WO2019015559A1

WO2019015559A1 - Heterocyclic compound acting as ask inhibitor and use thereof

Info

Publication number: WO2019015559A1
Application number: PCT/CN2018/095897
Authority: WO
Inventors: 王勇; 赵立文; 葛崇勋; 黄奕强; 曹陈; 李晴晴; 江宏; 韩伟; 张着伟; 张亚楠
Original assignee: 南京圣和药业股份有限公司
Priority date: 2017-07-18
Filing date: 2018-07-17
Publication date: 2019-01-24
Also published as: CN109265443B; CN109265443A; TW201908306A

Abstract

The present invention belongs to the field of medical chemistry, and relates to a class of heterocyclic compounds acting as ASK inhibitors and the use thereof. Specifically, provided are compounds as shown in formula A or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, methods for preparing same, pharmaceutical compositions containing these compounds and the use of these compounds or compositions in treating and/or preventing diseases associated with apoptosis signal-regulating kinase 1. The compounds of the present invention have an excellent apoptosis signal-regulating kinase 1 inhibitory activity, and show a great deal of promise in becoming therapeutic agents for diseases associated with apoptosis signal-regulating kinase 1.

Description

Heterocyclic compounds as ASK inhibitors and their applications

Technical field

The present invention belongs to the field of medical chemistry, and specifically relates to a heterocyclic compound or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof as an ASK inhibitor, a preparation method thereof, and a medicament containing the same Use of the compositions and these compounds or compositions for the treatment and/or prevention of apoptotic signaling modulating kinase 1 associated diseases.

Background technique

Natural organisms are usually exposed to various physical and chemical stresses, and the response of cells to external stimuli has a positive effect on maintaining physiological homeostasis. It is the self-realization of organisms through long-term development and evolution. The most fundamental means of renewal and self-protection. The mitogen-activated protein kinase (MAPK) cascade signaling pathway is thought to be the most important pathway regulating cellular oxidative stress, and its biological effects include regulation of cell growth, differentiation, inflammation, and apoptosis. Apoptosis signal-regulating kinase 1 (ASK1) is one of the major members of the mitogen-activated protein kinase kinase (MAP3Ks) family. ASK1 balances and integrates many endogenous and exogenous stimuli, allowing cells to respond appropriately to different stimuli. Under non-stress conditions, ASK1 puts ASK1 in an inactive state by binding to thioredoxin (Trx). When the body presents stress damage (such as oxidative stress, ROS, endoplasmic reticulum stress, calcium influx, etc.) and pro-inflammatory factors (H ₂ O ₂ , TNF-α, etc.), it induces ASK1 activation, activated ASK1. The downstream JNK and p38-MAPK kinase signaling pathways are sequentially activated to respond to stress by regulating cell growth, differentiation, inflammation, and apoptosis. ASK2 is a member of the MAP3K family with a 45% homologous sequence to ASK1. ASK2 and ASK1 are highly similar in the kinase region, ASK1 is widely distributed in various tissues, and ASK2 is only specifically distributed in tissues exposed to body surface. Such as skin, lung and gastrointestinal tract, it is generally believed that ASK1 and ASK2 interact to form an endogenous ASK1-ASK2 complex to play a physiological role.

Oxidative stress refers to the process in which the body's reactive oxygen species (ROS) are excessively produced and/or the antioxidant defense function is weakened, causing cell damage and death, resulting in tissue damage repair. In normal physiological processes, the production of reactive oxygen species ROS is at a lower level and can be rapidly degraded. In the process of disease development, such as inflammation, ischemia-reperfusion and neurodegenerative diseases, due to the continuous stimulation of virulence factors, the production of ROS is increased, and the body is in an oxidative stress state. ROS promotes Trx and ASK1. After isolation, ASK1 is activated and permanently aberrantly activated, which in turn regulates apoptosis and damage responses. Due to the important role of ASK1 in the process of apoptosis signaling, ASK1 is closely related to the occurrence and development of various diseases such as inflammation, metabolic syndrome, neurodegenerative diseases, cardiovascular diseases and tumors.

Organ fibrosis refers to the continuous excessive deposition of extracellular matrix (ECM) in tissues and organs caused by various pathogenic factors, which ultimately leads to structural changes and dysfunction of tissues and organs. Oxidative stress is one of the important pathogenesis of organ fibrosis. Long-term stimulation of various harmful factors leads to persistent damage to the liver, kidneys and alveoli, activation of oxidative stress pathways, repeated destruction, repair and reconstruction of organs. Oxidative stress plays an important role in the occurrence of liver fibrosis. Hepatic fibrosis (HF) is a necessary process and common pathway for various liver diseases to progress to cirrhosis, suffering from viral hepatitis, alcoholic liver disease and In chronic diseases such as steatohepatitis, the liver may be damaged. Liver damage and inflammation may induce the production of ROS, cause cytokines such as TNF-α and TGF-β1, and ROS and TNF-α may activate ASK1 and activate downstream. JNK and p38MAPK signaling pathways induce hepatocyte apoptosis and necrosis on the one hand, and activate ECM in hepatic stellate cells on the other hand. The persistent excessive deposition of ECM in liver tissue causes and accelerates the occurrence and development of liver fibrosis.

In recent years, several studies have found ASK1 inhibitors in chronic kidney disease (diabetic nephropathy, end-stage renal disease, renal fibrosis, etc.), cardiovascular disease (heart failure, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease and tumors have certain research and application, especially ASK1-targeted drugs have important clinical significance in the study of chronic liver diseases such as nonalcoholic steatohepatitis (NASH) and liver fibrosis, and A certain clinical effect has been achieved. However, there is still a need to develop more ASK1 inhibitors, making the drugs more excellent in properties such as better efficacy and less side effects for better prevention or treatment of ASK1-related diseases.

Summary of the invention

It is an object of the present invention to provide a compound having an apoptosis signal-modulating activity represented by Formula A, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

among them,

Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, Alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, dialkylamino, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;

Ring B is selected from the group consisting of a monocyclic aryl group, a bicyclic aryl group, a bicyclic heteroaryl group, and a bicyclic heterocyclic group, wherein the monocyclic aryl group, the bicyclic aryl group, the bicyclic heteroaryl group, and the bicyclic heterocyclic ring are described. The group is optionally selected from one or more of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, Alkynoylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;

Ring C is a monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic Or a heteroaryl group;

Ring D is selected from

And tetrazole, wherein the group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano a base, an amino group, a monoalkylamino group, an alkylacylamino group, an alkyl acyl group, an aminoacyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group or a heteroaryl group;

Z ¹ is an acyl group, an alkylene group or is absent;

Z ² is -CONH-, -NHCO- or does not exist;

R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl An acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

With the proviso that when Z ¹ is absent, ring A is heteroaryl and is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitrate Base, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl or oxo group Replace

When ring B is a monocyclic aryl group, ring D is tetrazolium.

Another object of the invention is to provide a process for the preparation of a compound of formula A of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.

A further object of the present invention is to provide a composition comprising a compound of the formula A of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a pharmaceutically acceptable carrier, and the present invention A compound of formula A or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug and a combination of another drug or drugs.

A further object of the present invention is to provide a compound of the formula A of the present invention or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof for the treatment and/or prevention of apoptosis signal-regulated kinase 1 A method of disease, and a compound of the formula A of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof thereof, for the preparation of a kinase 1 for the treatment and/or prevention of apoptosis The application of the disease in medicine.

In view of the above purposes, the present invention provides the following technical solutions:

In a first aspect, the present invention provides a compound of the formula A or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug,

among them,

Ring D is selected from

Z ¹ is an acyl group, an alkylene group or is absent;

Z ² is -CONH-, -NHCO- or does not exist;

When ring B is a monocyclic aryl group, ring D is tetrazolium.

In some preferred embodiments, the present invention provides a compound of Formula A, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein Formula A has the structure of Formula I below. ,

among them,

Ring B is selected from the group consisting of a bicyclic aryl group, a bicyclic heteroaryl group, and a bicyclic heterocyclic group, wherein the bicyclic aryl group, the bicyclic heteroaryl group, and the bicyclic heterocyclic group are optionally substituted by one or more halogens, Hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino Acyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;

Z ¹ is an acyl group, an alkylene group or is absent;

Z ² is -CONH-, -NHCO- or does not exist;

With the proviso that when Z ¹ is absent, ring A is heteroaryl and is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitrate Base, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl or oxo group Replace.

In some preferred embodiments, the compound of the invention is a compound of Formula A or Formula I, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

Ring A is selected from the group consisting of C _3-12 cycloalkyl, C _6-18 aryl and 5-20 membered heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogens, Hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkane Oxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl , Bi C _1-6 alkylamino, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic, 6-12 membered aryl, 5-12 Substituted aryl or oxo group;

Further preferably, ring A is selected from the group consisting of C _3-8 cycloalkyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally one or a plurality of halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy group, nitro group, carboxyl group, cyano group, amino group, mono C _1-6 alkylamino group, C _1-6 alkyl acylamino group, C _1-6 alkyl acyl group, amino acyl group, C _1-6 Alkylaminoacyl, bisC _1-6 alkylamino, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl , a 5-12 membered heteroaryl or oxo group;

Still more preferably, ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, iso Thiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein said group is optionally One or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, Hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _{1 -6} alkylamino acyl, bis C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 6-10 An aryl group, a 5-10 membered heteroaryl group or an oxo group is substituted.

Ring B is selected from the group consisting of a 10-18 membered bicyclic aryl group, a 9- or 10-membered bicyclic heteroaryl group, a 9- or 10-membered bicyclic heterocyclic group, wherein the bicyclic aryl group and the bicyclic heteroaryl group are described. And the bicyclic heterocyclic group are optionally substituted by one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, Halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _{1- 6} alkyl acyl, amino acyl, C _1-6 alkylamino acyl, bis C _1-6 alkylamino, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3- a 12-membered heterocyclic group, a 6-12 membered aryl group, a 5-12 membered heteroaryl group or an oxo group;

Further preferably, ring B is selected from the group consisting of naphthyl, 9- or 10-membered benzathione, 9- or 10-membered benzoxacyclic, 9- or 10-membered benzothiazepine, a 9- or 10-membered benzodiazepine group, a 9- or 10-membered benzodioxanylene group, a 9- or 10-membered benzodithioheterocyclyl group, a 9- or 10-membered benzophenone An oxazacycline, 9- or 10-membered benzothiazepine substrate, wherein said group is optionally substituted by one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl, bis C _1-6 alkylamino, C _2-10 olefin a C _2-10 alkynyl group, a C _3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a 6-12 membered aryl group, a 5-12 membered heteroaryl group or an oxo group;

Still more preferably, ring B is selected from the group consisting of naphthyl, anthracenyl, isodecyl, porphyrinyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, Dihydrobenzopyranyl, benzothienyl, dihydrobenzothiophenyl, benzoxazolinone, benzopyrazolyl, dihydrobenzopyrazole, benzimidazolyl, dihydrobenzene Imidazolyl, benzopyrazolyl, dihydrobenzopyrazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, dihydrobenzothiazolyl, benzisoxazole , dihydrobenzoisoxazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolinyl, dihydroquinoline , dihydroisoquinolyl, quinazolinyl, tetrahydroquinazolinyl, dihydroquinazolinyl, porphyrinyl, dihydroporphyrinyl, tetrahydroporphyrinyl, quinoxalinyl, Hydroquinoxalinyl, tetrahydroquinoxalinyl, benzoxazinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, benzodioxyl, benzo Morpholinyl, benzoxylthioxanyl and benzodioxole a group wherein the group is optionally substituted by one or more halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy Halogenated C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _{1 -3} alkyl acyl, amino acyl, C _1-3 alkylamino acyl, bis C _1-3 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3 -8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl or oxo group substituted.

Ring C is a 5-12 membered monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _{1 -6} alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino , C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl, bis C _1-6 alkylamino, C _2-10 alkenyl, C _2-10 Alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl;

Further preferably, ring C is a 5-6 membered monocyclic heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl , hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _{1- a 3-} alkylamino group, a C _1-3 alkyl acylamino group, a C _1-3 alkyl acyl group, an amino acyl group, a C _1-3 alkylamino acyl group, a bis C _1-3 alkylamino group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group;

Still more preferably, ring C is selected from the group consisting of furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl , oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,3,5-triazinyl, wherein said group is optionally substituted by one or more halogens, hydroxyl groups, C _{1- 3-} alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro , carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl, amino acyl, C _1-3 alkylamino acyl, di C _{1- 3} alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl.

Z ¹ is an acyl group, a C _1-6 alkyl acyl group or is absent;

Further preferably, Z ¹ is an acyl group, a C _1-6 alkyl acyl group or is absent;

Still more preferably, Z ¹ is

Or does not exist.

R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy a group, a hydroxy C _1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C _1-6 alkylamino group, a C _1-6 alkyl acylamino group, a C _1-6 alkyl acyl group, an amino acyl group, C _1-6 alkylamino acyl, bis C _1-6 alkylamino, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl and 3-12 membered heterocyclic, 6- 12-membered aryl or 5-12-membered heteroaryl;

Further preferably, R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halogenated C _{1 -3} alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl , aminoacyl, C _1-3 alkylamino acyl, bis C _1-3 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic ring a group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group;

Still more preferably, R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkane Oxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl, amino acyl, C _1-3 alkylamino acyl, bis C _1-3 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl A 3-8 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group.

