WO2018090869A1

WO2018090869A1 - Amide derivative and use thereof in medicine

Info

Publication number: WO2018090869A1
Application number: PCT/CN2017/110326
Authority: WO
Inventors: 杨新业; 潘圣强; 马发城; 张英勋; 陈红; 舒帆; 熊绍辉; 林继华; 王晓军; 张英俊
Original assignee: 广东东阳光药业有限公司
Priority date: 2016-11-16
Filing date: 2017-11-10
Publication date: 2018-05-24
Also published as: CN110036005B; CN110036005A

Abstract

Disclosed are an amide derivative and a use thereof in medicine. In particular, disclosed are a novel amide derivative for use as an ASK1 activity modulator, and a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the amide derivative, as well as the use of the derivative in the preparation of medicine for the treatment of ASK1-mediated diseases and/or conditions. Further disclosed are a pharmaceutical composition containing the compound and a method for treating ASK1-mediated diseases and/or conditions by using the compound or the pharmaceutical composition.

Description

Amide derivatives and their application in medicine

Field of invention

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

Background of the invention

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase (MAP3Ks) family, and MAP3Ks can activate c-Jun N. N-terminal protein kinase (JNK) and 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, also known as mitogen-activated protein kinase kinase 5 (MAPKKK5, MAP3K5), contains 1375 amino acid residues, which constitutes 11 kinase subdomains and one at the N-terminus and The serine/threonine kinase region in the middle of the side molecule of the C-terminal coiled-coil region (Wang et al. J. Biol. Chem. 1996, 271, 31607-31611, Ichijo et al. Science. 1997, 275, 90-94; Tobiume Et al. Biochem. Biophys. Res. Commun. 1997, 239, 905-910). ASK1 can be activated by a variety of stimuli such as oxidative stress, reactive oxygen species, endotoxin, tumor necrosis factor-α, endoplasmic reticulum stress, and intracellular calcium concentration.

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

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

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

Summary of invention

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

Specifically:

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

among them:

Q is hydrogen or C _1-3 alkyl;

X ¹ is C(R ¹ ) or N;

X ² is C(R ² ) or N;

X ³ is C(R ³ ) or N;

X ⁴ is C(R ⁴ ) or N;

X ⁵ is C(R ⁵ ) or N;

X ⁶ is C(R ⁶ ) or N;

X ⁷ is CH or N;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, halogen, hydroxy, decyl, amino, nitro, cyano, alkyl, haloalkyl, alkoxy, alkyl a thio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the hydroxy group, thiol group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, The cycloalkyl, heterocyclic, aryl and heteroaryl groups may be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, and a cyano group. Substituted by a group of a base, an alkyl group, a halogenated alkyl group, and an alkoxy group; or

R ² and R ³ or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic, heterocyclic, heteroaryl or benzene ring, wherein said carbocyclic, heterocyclic, heteroaryl and phenyl ring may be independently optionally substituted with 1, 2 or 3 substituents selected from halogen, hydroxy, oxo (= O), amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, and a C ₁ Substituted by a group of _-6 alkoxy groups;

The E ring is an aromatic ring or a heteroaryl ring;

Each R ^x is independently hydrogen, a halogen atom, a hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkyl a thiol group, a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-10 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein the C _{1 - 6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-10 membered heterocyclic The C _6-12 aryl group and the 5-10 membered heteroaryl group may be independently, optionally, 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, and C. Substituted by a group of _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy; or

The adjacent two R ^x and the atom to which they are attached form a C _4-8 carbocyclic ring, a 5-8 membered heterocyclic ring, a 5-10 membered heteroaryl ring or a benzene ring; wherein the C _4-8 carbon The ring, the 5-8 membered heterocyclic ring, the 5-10 membered heteroaryl ring and the benzene ring may be independently, optionally, 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, Substituted by a group of a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, and a C _1-6 haloalkoxy group;

Each R ^y is independently hydrogen, a halogen atom, hydroxyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy ;

R ^z is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _6-12 aryl or 5-10 a heteroaryl group, wherein R ^{z is} optionally 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, a C _1-6 alkane group Substituted by a group of a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;

m is 1, 2, 3, 4 or 5; and

n is 1, 2, 3 or 4.

In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, halo, hydroxy, decyl, amino, nitro, cyano, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _{6 a -12} aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _1-6 The alkylthio group, the C _1-6 alkylamino group, the C _3-8 cycloalkyl group, the 3-8 membered heterocyclic group, the C _6-12 aryl group and the 5-10 membered heteroaryl group may be independently optionally 1, 3, 4 or 5 substituents selected from halogen, hydroxy, oxo (= O), amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy Substituted by a group; or

R ² and R ³ or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _4-8 carbocyclic ring, a 5-8 membered heterocyclic ring, a 5-6 membered heteroaryl ring or a benzene ring, wherein The C _4-8 carbocyclic ring, the 5-8 membered heterocyclic ring, the 5-6 membered heteroaryl ring and the benzene ring may be independently, optionally, 1, 2 or 3 selected from a halogen atom, a hydroxyl group, an oxo group (=O), Substituted by a group of an amino group, a nitro group, a cyano group, a C _1-3 alkyl group, a C _1-3 haloalkyl group, and a C _1-3 alkoxy group.

In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, halo, hydroxy, decyl, amino, nitro, cyano, C _1-3 alkane , C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic, C _{a 6-10} aryl group or a 5-6 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C _1-3 alkyl group, C _1-3 haloalkyl group, C _1-3 alkoxy group, C _{1- 3} alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl may be independently and optionally 1 , 2, 3, 4 or 5 are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and Substituted by a C _1-3 alkoxy group; or

R ² and R ³ or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _4-6 carbocyclic ring, a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring or a benzene ring, wherein The C _4-6 carbocyclic ring, the 5-6 membered heterocyclic ring, the 5-6 membered heteroaryl ring and the benzene ring may be independently, optionally, 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, and oxo. Substitution with (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, and isopropyloxy groups.

In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thia An azole group, wherein the hydroxy group, hydrazino group, amino group, methyl group, ethyl group, n-propyl group, isopropyl group, difluoromethyl group, methoxy group, isopropyloxy group, methylthio group, methylamino group, Dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyran Base, right? Polinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl The thiazolyl and thiadiazolyl may be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano Substituted by a group of methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy groups.

In some embodiments, the E ring is a C _6-12 aromatic ring or a 5-10 membered heteroaryl ring.

In other embodiments, the E ring is a C _6-10 aromatic ring or a 5-6 membered heteroaryl ring.

In some embodiments, the E ring is a benzene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a furan ring, an oxazole ring, Oxadiazole ring, thiophene ring, thiazole ring or thiadiazole ring.

In some embodiments, each R ^{x is} independently hydrogen, halo, hydroxy, decyl, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy a C _1-4 alkylthio group, a C _1-4 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein The C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 alkylthio group, C _1-4 alkylamino group, C _3-6 cycloalkyl group, 3 The -6 membered heterocyclic group, the C _6-10 aryl group and the 5-6 membered heteroaryl group may be independently optionally 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, and a nitrate. Substituted by a group of a cyano group, a cyano group, a C _1-3 alkyl group, a C _1-3 haloalkyl group, and a C _1-3 alkoxy group;

The adjacent two R ^x and the atom to which they are attached form a C _4-6 carbocyclic ring, a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring or a benzene ring; wherein the C _4-6 carbon The ring, 5-6 membered heterocyclic ring, 5-6 membered heteroaryl ring and benzene ring may be independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyanide Base, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy and tri Substituted by a fluoromethoxy group.

In other embodiments, each R ^{x is} independently hydrogen, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tri Fluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine Base, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, A Base, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazole , imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently optional Ground cover 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Substituted by groups of methoxy, ethoxy and isopropyloxy groups.

In some embodiments, each R ^{y is} independently hydrogen, halo, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;

R ^z is C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, C _6-10 aryl or 5-6 a heteroaryl group, wherein R ^{z is} optionally 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, and a C _1-3 alkane. Substituted by a group of a C _1-3 haloalkyl group, a C _1-3 alkoxy group, a C _3-6 cycloalkyl group, and a 3-6 membered heterocyclic group.

In other embodiments, each R ^{y is} independently hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl Base, difluoromethyl, methoxy, isopropyloxy, trifluoromethoxy or difluoromethoxy;

R ^z is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein R ^{z is} optionally 1, 2, 3, 4 or 5 are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, Fluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazine Substituted by a group of a propyl group, a propylene oxide group, a tetrahydrofuranyl group, a tetrahydropyranyl group and a morpholinyl group.

