WO2021031071A1 - Amide derivative and use thereof in medicine - Google Patents

Abstract

Disclosed are an amide derivative and the use thereof. In particular, disclosed are an amide derivative and a pharmaceutical composition containing the compound. Also disclosed are a method for preparing the compound and the pharmaceutical composition, and the use thereof in the preparation of drugs for the treatment of ASK1-regulated diseases and/or conditions, in particular, the use thereof in the preparation of drugs for the treatment of non-alcoholic steatohepatitis.

Description

Amide derivatives and their application in medicine Invention field

The present invention belongs to the field of medicine, and specifically relates to an amide derivative with enzyme inhibitory activity and a pharmaceutical composition thereof. The compound and composition can be used to prepare a medicine for treating ASK1 regulated diseases.

Background technique

Data show that liver disease has become one of the main causes of human death. According to the duration of the disease, liver disease is generally divided into acute and chronic liver disease. Liver disease may be caused by infection, injury, medication, poisoning, drinking, unclean food, abnormal accumulation of normal components in the blood, autoimmunity, genetic defects or other unknown factors. Common liver diseases include chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury, and primary biliary cirrhosis Wait.

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase (MAP3Ks) family. MAP3Ks can activate c-Jun N N-terminal protein kinase (JNK) and p38MAP (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 is also called mitogen-activated protein kinase kinase 5 (mitogen-activated protein kinase kinase 5, MAPKKK5, MAP3K5), which contains 1375 amino acid residues, consisting of 11 kinase subdomains and one at the N-terminal and 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 stimulating factors, such as: oxidative stress, reactive oxygen species, endotoxin, tumor necrosis factor-α, endoplasmic reticulum stress, and intracellular calcium ion concentration.

Studies have shown that ASK1 not only regulates cell death, but also plays an important role in cell activities such as cytokine response, cell differentiation, and innate immune response. Regulating the activity of ASK1 can 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 pulmonary obstruction and acute lung injury) and liver diseases, ASK1 Regulators have great potential.

At present, researchers have carried out some studies in order to find therapeutic agents that can effectively inhibit the expression or activity of ASK1. PCT applications WO2009027283, WO2009123986, WO2010008843, WO2011008709, WO2011041293, WO2011097079, WO2012003387, WO2013112741, WO2014100541 and WO2015095059 disclose many small molecule compounds, which are used as ASK1 modulators to prevent or treat autoimmune diseases, inflammation, cardiovascular diseases, and neurodegenerative Sexual disease. PCT applications WO2015187499 and WO2016049070 disclose the use of ASK1 modulators to treat liver disease. However, there is still an urgent need for more and better ASK1 modulators.

Summary of the invention

The present invention provides a compound or a pharmaceutical composition thereof, which can be used as a modulator of ASK1. The present invention further relates to the use of the compound or its pharmaceutical composition for the preparation of a medicament, which modulates the activity of ASK1 through the compound to treat diseases and/or disorders. The present invention further describes the synthesis method of the compound. The compounds of the present invention show excellent biological activity and pharmacokinetic properties.

Specifically:

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, or nitroxide of a compound represented by formula (I) Compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

among them:

W is CH or N;

R ¹ is hydrogen, phenyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein The phenyl group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 3-8 membered heterocyclic group can be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _3-6 cycloalkyl group substituted;

R is

R ² is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group may be independently optionally selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, 1, 2, 3, 4 or 5 _{C 1-3} alkyl group, cyano group, C 1-3 alkyl group, C _1-3 haloalkyl group and C _1-3 alkoxy group;

Each R ^{x is} independently hydrogen, deuterium, halogen atom, amino group, cyano group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl;

Each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino , C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Group, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group may be independently optionally selected from deuterium, halogen atom, hydroxyl, oxygen Substituted (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups;

Each Y is independently a bond, -O-, -CR ^c R ^d -or -(CR ^e R ^f ) ₂ -;

R ^a , R ^b , R ^c , ^Rd , R ^e and R ^f are each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group may independently optionally By 1, 2, 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups are substituted.

In some embodiments, R ¹ is hydrogen, phenyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, or 3-6 membered hetero Cyclic group, wherein the phenyl group, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _3-6 cycloalkyl group and 3-6 membered heterocyclic group may be independently Optionally by 1, 2, 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _3-6 cycloalkyl groups are substituted.

In other embodiments, R ¹ is hydrogen, phenyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyl Baseoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyran Group or morpholinyl, wherein the phenyl, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl can be independent Optionally by 1, 2, 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, cyano, methyl, ethyl, trifluoromethyl , Difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl and cyclobutyl groups.

In some embodiments, R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group may be independently optionally selected from deuterium, halogen atom, hydroxyl, oxo ( =O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups.

In other embodiments, R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy , Trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piper Ridinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methyl Oxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , Pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl can be independently optionally selected from deuterium, 1,2, 3, 4 or 5 Fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and iso The propyloxy group is substituted.

In some embodiments, each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy , C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally selected from deuterium by 1, 2, 3, 4 or 5 , Halogen, hydroxy, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, Ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen heterocycle Butyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl Propyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2, 3 , 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, Methoxy, ethoxy and isopropyloxy groups are substituted.

In some embodiments, each R ^{x is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, Ethoxy, isopropyloxy, cyclopropyl or cyclobutyl.

In some embodiments, ^{embodiment, R a, R b, R} c, R d, R e and R ^{f are} each independently hydrogen, deuterium, a halogen atom, a hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein the C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered hetero The cyclic group can be independently optionally substituted by 1, 2, 3, 4, or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups are substituted.

In further embodiments ^{embodiment, R a, R b, R} c, R d, R e and R ^{f are} each independently hydrogen, deuterium, a halogen atom, hydroxyl, amino, cyano, methyl, ethyl, n Propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, two Methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl Or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methyl Amino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl , Tetrahydropyranyl and morpholinyl may be independently optionally selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro Substituted by groups including cyano, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In one aspect, the present invention relates to a pharmaceutical composition, which comprises the compound of formula (I) of the present invention, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate Substances, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

In one aspect, the present invention relates to the use of the aforementioned compound or its pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of ASK1 regulated diseases in patients.

In some embodiments, the diseases regulated by ASK1 of the present invention are autoimmune diseases, inflammations, cardiovascular diseases, heart and kidney diseases, fibrotic diseases, respiratory diseases, liver diseases or neurodegenerative diseases.

In another aspect, the present invention relates to methods for the preparation, separation and purification of the compounds contained in formula (I).

The foregoing content only outlines certain aspects of the present invention, but is not limited to these aspects. These and other aspects will be described in more detail and complete below.

Detailed instructions

Definitions and general terms

Now certain embodiments of the present invention are described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the scope of the present invention. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The invention is by no means limited to the methods and materials described herein. In the case where one or more of the combined documents, patents and similar materials are different or contradictory to this application (including but not limited to defined terms, term application, described technology, etc.), this Application shall prevail.

It should be further recognized that certain features of the present invention, for the sake of clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, the various features of the present invention are described in a single embodiment for the sake of brevity, but they can also be provided individually or in any suitable sub-combination.

Unless otherwise specified, all scientific and technological terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated into the present invention in their entirety by reference.

Unless otherwise stated, the following definitions used herein shall apply. For the purpose of the present invention, the chemical elements are consistent with the CAS version of the Periodic Table of Elements, and "Handbook of Chemistry and Physics", 75th Edition, 1994. In addition, the general principles of organic chemistry can be referred to 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 The description of, the entire content of which is incorporated herein by reference.

Unless otherwise stated or there is an obvious conflict in context, the articles "a", "an" and "said" used herein are intended to include "at least one" or "one or more." Therefore, these articles used herein refer to articles of one or more than one (ie at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.

The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, that is, includes the content specified in the present invention, but does not exclude other aspects.

"Stereoisomers" refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .

"Chiral" refers to a molecule that can not overlap with its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"Enantiomers" refer to two isomers of a compound that cannot be superimposed but are mirror images of each other.

"Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.

Any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention can exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)- configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereoisomer mixtures (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.

The racemate of any final product or intermediate obtained can be resolved into optical enantiomers by methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained Separate. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversion through the recombination of some bond-forming electrons. Specific examples of keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "optional" or "optionally" means that the event or situation described later can but does not necessarily occur, and the description includes situations in which the event or situation occurs and situations in which it does not occur. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

The term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples. A class of compounds. The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or replaced by...", that is, the structure is unsubstituted or substituted by one or more of the present invention Substituted.

Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions. The substituents mentioned herein can be, but are not limited to, hydrogen, deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkane Group, alkenyl, alkynyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy , Haloalkoxy, aryloxy, heteroaryloxy, alkylacyloxy, carboxy, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, hetero Arylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl and the like.

In addition, it should be noted that, unless clearly indicated in other ways, the description methods used in the present invention are interchangeable with "each ... independently being" and "... independently being" and "... independently being". Should be understood in a broad sense, it can mean that the specific options expressed between the same symbols in different groups do not affect each other, or it can mean the specific options expressed between the same symbols in the same group Do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. 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.

In each part of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the attached Alkylene group or arylene group.

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted by one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 -4 carbon atoms; also in some embodiments, the alkyl group contains 1-3 carbon atoms.

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-methyl -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, n-octyl, and so on.

The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-3 carbon atoms; also in some embodiments, the alkylene group contains 1-2 carbon atoms. Examples of such include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylene (-CH(CH ₃ )CH ₂ -) and the like.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp ² double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), and the like.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), etc. .

The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-but Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentoxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy Group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

The term "alkanoyl" or "alkylformyl" means that the alkyl group is connected to the rest of the molecule through a carbonyl group (-C(=O)-), wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkanoyl group contains 1-12 carbon atoms. In some embodiments, the alkanoyl group contains 1-6 carbon atoms; in other embodiments, the alkanoyl group contains 1-4 carbon atoms; in still other embodiments, the alkanoyl group contains 1 -3 carbon atoms. The alkanoyl group may be optionally substituted with one or more substituents described herein. Examples of alkanoyl groups include, but are not limited to, acetyl (-C(=O)CH ₃ ), propionyl (-C(=O)CH ₂ CH ₃ ), butyryl (-C(=O) CH ₂ CH ₂ CH ₃ ) and so on.

The term "sulfonyl", whether used alone or in combination with other terms like "alkylsulfonyl", respectively represents the divalent group -SO ₂ -.

The term "alkylsulfonyl" means that the alkyl group is _{connected to the rest of the molecule through a sulfonyl group (-SO 2} -), wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkylsulfonyl group contains 1-12 carbon atoms. In some embodiments, the alkylsulfonyl group contains 1 to 6 carbon atoms; in other embodiments, the alkylsulfonyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl Sulfonyl groups contain 1-3 carbon atoms. The alkylsulfonyl group may be optionally substituted with one or more substituents described herein. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl (-SO ₂ CH ₃ ), ethylsulfonyl (-SO ₂ CH ₂ CH ₃ ), and the like.

The terms "sulfamoyl", "aminosulfonyl" and "sulfamoyl" refer to a sulfonyl group substituted with an amino group, forming a sulfamoyl group (-SO ₂ NH ₂ ).

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Examples of such include, but are not limited to, Trifluoromethyl, trifluoromethoxy, etc.

The term "carbocyclic group" or "carbocyclic ring" means a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Carbobicyclic groups include spirocarbon bicyclic groups, fused carbon bicyclic groups and bridged carbon bicyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclic groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl Group, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

The term "cycloalkyl" means a monovalent or multivalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms. carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described in this invention.

The terms "heterocyclic", "heterocyclyl" or "heterocyclic" are used interchangeably herein and refer to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meaning as described in the present invention. The ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring is not allowed. In some embodiments, the "heterocyclic", "heterocyclyl" or "heterocyclic" group is a 3-8 membered monocyclic ring (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ ), or 7-12 membered bicyclic ring (4 -9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to form SO, SO ₂ , PO, PO ₂ groups). The heterocyclyl group is optionally substituted with one or more substituents described in the present invention.

The heterocyclic group can be a carbon group or a heteroatom group; wherein the -CH ₂ -group of the ring can be optionally replaced by -C(=O)-, and the sulfur atom of the ring can be optionally oxidized to S-oxidation Compounds, the nitrogen atoms of the ring can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl, Oxazepine

Diaza

Thiazepine

Group, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. _{Examples of the -CH 2} -group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidine, 2-piperidine Ketone, 3,5-dioxopiperidinyl, pyrimidinedione, etc. Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described in the present invention.

The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents described in the present invention.

The term "heteroaryl" or "heteroaryl ring" means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms A system in which at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In some embodiments, a heteroaryl group consisting of 5-10 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, 5-6 rings The heteroaryl group composed of atoms is a single ring system and contains 1, 2, 3, or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-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-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes the following bicyclics, but not limited to these bicyclics: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (Such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And [1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 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, [1,2,4]triazole And [1,5-a]pyridyl, etc.

The term "consisting of n atoms" or "n-membered", where n is an integer, typically describes the number of atoms forming a ring in a molecule, and the number of atoms forming a ring in the molecule is n. For example, piperidinyl is a 6-atom heterocyclic ring or 6-membered heterocyclic ring, and cyclohexyl is a 6-atom cycloalkyl or 6-membered cycloalkyl group.

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

The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, and tertiary amines and quaternary ammonium salt forms; or on the nitrogen atom in the heterocycle The form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).

The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "carboxyl" means -CO ₂ H, whether used alone or in combination with other terms, such as "carboxyalkyl"; the term "carbonyl" or "acyl" means -(C=O)-, whether used alone It is still used in conjunction with other terms, such as "aminocarbonyl" or "acyloxy".

The term "acyloxy" means -(C=O)O-, whether used alone or in combination with other terms, such as "alkyl acyloxy"; the term "alkyl acyloxy" means that the alkyl group passes through the acyl oxygen The group (-(C=O)O-) is connected to the rest of the molecule, where the alkyl group has the meaning as described in the present invention. The alkyl acyloxy group may be optionally substituted with one or more substituents described in the present invention

The term "aminocarbonyl" or "aminoacyl" means that the amino group is connected to the rest of the molecule through a carbonyl group (-(C=O)-), which may be optionally substituted by one or more substituents described in the present invention Replaced.

The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some examples, the alkylamino group is an _{alkylamino group formed by connecting one or two C 1-6} alkyl groups to a nitrogen atom. In other embodiments, the alkylamino group is an amino group substituted with _{one or two C 1-3 alkyl groups.} Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino and so on.

The term "arylamino" means that the amino group is substituted with one or two aryl groups. Examples of this include, but are not limited to, N-phenylamino. In some examples, the aromatic ring on the arylamino group may be further substituted.

The term "aryloxy" or "aryloxy" includes an optionally substituted aryl group, as defined in the present invention, attached to an oxygen atom and connected to the rest of the molecule by the oxygen atom, where the aryl group has As in the meaning of the present invention, such examples include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy and the like.

The term "heteroaryloxy" means that a heteroaryl group is connected to the rest of the molecule through an oxygen atom, wherein the heteroaryl group has the meaning described in the present invention. The heteroaryloxy group may be optionally substituted with one or more substituents described in the present invention. Such examples include, but are not limited to, pyridyloxy, pyrimidinyloxy and the like.

The term "aminoalkyl" includes C _1-10 linear or branched alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a C _1-6 aminoalkyl group substituted with one or more amino groups. Examples of this include, but are not limited to, aminomethyl, aminoethyl, and aminopropyl. , Aminobutyl and Aminohexyl.

The term "hydroxyalkyl" includes C _1-10 straight or branched chain alkyl groups substituted with one or more hydroxyl groups. In some embodiments, the hydroxyalkyl group is a C _1-6 "lower hydroxyalkyl group" substituted with one or more hydroxy groups. Examples of this include, but are not limited to, hydroxymethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The terms "cycloalkylalkylene", "heterocyclylalkylene", "arylalkylene" and "heteroarylalkylene" refer to cycloalkyl, heterocyclyl, aryl and heteroaryl It is connected to the rest of the molecule through an alkylene group, wherein the alkylene group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group all have the meaning as described in the present invention. The "cycloalkylalkylene", "heterocyclylalkylene", "arylalkylene", "heteroarylalkylene" groups are optionally described by one or more of the present invention The substituent is substituted.

As described in the present invention, the attachment point can be connected to the rest of the molecule at any linkable position on the ring. For example, the formula e represents that any position on the A ring or the B ring that may be connected can be used as the point of connection.

As described in the present invention, the group "-C(=O)N(R)-" has two connection sites that can be connected to the rest of the molecule, and the connection modes of the two connection sites can be interchanged. For example, the formula f represents the group -C(=O)N(R ¹³ )- can be connected to the rest of the molecule through the E or E'end.

The term "protecting group" or "PG" refers to when a substituent reacts with other functional groups, it is usually used to block or protect specific functionality. For example, "amino protecting group" refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group. Suitable protecting groups include acetyl and silyl. "Carboxy protecting group" refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc. For a general description of protecting groups, please refer to 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 "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient or base with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

The term "prodrug" as used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent structure in the blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters. For example, if a compound contains a hydroxyl group, it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group. For a complete discussion 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.

"Metabolite" refers to the product obtained by the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, acylating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound. Correspondingly, the present invention includes metabolites of compounds, including metabolites produced by adequately contacting the compounds of the present invention with mammals for a period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to the organic and inorganic salts of the compound of the present invention. Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: S.M. Berge et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts, such as Acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or other methods described in books and literature such as ion exchange methods to obtain these salts. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of groups I to XII of the periodic table, and organic base salts, such as those formed with primary, secondary, and tertiary amines salt.

The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to the association formed by the solvent molecule being water.

The term "treating" any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treatment" refers to the regulation of a disease or condition physically (for example, stabilizing the perceptible symptoms) or physiologically (for example, stabilizing the parameters of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

The term "therapeutically effective amount" means that when administered to a subject to treat a disease, the amount of the compound is sufficient for the treatment of the disease. The "therapeutically effective amount" can vary with the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.

The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate, etc.) of Na, Ca, Mg or K, or by reacting The free base form of these compounds is prepared by reacting a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use)", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can find a list of other suitable salts.