In some preferred embodiments, the compound of the invention is a compound of formula A or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

Ring D is selected from the group consisting of tetrazolium, which is optionally substituted with one or more R ² ;

Further preferably, ring D is selected from the group

Said group is optionally substituted by one or more R ² ;

Still more preferably, ring D is selected from the group

Wherein R ^{2 is} selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano , amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkyl amino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl And one or more of the oxo groups.

In some preferred embodiments, the invention provides a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug thereof,

among them,

Y is selected from the group consisting of alkylene, alkenylene and cycloalkylene, wherein the alkylene, alkenylene and cycloalkylene are optionally substituted by one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl a halogen, an oxo group, an alkoxy group, a carboxyl group, a cyano group, an amino group, a monoalkylamino group or a dialkylamino group, or when Y is an alkylene group and is substituted by two alkyl groups, the two Alkyl groups may form a cycloalkyl group together with the C atom to which they are attached;

W is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl Amino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

M is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl An amino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

The definition of R ¹ is as described above.

In some preferred embodiments, the compound of the invention is a compound of formula Ia or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

Y is selected from the group consisting of a C _1-6 alkyl group, a C _2-10 alkenylene group, and a C _3-10 cycloalkyl group, wherein the C _1-6 alkyl group, the C _2-10 alkenylene group, and the C ₃ group _-10 cycloalkylene may be one or more C _1-6 alkyl, halo C _1-6 alkyl, hydroxy, hydroxy C _1-6 alkyl, halogen, oxo, C _1-6 alkane Oxygen, carboxyl, cyano, amino, mono C _1-6 alkylamino or di C _1-6 alkylamino, or when Y is C _1-6 alkyl and substituted by two alkyl The two alkyl groups described may form a C _3-8 cycloalkyl group together with the C atom to which they are attached;

Further preferably, Y is selected from the group consisting of a C _1-3 alkyl group, a C _2-6 alkenylene group, and a C _3-6 cycloalkylene group, wherein the C _1-3 alkyl group, the C _2-6 alkylene group And C _3-6 cycloalkylene may be one or more C _1-3 alkyl, halo C _1-3 alkyl, hydroxy, hydroxy C _1-3 alkyl, halogen, oxo, C _1-3 alkoxy, carboxy, cyano, amino, mono C _1-3 alkylamino or di C _1-3 alkylamino, or when Y is C _1-3 alkyl and is dialkyl When substituted, the two alkyl groups may form a C _3-6 cycloalkyl group together with the C atom to which they are attached;

Still more preferably, Y is selected from the group consisting of a methylene group, an ethylene group, a propylene group, a vinylidene group, a propylene group, and a cyclopropylene group, wherein the methylene group, the ethylene group, the propylene group, and the sub The vinyl, propylene group and cyclopropylene are optionally substituted by one or more halogen, methyl, ethyl, propyl, isopropyl, oxo groups, or when Y is methylene and is When substituted with an alkyl group, the two alkyl groups may form a C ₃ -C ₆ cycloalkyl group together with the C atom to which they are attached.

M is selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy , hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl group, bis C _1-6 alkylamino group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 a aryl group or a 5-12 membered heteroaryl group;

Further preferably, M is selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halogen C _{1- 3} alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl, Aminoacyl group, C _1-3 alkylamino acyl group, bis C _1-3 alkylamino group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group , 6-10 membered aryl or 5-10 membered heteroaryl.

In some specific embodiments, a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein

Selected from

In some specific embodiments, a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein M is hydrogen,

W is selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy , hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl group, bis C _1-6 alkylamino group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 a aryl group or a 5-12 membered heteroaryl group;

Further preferably, W is selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halogen C _{1- 3} alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl, Aminoacyl group, C _1-3 alkylamino acyl group, bis C _1-3 alkylamino group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-10 cycloalkyl group, 3-10 membered heterocyclic group , 6-10 membered aryl or 5-10 membered heteroaryl;

Still more preferably, W is selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy , halogenated C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl group, amino acyl group, C _1-3 alkylamino acyl group, bis C _1-3 alkylamino group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group, 6-8 membered aryl group or 5-8 membered heteroaryl group.

In some specific embodiments, a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein:

structure

Selected from

M is hydrogen,

R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy a group, a hydroxy C _1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C _1-6 alkylamino group, a C _1-6 alkyl acylamino group, a C _1-6 alkyl acyl group, an amino acyl group, C _1-6 alkylamino acyl, bis C _1-6 alkylamino, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl and 3-12 membered heterocyclic, 6- 12-membered aryl or 5-12-membered heteroaryl.

In some preferred embodiments, the invention provides a compound of Formula Ib, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,

Wherein, W, R ¹ , Z ¹ , Z ² , ring B and ring C are as defined above.

In some preferred embodiments, the invention provides a compound of Formula Ic, or an isomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug thereof,

Wherein, W, R ¹ , Y and ring C are as defined above, and X ¹ and X ² are each independently selected from C(R ² ) and N, wherein R ^{2 is} selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino Acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In some preferred embodiments, the compound of the invention is a compound of formula Ic or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

R ^{2 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy a group, a hydroxy C _1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C _1-6 alkylamino group, a C _1-6 alkyl acylamino group, a C _1-6 alkyl acyl group, an amino acyl group, C _1-6 alkylamino acyl group, bis C _1-6 alkylamino group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6- 12-membered aryl or 5-12-membered heteroaryl;

Further preferably, R ^{2 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halogenated C _{1 -3} alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl , aminoacyl, C _1-3 alkylamino acyl, bis C _1-3 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic ring a group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group;

Still more preferably, R ^{2 is} selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkane Oxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl, amino acyl, C _1-3 alkylamino acyl, bis C _1-3 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl 3-8 membered heterocyclic group, 6-8 membered aryl group and 5-8 membered heteroaryl group.

In some embodiments, the invention provides a compound of the formula Id or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,

among them,

Ring B is selected from the group consisting of monocyclic aryl groups and

It is optionally selected from one or more selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl Amino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups Replace

R ^{2 is} selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino , monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxygen One or more of the generation groups; and

W, Z ² are as defined in the above formula A, I, Ia, Ib or Ic.

In some embodiments, a compound of Formula Id, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein Ring B is selected from phenyl and

It is optionally selected from one or more selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _{1 -6} alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl , aminoacyl group, C _1-6 alkylamino acyl group, bis C _1-6 alkylamino group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic ring Substituents of aryl, aryl, heteroaryl and oxo groups.

In some specific embodiments, the compound of Formula Ib, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, according to the invention, wherein Ring B is selected from the group consisting of phenyl and

The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:

In another aspect, the invention provides a process for the preparation of a compound of the formula of the invention, for example:

1) A process for the preparation of a compound of the formula Ia of the invention can be obtained by the following steps:

a) a compound of formula 1 is reacted with hydrazine hydrate to produce a compound of formula 2;

b) reacting a compound of formula 2 with N,N-dimethylformamide dimethyl acetal to produce a compound of formula 3;

c) reacting a compound of formula 3 with a compound of formula 4 to produce a compound of formula 5;

d) reacting a compound of formula 5 with a compound of formula 6 to produce a compound of formula 7;

e) A compound of formula 7 is reacted with a compound of formula 8 to produce a compound of formula Ia.

Wherein X is a halogen, preferably chlorine or bromine, and R ¹ , W, Y, M are as defined in the above formula Ia.

2) When Z ^{2 is} selected from -CONH-, the preparation method of the compound of the formula Id of the present invention can be obtained by reacting a compound of the formula Id-1 with a compound of the formula Id-2:

Wherein X is a halogen, preferably chlorine, bromine, R ² , W, Z ² and ring B are as defined in the above formula Id.

3) The preparation method of the compound of the formula A, I, Ib or Ic of the present invention can be carried out by referring to the preparation method of the formula Ia or by other technical means conventionally used by those skilled in the art.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, further comprising a group selected from the group consisting of One or more agents: one or more angiotensin converting enzyme (ACE) inhibitors, such as enalapril, captopril, ramipril, lisinopril, and quinapril; or blood vessels Angiotensin II receptor blockers (ARB), such as losartan, olmesartan, and irbesartan; or antihypertensive agents such as amlodipine, nifedipine, and felodipine; antibiotics, analgesics , antidepressants and / or anti-anxiety agents.

In some embodiments, the invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a compound comprising the same, or an isomer thereof, pharmaceutically acceptable A pharmaceutical composition of a salt, solvate, crystal or prodrug for use in the treatment and/or prevention of a cell apoptosis signal modulating kinase 1 associated disease.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

The compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or oral administration. Parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.

In a fourth aspect, the present invention provides a compound represented by the formula A, I, Ia, Ib, Ic or Id of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or comprises the same Use of a pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of an apoptosis signal that modulates kinase 1-related diseases, wherein the apoptosis-regulating kinase 1-related diseases or conditions include, but are not limited to, neurodegeneration Diseases, cardiovascular diseases, inflammation, autoimmune diseases, tumors and metabolic disorders, etc., in particular, ASK1 inhibitors for the treatment of diseases include: kidney diseases (such as diabetic nephropathy, diabetic nephropathy, end-stage renal disease, chronic kidney disease, etc.) ), fibrotic diseases (such as lung, kidney fibrosis, etc.), cardiovascular diseases (such as heart failure, etc.), respiratory diseases (such as chronic obstructive pulmonary disease (COPD), pulmonary hypertension, acute lung injury, etc.), acute and chronic Liver diseases (such as nonalcoholic steatohepatitis (NASH), alcoholic hepatitis (AH), liver fibrosis, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.) and tumors.

Terminology

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Hydrogen", "carbon", "oxygen" in the compounds of the invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers. For example, isotopes of hydrogen include ruthenium, osmium, and iridium, carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and isotopes of oxygen include ¹⁶ O and ¹⁸ O.

The "halogen" of the present invention means fluorine, chlorine, bromine or iodine. "Halo" as used in the present invention means substituted by fluorine, chlorine, bromine or iodine.

The "alkyl group" of the present invention means a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group having 1 to 6 carbon atoms, further preferably a linear or branched having 1 to 3 carbon atoms. Chain groups, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.

The "alkylene group" of the present invention means a group in which an alkyl group is formally removed from a hydrogen atom, such as a methylene group (-CH ₂ -), an ethylene group (-CH ₂ -CH ₂ -), A propylene group (-CH ₂ -CH ₂ -CH ₂ -), etc., and a "C _1-6 alkyl group" as used herein means that a C _1-6 alkyl group is formally removed from a hydrogen atom. The lower group, the "subC _1-3 alkyl group" means a group in which a C _1-3 alkyl group is formally removed from a hydrogen atom. The alkylene group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.

The "alkenylene group" of the present invention means a group in which an alkenyl group is formally removed from a hydrogen atom, such as a vinylidene group (-CH=CH-), a propenylene group (-CH=CH-CH ₂ - Or -CH ₂ -CH=CH-), etc., and "C _2-10 alkenyl" as used herein means a group in which a C _2-10 alkenyl group is formally removed from a hydrogen atom. The "subC _2-6 alkenyl group" means a group in which a C _2-6 alkenyl group is formally removed from a hydrogen atom.

The "cycloalkylene" of the present invention means a group in which a cycloalkyl group is formally removed from a hydrogen atom, such as a cyclopropylene group.

Cyclobutylene

And, as used herein, "C _3-10 cycloalkyl" refers to a group in which a C _3-10 cycloalkyl group is formally removed from a hydrogen atom, said "C _{3 - 3 6-} Cycloalkyl" means a group in which a C _3-6 cycloalkyl group is formally removed from a hydrogen atom.

The "alkylidinoyl group" of the present invention means a group in which an alkyl group is formally removed from a hydrogen atom, such as a methylene group (-CH ₂ CO-), an ethylene group (-CH ₂ CH). ₂ CO-), propylene amino group (-CH ₂ CH ₂ CH ₂ CO-), and the like.

The "acyl group" of the present invention means -CO-.

The "haloalkyl group" of the present invention means an alkyl group substituted with at least one halogen.

The "hydroxyalkyl group" of the present invention means an alkyl group substituted with at least one hydroxyl group.

The "alkoxy group" of the present invention means an -O-alkyl group. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like. The alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.

The "cycloalkyl group" of the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The "heterocyclyl" of the present invention means a 3- to 12-membered non-aromatic having 1 to 4 ring heteroatoms in which each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. a group of the ring system ("3-12 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. The heterocyclyl group may alternatively be a monocyclic ("monocyclic heterocyclic") or a fused, bridged or spiro ring system (eg, a bicyclic system ("bicyclic heterocyclyl")) And it can be saturated or can be partially unsaturated. The heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein a heterocycle, as defined above, is fused to one or more carbocyclyl groups (wherein the point of attachment is on a carbocyclic group or on a heterocyclic ring), or a ring system The heterocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocyclic ring), and in such cases, the number of ring members continues to be referred to as hetero The number of ring members in the ring system. Unless otherwise specified, each instance of a heterocyclic group is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero A cyclic group "), such as a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted bridged morphinolyl group, and the like. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl. Fused to the C ₆ aryl ring (also referred to as 5,6-bicyclic heterocycle) Exemplary 5-membered heterocyclyl groups include, but are not limited to, indolinyl, iso indolinyl, two Hydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and the like. .