In one aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) of the invention, or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate thereof And solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

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

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

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

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

Detailed description of the invention

Definitions and general terms

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is a _C1-6 alkylamino group or a ( _C1-6 alkyl)amino group. In other embodiments, the alkylamino group is a C _1-3 alkylamino group or a (C _1-3 alkyl)amino group. Such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino, and the like. The alkylamino group can be optionally substituted with one or more substituents described herein.

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

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

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

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

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

Base, diaza

Base

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The term "therapeutically effective amount" as used herein refers to an amount of a compound of formula (I) sufficient to achieve the stated effect. Thus, a therapeutically effective amount of a compound of formula (I) for treating a condition modulated by ASK1 will be an amount sufficient to treat a condition modulated by ASK1.

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

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

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

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

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

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

Description of the compounds of the invention

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

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

among them:

Q is hydrogen or C _1-3 alkyl;

X ¹ is C(R ¹ ) or N;

X ² is C(R ² ) or N;

X ³ is C(R ³ ) or N;

X ⁴ is C(R ⁴ ) or N;

X ⁵ is C(R ⁵ ) or N;

X ⁶ is C(R ⁶ ) or N;

X ⁷ is CH or N;

R ¹ is hydrogen, a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a hetero An aryl group wherein the hydroxy group, mercapto group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are independently optional The ground is substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group and an alkoxy group;

R ² is hydrogen, a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a hetero An aryl group wherein the hydroxy group, mercapto group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are independently optional The ground is substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group and an alkoxy group;

R ³ is hydrogen, a halogen atom, a hydroxyl group, a decyl group, an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a hetero An aryl group wherein the hydroxy group, mercapto group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are independently optional The ground is substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group and an alkoxy group;

R ⁴ is hydrogen, a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a hetero An aryl group wherein the hydroxy group, mercapto group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are independently optional The ground is substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group and an alkoxy group;

R ⁵ is hydrogen, a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a hetero An aryl group wherein the hydroxy group, mercapto group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are independently optional The ground is substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group and an alkoxy group;

R ⁶ is hydrogen, a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a cycloalkyl group, a heterocyclic group, an aryl group or a hetero An aryl group wherein the hydroxy group, mercapto group, amino group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkylamino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are independently optional The ground is replaced by 1, 2, 3, 4 or 5 groups selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, an alkyl group, a halogenated alkyl group and an alkoxy group;

The E ring is an aromatic ring or a heteroaryl ring;

R ^z is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _6-10 aryl or 5-10 a heteroaryl group, wherein R ^{z is} optionally 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, a C _1-6 alkane group Substituted by a group of a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;

m is 1, 2, 3, 4 or 5; and

n is 1, 2, 3 or 4.

In some embodiments, R ¹ is hydrogen, halogen, hydroxy, decyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1 a -6} alkylthio group, a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein said Hydroxy, mercapto, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 naphthenic The base, 3-8 membered heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from a halogen atom, a hydroxyl group, or an oxo group ( Substituted by a group of =O), amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy;

R ² is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, the fluorenyl group, the amino group, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 The heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, Substituted by a group of a nitro group, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, and a C _1-6 alkoxy group;

R ³ is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, the fluorenyl group, the amino group, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 The heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, Substituted by a group of a nitro group, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, and a C _1-6 alkoxy group;

R ⁴ is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, the fluorenyl group, the amino group, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 The heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, Substituted by a group of a nitro group, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, and a C _1-6 alkoxy group;

R ⁵ is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, the fluorenyl group, the amino group, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 The heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, Substituted by a group of a nitro group, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, and a C _1-6 alkoxy group;

R ⁶ is hydrogen, a halogen atom, a hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C _6-12 aryl group or a 5-10 membered heteroaryl group, wherein the hydroxy group, the fluorenyl group, the amino group, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 The heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, Substituted by a group of a nitro group, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, and a C _1-6 alkoxy group;

In other embodiments, R ¹ is hydrogen, halo, hydroxy, decyl, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _{a 1-3} alkylthio group, a C _1-3 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein Hydroxy, mercapto, amino, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 ring The alkyl group, the 3-6 membered heterocyclic group, the C _6-10 aryl group and the 5-6 membered heteroaryl group may be independently, optionally, 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine and iodine. , hydroxy, oxo (= O), amino, nitro, cyano, C _1-3 alkyl, substituted C _1-3 haloalkyl group and a C _1-3 alkoxy group;

R ² is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio a C _1-3 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein the hydroxy group, the thiol group, the amino group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 The heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (= Substituted by a group of O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy;

R ³ is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio a C _1-3 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein the hydroxy group, the thiol group, the amino group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 The heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (= Substituted by a group of O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy;

R ⁴ is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio a C _1-3 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein the hydroxy group, the thiol group, the amino group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 The heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (= Substituted by a group of O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy;

R ⁵ is hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio a C _1-3 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein the hydroxy group, the thiol group, the amino group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 The heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (= Substituted by a group of O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy;

R ⁶ is hydrogen, a halogen atom, a hydroxyl, mercapto, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio a C _1-3 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-10 aryl group or a 5-6 membered heteroaryl group, wherein the hydroxy group, the thiol group, the amino group, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 The heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (= Substituted by a group of O), amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy; or

In still other embodiments, R ¹ is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl , difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolium Or pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein said hydroxy, thiol, amino, methyl, ethyl Base, n-propyl, isopropyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazole The group, the triazolyl group, the tetrazolyl group, the pyridyl group, the pyrimidinyl group, the pyridazinyl group, the furyl group, the oxazolyl group, the oxadiazolyl group, the thienyl group, the thiazolyl group and the thiadiazolyl group may be independently and optionally 1, 2, 3, 4 or 5 are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoro Substituted by a group of methyl, methoxy, ethoxy, and isopropyloxy groups;

R ² is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, A Oxyl, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, methyl, ethyl, n-propyl, iso Propyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetra Azole , pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently, optionally selected 1, 2, 3, 4 or 5 From fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and Substituted by a group of isopropyloxy groups;

R ³ is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, A Oxyl, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, methyl, ethyl, n-propyl, iso Propyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetra Azole , pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently, optionally selected 1, 2, 3, 4 or 5 From fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and Substituted by a group of isopropyloxy groups;

R ⁴ is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, A Oxyl, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, methyl, ethyl, n-propyl, iso Propyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetra Azole , pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently, optionally selected 1, 2, 3, 4 or 5 From fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and Substituted by a group of isopropyloxy groups;

R ⁵ is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, A Oxyl, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, methyl, ethyl, n-propyl, iso Propyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetra Azole The base, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently, optionally 1, 2, 3, 4 or 5 Selected from fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy Substituted with a isopropyloxy group;

R ⁶ is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, A Oxyl, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, methyl, ethyl, n-propyl, iso Propyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetra Azole , pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently, optionally selected 1, 2, 3, 4 or 5 From fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and Substituted by a group of isopropyloxy groups.

In some embodiments, each R ^{x is} independently hydrogen, halo, hydroxy, decyl, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy a C _1-4 alkylthio group, a C _1-4 alkylamino group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a C _6-12 aryl group or a 5-6 membered heteroaryl group, wherein The C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 alkylthio group, C _1-4 alkylamino group, C _3-6 cycloalkyl group, 3 The -6 membered heterocyclic group, the C _6-12 aryl group and the 5-6 membered heteroaryl group may be independently optionally 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, and a nitrate. Substituted by a group of a cyano group, a cyano group, a C _1-3 alkyl group, a C _1-3 haloalkyl group, and a C _1-3 alkoxy group;

The adjacent two R ^x and the atom to which they are attached form a C _4-6 carbocyclic ring, a 5-6 membered heterocyclic ring, a 5-10 membered heteroaryl ring or a benzene ring; wherein the C _4-6 carbon The ring, 5-6 membered heterocyclic ring, 5-10 membered heteroaryl ring and benzene ring may be independently, optionally, 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), Amino, nitro, cyano, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, di Substituted by a group of a fluoromethoxy group and a trifluoromethoxy group.

In other embodiments, each R ^{x is} independently hydrogen, fluoro, chloro, bromo, iodo, hydroxy, decyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tri Fluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine Base, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein the hydroxy, thiol, amino, A Base, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazole , imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently optional The ground cover is 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo (=O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl Substituted by groups of methoxy, ethoxy and isopropyloxy groups.

R ^z is C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, C _6-12 aryl or 5-6 a heteroaryl group, wherein R ^{z is} optionally 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group (=O), an amino group, a nitro group, a cyano group, and a C _1-3 alkane. Substituted by a group of a C _1-3 haloalkyl group, a C _1-3 alkoxy group, a C _3-6 cycloalkyl group, and a 3-6 membered heterocyclic group.