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (such as ethanol, DMSO, etc.) and used for their crystallization. The compounds disclosed in the present invention may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.

Any structural formula given in the present invention is also intended to represent the non-isotopically enriched forms and isotopically enriched forms of these compounds. The isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. The isotope-enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or described in the examples and preparation procedures of the present invention using suitable isotope-labeled reagents instead of the previously used unlabeled reagents.

Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included in the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.

The term "cardiorenal disease" as used herein refers to diseases related to kidney function, which can be caused or aggravated by cardiovascular problems such as hypertension. It is generally believed that hypertension is the main cause of kidney disease.

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

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

As used herein, the term "liver fibrosis" includes liver fibrosis caused by any reason, including but not limited to virus-induced liver fibrosis such as liver fibrosis caused by hepatitis B and C; due to alcohol (alcoholic Liver disease), drug compounds, oxidative stress, cancer radiotherapy or liver fibrosis caused by industrial chemical exposure; and such as primary biliary cirrhosis, fatty liver, obesity, non-alcoholic 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 can bind to ASK1 and regulate its activity.

Unless otherwise stated herein or the context clearly has the opposite meaning, the terms "a", "an", "the" and the context of the present invention (especially in the context of the claims) used herein are used Similar terms can be interpreted to include both the singular and the plural.

Description of the compound of the present invention

The present invention provides a compound or a pharmaceutical composition thereof, which can be used as a modulator of ASK1. The present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament, which can treat diseases and/or disorders by modulating the activity of ASK1 with the compound. The present invention further describes the method of synthesizing the compound. The compounds of the present invention show improved biological activity and pharmacokinetic properties.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, or nitroxide of a compound represented by formula (I) Compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, each of R ¹ , R and W has the meaning described in the present invention.

In some embodiments, R is

^{Y, R 2, R 3,} R x, R a and R ^b, have the meanings according to the present invention.

In some embodiments, Y is -CR ^c R ^d - or _{^{- (CR e R f) 2}} -; R c, R d, R e and R ^f are have the meanings according to the present invention.

In some embodiments, R ¹ is hydrogen, phenyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, or 3-8 membered heterocycle Group, wherein the phenyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently selected Optionally by 1, 2, 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _{1 -3} alkoxy and C _3-6 cycloalkyl groups are substituted.

In other embodiments, R ¹ is hydrogen, phenyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, or 3-6 membered hetero Cyclic group, wherein the phenyl group, C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _3-6 cycloalkyl group and 3-6 membered heterocyclic group may be independently Optionally by 1, 2, 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _3-6 cycloalkyl groups are substituted.

In other embodiments, R ¹ is hydrogen, phenyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyl Oxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl Or morpholinyl, wherein the phenyl, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl can be independently selected Optionally by 1, 2, 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, cyano, methyl, ethyl, trifluoromethyl, Difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl and cyclobutyl groups are substituted.

In some embodiments, R ² is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _{3 -8} cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from deuterium, halogen atom, hydroxyl, oxo (= O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups are substituted.

In other embodiments, R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group may be independently optionally selected from deuterium, halogen atom, hydroxyl, oxo ( =O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups.

In other embodiments, R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, Trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidine Group, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, where the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl can be independently optionally selected from deuterium, fluorine by 1, 2, 3, 4 or 5 , Chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyl The oxy group is substituted.

In some embodiments, R ³ is hydrogen, deuterium, fluorine, chlorine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _{1- 6} alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1- 6} haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from deuterium, halogen atom, 1,2, 3, 4 or 5 Hydroxy, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups are substituted.

In other embodiments, R ³ is hydrogen, deuterium, fluorine, chlorine, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _{1 -4} alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein the C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _{1 -4} halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally selected from deuterium, halogen atom by 1, 2, 3, 4 or 5 , Hydroxy, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups.

In other embodiments, R ³ is hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, Isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, two Fluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl can be independently optionally substituted by 1, 2, 3, 4, or 5 One is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, Ethoxy and isopropyloxy groups are substituted.

In some embodiments, R ^x is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _3-6 cycloalkyl .

In other embodiments, R ^x is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy , Isopropyloxy, cyclopropyl or cyclobutyl.

In some embodiments, R ^a is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl Oxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl Oxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from 1, 2, 3, 4 or 5 It is substituted with deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, R ^a is hydrogen, deuterium, a halogen atom, a hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3, 4 or 5 Substituted by a group selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy .

In other embodiments, R ^a is hydrogen, deuterium, a halogen atom, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl Group, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Group, methoxy group, ethoxy group and isopropyloxy group.

In some embodiments, R ^b is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl Oxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl Oxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from 1, 2, 3, 4 or 5 It is substituted with deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, R ^b is hydrogen, deuterium, halogen, hydroxy, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3, 4 or 5 Substituted by a group selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy .

In other embodiments, R ^b is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl Group, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Group, methoxy group, ethoxy group and isopropyloxy group.

In some embodiments, R ^c is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl Oxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl Oxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from 1, 2, 3, 4 or 5 It is substituted with deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, R ^c is hydrogen, deuterium, halogen, hydroxy, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3, 4 or 5 Substituted by a group selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy .

In other embodiments, R ^c is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl Group, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Group, methoxy group, ethoxy group and isopropyloxy group.

In some embodiments, R ^d is hydrogen, deuterium, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl Oxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl Oxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from 1, 2, 3, 4 or 5 It is substituted with deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, R ^d is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3, 4 or 5 Substituted by a group selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy .

In other embodiments, R ^d is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl Group, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Group, methoxy group, ethoxy group and isopropyloxy group.

In some embodiments, R ^e is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl Oxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl Oxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from 1, 2, 3, 4 or 5 It is substituted with deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, R ^e is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3, 4 or 5 Substituted by a group selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy .

In other embodiments, R ^e is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl Group, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Group, methoxy group, ethoxy group and isopropyloxy group.

In some embodiments, R ^f is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl Oxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl Oxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group can be independently optionally selected from 1, 2, 3, 4 or 5 It is substituted with deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy group.

In other embodiments, R ^f is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3, 4 or 5 Substituted by a group selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy .

In other embodiments, R ^f is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy Group, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Etanyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl Group, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Group, methoxy group, ethoxy group and isopropyloxy group.

In another aspect, the present invention relates to one of the following compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, hydrates, metabolites, Ester, pharmaceutically acceptable salt or its prodrug, but not limited to:

In another aspect, the present invention relates to a pharmaceutical composition, the pharmaceutical composition comprising stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolic Products, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or any combination thereof.

In another aspect, the present invention relates to the use of the aforementioned compound or its pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of ASK1 regulated diseases in patients.

In some embodiments, the diseases regulated by ASK1 are autoimmune diseases, inflammation, cardiovascular diseases, heart and kidney diseases, fibrotic diseases, respiratory diseases, liver diseases, or neurodegenerative diseases.

In some examples, cardiovascular diseases include diabetes, diabetic nephropathy, and other complications of diabetes.

In some examples, fibrotic diseases include lung and kidney fibrosis.

In some examples, respiratory diseases include chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, and acute lung injury.

Some examples are that liver disease includes chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury, and primary Sexual biliary cirrhosis.

One aspect of the present invention relates to a method for preventing, treating or alleviating ASK1-modulated disease in a patient, which includes administering to the patient a pharmaceutically acceptable effective dose of the compound of the present invention.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of the aforementioned compounds.

Pharmaceutical composition, preparation, administration and use of the compound of the present invention

According to another aspect, the characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I), the compounds listed in the present invention, or the compounds of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the composition of the present invention can effectively treat or alleviate the patient's ASK1 regulated disease.

The compounds of the invention exist in free form, or are suitable as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of patients Adducts or derivatives, compounds described in other aspects of the invention, their metabolites or their residues.

As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carriers, adjuvants, or excipients, which, as used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms. As described in the following documents: 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 1988-J. 1999, Marcel Dekker, New York, combining the contents of the literature here, showed that different carriers can be used in the preparation of pharmaceutically acceptable compositions and their well-known preparation methods. Except for any conventional carrier media incompatible with the compounds of the present invention, such as any adverse biological effects or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, they The use of is also the scope of the present invention.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphate, glycine, sorbic acid, and sorbic acid. Potassium acid, a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed Acid; pyrogen-free water; isotonic salt; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coating materials, sweeteners, flavors and spices, preservatives and antioxidants.

Preferably, the compound is mixed and administered with a suitable pharmaceutical diluent, excipient, or carrier (herein referred to as a pharmaceutical carrier) selected according to the form of administration and conventional pharmaceutical practice. The administration method may be an oral tablet. Capsules, elixirs, syrups, etc.

For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, and methylcellulose. , Magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combinations such as ethanol, glycerin, water, etc. Moreover, when needed or necessary, suitable binders, lubricants, decomposing agents, and coloring agents can also be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene Ethylene glycol, wax, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and so on. Decomposers include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can be administered in the form of oral preparations, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , And emulsifier. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly. All dosage forms used are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but generally will be administered together with a pharmaceutical carrier selected based on the chosen mode of administration and standard pharmaceutical practice.

The compounds of the present invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or via transdermal route by using transdermal patches. When administered in the form of a transdermal delivery system, the dose administered throughout the medication period is continuous rather than intermittent.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

The compounds of the invention are also coupled to soluble polymers, which serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate amine-phenol, polyhydroxyethyl asparagine phenol, or polyethylene oxide-polyvinyl substituted with palmitoyl residues Acid. Moreover, the compounds of the present invention can be coupled with a class of biodegradable polymers to achieve controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyεcaprolactone Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

The dosage regimen of the compound of the present invention will vary with various known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health status, medical condition and weight of the recipient; The nature and extent of the symptoms; the types of concurrent treatments; the frequency of treatments; the route of administration, the patient's kidney and liver function, and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of medicine to prevent, offset or stop the development of thromboembolic disease.

According to general guidelines, in order to achieve the specified effect, the daily oral dose of each active ingredient used ranges from about 0.001 to 1000 mg/kg body weight, preferably, between about 0.01 to 100 mg/kg body weight . And, most preferably, it is between about 1.0 to 20 mg/kg body weight/day. For intravenous administration, the most preferred dosage range during infusion at a conventional rate is about 1 to about 10 mg/kg body weight/minute. The compound of the present invention may be administered once a day, or may be administered twice, three or four times a day.

Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 100 mg of active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.

When the compound of the present invention is administered with other therapeutic agents, generally, considering the additional or synergistic effects of the therapeutic agents when administered in combination, the amount of each component in a typical daily dosage and a typical dosage form is relative to The usual dose when administered alone can be reduced.

The compound of the present invention or its pharmaceutically acceptable salt or its hydrate can be effectively used to prevent, treat or alleviate the disease regulated by ASK1 in patients, in particular, it can effectively treat 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, non-alcoholic fatty liver, non-alcoholic fat Hepatitis, liver ischemia-reperfusion injury, primary biliary cirrhosis, and other hepatitis.

General synthesis process

To describe the present invention, examples are listed below. However, it needs to be understood that the present invention is not limited to these embodiments, but only provides methods for practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the definition of substituents is as described in the present invention. The following reaction schemes and examples are used to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to appropriately prepare other compounds of the present invention, and other methods for preparing the compounds of the present invention are all considered to be within the scope of the present invention . For example, the synthesis of non-exemplified compounds according to the present invention can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or The reaction conditions are modified regularly. In addition, the reactions disclosed in the present invention or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are set to degrees Celsius unless otherwise indicated. The reagents are purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and they are used without further purification. Unless otherwise indicated, the general reagents are from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd. The company, Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory purchased

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

The following reactions are generally performed under a positive pressure of nitrogen or argon or a drying tube (unless otherwise indicated) on an anhydrous solvent. The reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. The glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

¹ H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. ¹ H NMR spectrum uses CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiplet), br (broadened, broad peak), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets, doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

The measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1x30mm, 3.5 microns, 6min, flow rate 0.6mL/min. Mobile phase: 5% The ratio of 95% (CH ₃ CN containing 0.1% formic acid) in (H ₂ O containing 0.1% formic acid) was measured by electrospray ionization (ESI) at 210 nm/254 nm and UV detection.

The pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC), and UV detection is performed at 210nm/254nm.

The following abbreviations are used throughout the present invention:

DMF N,N-Dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d ₆ Deuterated Dimethyl Sulfoxide

THF Tetrahydrofuran

g gram

mg milligrams

M mole per liter

mM millimole per liter

mol mole

mmol

mL/ml ml

μL microliter

MPa MPa

Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium

Xant-Phos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

Pd(dppf) ₂ Cl ₂ [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride

DIBAL/DIBAL-H Diisobutyl aluminum hydride

DMFDMA N,N-Dimethylformamide dimethyl acetal

LiAlH ₄ lithium aluminum hydride

KCl potassium chloride

NaCl sodium chloride

ATP Adenosine Triphosphate

EDTA ethylenediaminetetraacetic acid

DTT Dithiothreitol

MOPS 3-(N-morpholino)propanesulfonic acid

hepes 4-hydroxyethylpiperazine ethanesulfonic acid

The following reaction scheme describes the steps for preparing the compounds of this invention. Unless otherwise indicated, wherein each ^{R 1, R 2, R 3} , R a, R b , and W have the definitions of the present invention.

Reaction scheme 1

The compound represented by formula ( 4 ) can be prepared by reaction scheme 1: the compound represented by formula ( 1 ) reacts with ethyl acrylate to obtain the compound represented by formula ( 2 ). The compound represented by formula ( 2 ) reacts under the action of potassium nitrate to obtain the compound represented by formula ( 3 ). The compound represented by formula ( 3 ) reacts with hydrogen to obtain the compound represented by formula ( 4 ).

Reaction scheme 2

The compound represented by formula ( 9 ) can be prepared by reaction scheme 2: the compound represented by formula ( 5 ) is reacted under the action of potassium nitrate to obtain the compound represented by formula ( 6 ). The compound represented by formula ( 6 ) reacts with hydrogen to obtain the compound represented by formula ( 7 ). The compound represented by formula ( 7 ) is reacted with 2-hydroxyacetic acid to obtain the compound represented by formula ( 8 ). The compound represented by formula ( 8 ) is reacted with sodium hydride to obtain the compound represented by formula ( 9 ).

Reaction scheme 3

The compound represented by formula ( 14 ) can be prepared by reaction scheme 3: the compound represented by formula (10 ) is reacted with methanol to obtain the compound represented by formula ( 11 ). The compound represented by formula ( 11 ) is reacted with potassium nitrate to obtain the compound represented by formula ( 12 ). The compound represented by formula ( 12 ) is reacted with ethyl bromoalkylate to obtain the compound represented by formula ( 13 ). The compound represented by formula ( 13 ) reacts with hydrogen to obtain the compound represented by formula ( 14 ).

Reaction Scheme 4

The compound represented by formula ( 19 ) can be prepared by reaction scheme 4: the compound represented by formula (15 ) is reacted under the action of ammonium chloride to obtain the compound represented by formula ( 16 ). The compound represented by formula ( 16 ) is reacted with 1-chloro-4-methylpent-3-en-2-one to obtain the compound represented by formula ( 17 ). The compound represented by formula ( 17 ) reacts under the action of aluminum chloride to obtain the compound represented by formula ( 18 ). The compound represented by formula ( 18 ) is reacted with methanol and carbon monoxide to obtain the compound represented by formula ( 19 ).

Reaction scheme 5

The compound represented by formula ( 25 ) can be prepared by reaction scheme 5: the compound represented by formula (20 ) is reacted with dimethyl malonate to obtain the compound represented by formula ( 21 ). The compound represented by formula ( 21 ) reacts under the action of hydrochloric acid to obtain the compound represented by formula ( 22 ). The compound represented by formula ( 22 ) reacts under the action of acetic acid and iron powder to obtain the compound represented by formula ( 23 ). The compound represented by formula ( 23 ) reacts with the compound represented by formula ( 31 ) to obtain the compound represented by formula ( 24 ). The compound represented by formula ( 24 ) reacts with a methanol solution of carbon monoxide and ammonia to obtain the compound represented by formula ( 25 ).

Reaction scheme 6

The compound represented by formula ( 30 ) can be prepared by reaction scheme 6: the compound represented by formula (26 ) is reacted with methyl crotonate to obtain the compound represented by formula ( 27 ). The compound represented by formula ( 27 ) reacts under the action of potassium nitrate to obtain the compound represented by formula ( 28 ). The compound represented by formula ( 28 ) reacts with hydrogen to obtain the compound represented by formula ( 29 ). The compound represented by formula ( 29 ) is reacted with acetic acid to obtain the compound represented by formula ( 30 ).

Reaction scheme 7

The compound represented by formula ( 36 ) can be prepared by reaction scheme 7: the compound represented by formula (33 ) is reacted with the compound represented by formula ( 31 ) to obtain the compound represented by formula (34). The compound represented by formula ( 34 ) reacts with a methanol solution of ammonia gas to obtain the compound represented by formula ( 35 ). The compound represented by formula ( 35 ) reacts with the compound represented by formula ( 32 ) to obtain the compound represented by formula ( 36 ).

Reaction scheme 8

The compound represented by formula ( 41 ) can be prepared by reaction scheme 8: the compound represented by formula (37 ) is combined with ethyl 2-oxoacetate and 1-(isocyanoethylsulfonyl)-4-methylbenzene The reaction obtains the compound represented by formula ( 38 ). The compound represented by formula ( 38 ) reacts with the compound represented by formula ( 32 ) to obtain the compound represented by formula ( 39 ). The compound represented by formula ( 39 ) reacts under the action of DIBAL to obtain the compound represented by formula ( 40 ). The compound represented by formula ( 40 ) reacts under the action of sodium hydride to obtain the compound represented by formula ( 41 ).

The following examples further illustrate the compounds, pharmaceutical compositions and applications of the present invention.

