CN109400625B - Fused bicyclic compound and application thereof in medicine - Google Patents

Abstract

The invention relates to a fused bicyclic compound and application thereof in medicines. Specifically, the invention discloses a novel fused bicyclic compound used as an ASK1 activity regulator, a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and application of the compound in preparing a medicament for treating ASK1 modulated diseases and/or symptoms. The invention further discloses pharmaceutical compositions comprising the compounds of the invention and methods of using the compounds of the invention or pharmaceutical compositions thereof to treat diseases and/or conditions modulated by ASK 1.

Description

Fused bicyclic compound and application thereof in medicine

Technical Field

The present invention relates to fused bicyclic compounds having enzyme inhibitory activity and pharmaceutical compositions thereof, which are useful in the preparation of medicaments for the treatment of ASK1 mediated diseases.

Background

Apoptosis signal-regulating kinase 1 (ASK 1) is one of the members of the mitogen-activated protein kinase kinase (MAP 3Ks) family, MAP3Ks is capable of activating c-Jun N-terminal protein kinase (N-terminal protein kinase, JNK) and p38MAP (mitogen-activated protein) kinase (Ichijo, h., Nishida, e., Irie, k., Dijke, p.t., Saitoh, Moriguchi, t., Matsumoto, k., miyazo, k., and Gotoh, Y. (1997) Science 275, 90-94).

ASK1, also known as mitogen-activated protein kinase kinase 5(mitogen-activated protein kinase 5, MAPKKKK 5, MAP3K5), comprises 1375 amino acid residues, constituting 11 kinase subdomains and a serine/threonine kinase domain located in the middle of the molecule flanking the N-and C-terminal coiled-coil regions (Wang et al.J.biol.chem.1996,271,31607-31611, Ichijo et al.science.1997,275, 90-94; Tobium et al.biochem.Biophys.Res.Commun.1997,239, 905-910). ASK1 can be activated by a variety of stimuli, such as: oxidative stress, active oxygen, endotoxin, tumor necrosis factor-alpha, endoplasmic reticulum stress, intracellular calcium ion concentration, and the like.

ASK1 has been shown to not only regulate cell death, but also play an important role in cellular activities such as cytokine responses, cell differentiation, innate immune responses, and the like. Modulating the activity of ASK1 can treat or prevent a variety of diseases including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders. ASK1 modulators have great potential, especially in the treatment of cardiorenal diseases (including kidney disease, diabetic nephropathy and chronic kidney disease), fibrotic diseases (including pulmonary fibrosis and renal fibrosis), respiratory diseases (including chronic obstructive pulmonary obstruction and acute lung injury) and liver diseases.

Data indicate that liver disease has now become one of the leading causes of human death. Liver diseases are generally classified into acute and chronic liver diseases according to the duration of the disease. Liver disease may be caused by infection, injury, medication, poisoning, drinking, poor food intake, abnormal accumulation of normal components in the blood, autoimmunity, genetic defects, or other unknown factors. Common liver diseases include chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and the like.

Currently, several studies have been carried out in humans in an attempt to find therapeutic agents that are effective in inhibiting the expression or activity of ASK 1. WO2009027283, WO2009123986, WO2010008843, WO2011008709, WO2011041293, WO2011097079, WO2012003387, WO2013112741, WO2014100541, WO2015095059 disclose small molecule compounds as ASK1 modulators for the prevention or treatment of autoimmune, inflammatory, cardiovascular and neurodegenerative diseases. WO2015187499 and WO2016049070 disclose the use of ASK1 modulators for the treatment of liver disease. However, there is still a need for more and better ASK1 modulators in the clinic.

Summary of The Invention

The present invention provides a compound, and pharmaceutical compositions thereof, which are useful as modulators of ASK 1. The invention further relates to the use of said compounds and pharmaceutical compositions thereof for the preparation of medicaments for the treatment of diseases and/or conditions by modulation of ASK1 activity by said compounds. The invention further describes a synthetic method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

Specifically, the method comprises the following steps:

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

wherein:

X¹is C (R)¹) Or N;

X²is C (R)²) Or N;

X³is C (R)³) Or N;

X⁴is C (R)⁴) Or N;

R¹、R²、R³and R⁴Each independently is hydrogen, deuterium, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3,4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy is substituted by the radical of alkoxy;

e is 5-6 membered heteroaryl;

each R^xIndependently is deuterium, halogen atom, hydroxyl, sulfydryl, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-to 10-membered heterocyclic group, wherein said hydroxyl, mercapto, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-10 membered heterocyclyl may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy is substituted by the radical of alkoxy;

each R^yIndependently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, acetyl, acetamido, -COOH, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy or C_1-4A haloalkoxy group;

g is a fused bicyclic ring;

each R^zIndependently hydrogen, deuterium, halogen atom, oxo (═ O), -OR^a、-N(R^b)₂、-N(R^b)C(＝O)R^c、-C(＝O)N(R^b)₂、-OC(＝O)R^c、-C(＝O)OR^d、-S(O)₂OR^d、-S(O)₂R^c、-N(R^b)S(O)₂R^c、-S(O)₂N(R^b)₂Mercapto, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy is substituted by the radical of alkoxy;

each R^a、R^b、R^cAnd R^dIndependently of one another is hydrogen, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy is substituted by the radical of alkoxy;

m is 1,2 or 3;

n is 1,2 or 3; and

k is 1,2,3,4 or 5;

with the proviso that the compound is not a compound represented by the following structure:

in some embodiments, R¹、R²、R³And R⁴Each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, methyl, trifluoromethyl, methyl, cyclopentyl, and the like, Piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups may be independently optionally substituted with 1,2,3,4 or 5 groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, or thiadiazolyl.

In some embodiments, each R is^xIndependently is deuterium, halogen atom, hydroxyl, sulfydryl, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy groups.

In other embodiments, each R is^xIndependently deuterium, fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may independently optionally be substituted with 1,2 or 3 groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, each R is^yIndependently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, acetyl, acetamido, -COOH, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, trifluoromethoxy, or difluoromethoxy.

In some embodiments, G is an 8-12 membered fused bicyclic ring.

In other embodiments, G is

Wherein the content of the first and second substances,

each W¹Independently is-O-, -S-or-NH-;

each W²、W³、W⁴And W⁵Independently CH or N;

each W⁶、W⁷And W⁸independently-O-, -S (O)_t-、-C(＝O)-、-CH₂-or-NH-;

w is- (CH)₂)_p-、-(CH₂)_pO-、-(CH₂)_pNH-or- (CH)₂)_pS(O)_t-; wherein each p is independently 0, 1,2 or 3 and each t is independently 0, 1 or 2.

In still other embodiments, G is

In some embodiments, each R is^zIndependently hydrogen, deuterium, halogen atom, oxo (═ O), -OR^a、-N(R^b)₂、-N(R^b)C(＝O)R^c、-C(＝O)N(R^b)₂、-OC(＝O)R^c、-C(＝O)OR^d、-S(O)₂OR^d、-S(O)₂R^c、-N(R^b)S(O)₂R^c、-S(O)₂N(R^b)₂Mercapto, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl radicalsAnd 5-10 membered heteroaryl may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy is substituted by the radical of alkoxy;

each R^a、R^b、R^cAnd R^dIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy groups.

In still other embodiments, each R is^zIndependently hydrogen, deuterium, halogen atom, oxo (═ O), -OR^a、-N(R^b)₂、-N(R^b)C(＝O)R^c、-C(＝O)N(R^b)₂、-OC(＝O)R^c、-C(＝O)OR^d、-S(O)₂OR^d、-S(O)₂R^c、-N(R^b)S(O)₂R^c、-S(O)₂N(R^b)₂Mercapto, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyloxy, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, or thiadiazolyl,wherein, the mercapto group, the methyl group, the ethyl group, the n-propyl group, the isopropyl group, the difluoromethyl group, the hydroxymethyl group, the hydroxyethyl group, the methoxy group, the isopropyloxy group, the methylthio group, the methylamino group, the dimethylamino group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the azetidinyl group, the pyrrolidinyl group, the piperidinyl group, the piperazinyl group, the glycidyloxy group, the tetrahydrofuranyl group, the tetrahydropyranyl group, the morpholinyl group, the phenyl group, the pyrrolyl group, the pyrazolyl group, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl may be independently optionally substituted with 1,2 or 3 groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy;

each R^a、R^b、R^cAnd R^dIndependently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyloxy, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, or thiadiazolyl, said methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and the like, Piperazinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl and thiadiazolyl groups may be optionally substituted with 1,2 or 3 substituents independently selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoro-diazolylMethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, the compound of the present invention is a compound of formula (IIa), (IIb), (IIc), (IId), or (IIe), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (IIa), (IIb), (IIc), (IId), or (IIe),

in another aspect, the present invention relates to a pharmaceutical composition comprising a compound as described above, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.

In one aspect, the invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention, treatment or alleviation of an ASK1 modulated disease in a patient.

In some embodiments, the ASK 1-mediated disease is an autoimmune disease, inflammation, cardiovascular disease, cardiorenal disease, fibrotic disease, respiratory disease, liver disease, or neurodegenerative disease.

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

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of terms, their usage, the techniques described, or the scope as controlled by the present application.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are defined in accordance with the periodic Table of the elements, CAS version and the handbook of Chemicals, 75, thEd, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, all of which are hereby incorporated by reference.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

Compounds as described herein may be optionally substituted with one or more substituents, such as compounds of the general formula in the present invention, or compounds of the type specifically exemplified, sub-classes, and encompassed by the present invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with 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 a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited toAnd are not limited to hydrogen, F, Cl, Br, I, nitro, cyano, oxo (═ O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, 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)₂OH, -O-alkylene-C (═ O) O-alkyl, -O-alkylene-S (═ O)₂-alkyl, -O-alkylene-S (═ O)₂-amino, -O-alkylene-S (═ O)₂OH、-C(＝O)NH₂-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)₂OH, -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) -alkylamino, -N (alkyl) C (═ O) O-alkyl, -NHC (═ O) O-haloalkyl, -N (alkyl) C (═ O) O-aminoalkyl, -NHC (═ O) -NH-haloalkyl₂-NHC (═ O) NH- (alkyl), -NHC (═ O) NH (haloalkyl), -NHC (═ O) N (alkyl) -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)₂OH、-C(＝NH)NH₂-C (═ NH) NH-alkyl, -C (═ NH) N (alkyl) -alkyl, -C (═ N-alkyl) -NH₂-C (═ O) NH-alkylene-S (═ O)₂OH, -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 to 20 carbon atomsOr a saturated, straight or branched chain, monovalent hydrocarbon group of 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group may independently be optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) T-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl and n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical resulting from the elimination of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene, and isopropylene, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one carbon-carbon is sp²Double bonds wherein an alkenyl group may be independently optionally substituted with one or more substituents as described herein, including where the group is "trans", "n" or "E" or "Z", where specific examples include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And alkenyl butyl (-CH)₂CH₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one of which is a sp triple bond, wherein the alkynyl radical may be independently optionally substituted with one or more substituents as described herein, specific examples including, but not limited to, ethynyl (-C ≡ CH) and propargyl (-CH)₂C≡CH)。

The term "heteroatom" means one or more of O, S, N, P and Si, including any oxidation state forms of C, N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, e.g., N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl); or-CH in a heterocyclic ring₂-is oxidized to form-C (═ O) -.

The term "halogen" refers to 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 herein, refers to an alkyl group, as defined herein, attached to the remainder of the compound molecule through an oxygen atom. In some embodiments, the alkoxy is C_1-4An alkoxy group; examples include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, and the like. And the alkoxy groups may independently be unsubstituted or substituted with one or more substituents as described herein.

The term "alkylthio" or "alkylthio" as used herein, relates to an alkyl group, as defined herein, attached to the remainder of the compound molecule through a sulfur atom. In some embodiments, the alkylthio group is C_1-6An alkylthio group; in other embodiments, the alkylthio group is C_1-3Alkylthio groups, and such examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like. And the alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkoxyalkyl" as used herein means that an alkyl group may be substituted with one or more alkoxy groups, the alkoxy and alkyl groups having the meaning as described herein. In some embodiments, the alkoxyalkyl is C_1-6Alkoxy radical C_1-6An alkyl group. In other embodiments, the alkoxyalkyl is C_1-3Alkoxy radical C_1-3An alkyl group. The "alkoxyalkyl" group may be independently optionally substituted with one or more substituents described herein.

The terms "haloalkyl", "haloalkenyl" and "haloalkyloxy" denote the case where an alkyl, alkenyl or alkyloxy group may be substituted with one or more halogen atoms. In some embodiments, haloalkyl is halo C_1-6An alkyl group. In other embodiments, the haloalkyl is halo C_1-3An alkyl group. In some embodiments, the haloalkyloxy or haloalkoxy is halo C_1-6Alkyloxy or halogeno C_1-6An alkoxy group. Other examplesIn the examples, haloalkyloxy or haloalkoxy is halogeno C_1-3Alkyloxy or halogeno C_1-3An alkoxy group. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, 2-chloro-vinyl, 2-difluoroethyl, difluoromethoxy, trifluoromethoxy, and the like. The "haloalkyl", "haloalkenyl" and "haloalkyloxy" groups may independently be optionally substituted with one or more substituents described herein.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is C_1-6Alkylamino or (C)_1-6Alkyl) amino groups. In other embodiments, the alkylamino group is C_1-3Alkylamino or (C)_1-3Alkyl) amino groups. Examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, 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 in no way containing an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkyloxy" denotes a cycloalkyl group attached to the rest of the compound molecule via an oxygen atom, wherein the cycloalkyl group has the meaning as described herein.

