2.15 ( m, 2H);

The second step is methyl 4-hydroxybenzofuran-2-carboxylate

Methyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate (1.3 g, 6.7 mmol) was dissolved in carbon tetrachloride (50 mL) then N-bromobutyl The diimide (1.2 g, 6.7 mmol) and azobisisobutyronitrile (0.11 g, 0.67 mmol) were warmed to 85 ° C, condensed reflux and stirred for 2 h. The reaction was quenched, and the solvent was evaporated, evaporated, evaporated, evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.00 (s, 1H), 8.14 (s, 1H), 7.30-7.26 (m, 1H), 7.06 (d, J = 8.3Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H).

The third step 4-(2-methoxyethoxy)benzofuran-2-carboxylic acid methyl ester

Methyl 4-hydroxybenzofuran-2-carboxylate (400 mg, 2.1 mmol), 2-bromoethyl methyl ether (0.3 mL, 3 mmol) and potassium carbonate (0.6 g, 4 mmol) were dissolved in N,N- Methylformamide (30 mL), warmed to 60 ° C, stirred overnight, cooled to room temperature, diluted with water (50 mL), ethyl acetate (50 mL × 2), and the organic phase washed with saturated brine (100 mL × 2) Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI, pos.) m/z: 251.1 [M+H] ⁺

The fourth step 4-(2-methoxyethoxy)benzofuran-2-carboxylic acid

Methyl 4-(2-methoxyethoxy)benzofuran-2-carboxylate (220 mg, 0.88 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and methanol (10 mL) 5 mL, 25 mmol, 5 mol/L), stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure, and the remaining aqueous solution was adjusted to pH = 4 with dilute hydrochloric acid. Ethyl acetate (50 mL × 2), EtOAc (EtOAc:EtOAc.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.38 (s, 1H), 7.36 (t, J = 8.2Hz, 1H), 7.30 (s, 1H), 6.86 (d, J = 7.9Hz, 1H), 4.46 -4.41 (m, 2H), 3.88-3.87 (m, 2H), 3.50 (s, 3H);

Step 5 4-(2-methoxyethoxy)benzofuran-2-carbonyl chloride

4-(2-methoxyethoxy)benzofuran-2-carboxylic acid (190 mg, 0.8 mmol) was dissolved in anhydrous dichloromethane (20 mL) under nitrogen. The acid chloride (1 mL, 12 mmol) and N,N-dimethylformamide (0.05 mL) were stirred at room temperature for 3 h. The reaction was quenched and EtOAc (EtOAc m.

Step 6 N-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(2-methoxyethoxy) Benzofuran-2-carboxamide

4-(2-Methoxyethoxy)benzofuran-2-carbonyl chloride (200 mg, 0.79 mmol) was dissolved in dichloromethane (30 mL) then 6-(4-isopropyl-4H- 1,2,4-Triazol-3-yl)pyridin-2-amine (130 mg, 0.64 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were stirred at room temperature overnight. The reaction was quenched by the addition of saturated sodium bicarbonate (20 mL). The organic layer was washed with brine (30 mL×2). The residue was purified with EtOAc EtOAcqqqqqqq

MS (ESI, pos.) m/z: 422.3 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.84 (s, 1H), 8.47-8.38 (m, 3H), 7.99-7.87 (m, 2H), 7.36 (t, J = 8.1Hz, 1H), 7.30 ( d, J = 8.3 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 5.55 - 5.43 (m, 1H), 4.44 - 4.39 (m, 2H), 3.79 - 3.74 (m, 2H), 2.97 (s, 3H), 1.52 (d, J = 6.8 Hz, 6H).

Example 7 N-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-(trifluoromethyl)- 1H-imidazol-1-yl)benzofuran-2-carboxamide

First step: 4-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Ethyl 4-bromobenzofuran-2-carboxylate (1 g, 4 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). - Imidazole (1 g, 7.35 mmol), potassium carbonate (1.5 g, 11 mmol), cuprous iodide (140 mg, 0.74 mmol) and N,N-dimethylglycine (77 mg, 0.74 mmol), and sealed to 160 C. overnight. The organic layer was cooled to room temperature, and the mixture was evaporated to ethyl ether (m. MS (ESI, pos.) m/z: 297.1 [M+H] ⁺

Second step: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-trifluoromethyl-1H -imidazol-1-yl)benzofuran-2-carboxamide

4-(4-Trifluoromethyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (280 mg, 0.95 mmol), 6-(4-isopropyl-4H-1, 2,4-triazol-3-yl)pyridin-2-amine (210 mg, 1 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl A mixture of urea hexafluorophosphate (720 mg, 1.9 mmol), N,N-dimethylformamide (30 mL) and N,N-diisopropylethylamine (0.5 mL, 3 mmol) was warmed to 50 ° C and stirred overnight. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc) (EtOAc) Methane/methanol (v/v) = 20:1)

MS (ESI, pos.) m/z: 482.3 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ 8.91 - 8.89 (m, 2H), 8.52 (s, 1H), 8.04 (s, 3H), 7.79 - 7.75 (m, 3H), 7.70 - 7.66 (m, 1H) ), 7.43 (d, J = 7.7 Hz, 1H), 5.66 - 5.58 (m, 1H), 1.67 (d, J = 6.5 Hz, 6H).

Example 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3-methylbenzofuran-2-carboxamide

First step 2-(2-acetyl-3-hydroxyphenoxy)acetate

Potassium carbonate (22.7 g, 164 mmol) and ethyl 2-bromoacetate (7.81 mL, 69.0 mmol) were added to a solution of 2,6-dihydroxyacetophenone (10.0 g, 65.7 mmol) in acetone (120 mL). After the addition, the system was heated to 60 ° C and stirred for 2 hours. Filtration and EtOAc (EtOAc)

The second step is ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate

A solution of sodium ethoxide in ethanol (38.7 mL) was slowly added dropwise to a solution of ethyl 2-(2-acetyl-3-hydroxyphenoxy)acetate (15.7 g, 65.9 mmol) in ethanol (120 mL). , 98.7 mmol), after completion of dropwise addition, slowly stirring to room temperature and stirring was continued overnight. The reaction mixture was stirred with EtOAc EtOAc EtOAc. Filtration, EtOAc (EtOAc) (EtOAc (EtOAc)

The third step is ethyl 3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylate

In a solution of 4-hydroxy-3-methylbenzofuran-2-carboxylic acid ethyl ester (2.00 g, 9.08 mmol), DIPEA (4.52 mL, 27.3 mmol) in dichloromethane (120 mL) Trifluoromethanesulfonic anhydride (2.32 mL, 13.7 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAcq. Filtration and concentration under reduced vacuo afforded title titled

Step 4 4-((tert-Butoxycarbonyl)amino)-3-methylbenzofuran-2-carboxylic acid ethyl ester

Ethyl 3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylate (3.20 g, 9.08 mmol), tert-butyl carbamate (1.30) g, 10.9 mmol), cesium carbonate (7.40 g, 22.7 mmol), palladium acetate (208 mg, 0.91 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (542 mg, 0.91 mmol) A solution of 1,4-dioxane (80 mL) was sealed and heated to 110 ° C overnight. After it was cooled to room temperature, it was diluted with EtOAc EtOAc (EtOAc) Filtration, the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjj

MS (ESI, pos.) m/z: 264.1 [M+H] ⁺

Step 5 4-Amino-3-methylbenzofuran-2-carboxylic acid ethyl ester

The ethyl 4-((tert-butoxycarbonyl)amino)-3-methylbenzofuran-2-carboxylate (751 mg, 2.351 mmol) was used as the starting material, and the synthesis method of the third step of Example 1 was used to prepare a pale yellow color. The title compound (351 mg, 68%).

Step 6 4-Carboxamido-3-methylbenzofuran-2-carboxylic acid ethyl ester

4-ethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester (1.39 g, 6.34 mmol) was used as the starting material. 96%);

Step 7 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-3-methylbenzofuran-2-carboxylic acid ethyl ester

The title compound (800 mg, m.p. 60%);

Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-methylbenzofuran-2-carboxylic acid ethyl ester

Ethyl 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-3-methylbenzofuran-2-carboxylate (1.30 g, 3.95 mmol) was used as a starting material. The title compound of the title compound (450 mg, 37%)

MS (ESI, pos.) m/z: 311.1 [M+H] ⁺

Step 9 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-methylbenzofuran-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (420 mg, 1.35 mmol) as a starting material, the synthesis of the seventh step of Example 1 was followed. The title compound (200 mg, 52%)

MS (ESI, pos.) m/z: 283.2 [M+H] ⁺

Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3-methylbenzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-methylbenzofuran-2-carboxylic acid (208 mg, 0.7368 mmol) and 6-(4-isopropyl-4H-1, 2,4-triazol-3-yl)pyridine-2-amino (130 mg, 0.64 mmol) was obtained as a starting material.

MS (ESI, pos.) m/z: 468.1 [M+H] ⁺

^{1 H NMR (600MHz, DMSO-} d 6) δ10.72 (s, 1H), 8.89 (s, 1H), 8.14 (d, J = 8.1Hz, 1H), 8.05-8.03 (m, 1H), 7.90- 7.88 (m, 2H), 7.80 (s, 1H), 7.64 - 7.62 (m, 1H), 7.37 - 7.36 (m, 1H), 7.28 (s, 1H), 5.75 - 5.66 (m, 1H), 2.17 ( s, 3H), 1.90 - 1.88 (m, 1H), 1.47 (d, J = 6.2 Hz, 6H), 0.84 - 0.83 (m, 2H), 0.74 - 0.73 (m, 2H).

Example 9(R)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2, 4-triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

First step (R)-2-(3-(6-bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propan-1-ol

To a solution of 6-bromo-N-[(E)-dimethylaminomethylenamino]pyridine-2-carboxamide (10.0 g, 36.9 mmol) in acetonitrile (60 mL) and acetic acid (20 mL) 2-Aminopropan-1-ol (5.54 g, 73.8 mmol), heated to reflux overnight. After being cooled to room temperature, the title compound was obtained (jjjjjjjjjj %);

The second step (R)-2-(3-(6-bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propyl acetate

(R)-2-(3-(6-Bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propan-1-ol (10.0 g, 35.3 mmol) and Acetic anhydride (11.6 mL, 124 mmol) was added to pyridine (7.11 mL, 88.4 mmol). The residue was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

The third step (R)-2-(3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-4H-1,2,4-triazol-4-yl)propyl Acid ester

(R)-2-(3-(6-Bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propyl acetate (2.00 g, 6.15 mmol) The title compound (320 mg, 14%) was obtained.

MS (ESI, pos.) m/z: 362.2 [M+H] ⁺

The fourth step (R)-2-(3-(6-aminopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propyl acetate

(R)-2-(3-(6-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-4H-1,2,4-triazol-4-yl)propyl acetate The title compound (200 mg, 86%) was obtained as a yellow solid.

MS (ESI, pos.) m/z: 262.2 [M+H] ⁺

The fifth step (R)-2-(3-(6-(4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxamido)pyridin-2-yl)- 4H-1,2,4-triazol-4-yl)propyl acetate

(R)-2-(3-(6-Aminopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propyl acetate (185 mg, 0.71 mmol) , the title compound (266 mg, 74%)

MS (ESI, pos.) m/z: 512.3 [M+H] ⁺

The sixth step (R)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2, 4-triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

To (R)-2-(3-(6-(4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxamido)pyridin-2-yl under nitrogen -4H-1,2,4-triazol-4-yl)propyl acetate (266 mg, 0.52 mmol) in MeOH (10 mL) hour. The system was quenched with water (10 mL)EtOAc. Filtration and concentrating under reduced pressure. EtOAc m.