Example

Example 1 6-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-oxo-1,2, 3,4-tetrahydroquinoline-7-carboxamide

The first step is the synthesis of (E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluorobenzoic acid methyl ester

Triphenylphosphine (0.34g, 1.30mmol), palladium acetate (0.30g, 1.30mmol), triethylamine (8.56g, 26.3mmol) and ethyl acrylate (1.55g, 15.5mmol) were sequentially added to 4-bromo In a solution of methyl-2-fluorobenzoate (3.02g, 13.0mmol) in 1,4-dioxane (15mL) under nitrogen protection, the reaction was stirred at 100°C for 8 hours, concentrated under reduced pressure to dryness, and then column chromatography Purification (methanol/dichloromethane (v/v) = 1/20) gave the title compound as a white solid (2.94 g, 90%).

MS (ESI, pos.ion) m/z: 253.2 [M+H] ⁺ .

The second step is the synthesis of (E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluoro-5-nitrobenzoic acid methyl ester

Potassium nitrate (1.35g, 13.4mmol) was added to (E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluorobenzoic acid methyl ester (2.60g, 10.3mmol) in sulfuric acid (15mL, 98%) solution, the reaction was stirred at 0°C for 2 hours, then 300mL of ice water was added for quenching, filtered to obtain the title compound as a white solid (2.82g, 92.0%).

MS (ESI, pos.ion) m/z: 298.1 [M+H] ⁺ .

The third step is the synthesis of methyl 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Add (E)-4-(3-ethoxy-3-oxyprop-1-en-1-yl)-2-fluoro-5-nitrobenzoic acid methyl ester (2.82g, 9.49mmol), 10% Palladium on carbon (400mg) and methanol (20mL) were added to the reaction flask in sequence, protected by hydrogen, stirred overnight at 50°C, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (1.4 g, 66.0%).

MS (ESI, pos.ion) m/z: 224.1 [M+H] ⁺ .

The fourth step is the synthesis of 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

The methanol solution of ammonia (10mL, 70mmol, 7mol/L) was added to methyl 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (150.0mg, 0.67mmol ) In methanol (3 mL), the flask was sealed at 80°C and stirred for 8 hours, filtered, and the reaction solution was concentrated to dryness to obtain the title compound as a yellow solid (110.0 mg, 78%).

MS (ESI, pos.ion) m/z: 209.2 [M+H] ⁺ .

The fifth step 6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-oxo-1,2, Synthesis of 3,4-tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (51.0mg, 0.05mmol), Xant-Phos (32.5mg, 0.104mmol), Cs ₂ CO ₃ (362.0mg, 1.11mmol) and 2-bromo-6-(4-isopropyl) -1,2,4-triazol-3-yl)pyridine (160.3mg, 0.61mmol) was added sequentially to 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-methan Amide (112.0mg, 0.54mmol) in 1,4-dioxane (15mL) solution, nitrogen protection, 100 ℃ stirring reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane ( v/v) = 1/20) to obtain the title compound as a yellow solid (130.2 mg, 61.3%). MS(ESI,pos.ion)m/z:395.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.75 (s, 1H), 10.28 (s, 1H), 8.87 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.03 (t,J=8.0Hz,1H), 7.90(d,J=7.6Hz,1H), 7.27(d,J=10.4Hz,1H), 7.18(d,J=6.2Hz,1H), 5.74–5.60 (m, 1H), 2.96 (t, J = 7.4 Hz, 2H), 2.47 (d, J = 7.3 Hz, 2H), 1.44 (d, J = 6.6 Hz, 6H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 170.3, 163.5, 156.0, 153.6, 151.4, 150.2, 146.7, 143.7, 140.2, 135.4, 129.7, 129.6, 122.7, 122.5, 119.7, 116.2, 116.0, 114.8, 63.3, 48.4, 30.2, 25.2, 23.7.

Example 2 6-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-2-oxo -1,2,3,4-tetrahydroquinoline-7-carboxamide

The first step is the synthesis of methyl 6-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Potassium tert-butoxide (208.6mg, 1.12mmol) was added to the DMF of 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-methyl formate (125.2mg, 0.561mmol) (5mL) in the solution, stirred at 0°C for 1 hour, then added methyl iodide (155.5mg, 1.10mmol), stirred at room temperature in the reaction flask for 3 hours, then added the reaction solution to 100mL of water, and then adjusted the pH to 7 with citric acid , Then add ethyl acetate (200mL) for extraction, the organic phase is dried over anhydrous magnesium sulfate, concentrated to dryness, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as Yellow solid (110.2 mg, 83%).

MS (ESI, pos.ion) m/z: 238.1 [M+H] ⁺ .

The second step is the synthesis of 6-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

The methanol solution of ammonia (10mL, 70mmol, 7mol/L) was added to methyl 6-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate ( In a methanol (3 mL) solution of 100.0 mg, 0.4 mmol), the flask was sealed and reacted at 80°C with stirring for 8 hours, filtered, and the reaction solution was concentrated to dryness to obtain the title compound as a yellow solid (80.0 mg, 85%).

MS (ESI, pos.ion) m/z: 223.1 [M+H] ⁺ .

The third step 6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-2-oxo -Synthesis of 1,2,3,4-tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (51.0mg, 0.05mmol), Xant-Phos (32.5mg, 0.104mmol), Cs ₂ CO ₃ (362.0mg, 1.11mmol) and 2-bromo-6-(4-isopropyl) -1,2,4-triazol-3-yl)pyridine (160.3mg, 0.61mmol) was added sequentially to 6-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquine In the 1,4-dioxane (15mL) solution of morpholine-7-carboxamide (120.0mg, 0.55mmol) under nitrogen protection, the reaction was stirred overnight at 100°C. The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol /Dichloromethane (v/v)=1/20) to obtain the title compound as a yellow solid (125.6 mg, 56%).

MS(ESI,pos.ion)m/z:409.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.83 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 8.0 Hz , 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 5.9 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 5.66 (dt, J = 13.2, 6.6 Hz ,1H), 3.30(s,3H), 2.95(t,J=7.3Hz,2H),2.61-2.55(m,2H),1.43(d,J=6.7Hz,6H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 169.5, 163.6, 156.3, 153.8, 151.4, 150.2, 149.6, 146.7, 143.7, 140.2, 138.1, 137.4, 132.2, 132.1, 124.8, 124.1, 122.7, 122.5, 119.7, 116.1, 115.8, 114.9, 48.4, 31.0, 29.8, 24.9, 23.7.

Example 3 7-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-3-oxo -3,4-Dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The first step is the synthesis of 2,4-difluoro-5-nitrobenzamide

Potassium nitrate (3.52g, 34.8mmol) was added to 2,4-difluorobenzonitrile (4.12g, 29.6mmol) in sulfuric acid (15mL, 98%) solution. The reaction was stirred at 0°C for 2 hours. The reaction solution was added to 300 mL of ice water was filtered to obtain the title compound as a white solid (4.29 g, 78.0%). MS (ESI, pos.ion) m/z: 203.1 [M+H] ⁺ .

The second step is the synthesis of 5-amino-2,4-difluorobenzamide

Add 2,4-difluoro-5-nitrobenzamide (3.5g, 17.4mmol), 10% palladium on carbon (500mg) and methanol (20mL) into the reaction flask in sequence, protected by hydrogen, and stirred at room temperature overnight. After filtration, the filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (2.3 g, 77.0%).

MS (ESI, pos.ion) m/z: 173.0 [M+H] ⁺ .

The third step is the synthesis of 2,4-difluoro-5-(2-hydroxyacetamide)benzamide

Add 5-amino-2,4-difluorobenzamide (1.05g, 6.10mmol) and 2-hydroxyacetic acid (0.71g, 1.50mmol) into the reaction flask, stir the reaction at 110°C for 4 hours, and cool to room temperature. 20 mL of methanol was added, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=1/30) to obtain the title compound as a white solid (1.0 g, 71.0%).

MS(ESI,pos.ion)m/z:231.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 9.47 (s, 1H), 8.11 (t, J = 8.3 Hz, 1H), 7.69 (s, 2H), 7.45 (t, J = 10.5 Hz , 1H), 5.83 (t, J = 5.8 Hz, 1H), 4.04 (d, J = 5.7 Hz, 2H).

The fourth step is the synthesis of 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Sodium hydride (560.6mg, 14.02mmol) was added to 2,4-difluoro-5-(2-hydroxyacetamide)benzamide (0.99g, 4.3mmol) in DMF (20mL), and the reaction was stirred at 60°C. After 8 hours, the reaction solution was added to 200 mL of water, then adjusted to pH 9 with citric acid, and then added with ethyl acetate (200 mL) for extraction. The organic phase was dried over anhydrous magnesium sulfate, concentrated to dryness, and then purified by column chromatography (methanol /Dichloromethane (v/v)=1/20) to obtain the title compound as a white solid (0.21 g, 23.0%).

MS (ESI, pos.ion) m/z: 211.1 [M+H] ⁺ .

The fifth step 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxo-3,4- Synthesis of dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (98.0mg, 0.107mmol), Xant-Phos (60.2mg, 0.104mmol), Cs ₂ CO ₃ (650.0mg, 1.995mmol) and 2-bromo-6-(4-isopropyl) -1,2,4-Triazol-3-yl)pyridine (295.5mg, 1.10mmol) was added to 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4] Oxazine-6-carboxamide (0.21g, 1.00mmol) in 1,4-dioxane (15mL) solution, protected by nitrogen, stirred at 100°C and reacted overnight, the reaction solution was concentrated to dryness, then the column layer Analytical purification (methanol/dichloromethane (v/v)=1/20) gave the title compound as a yellow solid (250.0 mg, 63.1%).

MS (ESI, pos.ion) m/z: 397.2 [M+H] ⁺ .

The sixth step 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-3-oxo Synthesis of -3,4-Dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Potassium tert-butoxide (60.5mg, 0.54mmol) was added to 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl )-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (100.0mg, 0.25mmol) in DMF (5mL) solution, 0℃ Stir the reaction for 1 hour, then add methyl iodide (155.5mg, 1.10mmol), stir the reaction in the reaction flask at room temperature for 3 hours, then add the reaction solution to 50mL water, then adjust the pH to 7 with citric acid, then add ethyl acetate (200mL ) Extraction, the organic phase was dried with anhydrous magnesium sulfate, concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a yellow solid (81.2 mg, 77%) .

MS(ESI,pos.ion)m/z:411.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.72 (s, 1H), 8.86 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.88(d,J=7.7Hz,1H),7.47(d,J=6.6Hz,1H),7.13(d,J=10.7Hz,1H),5.68–5.60(m,1H),4.78 (s,2H),3.33(s,3H),1.44(d,J=6.7Hz,6H);

¹³ _{C NMR (151MHz, DMSO-d 6} ): δ (ppm) 163.6, 163.1, 151.5, 149.6, 146.7, 143.7, 140.2, 126.5, 119.7, 114.9, 105.2, 67.5, 48.5, 28.4, 23.6.

Example 4 7-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxo-3,4- Dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (98.0mg, 0.107mmol), Xant-Phos (60.2mg, 0.104mmol), Cs ₂ CO ₃ (650.0mg, 1.995mmol) and 2-bromo-6-(4-isopropyl) -1,2,4-Triazol-3-yl)pyridine (295.5mg, 1.10mmol) was added to 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4] oxazine-6-carboxamide (0.21g, 1.00mmol) in 1,4-dioxane (15mL) solution, protected by nitrogen, stirred at 100°C and reacted overnight, the reaction solution was concentrated to dryness, and then the column layer Analytical purification (methanol/dichloromethane (v/v) = 1/20) gave the title compound as a white solid (250.0 mg, 63.1%).

MS(ESI,pos.ion)m/z:397.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.92 (s, 1H), 10.60 (d, J = 2.5 Hz, 1H), 8.87 (s, 1H), 8.19 (d, J = 8.3 Hz ,1H), 8.03(t,J=8.0Hz,1H),7.89(d,J=7.6Hz,1H), 7.27(d,J=7.1Hz,1H), 7.09(d,J=11.1Hz,1H ),5.68–5.59(m,1H),4.71(s,2H),1.45(d,J=6.7Hz,6H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 164.3, 163.0, 156.6, 155.0, 151.4, 150.2, 147.0, 146.9, 146.7, 143.8, 140.2, 124.4, 119.7, 117.5, 117.4, 116.8, 114.8, 105.3, 105.1, 67.21, 49.1, 48.4, 23.7.

Example 5 7-Fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (45.0mg, 0.049mmol), Xant-Phos (33.2mg, 0.057mmol), Cs ₂ CO ₃ (320.0mg, 0.98mmol) and 3-(3-bromophenyl)-4- Isopropyl-1,2,4-triazole (140.0mg, 0.52mmol) was added sequentially to 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4] In a 1,4-dioxane (15mL) solution of oxazine-6-carboxamide (0.10g, 0.48mmol) under nitrogen protection, the reaction was stirred overnight at 100°C. The reaction solution was concentrated to dryness, and then purified by column chromatography ( Methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (24.0 mg, 12.7%).

MS(ESI,pos.ion)m/z:396.0[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.92 (s, 1H), 10.49 (s, 1H), 8.86 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 7.5Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.34 (d, J = 6.3 Hz, 1H), 7.20 (d, J = 6.3 Hz, 1H), 7.06 (d, J = 10.5 Hz ,1H),4.69(s,2H),4.45(s,1H),1.43(d,J=5.5Hz,6H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 164.3, 162.7, 156.6, 154.2, 152.7, 146.6, 146.5, 142.7, 139.7, 130.0, 128.4, 124.6, 124.3, 121.5, 120.4, 118.3, 118.1, 116.6, 105.2, 104.9, 67.2, 48.0, 23.7.

Example 6 5-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1,3,3-trimethyl -2-oxoindole-6-carboxamide

The first step is the synthesis of 2-(4-bromo-5fluoro-2-nitrophenyl) dimethyl malonate

At 15℃, mix 1-bromo-2,4-difluoro-5-nitro-benzene (10.02g, 42.10mmol) and dimethyl malonate (6.72g, 50.9mmol) in 1,4-dioxide The solution of hexacyclic ring (30mL) was added to the 1,4-dioxane (15mL) suspension of sodium hydride (4.047g, 101.2mmol), the reaction was stirred at 15°C for 1 hour, and the reaction was transferred to room temperature to continue the reaction for 8 hours , The reaction was transferred to an ice bath, 150mL water was added, dichloromethane (150mL×3) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain the title compound mixture as a brown liquid (14.72g, 99.86%) ).

MS (ESI, pos.ion) m/z: 350.0 [M+H] ⁺ .

The second step is the synthesis of 2-(4-bromo-5-fluoro-2-nitro-phenyl)acetic acid

A suspension of 2-(4-bromo-5fluoro-2-nitrophenyl) dimethyl malonate (14.72g, 42.05mmol) in hydrochloric acid (160mL, 960mmol, 6mol/L) was heated to 100℃ and stirred Reacted for 24 hours, then brought to room temperature, filtered, and rinsed the solid with 20 mL of water to obtain the title compound mixture as a brown solid (11.69 g, 100%).

MS (ESI, pos.ion) m/z: 232.0 [MH] ^- .

The third step is the synthesis of 6-bromo-5-fluoroindol-2-one

Add iron powder (12.564g, 225.0mmol) to 2-(4-bromo-5-fluoro-2-nitro-phenyl)acetic acid (11.69g, 42.05mmol) in acetic acid (100mL) solution, and stir at 100°C React overnight, then cool to 50°C, filter, rinse the solid with DCM/MeOH (10:1, 1000mL), collect the filtrate, concentrate the filtrate to dryness, and then purify by column chromatography (methanol/dichloromethane (v/v) = 1/30) The title compound was obtained as a yellow solid (4.84 g, 50.0%).

MS(ESI,pos.ion)m/z:228.1[MH] ^- ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.46 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 5.8 Hz, 1H), 3.48 (s ,2H).

The fourth step is the synthesis of 6-bromo-5-fluoro-1,3,3-trimethylindol-2-one

Add methyl iodide (1.22mL, 19mmol) to a suspension of 6-bromo-5-fluoroindol-2-one (753.6mg, 3.276mmol) and potassium tert-butoxide (2.288g, 20.39mmol) in DMF (12mL) Stir the reaction at room temperature for 24 hours, then add the reaction solution to 60mL water, extract with ethyl acetate (50mL×5), wash the organic phase with saturated sodium chloride solution (50mL×10), concentrate the organic phase to dryness, and then column layer Analytical purification (ethyl acetate/petroleum ether (v/v)=2/9) gave the title compound as a reddish brown solid (340mg, 38.14%).

MS (ESI, pos.ion) m/z: 272.1 [M+H] ⁺ .

The fifth step is the synthesis of methyl 5-fluoro-1,3,3-trimethyl-2-oxoindole-6-carboxylate

Add 6-bromo-5-fluoro-1,3,3-trimethylindol-2-one (340mg, 1.2495mmol), Pd(dppf) ₂ Cl ₂ (201.9mg, 0.2472mmol), triethylamine ( 0.35mL, 2.5mmol) and methanol (12mL) were added to a 250mL autoclave, pressurized with CO and pressurized to 2.5MPa, stirred at 100℃ for 30 hours, the reaction solution was concentrated to dryness, and then purified by column chromatography (ethyl acetate /Petroleum ether (v/v)=1/1) to obtain the title compound as a white solid (192 mg, 61.17%).

MS(ESI,pos.ion)m/z:252.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.33 (d, J = 5.5 Hz, 1H), 7.02 (d, J = 9.7 Hz, 1H), 3.95 (s, 3H), 3.24 (s, 3H) ,1.38(s,6H).

The sixth step is the synthesis of 5-fluoro-1,3,3-trimethyl-2-oxoindole-6-carboxamide

Add 5-fluoro-1,3,3-trimethyl-2-oxoindole-6-methyl carboxylate (180mg, 0.7166mmol) and methanol solution of ammonia (10mL, 70mmol, 7mol/L) to 25mL The reaction mixture was stirred overnight at 70°C in an autoclave with a temperature of 70°C. The reaction solution was concentrated to dryness to obtain the title compound as a white solid (168 mg, 99.24%).

MS (ESI, pos.ion) m/z: 237.1 [M+H] ⁺ .