The term "cycloalkylalkyl" denotes a cycloalkyl group linked to the rest of the compound molecule through an alkyl group, wherein the cycloalkyl and alkyl groups have the meaning as described herein.

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

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing from 3 to 12 ring atoms, and in no way containing an aromatic ring in which at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3-10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3-8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5-8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3-6 ring atoms; also in one embodiment, "heterocyclyl" or "heterocycle" contains 5-6 ring atoms; unless otherwise indicated, heterocyclyl groups may be carbon-based or nitrogen-based, and heteroatoms have the meaning as indicated in the present invention. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, and oxazepanyl

Radical diaza

Radical, sulfur nitrogen hetero

Radicals and 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH₂Examples of-groups substituted with-C (═ O) -include, but are not limited to: 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "heterocyclylalkyl" means that a heterocyclyl group is attached to the rest of the compound molecule through an alkyl group, where heterocyclyl and alkyl groups have the meaning described herein.

The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3 to 7 atoms in the ring and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "arylalkyl" means an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meaning as described herein, examples of which include, but are not limited to, benzyl and phenethyl.

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

Examples of heteroaryl groups include, but are not limited to: furyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl), triazolyl, thienyl (e.g., 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-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3, 4-tetrahydroisoquinolyl, 1, 3-benzodioxolyl, indolinyl, isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-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 ] pyridyl, and the like.

The term "fused bicyclic ring" or "fused bicyclic group" means a monovalent or multivalent saturated, partially unsaturated, or aromatic bicyclic ring system containing 0, 1,2,3,4, 5,6 heteroatoms independently selected from N, O, S, P and Si. -CH in a ring₂-can be oxidized to form-C (═ O) -; n, S, P and Si in the ring may also be further oxidized. In one embodiment, a "fused bicyclic ring" or "fused bicyclic group" contains 4 to 16 ring atoms; in other embodiments, a "fused bicyclic ring" or "fused bicyclic group" contains 6 to 16 ring atoms; also in some embodiments, a "fused bicyclic ring" or "fused bicyclic group" contains 8 to 14 ring atoms; in still other embodiments, a "fused bicyclic ring" or "fused bicyclic group" comprises 8 to 12 ring atoms; in still other embodiments, a "fused bicyclic ring" or "fused bicyclic group" contains 8 to 10 ring atoms. Unless otherwise specified, the fused bicyclic group may be a carbon group or a nitrogen group. The fused bicyclic ring system may be [4,5 ]]、[4,6]、[4,7]、[4,8]、[5,5]、[5,6]、[5,7]、[5,8]、[6,6]、[6,7]Or [6,8 ]]And (4) preparing the system. Examples of fused bicyclic rings include, but are not limited to, 5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a]Pyridine, 6, 8-dihydro-5H- [1,2, 4%]Triazolo [3,4-c][1,4]Oxazines, 5,6,7, 8-tetrahydro- [1,2,4 [ ]]Triazolo [4,3-a]Pyrazine, 6, 8-dihydro-5H- [1,2,4]Triazolo [3,4-c][1,4]Thiazine-7, 7-dioxide, 6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazole, 6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazole, 5,6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridine, 6, 8-dihydro-5H-imidazo [2,1-c ]][1,4]Oxazines, 5,6,7, 8-tetrahydroimidazo [1,2-a ]]Pyrazine, 6, 8-dihydro-5H-imidazo [2, 1-c)][1,4]Thiazine-7, 7-dioxide, and the like. The "fused bicyclic ring" or "fused bicyclic group" may be optionally substituted with the substituent described herein.

As described herein, a ring system wherein a substituent is attached to the ring through a bond represents that the substituent may be substituted at any substitutable position on the ring system. For example, formula (a) represents a substituent R^oMay be mono-or polysubstituted in any of the possible substituted positions on the A and B rings as shown in formulae (B) to (h), wherein each R is^oCan be selected from the same or different substitutionsAnd (4) a base.

In addition, unless otherwise expressly indicated, the descriptions "… and … are each independently," "… and … are each independently," and "… and … are each independently" used throughout this document are interchangeable and should be broadly construed to mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

Unless otherwise indicated, the formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, geometric isomers or conformational isomers thereof are within the scope of the present invention.

Unless otherwise indicated, the structural formulae depicted herein and the compounds depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds that are individual stereochemically isomeric forms, enantiomeric forms, diastereomeric forms, geometric forms, conformational forms, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are also within the scope of the present invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

"metabolite" refers to a product obtained by the metabolism of a particular compound of the present invention or a pharmaceutically acceptable salt, analog or derivative thereof in vivo, which exhibits similar activity to the previously described compounds in vivo or in vitro. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage, among others. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane 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 chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50: 50 is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.

As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates; organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, salts of lactic acid, sodium, potassium, sodium, potassium, sodium, potassium, sodium, potassium, sodium, potassium, sodium, magnesium, sodium, magnesium, sodium, magnesium, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts obtained with suitable bases include, alkali metals, alkaline earth metals, ammonium andN⁺(C_1-4alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

The "hydrate" of the present invention means an association of water with the compound of the present invention.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

By "ester" in the context of the present invention is meant that the aforementioned compounds containing a hydroxyl group form an in vivo hydrolysable ester. Such esters are, for example, pharmaceutically acceptable esters which are hydrolysed in the human or animal body to yield the parent alcohol. The group of in vivo hydrolysable esters of the aforementioned compounds containing hydroxyl groups include, but are not limited to: phosphoric acid group, acetoxymethoxy group, 2-dimethylpropionyloxymethoxy group, alkanoyl group, benzoyl group, phenylacetyl group, alkoxycarbonyl group, dialkylcarbamoyl group, N- (dialkylaminoethyl) -N-alkylcarbamoyl group and the like.

"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514), for example by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

The term "prodrug", as used herein, means a compound that is converted in vivo to the compound described previously. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.

The term "protecting group" or "Pg" refers to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "protecting group for amino group" means that a substituent is attached to an amino group to block or protect the functionality of the amino group in the compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethylenoxycarbonyl (Fmoc), among others. Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include methyl, methoxymethyl, acetyl, and silyl groups, among others. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, and nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "therapeutically effective amount" as used herein refers to an amount of a compound as described previously sufficient to obtain the described effect. Thus, a therapeutically effective amount of a compound as hereinbefore described for use in the treatment of ASK1 modulated diseases would be an amount sufficient to treat ASK1 modulated diseases.

The term "cardiorenal disease" as used herein refers to a disease associated with renal function, which may be initiated or exacerbated by cardiovascular problems such as hypertension. Hypertension is widely recognized as 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 "non-alcoholic fatty liver disease (NAFLD)" as used herein is a metabolic disease associated with insulin resistance, including Simple Fatty Liver (SFL), non-alcoholic steatohepatitis (NASH), steatofibrosis and cirrhosis.

The term "liver fibrosis" as used herein includes liver fibrosis due to any cause, including but not limited to virus-induced liver fibrosis such as that caused by hepatitis b and hepatitis c; liver fibrosis due to exposure to alcohol (alcoholic liver disease), pharmaceutical compounds, oxidative stress, cancer radiation or industrial chemicals; and liver fibrosis caused by diseases such as primary biliary cirrhosis, fatty liver, obesity, non-alcoholic steatohepatitis, cystic fibrosis, hemochromatosis, and autoimmune hepatitis.

The term "ASK 1 modulator" as used herein refers to a substance that binds to and modulates the activity of ASK 1.

As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

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 ASK 1. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by modulating ASK1 activity with said compounds. The invention further describes methods for synthesizing the compounds. The compounds of the invention show improved biological activity and pharmacokinetic properties.

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

wherein, E, G, X¹、X²、X³、X⁴、R^x、R^y、R^zM, n and k have the meanings as described in the invention; with the proviso that the compound is not a compound represented by the following structure:

in some embodiments, X¹Is C (R)¹) Or N; r¹Have the meaning as described in the present invention.

In some embodiments, X²Is C (R)²) Or N; r²Having a composition as described in the inventionAnd (5) defining.

In some embodiments, X³Is C (R)³) Or N; r³Have the meaning as described in the present invention.

In some embodiments, X⁴Is C (R)⁴) Or N; r⁴Have the meaning as described in the present invention.

In some embodiments, R¹Is hydrogen, deuterium, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3,4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy groups.

In other embodiments, R¹Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidinyl, dimethylamino, ethoxy, dimethylamino, piperidinyl, dimethylamino, and the like, Glycidylalkyl, tetrahydrofuranyl, tetrahydropyranylAnd morpholinyl may be independently optionally substituted with 1,2,3,4 or 5 groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, R²Is hydrogen, deuterium, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3,4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy groups.

In other embodiments, R²Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidinyl, dimethylamino, ethoxy, dimethylamino, piperidinyl, dimethylamino, and the like, The glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups may be independently optionally substituted by 1,2,3,4 or 5Substituted with a group selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, R³Is hydrogen, deuterium, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3,4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy groups.

In other embodiments, R³Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidinyl, dimethylamino, ethoxy, dimethylamino, piperidinyl, dimethylamino, and the like, The glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups may be independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ i)O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, R⁴Is hydrogen, deuterium, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Alkylthio radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3,4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy groups.

In other embodiments, R⁴Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidinyl, dimethylamino, ethoxy, dimethylamino, piperidinyl, dimethylamino, and the like, The glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups may be optionally substituted with 1,2,3,4 or 5 substituents independently selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trisFluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, E is 5-6 membered heteroaryl.

In other embodiments, E is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, or thiadiazolyl.

In some embodiments, each R is^xIndependently is deuterium, halogen atom, hydroxyl, sulfydryl, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-to 10-membered heterocyclic group, wherein said hydroxyl, mercapto, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-10 membered heterocyclyl may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy groups.

In other embodiments, each R is^xIndependently is deuterium, halogen atom, hydroxyl, sulfydryl, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, wherein said hydroxy, mercapto, amino, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy groups.

In still other embodiments, each R is^xIndependently deuterium, fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl, wherein said hydroxy, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl may independently optionally be substituted with 1,2 or 3 groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxy.

In some embodiments, each R is^yIndependently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, acetyl, acetamido, -COOH, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy or C_1-4A haloalkoxy group.

In other embodiments, each R is^yIndependently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, acetyl, acetamido, -COOH, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, trifluoromethoxy, or difluoromethoxy.

In some embodiments, G is a fused bicyclic ring.

In other embodiments, G is an 8-12 membered fused bicyclic ring.

In still other embodiments, G is

Wherein, W¹、W²、W³、W⁴、W⁵、W⁶、、W⁷、W⁸、R^zAnd k has the meaning described in the present invention.

In still other embodiments, G is

Wherein R is^zAnd k has the meaning described in the present invention.

In some embodiments, W¹independently-O-, -S-or-NH-.

In some embodiments, W²Is CH or N.

In some embodiments, W³Is CH or N.

In some embodiments, W⁴Is CH or N.

In some embodiments, W⁵Is CH or N.

In some embodiments, W⁶is-O-, -S (O)_t-、-C(＝O)-、-CH₂-or-NH-, wherein t has the meaning described herein.

In some embodiments, W⁷is-O-, -S (O)_t-、-C(＝O)-、-CH₂-or-NH-, wherein t has the meaning described herein.

In some embodiments, W⁸is-O-, -S (O)_t-、-C(＝O)-、-CH₂-or-NH-, wherein t has a radical containingAnd (5) defining.

In some embodiments, W is- (CH)₂)_p-、-(CH₂)_pO-、-(CH₂)_pNH-or- (CH)₂)_pS(O)_t-; wherein p and t have the meanings as described in the invention.

In some embodiments, p is 0, 1,2, or 3.

In some embodiments, t is independently 0, 1, or 2.

In some embodiments, each R is^zIndependently hydrogen, deuterium, halogen atom, oxo (═ O), -OR^a、-N(R^b)₂、-N(R^b)C(＝O)R^c、-C(＝O)N(R^b)₂、-OC(＝O)R^c、-C(＝O)OR^d、-S(O)₂OR^d、-S(O)₂R^c、-N(R^b)S(O)₂R^c、-S(O)₂N(R^b)₂Mercapto, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy is substituted by the radical of alkoxy; wherein R is^a、R^b、R^cAnd R^dHave the meaning as described in the present invention.

In other embodiments, each R is^zIndependently hydrogen, deuterium, halogen atom, oxo (═ O), -OR^a、-N(R^b)₂、-N(R^b)C(＝O)R^c、-C(＝O)N(R^b)₂、-OC(＝O)R^c、-C(＝O)OR^d、-S(O)₂OR^d、-S(O)₂R^c、-N(R^b)S(O)₂R^c、-S(O)₂N(R^b)₂Mercapto, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy is substituted by the radical of alkoxy; wherein R is^a、R^b、R^cAnd R^dHave the meaning as described in the present invention.