The "aryl" of the present invention means an aromatic system which may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system containing from 6 to 18 carbon atoms, preferably from about 6 to about 12 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl. The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

The "heteroaryl group" of the present invention means an aryl group having at least one carbon atom replaced by a hetero atom, composed of 5-20 atoms (5-20 membered heteroaryl group), and further preferably composed of 5-12 atoms ( 5-12 membered heteroaryl), said hetero atom is O, S, N, including but not limited to imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl , furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, Pyrimidopyrazolyl, pyrimidoimidazolyl and the like. The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.

The "isomer" of the present invention is a compound having the same molecular formula but differing in nature or on the bond sequence of its atom or in the spatial arrangement of its atoms. Stereoisomers are isomers whose atoms are spatially distinct. Stereoisomers that are not mirror images of each other are diastereomers and that the stereoisomers that are non-overlapping mirror images of each other are enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described by Rahn and S-sequence rules of Cahn and Prelog, or by methods of rotating the plane of polarized light by molecules and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively. The chiral compound can exist as a single enantiomer or a mixture thereof. An equal proportion of mixtures comprising enantiomers is referred to as a "racemic mixture".

The "pharmaceutically acceptable salts" of the present invention refer to salts of the compounds of the present invention which are safe and effective for use in mammals and which have the desired biological activity.

The "solvate" of the present invention refers in a conventional sense to a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water). Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or a substituted amount thereof.

The in vivo action of a compound of formula (A) can be exerted, in part, by one or more metabolites formed in the human or animal body following administration of a compound of formula (A). As described above, the in vivo action of the compound of formula (A) can also be exerted via metabolism of the precursor compound ("prodrug"). The "prodrug" of the present invention refers to a compound which is converted into a compound of the formula (A) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound converted by oxidation, reduction, hydrolysis or the like of an enzyme. A compound of the compound of (A) and/or a compound which is converted into a compound of the formula (A) by a hydrolysis reaction such as gastric acid or the like.

The "crystallization" of the present invention means that the internal structure is a solid formed by regularly repeating constituent atoms (or a group thereof) in three dimensions, and is different from an amorphous solid having an internal structure not having such a regularity.

A "pharmaceutical composition" according to the invention is meant to include any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or A plurality of pharmaceutically acceptable carriers and/or mixtures of one or more drugs. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. The compositions are typically used in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by one or more kinases.

The "pharmaceutically acceptable carrier" of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersing agents, and surface active agents. Isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin and the like.

"Excipient" as used herein refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

Detailed ways

The following representative examples are intended to better illustrate the invention and are not intended to limit the scope of the invention. The materials used in the following examples are commercially available unless otherwise specified.

Example 1: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-oxo-2-phenyl Preparation of ethyl)-1H-benzo[d]imidazole-6-carboxamide

Step 1: Preparation of 6-aminopyridine-2-formylhydrazide

Methyl 6-aminopicolinate (15.0 g, 98.7 mmol) was added to a 250 mL single-necked flask, dissolved in methanol (150 mL), hydrated hydrazine (12.0 g, 198 mmol) was added and refluxed at 70 ° C for 5 h. After completion of the reaction, the title compound was obtained. LC-MS m/z: [M+H] ⁺ = 153.

Step 2: (E)-N'-(6-(2-((E)-(Dimethylamino)methylene)indole-1-carbonyl)pyridin-2-yl)-N,N-dimethyl Preparation of base formazan

The 6-aminopyridine-2-carboxylic acid hydrazide (12.0 g, 78.9 mmol) obtained in the step 1 was dissolved in a 250 mL single-mouth bottle containing 120 mL of N,N-dimethylformamide dimethyl acetal, and refluxed for 4 hours. . After the reaction was completed, the reaction mixture was washed with w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ LC-MS m/z: [M+H] ⁺ = 263.

Step 3: Preparation of 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine

(E)-N'-(6-(2-((E)-(dimethylamino)methylene)indole-1-carbonyl)pyridin-2-yl)-N,N obtained in Step 2 Dimethylformamidine (16.0 g, 60.8 mmol) was placed in a 500 mL single-necked flask, and acetonitrile (150 mL), acetic acid (50 mL) and isopropylamine (17.9 g, 304 mmol) were added and refluxed at 80 ° C overnight. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated LC-MS m/z: [M+H] ⁺ = 204.

Step 4: Preparation of methyl 1-(2-oxo-2-phenylethyl)-1H-benzo[d]imidazole-6-carboxylate

In a 100 mL single-mouth bottle, 2-bromo-1-phenylethan-1-one (1.00 g, 5.00 mmol) and methyl 1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (798 mg, 4.50 mmol) were added. After adding N,N-dimethylformamide (25.0 mL), it was dissolved, followed by potassium carbonate (1.00 g, 7.50 mmol), and reacted at room temperature for 4 h, and the reaction was completed. The reaction mixture was diluted with ethyl acetate (150 mL), and evaporated. LC-MS m/z: [M+H] ⁺ = 295.1.

Step 5: Preparation of 1-(2-oxo-2-phenylethyl)-1H-benzo[d]imidazole-6-carboxylic acid

In a 100 mL vial, 1-(2-oxo-2-phenylethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (800 mg, 2.72 mmol) was added and dissolved in 10.0 mL of ethanol. Subsequently, 8 mL of a 4 M aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 3 hours, and the reaction was completed; the reaction mixture was adjusted to pH 1 with 1M hydrochloric acid and extracted with dichloromethane/isopropanol 3:1. The organic phase was dried over anhydrous sodium sulfate and evaporated LC-MS m/z: [M+H] ⁺ = 281.1.

Step 6: N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-oxo-2-phenylethyl) Preparation of -1H-benzo[d]imidazole-6-carboxamide

In a 100 mL single-mouth bottle, 1-(2-oxo-2-phenylethyl)-1H-benzo[d]imidazole-6-carboxylic acid (910 mg, 3.25 mmol) and 6-(4-isopropyl) were added. -4H-1,2,4-triazol-3-yl)pyridin-2-amine (600 mg, 2.96 mmol), dissolved in o-xylene (15.0 mL), refluxed at 150 ° C for 5 min, then N, N 5 drops of dimethylformamide, adding o-xylene solution of PCl ₅ , reacting under the conditions for 40 min, the reaction is finished; the reaction solution is quenched with water, adjusted to pH 12 with 2M sodium hydroxide aqueous solution, with dichloromethane/methanol 3:1 extraction. The organic phase was dried over anhydrous sodium sulfate and evaporated ^{1 H NMR (400MHz, DMSO-} d 6) δ10.64 (s, 1H), 8.87 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.22 (d, 1H), 8.14 ( d, 2H), 8.00-8.08 (m, 1H), 7.80-7.92 (m, 2H), 7.67-7.78 (m, 2H), 7.62-7.67 (m, 2H), 6.09 (s, 2H), 5.75- 5.82 (m, 1H), 1.43 (d, 6H). LC-MS m/z: [M+H] ⁺ = 466.2.

Example 2: 2-(cyclopropanecarbonyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5 -formamide

Step 1: Preparation of 3,4-dibromomethyl-benzoic acid methyl ester

In a 250 mL single-mouth bottle, methyl 3,4-dimethylbenzoate (6.00 g, 36.6 mmol), benzoyl peroxide (900 mg, 3.66 mmol) and N-bromosuccinimide (13.0 g) were added. , 73.2 mmol), dissolved in chloroform (60 mL) and refluxed for 20 h. After the completion of the reaction, the insoluble material was removed by suction, and the filtrate was evaporated, evaporated, evaporated, evaporated. LC-MS m/z: [M+H] ⁺ = 321.

Step 2: Preparation of methyl 2-benzylisoindoline-5-carboxylate

3,4-Dibromomethyl-benzoate (12.0 g, 37.5 mmol) was dissolved in a one-neck flask containing 120 mL of tetrahydrofuran, and benzylamine (4.00 g, 37.5 mmol) and triethylamine (7.57 g, 75.0 mmol), stirred at room temperature overnight. After the reaction was completed, EtOAc EtOAc m. LC-MS m/z: [M+H] ⁺ = 268.

Step 3: Preparation of 2-benzylisoindoline-5-carboxylic acid

Methyl 2-benzylisoindoline-5-carboxylate (4.50 g, 16.9 mmol) was dissolved in methanol (40 mL) in water (100 mL) and water (10 mL) and lithium hydroxide (2.00 g, 84.3) Methyl), stirred at room temperature for 5 h. After completion of the reaction, the pH was adjusted to neutral, and dichloromethane (100 mL × 3) was evaporated. LC-MS m/z: [M+H] ⁺ =254.

Step 4: 2-Benzyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide preparation

2-Benzylisoindoline-5-carboxylic acid (2.00 g, 7.90 mmol) obtained in Step 3 was placed in a 100 mL single-necked flask, anhydrous dichloromethane (30 mL) was added, and oxalyl chloride (1. The mixture was stirred at room temperature for 2 h.

6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (1.30 g, 7.10 mmol) obtained in Step 3 of Example 1 was placed in a 100 mL single-mouth bottle. The residue was dissolved in anhydrous dichloromethane (30 mL). After completion of the reaction, the reaction mixture was washed with water (50 mL). LC-MS m/z: [M+H] ⁺ = 439.

Step 5: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide

Pd/C (60.0 mg, 10%) was placed in a 100 mL vial, methanol (30 mL) was added, and then 2-benzyl-N-(6-(4-isopropyl-4H-) obtained in Step 4 was added. 1,2,4-Triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide (600 mg, 1.38 mmol), 3 drops of concentrated hydrochloric acid was added dropwise, and the mixture was stirred three times with hydrogen and stirred at room temperature. After completion of the reaction, filtration, LC-MS m/z: [M+H] ⁺ =349.

Step 6: 2-(cyclopropanecarbonyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5- Preparation of formamide

N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide (200 mg, obtained in Step 5) 0.570 mmol) was dissolved in methylene chloride, and N,N-diisopropylethylamine (190 mg, 1.44 mmol) was added, and the mixture was stirred for 3 min, and then added with cyclopropylcarbonyl chloride (71.0 mg, 0.680 mmol). After the reaction was completed, the reaction mixture was diluted with water (50 mL), dichloromethane: EtOAc: EtOAc: EtOAc (EtOAc) The title compound was prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.8 (s, 1H), 8.88 (s, 1H), 8.17-8.20 (m, 1H), 8.01-8.05 (m, 1H), 7.93-7.97 (m) , 2H), 7.87 (d, 1H), 7.54 (d, 1H), 5.69-5.75 (m, 1H), 5.11 (s, 2H), 4.73 (s, 2H), 1.88-1.93 (m, 1H), 1.44 (d, 6H), 0.82-0.86 (m, 4H). LC-MS m/z: [M+H] ⁺ = 417.

Example 3: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-2-naphthalenecarboxamide

Step 1: Preparation of methyl 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-naphthoate

Methyl 6-bromo-2-naphthoate (491 mg, 1.85 mmol) and 4-cyclopropyl-1H-imidazole (200 mg, 1.85 mmol) were placed in a 100 mL single-necked flask, followed by the addition of 8-hydroxyquinoline (27.0 mg, 0.185 mmol), potassium carbonate (511 mg, 3.70 mmol) and cuprous iodide (35.2 mg, 0.185 mmol), and finally dissolved in dimethyl sulfoxide (5 mL). After nitrogen substitution, the mixture was heated to 120 ° C for 6 h. The reaction of the starting material was confirmed by LC-MS. Water (20 mL) and ethyl acetate (50 mL×3) were added to the mixture, and the residue was evaporated, evaporated, evaporated, evaporated. Column chromatography (petroleum ether: ethyl acetate = 10:1) gave LC-MS m/z: [M+H] ⁺ = 293.

Step 2: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-naphthoic acid

Methyl 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-naphthoate (800 mg, 2.74 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (3 mL), then hydrogen Lithium oxide (132 mg, 5.48 mmol) was reacted at 25 ° C for 3 h. The pH of the reaction mixture was adjusted to 3 with dilute hydrochloric acid (1 N), and extracted with dichloromethane (10 mL) (3 mL). The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The title compound was obtained afterwards. LC-MS m/z: [M+H] ⁺ = 279.

Step 3: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-2-naphthalenecarboxamide

6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-naphthoic acid (600 mg, 2.16 mmol) and 6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridin-2-amine (438 mg, 2.16 mmol) was dissolved in o-xylene (30 mL) and N,N-dimethylformamide (10 mL), then phosphorus pentachloride (225 mg, 1.08 mmol). Heat to 150 ° C for 3 h. LC-MS showed the end of the reaction. After removing o-xylene under reduced pressure, ethyl acetate (50 mL) and water (30 mL) were added and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×2). After concentration, the crude product was obtained, which was purified by preparative HPLC. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.98 (s, 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.18-8.35 (m, 4H), 8.00-8.13 (m, 3H ), 7.93 (d, 1H), 7.89 (d, 1H), 7.70 (s, 1H), 5.70-5.79 (m, 1H), 1.78-1.91 (m, 1H), 1.46 (d, 6H), 0.79- 0.85 (m, 2H) 0.68-0.75 (m, 2H). LC-MS m/z: [M+H] ⁺ = 464.2.

Example 4: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazole -4-yl)-isoindoline-1-one

Step 1: Preparation of methyl 4-bromo-1,3-thiazole-2-carboxylate

4-bromo-1,3-thiazole-2-carboxylic acid (2.00 g, 9.80 mmol) was added to a 100 mL one-necked flask, dissolved in methanol (20 mL), and thionyl chloride (1.16 g, 9.80 mmol) was added in an ice water bath. It was refluxed at 70 ° C for 3 h. After completion of the reaction, the reaction mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 222.