The seventh step 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1,3,3-trimethyl Synthesis of -2-oxoindole-6-carboxamide

Xant-Phos (37.2mg, 0.0643mmol), Pd ₂ (dba) ₃ (59.6mg, 0.0651mmol) and Cs ₂ CO ₃ (324.8mg, 0.9969mmol) were added to 5-fluoro-1,3,3- Trimethyl-2-oxoindole-6-carboxamide (150mg, 0.63495mmol) and 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine ( 171.9mg, 0.6435mmol) of 1,4-dioxane (6mL) suspension, nitrogen protection, 100 ℃ stirring reaction for 6 hours, the reaction solution was concentrated to dryness, and then column chromatography purification (methanol/dichloromethane ( v/v)=1/35) to obtain the title compound as a white solid (241 mg, 89.84%).

MS(ESI,pos.ion)m/z:423.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.90 (s, 1H), 8.86 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.03 (t, J = 8.0 Hz ,1H),7.91(d,J=7.6Hz,1H),7.54(d,J=9.4Hz,1H),7.32(d,J=5.4Hz,1H),5.77–5.65(m,1H),3.18 (s,3H),1.43(d,J=6.7Hz,6H),1.31(s,6H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 180.2, 164.0, 154.9, 151.4, 150.2, 146.7, 143.7, 140.4 (d, J = 8.6 Hz), 140.2, 139.2, 123.5 (d, J = 16.8 Hz), 119.6, 114.8, 112.1 (d, J=25.7 Hz), 109.0, 48.4, 44.6, 26.7, 24.1,23.7.

Example 7 4-Ethyl-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxo -3,4-Dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxo-3,4-dihydro -2H-benzo[b][1,4]oxazine-6-carboxamide (61.0mg, 0.154mmol), iodoethane (24.2mg, 0.155mmol), potassium tert-butoxide (52.2mg 0.46mmol) and DMF (10mL) was sequentially added to the reaction flask, stirred overnight at 40°C, then the reaction solution was added to 200mL of water, then adjusted to pH 9 with citric acid, and then added with ethyl acetate (200mL) for extraction, and the organic phase was extracted with anhydrous sulfuric acid It was dried over magnesium, concentrated to dryness, and purified by column chromatography (methanol/dichloromethane (v/v)=1/20) to obtain the title compound as a white solid (16.2 mg, 24.8%).

MS(ESI,pos.ion)m/z:425.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.75 (s, 1H), 8.87 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.89(d,J=7.6Hz,1H),7.50(d,J=6.7Hz,1H),7.15(d,J=10.6Hz,1H),5.71-5.60(m,1H),4.77 (s, 2H), 3.99 (d, J = 7.1 Hz, 2H), 1.44 (d, J = 6.7 Hz, 6H), 1.19 (t, J = 7.0 Hz, 3H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 163.1, 157.1, 154.7, 151.5, 150.2, 148.6, 146.7, 143.7, 140.2, 125.2, 119.7, 118.2, 118.1, 116.4, 114.8, 105.8, 105.5, 67.6, 48.4, 36.1,23.6, 12.7.

Example 8 7-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,2-dimethyl-3 -Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The first step is the synthesis of methyl 2-fluoro-4-hydroxybenzoate

Sulfuric acid (2.09ml, 38.4mmol, 98%) was added to the methanol (200mL) solution of 2-fluoro-4-hydroxy-benzoic acid (6.00g, 38.4mmol), refluxed and stirred overnight, the reaction solution was concentrated to dryness and added 50mL of ethyl acetate, then use saturated sodium bicarbonate aqueous solution to adjust the pH to 7, separation, collect the organic phase, the aqueous phase was extracted with ethyl acetate (2×50mL), the organic phase was washed with brine, dried with anhydrous sodium sulfate, filtered The filtrate was concentrated to dryness to obtain the title compound as a yellow solid (6.20 g, 94.8%).

MS (ESI, pos.ion) m/z: 171.1 [M+H] ⁺ .

The second step is the synthesis of methyl 2-fluoro-4-hydroxy-5-nitrobenzoate

Potassium nitrate (4.28g, 42.3mmol) was added to methyl 2-fluoro-4-hydroxybenzoate (6.00g, 35.3mmol) in sulfuric acid (100mL, 98%) solution, stirred at 0°C for 2 hours, and then added 200mL Water and filtration gave the title compound as a white solid (6.70 g, 88.3%). MS(ESI,pos.ion)m/z:216.0[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 12.47 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 6.99 (d, J = 12.2 Hz, 1H), 3.84 (s ,3H).

The third step is the synthesis of methyl 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-2-fluoro-5-nitrobenzoate

Add 2-bromo-2-methyl-propionic acid ethyl ester (14.1g, 72.5mmol) and potassium carbonate (6.67g, 48.3mmol) to 2-fluoro-4-hydroxy-5-nitrobenzoic acid methyl ester ( 5.20g, 24.2mmol) in DMF (70mL) solution, stirred at 100℃ for 1 hour, added 200mL of water, then added ethyl acetate (2×50mL) for extraction, collected the organic phase and washed with brine (2×100mL), organic The phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and then purified by column chromatography (ethyl acetate/petroleum ether (v/v)=1/10) to obtain the title compound as a white solid (1.05 g, 13.2%). ¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 8.43 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 12.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H ), 3.86 (s, 3H), 1.66 (s, 6H), 1.17 (t, J = 7.1 Hz, 3H).

The fourth step is the synthesis of methyl 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Add palladium on carbon (0.71g, 0.67mmol, 10%) to 4-((1-ethoxy-2-methyl-1-oxoprop-2-yl)oxy)-2-fluoro-5-nitro Methyl benzoate (1.10g, 3.34mmol) in methanol (50mL), protected by hydrogen, stirred overnight at 50°C, filtered, collected the filtrate, concentrated to dryness, and purified by column chromatography (ethyl acetate/petroleum Ether (v/v) = 1/10) to obtain the title compound as a white solid (0.65 g, 77.0%).

MS(ESI,pos.ion)m/z:254.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.82 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 11.5 Hz, 1H), 3.82 (s ,3H),1.44(s,6H).

The fifth step is the synthesis of 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester (0.20g, 0.79 mmol) and a methanol solution of ammonia (25mL, 175mmol, 7mol/L) were added to the reaction flask, stirred overnight at 70°C, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 3/100) to obtain the title compound as a white solid (0.16 g, 85.0%).

MS (ESI, pos.ion) m/z: 239.1 [M+H] ⁺ .

The sixth step 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,2-dimethyl-3 Synthesis of -oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

With 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (0.21g, 0.79mmol), Pd ₂ (dba) ₃ (0.13g, 0.14mmol), Xant-Phos (0.082g, 0.14mmol) and Cs ₂ CO ₃ (0.46g, 1.43mmol) were added to 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H in turn -Benzo[b][1,4]oxazine-6-carboxamide (0.17g, 0.71mmol) in 1,4-dioxane (30mL) solution, reflux and stir for 10 hours, the reaction solution is concentrated to Dry, and then column chromatography purification (methanol/dichloromethane (v/v)=3/100) to obtain the title compound as a yellow solid (0.16 g, 53.0%). MS(ESI,pos.ion)m/z:425.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.86 (s, 1H), 10.62 (d, J = 2.3 Hz, 1H), 8.87 (s, 1H), 8.20 (d, J = 8.2 Hz ,1H), 8.03(t,J＝8.0Hz,1H),7.90(d,J＝7.6Hz,1H), 7.28(d,J＝7.0Hz,1H), 7.09(d,J＝10.9Hz,1H ),5.77–5.56(m,1H),1.48–1.43(m,12H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 168.2, 163.0, 157.1, 154.7, 151.4, 150.2, 146.7, 145.8, 145.7, 143.7, 140.2, 124.9, 124.8, 119.6, 117.7, 117.5, 116.3, 116.3, 114.8, 106.0, 105.7, 79.0, 48.4, 24.0, 23.7.

Example 9 7-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,2,4-trimethyl -3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The first step 7-fluoro-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-methyl formate synthesis

Potassium tert-butoxide (0.35g, 3.16mmol) and methyl iodide (0.67g, 4.74mmol) were sequentially added to 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H -Benzo[b][1,4]oxazine-6-methyl carboxylate (0.40g, 1.58mmol) in DMF (50mL) solution, stir at room temperature overnight, add 200mL water, and then add ethyl acetate (50ml ×2) Extraction, wash the organic phase with brine (100mL×2), dry with anhydrous sodium sulfate, filter, collect the filtrate, concentrate the filtrate to dryness, and then purify by column chromatography (ethyl acetate/petroleum ether (v/v)= 1/10) The title compound was obtained as a white solid (0.40 g, 95.0%).

MS (ESI, pos.ion) m/z: 268.2 [M+H] ⁺ .

The second step is the synthesis of 7-fluoro-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Mix 7-fluoro-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester (0.40g , 1.50mmol) and a methanol solution of ammonia (25mL, 175mmol, 7mol/L) were added to the reaction flask, stirred overnight at 70°C, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) )=3/100) to obtain the title compound as a white solid (0.26 g, 69.0%).

MS(ESI,pos.ion)m/z:253.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 7.61 (d, J = 31.7 Hz, 2H), 7.40 (d, J = 7.0 Hz, 1H), 7.01 (d, J = 10.9 Hz, 1H ), 3.32(s, 3H), 1.44(s, 6H).

The third step 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,2,4-trimethyl Synthesis of -3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (0.23g, 0.87mmol), Pd ₂ (dba) ₃ (0.15g, 0.16mmol), Xant-Phos (0.091g, 0.16mmol) and Cs ₂ CO ₃ (0.52g, 1.59mmol) were added sequentially to 7-fluoro-2,2,4-trimethyl-3-oxo-3,4-dihydro -2H-benzo[b][1,4]oxazine-6-carboxamide (0.20g, 0.79mmol)) in 1,4-dioxane (30mL) solution, reflux and stir for 8 hours, react The liquid was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=3/100) to obtain the title compound as a yellow solid (0.26 g, 75.0%). MS(ESI,pos.ion)m/z:439.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.74 (s, 1H), 8.88 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.89(d,J=7.7Hz,1H),7.48(d,J=6.8Hz,1H),7.13(d,J=10.6Hz,1H),5.77–5.52(m,1H),3.35 (s, 3H), 1.47 (s, 6H), 1.44 (d, J = 6.7 Hz, 6H);

13C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 167.4, 163.2, 157.0, 155.3, 151.5, 150.2, 146.5, 146.4, 143.8, 140.2, 126.8 119.7, 118.0, 117.9, 116.4, 114.8, 108.2, 106.1, 105.9, 79.0, 48.4, 29.2, 24.2, 23.7.

Example 10 7-Fluoro-N-(6-(4-(1-hydroxyprop-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3- Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (45.0mg, 0.049mmol), Xant-Phos (28.2mg, 0.048mmol), Cs ₂ CO ₃ (320.0mg, 0.98mmol) and 2-(3-(6-bromopyridine-2 -Yl)-4H-1,2,4-triazol-4-yl)-1-propanol (140.0mg, 0.495mmol) was added to 7-fluoro-3-oxo-3,4-dihydro- In a solution of 2H-benzo[b][1,4]oxazine-6-carboxamide (0.10g, 0.48mmol) in 1,4-dioxane (15mL) under nitrogen protection, the reaction was stirred overnight at 100°C. The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (86.2 mg, 43.4%).

MS(ESI,pos.ion)m/z:413.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.93 (s, 1H), 10.57 (s, 1H), 8.78 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.02 (t,J=8.0Hz,1H), 7.88(d,J=7.6Hz,1H), 7.27(d,J=6.9Hz,1H), 7.10(d,J=11.0Hz,1H), 5.54(dd ,J=11.3,5.6Hz,1H), 4.95(s,1H), 4.71(s,2H), 3.64(s,2H), 1.44(d,J=6.8Hz,3H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 164.3, 163.0, 156.6, 155.0, 151.4, 150.2, 147.0, 146.9, 146.7, 143.7, 140.2, 124.4, 119.7, 117.5, 117.4, 116.8, 114.8, 105.3, 105.1, 67.2, 49.1, 48.4, 23.7.

Example 11 6-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4,4-dimethyl-2 -Oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

The first step is the synthesis of 3-bromo-4-fluoroaniline

Add water (10mL), ammonium chloride (1.95g, 36.5mmol) and iron powder (6.20g, 110.0mmol) to 2-bromo-1-fluoro-4nitrobenzene (4.02g, 18.3mmol) in methanol (100mL) solution, stirred at 80°C for 8 hours, the reaction solution was concentrated to dryness under reduced pressure, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a yellow solid (3.2g, 92.0%).

MS (ESI, pos.ion) m/z: 190.1 [M+H] ⁺ .

The second step is the synthesis of N-(3-bromo-4-fluorobenzene)-3-methylbut-2-enamide

Pyridine (2.62mg, 33.0mmol) and 1-chloro-4-methylpent-3-en-2-one (2.0g, 16.9mmol) were added to 3-bromo-4-fluoroaniline (3.14g, 16.5 mmol) in DCM (15mL) solution, stirred at room temperature overnight, added the reaction solution to 300mL water, adjusted pH to 6 with citric acid, extracted with ethyl acetate, dried the organic phase with anhydrous magnesium sulfate, filtered, and concentrated the filtrate to dryness. Then it was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a yellow solid (4.12 g, 91.0%).

MS (ESI, pos.ion) m/z: 272.1 [M+H] ⁺ .

The third step is the synthesis of 7-bromo-6-fluoro-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one

Combine N-(3-bromo-4-fluorobenzene)-3-methylbut-2-enamide (4.10g, 15.1mmol), anhydrous aluminum chloride (8.11g 60.8mmol) and dichloromethane (50mL) They were added to the reaction flask in turn, stirred at room temperature overnight, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a white solid (1.02g, 24.9%).

MS(ESI,pos.ion)m/z:272.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.24 (s, 1H), 7.26 (d, J = 9.7 Hz, 1H), 7.11 (d, J = 6.3 Hz, 1H), 2.33 (s , 2H), 1.18 (s, 6H).

The fourth step is the synthesis of methyl 6-fluoro-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Pd(dppf) ₂ Cl ₂ (210.2mg, 0.258mmol) and triethylamine (0.5mL, 4mmol) were sequentially added to 7-bromo-6-fluoro-4,4-dimethyl-3,4-dihydro Quinoline-2(1H)-one (500.0mg, 2.0mmol) in methanol (20mL), protected by hydrogen, stirred at 80°C for 20 hours, the reaction solution was concentrated to dryness, and then purified by column chromatography (ethyl acetate/ Petroleum ether (v/v) = 1/2) to obtain the title compound as a white solid (330.2 mg, 70%).

MS (ESI, pos.ion) m/z: 252.3 [M+H] ⁺ .

The fifth step is the synthesis of 6-fluoro-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

The methanol solution of ammonia (10mL, 70mmol, 7mol/L) was added to the methyl 6-fluoro-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-formic acid In a methanol (3 mL) solution of the ester (130.0 mg, 0.52 mmol), the reaction was stirred at 80°C for 8 hours in a sealed bottle, and the reaction solution was concentrated to dryness to obtain the title compound as a yellow solid (121.2 mg, 98.7%).

MS (ESI, pos.ion) m/z: 237.2 [M+H] ⁺ .

The sixth step 6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4,4-dimethyl-2 Synthesis of -oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (50.0mg, 0.05mmol), Xant-Phos (32.5mg, 0.104mmol), Cs ₂ CO ₃ (362.0mg, 1.11mmol) and 2-bromo-6-(4-isopropyl) -1,2,4-triazol-3-yl)pyridine (160.3mg, 0.61mmol) was added to 6-fluoro-4,4-dimethyl-2-oxo-1,2,3,4- In a suspension of tetrahydroquinoline-7-carboxamide (110.0mg, 0.46mmol) and 1,4-dioxane (15mL), under nitrogen protection, the reaction was stirred overnight at 100°C, the reaction solution was concentrated to dryness, and then column Purification by chromatography (methanol/dichloromethane (v/v)=1/20) gave the title compound as a yellow solid (160.2 mg, 81.4%).

MS(ESI,pos.ion)m/z:423.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.80 (s, 1H), 10.35 (s, 1H), 8.86 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.03 (t,J=7.8Hz,1H), 7.91(d,J=7.5Hz,1H), 7.32(d,J=10.9Hz,1H), 7.19(d,J=5.9Hz,1H), 5.76–5.64 (m, 1H), 2.39 (s, 2H), 1.43 (d, J = 6.4 Hz, 6H), 1.26 (s, 6H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 169.5, 163.5, 156.5, 154.1, 151.3, 150.2, 146.7, 143.7, 140.2, 138.0, 137.9, 134.0, 123.0, 122.8, 119.7, 116.4, 114.8, 113.3, 113.0, 48.4, 44.5, 34.5, 27.3, 23.7.

Example 12 7-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-2-oxo -2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

The first step is the synthesis of methyl (Z)-2-fluoro-4-(4-methoxy-4-oxobut-1-en-1-yl)benzoate

Methyl but-3-enoate (0.43g, 4.29mmol), palladium acetate (0.19g, 0.86mmol), triphenylphosphine (0.22g, 0.86mmol) and triethylamine (0.87g, 8.58mmol) in turn Add to 4-bromo-2-fluorobenzoic acid methyl ester (1.00g, 4.29mmol) in 1,4-dioxane (30mL) solution, reflux and stir to react overnight, the reaction solution is concentrated under reduced pressure to dryness, then column Chromatographic purification (ethyl acetate/petroleum ether (v/v)=1/10) gave the title compound as a yellow liquid (0.34g, 31.0%).

MS(ESI,pos.ion)m/z:253.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 7.84 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 13.5 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H ), 6.61–6.55(m, 2H), 3.84(s, 3H), 3.64(s, 3H), 3.34(d, J=5.5Hz, 2H).