In still other embodiments, each R is^zIndependently hydrogen, deuterium, halogen atom, oxo (═ O), -OR^a、-N(R^b)₂、-N(R^b)C(＝O)R^c、-C(＝O)N(R^b)₂、-OC(＝O)R^c、-C(＝O)OR^d、-S(O)₂OR^d、-S(O)₂R^c、-N(R^b)S(O)₂R^c、-S(O)₂N(R^b)₂Mercapto, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyloxy, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, trifluoromethyl, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, pyridyl, oxazolyl, and so-ylA mercapto group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxy group, an isopropyloxy group, a methylthio group, a methylamino group, a dimethylamino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a glycidyloxy group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a morpholinyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, 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 and a thiadiazolyl group may be independently and optionally substituted by 1,2 or 3 groups selected from deuterium, fluorine, chlorine, bromine, iodine, a hydroxyl group, an oxo (═ O), an amino group, a nitro group, a cyano group, a methyl group, an ethyl group, a trifluoromethyl group, a difluoromethyl group, Methoxy, ethoxy and isopropyloxy; wherein R is^a、R^b、R^cAnd R^dHave the meaning as described in the present invention.

In some embodiments, R^aIs hydrogen, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy groups.

In other embodiments, R^aIs hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy groups.

In still other embodiments, R^aIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, said methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, The epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, and thiadiazolyl groups may be independently optionally substituted with 1,2, or 3 groups selected from deuterium, a halogen atom, hydroxyl, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, and isopropyloxy.

In some embodiments, R^bIs hydrogen, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, saidC of (A)_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy groups.

In other embodiments, R^bIs hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy groups.

In still other embodiments, R^bIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, the methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl.The optionally substituted heteroaryl group may be independently substituted with 1,2 or 3 groups selected from deuterium, a halogen atom, hydroxy, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, and isopropyloxy.

In some embodiments, R^cIs hydrogen, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy groups.

In other embodiments, R^cIs hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy groups.

Also in some embodimentsIn the scheme, R^cIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, said methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, The epoxypropyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, and thiadiazolyl groups may be independently optionally substituted with 1,2, or 3 groups selected from deuterium, a halogen atom, hydroxyl, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, and isopropyloxy.

In some embodiments, R^dIs hydrogen, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6Alkoxy groups.

In other embodiments, R^dIs hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl or 5-to 10-membered heteroaryl, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl groups may be independently optionally substituted with 1,2 or 3 substituents selected from deuterium, halogen, hydroxy, oxo (═ O), amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy groups.

In still other embodiments, R^dIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl or thiadiazolyl, said methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclopropyl, trifluoromethyl, difluoromethyl, methoxy, isopropyloxy, methylthio, methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, The alkylene oxide group may be optionally substituted with 1,2 or 3 groups selected from deuterium, a halogen atom, hydroxyl, oxo (═ O), amino, nitro, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropyloxyGroup substitution.

In some embodiments, m is 1,2, or 3.

In some embodiments, n is 1,2, or 3.

In some embodiments, k is 1,2,3,4, or 5.

In some embodiments, the compound of the present invention is a compound of formula (IIa), (IIb), (IIc), (IId), or (IIe), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (IIa), (IIb), (IIc), (IId), or (IIe),

wherein, X is¹、X²、X³、X⁴、W、W¹、W²、W³、W⁴、W⁵、W⁶、W⁷、W⁸、R^x、R^y、R^zN and k have the meanings given in the description.

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

in another aspect, the present invention relates to a pharmaceutical composition comprising a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

In another aspect, the invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention, treatment or alleviation of an ASK1 modulated disease in a patient.

In some embodiments, the ASK 1-mediated disease is an autoimmune disease, an inflammatory disease, a cardiovascular disease, a cardiorenal disease, a fibrotic disease, a respiratory disease, a liver disease, or a neurodegenerative disease.

In some embodiments, cardiovascular disease includes diabetes, diabetic nephropathy, and other diabetic complications.

In some of these embodiments, the fibrotic disease comprises pulmonary and renal fibrosis.

In some embodiments, the respiratory disease comprises chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and acute lung injury.

In some embodiments, the liver disease comprises chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury, and primary biliary cirrhosis.

One aspect of the invention pertains to methods for preventing, treating or ameliorating an ASK1 modulated disorder in a subject comprising administering to the subject a pharmaceutically acceptable effective amount of a compound of the invention.

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

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

In another aspect, the pharmaceutical compositions of the invention are characterized by including a compound as set forth above, a compound as set forth herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the invention is effective to detectably treat or ameliorate an ASK 1-mediated disorder in a subject.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any solvent, diluent, or other liquid vehicle, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

The compounds of the present invention may be incorporated as the active ingredient in a homogeneous mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). When preparing compositions for oral dosage form, any conventional pharmaceutical media may be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the preparation of oral liquid preparations such as suspensions, elixirs and solutions; or in the preparation of oral solid preparations such as powders, hard capsules, soft capsules and tablets using, for example, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, wherein solid oral preparations are more preferable than liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated using standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. Of course, the percentage of active compound in these compositions may vary, and may conveniently be between about 2% to about 60% of the weight of the unit. The active compounds can be administered intranasally, for example, in the form of drops or sprays.

The tablets, pills, capsules, etc. may also comprise: binders (such as gum tragacanth, acacia, corn starch or gelatin); excipients (such as dicalcium phosphate); disintegrating agents (such as corn starch, potato starch, alginic acid); lubricants (such as magnesium stearate); and a sweetening agent (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, 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 propylparabens as preservatives, a dye and flavoring (e.g., cherry or orange flavor).

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

The compounds of the invention may also be administered parenterally. Solutions or suspensions of these actives can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersants may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

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

Any suitable method of administration may be employed to provide an effective dose of a compound of the invention to a mammal, especially a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like methods of administration may 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 the compounds, pharmaceutical compositions or combinations thereof of the present invention will depend on the species, weight, age and 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 conditions for which ASK1 is regulated as indicated by the compounds of the present invention, substantially satisfactory results are obtained when the compounds of the present invention are administered in daily doses of from about 0.1 mg to about 100mg per kilogram of animal body weight, preferably in single daily doses, or in divided doses from 2 to 6 times per day, or in continuous release form. For most large mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1mg to about 50 mg. For a 70 kg adult, the total daily dose is typically from 7mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.

The compound, the composition or the medicinal salt or the hydrate thereof can be effectively used for preventing, treating or relieving the ASK 1-regulated diseases of patients, and particularly can be effectively used for treating diabetes, diabetic nephropathy, other diabetic complications, chronic nephropathy, lung and kidney fibrosis, chronic embolic lung obstruction, idiopathic pulmonary fibrosis, acute lung injury, chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, other hepatitis and the like.

General synthetic methods

In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as previously defined. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. 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. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. The nuclear magnetic resonance spectrum is measured under the conditions of room temperature and a Bruker (Bruker) nuclear magnetic instrument with 400MHz or 600MHz and CDC1₃,DMSO-d₆,CD₃OD or d₆Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton, singlet), d (doublet ), t (triplet, triplet), m (multiplet ), br (broad, doublet), dd (doublet of doublets, doublet), q (quatet, quartet), dt (doublet of triplets, doublet), tt (triplet of triplets, triplets), dddd (doublet of doublet of doublets, doublet of doublets), qd (quatet of doublets, quartet of doublets), ddd (doublet of doublets ), td (triplet of doublets, triplets), dq (doublet of doublets ),double quartet), ddt (doublet of doublets, tdd (triplet of doublets), dtd (doublet of doublets ), and dtd (doublet of triplets, doublet of doublets). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

table 1: gradient elution conditions for low resolution mass spectrometry mobile phase

The purity of the compounds was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The following acronyms are used throughout the invention:

CDC1₃deuterated chloroform

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide

CD₃OD deuterated methanol

MeOH methanol

THF tetrahydrofuran

DCM dichloromethane

EtOAc, EA ethyl acetate

PE Petroleum Ether

Pd/C, Pd-C palladium/carbon

g

mg of

H₂O water

M mol per liter

mol mole of

mmol millimole

mL of

Microliter of μ L

Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. E, G, W, X unless otherwise stated¹、X²、X³、X⁴、R^x、R^y、R^zM, n and k have the meanings as described in the invention.

Synthetic schemes

Synthesis scheme 1

Wherein L is¹Is halogen.

The compound (I) can be obtained by reacting the compound (Ia) with the compound (Ib). The reaction starting materials may be reacted in a solvent in the presence of a base (e.g., N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.). The reaction is preferably carried out in a solvent inert to the reaction, including but not limited to dichloromethane, N-dimethylformamide, and the like.

Synthesis scheme 2

Wherein L is²As leaving groups, including but not limited to halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and the like.

The compound (I) can be obtained by coupling the compound (Ic) and the compound (Id) in the presence of a palladium catalyst. The reaction raw materials may be reacted in a solvent in the presence of a base (e.g., sodium carbonate, cesium carbonate, etc.). The reaction is preferably carried out in a solvent inert to the reaction, including but not limited to dioxane, tetrahydrofuran, and the like.

Synthesis scheme 3

The carboxylic acid compound (Ie) reacts with a chlorinating agent to obtain an acid chloride compound (If), and the acid chloride compound (If) reacts with ammonia water to obtain an amide compound (Ic).

Synthesis scheme 4

Wherein L is²As leaving groups, including but not limited to halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and the like.

The hydrazide compound (Ih) and the compound (Ii) are heated in an inert solvent to cause a ring-closing reaction to produce the compound (Ij).

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Detailed Description

Examples

Example 15- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide

First step 6-Bromopyridine carboxylic acid methyl ester

Concentrated sulfuric acid (5mL) is dripped into a methanol (350mL) solution of 6-bromopicolinic acid (50.0g,248mmol) at room temperature, after dripping, the solution is heated and refluxed until the reaction is finished, most of solvent is evaporated under reduced pressure, the residue is diluted by adding water (300mL), and the system is adjusted to be alkalescent by saturated sodium bicarbonate solution. Extraction with ethyl acetate (200mL × 2) and drying of the organic phase over anhydrous sodium sulfate, filtration and concentration gave the title compound as a white solid (51.5g, 96%).

Second step 6-bromopyridine carbohydrazide

To a solution of methyl 6-bromopicolinate (3.0g,14mmol) in methanol (50mL) was added hydrazine monohydrate (4mL, 80%), heated to reflux to completion and concentrated under reduced pressure to give the title compound as a yellow solid (2.9g, 97%).

The third step is 6-methoxy-2, 3,4, 5-tetrahydropyridine

To a solution of 2-piperidone (3.0g,30mmol) in dichloromethane (50mL) was added trimethyloxonium tetrafluoroborate (6.0g,41mmol) and the mixture was stirred at room temperature for 4 h. Adding saturated sodium bicarbonate water solution under ice bath to adjust the system to be neutral. Dichloromethane (50mL × 2) extraction, combined organic phases, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow clear oil (2.3g, 67%).

MS(ESI,pos.ion)m/z:114.1[M+1]⁺。

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

A solution of 6-bromopicolinohydrazide (3.0g,14mmol) and 6-methoxy-2, 3,4, 5-tetrahydropyridine (2.3g,20mmol) in dimethylsulfoxide (50mL) was heated to 90 ℃ and stirred overnight. After naturally cooling to room temperature, water (50mL) was added for dilution, ethyl acetate (100mL × 3) was extracted, the organic phases were combined, the organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane: methanol (v/v) ═ 30:1) to give the title compound as a yellow oil (1.0g, 26%).

MS(ESI,pos.ion)m/z:280.1[M+1]⁺。

The fifth step tert-butyl (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) carbamate

A solution of 3- (6-bromopyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine (1.0g,3.6mmol), tert-butyl carbamate (0.5g,4mmol), cesium carbonate (3.0g,9.2mmol), palladium acetate (80mg,0.36mmol), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (45mg,0.38mmol) in 1, 4-dioxane (30mL) was heated to 110 deg.C under nitrogen and stirred overnight. After naturally cooling to room temperature, the reaction was quenched by adding saturated ammonium chloride (50mL), extracted with ethyl acetate (100mL × 3), the organic phases were combined, washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane: methanol (v/v) ═ 30:1) to give the title compound as a yellow oil (250mg, 22%).

MS(ESI,pos.ion)m/z:316.2[M+1]⁺。

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

Trifluoroacetic acid (1mL) was added dropwise to a solution of tert-butyl (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) carbamate (250mg,0.8mmol) in dichloromethane (20mL) at room temperature, and stirring was continued for 3 h. The reaction solution was made weakly basic by saturated sodium bicarbonate (30mL), extracted with dichloromethane (30mL × 2), the organic phases were combined, washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane: methanol (v/v) ═ 20:1) to give the title compound as a yellow oil (50mg, 29%).

MS(ESI,pos.ion)m/z:216.2[M+1]⁺。

Seventh step 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide

Oxalyl chloride (0.5mL,6mmol) and N, N-dimethylformamide (0.05mL) were slowly added dropwise to 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid (100mg,0.3842mmol) in anhydrous dichloromethane (20mL) under nitrogen, stirred at room temperature for 2H, and the solvent was evaporated under reduced pressure to give 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-benzoyl chloride as a yellow solid, 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-benzoyl chloride was dissolved in dichloromethane (20mL), followed by addition of 6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-amine (50mg,0.23mmol) and 4-dimethylaminopyridine (10mg,0.082mmol) were stirred at room temperature overnight. The reaction was quenched by the addition of saturated sodium bicarbonate (20 mL). Dichloromethane (50mL × 2) was added for extraction, the organic phase was washed with saturated brine (30mL × 2), the organic phase was collected, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol (v/v) ═ 25:1) to give the title final product as a white solid powder (15mg, 14%).