In some embodiments, the invention comprises a stereoisomer, geometric isomer, tautomer, oxynitride, solvate, hydrate, metabolism of a compound of one of the following or a compound of one of the following: a product, an ester, a pharmaceutically acceptable salt or a prodrug thereof, but is in no way limited to:

In one aspect, the present invention relates to a pharmaceutical composition comprising a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a compound of the formula (I) of the present invention, Solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

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

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

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

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

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

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

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

In another aspect, the pharmaceutical compositions of the present invention comprise a compound of formula (I), a compound of the invention and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the compositions of the present invention is effective to detectably reduce or alleviate ASK1-regulated disease in a patient.

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

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

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

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

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

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

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

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

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

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

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

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

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

General synthetic method

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

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

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

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

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

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

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

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

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

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

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

The following abbreviations are used throughout the invention:

CDC1 ₃ deuterated chloroform

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d ₆ deuterated dimethyl sulfoxide

CD ₃ OD deuterated methanol

MeOH methanol

THF tetrahydrofuran

DCM dichloromethane

EtOAc, EA ethyl acetate

PE petroleum ether

Pd/C, Pd-C palladium/carbon

g g

Mg mg

H ₂ O water

M mole per liter

Mol Moore

Mm mmol

mL ml

μL microliter

A typical synthetic procedure for the preparation of the compounds disclosed herein is shown in the synthetic scheme below. Unless otherwise stated, the E ring, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , R ^x , R ^y , R ^z , m, n and Q have the meanings as described herein .

Synthetic scheme

Synthetic scheme 1

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

Synthetic scheme 2

G ₁ and G ₂ are an alkyl group; and M is a halogen.

Compound (2b) can be obtained by reacting compound (2a) with an hydrazine hydrate in an alcohol. In the reaction, the alcohol used includes, but is not limited to, methanol and the like.

The compound (2c) can be reacted with the N,N-dimethylformamide dimethyl acetal by the compound (2b), and the obtained intermediate and an amine (for example, isopropylamine, cyclopropylamine, etc.) are acid (for example, ice). It is obtained by reacting in a solvent in the presence of acetic acid or the like. The reaction is preferably carried out in a solvent inert to the reaction, including but not limited to acetonitrile and the like.

The compound (2d) can be obtained by subjecting the compound (2c) to a carbonylation reaction. In the reaction, the reaction raw material is in a carbon monoxide atmosphere, and the palladium catalyst (palladium catalyst includes, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, etc.) and an amine ( The reaction is carried out in a solvent in the presence of an amine such as, but not limited to, triethylamine or the like, and the solvent used includes, but not limited to, methanol and the like.

The general formula (2e) can be obtained by subjecting the compound (2d) to a hydrolysis reaction, and the hydrolysis reaction can be carried out by referring to "Protective Groups in Organic Synthesis".

Synthetic scheme 3

The F ring is a nitrogen-containing heteroaromatic ring and M is a halogen.

The compound (3c) can be obtained by a coupling reaction of the compound (3a) and the compound (3b) under the action of a catalyst, a ligand and a base. As the catalyst, it includes, but is not limited to, cuprous iodide or the like. As the ligand, it includes, but is not limited to, 8-hydroxyquinaldine and the like. The base includes, but is not limited to, potassium carbonate and the like. The reaction is carried out in a solvent inert to the reaction. Solvents used include, but are not limited to, dimethyl sulfoxide and the like.

The compound (3e) can be obtained by subjecting the compound (3c) and the compound (3d) to a coupling reaction under the action of a catalyst and a ligand, and under basic conditions. As the catalyst, there are, but not limited to, palladium acetate and the like. As the ligand, it includes, but is not limited to, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene and the like. As the base, there are, but not limited to, cesium carbonate and the like. The reaction is carried out in a solvent inert to the reaction, and the solvent used includes, but is not limited to, 1,4-dioxane and the like.

The compound (3f) can be obtained by subjecting the compound (3e) to a deprotection reaction, which can be carried out by referring to "Protective Groups in Organic Synthesis".

detailed description

Example

Example 1: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole Zol-3-yl)pyridine-2-carboxamide

First step 6-bromopyridine-2-formyl hydrazide

Methyl 6-bromopyridine-2-carboxylate (6.9 g, 32 mmol) was dissolved in MeOH (50 mL). The reaction mixture was cooled to room temperature.

The second step 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine

6-Bromopyridine-2-carboxylic acid hydrazide (6.9 g, 32 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (50 mL), and the mixture was warmed to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated evaporated evaporated evaporated evaporated. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water (50 mL) was evaporated, and then diluted with saturated sodium hydrogen carbonate aqueous solution to be diluted with methylene chloride (40 mL×2), and the organic phase was combined and the organic phase was saturated. Washed with brine (40 mL), dried over anhydrous sodium sulfate The obtained residue was purifiedjjjjjlililililililililililili

MS (ESI, pos.) m/z: 267.1 [M+H] ⁺

The third step is 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid methyl ester

2-Bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (2g, 7.5mmol), [1,1'-bis ( under a carbon monoxide atmosphere) Diphenylphosphino)ferrocene]palladium dichloride (109 mg, 0.15 mmol), triethylamine (2.08 mL, 15.0 mmol) was dissolved in methanol (50 mL). The reaction mixture was cooled to room temperature. EtOAc was evaporated (mjjjjjjj ).

MS (ESI, pos. ion) m/z: 247.3 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.52 (d, J = 7.9Hz, 1H), 8.41 (s, 1H), 8.16 (d, J = 7.8Hz, 1H), 8.00 (t, J = 7.9 Hz, 1H), 5.86 - 5.78 (m, 1H), 4.02 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H).

The fourth step 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid

Mixture of methyl 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxylate (1.8 g, 7.3 mmol) in methanol (20 mL) and THF (20 mL) A solution of sodium hydroxide (0.88 g, 22 mmol) in water (20 mL) was added, and then stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. EtOAc (EtOAc) The combined organics were dried with EtOAc EtOAcjjjjjjjj

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 13.40 (s, 1H), 8.92 (s, 1H), 8.34 (d, J = 7.3Hz, 1H), 8.23-8.07 (m, 2H), 5.62–5.56 (m, 1H), 1.50 (d, J = 6.7 Hz, 6H).

Step 5 2-Chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)pyridine

2-Chloro-4-iodopyridine (5 g, 20.9 mmol), cuprous iodide (79 mg, 0.41 mmol), 8-hydroxyquinaldine (132 mg, 0.83 mmol), 4-cyclopropyl -1H-imidazole (4.5 g, 42 mmol), potassium carbonate (7.2 g, 52 mmol) was dissolved in anhydrous dimethyl sulfoxide (20 mL) and warmed to 90 ° C overnight. After the reaction mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc m. . The residue was purified with EtOAc EtOAcjjjjjjj

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.45 (d, J = 5.5Hz, 1H), 7.89 (s, 1H), 7.35 (d, J = 1.8Hz, 1H), 7.25-7.23 (m, 1H), 7.10 (s, 1H), 1.96 - 1.86 (m, 1H), 0.98 - 0.89 (m, 2H), 0.88 - 0.80 (m, 2H).

Step 6 (4-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)carbamic acid tert-butyl ester

2-Chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)pyridine (200 mg, 0.91 mmol), tert-butyl carbamate (127 mg, 1.1 mmol), cesium carbonate 0.74 g, 2.3 mmol), palladium acetate (20 mg, 0.089 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (43 mg, 0.090 mmol) dissolved in anhydrous 1,4- In dioxane (20 mL), the mixture was heated to reflux at 110 ° C and allowed to react overnight. After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Filtered and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 301.3 [M+H] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.31 (d, J = 5.6Hz, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.17 (s, 1H), 6.98 (dd, J=5.6, 2.0 Hz, 1H), 1.95–1.88 (m, 1H), 1.58 (s, 9H), 0.94–0.88 (m, 2H), 0.86–0.76 (m, 2H) .

Step 7 4-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-amine

(4-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)carbamic acid tert-butyl ester (100 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL). Fluorineacetic acid (3 mL, 9 mmol) was stirred at room temperature for 1 hour. After a large portion of the solvent was evaporated under reduced pressure, the residue was evaporated to dryness eluted eluted eluted eluted eluted eluted Dry over sodium sulfate, filter, and concentrate EtOAc. The residue was purified by EtOAc EtOAcjjjjjjj

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.13 (d, J = 5.4Hz, 1H), 7.82 (s, 1H), 7.06 (s, 1H), 6.69-6.67 (m, 1H), 6.46 ( s, 1H), 4.67 (s, 2H), 1.94 - 1.88 (m, 1H), 0.93 - 0.89 (m, 2H), 0.85 - 0.83 (m, 2H).