Step 2: Preparation of 4-bromothiazole-2-formylhydrazide

In a 100 mL single-mouth bottle, methyl 4-bromo-1,3-thiazole-2-carboxylate (2.00 g, 9.01 mmol) was added, dissolved in ethanol (20 mL), and hydrazine hydrate (2.45 g, 50.1 mmol) was added at 80 ° C. Under reflux for 2 h. After the reaction was completed, the mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 222.

Step 3: Preparation of N'-(4-bromothiazole-2-carbonyl)-N,N-dimethylformamidine

The 4-bromothiazole-2-carboxylic acid hydrazide (1.50 g, 6.76 mmol) prepared in Step 2 was dissolved in a 100 mL single-mouth bottle containing 20 mL of N,N-dimethylformamide dimethyl acetal at 95 ° C. Stir for 2 h. After the reaction was completed, the reaction mixture was washed with w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ LC-MS m/z: [M+H] ⁺ =277.

Step 4: Preparation of 4-bromo-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazole

N'-(4-bromothiazole-2-carbonyl)-N,N-dimethylformamidine (1.80 g, 6.52 mmol) obtained in Step 3 was placed in a 100 mL single-mouth flask, and acetonitrile (20 mL) was added. (5 mL) and isopropylamine (1.93 g, 32.6 mmol) were stirred at 95 ° C for 3 h. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated LC-MS m/z: [M+H] ⁺ = 273.

Step 5: Preparation of 6-bromo-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one

4-Bromo-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazole (653 mg, 2.40 mmol), 6-bromoisoporphyrin- 1-ketone (422 mg, 2.00 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.200 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (347 mg, 0.600) Methyl acetate and potassium phosphate (84.8 mg, 0.400 mmol) were dissolved in a microwave tube containing toluene (15 mL), and subjected to a microwave reaction at 120 ° C for 1 h. After completion of the reaction, the mixture was filtered, and then filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjj Compound. LC-MS m/z: [M+H] ⁺ = 404.

Step 6: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazole- Preparation of 4-yl)-isoindoline-1-one

6-Bromo-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one obtained in Step 5 Ketone (403 mg, 1.00 mmol), 4-cyclopropyl-1(3)H-imidazole (119 mg, 1.10 mmol), cesium carbonate (652 mg, 2.00 mmol), cuprous iodide (19.0 mg, 0.100 mmol) and N N-Dimethylethylenediamine (88.0 mg, 0.100 mmol) was dissolved in dioxane (10 mL), and subjected to a nitrogen atmosphere and then reacted at 135 ° C for 3 h. After the completion of the reaction, the reaction mixture was filtered, and then evaporated, evaporated, evaporated, evaporated, ^{1 H NMR (400MHz, DMSO-} d 6) δ9.00 (s, 1H), 8.27 (d, 1H), 8.10 (s, 1H), 8.04 (d, 1H), 7.95-7.99 (m, 1H), 7.84-7.88(m,1H), 7.67(s,1H),5.44-5.53(m,1H),5.22(s,2H),1.81-1.91(m,1H),1.58(d,6H),0.80- 0.86 (m, 2H), 0.70-0.74 (m, 2H). LC-MS m/z: [M+H] ⁺ = 432.

Example 5: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,4-dihydroisoquinoline-1(2H)-one

Step 1: Preparation of 6-bromopyridine-2-formylhydrazide

Methyl 6-bromopicolinate (10.0 g, 46.5 mmol) was added to a 250 mL single-necked flask, dissolved in methanol (150 mL), and hydrazine hydrate (4.60 g, 93.0 mmol) was added and refluxed at 70 ° C for 5 h. After completion of the reaction, the title compound was obtained. LC-MS m/z: [M+H] ⁺ = 216.

Step 2: Preparation of N'-(6-bromo-1-carbonylpyridin-2-yl)-N,N-dimethylformamidine

6-Bromopyridine-2-carboxylic acid hydrazide (8.60 g, 40.0 mmol) obtained in Step 1 was dissolved in a 250 mL single-necked flask containing N,N-dimethylformamide dimethyl acetal (90 mL), refluxed Reaction 4h. After the reaction was completed, the reaction mixture was washed with w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ LC-MS m/z: [M+H] ⁺ = 271.

Step 3: Preparation of 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine

N'-(6-Bromo-1-carbonylpyridin-2-yl)-N,N-dimethylformamidine (8.60 g, 31.9 mmol) obtained in Step 2 was placed in a 250 mL single-necked flask, and acetonitrile was added. 60 mL), acetic acid (30 mL) and isopropylamine (9.40 g, 159 mmol). After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated LC-MS m/z: [M+H] ⁺ = 267.

Step 4: 7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline Preparation of -1(2H)-one

2-Bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (650 mg, 2.44 mmol), 7-bromo-3,4-, obtained in Step 3. Dihydroisoquinoline-1(2H)-one (660 mg, 2.93 mmol), tris(dibenzylideneacetone)dipalladium (223 mg, 0.244 mmol), 2-dicyclohexylphosphorus-2,4,6-tri Isopropylbiphenyl (423 mg, 0.732 mmol) and cesium carbonate (954 mg, 0.293 mmol) were dissolved in a 100 mL single-necked flask containing toluene (15 mL), and the mixture was stirred three times with nitrogen and stirred at 100 ° C for 6 h. After the reaction was completed, the title compound was obtained. LC-MS m/z: [M+H] ⁺ = 412.

Step 5: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-3,4-dihydroisoquinoline-1(2H)-one

7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-dihydrogen obtained in Step 4 Isoquinoline-1(2H)-one (200 mg, 0.480 mmol), 4-cyclopropyl-1H-imidazole (60.0 mg, 0.556 mmol), cuprous iodide (20.0 mg, 0.0240 mmol), 8-hydroxyquine The porphyrin (7.00 mg, 0.0480 mmol) and cesium carbonate (320 mg, 0.960 mmol) were placed in a reaction flask, dissolved in 1.4-dioxane (5 mL), replaced with nitrogen three times, and reacted at 135 ° C for 4 h. After the completion of the reaction, the mixture was filtered, and then filtered, evaporated, evaporated, evaporated. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.16 (s, 1H), 8.11 (d, 1H), 7.95-8.07 (m, 3H), 7.81-7.86 (m, 1H) ), 7.54 - 7.58 (m, 2H), 5.35 - 5.43 (m, 1H), 4.23-4.30 (m, 2H), 3.17 - 3.22 (m, 2H), 1.82-1.91 (m, 1H), 1.51 (d) , 6H), 0.78-0.84 (m, 2H), 0.70-0.74 (m, 2H). LC-MS m/z: [M+H] ⁺ = 440.

Example 6: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)isoindoline-1-one

Step 1: Preparation of 6-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one

6-Bromoisoindoline-1-one (1.00 g, 4.72 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (1.26 g, 4.72 mmol) and potassium phosphate (2.51 g, 11.8 mmol) were dissolved in dioxane (30 mL) and 4,5-bisdiphenylphosphino-9,9-dimethyloxaxene (Xant) -phos, 272 mg, 0.472 mmol) and tris(dibenzylideneacetone)dipalladium Pd ₂ (dba) ₃ (431 mg, 0.472 mmol), which was subjected to a nitrogen atmosphere and then reacted at 130 ° C for 70 min. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjj Title compound. LC-MS m/z: [M+H] ⁺ =398.

Step 2: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)isoindoline-1-one

6-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one obtained in the first step Ketone (0.500 g, 1.26 mmol), 4-cyclopropyl-1(3)H-imidazole (0.163 g, 1.50 mmol) and cesium carbonate (821 mg, 2.52 mmol) dissolved in dioxane (8 mL). Cuprous (24.0 mg, 0.126 mmol) and N,N-dimethylethylenediamine (11.1 mg, 0.126 mmol) were replaced with nitrogen and then subjected to microwave reaction at 130 ° C for 50 min. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated, mjjjjjjjjjjjjjjjjjjjjjjj 15:1) Preparation of the title compound was isolated. ^{1 H NMR (300MHz, DMSO-} d 6) δ8.95 (s, 1H), 8.66 (d, 1H), 8.28 (s, 1H), 8.06-8.13 (m, 2H), 7.86-8.01 (m, 3H ), 7.68 (s, 1H), 5.50-5.57 (m, 1H), 5.20 (s, 2H), 1.82-1.88 (m, 1H), 1.59 (d, 6H), 0.80-0.85 (m, 2H), 0.70-0.74 (m, 2H). LC-MS m/z: [M+H] ⁺ = 426.

Example 7: 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(4-methyl-1H-imidazole- 1-yl)isoindoline-1-one

The preparation method was similar to the preparation method of Example 6, except that the starting material 4-cyclopropyl-1(3)H-imidazole was replaced with 4-methyl-1(3)H-imidazole to give the title compound. ^{1 H NMR (300MHz, DMSO-} d 6) δ8.95 (s, 1H), 8.66 (d, 1H), 8.33 (s, 1H), 8.06-8.13 (m, 2H), 7.87-7.99 (m, 3H ), 7.64 (s, 1H), 5.48-5.57 (m, 1H), 5.20 (s, 2H), 2.19 (s, 3H), 1.59 (d, 6H). LC-MS m/z: [M+H ] ⁺ =400.

Example 8: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,3-dimethylisoindole-1-one

Step 1: 6-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,3-dimethylisoindole Preparation of indole-1-one

6-Bromo-3,3-dimethylisoindolin-1-one (1.13 g, 4.72 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-tri Zin-3-yl)pyridine (1.26 g, 4.72 mmol) and potassium phosphate (2.51 g, 11.8 mmol) were dissolved in dioxane (10 mL), and Xant-phos (272 mg, 0.472 mmol) and Pd ₂ (dba) were added. ₃ (431 mg, 0.472 mmol), after nitrogen substitution, microwave reaction at 130 ° C for 70 min. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjj Title compound. LC-MS m/z: [M+H] ⁺ =426.

Step 2: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-3,3-dimethylisoindole-1-one

6-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,3-dimethylate prepared in the first step Isoindolin-1-one (537 mg, 1.26 mmol), 4-cyclopropyl-1(3)H-imidazole (0.163 g, 1.50 mmol) and cesium carbonate (821 mg, 2.52 mmol) dissolved in dioxane (8 mL), copper iodide (24.0 mg, 0.126 mmol) and N,N-dimethylethylenediamine (11.1 mg, 0.126 mmol) were added, and the mixture was replaced with nitrogen, and then subjected to microwave reaction at 130 ° C for 90 min. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was filtered, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjj :1) Preparation of the title compound isolated. ^{1 H NMR (300MHz, DMSO-} d 6) δ8.97 (s, 1H), 8.27 (s, 1H), 8.09-8.17 (m, 2H), 7.92-8.03 (m, 4H), 7.67 (s, 1H ), 5.31-5.38 (m, 1H), 1.84-1.87 (m, 1H), 1.77 (s, 6H), 1.45 (d, 6H), 0.80-0.85 (m, 2H), 0.71-0.74 (m, 2H) ). LC-MS m/z: [M+H] ⁺ =454.

Example 9: 2-Benzoyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-A Amide

Step 1: Preparation of 3,4-dibromomethyl-benzoate

To a 250 mL single-mouth bottle, methyl 3,4-dimethylbenzoate (6.00 g, 36.6 mmol), benzoyl peroxide (900 mg, 3.66 mmol) and N-bromosuccinimide (13.0 g, 73.2 mmol), dissolved in chloroform (60 mL) and refluxed for 20 h. After the completion of the reaction, the insoluble material was removed by suction, and the filtrate was evaporated, evaporated, evaporated, evaporated. LC-MS m/z: [M+H] ⁺ = 323.

Step 2: Preparation of methyl 2-benzylisoindoline-5-carboxylate

3,4-Dibromomethylbenzoate (12.0 g, 37.5 mmol) was dissolved in a one-neck flask containing 120 mL of tetrahydrofuran, and benzylamine (4.00 g, 37.5 mmol) and triethylamine (7.57 g, 75.0) were added. Methyl), stirred at room temperature overnight. After the reaction was completed, EtOAc EtOAc m. LC-MS m/z: [M+H] ⁺ = 268.

Step 3: Preparation of 2-benzylisoindoline-5-carboxylic acid

Methyl 2-benzylisoindoline-5-carboxylate (4.50 g, 16.9 mmol) was dissolved in methanol (40 mL) in water (100 mL) and water (10 mL) and lithium hydroxide (2.00 g, 84.3) Methyl), stirred at room temperature for 5 h. The reaction was completed, the pH was taken to EtOAc (EtOAc) (EtOAc) LC-MS m/z: [M+H] ⁺ =254.

6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (1.30 g, 7.10 mmol) was placed in a 100 mL jar, anhydrous dichloromethane (30 mL) The solution was dissolved in EtOAc (EtOAc m. After the reaction was completed, the reaction mixture was washed with w~~~~~~~~~~~~~~~~~~~ LC-MS m/z: [M+H] ⁺ = 439.

Pd/C (60.0 mg, 10%) was placed in a 100 mL vial, methanol (30 mL) was added, and then 2-benzyl-N-(6-(4-isopropyl-4H-) obtained in Step 4 was added. 1,2,4-Triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide (600 mg, 1.38 mmol), 3 ml of concentrated hydrochloric acid, three times of hydrogen, and stirred at room temperature. After completion of the reaction, filtration, LC-MS m/z: [M+H] ⁺ =349.