MS(ESI,neg.ion)m/z:456.2[M-H]^-。

¹H NMR(400MHz,CDCl₃)δ9.05(d,J＝14.7Hz,1H),8.37(d,J＝8.2Hz,1H),8.08(t,J＝7.6Hz,2H),7.90(t,J＝8.0Hz,1H),7.46(s,1H),7.21(d,J＝12.3Hz,1H),6.81(s,1H),4.51(t,J＝5.9Hz,2H),3.10(t,J＝6.4Hz,2H),2.30(s,3H),2.08-2.06(m,1H),2.01-1.96(m,2H),1.94-1.91(m,2H),0.93-0.89(m,2H),0.86-0.82(m,2H)。

Example 25- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide

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

To a solution of tetrahydropyrrole-2-thione (4.33g,42.8mmol) in dichloromethane (20mL) was added dimethyl sulfate (8.10mL,85.6mmol) and the mixture was stirred at room temperature overnight. After quenching with saturated aqueous ammonium chloride (10mL), extraction with ethyl acetate (30 mL. times.2) was carried out, and the organic phases were combined, washed with saturated brine (20mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 4:1) to give the title compound as a pale yellow solid (4.93g, 100%).

MS(ESI,pos.ion)m/z:116.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ 4.20(t, J ═ 7.4Hz,2H),3.18(t, J ═ 8.0Hz,2H),2.87(s,3H),2.44-2.36(m, 2H). Second step 3- (6-Bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazole

5- (methylthio) -3, 4-dihydro-2H-pyrrole (500mg,4.3403mmol), 6-bromopicolinohydrazide (1.41g,6.53mmol), triethylamine (1.21mL,8.71mmol) and isopropanol (15mL) were added to a microwave tube and reacted at 150 ℃ for 3 hours with a microwave. After naturally cooling to room temperature, concentration was performed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 100:1) to give the title compound as a pale yellow solid (793mg, 69%).

MS(ESI,pos.ion)m/z:265.0[M+H]⁺。

¹H NMR(400MHz,CDCl₃)δ8.26-8.24(m,1H),7.68(t,J＝7.8Hz,1H),7.51-7.49(m,1H),4.50-4.41(m,2H),3.09-3.01(m,2H),2.87-2.79(m,2H)。

The third step is 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride

Oxalyl chloride (16mL,190mmol) was slowly added dropwise to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid (24.7g,94.9mmol), N-dimethylformamide (0.07mg,0.001mmol) in dichloromethane (100mL) under nitrogen protection in ice bath, after dropwise addition, stirred at room temperature for 3 hours, and concentrated under reduced pressure to give the title compound as a yellow solid (26.4g, 99.8%).

The fourth step is 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

To a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (26.4g,94.7mmol) in dichloromethane (30mL) was slowly added dropwise aqueous ammonia (73mL,1900mmol), and the mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 20/1) to give the title compound as an off-white solid (21.0g, 86%).

The fifth step is 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide

A solution of 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (291mg,1.01mmol), 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (259mg,1.0mmol), cesium carbonate (814mg,2.50mmol), palladium acetate (23mg,0.10mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (60mg,0.10mmol) in 1, 4-dioxane (10mL) was heated to 80 ℃ under nitrogen and stirred overnight. After naturally cooling to room temperature, the reaction was quenched by adding saturated aqueous ammonium chloride (10mL), extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with saturated brine (10mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound as a pale black solid (150mg, 34%).

MS(ESI,pos.ion)m/z:444.3[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆)δ10.91(s,1H),8.16(s,1H),8.00(s,1H),7.87(s,1H),7.71(s,1H),7.64-7.62(m,1H),7.50-7.48(m,1H),7.18(s,1H),4.40-4.38(m,2H),2.89-2.87(m,2H),2.70-2.68(m,2H),2.25(s,3H),1.89-1.84(m,1H),0.80-0.70(m,4H)。

Example 35- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide

First step 5-methoxy-3, 6-dihydro-2H-1, 4-oxazines

A100 mL single vial was taken and 3-morpholinone (2.0g,20mmol) was dissolved in dichloromethane (40mL) and trimethyloxonium tetrafluoroborate (4.0g,27mmol) was added and stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (50mL) in an ice bath and the pH was adjusted to neutral. Dichloromethane (50mL × 2) was added for extraction, and the mixture was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a transparent oil (1.0g, 44%).

¹H NMR(400MHz,CDCl₃)δ4.01(d,J＝1.2Hz,2H),3.65(d,J＝2.3Hz,3H),3.62(dd,J＝6.5,3.2Hz,2H),3.51(dd,J＝6.5,2.9Hz,2H)。

The second step is 3- (6-bromopyridine-2-yl) -6, 8-dihydro-5H- [1,2,4] triazole [3,4-c ] [1,4] oxazine

6-Bromopyridinecarboxhydrazide (1.9g,8.8mmol) and 5-methoxy-3, 6-dihydro-2H-1, 4-oxazine (1.0g,8.7mmol) were dissolved in dimethyl sulfoxide (50mL), heated to 100 ℃ and stirred overnight. Naturally cooled to room temperature, diluted with water (100mL) and the resulting solid filtered to give the title compound as a white flocculent solid (1.1g, 45%).

MS(ESI,pos.ion)m/z:281.0[M+1]⁺。

The third step is 5- (4-cyclopropyl-1H-imidazole-1-yl) -N- (6- (6, 8-dihydro-5H- [1,2,4] triazole [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide

Starting from 3- (6-bromopyridin-2-yl) -6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine (500mg,1.8mmol), 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (500mg,1.9mmol), the title compound was prepared as a white solid (400mg, 49%) by the synthesis in the fifth step of example 2.

MS(ESI,pos.ion)m/z:460.2[M+1]⁺。

¹HNMR(400MHz,DMSO-d₆)δ10.98(s,1H),8.20(d,J＝8.2Hz,1H),8.03(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),7.70(s,1H),7.63(d,J＝6.5Hz,1H),7.48(d,J＝10.7Hz,1H),7.18(s,1H),4.98(s,2H),4.57(t,J＝5.0Hz,2H),4.04(t,J＝5.1Hz,2H),2.25(s,3H),1.88-1.81(m,1H),0.84-0.77(m,2H),0.74-0.67(m,2H)。

Example 44- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) picolinamide

The first step is as follows: 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinic acid methyl ester

2-chloro-4- (4-cyclopropyl-1H-imidazol-1-yl) pyridine (1.0g,4.6mmol), triethylamine (1.3mL,9.4mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (330mg,0.45mmol) were dissolved in anhydrous methanol (50mL), replaced 3 times with carbon monoxide gas, placed in a carbon monoxide atmosphere, warmed to 100 ℃ and stirred for 48H. After naturally cooling to room temperature, the mixture was filtered through celite, the filter cake was washed with methanol, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1/1) to give a yellow oily compound (1.0g, 90%).

MS(ESI,pos.ion)m/z:244.1[M+H]⁺；

The second step is that: 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinic acid

To a solution of methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinate (800mg,3.3mmol) in methanol (25mL) at room temperature was added sodium hydroxide solution (10mL,5mol/L) and the mixture was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure and the residual aqueous solution was made weakly acidic with dilute hydrochloric acid. Filtration, washing of the filter cake with water and drying at 50 ℃ under reduced pressure gave the compound as a white solid (750mg, 100%).

MS(ESI,pos.ion)m/z:230.1[M+H]⁺；

The third step: 4- (4-cyclopropyl-1H-imidazol-1-yl) pyridinecarboxylic acid chlorides

Starting from 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinic acid (700mg,3.05mmol), the title compound (750mg, 99%) was prepared as a yellow solid according to the synthesis method of the third step of example 2

The fourth step: 4- (4-cyclopropyl-1H-imidazol-1-yl) pyridinecarboxamide

The title compound (400mg, 58%) was obtained as a white solid by the synthesis method according to the fourth step of example 2 using 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinoyl chloride (750mg,3.0mmol) as a starting material.

MS(ESI,pos.ion)m/z:229.2[M+H]⁺；

The fifth step: 4- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) picolinamide

Starting from 4- (4-cyclopropyl-1H-imidazol-1-yl) picolinamide (200mg,0.87mmol), the title compound (50mg, 14%) was prepared as a white solid according to the synthesis method in the fifth step of example 2.

MS(ESI,pos.ion)m/z:413.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ10.40(s,1H),8.73(d,J＝5.4Hz,1H),8.44(d,J＝8.1Hz,1H),8.33(d,J＝2.0Hz,1H),8.12(d,J＝7.6Hz,1H),8.04(d,J＝0.9Hz,1H),7.93(t,J＝8.0Hz,1H),7.53-7.51(m,1H),7.25(s,1H),4.58–4.52(m,2H),3.07(t,J＝7.7Hz,2H),2.92–2.83(m,2H),1.98–1.91(m,1H),0.98–0.92(m,2H),0.91–0.84(m,2H)。

Example 53- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide

The first step is as follows: 3-Aminobenzoic acid methyl ester

Pd/C (2g,18.79mmol) was added to a solution of methyl 3-nitrobenzoate (26.0g,144mmol) in methanol (300mL), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (21.7g, 100%) as a yellow oil.

The second step is that: 3- ((2-cyclopropyl-2-oxoethyl) amino) benzoic acid methyl ester

Potassium carbonate (23.6g,171mmol) and potassium iodide (26.0g,157mmol) were added to a solution of methyl 3-aminobenzoate (21.5g,142mmol) in DMF (300mL) under nitrogen, stirred at room temperature for 5 minutes, then alpha-bromocyclopropanone (35.0g,215mmol) was slowly added, and after dropwise addition, the reaction was allowed to warm to 60 deg.C, stirred overnight, and allowed to cool to room temperature. The reaction solution was filtered through celite, the filter cake was washed with ethyl acetate (200mL), the filtrate was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 8:1) to give the title compound (18.5g, 56%) as a yellow solid;

MS(ESI,pos.ion)m/z:234.4[M+H]⁺；

the third step: 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) benzoic acid methyl ester

To a solution of methyl 3- ((2-cyclopropyl-2-oxoethyl) amino) benzoate (18.5g,79.3mmol) in acetic acid (250mL) was added potassium thiocyanate (15.5g,159mmol), and the reaction was warmed to 120 ℃ and stirred overnight. After naturally cooling to room temperature, ethyl acetate (200 mL. times.3) was extracted, the organic phases were combined, the organic phases were washed with saturated brine (100mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21.8g, 100%) as a yellow solid.

MS(ESI,neg.ion)m/z:273.1[M-1]^-；

The fourth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid methyl ester

In a mixed solution of 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) benzoic acid methyl ester (21.8g,79.5mmol) in acetic acid (200mL) and water (80mL), hydrogen peroxide (25mL,831mmol) was slowly added dropwise, and after completion of addition, the reaction solution was heated to 45 ℃ and stirred for 1H. Most of the solvent was distilled off under reduced pressure, the residue was made weakly basic by a saturated sodium bicarbonate solution, dichloromethane (200mL × 2) was extracted, the organic phase was washed with a saturated saline (100mL × 2), the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1/1) to obtain the title compound (8.2g, 43%) as a yellow oil.

MS(ESI,pos.ion)m/z:243.1[M+H]⁺；

The fifth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid

Starting from methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate (2.90g,12.0mmol), the title compound was prepared as a yellow solid (1.5g, 55%) according to the synthesis procedure of the second step of example 4;

MS(ESI,pos.ion)m/z:229.1[M+H]⁺；

and a sixth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid (600mg,2.6mmol), the title compound was prepared as a yellow solid (620mg, 96%) according to the synthesis procedure in the third step of example 2;

the seventh step: 3- (4-cyclopropyl-1H-imidazol-1-yl) benzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride (500mg,2.0mmol), the title compound (100mg, 22%) was prepared as a yellow solid by the synthesis method according to the fourth step of example 2.

MS(ESI,pos.ion)m/z:228.1[M+H]⁺；

Eighth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) benzamide (100mg,0.44mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (120mg,0.45mmol), the title compound was prepared as a white solid (8mg, 4%) by the synthesis of the fifth step of example 2.