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

4-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-amine (100 mg, 0.50 mmol), 6-(4-isopropyl-4H-1,2, 4-triazol-3-yl)pyridinecarboxylic acid (127 mg, 0.55 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate (379 mg, 1.0 mmol), diisopropylethylamine (0.4 mL) was dissolved in N,N-dimethylformamide (10 mL). The reaction was quenched with EtOAc (EtOAc)EtOAc. After filtration, the filtrate was evaporated.jjjjjlililililililililililililili

MS (ESI, pos.) m/z: 415.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 10.22 (s, 1H), 8.61-8.55 (m, 2H), 8.50 (s, 1H), 8.40 (t, J = 6.8Hz, 2H), 8.16 ( t, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 7.17 - 7.10 (m, 1H), 5.58 - 5.51 (m, 1H), 1.98 - 1.92 (m, 1H) , 1.78 (d, J = 6.7 Hz, 6H), 0.95 - 0.92 (m, 2H), 0.90 - 0.86 (m, 2H).

Example 2: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole Zol-3-yl)pyridine amide

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

(E)-N'-(6-Bromopyridinyl)-N,N-dimethylformylhydrazide (7.0 g, 26 mmol) was dissolved in a mixed solvent of glacial acetic acid (30 mL) and acetonitrile (90 mL). Cyclopropylamine (10 mL, 144 mmol) was slowly added dropwise, and after the addition was completed, the mixture was warmed to 85 ° C, refluxed, and stirred overnight. The solvent was evaporated under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 30/1)

MS (ESI, pos.) m/z: 266.1 [M+H] ⁺ .

The second step 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine methyl ester

2-Bromo-6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine (6.5 g, 25 mmol), [1,1'-bis (under a carbon monoxide atmosphere) Diphenylphosphino)ferrocene]palladium dichloride (1.5 g, 2.1 mmol) and triethylamine (7 mL, 50.4 mmol) were dissolved in methanol (80 mL) and warmed to 100 ° C overnight. The reaction mixture was cooled to room temperature. EtOAcjjjjjjjj .

MS (ESI, pos.ion) m/z: 245.2 [M+H] ⁺

The third step 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid

A mixed solvent of 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine methyl ester (1.5 g, 6.1 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL) A solution of sodium hydroxide (5 mL, 4 mol/L) was added, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. EtOAc (EtOAc) The combined organics were dried with EtOAc EtOAcjjjjjjjj

MS (ESI, pos. ion) m/z: 231.1 [M+H] ⁺

Fourth step N-(4-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridine amide

4-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-amine (95 mg, 0.47 mmol) and 6-(4-cyclopropyl-4H-1,2,4-triazole -3-yl)picolinic acid (100 mg, 0.43 mmol) was used as a starting material.

MS (ESI, pos. ion) m/z: 413.2 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 10.57 (s, 1H), 8.62 (d, J = 7.8Hz, 1H), 8.57 (s, 1H), 8.40 (d, J = 8.0Hz, 1H) , 8.35 (d, J = 7.5 Hz, 2H), 8.15 (t, J = 7.8 Hz, 1H), 7.99 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 1.94-1.93 ( m, 1H), 1.53-1.51 (m, 1H), 0.95-0.87 (m, 8H).

Example 3: N-(2-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-4-yl)-6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridine amide

First step 4-bromo-2-iodopyridine

Under ice-cooling, a solution of 4-bromopyridin-2-amine (2.0 g, 12 mmol) in dichloromethane (20 mL) was slowly added dropwise t-butyl nitrite (1.5 mL, 13 mmol) and stirred for 5 min. 3.0 g, 12 mmol), stirred at room temperature overnight. The organic layer was washed with saturated brine (80 mL×2) and dried over anhydrous sodium sulfate. Purification by column chromatography (EtOAc/MeOH (EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.21 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 1.4 Hz, 1H), 7.46 (dd, J = 5.3, 1.7 Hz, 1H) .

The second step 4-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)pyridine

4-bromo-2-iodopyridine (1.4g, 4.9mmol) and 4-cyclopropyl-1H-imidazole (2.0g, 18mmol) were used as the starting materials, and the synthesis method of the fifth step of Example 1 was used to prepare a yellow oil-like title. Compound (700 mg, 54%);

MS (ESI, pos.) m/z: 265.0 [M+H] ⁺ .

The third step 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarbonyl chloride

Under nitrogen, 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid (250 mg, 1.1 mmol) in dry dichloromethane (20 mL) To a solution of anhydrous tetrahydrofuran (10 mL), oxalyl chloride (1 mL, 12 mmol) and N,N-dimethylformamide (0.05 mL) were slowly added dropwise, and the mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness crystall

The fourth step 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxamide

Slowly added dropwise to aqueous ammonia in 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarbonyl chloride (250 mg, 1.1 mmol) in dichloromethane (10 mL). (10 mL), stirring was continued for 30 min. Dichloromethane (50 mL × 3), EtOAc (EtOAc m. %). MS (ESI, pos.) m/z: 2321. [M+H] ⁺ .

Step 5: N-(2-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-4-yl)-6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridine amide

4-Bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)pyridine (100 mg, 0.38 mmol), 6-(4-isopropyl-4H-1, 2, 4 under N2. -Triazol-3-yl)pyridinecarboxamide (1 g, 3.8 mmol), cesium carbonate (3.1 g, 9.5 mmol), palladium acetate (85 mg, 0.38 mmol) and 4,5-bisdiphenylphosphino-9, A solution of 9-dimethylxanthene (90 mg, 0.77 mmol) in 1,4-dioxane (50 mL) was heated to 110 ° C and stirred overnight. After being cooled to room temperature, the reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) The mixture was concentrated with EtOAc EtOAc EtOAc.

MS (ESI, pos.) m/z: 415.2 [M+H] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 10.78 (s, 1H), 9.00 (s, 1H), 8.43 (s, 1H), 8.29 (d, J = 19.6Hz, 4H), 8.13 ( s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 5.31 (m, 1H), 1.91 (s, 1H), 1.53 (s, 6H), 0.85-0.82 (m, 2H), 0.75 -0.72 (m, 2H).

Example 4: N-(6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole Zol-3-yl)pyridine amide

First step 2-bromo-6-iodopyridine

A solution of n-butyllithium in n-hexane (2.1 mL, 4.60 mmol, 2.4 M) was slowly added dropwise to a solution of 2,6-dibromopyridine (1.0 g, 4.22 mmol) in dichloromethane (100 mL). After stirring for a further half hour, a solution of elemental iodine (1.08 g, 4.26 mmol) in dichloromethane (100 mL) was added dropwise and stirring was continued for 3 hr. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The title compound (0.91 g, EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.73 - 7.71 (m, 1H), 7.49-7.47 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H).

The second step 2-bromo-6-(4-cyclopropyl-1H-imidazol-1-yl)pyridine

2-bromo-4-iodopyridine (0.9 g, 3 mmol) and 4-cyclopropyl-1H-imidazole (1.0 g, 9.25 mmol) were used as the starting materials, and the synthesis method of the fifth step of Example 1 was used to prepare a yellow oil. Title compound (0.35 g, 40%)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.19 (d, J = 1.2Hz, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.39 (d, J = 7.7Hz, 1H), 7.34 (d , J = 1.1 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 1.96 - 1.87 (m, 1H), 0.95 - 0.88 (m, 2H), 0.87 - 0.80 (m, 2H).

The third step (6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)carbamic acid tert-butyl ester

Starting from 2-bromo-6-(4-cyclopropyl-1H-imidazol-1-yl)pyridine (0.35 g, 1.30 mmol), the title compound (0.35g, 88%);

MS (ESI, pos.ion) m/z: 301.1 [M+H] ⁺

The fourth step 6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-amine

The synthesis method of the seventh step of Example 1 was carried out using (6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)carbamic acid tert-butyl ester (0.35 g, 1.2 mmol) as a starting material. The title compound (190 mg, 81%)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.15 (d, J = 1.0Hz, 1H), 7.51 (t, J = 7.9Hz, 1H), 7.28 (d, J = 0.9Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.57 (s, 2H), 1.95 - 1.87 (m, 1H), 0.92 - 0.86 (m, 2H), 0.86 - 0.75 (m, 2H).

Step 5 N-(6-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridine amide

6-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-2-amine (190 mg, 0.95 mmol) and 6-(4-isopropyl-4H-1,2,4-triazole- 3-ethyl)picolinic acid (242 mg, 1.04 mmol) was used as a starting material.

MS (ESI, pos.ion) m/z: 415.1 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 10.25 (s, 1H), 9.05 (s, 1H), 8.44-8.39 (m, 1H), 8.34 (s, 1H), 8.31 (d, J =4.2 Hz, 2H), 8.20 (d, J = 8.1 Hz, 1H), 8.08 (t, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.51–5.37 (m, 1H), 1.89–1.81 (m, 1H), 1.69 (d, J=6.7 Hz, 6H), 0.87–0.82 (m, 2H), 0.73–0.67 (m, 2H).