MS (ESI, pos.) m/z: 470.3 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.96 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 8.13-8.01 (m, 3H), 7.90 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.59 - 7.49 (m, 2H), 4.93 (d, J = 5.0 Hz, 1H), 4.83–4.82 (m, 1H), 4.42–4.38 (m, 1H), 3.82 (s, 1H), 1.95–1.89 (m, 1H), 1.03 (d, J=6.2 Hz, 3H), 0.86–0.83 ( m, 2H), 0.78 - 0.76 (m, 2H).

Example 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyridin-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

First step 3-(6-bromopyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

6-Bromopyridine-2-formylhydrazide (11 g, 50.92 mmol) and 6-methoxy-2,3,4,5-tetrahydropyridine (6.0 g, 53 mmol) were dissolved in DMSO (150 mL). Stir at 100 ° C overnight. After naturally cooling to room temperature, dichloromethane (200 mL × 2) was extracted, and the organic phase was combined, and the organic phase was washed with saturated brine (150 mL × 2). Drying over anhydrous sodium sulfate, EtOAc (EtOAc m. , 47%);

MS (ESI, pos.) m/z: 280.1 [M+H] ⁺

The second step (6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)carbamic acid Tert-butyl ester

3-(6-Bromopyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (14.0 g, 50.2 mmol The title compound (10.0 g, 63%) was obtained as a yellow oil.

MS (ESI, pos.) m/z: 316.2 [M+H] ⁺

The third step 6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amine

(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)carbamic acid tert-butyl The title compound (4.5 g, 94%) was obtained as a white solid.

MS (ESI, pos.) m/z: 216.2 [M+H] ⁺

The fourth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyridin-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (600 mg, 2.24 mmol) and 6-(5,6,7,8-tetrahydro-[1,2 , 4] triazole [4,3-a]pyridin-3-yl)pyridin-2-amine (300 mg, 1.40 mmol) was used as a starting material, and the title compound of the first step of Example 1 was used to obtain a pale yellow solid title. Compound (20 mg, 3%);

MS (ESI, pos.) m/z: 466.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.18 - 8.00 (m, 2H), 7.93 - 7.87 (m, 2H), 7.70 - 7.55 (m, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.15 (s, 1H), 4.57 (s, 2H), 3.65 (d, J = 15.7 Hz, 2H), 3.12 (s, 2H) ), 2.32 - 2.24 (m, 1H), 2.04 - 1.99 (m, 2H), 1.02 - 0.95 (m, 2H), 0.92 - 0.88 (m, 2H).

Example 11 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[b]thiophene-2-carboxamide

First step 4-bromobenzo[b]thiophene-2-carboxylic acid

Potassium carbonate (5.75 g, 41.7 mmol) was added to a solution of 2,6-dibromobenzaldehyde (5 g, 18.95 mmol) in N,N-dimethylformamide (50 mL) at room temperature, followed by slow dropwise addition of thioglycolate The ester (2.04 mL, 22.7 mmol) was added dropwise and the reaction was heated to reflux overnight. Naturally, it was cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (50mL×2). The obtained aqueous phase was adjusted to weak acid with 1M hydrochloric acid, and then extracted with ethyl acetate (50mL×2). The mixture was washed with EtOAc EtOAc (EtOAc m. The title compound (4.3g, 88%) MS ( ESI, pos.ion) m / z: 259.0 [m + H] +;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.30 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H) , 7.45 (d, J = 7.9 Hz, 1H);

Step 2 4-Bromobenzo[b]thiophene-2-carboxylic acid methyl ester

Concentrated sulfuric acid (1.5 mL) was added to a solution of 4-bromobenzo[b]thiophene-2-carboxylic acid (4.3 g, 17 mmol) in methanol (50 mL). Most of the solvent was removed under reduced pressure. The residue was diluted with water (20 mL). EtOAc EtOAc (EtOAc) The residue was dried (MgSO4jjjjjjjjjjjj %);

¹ H NMR (600MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.9 Hz) , 1H), 3.99 (s, 3H);

Step 3 4-((tert-Butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylic acid methyl ester

Starting from 4-bromobenzo[b]thiophene-2-carboxylate (0.7 g, 3 mmol), the title compound (yield: 0.7 g, 90%) ;

¹ H NMR (400MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 8.0 Hz) , 1H), 6.88 (s, 1H), 3.98 (s, 3H), 1.58 (s, 9H);

The fourth step is 4-aminobenzo[b]thiophene-2-carboxylic acid methyl ester

Using 4-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylic acid methyl ester (4 g, 13.01 mmol) as a starting material, the title compound (2.0g, 74%);

Step 5 4-Methylamidobenzo[b]thiophene-2-carboxylic acid methyl ester

4-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (2 g, 9.04 mmol) was used as the starting material, the title compound (2 g, 89%)

Step 6 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzo[b]thiophene-2-carboxylic acid methyl ester

The title compound (3 g, 79%) was obtained as a yellow liquid, m. m. m. ;

MS (ESI, pos.) m/z: 318.0 [M+H] ⁺

Step 7 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carboxylic acid methyl ester

Starting from methyl 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)benzo[b]thiophene-2-carboxylate (3 g, 9.45 mmol), refer to Example 3 A six-step synthesis of the title compound (1.2 g, 43%)

MS (ESI, pos.) m/z: 298.9 [M+H] ⁺

Step 8 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carboxylic acid methyl ester (1.2 g, 4.0 mmol) as a starting material, the synthesis method of the seventh step of Example 1 was followed. , the title compound (726 mg, 64%)

MS (ESI, pos.) m/z: 285.0 [M+H] ⁺

Step 9 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carboxylic acid (200 mg, 0.70 mmol) was used as a starting material, and was prepared according to the synthesis method of the eighth step of Example 4. Yellow solid title compound (0.21 g, 99%);

Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[b]thiophene-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[b]thiophene-2-carbonyl chloride (210 mg, 0.69 mmol) and 6-(4-isopropyl-4H-1,2 , 4-triazol-3-yl)pyridin-2-amine (148 mg, 0.73 mmol), m.

MS (ESI, pos.) m/z: 470.1 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ11.23 (s, 1H), 9.52 (s, 1H), 9.04 (s, 1H), 8.48 (s, 1H), 8.37-8.35 (m, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.08 (t, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.79 - 7.71 (m, 2H) ), 5.55 - 5.50 (m, 1H), 2.15 - 2.05 (m, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.12 - 1.04 (m, 2H), 0.97 - 0.89 (m, 2H).

Example 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-1H-indole-2-carboxamide

First step: (E)-2-(2-(3-nitrophenyl)indenyl)propionic acid ethyl ester

Ethyl pyruvate (11 g, 94.730) was added dropwise to a solution of 3-nitrophenylhydrazine hydrochloride (18 g, 94.9 mmol) and sodium acetate (8.6 g, 100 mmol) in ethanol/water (5:7, 360 mL) at 60 °C. A solution of ethanol/water (10:1, 30 mL) was added dropwise and stirred at room temperature overnight. Filtration, EtOAc (EtOAc)

The second step: 4-nitro-1H-indole-2-carboxylic acid ethyl ester

To the ethyl (E)-2-(2-(3-nitrophenyl)hydrazinyl)propanoate (18 g, 71.6 mmol), polyphosphoric acid (200 mL) was added and the mixture was stirred at 90 ° C overnight. The reaction mixture was poured into ice water, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj The residue was concentrated under reduced pressure. EtOAcjjjjjjjj

The third step: 1-(tert-butyl)-2-ethyl-4-nitro-1H-indole-1,2-dicarboxylate

Add 4-dimethylaminopyridine (160 mg, 1.3 mmol) to a solution of 4-nitro-1H-indole-2-carboxylic acid ethyl ester (3.0 g, 13 mmol) in tetrahydrofuran (40 mL). Di-tert-butyl dicarbonate (8 mL, 35 mmol) was added dropwise and stirred at room temperature overnight. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjjjj

The fourth step: 1-(tert-butyl) 2-ethyl-4-amino-1H-indole-1,2-dicarboxylate

To a solution of 1-(tert-butyl)-2-ethyl-4-nitro-1H-indole-1,2-dicarboxylate (2.9 g, 8.7 mmol) in dry ethanol (50 mL) Powder (6.0 g, 92 mmol) and ammonium chloride (5.0 g, 93 mmol) were stirred at room temperature for 5 h. The residue was filtered over EtOAc EtOAc EtOAcjjjjjj

Step 5: 1-(tert-butyl) 2-ethyl 4-carboxamido-1H-indole-1,2-dicarboxylate

The synthesis of the fourth step of Example 3 was carried out using 1-(tert-butyl)-2-ethyl-4-amino-1H-indole-1,2-dicarboxylate (1.35 g, 4.4 mmol) as a starting material. The title compound (1.4 g, 95%)

Step 6: 1-(tert-butyl)2-ethyl 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamide)-1H-indole-1,2-dimethyl Acid ester

The synthesis of the first step of Example 3 was carried out using 1-(tert-butyl)2-ethyl-4-carboxamido-1H-indole-1,2-dicarboxylate (1.4 g, 4.2 mmol) as a starting material. The title compound (1.0 g, 57%)

MS (ESI, pos.) m/z: 415.3 [M+H] ⁺

Step 7: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid ethyl ester

1-(tert-butyl)-2-ethyl-4-(N-(2-cyclopropyl-2-oxoethyl)carboxamide)-1H-indole-1,2-dicarboxylic acid The ester (1.0 g, 2.4 mmol) was used as a starting material, and the title compound of the third step of Example 3 was obtained to obtain a yellow oil (350 mg, 49%);

MS (ESI, pos.) m/z: 296.3 [M+H] ⁺

Step 8: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid

4-(4-cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid ethyl ester (350 mg, 1.2 mmol) was used as a starting material, and was prepared according to the synthesis method of the seventh step of Example 1. The title compound (200 mg, 63%)

Step 9: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid (200 mg, 0.75 mmol) was used as a starting material, and the synthetic method of the eighth step of Example 4 was used to prepare a yellow color. The title compound (200 mg, 94%)

Step 10: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)-1H-indole-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carbonyl chloride (200 mg, 0.7 mmol) and 6-(4-isopropyl-4H-1,2, 4-Triazol-3-yl)pyridin-2-amine (140 mg, 0.69 mmol) was obtained from the title compound (m.

MS (ESI, pos.) m/z: 453.3 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.20 (s, 1H), 9.03 (s, 1H), 8.41 (s, 1H), 8.31 (d, J = 7.7Hz, 1H), 7.92-7.79 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.28 (s, 1H), 7.15 (d, J = 6.8 Hz, 2H), 5.48 - 5.40 (m, 1H) ), 2.04 - 2.01 (m, 1H), 1.29 (d, J = 7.5 Hz, 6H), 0.96 - 0.93 (m, 2H), 0.90 - 0.88 (m, 2H).