The second step is the synthesis of methyl (Z)-2-fluoro-4-(4-methoxy-4-oxbut-1-en-1-yl)-5-nitrobenzoate

Add potassium nitrate (0.044g, 0.44mmol) to methyl (Z)-2-fluoro-4-(4-methoxy-4-oxbut-1-en-1-yl)benzoate at 0°C (0.10g, 0.40mmol) in sulfuric acid (5mL, 98%) solution, stirred at 0°C for 2 hours, then added 200mL ice water, filtered, and purified by cake column chromatography (ethyl acetate/petroleum ether (v/v) )=1/10) to obtain the title compound as a yellow liquid (0.030 g, 25.5%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 8.44 (d, J = 6.7 Hz, 1H), 7.84 (d, J = 11.7 Hz, 1H), 6.90 (d, J = 15.7 Hz, 1H ), 6.72–6.63 (m, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 3.42 (d, J = 7.3 Hz, 2H).

The third step is the synthesis of methyl 5-amino-2-fluoro-4-(4-methoxy-4-oxobutyl)benzoate

Add palladium on carbon (0.29g, 0.27mmol, 10%) to (Z)-2-fluoro-4-(4-methoxy-4-oxobut-1-en-1-yl)-5-nitro Methyl benzoate (0.40g, 1.35mmol) in methanol (30mL) was protected by hydrogen. The reaction flask was stirred overnight at 50℃, filtered, and the filtrate was concentrated to dryness to obtain the title compound as a yellow liquid (0.36g, 100.0% ).

MS (ESI, pos.ion) m/z: 270.2 [M+H] ⁺ .

The fourth step is the synthesis of methyl 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-carboxylate

Add 5-amino-2-fluoro-4-(4-methoxy-4-oxobutyl) benzoic acid methyl ester (0.26g, 0.97mmol) and acetic acid (20mL) to the reaction flask, and reflux and stir to react. Overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=3/100) to obtain the title compound as a yellow solid (0.16 g, 70.0%).

MS(ESI,pos.ion)m/z:238.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 9.62 (s, 1H), 7.45 (d, J = 6.7 Hz, 1H), 7.32 (d, J = 11.2 Hz, 1H), 3.85 (s , 3H), 2.74 (t, J = 6.6 Hz, 2H), 2.19-2.08 (m, 4H).

The fifth step is the synthesis of methyl 7-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-carboxylate

Potassium tert-butoxide (0.15g, 1.35mmol) and methyl iodide (0.29g, 2.02mmol) were added to 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[ b] Azepine-8-methyl formate (0.16g, 0.67mmol) in DMF (20mL) solution, stir at room temperature overnight, add 20mL water, then add ethyl acetate (50ml×2) for extraction, organic phase brine (100ml×2), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v)=10/3) to obtain the title compound as white Solid (0.11 g, 65.0%).

MS (ESI, pos.ion) m/z: 252.2 [M+H] ⁺ .

The sixth step is the synthesis of 7-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-carboxamide

The methanol solution of ammonia (15mL, 105mmol, 7mol/L) and 7-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b) acridine Methyl-8-formate (0.11g, 0.44mmol) was sequentially added to the reaction flask, stirred at 70°C overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 3/100) to obtain the title compound as a white solid (0.095 g, 92.0%).

MS (ESI, pos.ion) m/z: 237.2 [M+H] ⁺ .

The seventh step 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-2-oxo Synthesis of -2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-carboxamide

Combine 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (0.12g, 0.43mmol), Pd2(dba)3 (0.065g, 0.072mmol), Xant -Phos (0.041g, 0.072mmol) and Cs ₂ CO ₃ (0.23g, 0.72mmol) were added to 7-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H in turn -Benzo[b] azepine-8-carboxamide (0.085g, 0.36mmol) in 1,4-dioxane (10mL) solution, reflux and stir for reaction overnight, the reaction solution is concentrated to dryness, then the column layer Analytical purification (methanol/dichloromethane (v/v)=3/100) gave the title compound as a yellow solid (0.11 g, 72.0%).

MS(ESI,pos.ion)m/z:423.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.89 (s, 1H), 8.87 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.90(d,J=7.6Hz,1H),7.68(d,J=6.4Hz,1H),7.36(d,J=10.3Hz,1H),5.76-5.55(m,1H),3.26 (s, 3H), 2.73 (t, J = 6.9 Hz, 2H), 2.18 (t, J = 6.6 Hz, 2H), 2.14-2.06 (m, 2H), 1.44 (d, J = 6.7 Hz, 6H) ；

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 172.0, 163.3, 158.0, 155.6, 151.4, 150.2, 146.7, 143.7, 140.9, 140.8, 140.3, 140.3, 140.2, 124.5, 124.4, 123.4, 123.2, 119.8,117.3,117.09,114.9,48.4,35.2,33.1,29.7,28.2,23.7.

Example 13 6-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1,4,4-trimethyl -2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

The first step is the synthesis of methyl 6-fluoro-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Potassium tert-butoxide (208.6mg, 1.12mmol) was added to methyl 6-fluoro-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate ( 190.0mg, 0.75mmol) in DMF (5mL) solution, stirred at 0°C for 1 hour, then added methyl iodide (155.5mg, 1.10mmol), stirred at room temperature for 3 hours, added the reaction solution to 100mL of water, adjusted the pH with citric acid To 7, ethyl acetate (200mL) extraction, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (ethyl acetate/petroleum ether (v/v) = 1/2) to obtain the title The compound was a yellow solid (160.2 mg, 79.6%).

MS (ESI, pos.ion) m/z: 266.2 [M+H] ⁺ .

The second step is the synthesis of 6-fluoro-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

The methanol solution of ammonia (10mL, 70mmol, 7mol/L) was added to 6-fluoro-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7- In a methanol (3 mL) solution of methyl formate (150.0 mg, 0.56 mmol), the flask was sealed and stirred at 80°C for 8 hours. The reaction solution was concentrated to dryness to obtain the title compound as a yellow solid (120.2 mg, 84.46%).

MS (ESI, pos.ion) m/z: 251.4 [M+H] ⁺ .

The third step 6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4,4-dimethyl-2 Synthesis of -oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (20.0mg, 0.02mmol), Xant-Phos (10.5mg, 0.02mmol), Cs ₂ CO ₃ (112.0mg, 0.33mmol) and 2-bromo-6-(4-isopropyl) -1,2,4-triazol-3-yl)pyridine (43.3mg, 0.16mmol) was added to 6-fluoro-1,4,4-trimethyl-2-oxo-1,2,3, 4-tetrahydroquinoline-7-carboxamide (40.0mg, 0.16mmol) in 1,4-dioxane (5mL) solution, protected by nitrogen, stirred at 100℃ overnight, the reaction solution was concentrated to dryness, then column Purification by chromatography (methanol/dichloromethane (v/v) = 1/20) gave the title compound as a yellow solid (51.2 mg, 73.4%).

MS(ESI,pos.ion)m/z:437.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.88 (s, 1H), 8.86 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.91(d,J＝7.6Hz,1H), 7.38(dd,J＝13.4,8.4Hz,2H), 5.70(dt,J＝13.3,6.7Hz,1H), 3.34(s,3H) ,2.50–2.49(m,2H),1.43(d,J=6.7Hz,6H),1.26(s,6H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 168.5, 163.6, 156.8, 154.3, 151.4, 150.2, 146.7, 143.7, 140.2, 136.1, 122.9, 122.8, 119.7, 116.6, 114.8, 113.2, 112.9, 55.4, 48.4, 45.0, 33.6, 29.7, 27.0, 23.7.

Example 14 N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-fluoro-1,4,4-trimethyl -2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (20.0mg, 0.02mmol), Xant-Phos (10.5mg, 0.02mmol), Cs ₂ CO ₃ (112.0mg, 0.33mmol) and 2-bromo-6-(4-cyclopropyl) -4H-1,2,4-triazol-3-yl)pyridine (53.3mg, 0.20mmol) was added to 6-fluoro-1,4,4-trimethyl-2-oxo-1,2, 3,4-Tetrahydroquinoline-7-carboxamide (50.0mg, 0.20mmol) in 1,4-dioxane (5mL) solution, protected by nitrogen, stirred overnight at 100°C, the reaction solution was concentrated to dryness, Then it was purified by column chromatography (methanol/dichloromethane (v/v)=1/20) to obtain the title compound as a yellow solid (72.3 mg, 83.3%).

MS(ESI,pos.ion)m/z:435.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.86 (s, 1H), 8.64 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.87(d,J=7.6Hz,1H),7.38(dd,J=13.3,8.4Hz,2H),4.21(d,J=4.1Hz,1H),3.33(s,3H),2.50 –2.49(m,2H),1.26(s,6H),1.01(d,J=7.4Hz,2H),0.95(s,2H);

¹³ C NMR(101MHz, DMSO-d ₆ ): δ(ppm) 168.5(s), 163.6(s), 156.4(s), 154.7(s), 152.6(s), 151.4(s), 146.1(s) ,145.5(s),140.1(d,J=10.5Hz),136.1(s),122.8(d,J=15.8Hz),119.3(s),116.6(s),114.6(s),113.3–113.2( m), 113.0 (d, J = 24.4 Hz), 49.1 (s), 45.0 (s), 33.6 (s), 29.7 (s), 29.1 (s), 27.0 (s), 7.7 (s).

Example 15 N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-3-oxo-3,4- Dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (45.0mg, 0.049mmol), Xant-Phos (33.2mg, 0.057mmol), Cs ₂ CO ₃ (320.0mg, 0.98mmol) and 2-bromo-6-(4-cyclopropyl) -4H-1,2,4-triazol-3-yl)pyridine (130.0mg, 0.495mmol) was added to 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] Oxazine-6-carboxamide (0.10g, 0.48mmol) in 1,4-dioxane (15mL) solution, protected by nitrogen, stirred at 100°C for overnight reaction, the reaction solution was concentrated to dryness, then Purification by column chromatography (methanol/dichloromethane (v/v) = 1/20) gave the title compound as a white solid (120.2 mg, 64.05%).

MS(ESI,pos.ion)m/z:395.3[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.92 (s, 1H), 10.56 (s, 1H), 8.64 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.03 (t,J=8.0Hz,1H), 7.85(d,J=7.6Hz,1H), 7.27(d,J=7.0Hz,1H), 7.07(d,J=11.1Hz,1H), 4.70(s ,2H),4.16(dd,J=7.2,3.4Hz,1H),1.02(d,J=7.1Hz,2H),0.96(s,2H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 164.3, 163.0, 157.0, 154.6, 152.7, 151.4, 147.0, 146.9, 146.1, 145.6, 140.0, 124.4, 124.4, 119.3, 117.5, 117.3, 116.8, 116.8,114.6,105.3,105.0,67.2,49.1,29.1,7.7.

Example 16 7-Fluoro-4-isopropyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxy Generation-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

The 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxo-3,4-dihydro -2H-Benzo[b][1,4]oxazine-6-carboxamide (130.2mg, 0.297mmol), 2-bromopropane (63.2mg, 0.514mmol), potassium tert-butoxide (180.0mg-1.606mmol) Add DMF and DMF (10mL) to the reaction flask successively, stir overnight at 40℃, then add the reaction solution to 200mL water, then adjust the pH to 9 with citric acid, and then add ethyl acetate (200mL) for extraction, and the organic phase is dried It was dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (31.2 mg, 14.0%).

MS(ESI,pos.ion)m/z:439.3[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.78 (s, 1H), 8.87 (s, 1H), 8.21 (d, J = 7.1 Hz, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.59 (s, 1H), 7.16 (d, J = 9.9 Hz, 1H), 5.65 (s, 1H), 4.65 (s, 3H), 1.52-1.41 (m, 12H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 165.0, 165.0, 163.1, 156.6, 155.0, 151.6, 151.5, 150.2, 150.0, 149.6, 149.5, 146.7, 146.7, 143.9, 143.8, 140.2, 140.1, 140.0,129.4,126.4,126.1,125.7,123.0,119.7,119.6,118.3,118.2,117.4,116.5,114.9,114.8,106.0,105.9,104.4,69.9,68.5,68.3,62.4,48.5,48.5,48.4,48.0, 23.7, 23.7, 23.6, 22.0, 21.1, 19.9, 19.7.

Example 17 7-Fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-1-methyl-2-oxo-2, 3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

Combine 3-(3-bromophenyl)-4-isopropyl-4H-1,2,4-triazole (0.067g, 0.25mmol), Pd ₂ (dba) ₃ (0.038g, 0.042mmol), Xant -Phos (0.024g, 0.042mmol) and Cs ₂ CO ₃ (0.14g, 0.42mmol) were added to 7-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H in turn -Benzo[b]azepine-8-carboxamide (0.050g, 0.21mmol) in 1,4-dioxane (25mL) solution, reflux and stir for reaction overnight, the reaction solution is concentrated to dryness, then the column layer Analytical purification (methanol/dichloromethane (v/v)=3/100) gave the title compound as a yellow solid (0.075g, 84.1%).

MS(ESI,pos.ion)m/z:422.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.65 (s, 1H), 8.87 (s, 1H), 8.01 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.64 (d,J=6.3Hz,1H),7.56(t,J=7.9Hz,1H),7.35(t,J=8.2Hz,2H),4.56–4.32(m,1H), 3.26(s,3H) , 2.72 (t, J = 6.8 Hz, 2H), 2.17 (d, J = 6.5 Hz, 2H), 2.10 (d, J = 6.5 Hz, 2H), 1.44 (d, J = 6.6 Hz, 6H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 172.2, 162.9, 157.9, 155.4, 152.7, 142.7, 140.6, 140.5, 140.2, 140.2, 139.7, 130.0, 128.4, 124.7, 124.2, 124.2, 123.8, 123.7, 121.5, 120.42, 117.3, 117.1, 48.0, 35.2, 33.0, 29.6, 28.2, 23.7.

Example 18 7-Fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-2-oxo-2,3,4,5 -Tetrahydro-1H-benzo[b]azepine-8-carboxamide

The first step is the synthesis of 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

The methanol solution of ammonia (15mL, 105mmol, 7mol/L) and 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)azepine-8-carboxylic acid Methyl ester (0.55g, 2.32mmol) was sequentially added to the reaction flask, stirred overnight at 70°C, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=3/100) The title compound was a white solid (0.45 g, 87.0%).

MS (ESI, pos.ion) m/z: 223.2 [M+H] ⁺ .

The second step 7-fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-2-oxo-2,3,4,5 Synthesis of -tetrahydro-1H-benzo[b]azepin-8-carboxamide

Combine 3-(3-bromophenyl)-4-isopropyl-4H-1,2,4-triazole (0.13g, 0.49mmol), Pd ₂ (dba) ₃ (0.082g, 0.090mmol), Xant -Phos (0.052g, 0.090mmol) and Cs ₂ CO ₃ (0.29g, 0.90mmol) were added to 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b ] Azepine-8-carboxamide (0.10g, 0.45mmol) in 1,4-dioxane (30mL) solution, reflux and stir the reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/ Dichloromethane (v/v)=3/100) gave the title compound as a yellow solid (0.080 g, 43.6%).

MS(ESI,pos.ion)m/z:408.2[M+H] ⁺ ;

1H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.61 (s, 1H), 9.64 (s, 1H), 8.87 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 8.2 Hz,1H),7.55(t,J=7.9Hz,1H),7.37–7.31(m,2H),7.24(d,J=6.4Hz,1H),4.56–4.32(m,1H),2.75(t ,J=6.5Hz,2H), 2.16(d,J=5.4Hz,2H), 1.44(d,J=6.7Hz,6H), 1.24(d,J=9.4Hz,2H);

_{13C NMR (151MHz, DMSO-d 6} ): δ (ppm) 173.6, 163.0, 156.8, 155.2, 152.7, 142.7, 139.7, 139.6, 139.5, 135.8, 130.0, 128.4, 124.7, 123.3, 123.2, 122.8, 121.4, 120.4 ,117.8,117.6,48.0,33.1,30.1,27.9,23.7.

Example 19 N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-fluoro-2-oxo-1,2, 3,4-tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (44.0mg, 0.05mmol), Xant-Phos (33.5mg, 0.057mmol), Cs ₂ CO ₃ (330.0mg, 1.01mmol) and 2-bromo-6-(4-cyclopropyl) -1,2,4-triazol-3-yl)pyridine (130.3mg, 0.491mmol) was added sequentially to 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-methan Amide (102.4mg, 0.49mmol) in 1,4-dioxane (15mL) solution, nitrogen protection, 100 ℃ stirring reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane ( v/v) = 1/20) to obtain the title compound as a yellow solid (80.0 mg, 41.4%). MS(ESI,pos.ion)m/z:393.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.72 (s, 1H), 10.28 (s, 1H), 8.65 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.03 (t,J=8.0Hz,1H), 7.86(d,J=7.6Hz,1H), 7.26(d,J=10.4Hz,1H), 7.17(d,J=6.2Hz,1H), 4.23–4.16 (m, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.47 (d, J = 7.3 Hz, 2H), 1.01 (d, J = 7.5 Hz, 2H), 0.95 (d, J = 4.1 Hz ,2H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 170.3, 169.6, 163.5, 160.6, 156.0, 154.4, 153.6, 152.6, 151.3, 149.9, 146.1, 145.5, 140.0, 139.5, 135.4, 135.4, 129.7, 129.6, 122.7, 122.5, 119.3, 116.1, 116.0, 115.9, 114.6, 49.1, 30.2, 29.1,25.2,7.7.

Example 20 6-Fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-2-oxo-1,2,3,4 -Tetrahydroquinoline-7-carboxamide

Pd ₂ (dba) ₃ (44.0mg, 0.05mmol), Xant-Phos (33.5mg, 0.057mmol), Cs ₂ CO ₃ (330.0mg, 1.01mmol) and 3-(3-bromophenyl)-4- Isopropyl-4H-1,2,4-triazole (133.3mg, 0.505mmol) was added sequentially to 6-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide (130.0mg, 0.62mmol) in 1,4-dioxane (15mL) solution, protected by nitrogen, stirred overnight at 100°C, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v /v) = 1/20) to obtain the title compound as a yellow solid (55.3 mg, 22.5%). MS(ESI,pos.ion)m/z:394.3[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.58 (s, 1H), 10.26 (s, 1H), 8.86 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 10.2 Hz, 1H), 7.11 (d, J = 6.1 Hz ,1H),4.51–4.40(m,1H),2.95(t,J=7.5Hz,2H),2.49–2.44(m,2H),1.44(s,3H),1.43(s,3H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 170.4, 163.2, 155.7, 153.3, 152.7, 142.7, 139.6, 135.3, 135.3, 130.0, 129.3, 129.2, 128.4, 124.7, 123.3, 123.1, 121.4, 120.4, 116.1, 115.9, 115.8, 48.0, 30.1, 25.1,23.7.