Step 6: 2-Benzoyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide Preparation

Benzoic acid (50.0 mg, 0.389 mmol) was placed in a 25 mL single-mouth bottle, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate was added. (246 mg, 0.646 mmol), N,N-diisopropylethylamine (90.0 mg, 0.646 mmol) was added under cooling, stirred for 10 min, then N-(6-(4-isopropyl)- 4H-1,2,4-Triazol-3-yl)pyridin-2-yl)isoindole-5-carboxamide (90.0 mg, 0.258 mmol). After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane:ethanol=5:1 (30mL×3), and the organic phase was combined and concentrated to give a crude product. The title compound was prepared. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.77 (d, 1H), 8.88 (d, 1H), 8.18 (d, 1H), 7.85-8.05 (m, 4H), 7.64-7.66 (m, 2H ), 7.45-7.60 (m, 4H), 5.66-5.74 (m, 1H), 4.96 (s, 2H), 4.87 (s, 2H), 1.42-1.46 (m, 6H).

LC-MS m/z: [M+H] ⁺ =453.

Example 10: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-1-ethyl-2-(6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridin-2-yl)-oxazol-3-one

Step 1: Preparation of 5-bromo-1-ethyloxazol-3-one

Dissolve 5-bromo-oxazol-3-one (3.00 g, 14.1 mmol) in N,N-dimethylformamide (30 mL), then add potassium carbonate (3.89 g, 28.2 mmol), slowly at 0 ° C Iodoethane (1.25 mL, 15.5 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 hours after completion of dropwise addition. After the reaction was completed, the mixture was filtered, filtered, evaporated, evaporated, evaporated, evaporated, evaporated 1) The title compound was isolated. LC-MS m/z: [M+H] ⁺ = 241.

Step 2: 5-Bromo-1-ethyl-2-(6-(4-isopropyl 4H-1,2,4-triazol-3-yl)pyridin-2-yl)-indazole-3- Preparation of ketone

5-Bromo-1-ethyloxazol-3-one (0.450 g, 1.87 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl Pyridine (0.599 g, 2.25 mmol) was dissolved in 15 mL of 1,4-dioxane, and tris(dibenzylideneacetone)dipalladium (0.172 g, 0.187 mmol), 4,5-bisdiphenylphosphine was added. -9,9-Dimethyloxanthene (0.326 g, 0.561 mmol) and potassium phosphate (0.596 g, 2.81 mmol) were replaced with nitrogen three times and reacted in a microwave at 105 ° C for 35 minutes. After the reaction was completed, the mixture was filtered, and then filtered, and the mixture was evaporated to ethyl acetate (5 mL, 3), and the organic phase was combined and dried over anhydrous sodium sulfate. 1:2) The title compound was isolated. LC-MS m/z: [M+H] ⁺ =427.

Step 3: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-1-ethyl-2-(6-(4-isopropyl-4H-1,2,4-triazole-3) Of -pyridyl-2-yl)-oxazol-3-one

5-Bromo-1-ethyl-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-oxazol-3-one (410 mg, 0.962 mmol) and 4-cyclopropyl-1H-imidazole (125 mg, 1.15 mmol) were dissolved in 10 mL of 1,4-dioxane, and cuprous iodide (18.0 mg, 0.0962 mmol), 8- Hydroxyquinoline (14.0 mg, 0.0962 mmol) and cesium carbonate (470 mg, 1.44 mmol) were replaced with nitrogen three times and reacted with microwave at 135 ° C for 4 hours. After the completion of the reaction, the mixture was filtered, and then filtered, evaporated, evaporated, evaporated. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.65 (s, 1H), 8.12 (t, 1H), 8.04 (s, 1H), 7.92 (dd, 2H), 7.74 (dd, 1H), 7.70 ( d,1H), 7.46 (s, 1H), 7.40 (d, 1H), 4.46-4.52 (m, 1H), 4.40-4.44 (m, 2H), 1.77-1.81 (m, 1H), 1.40 (t, 3H), 0.75-0.77 (m, 2H), 0.70 (d, 3H), 0.69 (d, 3H), 0.66-0.64 (m, 2H). LC-MS m/z: [M+H] ⁺ =455.

Example 11: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-1-methyl-1H-indole-4-carboxamide

Step 1: Preparation of 6-bromo-1-methyl-1H-indole-4-carboxylic acid methyl ester

Add 6-bromo-1H-indole-4-carboxylic acid methyl ester (2.00 g, 7.88 mmol) to a 100 mL vial, add anhydrous tetrahydrofuran (25.0 mL), and add NaH (350 mg, 8.64 mmol) under ice bath. After stirring for 15 min, CH ₃ I (1.23 g, 8.64 mmol) was added, and the mixture was reacted for 1 h at room temperature, and the reaction was completed. The reaction mixture was quenched with water and ethyl acetate. Drying and spinning off the solvent gave the title compound. LC-MS m/z: [M+H] ⁺ = 268.0.

Step 2: Preparation of methyl 6-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-4-carboxylate

In a 100 mL single-mouth bottle, methyl 6-bromo-1-methyl-1H-indole-4-carboxylate (2.50 g, 9.25 mmol) and 4-cyclopropyl-1H-imidazole (1.00 g, 9.25 mmol) were added. Add DMSO (dimethyl sulfoxide, 30.0 mL) to dissolve, add 2-acetylcyclopropanone (125 mg, 0.925 mmol), potassium carbonate (K ₂ CO ₃ , 2.55 g, 18.5 mmol) and cuprous iodide (175 mg) , 0.925mmol), nitrogen extraction 3 times, 120 ° C conditions for 1h, the reaction is completed; cooled to room temperature, suction filtration, ethyl acetate and water extraction, the organic phase was dried with anhydrous sodium sulfate, silica gel Column chromatography gave the title compound. LC-MS m/z: [M+H] ⁺ =296.1.

Step 3: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-4-carboxylic acid

In a 100 mL single-mouth bottle, 6-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-4-carboxylic acid methyl ester (700 mg, 2.38 mmol) was added and methanol was added. 15.0 mL) and water (3.0 mL) were dissolved, sodium hydroxide (100 mg, 2.38 mmol) was added, and the reaction was carried out at 60 ° C for 40 min, and the reaction was completed; the reaction solution was adjusted to pH 1 with 2M diluted hydrochloric acid, and dichloromethane/methanol was used. : 1 extraction. The organic phase was dried over anhydrous sodium sulfate and evaporated LC-MS m/z: [M+H] ⁺ = 282.1.

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

In a 100 mL single-mouth bottle, 6-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-1H-indole-4-carboxylic acid (260 mg, 0.93 mmol) was added, and 10.0 mL of pyridine was added to dissolve. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (267 mg, 1.40 mmol) was added under ice-cooling, stirring was continued for 20 min, and 6-(4-isopropyl- 4H-1,2,4-triazol-3-yl)pyridin-2-amine (207 mg, 1.02 mmol), was reacted for 1 h in ice-bath, the reaction was finished, pyridine was removed, and the residue was dissolved in dichloromethane and water. The mixture was adjusted to pH 6 with EtOAc EtOAc (EtOAc m. ^{1 H NMR (300MHz, DMSO-} d 6) δ10.69 (s, 1H), 8.87 (s, 1H), 8.26 (d, 1H), 8.19 (s, 1H), 8.35 (t, 1H), 7.99 ( s, 1H), 7.81-7.89 (m, 2H), 7.62 (s, 1H), 7.52-7.61 (m, 1H), 6.84 (d, 1H), 5.67 (t, 1H), 3.90 (s, 3H) , 1.85-1.91 (m, 1H), 1.43 (d, 6H), 0.81 - 0.84 (m, 2H), 0.71 - 0.81 (m, 2H). LC-MS m/z: [M+H] ⁺ = 467.2 .

Example 12: 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(4-(trifluoromethyl)- 1H-imidazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-one

7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1 -2H-ketone (200 mg, 0.480 mmol), 4-(trifluoromethyl)-1H-imidazole (72.0 mg, 0.0530 mmol), cuprous iodide (10.0 mg, 0.0530 mmol), 8-hydroxyquinoline (1.77) Mg, 0.0122 mmol), cesium carbonate (59.8 mg, 0.183 mmol) was added to a reaction flask, and 1,4-dioxane (5 mL) was dissolved, three times with nitrogen, and reacted at 135 ° C for 3 h. After the completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjj ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.54 - 8.58 (m, 2H), 8.26 (d, 1H), 8.04-8.09 (m, 1H), 7.93-8.02 (m) , 3H), 7.63 (d, 1H), 5.36-5.44 (m, 1H), 4.28 (t, 2H), 3.23 (t, 2H), 1.51 (d, 6H). LC-MS m/z: [M +H] ⁺ =468.

Example 13: 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(4-(trifluoromethyl)- 1H-imidazol-1-yl)isoquinoline-1(2H)-one

Step 1: 7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoquinolin-1(2H)-one Preparation

7-Bromoisoquinoline-1(2H)-one (0.600 g, 2.68 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl) pyridine (641mg, 2.41mmol) was dissolved in 15mL of toluene, was added copper iodide ^{(50.9mg, 0.268mmol), N 1} , N 2 - dimethyl-ethane- 1,2-diamine (23.6mg, 0.268mmol) Potassium phosphate (0.682 g, 3.22 mmol) was replaced with nitrogen three times and reacted in a microwave at 120 ° C for 1 hour. After the completion of the reaction, the mixture was filtered, filtered, evaporated, evaporated LC-MS m/z: [M+H] ⁺ = 410.

Step 2: 2-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(4-(trifluoromethyl)-1H Preparation of -imidazol-1-yl)isoquinoline-1(2H)-one

7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoquinolin-1(2H)-one (50.0 Mg, 0.122 mmol), 4-(trifluoromethyl)-1H-imidazole (20.0 mg, 0.147 mmol) was dissolved in 1,4-dioxane (10 mL), and cuprous iodide (2.32 mg, 0.0122) Methyl), 8-hydroxyquinoline (1.77 mg, 0.0122 mmol) and cesium carbonate (59.8 mg, 0.183 mmol) were replaced with nitrogen three times and reacted with microwave at 135 ° C for 3 hours. After the completion of the reaction, the mixture was filtered, and then filtered, evaporated, evaporated, evaporated. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.65-8.66 (m, 2H), 8.55 (d, 1H), 8.20-8.24 (m, 3H), 7.97-8.01 (m) , 2H), 7.91 (d, 1H), 6.92 (d, 1H), 5.29-5.36 (m, 1H), 1.50 (d, 3H), 1.49 (d, 3H). LC-MS m/z: [M+H] ⁺ = 466.

According to the synthesis method of Inventive Example 1-13, the compounds of Examples 14-27 were synthesized using different commercially available starting materials, and the characterization parameters of these compounds are shown in Table 1:

Table 1:

Example 15: 3-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Step 1: Preparation of 3-bromo-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

5-Bromopyridine-2,3-dicarboxylic acid (5.00 g, 20.3 mmol) was dissolved in acetic anhydride (4.41 mL, 46.7 mmol) and reacted at 120 ° C for 3 h. Concentrated under reduced pressure, ammonium acetate (3.44 g, 44.7 mmol) was added, and reacted at 100 ° C for 2.5 h. After completion of the reaction, the solid was precipitated, suction filtered, washed with water and dried LC-MS m/z: [M+H] ⁺ = 227.

Step 2: Preparation of 3-bromo-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

3-Bromo-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (2.70 g, 11.9 mmol) was dissolved in a mixed solvent of 15 mL of methanol and 15 mL of dichloromethane, -30 Sodium borohydride (0.681 g, 17.9 mmol) was added portionwise at ° C, and the mixture was reacted at this temperature for 0.5 h. After completion of the reaction, the mixture was slowly added dropwise with 2N hydrochloric acid, and then the mixture was stirred and evaporated to pH 3 and stirred for 10 min, and then, 1M sodium hydroxide was slowly added dropwise to adjust the pH to 9 to precipitate a solid, which was filtered, dried and evaporated to give the title compound. LC-MS m/z: [M+H] ⁺ = 229.

Step 3: Preparation of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Dissolve 3-bromo-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (740 mg, 3.24 mmol) in 10 mL of dichloromethane and add triethyl Silane (753 mg, 6.48 mmol), trifluoroacetic acid (3.05 mL, 38.9 mmol) was reacted at room temperature for 0.5 h. After the reaction was completed, the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS m/z: [M+H] ⁺ = 213.

Step 4: 3-Bromo-6-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6,7-dihydro-5H- Preparation of pyrrolo[3,4-b]pyridin-5-one

3-Bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (510 mg, 2.41 mmol), 2-bromo-6-(4-isopropyl-4H- 1,2,4-Triazol-3-yl)pyridine (768 mg, 2.89 mmol) was dissolved in 10 mL of 1,4-dioxane, and cuprous iodide (46.3 mg, 0.241 mmol), N, N' -Dimethylethylenediamine (21.2 mg, 0.241 mmol), cesium carbonate (1.18 g, 3.62 mmol), was charged with nitrogen and reacted for 1 hour at 120 ° C under microwave. After the completion of the reaction, the mixture was filtered with suction, and the solvent was evaporated. LC-MS m/z: [M+H] ⁺ =399.