MS(ESI,pos.ion)m/z:412.1[M+H]⁺；

¹HNMR(400MHz,CDCl₃)δ8.62(s,1H),8.37(d,J＝8.1Hz,1H),8.06(d,J＝7.5Hz,1H),8.02(s,1H),7.95–7.90(m,1H),7.90–7.84(m,2H),7.65(t,J＝7.6Hz,1H),7.60(d,J＝7.7Hz,1H),7.14(s,1H),4.48–4.33(m,2H),3.08–2.95(m,2H),2.87–2.74(m,2H),2.07–1.96(m,1H),0.96–0.90(m,2H),0.87–0.81(m,2H)。

Example 65- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluorobenzamide

First step methyl 2-fluoro-5-nitrobenzoate

Starting from 2-fluoro-5-nitrobenzoic acid (10.0g,54.0mmol), the title compound was prepared as a yellow solid (10.0g, 93%) according to the synthetic method of the first step of example 1;

second step methyl 5-amino-2-fluorobenzoate

Concentrated hydrochloric acid (4.60mL,55.2mmol) was added to a mixture of iron powder (11.2g,200mmol) and water (20mL) at room temperature to adjust the pH to 1, the reaction was allowed to warm to 60 ℃ and stirred for 15 minutes, after which a solution of methyl 2-fluoro-5-nitrobenzoate (10.0g,50.2mmol) in methanol (60mL) was slowly added dropwise. After dropping, the pH was adjusted to 3 with concentrated hydrochloric acid (4.60mL,55.2mmol), and the reaction was stirred under reflux for h. Naturally cooling to room temperature, dropwise adding sodium hydroxide aqueous solution to adjust pH to 8, heating to 50 ℃, carrying out suction filtration, washing a filter cake with ethyl acetate, evaporating the solvent from the filtrate under reduced pressure, extracting with ethyl acetate (200mL multiplied by 2), combining organic phases, washing the organic phases with saturated saline (100mL), and drying with anhydrous sodium sulfate. Filtration, evaporation of the solvent under reduced pressure and silica gel column chromatography of the residue (petroleum ether: ethyl acetate (v/v) ═ 10/1) gave the title compound as a yellow solid (4.50g, 53%);

¹HNMR(400MHz,CDCl₃)δ7.22–7.20(m,1H),6.97–6.92(m,1H),6.85–6.77(m,1H),3.93(s,3H),3.66(s,2H)。

the third step, methyl 5- ((2-cyclopropyl-2-oxoethyl) amino) -2-fluorobenzoate

Starting from methyl 5-amino-2-fluorobenzoate (2.24g,13.2mmol), the title compound (3.33g, 100%) was prepared as a yellow solid according to the synthesis of the second step of example 5;

MS(ESI,pos.ion)m/z:252.1[M+H]⁺；

the fourth step 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluorobenzoic acid methyl ester

Starting from methyl 5- ((2-cyclopropyl-2-oxoethyl) amino) -2-fluorobenzoate (3.33g,13.3mmol), the title compound (3.87g, 100%) was prepared as a yellow solid according to the synthesis procedure of the third step of example 5;

fifth step 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoic acid methyl ester

Starting from methyl 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluorobenzoate (3.87g,13.2mmol), the title compound was prepared as a yellow solid (250mg, 7%) by the synthetic method according to the fourth step of example 5;

MS(ESI,pos.ion)m/z:261.2[M+H]⁺；

the sixth step is 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoic acid

Starting from methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoate (250mg,0.96mmol), the title compound (236mg, 100%) was prepared as a pale yellow solid according to the synthesis procedure of the second step of example 4;

MS(ESI,pos.ion)m/z:247.2[M+H]⁺；

seventh step 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoyl chloride

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoic acid (236mg,0.96mmol), according to the synthesis method of the third step of example 2, the title compound (253mg, 100%) was prepared as a yellow solid;

eighth step 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluorobenzamide

5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluorobenzoyl chloride (252mg,0.95mmol) was dissolved in dichloromethane (30mL), followed by the addition of 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (146mg,0.73mmol) and 4-dimethylaminopyridine (9mg,0.074mmol), and stirring at room temperature overnight. The reaction was quenched by addition of saturated sodium bicarbonate (20mL), extracted with dichloromethane (50mL × 2), the organic phase was washed with saturated brine (30mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was purified by column chromatography (dichloromethane: methanol (v/v) ═ 20:1) to give the title compound (40mg, 13%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:430.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ9.12–9.09(m,1H),8.39–8.37(m,1H),8.23–8.21(m,2.8Hz,1H),8.13(d,J＝7.6Hz,1H),7.93(t,J＝8.0Hz,1H),7.79(s,1H),7.64–7.54(m,1H),7.37–7.35(m,1H),7.08(s,1H),4.47(t,J＝7.2Hz,2H),3.07(t,J＝7.6Hz,2H),2.93–2.80(m,2H),1.96–1.91(m,1H),0.96–0.91(m,2H),0.87–0.82(m,2H)。

Example 73- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide

First step methyl 4-methyl-3-nitrobenzoate

Starting from 4-methyl-3-nitrobenzoic acid (4.70g,25.9mmol), the title compound was prepared as a pale yellow solid (5.00g, 99%) according to the synthesis procedure of the first step of example 1;

second step methyl 3-amino-4-methylbenzoate

Starting from methyl 4-methyl-3-nitrobenzoate (5.00g,25.6mmol), the title compound was prepared as a pale yellow solid (4.23g, 100%) according to the synthetic method of the first step of example 5;

the third step methyl 3- ((2-cyclopropyl-2-oxoethyl) amino) -4-methylbenzoate

Starting from methyl 3-amino-4-methylbenzoate (4.23g,25.6mmol), the title compound (6.33g, 100%) was prepared as a yellow solid according to the synthesis of the second step of example 5;

the fourth step 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -4-methylbenzoic acid methyl ester

Starting from methyl 3- ((2-cyclopropyl-2-oxoethyl) amino) -4-methylbenzoate (6.33g,25.6mmol), the title compound was prepared as a yellow solid (7.38g, 100%) by reference to the synthesis procedure in the third step of example 5;

fifth step methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoate

Starting from methyl 3- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -4-methylbenzoate (7.38g,25.6mmol), the title compound was prepared as a yellow solid (1.70g, 26%) by reference to the synthesis in the fourth step of example 5;

MS(ESI,pos.ion)m/z:257.2[M+H]⁺；

the sixth step is 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoic acid

Starting from methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoate (1.70g,6.63mmol), the title compound was prepared as a pale yellow solid (1.10g, 68%) according to the synthesis procedure of the second step of example 4;

¹HNMR(400MHz,DMSO)δ7.91–7.90(m,1H),7.73(s,2H),7.54(d,J＝8.0Hz,1H),7.19(s,1H),2.24(s,3H),1.86–1.82(m,1H),0.85–0.77(m,2H),0.74–0.67(m,2H)。

seventh step 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoic acid (309mg,1.28mmol), according to the synthesis procedure of the third step of example 2, the title compound (332mg, 100%) was prepared as a yellow solid;

eighth step 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylbenzoyl chloride (331mg,1.27mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (213mg,1.06mmol), the title compound was prepared as a pale yellow solid (80mg, 18%) according to the synthesis procedure of the eighth step of example 6;

MS(ESI,pos.ion)m/z:426.4[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ10.76(s,1H),8.14(d,J＝7.8Hz,1H),7.99–7.97(m,2H),7.92(s,1H),7.85(d,J＝7.3Hz,1H),7.78(s,1H),7.59(d,J＝7.6Hz,1H),7.25(s,1H),4.48–4.44(m,2H),2.31–2.87(m,2H),2.72–2.68(m,2H),2.28(s,3H),1.89–1.85(m,1H),0.82–0.80(m,2H),0.73–0.71(m,2H)。

EXAMPLE 8N- (6- ([1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

The first step is as follows: 2-bromo-6- ((2- (pyridin-2-yl) hydrazono) methyl) pyridine

2-hydrazinopyridine (1.0g,9.2mmol) and 6-bromopyridine-2-carbaldehyde (1.8g,9.7mmol) were dissolved in anhydrous ethanol (30mL), glacial acetic acid (0.05mL) was added dropwise, the temperature was raised to 80 ℃, the mixture was condensed under reflux, and the mixture was stirred overnight. Suction filtration gave the title compound as a pale yellow solid (2.0g, 79%).

MS(ESI,pos.ion)m/z:278.1[M+H]⁺；

The second step is that: 3- (6-bromopyridin-2-yl) - [1,2,4] triazolo [4,3-a ] pyridine

2-bromo-6- ((2- (pyridin-2-yl) hydrazylidene) methyl) pyridine (2.0g,7.2mmol) and iodophenylenediacetic acid (6.0g,18mmol) were dissolved in dichloromethane (30mL) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 1/1) to give the title compound as a white solid (1.9g, 96%).

MS(ESI,pos.ion)m/z:276.0[M+H]⁺；

The third step: n- (6- ([1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (470mg,1.8mmol) and 3- (6-bromopyridin-2-yl) - [1,2,4] triazolo [4,3-a ] pyridine (500mg,1.8mmol), the title compound was prepared as a white solid (240mg, 29%) by the fifth synthesis procedure of example 2.

MS(ESI,pos.ion)m/z:454.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ9.61(d,J＝7.1Hz,1H),9.20(d,J＝14.5Hz,1H),8.39(d,J＝8.2Hz,1H),8.34(d,J＝7.6Hz,1H),8.07(d,J＝7.3Hz,1H),7.97(t,J＝8.0Hz,1H),7.88(d,J＝9.2Hz,1H),7.46(s,1H),7.39–7.35(m,1H),7.22(d,J＝12.2Hz,1H),6.99(t,J＝6.6 Hz,1H),6.82(s,1H),2.31(s,3H),1.94–1.88(m,1H),0.94–0.88(m,2H),0.87–0.80(m,2H)。

Example 92- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) isonicotinamide

The first step is as follows: 2-carboxamidoisoinicotinic acid methyl ester

Formic acid (1.5mL,40mmol) was slowly added dropwise to acetic anhydride (4mL,42.6mmol) and after addition, the temperature was raised to 65 ℃ and stirred for 2h and then cooled to room temperature, the reaction solution was slowly added dropwise to a solution of 2-aminoisonicotinic acid methyl ester (2.0g,13mmol) in tetrahydrofuran (20mL) in ice bath and after addition, the solution was raised to room temperature and stirred overnight. Most of the solvent was distilled off under reduced pressure, and the obtained residue was made weakly alkaline with saturated sodium bicarbonate (50mL), extracted with ethyl acetate (50 mL. times.2), washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound as a white solid (2.0g, 84%);

MS(ESI,pos.ion)m/z:181.1[M+H]⁺；

the second step is that: 2- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) isonicotinic acid methyl ester

A-bromocyclopropanone (2.7mL,28mmol) was slowly added dropwise to a solution of methyl 2-carboxamidoisonoate (2.0g,11mmol), potassium iodide (180mg,1.1mmol) and potassium phosphate (8.2g,39mmol) in N, N-dimethylformamide (40mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50mL), extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 3/1) to give the title compound as a yellow oil (2.8g, 96%);

MS(ESI,pos.ion)m/z:263.1[M+H]⁺；

the third step: 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinic acid methyl ester

Methyl 2- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) isonicotinite (2.5g,9.5mmol) was dissolved in glacial acetic acid (40mL), ammonium acetate (2.2g,29mmol) was added, the temperature was raised to 120 ℃ and stirring was carried out under reflux overnight. Naturally cooling to room temperature, and evaporating a large amount of solvent under reduced pressure. The reaction mixture was diluted with water (20mL), made weakly basic with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1/1) to give the title compound (880mg, 38%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:244.2[M+H]⁺；

The fourth step: 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinic acid

Starting from methyl 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinate (880mg,3.6mmol), the title compound was prepared as a pale yellow solid (550mg, 66%) according to the synthesis procedure of the second step of example 4;

the fifth step: 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinoyl chloride

Starting from 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinic acid (300mg,1.3mmol), the title compound was prepared as a white solid (300mg, 93%) according to the synthesis procedure in the third step of example 2;

and a sixth step: 2- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) isonicotinamide

Starting from 2- (4-cyclopropyl-1H-imidazol-1-yl) isonicotinoyl chloride (300mg,1.2mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (240mg,1.19mmol), the title compound was prepared as a white solid (320mg, 64%) according to the synthesis procedure of the eighth step of example 6;

MS(ESI,pos.ion)m/z:413.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ11.03(s,1H),8.67(d,J＝5.0Hz,1H),8.49(s,1H),8.18(d,J＝5.6Hz,2H),8.05(t,J＝7.9Hz,1H),7.91(d,J＝7.6Hz,1H),7.81(s,1H),7.75(d,J＝5.0Hz,1H),4.45(t,J＝7.1Hz,2H),2.91(t,J＝7.5Hz,2H),2.75–2.67(m,2H),1.93–1.85(m,1H),0.86–0.81(m,2H),0.76–0.70(m,2H)。

example 103- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- (methylthio) benzamide

The first step is as follows: 3-amino-4-fluorobenzoic acid methyl ester

Starting from methyl 4-fluoro-3-nitrobenzoate (5g,25mmol), the title compound was prepared as a pale yellow solid (4.00g, 94%) according to the synthetic procedure of the first step of example 5;

the second step is that: 4-fluoro-3-carboxamidobenzoic acid methyl ester

Starting from methyl 3-amino-4-fluorobenzoate (4.0g,22mmol), the title compound (4.3g, 97%) was prepared as a white solid according to the synthesis procedure of the first step of example 9;

the third step: 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -4-fluorobenzoic acid methyl ester

Starting from methyl 4-fluoro-3-carboxamidobenzoate (4.0g,22mmol), the title compound was prepared as a yellow oil (5.8g, 97%) according to the synthesis procedure of the second step of example 9;

MS(ESI,pos.ion)m/z:280.3[M+H]⁺；

the fourth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluorobenzoic acid methyl ester

Using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -4-fluorobenzoate (6.0g,21mmol) as a starting material, the title compound (4.0g, 72%) was prepared as a yellow oil according to the synthesis method of the third step of example 9;

MS(ESI,pos.ion)m/z:260.5[M+H]⁺；

the fifth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoic acid

To a solution of methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluorobenzoate (2.1g,8.1mmol) in N, N-dimethylformamide (30mL) under ice-bath conditions was added sodium methyl mercaptide (0.9g,10mmol) and stirring was continued for 3H. The reaction mixture was diluted with water (50mL), diluted with dilute hydrochloric acid to be weakly acidic, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 10/1) to give the title compound (1.4g, 63%) as a yellow solid.