Example 13 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2, 4]Triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

First step 5-(methyl decyl)-3,4-dihydro-2H-pyrrole

Dimethyl sulphate (8.10 mL, 85.6 mmol) was added to a solution of tetrahydropyrrole-2-thione (4.33 g, 42.8 mmol) in dichloromethane (20 mL). The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc) Filtration, the solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

MS (ESI, pos.) m/z: 116.2 [M+H] ⁺

The second step 3-(6-bromopyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

5-(methylindenyl)-3,4-dihydro-2H-pyrrole (500 mg, 4.34 mmol), 6-bromopyridinecarboxhydrazide (1.41 g, 6.53 mmol), triethylamine (1.21 mL, 8.71 mmol) A mixed solution of isopropyl alcohol (15 mL) was subjected to microwave reaction at 150 ° C for 3 hours. The mixture was cooled to EtOAc (mjqqqqqqqq (ESI, pos.ion) m/z: 265.0 [M+H] ⁺ ;

The third step 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-1H-indole-2-carboxylic acid (300 mg, 1.12 mmol) was used as a starting material, and the synthesis method of the eighth step of Example 4 was used to prepare a yellow color. Solid title compound (320 mg, 99.8%);

The fourth step 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxamide

Add ammonia water to a solution of 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (320 mg, 1.12 mmol) in tetrahydrofuran (20 mL) and dichloromethane (20 mL) 0.86 mL, 22 mmol), stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. EtOAc mjjjjjjjj

MS (ESI, pos.) m/z: 268.2 [M+H] ⁺

Step 5 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2, 4]Triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

3-(6-Bromopyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (202 mg, 0.76 mmol) and 4 -(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxamide (285 mg, 1.07 mmol) was used as a starting material, and the title compound of the second step of Example 1 was used to obtain a pale yellow solid title. Compound (120 mg, 35%);

MS (ESI, pos. ion) m/z: 452.3 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.86 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.14 (d, J = 8.3Hz, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.59 (s, 1H) , 7.53 (d, J = 7.8 Hz, 1H), 4.49 (t, J = 7.1 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.77 - 2.72 (m, 2H), 1.97-1.90 ( m, 1H), 0.90 - 0.82 (m, 2H), 0.80 - 0.78 (m, 2H).

Example 14 7-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide

First step 2-hydroxy-3-nitrobenzaldehyde

In a solution of salicylaldehyde (8.8 mL, 83 mmol) in glacial acetic acid (100 mL), EtOAc (EtOAc) It was then stirred to 40 ° C and stirred overnight. The reaction solution was poured slowly into an ice water mixture (200 mL) and stirred at room temperature for 10 min. Filtration and filtration of EtOAc EtOAc (EtOAc:EtOAc:

^{_{1 H NMR (400MHz, CDCl 3}} ) δ11.45 (s, 1H), 10.42 (s, 1H), 8.37-8.36 (m, 1H), 8.13-8.11 (m, 1H), 7.15 (d, J = 1.9 Hz, 1H);

The second step is 7-nitrobenzofuran-2-carboxylic acid ethyl ester

2-hydroxy-3-nitrobenzaldehyde (7.0 g, 41.9 mmol) was used as the starting material.

The third step is 7-aminobenzofuran-2-carboxylic acid ethyl ester

Pd/C (0.6 g) was added to a solution of ethyl 7-nitrobenzofuran-2-carboxylate (6.0 g, 25.5 mmol) in methanol (50 mL). Filtration, the filter cake was washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.40 (d, J = 7.6Hz, 2H), 6.92 (d, J = 2.1Hz, 1H), 6.87-6.84 (m, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H);

The fourth step is 7-formamide benzofuran-2-carboxylic acid ethyl ester

Starting from ethyl 7-aminobenzofuran-2-carboxylate (3.0 g, 14.62 mmol), the title compound (2.3 g, 67%)

MS (ESI, pos.) m/z: 234.0 [M+H] ⁺

Step 5 7-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylic acid ethyl ester

The title compound (2.5 g, 80%) was obtained as a yellow liquid, m.p.

MS (ESI, pos.) m/z: 316.2 [M+H] ⁺

Step 6 7-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester

Taking 7-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)benzofuran-2-carboxylic acid ethyl ester (2.5 g, 7.9 mmol) as a starting material, refer to the sixth step of Example 4. The title compound (1.0 g, 43%)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.71 (d, J = 1.0Hz, 1H), 7.67 (d, J = 8.9Hz, 1H), 7.65 (d, J = 2.1Hz, 1H), 7.56 (s , 1H), 7.45 - 7.44 (m, 1H), 7.04 (d, J = 0.9 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.96 - 1.89 (m, 1H), 1.46 (t, J = 7.1 Hz, 3H), 0.93 - 0.87 (m, 2H), 0.85 - 0.83 (m, 2H);

Step 7 7-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Using 7-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid ethyl ester (1.0 g, 3.37 mmol) as a starting material, the synthesis method of the seventh step of Example 1 was prepared. White solid target compound (420 mg, 46%);

MS (ESI, pos.) m/z: 269.1 [M+H] ⁺

Step 8 7-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride

Using 7-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (200 mg, 0.74 mmol) as a starting material, the title compound of the fourth step of Example 4 was used to prepare a yellow solid title. Compound (0.21 g, 98%);

The ninth step 7-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzofuran-2-carboxamide

7-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (210 mg, 0.73 mmol) was used as a starting material, and the synthesis method of the ninth step of Example 4 was used to prepare a white solid. The title compound (10 mg, 3%);

MS (ESI, pos.) m/z: 454.1 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ11.10 (s, 1H), 9.59 (s, 1H), 9.08 (s, 1H), 8.27 (d, J = 1.8Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.13–8.01 (m, 4H), 7.99–7.84 (m, 2H), 5.77–5.71 (m, 1H), 2.11–1.99 (m, 1H), 1.49 (d, J= 6.6 Hz, 6H), 1.12–1.01 (m, 2H), 0.95–0.84 (m, 2H);

Example 15 N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(pyridin-3-yl)benzofuran -2-carboxamide

First step: 4-(pyridin-3-yl)benzofuran-2-carboxylic acid

Ethyl 4-bromobenzofuran-2-carboxylate (1.2 g, 4.5 mmol), potassium carbonate (2.6 g, 26 mmol), benzoic acid pinacol ester (2.3 g, 9.1 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride methylene chloride complex (300 mg, 0.37 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL) and warmed to 130 ° C. 1h. 3-Bromopyridine (1.3 mL, 13 mmol) and aqueous sodium hydroxide (9 mL, 3 mol/L) were then weighed and then stirred at 130 ° C for 3 h. The reaction mixture was diluted with water (100 mL), EtOAc (EtOAc (EtOAc) (EtOAc) The title compound (100 mg, 9%) was obtained.

MS (ESI, pos. ion) m/z: 240.0 [M+H] ⁺

Second step: 4-(pyridin-3-yl)benzofuran-2-carbonyl chloride

4-(Pyridin-3-yl)benzofuran-2-carboxylic acid (85 mg, 0.36 mmol) was used as a starting material.

The third step: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(pyridin-3-yl)benzo Furan-2-carboxamide

Starting from 4-(pyridin-3-yl)benzofuran-2-carbonyl chloride (90 mg, 0.35 mmol) ;

MS (ESI, pos.) m/z: 425.0 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (d, J = 18.8 Hz, 2H), 8.72 (s, 1H), 8.48 - 8.38 (m, 2H), 8.09 - 7.79 (m, 2H), 7.99 - 7.92 (m, 1H), 7.83 (s, 1H), 7.71 - 7.66 (m, 1H), 7.65 - 7.60 (m, 1H), 7.56 - 7.50 (m, 1H), 7.50 - 7.44 (m, 1H), 5.62–5.53 (m, 1H), 1.63 (d, J = 6.0 Hz, 6H).

Example 16 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)imidazo[1,2-a]pyridine-2-carboxamide

First step: ethyl 5-bromoimidazo[1,2-a]pyridine-2-carboxylate

To a solution of ethyl 3-bromopyruvate (2.6 mL, 21 mmol) in EtOAc (50 mL)EtOAc. The residue was concentrated under reduced EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS (ESI, pos.) m/z: 270.1 [M+H] ⁺

Second step: ethyl 5-((tert-butoxycarbonyl)amino)imidazo[1,2-a]pyridine-2-carboxylate

The title compound (3.0 g, m.p., m.j.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 83%);

MS (ESI, pos.) m/z: 306.1 [M+H] ⁺

The third step: ethyl 5-aminoimidazo[1,2-a]pyridine-2-carboxylate

Prepared by the synthesis method of the third step of Example 1 using 5-((tert-butoxycarbonyl)amino)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (3.0 g, 9.8 mmol) as a starting material. The title compound (1.5 g, 74%)

MS (ESI, pos.) m/z: 206.0 [M+H] ⁺

The fourth step: ethyl 5-carboxamidomidazo[1,2-a]pyridine-2-carboxylate

The title compound (1.0 g) was obtained as a yellow solid, m.p. , 55%);

MS (ESI, pos.) m/z: 234.2 [M+H] ⁺

Step 5: 5-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

The title compound (yield as a yellow oil) was obtained from the title compound (yield: 750mg, 55%);

MS (ESI, pos.) m/z: 316.2 [M+H] ⁺

Step 6: 5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

Using 5-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (750 mg, 2.4 mmol) as a starting material, The title compound of the title compound (70 mg, 10%)

MS (ESI, pos.) m/z: 297.1 [M+H] ⁺

Step 7: 5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid

Taking 5-(4-cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (76 mg, 0.26 mmol) as a starting material, refer to the seventh step of Example 1. The title compound (68 mg, 99%)

Step 8: 5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carbonyl chloride

Using 5-(4-cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carboxylic acid (70 mg, 0.26 mmol) as a starting material, the synthesis of the eighth step of Example 4 was followed. The title compound (70 mg, 94%)

Step 9: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carbonyl chloride (70 mg, 0.25 mmol) and 6-(4-isopropyl-4H -1,2,4-triazol-3-yl)pyridin-2-amine (50 mg, 0.25 mmol) was obtained as the title compound (m. %);

MS (ESI, pos.) m/z: 454.3 [M+H] ⁺

¹ H NMR (600 MHz, CDCl ₃ ) δ 9.72 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.94 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.74 (s, 1H), 7.48 - 7.42 (m, 1H), 7.13 (s, 1H), 6.96 (d, J = 6.9 Hz, 1H), 5.71 - 5.63 (m, 1H), 2.02 - 1.96 (m, 1H), 1.64 (d, J = 6.6 Hz, 6H), 1.03 - 0.95 (m) , 2H), 0.96–0.90 (m, 2H).

Example 17 N-(6-(5-Chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-cyclopropyl -1H-imidazol-1-yl)benzofuran-2-carboxamide

First step: 2-bromo-6-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine

Add N-chlorosuccinyl to a solution of 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (1 g, 3.74 mmol) in EtOAc (10 mL) The imine (1 g, 7.49 mmol) was heated to reflux overnight. The residue was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS (ESI, pos.) m/z: 300.8 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 5.65 - 5.51 (m, 1H), 1.66 (d, J = 7.0 Hz, 6H);

Second step: 6-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine

2-Bromo-6-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (0.4 g, 1 mmol) was dissolved in aqueous ammonia (20 mL) at room temperature The seal was heated to 140 ° C and stirred overnight. After being cooled to room temperature, the solvent was evaporated,jjjjjjjjjjjjjjj

MS (ESI, pos.) m/z: 238.0 [M+H] ⁺

¹ H NMR (600MHz, CDCl ₃ ) δ 7.59 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 5.62 - 5.50 (m, 1H), 4.56 (s, 2H), 1.62 (d, J = 7.0 Hz, 6H);

The third step: 4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (200 mg, 0.8 mmol) was used as a starting material, and the title compound of the fourth step of Example 4 was used to prepare a yellow solid title. Compound (230 mg, 99%);

The fourth step: N-(6-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-cyclopropane keto-1H-imidazol-1-yl)benzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (230 mg, 0.8 mmol) and 6-(5-chloro-4-isopropyl-4H-1, 2,4-triazol-3-yl)pyridin-2-amine (200 mg, 0.8 mmol) was obtained from the title compound (m. );

MS (ESI, pos.) m/z: 488.0 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ11.21 (s, 1H), 9.58 (s, 1H), 8.33-8.27 (m, 1H), 8.17 (d, J = 8.2Hz, 1H), 8.11 ( t, J = 7.9 Hz, 1H), 8.06 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 5.64 - 5.56 (m, 1H), 2.11 - 2.05 (m, 1H), 1.55 (d, J = 6.9 Hz, 6H), 1.10 - 1.04 (m) , 2H), 0.98–0.93 (m, 2H).