Example 21 7-Fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-oxo-2,3, 4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

The 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (0.13g, 0.49mmol), Pd ₂ (dba) ₃ (0.082g, 0.090mmol), Xant-Phos (0.052g, 0.090mmol) and Cs ₂ CO ₃ (0.29g, 0.90mmol) were added to 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[ b] Azepine-8-carboxamide (0.10g, 0.45mmol) in 1,4-dioxane (10mL) solution, reflux and stir the reaction overnight, the reaction solution is concentrated to dryness, and then purified by column chromatography (methanol /Dichloromethane (v/v)=3/100) to obtain the title compound as a yellow solid (0.090 g, 49.0%). MS(ESI,pos.ion)m/z:409.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.80 (s, 1H), 9.66 (s, 1H), 8.87 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.03 (t,J=8.0Hz,1H),7.91(d,J=7.6Hz,1H),7.35(d,J=10.4Hz,1H),7.30(d,J=6.4Hz,1H),5.78–5.58 (m, 1H), 2.77 (t, J = 6.3 Hz, 2H), 2.17 (dd, J = 12.0, 5.8 Hz, 4H), 1.44 (d, J = 6.6 Hz, 6H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 173.4, 163.3, 157.5, 155.0, 151.3, 150.2, 146.7, 143.7, 140.2, 139.9, 139.8, 136.0, 135.9, 123.0, 122.8, 122.7, 119.7, 117.9, 117.6, 114.9, 48.4, 33.2, 30.2, 27.8, 23.7.

Example 22 7-Fluoro-N-(6-(4-(1-hydroxyprop-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1- Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

Combine 2-(3-(6-bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)-1-propanol (0.089g, 0.32mmol), Pd ₂ (dba) ₃ (0.058g, 0.063mmol), Xant-Phos (0.036g, 0.063mmol) and Cs ₂ CO ₃ (0.21g, 0.63mmol) were added to 7-fluoro-1-methyl-2-oxo-2, 3,4,5-tetrahydro-1H-benzo[b]azepin-8-carboxamide (0.075g, 0.32mmol) in 1,4-dioxane (30mL) solution, reflux and stir overnight The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=5/100) to obtain the title compound as a yellow solid (0.035 g, 25.1%).

MS(ESI,pos.ion)m/z:439.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.89 (s, 1H), 8.78 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz ,1H),7.89(d,J=7.6Hz,1H),7.68(d,J=6.3Hz,1H),7.36(d,J=10.4Hz,1H),5.62–5.51(m,1H),4.99 (t,J=5.4Hz,1H),3.63-3.52(m,2H), 3.27(s,3H), 2.73(t,J=6.8Hz,2H), 2.18(d,J=6.6Hz,2H) ,2.10(d,J=6.4Hz,2H),1.43(d,J=6.9Hz,3H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 172.0, 163.4, 157.6, 156.0, 151.3, 150.8, 146.9, 144.3, 140.9, 140.3, 140.1, 124.5, 123.3, 119.9, 117.3, 117.1, 114.8, 64.9, 53.8, 35.3, 33.1, 29.6, 28.2, 18.1.

Example 23 N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-1-methyl-2-oxo -2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

With 2-bromo-6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine (0.084g, 0.32mmol), Pd ₂ (dba) ₃ (0.058g, 0.063mmol) ), Xant-Phos (0.036g, 0.063mmol) and Cs ₂ CO ₃ (0.21g, 0.63mmol) were added to 7-fluoro-1-methyl-2-oxo-2,3,4,5-tetra Hydrogen-1H-benzo[b]azepine-8-carboxamide (0.075g, 0.32mmol) in 1,4-dioxane (30mL) solution, reflux and stir for reaction overnight, the reaction solution is concentrated to dryness, Then it was purified by column chromatography (methanol/dichloromethane (v/v)=3/100) to obtain the title compound as a yellow solid (0.089 g, 66.7%).

MS(ESI,pos.ion)m/z:421.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.86 (s, 1H), 8.65 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.05 (t, J = 8.0 Hz ,1H),7.86(d,J=7.6Hz,1H), 7.67(d,J=6.3Hz,1H), 7.35(d,J=10.4Hz,1H), 4.69-4.01(m,1H), 3.26 (s, 3H), 2.73 (t, J = 6.9 Hz, 2H), 2.18 (t, J = 6.6 Hz, 2H), 2.14-2.04 (m, 2H), 1.05-0.98 (m, 2H), 0.95 ( d, J=4.2Hz, 2H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 172.5, 163.9, 158.1, 156.5, 153.2, 151.9, 146.6, 146.1, 141.4, 141.3, 140.8, 140.8, 140.6, 125.0, 124.9, 123.9, 123.8, 119.9, 117.8, 117.6, 115.2, 35.8, 33.6, 30.2, 29.5, 28.7, 8.2.

Example 24 N-(6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-3-oxo-3,4- Dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (45.0mg, 0.049mmol), Xant-Phos (33.2mg, 0.057mmol), Cs ₂ CO ₃ (320.0mg, 0.98mmol) and 2-bromo-6-(4-cyclopentyl) -4H-1,2,4-triazol-3-yl)pyridine (130.0mg, 0.495mmol) was added to 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] Oxazine-6-carboxamide (0.21g, 1.00mmol) in 1,4-dioxane (15mL) solution, under nitrogen protection, stirred at 100°C for overnight reaction, the reaction solution was concentrated to dryness, then Purification by column chromatography (methanol/dichloromethane (v/v) = 1/20) gave the title compound as a white solid (45.0 mg, 34.6%).

MS(ESI,pos.ion)m/z:423.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.93 (s, 1H), 10.52 (s, 1H), 8.82 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.02 (t,J=8.0Hz,1H), 7.86(d,J=7.6Hz,1H), 7.29(d,J=7.0Hz,1H), 7.09(d,J=11.1Hz,1H), 5.68–5.58 (m, 1H), 3.17 (d, J = 4.3 Hz, 2H), 2.17 (d, J = 7.1 Hz, 2H), 1.80 (d, J = 2.3 Hz, 4H), 1.67 (d, J = 3.5 Hz ,2H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 165.0, 163.1, 157.0, 154.6, 151.5, 150.2, 149.7, 149.5, 146.6, 143.7, 140.2, 126.4, 119.7, 118.2, 118.1, 117.4, 114.9, 106.1, 105.8, 68.5, 48.5, 48.0, 23.6, 19.9.

Example 25 N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-2-oxo-2,3, 4,5-tetrahydro-1H-benzo[b]azepine-8-carboxamide

The first step is the synthesis of 6-bromopicolinic hydrazide

Add hydrazine hydrate (2.36g, 46.3mmol, 98%) to a solution of methyl 6-bromopicolinate (5.00g, 23.1mmol) in ethanol (50mL), stir at reflux for 1 hour, filter the reaction solution, and collect the filter cake The title compound was obtained as a white solid (4.40 g, 88.0%).

MS (ESI, pos.ion) m/z: 216.2 [M+H] ⁺ .

The second step is the synthesis of (Z)-N'-(6-bromopicolinoyl)-N,N-dimethyl hydrazide amide

DMFDMA (9.71g, 81.46mmol) was added to a solution of 6-bromopicolinic hydrazide (4.40g, 20.36mmol) in acetonitrile (50mL), and the reaction was stirred overnight under reflux. The reaction solution was concentrated to dryness to obtain the title compound as a yellow solid (5.52g, 100.0%).

MS (ESI, pos.ion) m/z: 271.2 [M+H] ⁺ .

The third step is the synthesis of 2-bromo-6-(4-cyclopropyl-1,2,4-triazol-3-yl)pyridine

Cyclopropylamine (4.63g, 81.1mmol) and acetic acid (1.83g, 30.4mmol) were added to (Z)-N'-(6-bromopicolinoyl)-N,N-dimethylformamide ( 5.50g, 20.3mmol) in acetonitrile (50mL) solution, reflux and stir the reaction for 5 hours, the reaction solution was concentrated to dryness, and then purified by column chromatography (ethyl acetate/petroleum ether (v/v)=80/100) to obtain the title The compound is a yellow solid (2.03 g, 37.7%).

MS (ESI, pos.ion) m/z: 265.2 [M+H] ⁺ .

The fourth step N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-2-oxo-2,3, Synthesis of 4,5-Tetrahydro-1H-benzo[b]azepin-8-carboxamide

The 2-bromo-6-(4-cyclopropyl-1,2,4-triazol-3-yl)pyridine (0.20g, 0.76mmol), Pd ₂ (dba) ₃ (0.14g, 0.15mmol), Xant-Phos (0.088g, 0.15mmol) and Cs ₂ CO ₃ (0.50g, 1.53mmol) were added to 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[ b] Azepine-8-carboxamide (0.17g, 0.76mmol) in 1,4-dioxane (30mL) solution, reflux and stir the reaction overnight, the reaction solution is concentrated to dryness, and then purified by column chromatography (methanol /Dichloromethane (v/v)=3/100) to obtain the title compound as a yellow solid (0.12 g, 39.0%).

MS(ESI,pos.ion)m/z:407.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.76 (s, 1H), 9.65 (s, 1H), 8.65 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.04 (t,J=8.0Hz,1H), 7.87(d,J=7.6Hz,1H), 7.34(d,J=10.5Hz,1H), 7.29(d,J=6.5Hz,1H), 4.24–4.15 (m,1H), 2.76(t,J=6.5Hz,2H), 2.24–2.08(m,4H), 1.07–0.90(m,4H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 173.4, 163.4, 157.5, 155.0, 152.7, 151.3, 146.1, 145.5, 140.1, 139.9, 139.8, 136.0, 135.9, 123.0, 123.0, 122.8, 122.6, 119.3,117.8,117.6,114.7,33.2,30.2,29.1,27.8,7.7.

Example 26 7-Fluoro-N-(6-(4-(1-hydroxyprop-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2- Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-carboxamide

Combine 2-(3-(6-bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)-1-propanol (0.095g, 0.34mmol), Pd ₂ (dba) ₃ (0.062g, 0.067mmol), Xant-Phos (0.039g, 0.067mmol) and Cs ₂ CO ₃ (0.22g, 0.67mmol) were added to 7-fluoro-2-oxo-2,3,4,5 in sequence -Tetrahydro-1H-benzo[b]azepin-8-carboxamide (0.075g, 0.34mmol) in 1,4-dioxane (30mL) solution, reflux and stir for 5 hours, the reaction solution is concentrated To dryness, then column chromatography purification (methanol/dichloromethane (v/v) = 5/100) to obtain the title compound as a yellow solid (0.070 g, 48.9%).

MS(ESI,pos.ion)m/z:425.2[M+H] ⁺ ;

1H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.75 (s, 1H), 9.65 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.03 ( t,J=8.0Hz,1H),7.89(d,J=7.6Hz,1H), 7.35(d,J=10.5Hz,1H), 7.30(d,J=6.4Hz,1H), 5.57(dd, J = 11.9, 5.8 Hz, 1H), 4.94 (t, J = 5.4 Hz, 1H), 3.63 (dd, J = 9.5, 5.1 Hz, 2H), 2.77 (t, J = 6.6 Hz, 2H), 2.22- 2.08 (m, 4H), 1.44 (d, J = 6.9 Hz, 3H);

_{13C NMR (151MHz, DMSO-d 6} ): δ (ppm) 173.5, 163.4, 157.0, 155.4, 151.3, 150.8, 146.9, 144.3, 140.2, 139.9, 139.9, 136.0, 136.0, 123.0, 123.0, 122.8, 122.7, 119.9 ,117.9,117.7,114.8,64.9,53.8,33.2,30.2,27.8,18.1.

Example 27 7-Fluoro-3-oxo-N-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-bis Hydrogen-2H-benzo[b][1,4]oxazine-6-carboxamide

Pd ₂ (dba) ₃ (38.2mg, 0.047mmol), Xant-Phos (33.2mg, 0.057mmol), Cs ₂ CO ₃ (120.0mg, 0.37mmol) and 2-bromo-6-(4-phenyl- 4H-1,2,4-triazol-3-yl)pyridine (88.2mg, 0.29mmol) was added to 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][ 1,4] oxazine-6-carboxamide (60.6mg, 0.28mmol) in 1,4-dioxane (15mL) solution, protected by nitrogen, stirred and reacted overnight at 100°C, the reaction solution was concentrated to dryness, then column Purification by chromatography (methanol/dichloromethane (v/v) = 1/20) gave the title compound as a white solid (78.5 mg, 63.3%).

MS (ESI, pos.ion) m/z: 431.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.91 (s, 1H), 9.59 (d, J = 7.9 Hz, 1H), 8.93 (s, 1H), 8.19 (d, J = 8.3 Hz ,1H),7.97(t,J=8.0Hz,1H),7.65(d,J=7.5Hz,1H),7.52-7.47(m,3H),7.46-7.41(m,2H),7.32(d, J = 7.3 Hz, 1H), 7.04 (d, J = 11.7 Hz, 1H), 4.70 (s, 2H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 164.2, 162.0, 162.0, 157.2, 154.8, 151.4, 151.1, 147.5, 147.4, 146.4, 145.4, 140.1, 135.2, 129.5, 129.4, 126.6, 124.5, 124.5, 120.5, 117.2, 117.2, 115.8, 115.7, 115.0, 105.2, 104.9, 67.2.

Example 28 7-Fluoro-N-(6-(4-(1-hydroxyprop-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4H- Benzo[b]imidazo[1,5-d][1,4]oxazine-8-carboxamide

The first step is the synthesis of 1-(5-carbamoyl-2,4-difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester

1,2-Dimethoxyethane (150mL) and 2-oxoethyl acetate (12.85g, 62.93mmol) were added to 5-amino-2,4-difluoro-benzamide (8.88g, 51.6mmol) in a methanol (300mL) solution, return to 80°C under reflux and stir the reaction for 12 hours, cool to room temperature, and then add 1-(isocyanomethylsulfonyl)-4-methyl-benzene (30.500g, 156.22mmol) ) And potassium carbonate (14.40g, 103.2mmol), the reaction was stirred at room temperature for 24 hours, the reaction solution was concentrated to dryness, water (100mL) was added, and then dichloromethane (300ml, 150mL, 150mL) was added for extraction, the organic phase was anhydrous sulfuric acid After drying with sodium, the organic phase was concentrated to dryness under reduced pressure, and then purified by column chromatography (ethyl acetate/petroleum ether (v/v)=100/100) to obtain the title compound as a yellow solid (6.00 g, 41.4%).

MS(ESI,pos.ion)m/z:281.2[M+H] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ): δ (ppm) 8.16 (s, 1H), 7.87 (m, 3H), 7.80 (s, 1H), 7.65 (t, J = 10.1Hz, 1H), 4.21 – 4.10 (m, 1H), 3.70 (s, 3H).

The second step 1-(2,4-difluoro-5-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl )Phenyl)-1H-imidazole-5-carboxylic acid methyl ester

With 2-bromo-6-(4-isopropyl-1,2,4-triazol-3-yl)pyridine (1.00g, 3.74mmol), Pd ₂ (dba) ₃ (0.34g, 0.36mmol), Xant-Phos (0.21g, 0.36mmol) and Cs ₂ CO ₃ (2.30g, 7.05mmol) were added to 1-(5-carbamoyl-2,4-difluorophenyl)-1H-imidazole-5- Methyl formate (1.00g, 3.56mmol) in 1,4-dioxane (50mL) solution, reflux and stir the reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/ v)=15/100) to obtain the title compound as a white solid (1.50 g, 50.0%).

MS(ESI,pos.ion)m/z:468.5[M+H] ⁺ ;

The third step 2,4-difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4- Synthesis of triazol-3-yl)pyridin-2-yl)benzamide

At -2℃, DIBAL (3.00ml, 4.50mmol, 1.5mol/L toluene solution) was added to 1-(2,4-difluoro-5-((6-(4-isopropyl-4H-1, 2,4-Triazol-3-yl)pyridin-2-yl)carbamoyl)phenyl)-1H-imidazole-5-carboxylic acid methyl ester (0.50mg, 1.07mmol) in THF (6mL) solution at room temperature The reaction was stirred for 12 hours, 450 mL ice water was added, and then extracted with dichloromethane (100 mL×2), the organic phase was washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography Purification (methanol/dichloromethane (v/v)=10/100) gave the title compound as a white liquid (0.28 g, 58.7%).

MS (ESI, pos.ion) m/z: 440.5 [M+H] ⁺ .

The fourth step 7-fluoro-N-(6-(4-(1-hydroxyprop-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4H- Synthesis of Benzo[b]imidazo[1,5-d][1,4]oxazine-8-carboxamide

Sodium hydride (0.045g, 1.10mmol, 60%) was added to 2,4-difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-N-(6-(4- Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzamide (0.14g, 0.32mmol) in DMF (4mL) solution, stirred at 60°C for 3 hours, The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=10/100) to obtain the title compound as a white solid (0.050 g, 50.0%).

MS(ESI,pos.ion)m/z:420.5[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.83 (s, 1H), 8.92-8.81 (m, 1H), 8.57 (s, 1H), 8.31 (d, J = 6.9 Hz, 1H) , 8.22 (d, J = 8.3 Hz, 1H), 8.05 (t, J = 8.0 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 10.9 Hz, 1H), 6.99 (d,J=8.3Hz,1H), 5.65(m,1H), 5.38(d,J=7.4Hz,2H), 1.47-1.37(m,6H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 162.5, 158.2, 156.5, 151.0, 149.7, 146.3, 143.3, 139.8, 132.9, 129.7, 123.8, 121.6, 120.7, 119.3, 117.9, 114.4, 106.4, 62.5, 48.0, 23.2.