MS(ESI,pos.ion)m/z:275.1[M+H]⁺；

And a sixth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoic acid (800mg,2.92mmol), the title compound (850mg, 100%) was prepared as a pale yellow solid according to the synthesis procedure of the third step of example 2;

the seventh step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- (methylthio) benzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4- (methylthio) benzoyl chloride (850mg,2.9mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (500mg,2.5mmol), the title compound was prepared as a white solid (550mg, 41%) according to the synthesis procedure of the eighth step of example 6;

MS(ESI,pos.ion)m/z:458.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ10.69(s,1H),8.14(d,J＝8.2Hz,1H),8.09–8.06(m,1H),7.99(t,J＝8.0Hz,1H),7.95(d,J＝1.7Hz,1H),7.86(d,J＝7.4Hz,1H),7.70(s,1H),7.58(d,J＝8.5Hz,1H),7.17(s,1H),4.48–4.41(m,2H),2.93–2.87(m,2H),2.75–2.66(m,2H),2.52(s,3H),1.92–1.83(m,1H),0.85–0.79(m,2H),0.74–0.68(m,2H)。

example 113- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- (methylsulfonyl) benzamide

To a solution of 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- (methylthio) benzamide (example 10) (320mg,0.7mmol) in methanol (15mL) was added potassium peroxymonosulfonate (850mg,1.4mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the reaction was washed with saturated sodium bicarbonate solution (10 mL). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 20/1) to give the title compound (150mg, 70.1%) as a white solid;

MS(ESI,pos.ion)m/z:490.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ8.74(s,1H),8.40(d,J＝8.2Hz,1H),8.35(d,J＝8.2Hz,1H),8.16–8.14(m,1H),8.08(d,J＝7.6Hz,1H),7.97(d,J＝1.4Hz,1H),7.93(t,J＝8.0Hz,1H),7.74(s,1H),7.10(s,1H),4.42(t,J＝7.1Hz,2H),3.03(t,J＝7.7Hz,2H),2.87–2.78(m,2H),2.73(s,3H),1.97–1.89(m,1H),0.96–0.91(m,2H),0.89–0.84(m,2H)。

EXAMPLE 12N- (6- ([1,2,4] triazolo [4,3-a ] pyrimidin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

The first step is as follows: 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) pyrimidine

Starting from 2-hydrazinopyrimidine (500mg,4.5mmol) and 6-bromopyridine-2-carbaldehyde (850mg,4.5mmol), the title compound (400mg, 32%) was prepared as a pale yellow solid according to the synthetic method of the first step of example 8;

the second step is that: 3- (6-bromopyridin-2-yl) - [1,2,4] triazolo [4,3-a ] pyrimidine

Starting from 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) pyrimidine (400mg,1.4mmol), the title compound was prepared as a white solid (340mg, 86%) according to the synthesis procedure of the second step of example 8;

the third step: n- (6- ([1,2,4] triazolo [4,3-a ] pyrimidin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (290mg,1.12mmol) and 3- (6-bromopyridin-2-yl) - [1,2,4] triazolo [4,3-a ] pyrimidine (340mg,1.23mmol), the title compound was prepared as a white solid (5mg, 1%) by the fifth synthesis procedure of example 2.

MS(ESI,pos.ion)m/z:455.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ9.23(s,1H),8.97–8.95(m,2H),8.59–8.48(m,1H),8.35–8.25(m,1H),8.01(s,2H),7.56–7.45(m,1H),7.19(d,J＝21.8Hz,2H),6.84–6.79(m,1H),2.31(s,3H),2.09–2.01(m,1H),0.96–0.90(m,2H),0.89–0.84(m,2H)。

Example 134- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methoxypyridin-amide

First step 2-chloro-5-fluoro-4-iodopyridine

Under the protection of nitrogen, a lithium diisopropylamide solution (77mL,150mmol) was slowly added dropwise to a tetrahydrofuran (100mL) solution of 2-chloro-5-fluoropyridine (16.8g,128mmol) at-78 deg.C, and after stirring was continued for 2 hours, a tetrahydrofuran (100mL) solution of iodine (35.7g,141mmol) was slowly added dropwise and stirring was continued for 1 hour. After the reaction mixture was warmed to room temperature, a saturated sodium sulfite solution (200mL) was added to the reaction mixture to quench the reaction, and the reaction mixture was extracted with ethyl acetate (200 mL. times.2), and the organic phases were combined, washed with a saturated brine (200mL) and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 20/1) to give the title compound (23.0g, 70%) as a pale yellow solid;

¹HNMR(400MHz,CDCl₃)δ8.15(s,1H),7.78(d,J＝4.3Hz,1H)。

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

2-chloro-5-fluoro-4-iodopyridine (23.0g,89.3mmol), 4-cyclopropyl-1H-imidazole (29.0g,268mmol), potassium carbonate (30.8g,223mmol), cuprous iodide (340mg,1.79mmol), 8-hydroxyquinaldine (569mg,3.57mmol) and dimethylsulfoxide (80mL) were added to a reaction flask under nitrogen, and the system was raised to 90 ℃ and stirred overnight. After cooling to room temperature, the reaction was quenched with water (100mL), extracted with ethyl acetate (200 mL. times.2), and the organic phases were combined, washed with saturated brine (100mL) and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate (v/v) ═ 10/1-5/1) to give the title compound (4.50g, 21%) as a yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.40(d,J＝2.7Hz,1H),7.92(s,1H),7.38(d,J＝5.4Hz,1H),7.11(s,1H),1.96–1.82(m,1H),0.96–0.87(m,2H),0.86–0.80(m,2H)。

the third step is 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypyridinecarboxylic acid methyl ester

2-chloro-4- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluoropyridine (8.50g,35.8mmol), [ (R) - (+) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] palladium dichloride (114mg,0.14mmol), triethylamine (9.94mL,71.5mmol) and methanol (60mL) were added to an autoclave, carbon monoxide was introduced, and the mixture was heated to 90 ℃ and stirred overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50/1) to give the title compound (2.30g, 24%) as a yellow solid;

the fourth step is 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypyridinecarboxylic acid

Starting from methyl 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinate (2.35g,8.60mmol), the title compound was prepared as a yellow solid (2.20g, 99%) according to the synthesis procedure of the second step of example 4;

the fifth step is 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypyridinecarboxylic acid chloride

Starting from 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypicolinic acid (310mg,1.20mmol), the title compound was prepared as a yellow solid (332mg, 100%) by the synthetic method according to the third step of example 2;

the sixth step is 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypyridinecarboxamide

Using 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypyridinecarbonyl chloride (332mg,1.20mmol) as a starting material, the title compound (200mg, 65%) was prepared as a pale yellow solid according to the synthesis method in the fourth step of example 2.

Seventh step 4- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methoxypyridinamide

Starting from 4- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxypyridinecarboxamide (200mg,0.77mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (226mg,0.85mmol), the title compound was prepared as a pale yellow solid (130mg, 38%) by the method of synthesis in the fifth step of example 2.

MS(ESI,pos.ion)m/z:443.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.76(s,1H),8.30(d,J＝8.2Hz,1H),8.23(s,1H),8.16(s,1H),8.06(t,J＝8.0Hz,1H),7.92(d,J＝7.2Hz,1H),7.57(s,1H),4.49–4.44(m,2H),4.13(s,3H),2.94–2.91(m,2H),2.77–2.74(m,2H),1.91–1.87(m,1H),0.85–0.81(m,2H),0.75–0.71(m,2H)。

Example 143- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-methylbenzamide

The first step is as follows: 3-carboxamido-2-methylbenzoic acid methyl ester

Starting from methyl 3-amino-2-methylbenzoate (5.0g,30mmol), the title compound (5.7g, 99%) was prepared as a white solid according to the synthetic method of the first step of example 9;

MS(ESI,pos.ion)m/z:194.1[M+H]⁺；

the second step is that: 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -2-methylbenzoic acid methyl ester

Starting from methyl 3-carboxamido-2-methylbenzoate (5.7g,30mmol), the title compound was prepared as a pale yellow solid (3.2g, 39%) according to the synthesis of the second step of example 9;

MS(ESI,pos.ion)m/z:276.3[M+H]⁺；

the third step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid methyl ester

Using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -2-methylbenzoate (3.5g,13mmol) as a starting material, the title compound (2.75g, 84%) was prepared as a yellow oil according to the synthesis procedure of the third step of example 9;

MS(ESI,pos.ion)m/z:257.2[M+H]⁺；

the fourth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid

Starting from methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoate (2.7g,11mmol), the title compound was prepared as a white solid (1.6g, 63%) according to the synthesis procedure of the second step of example 4;

MS(ESI,pos.ion)m/z:243.3[M+H]⁺；

the fifth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid (270mg,1.1mmol), according to the synthesis procedure of the third step of example 2, the title compound (280mg, 96%) was prepared as a pale yellow solid;

and a sixth step: 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-methylbenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride (280mg,1.1mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (200mg,1.0mmol), the title compound was prepared as a white solid (150mg, 33%) according to the synthesis procedure of the eighth step of example 6;

MS(ESI,pos.ion)m/z:426.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ8.38(d,J＝8.1Hz,1H),8.18(s,1H),8.10(d,J＝7.6Hz,1H),7.92(t,J＝8.0Hz,1H),7.64(d,J＝7.2Hz,1H),7.46(s,1H),7.43(t,J＝7.7Hz,1H),7.39(d,J＝7.5Hz,1H),6.82(s,1H),4.41–4.35(m,2H),3.03(t,J＝7.7Hz,2H),2.82–2.74(m,2H),2.33(s,3H),1.96–1.89(m,1H),0.95–0.89(m,2H),0.88–0.82(m,2H)。

example 155- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-methylbenzamide

The first step is as follows: 5-amino-2-methylbenzoic acid methyl ester

Starting from 5-amino-2-methylbenzoic acid (5g,32.4mmol), the title compound was prepared as a yellow oil (5.3g, 97%) according to the synthetic method of the first step of example 1;

the second step is that: 5-carboxamido-2-methylbenzoic acid methyl ester

Starting from methyl 5-amino-2-methylbenzoate (5.0g,30mmol), the title compound was prepared as a yellow solid (5.6g, 98%) by the synthetic method of the first step of example 9;

MS(ESI,pos.ion)m/z:194.1[M+H]⁺；

the third step: 5- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -2-methylbenzoic acid methyl ester

Starting from methyl 5-carboxamido-2-methylbenzoate (5.6g,29mmol), the title compound was prepared as a yellow oil (6.2g, 78%) according to the synthesis of the second step of example 9;

MS(ESI,pos.ion)m/z:276.3[M+H]⁺；

the fourth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid methyl ester

Using methyl 5- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -2-methylbenzoate (6.2g,23mmol) as a starting material, the title compound (2.0g, 35%) was prepared as a yellow oil according to the synthesis procedure of the third step of example 9;

MS(ESI,pos.ion)m/z:257.3[M+H]⁺；

the fifth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid

Starting from methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoate (2.0g,7.8mmol), the title compound was prepared as a pale yellow solid (1.2g, 63%) according to the synthesis procedure of the second step of example 4;

and a sixth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoic acid (300mg,1.24mmol), according to the synthesis procedure in the third step of example 2, the title compound (300mg, 93%) was prepared as a pale yellow solid;

the seventh step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-methylbenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methylbenzoyl chloride (300mg,1.2mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (230mg,1.2mmol), the title compound was prepared as a white solid (35mg, 7%) according to the synthesis procedure of the eighth step of example 6;

MS(ESI,pos.ion)m/z:426.4[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ8.35(d,J＝8.2Hz,1H),8.06(s,1H),8.02(t,J＝8.0Hz,1H),7.93(d,J＝7.6Hz,1H),7.74(d,J＝2.3Hz,1H),7.62–7.60(m,1H),7.49(d,J＝8.2Hz,1H),7.37(s,1H),4.54–4.49(m,2H),3.23(s,1H),3.02(t,J＝7.6Hz,2H),2.86–2.77(m,2H),2.53(s,3H),1.95–1.87(m,1H),0.93–0.87(m,2H),0.79–0.73(m,2H)。

example 163- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylbenzamide

First step methyl 3-methyl-5-nitrobenzoate

Starting from 3-methyl-5-nitrobenzoic acid (5.00g,27.6mmol), the title compound was prepared as a pale yellow solid (5.39g, 100%) according to the synthesis procedure of the first step of example 1;

second step methyl 3-amino-5-methylbenzoate

Starting from methyl 3-methyl-5-nitrobenzoate (5.39g,27.6mmol), the title compound was prepared as a yellow solid (4.56g, 100%) according to the synthetic method of the first step of example 5;

the third step is 3-carboxamido-5-methylbenzoic acid methyl ester

Starting from methyl 3-amino-5-methylbenzoate (4.56g,27.6mmol), the title compound (5.33g, 100%) was prepared as a pale yellow solid according to the synthesis procedure of the first step of example 9;

the fourth step methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -5-methylbenzoate

Starting from methyl 3-carboxamido-5-methylbenzoate (5.33g,27.6mmol), the title compound (7.59g, 100%) was prepared as a yellow solid according to the synthesis of the second step of example 9;

MS(ESI,pos.ion)m/z:276.1[M+H]⁺；

fifth step methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoate

Using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -5-methylbenzoate (7.59g,27.6mmol) as a starting material, the title compound (4.00g, 57%) was prepared as a yellow solid according to the synthesis procedure of the third step of example 9;

MS(ESI,pos.ion)m/z:257.1[M+H]⁺；

the sixth step is 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoic acid

Starting from methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoate (1.91g,7.45mmol), the title compound was prepared as a yellow solid (1.50g, 83%) according to the synthesis procedure of the second step of example 4;

seventh step 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoic acid (411mg,1.70mmol), according to the synthesis procedure of the third step of example 2, the title compound (442mg, 100%) was prepared as a pale yellow solid;

eighth step 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzoyl chloride (442mg,1.7mmol), the title compound (409mg, 100%) was prepared as a pale yellow solid according to the synthesis procedure for the fourth step of example 2;

ninth step 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylbenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylbenzamide (87mg,0.36mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (108mg,0.41mmol), the title compound was prepared as a pale yellow solid (60mg, 39%) by the synthesis in the fifth step of example 2.