Example 18 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-1-methyl-1H-indole-2-carboxamide

First step: 1-methyl-4-nitro-1H-indole-2-carboxylic acid ethyl ester

Add cesium carbonate (4.0 g, 12 mmol) and iodine to a solution of ethyl 4-nitro-1H-indole-2-carboxylate (1.9 g, 8.1 mmol) in N,N-dimethylformamide (30 mL) Methane (0.8 mL, 10 mmol) was stirred at room temperature overnight. Diluted with water (100 mL).

MS (ESI, pos. ion) m/z: 248.9 [M+H] ⁺

The second step: ethyl 4-amino-1-methyl-1H-indole-2-carboxylate

To a solution of 1-methyl-4-nitro-1H-indole-2-carboxylic acid ethyl ester (2.0 g, 8.1 mmol) in dry ethanol (40 mL), palladium carbon (0.5 g, 10%), hydrogen atmosphere Stir at room temperature overnight. The mixture was filtered through EtOAc (EtOAc)EtOAc MS (ESI, pos.) m/z: 219.0 [M+H] ⁺

The third step: ethyl 4-carboxamido-1-methyl-1H-indole-2-carboxylate

4-ethyl-1-methyl-1H-indole-2-carboxylic acid ethyl ester (1.4 g, 6.4 mmol) was used as the starting material. , 82%);

Fourth step: 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-1-methyl-1H-indole-2-carboxylic acid ethyl ester

Starting from 4-methylamido-1-methyl-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 5.3 mmol), the title compound 900mg, 52%);

MS (ESI, pos.) m/z: 329.1 [M+H] ⁺

Step 5: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carboxylic acid ethyl ester

4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-1-methyl-1H-indole-2-carboxylic acid ethyl ester (900 mg, 2.7 mmol) was used as a starting material. The title compound of the title compound (320 mg, 38%)

MS (ESI, pos.) m/z: 310.3 [M+H] ⁺

Step 6: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carboxylic acid

Taking 4-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carboxylic acid ethyl ester (320 mg, 1.0 mmol) as a starting material, refer to the seventh step of Example 1. The title compound (150 mg, 52%)

MS (ESI, pos.) m/z: 282.2 [M+H] ⁺

Step 7: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carboxylic acid (110 mg, 0.39 mmol) was used as a starting material, and the synthesis of the eighth step of Example 4 was followed. The title compound (110 mg, 94%)

Step 8: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)-1-methyl-1H-indole-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-2-carbonyl chloride (110 mg, 0.37 mmol) and 6-(4-isopropyl-4H -1,2,4-triazol-3-yl)pyridin-2-amine (75 mg, 0.37 mmol) was obtained as a starting material. %);

MS (ESI, pos.) m/z: 467.1 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.89 (s, 1H), 8.89 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.05 (t, J = 7.9Hz, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 5.67–5.58 (m, 1H), 4.10 (s, 3H), 2.03–1.94 (m, 1H), 1.44 (d, J=6.6 Hz, 6H), 0.87–0.83 (m, 2H), 0.80 –0.74 (m, 2H).

Example 19 4-(4-Fluoro-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 -yl)benzofuran-2-carboxamide

First step: methyl 4-iodobenzofuran-2-carboxylate

Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of methyl 4-aminobenzofuran-2-carboxylate (3.0 g, 16 mmol) in water (20 mL) at 0 ° C. After the addition was completed, the temperature was lowered to -10 ° C. An aqueous solution (20 mL) of sodium nitrite (1.4 g, 20 mmol) was added and stirred for 1 h. Acetone (30 mL) was further added, and an aqueous solution (20 mL) of potassium iodide (3.1 g, 19 mmol) was slowly added dropwise thereto, and the mixture was poured to 0 ° C and stirred for 4 h. The organic phase was washed with saturated aqueous sodium chloride (30 mL×2), and the organic phase was combined and evaporated. The residue was purified byjjjjlilililililililililililililili

The second step: methyl 4-(4-fluoro-1H-imidazol-1-yl)benzofuran-2-carboxylate

Methyl 4-iodobenzofuran-2-carboxylate (700 mg, 2.32 mmol), 4-fluoro-1H-imidazole (250 mg, 2.91 mmol), potassium carbonate (400 mg, 2.89 mmol), 8-hydroxyl. Quinaldine (35 mg, 0.22 mmol) and cuprous iodide (44 mg, 0.23 mmol) in anhydrous dimethyl sulfoxide (30 mL) were stirred and stirred at 90 ° C overnight. The reaction mixture was diluted with water (50 mL), EtOAc (EtOAc (EtOAc) Ethyl acetate (v/v) = 5:1)

MS (ESI, pos.) m/z: 261.0 [M+H] ⁺

The third step: 4-(4-fluoro-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Using 4-(4-fluoro-1H-imidazol-1-yl)benzofuran-2-carboxylic acid methyl ester (65 mg, 0.25 mmol) as a starting material, the title compound of the seventh step of Example 1 was used to prepare a white solid title. Compound (50 mg, 81%);

The fourth step: 4-(4-fluoro-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride

4-(4-Fluoro-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (50 mg, 0.20 mmol) was used as the starting material. 50mg, 93%);

Step 5: 4-(4-Fluoro-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- 2-based) benzofuran-2-carboxamide

4-(4-Fluoro-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (50 mg, 0.19 mmol) and 6-(4-isopropyl-4H-1,2,4-triazole Oxazol-3-yl)pyridin-2-amine (35 mg, 0.17 mmol) was obtained from the title compound (30 mg, 37%)

MS (ESI, pos.) m/z: 432.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 5.60 - 5.51 (m, 1H), 1.63 (d, J = 7.0 Hz, 6H).

Example 20 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3 -yl)pyridin-2-yl)benzofuran-2-carboxamide

First step 2-bromo-3,6-difluorobenzaldehyde

Under a nitrogen atmosphere, a solution of 2-bromo-1,4-difluorobenzene (5 g, 25.91 mmol) in tetrahydrofuran (60 mL) was cooled to -78 ° C, and then slowly dropped into LDA (16.84 mL, 33.68 mmol). After stirring for 1 hour, N,N-dimethylformamide (6 mL, 77.8 mmol) was slowly added dropwise, and the mixture was stirred for 2 hours. After the mixture was warmed to room temperature, EtOAc (EtOAc m. Filtration, EtOAc (EtOAc) (EtOAc)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.35 (s, 1H), 7.41-7.30 (m, 1H), 7.22-7.10 (m, 1H);

The second step 2-bromo-3-fluoro-6-methoxybenzaldehyde

2-Bromo-3,6-difluorobenzaldehyde (2.6 g, 12 mmol) was dissolved in a mixed solution of tetrahydrofuran (15 mL) and methanol (30 mL). After warming to 60 ° C, sodium methoxide (0.72 g, A solution of 13 mmol) in MeOH (15 mL) was stirred overnight. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. (petroleum ether / ethyl acetate (v/v) = 20/1)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.40 (s, 1H), 7.33-7.28 (m, 1H), 6.96-6.94 (m, 1H), 3.93 (s, 3H);

The third step 2-bromo-3-fluoro-6-hydroxybenzaldehyde

Under a nitrogen atmosphere, a solution of 2-bromo-3-fluoro-6-methoxybenzaldehyde (1.6 g, 6.9 mmol) in dichloromethane (50 mL) was reduced to -78 ° C, and then boron tribromide was slowly added dropwise. A solution of methylene chloride (1M, 10 mL, 10 mmol) was evaporated and evaporated. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc) The mixture was concentrated with EtOAc EtOAc EtOAcjjjjjjj

^{_{1 H NMR (400MHz, CDCl 3}} ) δ11.79 (s, 1H), 10.36 (s, 1H), 7.36-7.29 (m, 1H), 6.99-6.91 (m, 1H);

The fourth step 4-bromo-5-fluorobenzofuran-2-carboxylic acid ethyl ester

Using 2-bromo-3-fluoro-6-hydroxybenzaldehyde (1.6 g, 7.3 mmol) as the starting material, the title compound (1.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.57 (s, 1H), 7.53-7.81 (m, 1H), 7.28 (s, 1H), 4.48 (q, J = 7.1Hz, 2H), 1.46 (t, J=7.1Hz, 3H);

Step 5 4-((tert-Butoxycarbonyl)amino)-5-fluorobenzofuran-2-carboxylic acid ethyl ester

4-ethyl bromide-5-fluorobenzofuran-2-carboxylic acid ethyl ester (1 g, 3.48 mmol) was used as the starting material. ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.75 (s, 1H), 7.33 (dd, J = 9.0,3.7Hz, 1H), 7.22 (dd, J = 10.6,9.1Hz, 1H), 6.70 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.58 (s, 9H), 1.45 (t, J = 7.1 Hz, 3H);

Step 6 4-Amino-5-fluorobenzofuran-2-carboxylic acid ethyl ester

4-((tert-Butoxycarbonyl)amino)-5-fluorobenzofuran-2-carboxylic acid ethyl ester (1.8 g, 5.6 mmol) was used as a starting material, and the synthesis method of the third step of Example 1 was carried out to obtain a yellow solid. The title compound (1.2 g, 97%);

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.53 (s, 1H), 7.14 (dd, J = 11.3,9.0Hz, 1H), 6.92 (dd, J = 8.9,3.2Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 1.44 (t, J = 7.1 Hz, 3H).

Step 7 5-Fluoro-4-carboxamidobenzofuran-2-carboxylic acid ethyl ester

4-Amino-5-fluorobenzofuran-2-carboxylic acid ethyl ester (1.8 g, 8.1 mmol) was used as the starting material. )

MS (ESI, pos.ion) m/z: 252.2 [M+H] ⁺

Step 8 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-5-fluorobenzofuran-2-carboxylic acid ethyl ester

The title compound (1.3 g, m.p., m. 75%);

MS (ESI, pos.) m/z: 334.2 [M+H] ⁺

Step 9 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carboxylic acid ethyl ester

Ethyl 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-5-fluorobenzofuran-2-carboxylate (1.4 g, 4.2 mmol) was used as a starting material. 4 Synthesis of the sixth step, the title compound was obtained as the title compound ( 680 mg, 52%)

MS (ESI, pos.) m/z: 315.2 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.76 (s, 1H), 7.61-7.54 (m, 2H), 7.38 (dd, J = 10.4,9.2Hz, 1H), 7.06 (s, 1H), 1.99- 1.96 (m, 1H), 1.47 - 1.43 (m, 3H), 0.99 - 0.90 (m, 4H).

Step 10 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carboxylic acid ethyl ester (680 mg, 2.16 mmol) as a starting material, the synthesis method of the seventh step of Example 1 was followed. , the title compound (600 mg, 97%)

MS (ESI, pos.) m/z: 287.3 [M+H] ⁺

The eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carboxylic acid (200 mg, 0.70 mmol) was used as a starting material, and was prepared according to the synthesis method of the eighth step of Example 4. Obtained as a title compound (m.