Example 5: N-(5-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)-6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridinecarboxamide

First step 3-bromo-5-(4-cyclopropyl-1H-imidazol-1-yl)pyridine

3-bromo-5-iodo-pyridine (2.0 g, 7.0 mmol), 4-cyclopropyl-1H-imidazole (1.5 g, 14 mmol) was used as the starting material, and the fifth step of Example 1 was followed. The title compound (1.5 g, 81%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.66 (dd, J = 4.8,1.9Hz, 2H), 7.87 (t, J = 2.1Hz, 1H), 7.75 (s, 1H), 7.04 (s, 1H), 1.96–1.88 (m, 1H), 0.96–0.90 (m, 2H), 0.86–0.81 (m, 2H).

Second step (5-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)amino-tert-butyl ester

3-bromo-5-(4-cyclopropyl-1H-imidazol-1-yl)pyridine (850 mg, 3.2 mmol) was used as the starting material. (600 mg, 62%).

MS (ESI, pos.ion) m/z: 301.1 [M+H] ⁺

The third step 5-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-amine

Prepared by the synthesis method of the seventh step of Example 1 using (5-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)amino-tert-butyl ester (640 mg, 2.1 mmol) as a starting material. The title compound (210 mg, 49.2%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.06-8.09 (m, 2H), 7.69 (s, 1H), 6.99 (d, J = 1.1Hz, 1H), 6.93 (t, J = 2.3Hz, 1H), 4.02 (s, 2H), 1.94–1.88 (m, 1H), 0.93–0.86 (m, 2H), 0.87–0.79 (m, 2H).

The fifth step N-(5-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)-6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridinecarboxamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)pyridin-3-amine (120 mg, 0.60 mmol), 6-(4-isopropyl-4H-1,2,4-triazole The -3-yl)picolinic acid (150 mg, 0.65 mmol) was obtained from the title compound (25 mg, 10%).

MS (ESI, pos.) m/z: 415.1 [M+H] ⁺ .

^{_{1 H NMR (600MHz, CDCl 3}} ) δ (ppm) 10.00 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.44 ( d, J = 7.3 Hz, 1H), 8.39 (d, J = 7.3 Hz, 1H), 8.15 (t, J = 7.4 Hz, 1H), 7.90 (s, 1H), 7.14 (s, 1H), 5.37 - 5.30 (m, 1H), 2.00-1.96 (m, 1H), 1.73 (d, J = 6.7 Hz, 6H), 0.96 - 0.93 (m, 2H), 0.87 - 0.84 (m, 2H).

Example 6: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-6-methylpyridin-2-yl)-6-(4-isopropyl-4H-1,2 ,4-triazol-3-yl)pyridinecarboxamide

First step: 4-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-6-methylpyridine

2-fluoro-4-iodo-6-methylpyridine (1.0 g, 4.2 mmol) was used as a starting material.

MS (ESI, pos.) m/z: 218.2 [M+H] ⁺ .

Second step: 4-(4-cyclopropyl-1H-imidazol-1-yl)-6-methylpyridin-2-amine

Under microwave conditions, 4-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-6-methylpyridine (120 mg, 0.55 mmol) and aqueous ammonia (5 mL) were stirred at 150 ° C for 3 h. After the organic layer was cooled to room temperature, ethyl acetate (30 mL × 3) was evaporated, evaporated, evaporated, evaporated, evaporated Purification (dichloromethane:methanol (v/v) = 25:1)

MS (ESI, pos.) m/z: 215.1 [M+H] ⁺ .

The third step: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-6-methylpyridin-2-yl)-6-(4-isopropyl-4H-1,2 ,4-triazol-3-yl)pyridinecarboxamide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-6-methylpyridin-2-amine (100 mg, 0.47 mmol), 6-(4-isopropyl-4H-1,2, 4-triazol-3-yl) Pyridinecarboxylic acid (120 mg, 0.52 mmol) was used as a starting material.

MS (ESI, pos.) m/z: 429.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.21 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.50 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H) , 8.35(s,1H), 8.16(s,1H),8.03(s,1H),7.22(s,1H),6.99(s,1H),5.62-5.58(m,1H),2.55(s,3H ), 1.97-1.94 (m, 1H), 1.80 (d, J = 6.8 Hz, 6H), 0.96-0.93 (m, 2H), 0.89-0.86 (m, 2H).

Example 7: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridin-2-yl)-6-(4-isopropyl-4H-1,2 ,4-triazol-3-yl)pyridine amide

First step 2-chloro-4-iodo-5-methylpyridine

2-Chloro-5-methyl-pyridin-4-amine (2 g, 14.03 mmol) was dissolved in water (33 mL), reduced to 0 ^{° C} , then concentrated sulfuric acid (0.9 mL) was added dropwise, then cooled to -10 ° C, A solution of sodium nitrite (1.26 g, 18.3 mmol) in water (33 mL) was slowly added dropwise, and the mixture was stirred for 1 hour. After adding acetone (48 mL), potassium iodide (2.79 g, 16.8 mmol) in water (33 mL) was added dropwise. The solution was stirred at 0 ° C for 4 hours. The organic phase was extracted with ethyl acetate (50 mL×2), and the organic phase was combined and washed with saturated brine (50 mL). The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI, pos.ion) m/z: 254.0 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.16 (s, 1H), 7.81 (s, 1H), 2.40 (s, 3H).

The second step 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridine

2-chloro-4-iodo-5-methylpyridine (2.4 g, 9.5 mmol) was used as the starting material. The title compound (yield: 0.88 g, 40%) .

MS (ESI, pos. ion) m/z: 234.0 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.38 (s, 1H), 7.55 (s, 1H), 7.23 (s, 1H), 6.88 (s, 1H), 2.32 (s, 3H), 1.96- 1.86 (m, 1H), 0.95 - 0.88 (m, 2H), 0.87 - 0.79 (m, 2H).

The third step (4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridin-2-yl)carbamic acid tert-butyl ester

Prepared by the synthesis method of the sixth step of Example 1 using 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridine (0.88 g, 3.8 mmol) as a starting material. The title compound (800 mg, 68%) was obtained.

MS (ESI, pos. ion) m/z: 315.2 [M+H] ⁺

The fourth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridin-2-amine

Using (4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridin-2-yl)carbamic acid tert-butyl ester (800 mg, 2.55 mmol) as a starting material, refer to Example 7 The title compound (320 mg, 59%)

MS (ESI, pos.ion) m/z: 215.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.04 (s, 1H), 7.51 (s, 1H), 6.84 (s, 1H), 6.37 (s, 1H), 4.50 (s, 2H), 2.15 ( s, 3H), 1.97–1.85 (m, 1H), 0.94–0.88 (m, 2H), 0.86–0.81 (m, 2H).

The fifth step N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridin-2-yl)-6-(4-isopropyl-4H-1,2, 4-triazol-3-yl)pyridine amide

4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylpyridin-2-amine (100 mg, 0.47 mmol) and 6-(4-isopropyl-4H-1,2, 4-Triazol-3-yl)picolinic acid (119 mg, 0.51 mmol) eluted

MS (ESI, pos. ion) m/z: 429.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.16 (s, 1H), 8.58 (d, J = 7.9 Hz, 1H), 8.49 (s, 1H), 8.39 (d, J = 9.5 Hz, 2H) , 8.33(s,1H), 8.15(t,J=7.9Hz,1H), 7.64(s,1H),6.96(s,1H),5.58-5.51(m,1H),2.33(s,3H), 1.92-1.90 (m, 1H), 1.78 (d, J = 6.7 Hz, 6H), 0.98-0.90 (m, 2H), 0.87-0.72 (m, 2H).

Example 8: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinidin-2-yl)-6-(4-isopropyl-4H-1,2 ,4-triazol-3-yl)pyridinecarboxamide

First step 2-Chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine

2-chloro-5-fluoro-4-iodopyridine (23.0 g, 89.3 mmol) was used as the starting material.

The second step 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinic acid methyl ester

2-Chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (5.50 g, 23.1 mmol), [1,1'-double in an autoclave under a carbon monoxide atmosphere (Diphenylphosphino)ferrocene]palladium dichloride (370 mg, 0.4625 mmol), triethylamine (6.43 mL, 46.3 mmol), and methanol (80 mL), and stirred at 80 ° C overnight. After being cooled to room temperature, EtOAc EtOAc m.