MS(ESI,pos.ion)m/z:426.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ8.44(s,1H),8.37(d,J＝8.2Hz,1H),8.08(d,J＝7.6Hz,1H),7.92(t,J＝7.9Hz,1H),7.81(s,1H),7.75(s,1H),7.67(s,1H),7.41(s,1H),7.11(s,1H),4.43(t,J＝7.1Hz,2H),3.04(t,J＝7.6Hz,2H),2.87–2.79(m,2H),2.55(s,3H),1.97–1.90(m,1H),0.93–0.90(m,2H),0.89–0.80(m,2H)。

Example 173- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-fluorobenzamide

First step methyl 3-fluoro-5-carboxamidobenzoate

Starting from methyl 3-amino-5-fluorobenzoate (5.00g,29.6mmol), the title compound (5.70g, 98%) was prepared as a pale yellow solid according to the synthesis method of the first step of example 9;

second step methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -5-fluorobenzoate

Starting from methyl 3-fluoro-5-carboxamidobenzoate (5.70g,28.9mmol), the title compound (8.07g, 100%) was prepared as a yellow solid according to the synthesis of the second step of example 9;

MS(ESI,pos.ion)m/z:280.2[M+H]⁺；

the third step is 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoic acid methyl ester

Using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -5-fluorobenzoate (8.07g,28.9mmol) as a starting material, the title compound (6.00g, 80%) was prepared as a yellow solid according to the synthesis method of the third step of example 9;

the fourth step is 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoic acid

Starting from methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoate (2.26g,8.68mmol), the title compound was prepared as a yellow solid (1.50g, 70%) according to the synthesis procedure of the second step of example 4;

¹H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.95(s,1H),7.89(d,J＝9.9Hz,1H),7.64(s,1H),7.60(d,J＝8.7Hz,1H),1.90–1.78(m,1H),0.86–0.75(m,2H),0.71(d,J＝3.0Hz,2H)。

the fifth step 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoic acid (300mg,1.22mmol), according to the synthesis method of the third step of example 2, the title compound (322mg, 100%) was prepared as a pale yellow solid;

the sixth step is 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzoyl chloride (322mg,1.22mmol), the title compound was prepared as a pale yellow solid (290mg, 97.22%) by the synthesis method of the fourth step of example 2;

MS(ESI,pos.ion)m/z:246.2[M+H]⁺；

seventh step 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-fluorobenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -5-fluorobenzamide (87mg,0.35mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (122mg,0.46mmol), the title compound was prepared as a pale yellow solid (110mg, 72%) by the synthesis in the fifth step of example 2.

MS(ESI,pos.ion)m/z:430.4[M+H]⁺；

1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.29(s,1H),8.15(d,J＝8.2Hz,1H),8.09–7.98(m,2H),7.88(d,J＝7.9Hz,2H),7.68(d,J＝7.9Hz,2H),4.46(t,J＝7.1Hz,2H),2.90(t,J＝7.5Hz,2H),2.75–2.67(m,2H),1.89–1.82(m,1H),0.87–0.78(m,2H),0.72–0.70(m,2H)。

Example 183- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methoxybenzamide

First step methyl 4-methoxy-3-nitrobenzoate

Starting from 4-methoxy-3-nitrobenzoic acid (7.50g,38.0mmol), the title compound was prepared as a pale yellow solid (8.00g, 100%) according to the synthesis procedure of the first step of example 1;

¹H NMR(400MHz,CDCl₃)δ8.53(d,J＝2.1Hz,1H),8.25–8.23(m,1H),7.16(d,J＝8.8Hz,1H),4.05(s,3H),3.95(s,3H)。

second step methyl 3-amino-4-methoxybenzoate

Starting from methyl 4-methoxy-3-nitrobenzoate (8.00g,37.9mmol), the title compound was prepared as a yellow solid (6.86g, 100%) according to the synthetic method of the first step of example 5;

the third step is 3-formamido-4-methoxybenzoic acid methyl ester

Using methyl 3-amino-4-methoxybenzoate (6.86g,37.9mmol) as a starting material, the title compound (7.92g, 100%) was prepared as a pale yellow solid according to the synthesis method of the first step of example 9;

MS(ESI,pos.ion)m/z:210.2[M+H]⁺；

the fourth step is 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -4-methoxybenzoic acid methyl ester

Starting from methyl 3-carboxamido-4-methoxybenzoate (7.92g,37.9mmol), the title compound was prepared as a yellow solid (11.0g, 100%) according to the synthesis procedure of the second step of example 9;

MS(ESI,pos.ion)m/z:292.2[M+H]⁺；

fifth step methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoate

Using methyl 3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -4-methoxybenzoate (11.0g,37.8mmol) as a starting material, the title compound (4.00g, 39%) was prepared as a yellow solid according to the synthesis procedure of the third step of example 9;

MS(ESI,pos.ion)m/z:273.2[M+H]⁺；

the sixth step is 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoic acid

Using methyl 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoate (2.12g,7.79mmol) as a starting material, the title compound was prepared as a pale yellow solid (1.80g, 90%) according to the synthesis method of the second step of example 4;

seventh step 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoyl chloride

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoic acid (550mg,2.13mmol), according to the synthesis procedure in the third step of example 2, the title compound (589mg, 100%) was prepared as a pale yellow solid;

eighth step 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzoyl chloride (322mg,1.22mmol), the title compound was prepared as a pale yellow solid (365mg, 67%) by the synthetic method according to the fourth step of example 2;

MS(ESI,pos.ion)m/z:258.1[M+H]⁺；

ninth step 3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methoxybenzamide

Starting from 3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methoxybenzamide (87mg,0.35mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (108mg,0.41mmol), the title compound was prepared as a pale yellow solid (60mg, 40%) by the synthesis in the fifth step of example 2.

MS(ESI,pos.ion)m/z:442.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ8.46–8.30(m,2H),8.06(d,J＝7.6Hz,1H),7.99–7.92(m,1H),7.94–7.88(m,1H),7.89–7.85(m,1H),7.73(s,1H),7.18(d,J＝8.7Hz,1H),7.01(s,1H),4.44(t,J＝7.1Hz,2H),3.98(s,3H),3.05(t,J＝7.6Hz,2H),2.87–2.82(m,2H),1.98–1.90(m,1H),0.92–0.88(m,2H),0.87–0.83(m,2H)。

Example 195- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-yl) -2-methoxybenzamide

The first step is as follows: 5-amino-2-methoxybenzoic acid methyl ester

Starting from methyl 2-methoxy-5-nitrobenzoate (5g,23.2mmol), the title compound was prepared as a brown oil (4.0g, 94%) according to the synthetic method of the first step of example 5;

MS(ESI,pos.ion)m/z:182.2[M+H]⁺；

the second step is that: 5-carboxamido-2-methoxybenzoic acid methyl ester

Starting from methyl 5-amino-2-methoxybenzoate (4.2g,23mmol), the title compound was prepared as a yellow solid (3.2g, 66%) by the synthetic method of the first step of example 9;

the third step: 5- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -2-methoxybenzoic acid methyl ester

Using methyl 5-carboxamido-2-methoxybenzoate (3.2g,15mmol) as a starting material, the title compound was prepared as a yellow oil (4.2g, 94%) according to the synthesis procedure of the second step of example 9;

MS(ESI,pos.ion)m/z:292.2[M+H]⁺；

the fourth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoic acid methyl ester

Using methyl 5- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) -2-methoxybenzoate (4.2g,14mmol) as a starting material, the title compound (2.0g, 51%) was prepared as a yellow oil according to the synthesis procedure of the third step of example 9;

MS(ESI,pos.ion)m/z:273.1[M+H]⁺；

the fifth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoic acid

Starting from methyl 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoate (600mg,2.2mmol), the title compound was prepared as a yellow oil (550mg, 97%) according to the synthesis procedure of the second step of example 4;

and a sixth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoyl chloride

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoic acid (500mg,1.9mmol), according to the synthesis procedure in the third step of example 2, the title compound (500mg, 93%) was prepared as a pale yellow solid;

the seventh step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzoyl chloride (500mg,1.8mmol), the title compound was prepared as a pale yellow solid (300mg, 65%) by the synthetic method according to the fourth step of example 2;

MS(ESI,pos.ion)m/z:258.2[M+H]⁺；

eighth step: : 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-yl) -2-methoxybenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxybenzamide (200mg,0.78mmol) and 3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole (230mg,0.87mmol), prepared according to the synthesis in the fifth step of example 2 as a white solid the title compound (90mg, 26%);

MS(ESI,pos.ion)m/z:442.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ10.39(s,1H),8.41(d,J＝8.2Hz,1H),8.32(d,J＝2.7Hz,1H),8.07(d,J＝7.6Hz,1H),7.89(t,J＝8.0Hz,1H),7.74(s,1H),7.55–7.53(m,1H),7.18(d,J＝8.8Hz,1H),7.06(s,1H),4.48(t,J＝7.1Hz,2H),4.15(s,3H),3.07(t,J＝7.7Hz,2H),2.90–2.82(m,2H),1.96–1.89(m,1H),0.95–0.90(m,2H),0.86–0.81(m,2H)。

example 204-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide

The first step is as follows: 4-chloro-3-carboxamidobenzoic acid methyl ester

Starting from methyl 3-amino-4-chlorobenzoate (5.0g,27mmol), the title compound was prepared as a white solid (5.7g, 99%) by the synthetic method of the first step of example 9;

the second step is that: 4-chloro-3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) benzoic acid methyl ester

Starting from methyl 4-chloro-3-formylbenzoate (5.7g,27mmol), the title compound (7.5g, 95%) was prepared as a pale yellow solid according to the synthesis procedure of the second step in example 9;

MS(ESI,pos.ion)m/z:296.0[M+H]⁺；

the third step: 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid methyl ester

Using methyl 4-chloro-3- (N- (2-cyclopropyl-2-oxoethyl) carboxamido) benzoate (7.5g,25mmol) as a starting material, the title compound (5.0g, 71%) was prepared as a yellow oil according to the synthesis procedure of the third step of example 9;

MS(ESI,pos.ion)m/z:277.1[M+H]⁺；

the fourth step: 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid

Starting from methyl 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoate (350mg,1.27mmol), the title compound was prepared as a yellow solid (280mg, 84%) according to the synthesis procedure of the second step of example 4;

the fifth step: 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride

Starting from 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoic acid (280mg,1.1mmol), the title compound (290mg, 97%) was prepared as a yellow solid according to the synthesis procedure of the third step of example 2;

and a sixth step: 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide

Starting from 4-chloro-3- (4-cyclopropyl-1H-imidazol-1-yl) benzoyl chloride (280mg,0.99mmol) and 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (200mg,0.99mmol), the title compound was prepared as a white solid (240mg, 54%) according to the synthesis procedure of the eighth step of example 6;

MS(ESI,pos.ion)m/z:466.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ8.80(s,1H),8.34(d,J＝8.2Hz,1H),8.05(d,J＝7.6Hz,1H),8.00–7.94(m,2H),7.90(t,J＝8.0Hz,1H),7.72(d,J＝8.6Hz,1H),7.62(d,J＝0.9Hz,1H),6.96(d,J＝0.8Hz,1H),4.37(t,J＝7.1Hz,2H),3.00(t,J＝7.7Hz,2H),2.83–2.72(m,2H),1.96–1.86(m,1H),0.94–0.87(m,2H),0.86–0.79(m,2H)。

example 21N- (6- ([1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

The first step is as follows: 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) pyrazine

Starting from pyrazine-2-hydrazine (1.0g,9.1mmol), the title compound was prepared as a pale yellow solid (1.8g, 71%) according to the synthetic method of the first step of example 8;

MS(ESI,pos.ion)m/z:279.1.1[M+H]⁺；

the second step is that: 3- (6-bromopyridin-2-yl) - [1,2,4] triazolo [4,3-a ] pyrazines

Starting from 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) pyrazine (500mg,1.8mmol), the title compound was prepared as a white solid (480mg, 97%) according to the synthesis procedure of the second step of example 8;

MS(ESI,pos.ion)m/z:277.1[M+H]⁺；

the third step: n- (6- ([1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (190mg,0.73mmol) and 3- (6-bromopyridin-2-yl) - [1,2,4] triazolo [4,3-a ] pyrazine (200mg,0.72mmol), the title compound was prepared as a pale yellow solid (80mg, 24%) by reference to the synthesis in the fifth step of example 2.