The twelfth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridin-2-yl)benzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carbonyl chloride (0.21 g, 0.69 mmol) and 6-(4-isopropyl-4H-1 , 2,4-triazol-3-yl)pyridin-2-amine (0.17 g, 0.84 mmol), m. %);

MS (ESI, pos.) m/z: 4721. [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ11.05 (s, 1H), 8.88 (s, 1H), 8.12 (d, J = 7.6Hz, 2H), 8.05 (t, J = 7.9Hz, 1H) , 7.97 (s, 1H), 7.87 (d, J = 7.0 Hz, 2H), 7.64 (t, J = 10.0 Hz, 1H), 7.42 (s, 1H), 5.70 - 5.56 (m, 1H), 1.99 - 1.86 (m, 1H), 1.44 (d, J = 6.6 Hz, 6H), 0.88 - 0.81 (m, 2H), 0.80 - 0.71 (m, 2H).

Example 21 4-(4-Cyclopropyl-1H-imidazol-1-yl)-6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3 -yl)pyridin-2-yl)benzofuran-2-carboxamide

First step 4-fluoro-2,6-dimethoxybenzaldehyde

At -5 ° C, in a solution of 1-fluoro-3,5-dimethoxybenzene (10.0 g, 64.0 mmol) in DMF (5.18 mL, 67.2 mmol), slowly added phosphorus oxychloride (5.97 mL, 64.0) Methyl), after completion, the mixture was heated to 60 ° C and stirred for 2 hours. After cooling to room temperature, the reaction was quenched with EtOAc (EtOAc) (EtOAc) Dry over anhydrous sodium sulfate. Filtration, the solvent was evaporated,jjjjjjjjjjjjjjjjjjjj

MS (ESI, pos.) m/z: 185.0 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.29 (d, J = 0.8 Hz, 1H), 6.28 (t, J = 5.4 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H).

The second step 4-fluoro-2-hydroxy-6-methoxybenzaldehyde

At -10 ° C, in a solution of 4-fluoro-2,6-dimethoxybenzaldehyde (10.9 g, 59.2 mmol) in dichloromethane (100 mL), slowly added boron tribromide (71.0 mL, 71.0 mmol) ), stirring at room temperature for 4 hours. The reaction mixture was poured into ice water, dichloromethane (500 mL × 2) was evaporated. Filtration, the solvent was evaporated, EtOAcjjjjjjjjjj

^{_{1 H NMR (400MHz, CDCl 3}} ) δ11.92 (s, 1H), 10.06 (s, 1H), 6.24-6.20 (m, 2H), 3.87 (s, 3H);

The third step is 6-fluoro-4-methoxybenzofuran-2-carboxylic acid ethyl ester

4-Fluoro-2-hydroxy-6-methoxybenzaldehyde (860 mg, 5.05 mmol) was used as the starting material.

MS (ESI, pos.) m/z: 239.0 [M+H] ⁺

The fourth step 6-fluoro-4-hydroxybenzofuran-2-carboxylic acid

The title compound (6.50 g, 99.9%) was obtained as a yellow solid (yield: EtOAc (EtOAc) ;

MS (ESI, neg.ion) m/z: 195.1 [MH] ^- ;

The fifth step is 6-fluoro-4-hydroxybenzofuran-2-carboxylic acid ethyl ester

Concentrated sulfuric acid (0.99 mL, 17 mmol) was added dropwise to a solution of 6-fluoro-4-hydroxybenzofuran-2-carboxylic acid (6.50 g, 33.1 mmol) in ethanol (80 mL) at room temperature, and the mixture was stirred and refluxed. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. Filtration, the solvent was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 225.1 [M+H] ⁺ ;

The sixth step is 6-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylic acid ethyl ester

The title compound (3.83 g, 59%) was obtained as a yellow solid (yield: EtOAc, m. )

Step 7 4-((tert-Butoxycarbonyl)amino)-6-fluorobenzofuran-2-carboxylic acid ethyl ester

Using 6-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylic acid ethyl ester (3.83 g, 10.8 mmol) as a starting material, the synthesis of the fourth step of Example 8 was followed. The title compound (1.66 g, 48%)

MS (ESI, pos.) m/z: 324.2 [M+H] ⁺

Step 8 4-Amino-6-fluorobenzofuran-2-carboxylic acid ethyl ester

4-((tert-Butoxycarbonyl)amino)-6-fluorobenzofuran-2-carboxylic acid ethyl ester (2.00 g, 6.19 mmol) was used as a starting material, and the synthesis method of the third step of Example 1 was carried out to obtain a pale yellow color. Solid title compound (1.00 g, 72%);

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.48 (s, 1H), 6.63 (s, 1H), 6.40-6.37 (m, 1H), 4.43 (q, J = 7.1Hz, 2H), 4.04 (s, 2H), 1.43 (t, J = 7.1 Hz, 3H);

The ninth step 6-fluoro-4-carboxamidobenzofuran-2-carboxylic acid ethyl ester

4-ethyl-6-fluorobenzofuran-2-carboxylic acid ethyl ester (1.89 g, 8.47 mmol) was used as the starting material. );

MS (ESI, pos.) m/z: 252.2 [M+H] ⁺

Step 10 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-6-fluorobenzofuran-2-carboxylic acid ethyl ester

Preparation of the title compound (2.83 g, EtOAc, m. 100%);

MS (ESI, pos.) m/z: 334.2 [M+H] ⁺

The eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carboxylic acid ethyl ester

Ethyl 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-6-fluorobenzofuran-2-carboxylate (2.83 g, 8.49 mmol) was used as a starting material. The title compound (1.40 g, 53%)

MS (ESI, pos.) m/z: 315.0 [M+H ⁺ ;

Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carboxylic acid ethyl ester (1.40 g, 4.45 mmol) as a starting material, the synthesis of the seventh step of Example 1 was followed. The title compound (1.10 g, 86%)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.71 - 7.62 (m, 2H), 1.86 - 1.82 (m, 1H) ), 0.83–0.80 (m, 2H), 0.73–0.65 (m, 2H);

Step 13 4-(4-Cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carboxylic acid (200 mg, 0.70 mmol) was used as a starting material, and was prepared according to the synthesis method of the eighth step of Example 4. The title compound (212 mg, 99.6%)

Fourteenth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridin-2-yl)benzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-6-fluorobenzofuran-2-carbonyl chloride (211 mg, 0.69 mmol) and 6-(4-isopropyl-4H-1, 2,4-Triazol-3-yl)pyridin-2-amine (128 mg, 0.63 mmol) was obtained from the title compound (yield: ;

MS (ESI, pos.) m/z: 472.4 [M+H] ⁺

¹ H NMR (600MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.41 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 12.3 Hz, 2H), 7.46 (s, 1H), 7.15 (d, J = 9.4 Hz, 1H), 7.10 (s, 1H), 5.57 -5.52 (m, 1H), 1.96 - 1.92 (m, 1H), 1.62 (d, J = 6.7 Hz, 6H), 1.00 - 0.89 (m, 2H), 0.91 - 0.79 (m, 2H).

Example 22 N-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-(methylindenyl)-1H- Imidazol-1-yl)benzofuran-2-carboxamide

First step: 4-iodo-1-trityl-1H-imidazole

Triethylamine (15 mL) was slowly added dropwise to 4-iodo-1H-imidazole (10 g, 51.6 mmol) and triphenylchloromethane (22 g, 78.9 mmol) in anhydrous tetrahydrofuran (300 mL). Heat to 80 ° C and stir overnight. The reaction was quenched with saturated sodium bicarbonate (50 mL). Ethyl acetate (50 mL × 2) was extracted, and the organic layer was combined, evaporated, evaporated, evaporated, evaporated Ether/dichloromethane (v/v) = 1:1)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 - 7.36 (m, 9H), 7.35 (d, J = 1.3 Hz, 1H), 7.17 - 7.10 (m, 6H), 6.94 (d, J = 1.4 Hz, 1H);

Second step: 4-(methylindenyl)-1-trityl-1H-imidazole

4-iodo-1-trityl-1H-imidazole (10 g, 22.92 mmol) was dissolved in dichloromethane (100 mL) under nitrogen, and ethyl brunium bromide in anhydrous tetrahydrofuran (25 mL, 1.0) Mol/L), stirring for 30 min under ice-cooling, dimethyl disulfide (2.7 mL, 30 mmol) was slowly added dropwise, and stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride (100 mL). The mixture was extracted with dichloromethane (100 mL×2). v) = 3 / 1), the title compound (800 mg, 10%)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.45 (d, J = 1.0Hz, 1H), 7.37-7.34 (m, 10H), 7.18-7.13 (m, 7H), 6.82 (d, J = 1.2Hz, 1H), 2.44 (s, 3H);

The third step: 4-(methylindenyl)-1H-imidazole

4-(Methyl decyl)-1-trityl-1H-imidazole (800 mg, 2.24 mmol) was dissolved in methanol (30 mL), glacial acetic acid (5 mL) was added, warmed to 80 ° C, condensed reflux and stirred 5h. The solvent was evaporated under reduced pressure.

^{_{1 H NMR (600MHz, CDCl 3}} ) δ7.73 (s, 1H), 7.12 (s, 1H), 2.42 (s, 3H);

Step 4: Methyl 4-(4-(methylindolyl)-1H-imidazol-1-yl)benzofuran-2-carboxylate

Taking 4-iodobenzofuran-2-carboxylic acid ethyl ester (800 mg, 2.53 mmol) and 4-(methylindolyl)-1H-imidazole (200 mg, 1.75 mmol) as a starting material, the synthesis method of the second step of Example 20 was carried out. Preparation of the title compound (100 mg, 19%)

MS (ESI, pos.) m/z: 303.0 [M+H] ⁺

Step 5: 4-(4-(Methyl)-1H-imidazol-1-yl)benzofuran-2-carboxylic acid

Using 4-(4-(methylindolyl)-1H-imidazol-1-yl)benzofuran-2-carboxylic acid methyl ester (100 mg, 0.33 mmol) as a starting material, the synthesis method of the seventh step of Example 1 was prepared. White solid the title compound (70 mg, 77%);

Step 6: 4-(4-(Methylthio)-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride

4-(4-(methylindolyl)-1H-imidazol-1-yl)benzofuran-2-carboxylic acid (70 mg, 0.26 mmol) was used as a starting material. For the title compound (70 mg, 94%);

Step 7: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-(methylindenyl)-1H -imidazol-1-yl)benzofuran-2-carboxamide

4-(4-(methylindolyl)-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (70 mg, 0.24 mmol) and 6-(4-isopropyl-4H-1,2,4 - a triazol-3-yl)pyridin-2-amine (50 mg, 0.25 mmol) was obtained as a starting material.

MS (ESI, pos.) m/z: 460.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.43 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 5.61 - 5.51 (m, 1H), 2.58 (s, 3H), 1.63 (d, J = 6.6 Hz, 6H).

Example 23 N-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-(methylsulfonyl)-1H -imidazol-1-yl)benzofuran-2-carboxamide

N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(4-(methylindolyl)-1H-imidazole- To a solution of 1-yl)benzofuran-2-carboxamide (55 mg, 0.12 mmol) in MeOH (15 mL). Filter through celite, sat. aq. sodium hydrogen carbonate (10 mL) and stir for 30 min. The solvent was evaporated to drynesshhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS (ESI, pos.) m/z: 4921. [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 5.1 Hz, 2H), 7.98 (t, J = 7.9 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.68 (t, J = 8.1 Hz) , 1H), 7.43 (d, J = 7.7 Hz, 1H), 5.58 - 5.50 (m, 1H), 3.31 (s, 3H), 1.63 - 1.61 (m, 6H).