Step 5: 3-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

3-Bromo-6-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6,7-dihydro-5H-pyrrole [3,4-b]pyridin-5-one (230 mg, 0.578 mmol), 4-cyclopropyl-1H-imidazole (93.6 mg, 0.867 mmol) was dissolved in 5 mL of 1,4-dioxane. Cuprous (11.0 mg, 0.0578 mmol), 8-hydroxyquinoline (8.38 mg, 0.0578 mmol), cesium carbonate (377 mg, 1.16 mmol), was charged with nitrogen, and reacted at 130 ° C for 80 min. After completion of the reaction, the mixture was filtered with suction, and the solvent was evaporated evaporated evaporated. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.95 (d, 1H), 8.74 (dd, 1H), 8.43 (s, 1H), 8.21 (d, 1H), 8.20 (dd, 1H), 8.00 ( t,1H),7.86(s,1H),7.15(d,1H),5.62-5.69(m,1H), 5.20(s,2H),1.93-2.00(m,1H),1.67-1.68(m, 6H), 0.92-0.98 (m, 2H), 0.86-0.90 (m, 2H). LC-MS m/z: [M+H] ⁺ = 427.

Example 28: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-isopropyl-1H-tetrazol-1-yl)pyridin-2-yl)- 2-fluoro-4-methylbenzamide

Step 1: Preparation of 5-amino-2-fluoro-4-methylbenzonitrile

5-Bromo-4-fluoro-2-methylaniline (10.0 g, 49 mmol) was dissolved in N-methylpyrrolidone (50 mL), and then copper cyanide (8.8 g, 98 mmol) was added to the solution. Heat to 180 ° C under argon protection and stir for 3 h. After cooling to room temperature, water (100 mL) and aqueous ammonia (150 mL) were added to the reaction mixture, and the mixture was stirred for 0.5 hr. LC-MS m/z [M+H] ⁺ = 151.

Step 2: Preparation of 5-((2-cyclopropyl-2-oxoethyl)amino)-2-fluoro-4-methylbenzonitrile

5-Amino-2-fluoro-4-methylbenzonitrile (3.5 g, 23.3 mmol) was dissolved in N,N-dimethylformamide (50 mL) and potassium carbonate (3.8 g, 28 mmol) and potassium iodide ( 4.3 g, 25.6 mmol), the reaction was stirred at room temperature for 5 min, then 1-cyclopropyl-2-bromoethyl ketone (8.5 g, 52.5 mmol) was added and heated to 60 ° C for 3 h. The reaction mixture was concentrated under reduced pressure to drynessnessnessnessssssssssssssssssssssssssssssss The title compound was obtained. LC-MS m/z [M+H] ⁺ = 233.

Step 3: Preparation of 5-(4-cyclopropyl-2-indolyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile

5-((2-Cyclopropyl-2-oxoethyl)amino)-2-fluoro-4-methylbenzonitrile (1.0 g, 4.3 mmol) was dissolved in glacial acetic acid (15 mL). Potassium acid (0.8 g, 8.6 mmol) was heated to 110 ° C for 4 h. The reaction mixture was concentrated under reduced pressure of EtOAc (EtOAc)EtOAc. LC-MS m/z [M+H] ⁺ = 274.

Step 4: Preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile

Hydrogen peroxide (1.4 mL) was added to a mixed solvent of acetic acid (18 mL) and water (3.5 mL), and the mixture was heated to 45 ° C, then 5-(4-cyclopropyl-2-indolyl-1H-imidazole-1- 2-fluoro-4-methylbenzonitrile (1.1 g, 4 mmol), maintained at an internal temperature not higher than 55 ° C, stirred at 45 ° C for 0.5 h, then cooled to room temperature. After adding a 20% sodium sulfite solution and stirring for 0.5 h, the starch potassium iodide test paper was not discolored, and dichloromethane (100 mL) was added thereto, and the organic layer was dried over anhydrous sodium sulfate. LC-MS m/z [M+H] ⁺ = 242.

Step 5: Preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile (0.5 g, 2 mmol) was dissolved in dimethyl sulfoxide (5 mL), cooled in ice bath Potassium carbonate (0.5 g, 4 mmol) and hydrogen peroxide (1 mL) were added, and the reaction was stirred for 10 min. After adding water (20 mL), the mixture was filtered and evaporated. LC-MS m/z [M+H] ⁺ = 260.

Step 6: Preparation of N-(6-chloropyridin-2-yl)isobutyramide

Isobutyryl chloride (0.1 g, 1.1 mmol) was dissolved in dichloromethane (5 mL) and the obtained solution was added dropwise to 6-chloro-2-aminopyridine (0.1 g, 1.0 mmol) and N,N-diisopropyl Ethylamine (0.4 g, 3.0 mmol) in dichloromethane (10 mL) was evaporated. The reaction mixture was concentrated under reduced pressure. LC-MS m/z [M+H] ⁺ = 199.

Step 7: Preparation of 2-chloro-6-(5-isopropyl-1H-tetrazol-1-yl)pyridine

The crude N-(6-chloropyridin-2-yl)isobutyramide (0.2 g, 1.0 mmol) and triphenylphosphine (0.5 g, 2.0 mmol) were dissolved in acetonitrile (5 mL). h, carbon tetrachloride (0.3 g, 2 mmol) was added, and the mixture was heated under reflux for 4 h. After cooling to room temperature, azidotrimethylsilane (0.2 g, 1.5 mmol) was slowly added dropwise, and after completion of the dropwise addition, the mixture was heated under reflux for 8 h. The reaction was quenched with EtOAc EtOAc EtOAc. LC-MS m/z [M+H] ⁺ = 224.

Step 8: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-isopropyl-1H-tetrazol-1-yl)pyridin-2-yl)-2 -Preparation of fluoro-4-methylbenzamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide (0.1 g, 0.5 mmol), 2-chloro-6-(5-isopropyl -1H-tetrazol-1-yl)pyridine (0.1 g, 0.5 mmol), tris(dibenzylidenefluoreneacetone) dipalladium (0.05 g, 0.05 mmol), 4,5-bisdiphenylphosphino-9, 9-Dimethyl xanthene (0.03 g, 0.05 mmol), cesium carbonate (0.3 g, 1 mmol) was added to dioxane (10 mL), and then heated to 110 ° C under argon for 3 h. Water (50 mL) and dichloromethane (50 mL) were evaporated. ^{1 H NMR (400MHz, DMSO-} d 6) δ11.19 (s, 1H), 8.33 (d, J = 8.3Hz, 1H), 8.23 (d, J = 7.9Hz, 1H), 7.68 (dd, J = 25.9, 7.3 Hz, 3H), 7.47 (d, J = 10.8 Hz, 1H), 7.18 (s, 1H), 3.98 - 3.80 (m, 1H), 2.24 (s, 3H), 1.94 - 1.79 (m, 1H) ), 1.30 (d, J = 6.8 Hz, 6H), 0.80 (dd, J = 5.4, 2.7 Hz, 2H), 0.69 (d, J = 2.8 Hz, 2H). LC-MS m/z [M+H ] ⁺ = 447.2.

Example 29: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)- 2-fluoro-4-methylbenzamide

Step 1: Preparation of 6-bromo-N-isopropylpyridine amide

6-Bromo-2-pyridinecarboxylic acid (3.0 g, 15 mmol) was added to thionyl chloride (11 mL), heated to 85 ° C under argon and stirred for 2 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove thionyl chloride. Dichloromethane (100 mL) was added to the obtained product, cooled to -10 ° C, and a solution of N-ethyldiisopropylamine (9.5 g, 74 mmol) and isopropylamine (2.6 g, 44 mmol) in dichloromethane (10 mL) The reaction was stirred at room temperature for 0.5 h. The reaction was quenched by the addition of water (50 mL), and then evaporated. LC-MS m/z [M+H] ⁺ = 243.

Step 2: Preparation of 2-bromo-6-(1-isopropyl-1H-tetrazol-5-yl)pyridine

6-Bromo-N-isopropylpyridine amide (0.5 g, 2.0 mmol) was dissolved in acetonitrile (5 mL), cooled to -15 ° C, and trifluoromethanesulfonic acid anhydride (0.7 g, 4 mmol). The reaction was stirred for 10 min, and azidotrimethylsilane (1.1 mL, 8.3 mmol) was slowly added dropwise. After the addition was completed, it was returned to room temperature for 1.5 h. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc)EtOAc. -(1-Isopropyl-1H-tetrazol-5-yl)pyridine. LC-MS m/z [M+H] ⁺ = 268.

Step 3: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-2 -Preparation of fluoro-4-methylbenzamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide (0.2 g, 0.8 mmol), 2-bromo-6-(1-isopropyl -1H-tetrazol-5-yl)pyridine (0.2 g, 0.7 mmol), tris(dibenzylidenefluoreneacetone) dipalladium (0.07 g, 0.08 mmol), 4,5-bisdiphenylphosphino-9, 9-Dimethyl xanthene (0.04 g, 0.07 mmol), cesium carbonate (0.5 g, 1.5 mmol) was added to dioxane (10 mL), and then warmed to 110 ° C under argon for 2 h. Water (50 mL) and dichloromethane (50 mL) were added, and the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to afford 5-(4-cyclopropyl-1H-imidazol-1-yl )-N-(6-(1-Isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.13 (t, J = 8.0 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 6.6 Hz, 1H), 7.50 (d, J = 10.8 Hz, 1H), 7.19 (s, 1H), 6.07 - 5.91 (m, 1H), 2.25 (s, 3H), 1.91 - 1.79 (m, 1H), 1.54 (d, J = 6.6 Hz, 6H), 0.87 - 0.76 (m, 2H), 0.74 - 0.65 (m, 2H). - MS m/z [M+H] ⁺ = 447.2.

Example 30: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)benzo[d][1,3]dioxole-5-carboxamide

Step 1: 7-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzo[d][1,3] Preparation of m-dioxole-5-carboxamide

7-Bromobenzo[d][1,3]dioxole-5-carboxylic acid (300 mg, 1.23 mmol), 6-(4-isopropyl-4H-1,2,4- Triazol-3-yl)pyridin-2-amine (250 mg, 1.23 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate The ester (934 mg, 2.46 mmol) was dissolved in 10 mL of dichloromethane, and N,N-diisopropylethylamine (397 mg, 3.07 mmol) was added to react at 25 ° C for 2-3 hours. After the completion of the reaction, the reaction mixture was evaporated. mjjjjlililililililililililililililililili LC-MS m/z: [M+H] ⁺ = 430.

Step 2: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)benzo[d][1,3]dioxol-5-carboxamide

7-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzo[d][1] prepared in Step 1. ,3]dioxol-5-carboxamide (230 mg, 0.535 mmol), 4-cyclopropyl-1(3)H-imidazole (0.163 g, 1.50 mmol), cesium carbonate (348 mg, 1.07 mmol) Soluble in 1,4-dioxane (8 mL), add CuI (24.0 mg, 0.126 mmol) and N,N-dimethylethylenediamine (11.1 mg, 0.126 mmol), after nitrogen replacement at 130 ° C Microwave reaction for 90 min. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjj Title compound. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.73 (s, 1H), 8.89 (s, 1H), 8.16 (d, 2H), 8.02-8.06 (m, 1H), 7.84 (d, 2H), 7.51-7.56 (m, 2H), 6.30 (s, 2H), 5.58-5.65 (m, 1H), 1.86-1.93 (m, 1H), 1.44 (d, 6H), 0.82-0.86 (m, 2H), 0.71-0.76 (m, 2H). LC-MS m/z: [M+H] ⁺ = 458.

Example 31: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(5-methyl-5,6-dihydrobenzo[f] [1,2,4]triazolo[4,3-d][1,4]oxazepine-8-yl)benzamide

Step 1: Preparation of methyl 2-(2-((tert-butoxycarbonyl)amino)propoxy)-3-nitrobenzoate

N-Boc-DL-alanine (2.90 g, 16.6 mmol) was added to a 100 mL vial, dissolved in tetrahydrofuran (30 mL), and sodium hydride (540 mg, 22.5 mmol) was added in an ice water bath, stirred for 10 min, and added 2- Fluor-3-nitroanisole (3.00 g, 15.0 mmol) was stirred at room temperature. After the reaction was completed, EtOAc (EtOAc m. LC-MS m/z: [M+H] ⁺ =355.

Step 2: Preparation of (2-((tert-butoxycarbonyl)amino)propoxy)-3-nitrobenzoic acid

Methyl 2-(2-((tert-butoxycarbonyl)amino)propoxy)-3-nitrobenzoate (1.50 g, 4.23 mmol) obtained in Step 1 was dissolved in 50 mL of a ss. Water (4 mL) and lithium hydroxide (516 mg, 21.6 mmol) were added to the flask, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was evaporated. LC-MS m/z: [MH] ^- = 339.

Step 3: Preparation of 2-(2-aminopropoxy)-3-nitrobenzoic acid

(2-((tert-Butoxycarbonyl)amino)propoxy)-3-nitrobenzoic acid (1.50 g, 4.42 mmol) obtained in Step 2 was dissolved in a 100 mL single-mouth bottle containing 30 mL of dichloromethane. Trifluoroacetic acid (10 mL) was added and stirred at room temperature. After the reaction was completed, the reaction mixture was evaporated. LC-MS m/z: [M+H] ⁺ =241.

Step 4: Preparation of 3-methyl-9-nitro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

2-(2-Aminopropoxy)-3-nitrobenzoic acid (480 mg, 2.00 mmol) obtained in Step 3 was placed in a 100 mL single-necked flask, dissolved in dichloromethane (60 mL), and 2-(7) -Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (912 mg, 2.40 mmol), N,N-diisopropylethylamine (516 mg, 4.00 mmol) Stir at room temperature overnight. After the reaction was completed, EtOAc EtOAc m. LC-MS m/z: [M+H] ⁺ = 223.