Example 29 N-(6-(4-Cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-4H-benzo[b]imidazo [1,5-d][1,4]oxazine-8-carboxamide

The first step 1-(5-((6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2,4-di Synthesis of fluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester

With 2-bromo-6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine (189.5mg, 0.714mmol), Pd ₂ (dba) ₃ (74.0mg, 0.08mmol) ), Xant-Phos (43.5mg, 0.08mmol) and potassium carbonate (213.0mg, 1.54mmol) were added to 1-(5-carbamoyl-2,4-difluorophenyl)-1H-imidazole-5- In a solution of methyl formate (200.0mg, 0.7115mmol) in 1,4-dioxane (10mL) under nitrogen protection, the reaction was stirred overnight at 100°C, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloro Methane (v/v)=1/20) gave the title compound as a yellow solid (230.1 mg, 69.5%).

MS(ESI,pos.ion)m/z:466.1[M+H] ⁺ ;

The second step N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,4-difluoro-5-(5-( Synthesis of hydroxymethyl)-1H-imidazol-1-yl)benzamide

Add DIBAL-H (2.9mL, 4.4mmol, 1.5mmol/L) to 1-(5-((6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)carbamoyl)-2,4-difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester (200.1mg, 0.43mmol) in THF (15mL, 98%) solution, nitrogen protection, The reaction was stirred at -10°C for 1 hour. The reaction solution was added to 300 mL of water, then extracted with ethyl acetate (200 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane ( v/v)=1/10) to obtain the title compound as a yellow solid (140.0 mg, 74.3%).

MS (ESI, pos.ion) m/z: 438.2 [M+H] ⁺ .

The third step N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-4H-benzo[b]imidazo Synthesis of [1,5-d][1,4]oxazine-8-carboxamide

The N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,4-difluoro-5-(5-(hydroxymethyl (Base)-1H-imidazol-1-yl)benzamide (130.2mg, 0.297mmol), sodium hydride ((70.0mg -1.75mmol, 60mass%) and DMF (5ml) were added to the reaction flask, stirred at 60℃ for 3 hours The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=1/20) to obtain the title compound as a white solid (20.1 mg, 16.2%).

MS(ESI,pos.ion)m/z:418.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.86 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.33-8.25 (m, 2H), 8.06 (t, J = 7.9Hz, 1H), 7.87 (d, J = 7.5Hz, 1H), 7.28 (d, J = 10.9Hz, 1H), 7.00 (s, 1H), 5.39 (s, 2H), 4.19 (s, 1H),1.02(d,J=6.2Hz,2H),0.95(s,2H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 163.0, 158.6, 156.9, 152.7, 151.4, 149.1, 149.0, 146.1, 145.6, 140.1, 133.3, 124.3, 122.0, 121.1, 119.4, 118.7, 118.6, 118.3,114.6,111.0,106.9,106.7,64.4,63.0,53.6,49.1,29.0,7.7.

Example 30 N-(6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-4H-benzo[b]imidazo [1,5-d][1,4]oxazine-8-carboxamide

The first step 1-(5-((6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2,4-di Synthesis of fluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester

With 2-bromo-6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridine (461.5mg, 1.57mmol), Pd ₂ (dba) ₃ (144.0mg, 0.16mmol) ), Xant-Phos (93.2mg, 0.16mmol) and potassium carbonate (413.0mg, 2.98mmol) were added to 1-(5-carbamoyl-2,4-difluorophenyl)-1H-imidazole-5- Methyl formate (410.0mg, 1.458mmol) in 1,4-dioxane (15mL) solution, protected by nitrogen, stirred overnight at 100℃, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloro Methane (v/v) = 1/20) gave the title compound as a yellow solid (512.5 mg, 72.1%).

MS(ESI,pos.ion)m/z:494.1[M+H] ⁺ ;

The second step N-(6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,4-difluoro-5-(5-( Synthesis of hydroxymethyl)-1H-imidazol-1-yl)benzamide

Add DIBAL-H (4.9mL, 7.4mmol, 1.5mmol/L) to 1-(5-((6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)carbamoyl)-2,4-difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester (300.1mg, 0.61mmol) in THF (15mL, 98%) solution, nitrogen protection, The reaction was stirred at -10°C for 1 hour. The reaction solution was added to 300 mL of water, and then extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloro Methane (v/v)=1/10) to obtain the title compound as a yellow solid (98.5 mg, 34.7%).

MS (ESI, pos.ion) m/z: 466.4 [M+H] ⁺ .

The third step N-(6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-4H-benzo[b]imidazo Synthesis of [1,5-d][1,4]oxazine-8-carboxamide

The N-(6-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,4-difluoro-5-(5-(hydroxymethyl (Base)-1H-imidazol-1-yl)benzamide (70.2mg, 0.15mmol), sodium hydride (35.0mg 0.87mmol, 60mass%) and DMF (5ml) were added to the reaction flask and stirred at 60°C for 3 hours. The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (31.5 mg, 46.9%).

MS(ESI,pos.ion)m/z:446.4[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.81 (s, 1H), 8.82 (s, 1H), 8.58 (s, 1H), 8.32 (d, J = 6.9 Hz, 1H), 8.23 (d,J=8.2Hz,1H), 8.05(t,J=8.0Hz,1H), 7.88(d,J=7.6Hz,1H), 7.29(d,J=11.0Hz,1H), 7.00(s ,1H),5.70–5.61(m,1H),5.39(s,2H),2.17(d,J=7.2Hz,2H),1.80(d,J=2.1Hz,4H),1.67(s,2H) ；

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 162.8, 159.6, 158.7, 157.0, 151.4, 151.0, 149.2, 149.1, 146.7, 144.0, 140.2, 138.5, 133.3, 124.3, 122.0, 121.2, 120.0, 118.7, 118.5, 118.4, 118.4, 114.8, 112.0, 108.9, 106.9, 106.7, 63.0, 57.4, 33.7, 24.0.

Example 31 N-(6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-4H-benzo[ b]imidazo[1,5-d][1,4]oxazine-8-carboxamide

The first step is the synthesis of 2-bromo-6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridine

Add cyclopropylmethylamine (2.10g, 29.5mmol) and acetic acid (0.66g, 11.1mmol) to (Z)-N'-(6-bromopicolinoyl)-N,N-dimethylformhydrazide Amide (2.00g, 7.38mmol) in acetonitrile (50mL) solution, reflux and stir the reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (ethyl acetate/petroleum ether (v/v)=80/100) to obtain The title compound was a yellow solid (0.80 g, 39.0%).

MS (ESI, pos.ion) m/z: 279.2 [M+H] ⁺ .

The second step 1-(5-((6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)-2 ,4-Difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester

The 2-bromo-6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (0.22g, 0.78mmol), Pd ₂ (dba) ₃ (0.13 g, 0.14mmol), Xant-Phos (0.082g, 0.14mmol) and Cs ₂ CO ₃ (0.46g, 1.42mmol) were added to 1-(5-carbamoyl-2,4-difluorophenyl)- 1H-imidazole-5-carboxylic acid methyl ester (1.00g, 3.56mmol) in 1,4-dioxane (30mL) solution, reflux and stir the reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/ Dichloromethane (v/v)=3/100) gave the title compound as a yellow solid (0.21 g, 62.0%). MS(ESI,pos.ion)m/z:480.2[M+H] ⁺ ;

The third step N-(6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,4-difluoro-5- Synthesis of (5-(hydroxymethyl)-1H-imidazol-1-yl)-benzamide

At -10℃, add DIBAL (5.56ml, 8.34mmol, 1.5mol/L toluene solution) to 1-(5-((6-(4-(cyclopropylmethyl)-4H-1,2,4 -Triazol-3-yl)pyridin-2-yl)carbamoyl)-2,4-difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester (0.20g, 0.42mmol) in THF (20mL) In the solution, the reaction was stirred at -10°C for 2 hours, methanol (3mL) and brine (30mL) were added, and then extracted with dichloromethane (50mL×2). The organic phase was washed with brine (100mL×2) and dried over anhydrous sodium sulfate After filtering, the filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=5/100) to obtain the title compound as a white solid (0.13 g, 69.0%).

MS(ESI,pos.ion)m/z:452.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.06 (s, 1H), 8.72 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.04 (q, J = 7.7 Hz ,2H),7.93(d,J=7.6Hz,1H),7.90–7.76(m,2H),7.05(s,1H),5.06(t,J=5.3Hz,1H), 4.49(d,J= 7.4 Hz, 2H), 4.37 (d, J = 5.3 Hz, 2H), 1.23-1.17 (m, 1H), 0.50-0.43 (m, 2H), 0.34 (d, J = 4.2 Hz, 2H).

The fourth step N-(6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-fluoro-4H-benzo[ b] Synthesis of imidazo[1,5-d][1,4]oxazine-8-carboxamide

Sodium hydride (0.057g, 1.44mmol, 60%) was added to N-(6-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)pyridine-2- Yl)-2,4-difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-benzamide (0.13g, 0.29mmol) in DMF (20ml) solution, 60℃ The reaction was stirred for 3 hours, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=4/100) to obtain the title compound as a white solid (0.060 g, 48.3%).

MS(ESI,pos.ion)m/z:432.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.89 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.31 (d, J = 6.9 Hz, 1H), 8.22 (d,J=8.2Hz,1H), 8.05(t,J=8.0Hz,1H), 7.93(d,J=7.6Hz,1H), 7.29(d,J=10.9Hz,1H), 7.00(s ,1H),5.40(s,2H),4.50(d,J=7.4Hz,2H),1.23(s,1H),0.51-0.43(m,2H),0.34(d,J=4.3Hz,2H) ；

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 162.9, 159.0, 156.5, 151.4, 150.5, 149.2, 149.0, 146.7, 146.6, 140.3, 133.3, 124.3, 122.0, 121.1, 119.3, 118.7, 118.6, 118.4, 118.3, 114.8, 106.9, 106.6, 63.0, 50.4, 12.3, 4.2.

Example 32 N-(3-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)-7-fluoro-4H-benzo[b]imidazole And [1,5-d][1,4]oxazine-8-carboxamide

The first step is the synthesis of 3-bromobenzoyl hydrazide

Add hydrazine hydrate (2.38g, 46.5mmol, 98%) to a solution of methyl 3-bromobenzoate (5.00g, 23.3mmol) in ethanol (50mL), stir at reflux for 1 hour, filter the reaction solution, and collect the filter cake The title compound was obtained as a white solid (4.00 g, 80.0%).

MS (ESI, pos.ion) m/z: 215.2 [M+H] ⁺ .

The second step is the synthesis of (Z)-N'-(3-bromobenzoyl)-N,N-dimethyl hydrazide amide

DMFDMA (4.43g, 37.2mmol) was added to a solution of 3-bromobenzoyl hydrazide (2.00g, 9.30mmol) in acetonitrile (50mL), and the reaction was stirred overnight under reflux. The reaction solution was concentrated to dryness to obtain the title compound as a yellow solid (2.52g, 100.0%).

MS (ESI, pos.ion) m/z: 270.2 [M+H] ⁺ .

The third step is the synthesis of 3-(3-bromophenyl)-4-(cyclopropylmethyl)-4H-1,2,4-triazole

Add cyclopropylmethylamine (2.11g, 29.6mmol) and acetic acid (0.66g, 11.1mmol) to (Z)-N'-(3-bromobenzoyl)-N,N-dimethylformhydrazide Amide (2.00g, 7.40mmol) in acetonitrile (50mL) solution, reflux and stir the reaction overnight, the reaction solution is concentrated to dryness, and then purified by column chromatography (ethyl acetate/petroleum ether (v/v)=80/100) to obtain The title compound was a yellow solid (0.65 g, 32.0%).

MS(ESI,pos.ion)m/z:278.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 8.74 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.8 Hz ,1H),7.52(t,J=7.9Hz,1H),3.95(d,J=7.2Hz,2H),1.90–1.02(m,1H),0.56–0.46(m,2H),0.33–0.25( m,2H).

The fourth step 1-(5-((3-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)carbamoyl)-2,4- Synthesis of difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester

Combine 3-(3-bromophenyl)-4-(cyclopropylmethyl)-4H-1,2,4-triazole (0.30g, 1.10mmol), Pd ₂ (dba) ₃ (0.18g, 0.20 mmol), Xant-Phos (0.12g, 0.20mmol) and Cs ₂ CO ₃ (0.65g, 2.00mmol) were sequentially added to 3-(5-carbamoyl-2,4-difluoro-phenyl)imidazole-4 -Methyl formate (0.28g, 0.99mmol) in 1,4-dioxane (30mL) solution, reflux and stir the reaction overnight, the reaction solution is concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v /v)=3/100) to obtain the title compound as a yellow solid (0.28 g, 59.0%).

MS(ESI,pos.ion)m/z:479.2[M+H] ⁺ ;

The fifth step N-(3-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)-2,4-difluoro-5-(5- Synthesis of (hydroxymethyl)-1H-imidazol-1-yl)benzamide

At -10°C, LiAlH ₄ (0.20g, 5.20mmol) was added to 1-(5-((3-(4-(cyclopropylmethyl)-4H-1,2,4-triazole-3- (Yl)phenyl)carbamoyl)-2,4-difluorophenyl)-1H-imidazole-5-carboxylic acid methyl ester (0.25g, 0.52mmol) in THF (20mL) solution, stirring at -10℃, reaction 2 After hours, water (10mL) was added, and then extracted with ethyl acetate (50mL×2), the organic phase was washed with brine (100mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography ( Methanol/dichloromethane (v/v) = 6/100) to obtain the title compound as a white solid (0.15 g, 63.7%).

MS (ESI, pos.ion) m/z: 451.2 [M+H] ⁺ .

The sixth step N-(3-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)-7-fluoro-4H-benzo[b]imidazole Synthesis of [1,5-d][1,4]oxazine-8-carboxamide

Sodium hydride (0.062g, 1.55mmol, 60%) was added to N-(3-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)- 2,4-Difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)benzamide (0.14g, 0.31mmol) in DMF (20ml) solution, stirred at 60℃ for 3 hours The reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v)=4/100) to obtain the title compound as a white solid (0.080 g, 59.8%).

MS(ESI,pos.ion)m/z:431.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.65 (s, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.29 (d, J = 6.9 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 10.7 Hz ,1H),7.00(s,1H),5.39(s,2H),3.98(d,J=7.3Hz,2H),1.17–1.11(m,1H),0.55–0.49(m,2H),0.32( q, J = 4.7 Hz, 2H); ¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 162.4, 158.8, 156.3, 153.0, 148.8, 148.7, 145.4, 139.7, 133.3, 130.0, 128.4, 124.3, 122.0, 121.4, 121.1, 121.1, 120.2, 119.3, 119.1, 118.1, 118.1, 106.9, 106.6, 62.9, 49.6, 11.8, 4.3.

Example 33 7-Fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-4H-benzo[b]imidazo[1, 5-d][1,4]oxazine-8-carboxamide

The first step 1-(2,4-difluoro-5-((3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)carbamoyl)phenyl ) Synthesis of -1H-imidazole-5-carboxylic acid methyl ester

Combine 3-(3-bromophenyl)-4-isopropyl-4H-1,2,4-triazole (320.6mg, 1.20mmol), Pd ₂ (dba) ₃ (100.0mg, 0.11mmol), Xant -Phos (103.2mg, 0.17mmol) and Cs ₂ CO ₃ (693.0mg, 2.17mmol) were added to 1-(5-carbamoyl-2,4-difluorophenyl)-1H-imidazole-5-carboxylic acid Methyl ester (300.0mg, 1.06mmol) in 1,4-dioxane (15mL) solution, reflux and stir the reaction overnight, the reaction solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) ) = 1/20) to obtain the title compound as a yellow solid (205.5 mg, 41.2%).

MS (ESI, pos.ion) m/z: 467.2 [M+H] ⁺ .

The second step 2,4-difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-N-(3-(4-isopropyl-4H-1,2,4- Synthesis of triazol-3-yl)phenyl)benzamide

_{LiAlH 4} (232.5mg, 6.16mmol) was added to 1-(2,4-difluoro-5-((3-(4-isopropyl-4H-1,2,4-triazol-3-yl) (Phenyl)carbamoyl)phenyl)-1H-imidazole-5-carboxylic acid methyl ester (273.5mg, 0.58mmol) in THF (15mL) solution under nitrogen protection, stirring at -10°C for 1 hour, adding water (300mL ), then extracted with ethyl acetate (200 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/10) to obtain the title compound as Yellow solid (235.0 mg, 91.4%).

MS (ESI, pos.ion) m/z: 439.1 [M+H] ⁺ .

The third step 7-fluoro-N-(3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-4H-benzo[b]imidazo[1, Synthesis of 5-d][1,4]oxazine-8-carboxamide

2,4-Difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-N-(3-(4-isopropyl-4H-1,2,4-triazole -3-yl)phenyl)benzamide (210.2mg, 0.48mmol), sodium hydride (105.0mg 2.65mmol, 60mass%) and DMF (5ml) were added to the reaction flask in sequence, and the reaction was stirred at 60°C for 3 hours. The solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (31.5 mg, 46.9%).

MS(ESI,pos.ion)m/z:419.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.66 (s, 1H), 8.87 (s, 1H), 8.57 (s, 1H), 8.28 (d, J = 6.6 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 10.7 Hz ,1H),7.00(s,1H),5.39(s,2H),4.53–4.42(m,1H),1.45(d,J=6.5Hz,6H);

¹³ C NMR (151MHz, DMSO-d ₆ ): δ (ppm) 162.5, 158.4, 156.7, 152.7, 148.8, 148.7, 142.7, 139.7, 133.3, 130.1, 128.5, 124.7, 124.3, 122.1, 121.3, 121.1, 120.3, 119.3, 119.2, 118.2, 106.9, 106.7, 62.9, 48.0, 23.7.