Example 24 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2, 4]Triazol-3-yl)pyridin-2-yl)-5-fluorobenzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluorobenzofuran-2-carbonyl chloride (0.21 g, 0.69 mmol) and 6-(6,7-dihydro-5H- Pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (0.17 g, 0.84 mmol) was used as a starting material, and the synthesis method of the ninth step of Example 4 was carried out. The title compound (31 mg, 10%)

MS (ES-API, pos. ion) m/z: 470.3 [M+H] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ10.96 (s, 1H), 8.15-8.07 (m, 2H), 8.02-7.98 (m, 2H), 7.91-7.84 (m, 2H), 7.64-7.62 (m, 1H), 7.43 (s, 1H), 4.48 (t, J = 7.1 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.79 - 2.66 (m, 2H), 1.97 - 1.90 ( m, 1H), 0.87 - 0.82 (m, 2H), 0.80 - 0.74 (m, 2H).

Example 25 4-(4-Chloro-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 -yl)benzofuran-2-carboxamide

4-chloro-1H-imidazole (400 mg, 3.9 mmol) was obtained from the title compound (30 mg, 37%)

MS (ESI, pos.) m/z: 448.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.63 (t, J = 8.1 Hz) , 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 5.60 - 5.49 (m, 1H), 1.62 (d, J = 6.7 Hz, 6H).

Example 26 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)-N-(6-(4-isopropyl-4H-1,2,4- Triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

First step 4-acetoxy-3-methylbenzofuran-2-carboxylic acid ethyl ester

Ethyl acetic anhydride (32.8 mL, 349 mmol) was slowly added dropwise to a solution of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (22.0 g, 99.9 mmol) in pyridine (20.1 mL). overnight. The solvent was evaporated to drynesshhhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 - 7.39 (m, 2H), 7.04 - 7.02 (m, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.66 (s, 3H), 2.41 ( s, 3H), 1.46 (t, J = 7.1 Hz, 3H);

The second step is ethyl 4-acetoxy-3-(dibromomethyl)benzofuran-2-carboxylate

Add N-bromosuccinimide to a solution of ethyl 4-acetoxy-3-methylbenzofuran-2-carboxylate (20.1 g, 76.6 mmol) in carbon tetrachloride (200 mL) at room temperature (54.6 g, 307 mmol) and benzoyl peroxide (1.86 g, 7.68 mmol). After the addition, the temperature was raised to reflux and stirred overnight. The reaction mixture was diluted with methylene chloride (200 mL) and evaporated. Petroleum ether / ethyl acetate (v / v) = 20 / 1-1 / /

The third step 4-acetoxy-3-formylbenzofuran-2-carboxylic acid ethyl ester

Add silver nitrate (17.5 g, 104 mmol) to a solution of ethyl 4-acetoxy-3-(dibromomethyl)benzofuran-2-carboxylate (14.5 g, 34.5 mmol) in EtOAc (EtOAc) 8 hours. The organic layer was cooled to room temperature, and filtered. Filtration and evaporation of EtOAcqqqqqqqqq

The fourth step is ethyl 4-acetoxy-3-(difluoromethyl)benzofuran-2-carboxylate

To a solution of ethyl 4-acetoxy-3-formylbenzofuran-2-carboxylate (9.54 g, 34.5 mmol) in toluene (120 mL), EtOAc. ), stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Filtration, and the solvent was evaporated.jjjjjjjjjjjj ;

¹ H NMR (400MHz, CDCl ₃ ) δ 7.67 (s, 1H), 7.61 - 7.50 (m, 2H), 7.19 - 7.17 (m, 1H), 4.57 - 4.48 (m, 2H), 2.44 - 2.36 (m , 3H), 1.52–1.44 (m, 3H);

Step 5 3-(Difluoromethyl)-4-hydroxybenzofuran-2-carboxylic acid methyl ester

Potassium carbonate (7.92 mg, in a solution of ethyl 4-acetoxy-3-(difluoromethyl)benzofuran-2-carboxylate (8.56 g, 28.7 mmol) in MeOH (40 mL) The mixture was stirred at room temperature for 1 hr. EtOAc (EtOAc)EtOAc. Filtration, the solvent was evaporated,jjjjjjjjjjjjjjjjjjjj

^{_{1 H NMR (600MHz, CDCl 3}} ) δ7.74 (d, J = 55.2Hz, 1H), 7.45 (t, J = 8.2Hz, 1H), 7.21 (d, J = 8.4Hz, 1H), 6.93 (d , J = 8.0 Hz, 1H), 6.18 (t, J = 8.5 Hz, 1H), 4.06 (d, J = 1.1 Hz, 3H);

Step 6 3-(Difluoromethyl)-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylic acid methyl ester

The title compound was obtained as a yellow solid (yield: m. 4.80g, 78%);

Step 7 4-((tert-Butoxycarbonyl)amino)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester

Starting from methyl 3-(difluoromethyl)-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylate (3.82 g, 10.2 mmol), refer to Example 8 The title compound of the title compound (890 mg, 26%)

MS (ESI, pos. ion) m/z: 242.2 [M+H-100] ⁺ ;

Step 8 4-Amino-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester

Using 4-((tert-butoxycarbonyl)amino)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester (890 mg, 2.61 mmol) as a starting material, refer to the synthesis method of the third step of Example 1, The title compound (550 mg, 88%)

Step 9 3-(Difluoromethyl)-4-carboxamidobenzofuran-2-carboxylic acid methyl ester

The title compound was obtained as a pale yellow solid (yield: m. 450mg, 64%);

MS (ESI, pos.) m/z: 270.0 [M+H] ⁺

Step 10 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester

The title compound was obtained as a yellow solid. m. m. m. (584 mg, 99.9%);

MS (ESI, pos.) m/z: 352.2 [M+H] ⁺

The eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester

Starting from methyl 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-3-(difluoromethyl)benzofuran-2-carboxylate (170 mg, 0.48 mmol) , the title compound (48 mg, 30%)

Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carboxylic acid methyl ester (118 mg, 0.36 mmol) as a starting material, refer to Example 1 The title compound (95 mg, 84%)

Step 13 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carboxylic acid (95 mg, 0.3 mmol) was used as the starting material, and the eighth step of Example 4 was followed. , the title compound (100 mg, 99.5%);

Step 16 4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)-N-(6-(4-isopropyl-4H-1,2,4 -triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

4-(4-cyclopropyl-1H-imidazol-1-yl)-3-(difluoromethyl)benzofuran-2-carbonyl chloride (100 mg, 0.30 mmol) was used as the starting material, and the ninth example was used. The title compound (4 mg, 3%)

MS (ESI, pos.) m/z: 504.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 8.41 (d, J = 9.7 Hz, 2H), 8.10 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 8.0 Hz) , 1H), 7.83–7.77 (m, 1H), 7.68–7.55 (m, 3H), 7.38 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 5.55–5.49 (m, 1H), 2.00–1.94 (m, 1H), 1.62 (d, J = 6.7 Hz, 6H), 0.93–0.89 (m, 2H), 0.88–0.84 (m, 2H).

Example 27 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[d]thiazole-2-carboxamide

First step 2-((2-bromophenyl)amino)-2-oxoethylacetate

Diethyl oxalate (71.1 mL, 523 mmol) was added to 2-bromoaniline (30.0 g, 174 mmol), and the mixture was stirred at 150 ° C for 4 hours. After cooling to rt, EtOAc (EtOAc (EtOAc)

Step 2 2-((2-Bromophenyl)amino)-2-thioethylacetate

In a solution of 2-((2-bromophenyl)amino)-2-oxoacetate (47.5 g, 175 mmol) in toluene (300 mL), EtOAc (36.4 g, 87.3 mmol) After stirring to 70 ° C, the title compound (50.3 g, m. 100%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.06 (s, 1H), 8.96 - 8.94 (m, 1H), 7.69 - 7.67 (m, 1H), 7.46 - 7.35 (m, 1H), 7.21 - 7.17 (m) , 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);

The third step 2-((2-bromophenyl)amino)-2-thioacetic acid

The title compound (46.8 g) was obtained as a yellow solid (m. , 100%);

The fourth step 4-bromobenzo[d]thiazole-2-carboxylic acid

Potassium ferricyanide (178 g, 540.63 mmol) was added to a solution of 2-((2-bromophenyl)amino)-2-thioacetic acid (46.8 g, 180 mmol) in water (100 mL). . The solvent was evaporated under reduced pressure. the residue was evaporated to mjjjjjjjjjjjjjjjjjjjjjjj Yellow solid title compound (26.0 g, 56%);

MS (ESI, pos.) m/z: 259.9 [M+H] ⁺

Step 5 4-Bromobenzo[d]thiazole-2-carbonyl chloride

4-bromobenzo[d]thiazole-2-carboxylic acid (500 mg, 1.94 mmol) was used as the starting material, the title compound ( 535 mg, 99.9%)

Step 6 4-Bromobenzo[d]thiazole-2-carboxylic acid methyl ester

A solution of 4-bromobenzo[d]thiazole-2-carbonyl chloride (535 mg, 1.93 mmol) in dichloromethane (20 mL) was evaporated. The aqueous solution was diluted with aq. EtOAc (EtOAc) Filtration and evaporation of EtOAc. ;

MS (ESI, pos.) m/z: 2721. [M+H] ⁺

Step 7 4-((tert-Butoxycarbonyl)amino)benzo[d]thiazole-2-carboxylic acid methyl ester

Using 4-bromobenzo[d]thiazole-2-carboxylic acid methyl ester (4.00 g, 14.7 mmol) as the starting material, the title compound of the title compound (1. );

Step 8 4-Aminobenzo[d]thiazole-2-carboxylic acid methyl ester

Using 4-((tert-butoxycarbonyl)amino)benzo[d]thiazole-2-carboxylic acid methyl ester (4.00 g, 14.7 mmol) as a starting material, the title compound of the first step of Example 1 was used to prepare a yellow solid title. Compound (600 mg, 59%);

MS (ESI, pos.) m/z: 209.2 [M+H] ⁺

Step 9 4-Methylamidobenzo[d]thiazole-2-carboxylic acid methyl ester

4-methylbenzo[d]thiazole-2-carboxylic acid methyl ester (690 mg, 3.31 mmol) was used as the starting material, the title compound (740 mg, 95%)

MS (ESI, pos.) m/z: 237.2 [M+H] ⁺

Step 10 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)benzo[d]thiazole-2-carboxylic acid methyl ester

Using 4-methylamidobenzo[d]thiazole-2-carboxylic acid methyl ester (740 mg, 3.13 mmol) as the starting material, the title compound (yield: 997 mg, 99.9%)

MS (ESI, pos.) m/z: 319.1 [M+H] ⁺

The eleventh step 4-(4-cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carboxylic acid methyl ester

Using 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)benzo[d]thiazole-2-carboxylic acid methyl ester (997 mg, 3.13 mmol) as a starting material, refer to Example 4 A six-step synthesis of the title compound (100 mg, 11%)

MS (ESI, pos.) m/z: 300.0 [M+H] ⁺

Step 12 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carboxylic acid methyl ester (100 mg, 0.33 mmol) as a starting material, referring to the synthesis method of the seventh step of Example 1, The title compound (95 mg, 99.7%)

MS (ESI, pos.) m/z: 286.0 [M+H] ⁺

Step 13 4-(4-Cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carboxylic acid (95 mg, 0.33 mmol) was used as a starting material, and was prepared according to the synthesis method of the eighth step of Example 4. The title compound (101 mg, 99.8%);

Fourteenth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Pyridin-2-yl)benzo[d]thiazole-2-carboxamide

4-(4-cyclopropyl-1H-imidazol-1-yl)benzo[d]thiazole-2-carbonyl chloride (101 mg, 0.33 mmol) was used as a starting material, and was prepared according to the synthesis method of the ninth step of Example 4. The title compound (40 mg, 28%)

MS (ESI, pos.) m/z: 471.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.75 - 9.61 (m, 1H), 8.46 - 8.34 (m, 2H), 8.26 - 8.14 (m, 2H), 8.06 - 7.94 (m, 2H), 7.71 - 7.63 (m, 1H), 7.63–7.52 (m, 1H), 7.34–7.30 (m, 1H), 5.66–5.53 (m, 1H), 2.01–1.91 (m, 1H), 1.68–1.67 (m, 6H) , 0.97–0.87 (m, 4H).