Step 3 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-morpholinecarboxylic acid methyl ester

Methyl 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinate (800 mg, 3.06 mmol), potassium carbonate (1.27 g, 9.20 mmol), morpholine A solution of 0.80 mL, 9.2 mmol) in EtOAc (20 mL), EtOAc (EtOAc) (EtOAc) Washed and dried over anhydrous sodium sulfate. Filtration and concentrating under reduced pressure afforded EtOAcqqqqqqqq MS (ESI, pos.ion) m/z: 329.3 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.45 (s, 1H), 7.95 (s, 2H), 7.12 (s, 1H), 4.01 (s, 3H), 3.80-3.74 (m, 4H), 2.91 (d, J = 4.6 Hz, 4H), 1.95 - 1.91 (m, 1H), 0.95 - 0.90 (m, 2H), 0.82 - 0.81 (m, 2H).

Step 4 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-morpholinepicamic acid

Methyl 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinium picolinate (900 mg, 2.74 mmol) in tetrahydrofurane (8.2 mL) Aqueous sodium hydroxide solution (328 mg, 8.2 mmol, 8.2 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Compound (860 mg, 99.8%).

MS (ESI, pos. ion) m/z: 315.2 [M+H] ⁺

Step 5 (4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-morpholinpyridin-2-yl)carbamic acid tert-butyl ester

Add 3-ethylamine (0.76 mL, 5.5 mmol) to a solution of 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinecarboxylic acid (860 mg, 2.736 mmol) in tert-butanol (20 mL) And diphenylphosphoryl azide (1.50 mL, 6.82 mmol), heated to 90 ° C and stirred for 12 hours. Saturated carbon The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Filtration and concentrating under reduced EtOAc.

MS (ESI, pos.ion) m/z: 386.2 [M+H] ⁺

Step 6 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-morpholinidin-2-amine

Using (4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinpyridin-2-yl)carbamic acid tert-butyl ester (200 mg, 0.52 mmol) as a starting material, refer to Example 7 The title compound (40 mg, 27%).

Seventh step N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinidin-2-yl)-6-(4-isopropyl-4H-1,2, 4-triazol-3-yl)pyridinecarboxamide

4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinidin-2-amine (30 mg, 0.10 mmol) was used as a starting material, and the synthesis method of the eighth step of Example 1 was used to prepare the preparation. The title compound (8 mg, 15%).

MS (ESI, pos.ion) m/z: 500.2 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 10.38 (s, 1H), 9.36 (s, 1H), 9.05 (s, 1H), 8.39 (s, 3H), 8.29 (s, 2H), 7.91(s,1H), 5.38(s,1H), 3.90(s,4H), 2.79(s,4H),2.04(s,1H),1.63(s,6H),1.03(s,2H),0.86 (s, 2H).

Example 9: (R)-N-(4-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-(1-methoxypropan-2-yl) )-4H-1,2,4-triazol-3-yl)pyridinecarboxamide

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

6-bromopyridinecarboxamide (20.0 g, 92.6 mmol) and (R)-1-methoxy-2-propylamine hydrochloride (3.67 g, 29.2 mmol) were used as the starting materials, and the second step of Example 1 was followed. The title compound (5.00 g, 69%) was obtained.

MS (ESI, pos.ion) m/z: 297.2 [M+H] ⁺

The second step (R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid

(R)-2-bromo-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine (5.00 g, under N2) 16.8 mmol), acetic anhydride (3.18 mL, 33.6 mmol), sodium formate (3.47 g, 50.5 mmol), palladium acetate (378 mg, 1.68 mmol), N,N-diisopropylethylamine (5.56 mL, 33.6 mmol), A mixture of 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (819 mg, 1.68 mmol) and DMF (80 mL) was stirred at 80 ° C overnight. The organic layer was cooled to room temperature, and the residue was evaporated to dryness. After concentrating under reduced pressure, EtOAc EtOAc m.

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

The third step (R)-N-(4-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-2-yl)-6-(4-(1-methoxypropan-2-yl) -4H-1,2,4-triazol-3-yl)pyridinecarboxamide

(R)-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid (30 mg, 0.10 mmol) and 4-(4) -cyclopropyl-1H-imidazol-1-yl)pyridin-2-amine (130 mg, 0.65 mmol) as a starting material, which was prepared according to the synthesis of the eighth step of Example 1, to give a pale yellow solid. Compound (30 mg, 10%).

MS (ESI, pos.ion) m/z: 445.2 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 10.42 (s, 1H), 8.98 (s, 1H), 8.47 (d, J = 5.6Hz, 1H), 8.43 (s, 1H), 8.39- 8.37 (m, 1H), 8.33 (s, 1H), 8.32-8.26 (m, 2H), 7.63 (s, 1H), 7.58-7.43 (m, 1H), 5.52-5.47 (m, 1H), 3.88- 3.70 (m, 2H), 3.23 (s, 3H), 1.94-1.86 (m, 1H), 1.60 (d, J = 6.9 Hz, 3H), 0.86-0.82 (m, 2H), 0.76-0.72 (m, 2H).

Example 10: 6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)-N-(4-(4,5,6,7-tetrahydro-1H-benzene) And [d]imidazol-1-yl)pyridin-2-yl)pyridine amide

First step 4,5,6,7-tetrahydro-1H-benzo[d]imidazole

The benzimidazole (5 g, 42.32 mmol) was dissolved in glacial acetic acid (50 mL), palladium/carbon (0.5 g) was added, and the mixture was heated to 100 ° C under stirring overnight. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated. The solvent was evaporated, and the residue was diluted with water (50 mL). The organic phase was washed with EtOAc EtOAc m.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.49 (s, 1H), 2.60-2.56 (m, 4H), 1.83-1.79 (m, 4H).

The second step 1-(2-chloropyridin-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole

2-chloro-4-iodo-pyridine (1.47 g, 6.1 mmol) and 4,5,6,7-tetrahydro-1H-benzo[d]imidazole (500 mg, 4.09 mmol) were used as the starting materials, and Example 1 was used. The title compound of the title compound (660 mg, 69%)

MS (ESI, pos. ion) m/z: 234.0 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.50 (d, J = 5.4Hz, 1H), 7.71 (s, 1H), 7.33 (s, 1H), 7.23 (d, J = 5.4Hz, 1H) , 2.69-2.67 (m, 4H), 1.90 - 1.86 (m, 4H).

The third step (4-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)carbamic acid tert-butyl ester

Taking 1-(2-chloropyridin-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (660 mg, 2.82 mmol) as a starting material, refer to the sixth step of Example 1. A synthetic method to prepare a yellow liquid target compound (800 mg, 90%)

MS (ESI, pos. ion) m/z: 315.3 [M+H] ⁺

The fourth step 4-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)pyridin-2-amine

(4-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)carbamic acid tert-butyl ester (800 mg, 2.5 mmol) was used as a starting material. The synthesis method of the seventh step of Example 1 gave the title compound (200 mg, 37%)

MS (ESI, pos. ion) m/z: 215.0 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.15 (d, J = 5.5Hz, 1H), 7.64 (s, 1H), 6.64 (d, J = 3.9Hz, 1H), 6.42 (s, 1H) , 4.65 (s, 2H), 2.71-2.94 (m, 4H), 1.88-1.84 (m, 4H).

Step 5 6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)-N-(4-(4,5,6,7-tetrahydro-1H-benzo) [d]imidazol-1-yl)pyridin-2-yl)pyridine amide

4-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)pyridin-2-amine (200 mg, 0.93 mmol) and 6-(4-isopropyl-1 , 2,4-triazol-3-yl)picolinic acid (238 mg, 1.02 mmol) was used as a starting material.

MS (ESI, pos.ion) m/z: 429.1 [M+H] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 10.26 (s, 1H), 8.59 (d, J = 7.8Hz, 1H), 8.53 (d, J = 12.3Hz, 2H), 8.46-8.40 (m, 2H), 8.16 (t, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.15 (s, 1H), 5.59 - 5.52 (m, 1H), 2.79 - 2.74 (m, 4H), 1.93 - 1.90 (m, 4H), 1.79 (d, J = 6.7 Hz, 6H).

Example 11: N-([3,4'-Dipyridyl]-2'-yl)-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxamide

First step N-(4-bromopyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxamide

2-amino-4-bromopyridine (335 mg, 1.94 mmol) and 6-(4-isopropyl-1,2,4-triazol-3-yl)pyridinecarboxylic acid (410 mg, 1.77 mmol) were used as the starting materials. The title compound (500 mg, 73%) was obtained as a white solid.

Second step N-([3,4'-bipyridine]-2'-yl)-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxamide

N-(4-Bromopyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxamide (100 mg, 0.26 mmol) , 3-pyridineboronic acid (63 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19 mg, 0.025 mmol) and potassium carbonate (72 mg, 0.52 mmol) Toluene (2 mL), water (1 mL) and methanol (1 mL) were added, and the mixture was heated to 90 ° C. The reaction was stirred for 8 hours, then cooled to room temperature, and the solvent was evaporated under reduced pressure. (v/v) = 10/1) gave the title compound (30 mg, 30%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.21 (s, 1H), 8.99 (s, 1H), 8.73 (d, J = 5.7 Hz, 2H), 8.58 (d, J = 7.9 Hz, 1H) , 8.51–8.38 (m, 3H), 8.15 (t, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.48 - 7.45 (m, 1H), 7.35 (d, J = 5.1) Hz, 1H), 5.62–5.55 (m, 1H), 1.79 (d, J = 6.7 Hz, 6H).