Step 5: Preparation of 3-methyl-9-nitro-3,4-dihydrobenzo[f][1,4]oxaza-5(2H)-thione

3-Methyl-9-nitro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (222 mg, 1.00 mmol) was placed in a 25 mL single-necked flask. Toluene (15 mL) and Lawson's reagent (606 mg, 1.5 mmol) were added, and the reaction was carried out at 110 ° C overnight. After the reaction was completed, EtOAc (EtOAc)EtOAc. LC-MS m/z: [M+H] ⁺ = 239.

Step 6: Preparation of (Z)-5-fluorenylene-3-methyl-9-nitro-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine

Dissolving 3-methyl-9-nitro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-thione (150 mg, 0.630 mmol) prepared in Step 5 To a 25 mL single-mouth flask containing 5 mL of ethanol, hydrazine hydrate (94.0 mg, 1.89 mmol) was added, and the mixture was stirred at 40 °C. After the reaction, the reaction mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 237.

Step 7: 5-Methyl-8-nitro-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine preparation

(Z)-5-fluorenylene-3-methyl-9-nitro-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine prepared in step 6. (120 mg, 0.500 mmol) was dissolved in a 25 mL single-mouth flask containing 5 mL of triethyl orthoformate, and stirred at 90 ° C for 3 h. After the reaction, the reaction mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 247.

Step 8: Preparation of 5-methyl-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine-8-amine

5-Methyl-8-nitro-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxy which was prepared in Step 7. Aza (80.0 mg, 0.325 mmol) was dissolved in a 25 mL single-mouth flask containing 5 mL of methanol, and 10% Pd/C (10 mg) was added and stirred at room temperature. After completion of the reaction, the mixture was filtered. LC-MS m/z: [M+H] ⁺ = 217.

Step 9: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(5-methyl-5,6-dihydrobenzo[f][ Preparation of 1,2,4]triazolo[4,3-d][1,4]oxazepine-8-yl)benzamide

5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid (86.0 mg, 0.330 mmol), 1-(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (115 mg, 0.600 mmol) was placed in a 25 mL single-necked flask, 3 mL of pyridine was added, stirred for 15 min in an ice water bath, then 5-methyl-5,6-dihydrobenzo[f [1,2,4]Triazolo[4,3-d][1,4]oxazepine-8-amine (65.0 mg, 0.300 mmol) in pyridine (5 mL) After completion of the reaction, the reaction mixture was diluted with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.85 (d, 1H), 8.79 (s, 1H), 8.24 - 8.27 (m, 1H), 8.11 - 8.15 (m, 1H), 7.67 - 7.77 (m) , 2H), 7.49 (d, 1H), 7.18-7.25 (m, 2H), 4.52-4.58 (m, 1H), 4.34-4.44 (m, 2H), 2.24 (s, 3H), 1.82-1.89 (m , 1H), 1.51 (d, 3H), 0.780-0.850 (m, 2H), 0.680-0.730 (m, 2H). LC-MS m/z: [M+H] ⁺ =459.

Example 32: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)isoindoline-1-one

Step 1: Preparation of 5-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one

5-Bromoisoindolin-1-one (600 mg, 2.84 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (718 mg) , 2.70 mmol) dissolved in 10 mL of 1,4-dioxane, added cuprous iodide (54.0 mg, 0.284 mmol), N,N'-dimethylethylenediamine (25.0 mg, 0.284 mmol), phosphoric acid Potassium (903 mg, 4.26 mmol) was charged with nitrogen and reacted at 120 ° C for 3 h. After the completion of the reaction, the mixture was filtered with suction, and the solvent was evaporated. LC-MS m/z: [M+H] ⁺ =398.

Step 2: 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)isoindoline-1-one

5-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one (400 mg, 1.01) Methyl) 4-cyclopropyl-1H-imidazole (131 mg, 1.21 mmol) was dissolved in 10 mL of 1,4-dioxane, and cuprous iodide (19.2 mg, 0.101 mmol), 8-hydroxyquinoline ( 14.6 mg, 0.101 mmol), cesium carbonate (493 mg, 1.51 mmol), was charged with nitrogen, and reacted in a microwave at 130 ° C for 5 h. After completion of the reaction, the mixture was filtered with suction, and the solvent was evaporated evaporated evaporated. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.96 (s, 1H), 8.64 (d, 1H), 8.30 (s, 1H), 8.09 (t, 1H), 8.04 (s, 1H), 7.87- 7.97 (m, 2H), 7.84 (d, 1H), 7.67 (s, 1H), 5.51-5.58 (m, 1H), 5.20 (s, 2H), 1.84-1.91 (m, 1H), 1.59-1.61 ( m, 6H), 0.82 - 0.86 (m, 2H), 0.71 - 0.74 (m, 2H). LC-MS m/z: [M+H] ⁺ = 426.

Example 33: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethyl-2-(2-(4-(1,1,1-trifluoroprop-2) -yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one

Step 1: Preparation of 4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carboxamide

4-bromo-1,3-thiazole-2-carboxylic acid (2.06 g, 10.0 mmol) was added to a 100 mL vial, dissolved in dichloromethane (30 mL), and thionyl chloride (1.19 g, 10.0) was added to the ice water bath. Methyl), LC-MS detected the end of the reaction, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then 2-amino-1,1,1-trifluoropropane hydrochloride (l.0 g, 10.0 mmol), triethylamine (1 ml). After the reaction was completed, EtOAc (EtOAc m. LC-MS m/z: [M+H] ⁺ =303.

Step 2: Preparation of 4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-thiocarboxamide

4-Bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carboxamide (2.00 g, 6.62 mmol) obtained in Step 1 was dissolved in a 100 mL single-mouth bottle containing 30 mL of toluene. Among them, Lawson's reagent (4.00 g, 4.96 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, EtOAc (3 mL)EtOAc. LC-MS m/z: [M+H] ⁺ = 319.

Step 3: Preparation of 4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-aminocarboxamidine

4-Bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-thiocarboxamide (2.00 g, 6.29 mmol) obtained in Step 2 was dissolved in 30 mL of hydrazine hydrate. In a 100 mL single-mouth bottle, reflux for 2 h. After the reaction was completed, EtOAc (3 mL, dry. LC-MS m/z: [M+H] ⁺ = 317.

Step 4: Preparation of 4-bromo-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazole

4-Bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-aminocarboxamidine (1.45 g, 4.59 mmol) obtained in Step 3 was dissolved in 20 mL of triethyl orthoformate. The mixture was stirred at 90 ° C for 3 h in an ester 50 mL single-mouth bottle. After the reaction was completed, the reaction mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 327.

Step 5: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(4-methoxybenzyl)-3,3-dimethylisoindoline-1-one

6-Bromo-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one (1.20 g, 3.34 mmol) was dissolved in N-methylpyrrolidone (20 mL) To a 100 mL single-mouth bottle, potassium carbonate (922 mg, 6.69 mmol), 2-acetylcyclohexyl ketone (47 mg, 0.334 mmol), 4-cyclopropyl-1H-imidazole (397 mg, 3.67 mmol), 150 ° C Stir overnight. After the reaction was completed, EtOAc (3 mL, dry. LC-MS m/z: [M+H] ⁺ = 388.

Step 6: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-3,3-dimethylisoindoline-1-one

6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(4-methoxybenzyl)-3,3-dimethylisoindoline-1-prepared in step 5 The ketone (600 mg, 1.55 mmol) was placed in a sip, and trifluoroacetic acid (5 mL) was added and reacted at 160 ° C for 6 h. After the reaction was completed, the reaction mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 268.

Step 7: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethyl-2-(2-(4-(1,1,1-trifluoroprop-2-) Of 4-)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)isoindolin-1-one

6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethylisoindolin-1-one (100 mg, 0.375 mmol) prepared in step 6 was placed in a microwave tube , 4-bromo-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazole prepared in Step 4 (146 mg) , 0.450 mmol), cuprous iodide (14.0 mg, 0.0750 mmol), N,N-dimethylethylenediamine (6.60 mg, 0.0750 mmol), potassium carbonate (103 mg, 0.750 mmol), dioxane (8 mL) ), nitrogen was pumped 3 times, and reacted at 110 ° C for 80 min. After completion of the reaction, the mixture was filtered, and then filtered,jjjjjjjjjjjjjjjj ^{1 H NMR (400MHz, DMSO-} d 6) δ9.32 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.95-8.04 (m, 3H), 7.68 (s, 1H), 6.31-6.42(m,1H), 1.89(d,3H),1.86(s,3H),1.76(s,3H),1.20-1.27(m,1H),0.790-0.870(m,2H),0.690- 0.770 (m, 2H). LC-MS m/z: [M+H] ⁺ = 514.

Example 34: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-5-morpholinopidoindolin-1-one

Step 1: Preparation of methyl 4-fluoro-2-methylbenzoate

4-Fluoro-2-methylbenzoic acid (25.0 g, 162 mmol) was dissolved in 300 mL of methanol, and thionyl chloride (23.1 g, 194 mmol) was slowly added at 0 ° C. After the addition, the reaction was transferred to oil at 60 ° C. The reaction was heated in a bath for 2 hours. After the reaction was completed, the title compound was evaporated.

Step 2: Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate

Methyl 4-fluoro-2-methylbenzoate (25.0 g, 148 mmol), N-bromosuccinimide (31.6 g, 178 mmol) was dissolved in 300 mL of carbon tetrachloride and benzoyl peroxide was added. 3.58 g, 14.8 mmol) was heated in an oil bath at 80 ° C for 16 hours. After the completion of the reaction, the reaction mixture was filtered. LC-MS m/z: [M+H] ⁺ = 247.

Step 3: Preparation of 5-fluoroisoindol-1-one

Methyl 2-(bromomethyl)-4-fluorobenzoate (31.6 g, 128 mmol) was dissolved in 150 mL of methanol, and 50 mL of aqueous ammonia was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was evaporated to give a white solid. LC-MS m/z: [M+H] ⁺ = 152.

Step 4: Preparation of 5-fluoro-6-nitroisoindol-1-one

The 5-fluoroisoindol-1-one (16.0 g, 105 mmol) obtained in the step 3 was dissolved in 150 mL of concentrated sulfuric acid, and the fuming nitric acid (5.14 mL, 126 mmol) was slowly added at 0 ° C. The reaction was carried out at this temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into ice water (300 mL), and the mixture was evaporated. LC-MS m/z: [M+H] ⁺ = 197.

Step 5: Preparation of 5-morpholino-6-nitroisoindol-1-one

5-Fluoro-6-nitroisoindol-1-one (1.00 g, 5.07 mmol), morpholine (661 mg, 7.61 mmol), potassium carbonate (1.40 g, 10.1 mmol) was dissolved in 15 mL of N,N- The reaction was stirred at room temperature for 1 hour in methylformamide. After completion of the reaction, the reaction mixture was poured into EtOAc (EtOAc) LC-MS m/z: [M+H] ⁺ =264.

Step 6: Preparation of 5-morpholino-6-nitro-1-oxoisoindoline-2-carboxylic acid tert-butyl ester

5-morpholino-6-nitroisoindol-1-one (1.20 g, 4.54 mmol), di-tert-butyl dicarbonate (1.18 g, 5.45 mmol) was dissolved in 15 mL of dichloromethane. -Dimethyl-4-pyridinamine (55 mg, 0.454 mmol) was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed with water and evaporated LC-MS m/z: [M+H] ⁺ =364.

Step 7: Preparation of 6-amino-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester

tert-Butyl 5-morpholino-6-nitro-1-oxoisoindoline-2-carboxylate (1.40 g, 3.84 mmol), Pd/C (140 mg) dissolved in 20 mL of methanol, hydrogen atmosphere The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was filtered and evaporated to dry LC-MS m/z: [M+H] ⁺ = 334.

Step 8: Preparation of 6-((2-cyclopropyl-2-oxoethyl)amino)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester

6-Amino-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester obtained in Step 7 (1.21 g, 3.62 mmol), potassium carbonate (750 mg, 5.43 mmol), potassium iodide (720 mg, 4.34 mmol) was dissolved in 15 mL of N,N-dimethylformamide and stirred at room temperature for 10 min under nitrogen. 2-Bromocyclopropyl-1-one (703 mg, 4.34 mmol) was added and reacted at 60 ° C for 4 hours. After the reaction was completed, the reaction mixture was cooled and poured into ice water (100 mL), ethyl acetate (50 mL×3), and the organic phase was combined and concentrated to give a crude product which was separated by column ( petroleum ether: ethyl acetate = 1:1). The title compound was obtained. LC-MS m/z: [M+H] ⁺ =416.

Step 9: 6-(N-(2-Cyclopropyl-2-oxoethyl)formylamino)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester preparation

6-((2-Cyclopropyl-2-oxoethyl)amino)-5-morpholino-1-oxoisoindoline-2-carboxylic acid t-branches obtained in step 8 at 0 ° C Butyl ester (0.920 g, 2.21 mmol) was dissolved in a mixture of 5 mL of acetic anhydride and 10 mL of formic acid at this temperature for 30 min. After the reaction was completed, the reaction mixture was evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssss . LC-MS m/z: [M+H] ⁺ =444.