MS(ESI,pos.ion)m/z:455.3[M+H]⁺；

¹HNMR(600MHz,CDCl₃)δ9.49(d,J＝1.4Hz,1H),9.49–9.47(m,1H),9.18(d,J＝15.2Hz,1H),8.47(d,J＝8.3Hz,1H),8.40(d,J＝7.6Hz,1H),8.11(d,J＝7.3Hz,1H),8.09(d,J＝4.8Hz,1H),8.04(t,J＝8.0Hz,1H),7.48(d,J＝0.9Hz,1H),7.27(d,J＝12.4Hz,1H),6.83(d,J＝0.8Hz,1H),2.34(s,3H),1.97–1.91(m,1H),0.94–0.91(m,2H),0.87–0.84(m,2H)。

EXAMPLE 22N- (6- (5-chloro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

First step 2-bromo-6- ((2- (6-chloropyridin-2-yl) hydrazono) methyl) pyridine

Starting from 2-chloro-6-hydrazinopyridine (500mg,3.48mmol), the title compound was prepared as a pale yellow solid (1.00g, 92%) by the synthetic method of the first step of example 8;

¹H NMR(400MHz,CDCl₃)δ8.61(s,1H),7.95(d,J＝7.8Hz,1H),7.81(s,1H),7.60–7.57(m,2H),7.44(d,J＝7.8Hz,1H),7.27(s,1H),6.88(d,J＝7.6Hz,1H)。

the second step is 3- (6-bromopyridin-2-yl) -5-chloro- [1,2,4] triazolo [4,3-a ] pyridine

Starting from 2-bromo-6- ((2- (6-chloropyridin-2-yl) hydrazono) methyl) pyridine (1.00g,3.21mmol), the title compound was prepared as a pale yellow solid (900mg, 91%) by reference to the synthesis in the second step of example 8;

MS(ESI,pos.ion)m/z:309.1[M+H]⁺；

the third step is N- (6- (5-chloro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (100mg,0.39mmol) and 3- (6-bromopyridin-2-yl) -5-chloro- [1,2,4] triazolo [4,3-a ] pyridine (143mg,0.46mmol), the title compound was prepared as a pale yellow solid (30mg, 16%) by the fifth synthesis procedure of example 2;

MS(ES-API,pos.ion)m/z:488.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.39(d,J＝8.5Hz,1H),8.08(t,J＝7.9Hz,1H),7.94(d,J＝9.1Hz,1H),7.67(d,J＝5.9Hz,2H),7.62(d,J＝6.6Hz,1H),7.53–7.44(m,1H),7.41(d,J＝11.0Hz,1H),7.25(d,J＝7.0Hz,1H),7.16(s,1H),2.22(s,3H),1.87–1.80(m,1H),0.80–0.78(m,2H),0.70–0.67(m,2H)。

example 23N- (6- (8-chloro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

The first step is as follows: 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) -3-chloropyridine

Starting from 3-chloro-2-hydrazinylpyridine (500mg,3.5mmol), the title compound was prepared as a pale yellow solid (1.05g, 97%) by the synthetic method of the first step of example 8;

MS(ESI,pos.ion)m/z:312.1[M+H]⁺；

the second step is that: 3- (6-bromopyridin-2-yl) -8-chloro- [1,2,4] triazolo [4,3-a ] pyridine

Starting from 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) -3-chloropyridine (1.0g,3.2mmol), the title compound was prepared as a white solid (0.90g, 91%) according to the synthesis procedure of the second step of example 8;

MS(ESI,pos.ion)m/z:309.1[M+H]⁺；

the third step: n- (6- (8-chloro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (175mg,0.67mmol) and 3- (6-bromopyridin-2-yl) -8-chloro- [1,2,4] triazolo [4,3-a ] pyridine (210mg,0.68mmol), the title compound was prepared as a pale yellow solid (50mg, 15%) by the fifth synthesis procedure of example 2;

MS(ESI,pos.ion)m/z:488.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ9.59(d,J＝7.0Hz,1H),9.14(d,J＝14.9Hz,1H),8.43(d,J＝8.3Hz,1H),8.38(d,J＝7.7Hz,1H),8.10(d,J＝7.3Hz,1H),8.00(t,J＝8.0Hz,1H),7.47(d,J＝6.3Hz,1H),7.45(d,J＝7.1Hz,1H),7.24(d,J＝12.3Hz,1H),6.97(t,J＝7.1Hz,1H),6.83(s,1H),2.33(s,3H),1.98–1.90(m,1H),0.95–0.90(m,2H),0.88–0.83(m,2H)。

example 245- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide

The first step is as follows: 2-bromo-6- ((2- (6-methylpyridin-2-yl) hydrazono) methyl) pyridine

Starting from 2-hydrazino-6-methylpyridine hydrochloride (500mg,3.1mmol), the title compound was prepared as a yellow solid (650mg, 71%) by the synthetic method of the first step of example 8;

MS(ESI,pos.ion)m/z:291.0[M+H]⁺；

the second step is that: 3- (6-bromopyridin-2-yl) -5-methyl- [1,2,4] triazolo [4,3-a ] pyridine

Starting from 2-bromo-6- ((2- (6-methylpyridin-2-yl) hydrazono) methyl) pyridine (180mg,0.62mmol), the title compound was prepared as a pale yellow solid (50mg, 28%) by the second-step synthesis of example 8;

MS(ESI,pos.ion)m/z:289.1[M+H]⁺；

the third step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (50mg,0.19) and 3- (6-bromopyridin-2-yl) -5-methyl- [1,2,4] triazolo [4,3-a ] pyridine (50mg,0.17mmol), the title compound was prepared as a white solid (8mg, 10%) according to the synthesis in the fifth step of example 2;

MS(ESI,pos.ion)m/z:468.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ9.10(d,J＝14.0Hz,1H),8.54(d,J＝8.4Hz,1H),8.07(d,J＝7.2Hz,1H),8.00–7.96(m,1H),7.78(d,J＝9.7Hz,1H),7.75(d,J＝7.4Hz,1H),7.46(d,J＝7.5Hz,1H),7.30(s,1H),7.19(d,J＝12.1Hz,1H),6.81(s,1H),6.68(d,J＝6.6Hz,1H),2.44(s,3H),2.30(s,3H),1.96–1.90(m,1H),0.93–0.90(m,2H),0.87–0.83(m,2H)。

example 255- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (8-methyl- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide

The first step is as follows: 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) -3-methylpyridine

Starting from 2-hydrazino-3-methylpyridine (500mg,4.1mmol), the title compound was prepared as a yellow solid (1.1g, 93%) by the synthetic method of the first step of example 8;

MS(ESI,pos.ion)m/z:291.0[M+H]⁺；

the second step is that: 3- (6-bromopyridin-2-yl) -8-methyl- [1,2,4] triazolo [4,3-a ] pyridine

Starting from 2- (2- ((6-bromopyridin-2-yl) methylene) hydrazino) -3-methylpyridine (1.1g,3.8mmol), the title compound was prepared as a pale yellow solid (600mg, 55%) according to the synthesis procedure of the second step of example 8;

MS(ESI,pos.ion)m/z:289.1[M+H]⁺；

the third step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (8-methyl- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide

Starting from 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide (225mg,0.87) and 3- (6-bromopyridin-2-yl) -8-methyl- [1,2,4] triazolo [4,3-a ] pyridine (250mg,0.86mmol), the title compound was prepared as a white solid (80mg, 20%) by the fifth synthesis of example 2;

MS(ESI,pos.ion)m/z:468.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ9.48(d,J＝6.9Hz,1H),9.14(d,J＝14.7Hz,1H),8.41(d,J＝8.2Hz,1H),8.38(d,J＝7.6Hz,1H),8.11(d,J＝7.2Hz,1H),7.99(t,J＝8.0Hz,1H),7.48(s,1H),7.25(d,J＝12.2Hz,1H),7.16(d,J＝6.5Hz,1H),6.94(t,J＝6.8Hz,1H),6.83(s,1H),2.77(s,3H),2.33(s,3H),1.98–1.91(m,1H),0.95–0.91(m,2H),0.89–0.84(m,2H)。

biological activity assay

ASK 1(apoptosis signal-regulating kinase 1) inhibitory Activity test

(1) Test method

Compounds were treated with kinase buffer (20mM HEPES, pH 7.5; 0.01% Triton X-100; 25mM MgCl)₂(ii) a 2mM DTT) were sequentially diluted 3-fold to give 10 concentration solutions from 2000nM to 0.102nM, which were added at 2.5 μ L/well to a 384 well plate so that the final concentration of the compound in the kinase assay was 500-0.025 nM; then 2.5. mu.L of ASK1 with a concentration of 200nM per well, 5. mu.L of substrate solution (MBP (Myelin basic protein) with a concentration of 1000. mu.M and ATP with a concentration of 300. mu.M) per well after shaking to homogeneity]Oscillating, wherein the final concentrations of ASK1, MBP and ATP are respectively 50nM, 500. mu.M and 150. mu.M; simultaneously arranging a buffer hole (without a compound, adding an enzyme and a substrate with the same concentration) and a negative hole (without a compound and an enzyme, adding a substrate with the same concentration); after incubation for 1 hour at 37 ℃ in a sealing plate, kinase activity was detected using an ADP-Glo kinase detection kit (Promage, Cat. No. v9102/3, Lot. No.314795), Relative light emission values (RLU) were read, and a compound was calculated by the following formulaCalculating IC by using GraphPad Prism 5 after inhibiting ASK1 activity by the substance₅₀。

Inhibition ratio (%) ═ (RLU)_{Buffer liquid hole}-RLU_{Medicine hole})/(RLU_{Buffer liquid hole}-RLU_{Negative hole})×100

(2) Results of the experiment

Compound numbering	IC50(nM)	Compound numbering	IC50(nM)
				Example 1	18	Example 10	6.7
Example 2	6.1	Example 13	7.8
				Example 4	4.9	Example 16	14
Example 5	10	Example 18	6.7
				Example 6	9.4	Example 19	4.1
Example 7	9.1	Example 20	11
				Example 8	9.7	Example 23	18

2. Pharmacokinetic testing

(1) Test method

Experimental animals: healthy adult male SD rats (purchased from slykhstaka laboratory animals ltd, han, hu) were divided into two groups of 3 rats and administered by intravenous injection and oral gavage, respectively.

The preparation of the medicine comprises the following steps: 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 a target concentration.

Administration and sample collection: animals were fasted for 12h before administration and fed for 3h after administration, and administered intravenously (iv, 1mg/kg) and orally via gavage (po,5mg/kg) via hind limb veins of SD rats, respectively. Then blood is collected in the tail vein of the rat at time points 0, 0.083, 0.25, 0.5, 1,2,4, 6,8 and 24h respectively, and the blood collection amount is about 200-. After collecting whole blood at each time point, set K₂And (4) placing the EDTA anticoagulation test tube into an incubator with an ice bag for preservation. All samples were centrifuged at 4600r/min at 4 ℃ for 5min within 15min, plasma was separated and the LC/MS/MS method was used to determine the size of the different compounds after administrationConcentration in rat plasma pharmacokinetic parameters were calculated from the drug concentration-time curve.

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

(2) Test results

After oral administration, the compound has higher blood concentration and exposure level in rats, lower clearance rate, better bioavailability and favorable pharmacokinetic characteristic.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention have been described for illustrative purposes, but are not limited to the description of the present invention, and it is to be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (14)

1.A compound is a compound shown as a formula (I), or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt of the compound shown as the formula (I),

wherein the content of the first and second substances,

X¹is C (R)¹) Or N;

X²is C (R)²) Or N;

X³is C (R)³) Or N;

X⁴is C (R)⁴) Or N;

R¹、R²、R³and R⁴Each independently is hydrogen, deuterium, a halogen atom, hydroxyl, mercapto, amino, nitro, cyano or C_1-3An alkyl group;

e is imidazolyl;

each R^xIndependently is C_3-6A cycloalkyl group;

each R^yIndependently is a hydrogen, deuterium or halogen atom;

g is

Wherein the content of the first and second substances,

each W¹Independently is-O-, -S-or-NH-;

each W²、W³、W⁴And W⁵Independently CH or N;

each R^zIndependently hydrogen, deuterium, halogen atom or C_1-4An alkyl group;

m is 1,2 or 3;

n is 1,2 or 3; and

k is 1,2,3,4 or 5.

2. The compound of claim 1, wherein R¹、R²、R³And R⁴Each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, nitro, cyano, methyl, ethyl, n-propyl or isopropyl.

3. The compound of claim 1, wherein each R^xIndependently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

4. The compound of claim 1, wherein each R^yIndependently hydrogen, fluorine, chlorine, bromine or iodine.

5. The compound of claim 1, wherein G is

6. The compound of claim 1, wherein each R^zIndependently hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl or isopropyl.

7. The compound of claim 1, which is a compound of formula (IId), (IIe) or (IIf), or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of a compound of formula (IId), (IIe) or (IIf),

8. the compound of claim 1, said compound having the structure of one of:

or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of one of the structures.

9. A compound having the structure of one of:

or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of one of the structures.

10. A pharmaceutical composition comprising a compound of any one of claims 1-9.

11. The pharmaceutical composition of claim 10, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

12. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 11 in the manufacture of a medicament for the prevention, treatment or alleviation of an ASK1 modulated disease in a patient.

13. The use according to claim 12, wherein the ASK1 mediated disease is an autoimmune disease, inflammation, cardiovascular disease, cardiorenal disease, fibrotic disease, respiratory disease, liver disease or neurodegenerative disease.

14. The use of claim 13, wherein the cardiovascular disease comprises diabetes, diabetic nephropathy and other diabetic complications;

the fibrotic diseases include pulmonary fibrosis and renal fibrosis;

the respiratory diseases include chronic embolic lung obstruction, idiopathic pulmonary fibrosis and acute lung injury;

the liver disease comprises chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic ischemia-reperfusion injury and primary biliary cirrhosis.