Example 12: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridin-2-yl)-6-(4-isopropyl-4H-1,2, 4-triazol-3-yl)pyridinecarboxamide

First step (4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridin-2-yl)carbamic acid tert-butyl ester

2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (3.00 g, 12.6 mmol) was used as a starting material, and the synthesis method of the sixth step of Example 1 was prepared. Yellow liquid target compound (3.00 g, 75%);

MS (ESI, pos.ion) m/z: 319.3 [M+H] ⁺

Step 2 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridin-2-amine

(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridin-2-yl)carbamic acid tert-butyl ester (3.00 g, 9.42 mmol) was used as a starting material, and reference was made to the seventh example. The title compound was obtained as a pale yellow solid title compound (1.00 g, 49%);

^{_{1 HNMR (400MHz, CDCl 3)}} δ (ppm) 8.09 (d, J = 3.0Hz, 1H), 7.84 (s, 1H), 7.07 (s, 1H), 6.46 (d, J = 5.0Hz, 1H), 4.54 (s, 2H), 1.92-1.90 (m, 1H), 0.91 (m, 2H), 0.85 (m, 2H).

The third step N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridin-2-yl)-6-(4-isopropyl-4H-1,2,4 -triazol-3-yl)pyridinecarboxamide

Oxalyl chloride was slowly added dropwise to a solution of 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridinecarboxylic acid (88 mg, 0.37892 mmol) in dichloromethane (20 mL). (0.06 mL, 0.7 mmol) and DMF (3.0 mg, 0.04 mmol). stress reliever Concentrated, the crude yellow solid was dissolved in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; And DMAP (4 mg, 0.033 mmol), stirred at room temperature for 20 hours. The residue was concentrated under reduced EtOAcqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS (ESI, pos.ion) m/z: 433.3 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.38 (s, 1H), 9.01 (s, 1H), 8.65 (s, 1H), 8.49 (d, J = 5.6Hz, 1H), 8.39 (s, 1H), 8.30 (s, 2H), 8.10 (s, 1H), 7.51 (s, 1H), 5.45 - 5.35 (m, 1H), 1.98-1.90 (m, 1H), 1.62 (d, J = 6.4 Hz) , 6H), 0.84 (d, J = 7.0 Hz, 2H), 0.75 (d, J = 7.0 Hz, 2H).

Example 13: N-(4-(1H-benzo[d]imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole- 3-based carboxamide

First step 1-(5-chloropyridin-3-yl)-1H-benzo[d]imidazole

2-chloro-4-iodo-pyridine (5.0 g, 20.8 mmol) and benzimidazole (3 g, 25.4 mmol) were used as the starting material. , 98%);

MS (ESI, pos.ion) m/z: 230.1 [M+H] ⁺

The second step (5-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)carbamic acid tert-butyl ester

Using 1-(5-chloropyridin-3-yl)-1H-benzo[d]imidazole (4.7 g, 20.6 mmol) as a starting material, the title compound of the first step of Example 1 was prepared to obtain a pale yellow solid target compound. (1.32g, 21%);

MS (ESI, pos. ion) m/z: 311.1 [M+H] ⁺

The third step 5-(1H-benzo[d]imidazol-1-yl)pyridin-3-amine

Taking (5-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)carbamic acid tert-butyl ester (1.3 g, 4.2 mmol) as a starting material, referring to the synthesis method of the seventh step of Example 1, The title compound (0.61 g, 68%)

MS (ESI, pos.ion) m/z: 201.1 [M+H] ⁺

The fourth step N-(4-(1H-benzo[d]imidazol-1-yl)pyridin-2-yl)-6-(4-isopropyl-4H-1,2,4-triazole-3 -based carboxamide

5-(1H-Benzo[d]imidazol-1-yl)pyridin-3-amine (200 mg, 1 mmol) and 6-(4-isopropyl-1,2,4-triazol-3-yl) Pyridinecarboxylic acid (0.3 g, 1 mmol) was used as a starting material, and the title compound (0.3 g, 70%)

MS (ESI, pos.ion) m/z: 425.1 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 10.49 (s, 1H), 9.20 (s, 1H), 9.12 (s, 1H), 8.74 (d, J = 1.8Hz, 1H), 8.66 ( d, J = 5.5 Hz, 1H), 8.44 - 8.43 (m, 1H), 8.38 - 8.31 (m, 2H), 7.94 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H) ), 7.69–7.68 (m, 1H), 7.51–7.50 (m, 2H), 5.44–5.42 (m, 1H), 1.68 (d, J=6.7 Hz, 6H).

Example 14: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridin-2-yl)-6-(4-isopropyl-4H-1, 2,4-triazol-3-yl)pyridinecarboxamide

First step 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridinecarboxylic acid methyl ester

Using 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (200 mg, 0.52 mmol) as a starting material, the synthetic method of the second step of Example 8 was used to prepare a yellow color. Solid title compound (700 mg, 20%)

MS (ESI, pos. ion) m/z: 274.1 [M+H] ⁺

Step 2 4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methoxypicolinic acid

Using 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypicolinic acid methyl ester (340 mg, 1.24 mmol) as a starting material, the synthesis method of the fourth step of Example 8 was prepared. Light yellow solid title compound (320 mg, 99%)

MS (ESI, pos.ion) m/z: 260.2 [M+H] ⁺

Step 3 (4-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridin-2-yl)carbamic acid tert-butyl ester

4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypicolinic acid (320 mg, 1.23 mmol) was used as the starting material, and the synthesis method of the fifth step of Example 8 was used to prepare a pale yellow color. Solid title compound (100 mg, 25%)

MS (ESI, pos.ion) m/z: 331.1 [M+H] ⁺

The fourth step 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridin-2-amine

Taking (4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridin-2-yl)carbamic acid tert-butyl ester (100 mg, 0.30 mmol) as a starting material, refer to Example 1 The title compound (40 mg, 57%)

MS (ESI, pos. ion) m/z: 231.1 [M+H] ⁺

The fifth step N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridin-2-yl)-6-(4-isopropyl-4H-1,2 ,4-triazol-3-yl)pyridinecarboxamide

4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methoxypyridin-2-amine (40 mg, 0.17 mmol) was used as a starting material, and was prepared according to the synthesis method of the eighth step of Example 1. The title compound (10 mg, 13%)

MS (ESI, pos.ion) m/z: 445.2 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 10.25 (s, 1H), 9.02 (s, 1H), 8.53-8.24 (m, 5H), 8.09-8.03 (m, 1H), 7.40 (s , 1H), 5.41–5.38 (m, 1H), 3.98 (s, 3H), 1.95–1.90 (m, 1H), 1.67–1.63 (m, 6H), 0.83-0.74 (m, 4H).

Example 15: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(methylindolyl)pyridin-2-yl)-6-(4-isopropyl-4H-1 ,2,4-triazol-3-yl)pyridinecarboxamide

First step: 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridylpyridine

2-Chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (1.1 g, 4.6 mmol) was dissolved in N,N-dimethylformamide (30 mL) Sodium methylthiolate (0.36 g, 5.1 mmol) was added under ice-cooling, and the mixture was added to room temperature. The reaction was quenched with EtOAc (EtOAc (EtOAc) (EtOAc) The product was purified by EtOAc EtOAcjjjjjjjj MS (ESI, pos.ion) m / z: 266.3 [M + H] +.

Second step: N-(4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(methylindolyl)pyridin-2-yl)-6-(4-isopropyl-4H-1 , 2,4-triazol-3-yl)pyridine amide

2-Chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylpyridylpyridine (800 mg, 3 mmol), 6-(4-isopropyl-4H-1). , 2,4-triazol-3-yl)pyridine amide (760 mg, 3.3 mmol), cesium carbonate (2.5 g, 7.7 mmol), palladium acetate (68 mg, 0.3 mmol) and 4,5-bisdiphenylphosphine A solution of -9,9-dimethyloxaxan (170 mg, 0.3 mmol) in 1,4-dioxane (40 mL) was heated to 110 ° C and stirred overnight. Full The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc. The title compound (300 mg, 22%).