Example 28(R)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-(1-methoxypropan-2-yl)-4H-1,2 ,4-triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

First step: (R)-2-bromo-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine

(R)-1-methoxypropan-2-amine hydrochloride (3.67 g, 29.2 mmol) was used as the starting material. %);

MS (ESI, pos.) m/z: 297.2 [M+H] ⁺

Step 2: (R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid

(R)-2-Bromo-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine (5.00 g under N2) , 16.8 mmol), acetic anhydride (3.18 mL, 33.6 mmol), sodium formate (3.47 g, 50.5 mmol), palladium acetate (378 mg, 1.68 mmol), N,N-diisopropylethylamine (5.56 mL, 33.6 mmol) , a solution of 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (819 mg, 1.68 mmol) in N,N-dimethylformamide (80 mL) was stirred at 80 ° C overnight; Solvent, saturated aqueous sodium carbonate solution was made to be weakly basic, ethyl acetate (20 mL×2) was extracted, the aqueous phase was diluted with dilute hydrochloric acid to weak acid, and the solvent was evaporated under reduced pressure. Methanol (v/v) = 10/1 - 2 / 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.05 - 8.04 (m, 1H), 7.98 - 7.95 (m, 2H), 5.85 - 5.80 (m, 1H), 3.72 - 3.68 (m, 1H), 3.61–3.58 (m, 1H), 3.16 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H);

The third step: (R)-(6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamic acid Tert-butyl ester

Tert-butyl (R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid (4.00 g, 15.3 mmol) Triethylamine (5.30 mL, 38.1 mmol) and diphenylphosphoryl azide (8.39 mL, 38.2 mmol) were added to a solution of alcohol (80 mL), and the reaction was stirred at 90 ° C overnight. The solvent was evaporated to drynesshhhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS (ESI, pos.) m/z: 334.2 [M+H] ⁺

Step 4: (R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine

(R)-(6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamic acid tert-butyl ester Hydrochloric acid / 1,4-dioxane (22 mL, 88 mmol) was added to (1.50 g, 4.50 mmol), and the mixture was reacted at room temperature for 2 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m.) Filtration and evaporation of EtOAcqqqqqqqqq

The fifth step: (R)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-(1-methoxypropan-2-yl)-4H-1, 2,4-triazol-3-yl)pyridin-2-yl)benzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)benzofuran-2-carbonyl chloride (212 mg, 0.74 mmol) and (R)-6-(4-(1-methoxypropane-2) -Based on -4H-1,2,4-triazol-3-yl)pyridin-2-amine (144 mg, 0.62 mmol) as a starting material. For the title compound (80 mg, 27%);

MS (ESI, pos.) m/z: 484.2 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.99 (s, 1H), 8.83 (s, 1H), 8.21 (s, 1H), 8.19-7.99 (m, 3H), 7.88 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.62 - 7.36 (m, 2H), 5.80 (s, 1H), 3.68 - 3.62 (m , 1H), 3.57–3.53 (m, 1H), 3.16 (s, 3H), 1.96–1.90 (m, 1H), 1.48 (d, J=6.5 Hz, 3H), 0.86–0.84 (m, 2H), 0.78–0.76 (m, 2H).

Example 29 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2, 4]Triazol-3-yl)pyridin-2-yl)-5-methylbenzofuran-2-carboxamide

First step: 2-bromo-6-fluoro-3-methylbenzaldehyde

2-bromo-4-fluoro-1-methylbenzene (10 g, 52.9 mmol) was used as the starting material, the title compound (9.5 g, 83%)

Second step: 2-bromo-6-methoxy-3-methylbenzaldehyde

Using 2-bromo-6-fluoro-3-methylbenzaldehyde (9.5 g, 43 mmol) as the starting material, the title compound (7.1 g, 72%)

The third step: 2-bromo-6-hydroxy-3-methylbenzaldehyde

2-Bromo-6-methoxy-3-methylbenzaldehyde (7.1 g, 31 mmol) was used as the starting material. );

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.01 (s, 1H), 10.45 (s, 1H), 7.38 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 2.41 (s, 3H);

The fourth step: ethyl 4-bromo-5-methylbenzofuran-2-carboxylate

Starting from 2-bromo-6-hydroxy-3-methylbenzaldehyde (5.1 g, 24 mmol), the title compound (4.5 g, 67%)

Step 5: 4-((tert-Butoxycarbonyl)amino)-5-methylbenzofuran-2-carboxylic acid ethyl ester

4-ethyl bromide-5-methylbenzofuran-2-carboxylic acid ethyl ester (4.5 g, 16 mmol) was used as the starting material. %);

MS (ESI, neg.ion) m/z: 318.2 [MH] ^-

Step 6: Ethyl 4-amino-5-methylbenzofuran-2-carboxylate

Ethyl 4-((tert-butoxycarbonyl)amino)-5-methylbenzofuran-2-carboxylate (3.3 g, 10 mmol) was dissolved in ethyl acetate (30 mL, 4 mol/L) at room temperature Stir overnight. The title compound (1.9 g, 84%)

Step 7: 4-formamide-5-methylbenzofuran-2-carboxylic acid ethyl ester

4-ethyl-5-methylbenzofuran-2-carboxylic acid ethyl ester (1.9 g, 7.4 mmol) was used as the starting material. %);

MS (ESI, neg.ion) m/z: 246.2 [MH] ^-

Step 8: 4-(N-(2-Cyclopropyl-2-oxoethyl)carboxamido)-5-methylbenzofuran-2-carboxylic acid ethyl ester

The title compound (1.6) was obtained as a pale yellow solid, m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m g, 80%);

MS (ESI, pos.) m/z: 330.1 [M+H] ⁺

Step 9: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxylic acid ethyl ester

Using 4-(N-(2-cyclopropyl-2-oxoethyl)carboxamido)-5-methylbenzofuran-2-carboxylic acid ethyl ester (1.0 g, 3.2 mmol) as a starting material, The title compound of the title compound (1.0 g, 66%)

MS (ESI, pos.) m/z: 311.2 [M+H] ⁺

Step 10: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxylic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxylic acid ethyl ester (500 mg, 1.6 mmol) as a starting material, the synthesis of the seventh step of Example 1 was followed. The title compound (260 mg, 57%)

The eleventh step: 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carbonyl chloride

4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxylic acid (260 mg, 0.92 mmol) was used as a starting material, and was prepared according to the synthesis method of the eighth step of Example 4. The title compound (270 mg, 98%)

Step 12: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxamide

4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carbonyl chloride (270 mg, 0.9 mmol) was used as a starting material, and the synthesis method of the fourth step of Example 13 was followed. The title compound (220 mg, 87%)

MS (ESI, pos.) m/z: 282.2 [M+H] ⁺

Step 13: 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1, 2,4]triazol-3-yl)pyridin-2-yl)-5-methylbenzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carboxamide (220 mg, 0.73 mmol) and 3-(6-bromopyridin-2-yl) -6,7-Dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (200 mg, 0.75 mmol) was used as a starting material, and was prepared according to the synthesis method of the second step of Example 1. The title compound (120 mg, 35%)

MS (ESI, pos.) m/z: 466.4 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 8.0 Hz) , 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 0.9 Hz, 1H), 7.46 (t, J = 4.2 Hz, 2H), 6.89 (d, J = 0.9 Hz, 1H) ), 4.53 (t, J = 7.1 Hz, 2H), 3.08 (t, J = 7.7 Hz, 2H), 2.94 - 2.84 (m, 2H), 2.34 (s, 3H), 2.01 - 1.94 (m, 1H) , 1.00–0.93 (m, 2H), 0.93–0.88 (m, 2H).

Example 30 4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-5-methylbenzofuran-2-carboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylbenzofuran-2-carbonyl chloride (270 mg, 0.89 mmol) and 6-(4-isopropyl-4H-1, 2,4-Triazolyl-3-yl)pyridin-2-amine (180 mg, 0.89 mmol) was obtained from the title compound (m. ;

MS (ESI, pos.) m/z: 466.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.41 (s, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 6.89 (s, 1H), 5.60 –5.52(m,1H), 2.34(s,3H), 2.01–1.94(m,1H),1.62(d,J=6.7Hz,6H),0.98–0.92(m,2H),0.92–0.88(m , 2H).

Example 31 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2, 4]Triazol-3-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carbonyl chloride (100 mg, 0.35 mmol) and 6-(6,7-dihydro- 5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (70 mg, 0.35 mmol) was used as a starting material, and the synthesis method of the ninth step of Example 4 was followed. The title compound (25 mg, 16%)

MS (ESI, pos.) m/z: 4521. [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.69 (s, 1H), 8.41 (d, J = 8.2Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 7.5Hz, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.72 (s, 1H), 7.49 - 7.41 (m, 1H), 7.13 (s, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.57 (t, J = 7.1 Hz, 2H), 3.08 (t, J = 7.5 Hz, 2H), 2.94 - 2.83 (m, 2H), 2.04 - 1.95 (m, 1H), 1.03–0.96 (m, 2H), 0.96–0.90 (m, 2H).

Example 32 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[ 4,3-a]pyridin-3-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)imidazo[1,2-a]pyridine-2-carbonyl chloride (200 mg, 0.70 mmol) and 6-(5,6,7,8 -tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-amine (150 mg, 0.70 mmol) as a starting material, referring to the ninth step of Example 4 Synthesis of the title compound (30 mg, 9%)

MS (ESI, pos.) m/z: 466.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.70 (s, 1H), 8.43 (d, J = 8.2Hz, 1H), 8.20 (s, 1H), 8.10 (d, J = 7.6Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.73 (s, 1H), 7.47-7.43 (m, 1H), 7.13 (s, 1H), 6.96 (d, J=7.0 Hz, 1H), 4.61 (t, J=6.0 Hz, 2H), 3.12 (t, J=6.4 Hz, 2H), 2.16–2.08 (m, 2H), 2.03–1.99 (m, 2H), 1.99–1.94 (m, 1H), 1.02–0.96 (m, 2H), 0.96–0.91 (m, 2H).

Example 33 7-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[d]thiazole-2-carboxamide

Using 3-bromoaniline (30.0 g, 174 mmol) as the starting material, the title compound (2 mg, 7%)

MS (ESI, pos.) m/z: 471.1 [M+H] ⁺

¹ H NMR (600MHz, CDCl ₃ ) δ 9.69 (s, 1H), 8.54 - 8.38 (m, 2H), 8.22 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H) , 8.00 (t, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H) , 5.65 - 5.61 (m, 1H), 2.07 - 2.01 (m, 1H), 1.65 (d, J = 6.7 Hz, 6H), 1.02 - 0.95 (m, 2H), 0.91 - .88 (m, 2H).