Example 34 7-Fluoro-N-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4H-benzo[b]imidazo[ 1,5-d][1,4]oxazine-8-carboxamide

The first step 1-(2,4-difluoro-5-((6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl) Synthesis of phenyl)-1H-imidazole-5-carboxylic acid methyl ester

Combine 2-bromo-6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridine (305.6mg, 1.01mmol), Pd ₂ (dba) ₃ (100.0mg, 0.11mmol) , Xant-Phos (103.2mg, 0.17mmol) and Cs ₂ CO ₃ (693.0mg, 2.17mmol) were sequentially added to 1-(5-carbamoyl-2,4-difluorophenyl)-1H-imidazole-5 -Methyl formate (260.0mg, 0.92mmol) in 1,4-dioxane (15mL) solution, nitrogen protection, 100 ℃ stirring reaction overnight, the reaction solution was concentrated to dryness, and then column chromatography purification (methanol / two Chloromethane (v/v) = 1/20) to obtain the title compound as a yellow solid (360.2 mg, 77.67%).

MS(ESI,pos.ion)m/z:502.0[M+H] ⁺ ;

1H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.63 (s, 1H), 8.96 (s, 1H), 8.18 (dd, J = 16.4, 7.3 Hz, 2H), 7.97 (dd, J = 17.0 ,8.7Hz,2H),7.87(d,J=6.3Hz,1H),7.73(t,J=10.1Hz,1H),7.54(d,J=7.5Hz,1H),7.46(dt,J=18.4 ,7.6Hz,5H), 3.72(s,3H).

The second step 2,4-difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-N-(6-(4-phenyl-4H-1,2,4-tri Synthesis of (azol-3-yl)pyridin-2-yl)benzamide

Add DIBAL-H (5.5mL, 8.3mmol, 1.5mmol/L) to 1-(2,4-difluoro-5-((6-(4-phenyl-4H-1,2,4-triazole -3-yl)pyridin-2-yl)carbamoyl)phenyl)-1H-imidazole-5-carboxylic acid methyl ester (370.2mg, 0.73mmol) in THF (15mL, 98%) solution, nitrogen protection,- The reaction was stirred at 10°C for 1 hour. The reaction solution was added to 300 mL of water, and then extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane). (v/v)=1/10) to obtain the title compound as a yellow solid (63.2 mg, 18.1%).

MS (ESI, pos.ion) m/z: 474.1 [M+H] ⁺ .

The third step 7-fluoro-N-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4H-benzo[b]imidazole[1 Synthesis of ,5-d][1,4]oxazine-8-carboxamide

2,4-Difluoro-5-(5-(hydroxymethyl)-1H-imidazol-1-yl)-N-(6-(4-phenyl-4H-1,2,4-triazole- 3-yl)pyridin-2-yl)benzamide (60.2mg, 0.12mmol), sodium hydride (25.0mg 0.62mmol, 60mass%) and DMF (5ml) were added to the reaction flask, and the reaction was stirred at 60°C for 3 hours. The solution was concentrated to dryness, and then purified by column chromatography (methanol/dichloromethane (v/v) = 1/20) to obtain the title compound as a white solid (23.2 mg, 40.2%).

MS(ESI,pos.ion)m/z:454.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 10.23 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 8.25 (t, J = 8.1 Hz, 2H), 7.99 (t,J=8.0Hz,1H),7.57(d,J=7.5Hz,1H),7.46(dt,J=7.7,4.2Hz,5H),7.23(d,J=11.3Hz,1H),6.99 (s,1H),5.39(s,2H);

¹³ C NMR (101MHz, DMSO-d ₆ ): δ (ppm) 162.3, 159.2, 156.8, 151.5, 151.4, 149.5, 149.4, 146.2, 145.5, 140.0, 135.0, 133.3, 129.7, 129.3, 126.4, 124.3, 122.0, 121.2, 121.0, 118.6, 117.6, 117.4, 115.2, 106.8, 106.6, 63.0.

Biological test

The analytical LC/MS/MS system includes Agilent 1200 series vacuum degasser, binary pump, orifice automatic sampler, column thermostat, Agilent G6430 triple quadrupole mass spectrometer with electrospray ionization (ESI) source. The quantitative analysis is carried out in MRM mode, and the mass spectrometry conditions are shown in Table A:

Table A

Multiple reaction detection scan	490.2→383.1
Fragmentation voltage	230V
Capillary voltage	55V
Dryer temperature	350°C
Atomizer	40psi
Dryer flow rate	10L/min

Waters XBridge C18, 2.1×50mm, 3.5μM chromatographic column was used for analysis, and 5μL of sample was injected. Analysis conditions: the mobile phase is water (containing 0.1% formic acid and 2m ammonium formate) (A) and 0 methanol (containing 0.1% formic acid and 2m ammonium formate) (B). The flow rate is 0.4 mL/min. The mobile phase gradient is shown in Table B:

Table B

time	Gradient of mobile phase B
0.5min	5%
1.0min	95%
2.2min	95%
2.3min	5%
5.0min	termination

In addition, Agilent 6330 series LC/MS/MS mass spectrometers are used for analysis, equipped with G1312A binary pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS mass spectrometer uses ESI ion source. Use standard solutions to optimize MS conditions for each analyte. During the analysis, a Waters XBridge C18 column was used, the specification was: 50×2.1mm I.D., 3.5μM. The mobile phase is water (containing 5mM ammonium acetate and 0.1% formic acid) (A): Acetonitrile (containing 5mM ammonium acetate and 0.1% formic acid) solution (B) (70:30, v/v); the flow rate is 0.6mL/min; Keep the column temperature at room temperature; inject 20 μL of sample.

Example A Stability in human and rat liver microsomes

Place human or rat liver microsomes in a polypropylene test tube and incubate in double holes. A typical incubation mixture includes human or rat liver microsomes (0.5mg protein/mL), target compound (1μM) and a total volume of 15μL NADPH (2.0mM) potassium phosphate buffer (PBS, 100mM, pH 7.4) ), the test compound is dissolved in DMSO and diluted with PBS to make the final DMSO solution concentration of 0.05%. Incubate in a water bath open to air at 37°C. After pre-incubating for 3 minutes, add protein to the mixture and start the reaction. At different time points (0, 5, 10, 15, 30 and 60 minutes), the same volume of ice-cold acetonitrile was added to terminate the reaction. The samples were stored at -80°C until LC/MS/MS analysis.

The concentration of the compound in the incubation mixture of human or rat liver microsomes is determined by the method of LC/MS/MS.

The parallel incubation test used denatured microsomes as a negative control, incubated at 37°C, and the reaction was terminated at different time points (0, 15 and 60 minutes).

Verapamil (1 μM) was used as a positive control, incubated at 37°C, and the reaction was terminated at different time points (0, 5, 10, 15, 30 and 60 minutes).

data analysis

For each reaction, the concentration of the compound in human or rat liver microsomes incubation (expressed as a percentage) is plotted as a percentage relative to the zero time point to infer the intrinsic liver clearance in vivo CLint (ref.:Naritomi Y) ,Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animal 24 and human position 24 Disposal 24, 2001, 316 .). The results are shown in Table 1. Table 1 shows the experimental results of the stability of the compounds provided in some examples of the present invention in human and rat liver microparticles.

Table 1 Experimental results of the stability of the compounds provided in some examples of the present invention in human and rat liver microparticles

It can be seen from Table 1 that when the compound of the present invention is incubated in human and rat liver microsomes, the compound of the present invention shows suitable stability.

Example B Pharmacokinetic evaluation of the compound of the present invention after oral or intravenous injection in mice, rats, dogs and cynomolgus monkeys

The pharmacokinetic studies of the compounds of the invention in mice, rats, dogs or cynomolgus monkeys were evaluated. The compound of the present invention is administered with 5%-10% DMSO, 5%-10% Kolliphor HS15 and 80%-90% physiological saline solution, or 5%-10% DMSO, 60% PEG400 and 35% physiological saline solution. medicine. For intravenous administration, animals are given a dose of 0.5 or 1 mg/kg. For oral dosage (p.o.), it is 2.5 mg/kg or 5 mg/kg for rats, mice, dogs and cynomolgus monkeys. Blood was collected at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours (additional 0.083 hours for the intravenous group) (0.05 mL for mice, 0.05 mL for rats, 0.3 for dogs and cynomolgus monkeys) mL), and centrifuge at 3,000 or 4,000 rpm for 10 minutes. The plasma solution was collected and stored at -20°C or -70°C until the aforementioned LC/MS/MS analysis. The results are shown in Table 2. Table 2 shows the experimental results of the pharmacokinetic characteristics of the compounds provided in some examples of the present invention in rats.

Table 2 Experimental results of the pharmacokinetic characteristics of the compounds provided in some examples of the present invention in rats

It can be seen from Table 2 that when the compound provided by the present invention is administered by intravenous injection or oral administration, the compound of the present invention exhibits good pharmacokinetic properties, is well absorbed and has an ideal half-life (T _1/2 ) and Higher oral bioavailability (F).

Example C Kinase activity test

The effectiveness of the compounds disclosed in the present invention as protein kinase inhibitors can be evaluated by the following experiments.

General description of the kinase test

The kinase test is done by detecting myelin base protein (MBP) ^{incorporated into γ-33 P-ATP.} Prepare 20μg/ml MBP (Sigma#M-1891) Tris Buffered Salt Solution (TBS; 50mM Tris pH 8.0, 138mM NaCl, 2.7mM KCl), and coat the high binding white 384-well plate (Greiner ), 60μL per well. Incubate for 24 hours at 4°C. Then the plate was washed 3 times with 100 μL TBS. Kinase reaction in a total volume of 34μL kinase buffer (prepared as needed, for example, 5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl ₂ , 1mM DTT, 0.02% TritonX -100). The compound was dissolved in DMSO and added to each well. The final concentration of the compound in the DMSO solution was 1%. At least two tests are performed for each compound. For example, the final concentration of the enzyme is 10 nM or 20 nM. Add unlabeled ATP (10 μM) and γ- ³³ P labeled ATP (2×10 ⁶ cpm per well, 3000 Ci/mmol) to start the reaction. The reaction was carried out with shaking at room temperature for 1 hour. The 384-well plate was washed with 7× PBS, and then 50μL of scintillation fluid per well was added. Check the results with a Wallac Trilux counter. For those skilled in the art, this is only one of many detection methods, and other methods are also possible.

Test method described above can be obtained IC ₅₀ and / or suppression of the inhibitory constant K _i. IC ₅₀ is defined as the test conditions, the concentration of the compound inhibiting 50% of enzyme activity. Use 1/2log dilution factor to make a curve containing 10 concentration points, and estimate IC ₅₀ value (for example, make a typical curve with the following compound concentration: 3μM, 1μM, 0.3μM, 0.1μM, 0.03μM, 0.01μM , 0.003μM, 0.001μM, 0.0003μM, 0μM).

ASK1(h)

ASK1(h) is incubated with 8mM MOPS pH 7.0, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [γ-33P-ATP] (specific activity is about 500cpm/pmol, the concentration is determined according to requirements) . The reaction is initiated by adding the MgATP mixture. After incubating for 40 minutes at room temperature, the reaction was terminated by adding a 3% phosphoric acid solution. Then 10 μL of the reaction was spotted on a P30 filter pad, washed 3 times in 75 mM phosphoric acid for 5 minutes each time, washed once in methanol, and then dried and scintillated counted.

The kinase test in the present invention was done by Eurofins, a British company. See Table 3 for the kinase activity test results.

In addition, the kinase activity of the compound can be ^{detected by KINOMEscan TM} , which is based on the quantitative detection of the compound using an active site-directed competitive binding assay. The test is carried out by combining with three compounds, namely DNA labeling enzyme, immobilized ligand and detection compound, and qPCR is performed to detect the competitiveness of the compound and the immobilized ligand by DNA labeling.

In most experiments, the kinase-labeled T7 bacteriophage strain was cultured from the E. coli host derived from the BL21 strain. After the E. coli in the logarithmic growth phase was infected with the T7 bacteriophage, the bacteriophage was incubated at 32°C with shaking to remove the lysate by centrifugal filtration Cell debris, the remaining kinases are transferred to HEK-293 cells and DNA-labeled for qPCR detection. After streptavidin-coated particles are treated with biotinylated small molecule ligands for 30 minutes at room temperature, affinity resins can be produced for kinase experiments. After the ligand particles are blocked by excess biotin, the ^{unbound ligand is washed with a blocking solution (SEABLOCK TM} (Pierce), 1% bovine serum albumin, 0.05% Tween 20, 1 mM DTT) to reduce non-specific binding. By combining the kinase in 1× binding buffer (20% SEABLOCK ^TM , 0.17× phosphate buffer solution, 0.05% Tween 20, 6mM DTT), the ligand affinity particle and the test compound undergo a binding reaction. All reactions are Carry out in a 96-well plate, the final volume of the reaction is 0.135mL, incubate with shaking at room temperature for 1 hour, add washing buffer (1×phosphate buffer solution, 0.05% Tween 20) to wash the affinity particles, add elution buffer to resuspend (1×phosphate buffer solution, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand), incubate with shaking at room temperature for 30 minutes, and detect the kinase concentration in the eluate by qPCR.

Table 3 ASK1 kinase test results of the compounds provided in some examples of the present invention

Example number	IC50(nM)
Example 1	19
Example 2	29
Example 3	26
Example 6	90
Example 8	49
Example 10	147
Example 12	161
Example 13	63
Example 28	31

It can be seen from Table 3 that the compound of the present invention shows better ASK1 kinase inhibitory activity in the kinase experiment.

In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structure, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above-mentioned terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine the different embodiments or examples and the features of the different embodiments or examples described in this specification without contradicting each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can comment on the above-mentioned The embodiment undergoes changes, modifications, substitutions and modifications.

Claims (15)

1. A compound that is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolism of a compound represented by formula (I) Product, pharmaceutically acceptable salt or its prodrug,

   

   among them:

   W is CH or N;

   R ¹ is hydrogen, phenyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein The phenyl group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 3-8 membered heterocyclic group can be independently optionally substituted by 1, 2 , 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _3-6 cycloalkyl group substituted;

   R is

   

   

   R ² is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group may be independently optionally selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, 1, 2, 3, 4 or 5 _{C 1-3} alkyl group, cyano group, C 1-3 alkyl group, C _1-3 haloalkyl group and C _1-3 alkoxy group;

   Each R ^{x is} independently hydrogen, deuterium, halogen atom, amino group, cyano group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl;

   Each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino , C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Group, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group may be independently optionally selected from deuterium, halogen atom, hydroxyl, oxygen Substituted (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups;

   Each Y is independently a bond, -O-, -CR ^c R ^d -or -(CR ^e R ^f ) ₂ -;

   R ^a , R ^b , R ^c , ^Rd , R ^e and R ^f are each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 3-8 membered heterocyclic group may independently optionally By 1, 2, 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups are substituted.
2. The compound according to claim 1, wherein R ¹ is hydrogen, phenyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 3- 6-membered heterocyclic group, wherein the phenyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl and 3-6 membered heterocyclic ring The group can be independently optionally selected by 1, 2, 3, 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, cyano, C _1-3 alkyl, C _1-3 haloalkane Group, C _1-3 alkoxy and C _3-6 cycloalkyl group.
3. The compound according to claim 1 or 2, wherein R ¹ is hydrogen, phenyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy Group, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, Tetrahydropyranyl or morpholinyl, wherein the phenyl, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, and Alkaline groups can be independently optionally selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, cyano, methyl, ethyl, Trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl and cyclobutyl groups are substituted.
4. The compound according to any one of claims 1-3, wherein R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally selected from deuterium, 1,2, 3, 4 or 5 a halogen atom, a hydroxyl group, oxo (= O), amino, nitro, cyano, C _1-3 alkyl, substituted C _1-3 haloalkyl group and a C _1-3 alkoxy group.
5. The compound according to any one of claims 1 to 4, wherein R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy Group, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine Group, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuryl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl , Difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl can be independently optionally substituted by 1, 2, 3, 4 Or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy , Ethoxy and isopropyloxy groups.
6. The compound according to any one of claims 1-5, wherein each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein said C _1-4 alkyl, C _1-4 haloalkyl , C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclic group can be independently optionally substituted by 1, 2, 3 , 4 or 5 selected from deuterium, halogen atom, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy The group is substituted.
7. The compound according to any one of claims 1 to 6, wherein each R ^{3 is} independently hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoro Methyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl Group, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl can be independently selected Ground cover 1, 2, 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl , Difluoromethyl, methoxy, ethoxy and isopropyloxy groups.
8. The compound according to any one of claims 1-7, wherein each R ^{x is} independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, trifluoromethyl, two Fluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl or cyclobutyl.
9. The compound of claims 1-8 according to any one, wherein ^{R a, R b, R c} , R d, R e and R ^{f are} each independently hydrogen, deuterium, a halogen atom, a hydroxyl group, an amino group, a cyano group, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl or 3-6 membered hetero Cyclic group, wherein the C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 alkylamino group, C _3-6 ring Alkyl and 3-6 membered heterocyclic groups may be independently optionally selected from deuterium, halogen atoms, hydroxyl, oxo (=O), amino, nitro, cyano, 1, 2, 3, 4, or 5 C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy groups are substituted.
10. The compound of any one of claims 1-9, wherein ^{R a, R b, R c} , R d, R e and R ^{f are} each independently hydrogen, deuterium, a halogen atom, a hydroxyl group, an amino group, a cyano group, Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, Methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuran Group, tetrahydropyranyl or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, Difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, The glycidyl group, tetrahydrofuranyl group, tetrahydropyranyl group and morpholinyl group may be independently optionally substituted by 1, 2, 3, 4 or 5 selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo ( =O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy groups.
11. The compound according to any one of claims 1-10, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound having one of the following structures Substance, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:

    

    

    
12. A pharmaceutical composition comprising the compound of any one of claims 1-11; and

    The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
13. Use of the compound according to any one of claims 1-11 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing, treating or alleviating ASK1 regulated diseases in patients.
14. The use according to claim 13, wherein the disease regulated by ASK1 is autoimmune disease, inflammation, cardiovascular disease, heart and kidney disease, fibrotic disease, respiratory disease, liver disease or neurodegenerative disease.
15. The use according to claim 14, wherein the cardiovascular disease is diabetes, diabetic nephropathy or other diabetic complications;

    The fibrotic disease is pulmonary fibrosis or renal fibrosis;

    The respiratory disease is chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis or acute lung injury;

    The liver disease reported is chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury, or primary biliary liver hardening.