MS (ESI, pos.) m/z: 461.1 [M+H] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 10.19 (s, 1H), 8.63-8.56 (m, 1H), 8.49 (s, 1H), 8.42 (d, J = 3.0Hz, 2H), 8.39 ( d, J = 7.8 Hz, 1H), 8.15 (t, J = 7.9 Hz, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 5.57-5.50 ( m, 1H), 2.36 (s, 3H), 1.99-1.92 (m, 1H), 1.78 (d, J = 6.7 Hz, 6H), 0.97 - 0.91 (m, 2H), 0.89 - 0.86 (m, 2H) .

Example 16: ASK1 (apoptosis signal-regulated kinase 1) inhibitory activity assay

Test method

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

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

2. Experimental results

化合物编号Compound number	IC₅₀(nM)IC ₅₀ (nM)
实施例1Example 1	0.70.7
实施例2Example 2	2.432.43
实施例3Example 3	2.342.34
实施例6Example 6	1.221.22
实施例7Example 7	0.610.61
实施例8Example 8	0.460.46
实施例9Example 9	2.102.10
实施例12Example 12	1.341.34
实施例13Example 13	0.430.43
实施例14Example 14	0.460.46
实施例15Example 15	0.280.28

Example 17: Pharmacokinetic Testing

Test method

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

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

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

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

2. Test results

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

Example 18: Rat model of unilateral ureteral obstruction (UUO) renal fibrosis

Test method

Male SD rats were weighed overnight (free drinking water), and were randomly divided according to body weight, including sham operation group, model group and each administration group; model group and each administration group were treated with 3% pentobarbital sodium peritoneal cavity. Intra-injection anesthesia, longitudinal incision from the right side of the left side of the rat, fully expose the left kidney, separate the ureter and suture the layer and suture the incision layer by layer, routine disinfection; sham operation group, except for no ligation, all other treatments . The rats were administered by intragastric administration, once before modeling, once a day after modeling, and continuously for 14 days; after 14 days of administration, the animals were anesthetized with 3% pentobarbital sodium, and the kidney tissues were taken, weighed, and used. The left kidney was fixed in 10% formalin, and Sirius eosin staining was performed to quantitatively evaluate the degree of fibrosis.

2. Test results

The test results show that the compounds of the present invention can significantly reduce the level of renal fibrosis in rats.

Example 19: Drug tissue distribution study

Test method

Male SD rats were weighed overnight (free drinking water), and the drugs were administered at a dose of 5 mg/kg. Animals were anesthetized at 1, 4, and 8 h after administration, and plasma, heart, liver, spleen, lung, kidney, and stomach were collected. , small intestine, fat, brain, testis, LC-MS/MS was used to determine the concentration of the drug in the corresponding tissue.

2. Test results

The test results indicate that the concentration of the compound of the present invention in rat liver and kidney organs is high.

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

Claims

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

among them:

Q is hydrogen or C 1-3 alkyl;

X 1 is C(R 1 ) or N;

X 2 is C(R 2 ) or N;

X 3 is C(R 3 ) or N;

X 4 is C(R 4 ) or N;

X 5 is C(R 5 ) or N;

X 6 is C(R 6 ) or N;

X 7 is CH or N;

R 1, R 2, R 3 , R 4, R 5 and R 6 are each independently hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl , C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5 a -6 membered heteroaryl group, wherein the hydroxy group, fluorenyl group, amino group, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, C 1-3 alkylthio group, C 1-3 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are independently optionally 1, 2, 3, 4 or 5 Substituted by a group selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy ;or

R 2 and R 3 or R 3 and R 4 together with the carbon atom to which they are attached form a C 4-6 carbocyclic ring, a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring or a benzene ring, wherein The C 4-6 carbocyclic ring, the 5-6 membered heterocyclic ring, the 5-6 membered heteroaryl ring and the benzene ring are independently optionally 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo, Substituted by a group of amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy groups;

The E ring is a C 6-10 aromatic ring or a 5-6 membered heteroaryl ring;

Each R x is independently hydrogen, a halogen atom, a hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl a thiol group, a C 1-6 alkylamino group, a C 3-8 cycloalkyl group, a 3-10 membered heterocyclic group, a C 6-12 aryl group or a 5-10 membered heteroaryl group, wherein the C 1 - 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-10 membered heterocyclic The C 6-12 aryl group and the 5-10 membered heteroaryl group are independently optionally 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group, an amino group, a nitro group, a cyano group, and a C 1-6 alkyl group. Substituted by a C 1-6 haloalkyl group and a C 1-6 alkoxy group; or

The adjacent two R x and the atoms connected thereto form a C 4-8 carbocyclic ring, a 5-8 membered heterocyclic ring, a 5-10 membered heteroaryl ring or a benzene ring; wherein the C 4-8 carbon The ring, the 5-8 membered heterocyclic ring, the 5-10 membered heteroaryl ring and the benzene ring are independently optionally 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group, an amino group, a nitro group, a cyano group, and a C 1 group. Substituted by a group of a -6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group;

Each R y is independently hydrogen, a halogen atom, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy ;

R z is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 6-12 aryl or 5-10 a heteroaryl group, wherein R z is optionally 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group, an amino group, a nitro group, a cyano group, a C 1-6 alkyl group, and a C 1 group ; Substituted by a group of -6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

m is 1, 2, 3, 4 or 5; and

n is 1, 2, 3 or 4.
The compound according to claim 1, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro , cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrole Base, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazole a hydroxy group, a thiol group, an amino group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a difluoromethyl group, a methoxy group, an isopropyloxy group, a methylthio group, a methylamino group, and a second group. Methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, Phenyl Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiazepine The azole group is optionally independently 1, 2, 3, 4 or 5 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, trifluoromethyl Substituted by a group of difluoromethyl, methoxy, ethoxy and isopropyloxy groups.
The compound according to claim 1, wherein the E ring is a benzene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a furan ring, An oxazole ring, an oxadiazole ring, a thiophene ring, a thiazole ring or a thiadiazole ring.
The compound according to claim 1, wherein each R x is independently hydrogen, a halogen atom, a hydroxyl, mercapto, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl -alkyl, C 1 -4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 aryl or 5-6 membered An aryl group, wherein the C 1-4 alkyl group, C 1-4 haloalkyl group, C 1-4 alkoxy group, C 1-4 alkylthio group, C 1-4 alkylamino group, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, the C 6-10 aryl group and the 5-6 membered heteroaryl group are independently optionally 1, 2 or 3 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group, an amino group, and a nitrate. Substituted by a group of a cyano group, a cyano group, a C 1-3 alkyl group, a C 1-3 haloalkyl group, and a C 1-3 alkoxy group;

The adjacent two R x and the atoms connected thereto form a C 4-6 carbocyclic ring, a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring or a benzene ring; wherein the C 4-6 carbon The ring, 5-6 membered heterocyclic ring, 5-6 membered heteroaryl ring and benzene ring are independently optionally 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, Cyano, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy and Substituted by a trifluoromethoxy group.
The compound according to claim 1 or 4, wherein each R x is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, thiol, amino, nitro, cyano, methyl, ethyl, n-propyl , isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a furyl group, an oxazolyl group, an oxadiazolyl group, a thienyl group, a thiazolyl group or a thiadiazolyl group, wherein the hydroxy group is , mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, benzene , pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thio The oxazolyl is optionally independently 1, 2 or 3 selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoro. Substituted by groups of methyl, methoxy, ethoxy and isopropyloxy groups.
The compound according to claim 1, wherein each R y is independently hydrogen, a halogen atom, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

R z is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 aryl or 5-6 a heteroaryl group, wherein R z is optionally 1, 2, 3, 4 or 5 selected from the group consisting of a halogen atom, a hydroxyl group, an oxo group, an amino group, a nitro group, a cyano group, a C 1-3 alkyl group, a C 1 group ; Substituents of -3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are substituted.
The compound according to claim 1 or 6, wherein each R y is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, unter Butyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, trifluoromethoxy or difluoromethoxy;

R z is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, wherein R z is optionally 1, 2, 3, 4 or 5 are selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, Methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, epoxy Substituted by a group of a propanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and a morpholinyl group.
The compound according to claim 1, which has a structure as follows:

Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of one of the structures.
A pharmaceutical composition comprising the compound of any one of claims 1-8.
The composition of claim 9 further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.
Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 10 for the manufacture of a medicament for the prevention, treatment or alleviation of a disease modulated by ASK1 in a patient.
The use according to claim 11, wherein the ASK1-mediated disease is an autoimmune disease, inflammation, cardiovascular disease, cardio-renal disease, fibrotic disease, respiratory disease, liver disease or neurodegenerative disease.
The use according to claim 12, wherein the cardiovascular disease is diabetes, diabetic nephropathy or other diabetic complications.
The use according to claim 12, wherein 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 use according to claim 12, wherein the liver disease is chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, hepatic ischemia - Reperfusion injury or primary biliary cirrhosis.