Biological activity test

1. ASK1 (apoptosis signal-regulated kinase 1) inhibitory activity test

(1) Test method

The compound was diluted 3 times in a kinase buffer (20 mM HEPES, pH 7.5; 0.01% Triton X-100; 25 mM MgCl ₂ ; 2 mM DTT) to obtain 10 concentration solutions from 2000 nM to 0.102 nM, and the above 10 concentration solutions were 2.5. μL/well was added to the 384-well plate so that the final concentration of the compound in the kinase assay was 500-0.025 nM; then 2.5 μL of ASK1 at a concentration of 200 nM was added to each well, and the mixture was shaken evenly and 5 μL of substrate solution was added to each well [MBP (Myelin basic) Protein, myelin basic protein concentration of 1000μM, ATP concentration of 300μM], shaking, the final concentration of ASK1, MBP, ATP is 50nM, 500μM, 150μM, respectively; at the same time set buffer hole (no compound, add the same concentration of enzyme And substrate) and negative wells (no compound and enzyme, adding the same concentration of substrate); sealing plate, 1 hour incubation at 37 ° C using ADP-Glo kinase detection kit (Promege, Cat. No.v9102/3, Lot. No. 314795) The kinase activity was detected, and the relative light unit (RLU) was read. The inhibition rate of the compound inhibiting ASK1 activity was calculated by the following formula, and the IC _{50 was} calculated using GraphPad Prism 5.

Inhibition rate (%) = (RLU _{buffer well -} RLU _{drug well} ) / (RLU _{buffer well -} RLU _{negative well} ) × 100

(2) Experimental results

化合物编号Compound number	IC ₅₀(nM) IC ₅₀ (nM)	化合物编号Compound number	IC ₅₀(nM) IC ₅₀ (nM)
实施例1Example 1	5.85.8	实施例22Example 22	4.04.0
实施例7Example 7	5.45.4	实施例23Example 23	5.45.4
实施例9Example 9	4.24.2	实施例24Example 24	1010
实施例10Example 10	1010	实施例25Example 25	4.94.9
实施例12Example 12	1010	实施例28Example 28	7.27.2
实施例13Example 13	5.95.9	实施例29Example 29	7.47.4
实施例16Example 16	3.93.9	实施例30Example 30	3.53.5
实施例20Example 20	3.63.6	实施例31Example 31	5.75.7

2. Pharmacokinetic testing

(1) Test method

Experimental animals: Six healthy adult male SD rats (purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.) were divided into two groups, three in each group, and intravenous intravenous injection and oral gavage were administered separately.

Drug configuration: A certain amount of the compound of the invention was weighed, and 5% DMSO, 10% Kolliphor HS15 and 85% saline (0.9%) were added to the target concentration of the compound solution.

Administration and sample collection: Animals were fasted for 12 h before administration and 3 h after administration. They were administered intravenously to the hind paws of SD rats (iv, 1 mg/kg) and orally (po, 5 mg). /kg). Then, blood was collected from the tail vein of the rats at time points 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h, and the blood collection amount was about 200-400 μL/time point. After collecting whole blood at each time point, place it in a K ₂ EDTA anticoagulation tube and store it in an incubator with an ice pack. All samples were separated in 4 min at 4600 r/min and 4 ° C for 5 min. The plasma concentrations of the rats after administration of different compounds were determined by LC/MS/MS. The drug concentration was calculated according to the drug concentration-time curve. Learning parameters.

The pharmacokinetic properties of the compounds of the invention were tested by the above tests.

(2) Test results

The compound of the present invention has higher blood drug concentration and exposure level after oral administration, lower clearance rate, better bioavailability, and good pharmacokinetic characteristics.

Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention are to be construed as illustrative, but not limited to the description of the present invention, and may be modified within the scope of the invention or equivalents in the claims. All publications or patents cited herein are hereby incorporated by reference.

Claims

a compound which is a compound represented by the formula (I) or a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate or a solvent of the compound represented by the formula (I). a metabolite, a pharmaceutically acceptable salt or a prodrug,

among them:

for

Each W 1 is independently O, S or N(R x );

Each W 2 is independently CH or N;

Each W 3 is independently CH or N;

Each W 4 is independently CH or N;

Each W 5 is independently CH or N;

W 6 is C(R a ) or N;

W 7 is C(R b ) or N;

X is -C(=O)- or -S(O) 2 -;

Y is -O- or -N(R y )-;

R a and R b are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1- alkoxy or a C 1-3 haloalkoxy;

Each R x and R y is independently hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

Each R 1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 6 a -10 aryl or 5-10 membered heteroaryl group, wherein said hydroxy, fluorenyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5 The -10 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, oxo (=O), amino, nitro, cyano Substituted by a group of a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a C 1-6 alkoxy group;

Each of R 2 and R 3 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy or C 1-4 haloalkoxy;

R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1- 4 -haloalkoxy;

R is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or a 5-10 membered heteroaryl group, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino Substituted by a group of a nitro group, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;

Or R, R 4 together with the atoms to which they are attached form a 3-8 membered heterocyclic ring, which may optionally be 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, Anthracene, oxo (=O), hydroxy, decyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy Replaced by a group;

L is a bond, -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -C(=O)-O-, -OC(=O)-, -S( O) 2 -, -NHC(=O)NH-, -C 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-NH-, -S (O) 2 -NH-, C 6-10 arylene or 5-10 membered heteroarylene; said C 6-10 arylene and 5-10 membered heteroarylene optionally being 1, 2 or 3 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkane Substituted by a group of oxy groups;

Q is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O) 2 -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, C 3 -8 cycloalkyl, 3-8 membered heterocyclic, C 6-12 aryl or 5-10 membered heteroaryl;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3; and

r is 0, 1, 2 or 3.
The compound according to claim 1, wherein
for
The compound according to claim 1 or 2, wherein R a and R b are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, methyl, and B. Base, isopropyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or Trifluoromethoxy.
The compound according to any one of claims 1 to 3, wherein each of R x and R y is independently hydrogen, hydrazine, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, or ring. Propyl, cyclobutyl, cyclopentyl or cyclohexyl.
The compound according to any one of claims 1 to 4, wherein each R 1 is independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3 a -6 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C 1-3 alkyl group, C 2− 4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, The 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl may be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, oxo (= O), amino, nitro, cyano, C 1-3 alkyl, substituted C 1-3 haloalkyl group and a C 1-3 alkoxy group.
The compound according to any one of claims 1 to 5, wherein each R 1 is independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, methyl, ethyl Base, isopropyl, allyl, propenyl, propargyl, propynyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl , methoxy, ethoxy, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine Base, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, decyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazole a thiol, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, fluorenyl or quinolyl group, wherein the hydroxy, thiol, amino, methyl, ethyl, Isopropyl, allyl, propenyl, propargyl, propynyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, A Oxy, ethoxy, methylthio, ethylthio, A Base, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, benzene Base, fluorenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazine The benzyl, benzimidazolyl, fluorenyl and quinolyl groups may be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O). , amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, A Substituted by groups of oxy and ethoxy groups.
The compound according to any one of claims 1 to 6, wherein each of R 2 and R 3 is independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, Ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy Or trifluoromethoxy.
The compound according to any one of claims 1 to 7, wherein R 4 is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl , difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy .
The compound according to any one of claims 1-8, wherein R is hydrogen, hydrazine, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl a 3-6 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, wherein the C 1-4 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, fluorine and chlorine. , bromine, iodine, hydroxy, oxo (=O), amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 naphthenic The group is substituted with a group of a 3-6 membered heterocyclic group.
The compound according to any one of claims 1 to 9, wherein R is hydrogen, hydrazine, methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, allyl, ethynyl, Propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyran , morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl , a thienyl group, a thiazolyl group or a thiadiazolyl group, wherein the methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, vinyl group, allyl group, ethynyl group, propargyl group, cyclopropyl group Base, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, Phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, The oxazolyl and thiadiazolyl are optionally 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl , ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, Substituted by pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups.
The compound according to any one of claims 1 to 10, wherein R, R 4 and the atom to which they are each attached form a 3-8 membered heterocyclic ring, and the 3-8 membered heterocyclic ring may optionally be 1 , 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydrazine, oxo (=O), hydroxy, decyl, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, The C 1-3 alkoxy group and the C 1-3 haloalkoxy group are substituted.
The compound according to any one of claims 1 to 11, wherein R, R 4 and the atom to which they are each attached together form a 3-6 membered heterocyclic ring, which may optionally be 1 , 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydrazine, oxo (=O), hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl , trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
The compound according to any one of claims 1 to 12, wherein L is a bond, -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -C(=O )-O-, -OC(=O)-, -S(O) 2 -, -NHC(=O)NH-, -C 1-3 alkylene-, -C 1-3 alkylene-O -, -C 1-3 alkylene-NH-, -S(O) 2 -NH-, C 6-10 arylene or 5-6 membered heteroarylene; said C 6-10 arylene And a 5-6 membered heteroarylene group may be optionally 1, 2 or 3 selected from the group consisting of hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 Substituted by a group of a haloalkyl group, a C 1-3 alkoxy group and a C 1-3 haloalkoxy group.
The compound according to any one of claims 1 to 13, wherein L is a bond, -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -C(=O )-O-, -OC(=O)-, -S(O) 2 -, -NHC(=O)NH-, -C 1-3 alkylene-, -C 1-3 alkylene-O -, -C 1-3 alkylene-NH-, -S(O) 2 -NH-, phenylene, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridylene or a pyrimidylene group; the phenylene group, pyrazolyl group, imidazolyl group, thiazolyl group, oxazolyl group, pyridylene group, and pyrimidinyl group may be optionally selected from 1, 2 or 3, Fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2- Substituted by a group of trifluoroethyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.
The compound according to any one of claims 1 to 14, wherein Q is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, thiol, amino, nitro, cyano, methyl, ethyl, isopropyl , difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy Base, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, butyryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidyl Azinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, Pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl.
The compound according to any one of claims 1 to 15, which is a compound represented by the formula (II), or a stereoisomer, geometric isomer, tautomer of the compound represented by the formula (II). Body, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
The compound according to any one of claims 1 to 16, which is a stereoisomer or a geometry of a compound represented by formula (III) or (IV) or a compound represented by formula (III) or (IV). Isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
A compound having the structure of one of the following:

Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of one of the structures.
A pharmaceutical composition comprising the compound of any one of claims 1-18.
The pharmaceutical composition according to claim 19, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or any combination thereof.
Use of a compound according to any one of claims 1 to 18 or a pharmaceutical composition according to any one of claims 19 to 20 for the manufacture of a medicament for the prevention, treatment or alleviation of a disease modulated by ASK1 in a patient.
The use according to claim 21, wherein the ASK1 regulated disease is an autoimmune disease, inflammation, cardiovascular disease, heart and kidney disease, fibrotic disease, respiratory disease, liver disease or neurodegenerative disease.
The use according to claim 21, wherein the cardiovascular disease comprises diabetes, diabetic nephropathy and other diabetic complications.
The use according to claim 21, wherein the fibrotic disease comprises pulmonary fibrosis and renal fibrosis;

The respiratory diseases include chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, and acute lung injury.
The use according to claim 21, wherein the liver disease comprises chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia - Reperfusion injury and primary biliary cirrhosis.