Step 10: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester

6-(N-(2-Cyclopropyl-2-oxoethyl)formylamino)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (1.00 g The crude product was dissolved in 15 mL of AcOH, and then NH ₄ OAc (867 mg, 11.2 mmol) was added and reacted at 110 ° C for 4 hours. After completion of the reaction, the reaction solution was added water spin-dries the crude (100 mL) was dissolved, NaHCO ₃ solution to a pH = 8, ethyl acetate (50mL × 3). The combined organic phase was dried and concentrated to give the crude product by column (petroleum ether: The title compound was isolated from ethyl acetate = 1 : 2). LC-MS m/z: [M+H] ⁺ = 425.

Step 11: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholinopidoindolin-1-one

6-(4-Cyclopropyl-1H-imidazol-1-yl)-5-morpholino-1-oxoisoindoline-2-carboxylic acid tert-butyl ester prepared in Step 10 (490 mg, 1.15 Methyl) was dissolved in 10 mL of DCM and added to TFA (3 mL). After completion of the reaction, the reaction solution was spin-dries the crude with water (100 mL) was dissolved, NaHCO ₃ solution to a pH = 8, ethyl acetate (50mL × 3). The combined organic phase was dried and concentrated to give crude product was purified by column chromatography (ethyl acetate The title compound was isolated. LC-MS m/z: [M+H] ⁺ = 325

Step 12: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl)-5-morpholinopidoindolin-1-one

6-(4-Cyclopropyl-1H-imidazol-1-yl)-5-morpholinopidoindolin-1-one (230 mg, 0.707 mmol) obtained in Step 11, 2-bromo-6- (4-isopropyl-triazol-3-yl -4H-1,2,4-) pyridine _{(188mg, 0.707mmol), Cs 2} CO 3 (460mg, 1.41mmol) was dissolved in dioxane (8mL), CuI (24.0 mg, 0.126 mmol) and N,N-dimethylethylenediamine (11.1 mg, 0.126 mmol) were added, and the mixture was replaced with nitrogen, and then subjected to microwave reaction at 130 ° C for 90 min. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs Compound. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.94 (s, 1H), 8.62 (d, 1H), 8.05-8.09 (m, 1H), 7.90-7.95 (m, 2H), 7.65 (s, 1H ), 7.50 (s, 1H), 7.35 (s, 1H), 5.49-5.59 (m, 1H), 5.14 (s, 2H), 3.62 (d, 4H), 2.73 (d, 4H), 1.86-1.92 ( m, 1H), 1.59 (d, 6H), 0.80-0.85 (m, 2H), 0.68-0.72 (m, 2H). LC-MS m/z: [M+H] ⁺ = 511.

Example 27: 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-6-(4-cyclopropyl-1H-imidazole-1 -yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one

The preparation method was similar to the preparation method of Example 34, except that the starting material morpholine was replaced with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. Title compound. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.93 (s, 1H), 8.62 (d, 1H), 8.03-8.07 (m, 1H), 7.88 (d, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 5.48-5.55 (m, 1H), 5.10 (d, 2H), 4.50 (s, 1H), 4.15 (s, 1H) , 3.84(d,1H), 3.71(d,1H), 2.70(d,2H),1.80-1.85(m,3H),1.59(d,6H),0.79-0.82(m,2H),0.67-0.70 (m, 2H). LC-MS m/z: [M+H] ⁺ = 523.

Example 35: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)- 3,3-dimethylisoindoline-1-one

Step 1: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-3 Preparation of 3-dimethylisoindoline-1-one

6-(4-Cyclopropyl-1H-imidazol-1-yl)-3,3-dimethylisoindolin-1-one (100 mg, 0.374 mmol), 2-bromo- 6-(1-Isopropyl-1H-tetrazol-5-yl)pyridine (100 mg, 0.373 mmol); dissolved by stirring with 5 mL of 1,4-dioxane; then cesium carbonate (243 mg, 0.746 mmol) , cuprous iodide (14.2 mg, 0.0746 mmol), N,N'-dimethylethylenediamine (7.00 mg, 0.0746 mmol); reaction at 130 ° C for 75 min. The title compound was isolated by prep-TLC (DCM:MeOH = 30:1). ^{1 H NMR (400MHz, DMSO-} d 6) δ8.24 (dd, 3H), 8.12-8.00 (m, 3H), 7.94 (d, 1H), 7.68 (s, 1H), 5.66 (dq, 1H), 1.87 (td, 1H), 1.84–1.71 (m, 6H), 1.60 (t, 6H), 0.86–0.79 (m, 2H), 0.76–0.69 (m, 2H). LC-MS m/z: [M +H] ⁺ =455.

Experimental Example 1 In vitro apoptosis signal-regulated kinase 1 (ASK1) inhibition assay

Experimental material

1.1 Kinase: ASK1, purchased from Carna Bioscience;

1.2 reagent: Poly (Glu, Tyr) sodium salt, purchased from sigma;

Staurosporine, purchased from BioAustralis;

ADP-Glo Kinase Assay, purchased from Promega;

1.3 Test compound The compound of the invention prepared in the above examples.

2. Experimental methods

2.1 compound dilution

1) Dilute the test compound to 1.11 mM or 1 mM using DMSO;

2) using a TECAN EVO200 system, 3 times gradient dilution of the compound to 11 concentrations;

3) Transfer 20 nL of compound to a 384-well plate using Echo550. The highest concentration of test compound for kinase ASK1 detection was 1.11 μM or 1 μM.

2.2 Enzyme reaction experiment

1) Configure a 1.3× enzyme reaction system as described in Table 2, which contains a kinase, a fluorescently labeled substrate, and a factor required for the reaction;

2) 15 μL of a 1.3× enzyme reaction system was added to the reaction well, followed by incubation at room temperature for 30 minutes.

Table 2. 1.3× Enzyme Reaction System

3) The enzyme reaction was initiated by adding 5 μL of 4×ATP solution to each well as described in Table 3.

Table 3. 4×ATP solution

4) After the reaction system was placed at 25 ° C for 90 minutes, it was incubated with 20 μL of ADP-Glo Reagent for 40 min.

5) Incubate with 40 μL of Kinase Detection Reagent for 35 min, and EnSpire reads the fluorescence value.

3. Experimental data processing

1) Calculate the remaining enzyme activity (%Remaining Activity) using the following formula:

High control (HC): DMSO; Low control (LC): staurosporine 1 μM;

2) Calculate the IC ₅₀ value using XLfit.

4 experimental results (see Table 4)

Table 4

"-" means untested

The above experimental results show that the compound of the present invention has a good inhibitory activity against ASK1.

Experimental Example 2 Evaluation of liver distribution in mice

Experimental material

1.1 animals

Male BALB/c mice, SPF grade, purchased from Changzhou Cavans Laboratory Animal Co., Ltd.; 17-21 g, license number: SCXK (Su) 2016-0010; 2 to 3 days acclimation period before the experiment.

1.2 main reagent

Methanol and acetonitrile were purchased from Merck; anhydrous ethanol, PEG200 and physiological saline were purchased from Nanjing Kaiji Biotechnology Development Co., Ltd.; o-toluene was purchased from Shanghai Ziqi Biotechnology Co., Ltd.

1.3 instruments

API 4000 triple quadrupole LC/MS, Analyst QS A01.01 chromatography workstation were purchased from AB SCIEX, USA; Milli-Q ultrapure water was purchased from Millipore; CF16R XII desktop high speed refrigerated centrifuge was purchased from Hitachi The company; Qilinbeier Vortex-5 oscillator was purchased from Germany IKA company; electric thermostatic water bath was purchased from Changzhou Guohua Electric Co., Ltd.; electric pipette was purchased from Thermo Company, USA; microanalytical balance was purchased from Shanghai METTLER Co., Ltd.

2. Experimental methods

2.1 Preparation of test drugs

Weigh 1.5 mg of the test compound (as free base), add to 7.5 mL of ethanol-PEG200-normal saline (5:20:75), vortex for 2 min, sonicate for 3 min, and prepare a concentration of 0.2 mg/mL. The solution is used for oral administration; 100 μL of the test solution is made up to 10 ng/mL with methanol, and the same concentration of the reference substance is prepared at the same time. The concentration of the test sample and the reference solution is detected by HPLC, and the test sample is calculated. Accuracy.

2.2 sample collection

BALB/c mice were given a single oral administration of 2 mg/kg of test compound at a dose of 10 mL/kg. After administration, the mice were bled at 1, 4, and 6 h and sacrificed. Blood and whole liver were collected and placed on ice. on.

2.3 Liver sample processing and analysis

Weigh all the liver, cut it, add 4 volumes of methanol-water (50:50) homogenate, then homogenize, centrifuge the homogenate (centrifugation conditions: 8000 rpm / min, 5 min, 4 ° C), transfer the supernatant 40 μL, add 400 μL methanol-acetonitrile (50:50) precipitant (containing 5 ng / mL o-tolylamine), shake for 3 min, centrifuge (4500 rpm, 5 min, 4 ° C), take the supernatant, add the mobile phase and dilute, use The content of the compound in the supernatant sample was analyzed by LC-MS/MS.

2.4 plasma sample processing and analysis

The whole blood was anticoagulated with heparin sodium and centrifuged (centrifugation conditions: 8000 rpm/min, 5 min, 4 ° C), 40 μL of the upper layer plasma was transferred, and 400 μL of methanol-acetonitrile (50:50) precipitant (containing 5 ng/mL o-toluene) was added. After shaking for 3 min, centrifugation (4500 rpm, 5 min, 4 ° C), the supernatant was added to the mobile phase for dilution, and the supernatant was taken. The content of the compound in the supernatant sample was analyzed by LC-MS/MS. The results are shown in Table 5.

3 experimental results

table 5

The higher the concentration of the compound in the liver, the higher the potency of treating liver disease, the better the effect at the same dose, and the higher the liver/plasma ratio, indicating that the target organ selectivity of the test compound is stronger, and the safety of the compound may be The better. As can be seen from the above results, the compounds of the present invention have a high distribution in the liver, and the liver selectivity and targeting are good. Therefore, the compound of the present invention is expected to be a more effective and safer drug for treating metabolic liver diseases such as fatty liver and nonalcoholic fatty liver hepatitis (NASH).

Experimental Example 3 Evaluation of efficacy of NASH and liver fibrosis induced by HFD-CCL4

Liver steatosis was induced by high-fat diet (HFD). On the basis of this, carbon tetrachloride (CCL4) was used to induce liver inflammation, necrosis and fibrosis. This model is similar to the pathogenesis and pathological phenomenon of human NASH disease. The purpose of this experiment was to evaluate the efficacy of the compounds of the invention in HFD-CCL4-induced NASH models of C57BL/6 mice using GS-4997 as a control compound. HFD-CCL4 was induced for 10 weeks, and drug intervention was performed for 4 weeks to observe the therapeutic effect of the drug on NASH and liver fibrosis.

Experimental material

1.1 Instrument

Deica Leica HistoCore PEARL; paraffin embedding machine Leica HistoCore Arcadia C&H; paraffin slicer Leica RM2235; automatic staining agent Leica ST5020; scanner HAMAMATSU NANO Zoomer S210; SR staining analysis software Visiopharm VIS 6.6.0.2516.

1.2 Control compound

The compound represented by the following formula (a) (i.e., GS-4997) disclosed in WO2013/112741 (PCT/US2013/022997) is used as a positive control.

This compound was prepared by the method described in WO2013/112741 and identified by hydrogen spectroscopy and mass spectrometry.

1.3 animals

C57BL/6 mice (male, 18-20 g) were purchased from Beijing Weitong Lihua Co., Ltd. Experimental Animal Feeding All experimental procedures were approved by the KCI Animal Use and Welfare Committee (IACUC). The conditions for feeding the mice were as follows: temperature 20–25 ° C, humidity 40%–70%, alternating day and night light and dark 12 hours/12 hours. Change the litter twice a week.

2. Experimental methods

2.1 compound preparation

The test compound and GS-4997 of the examples of the present invention were diluted to 0.3 mg/mL, 1 mg/mL, and 3 mg/mL with a solution of 0.045 M hydrochloric acid-propylene glycol (50:50), and were administered alternately.

2.2 Animal modeling

HFD-CCL4 induces C57BL/6 mouse NASH model: After 3-7 days of adaptive feeding in the SPF barrier of KCI experimental animal center, the animals were replaced with HFD feed, and the feeding cycle was 10 weeks. At the end of the 6th week of HFD feeding, the HFD group was randomized according to the body weight of the animals, and 10 rats in each group were orally administered with CCl4 (three times a week, 9-10 am) for 4 weeks. Detailed Modeling Method The HCD-CCl4-induced male C57BL/6 mouse NASH model was established according to the established method of KCI. The modeling agent was Olive Oil+CCl4 solution (formulated by KCI). Six animals randomly assigned to the normal maintenance diet were fed as a normal control group.

The animals were divided into a normal control group, a HFD-CCL4 model control group (model group, 0.045 M hydrochloric acid-propylene glycol (50:50)), and a compound group (test compound group of the present invention, GS-4997 group).

2.3 Compound dosage regimen

After the end of the sixth week of HFD feeding, the test compound of the present invention and GS-4997 were administered intragastrically once a day for 4 weeks, and the administration was terminated at the 10th week. Wherein, the dose of the test compound group of the present invention is 3 mg/kg/d, and the dose of the GS-4997 group is 30 mg/kg/d, that is, the dose of the test compound group of the present invention is administered by the GS-4997 group. One tenth of the dose.

2.4 Experimental sample collection

Animals in each group were fasted for six hours after the last administration of CCl4 on the next day after the end of the last administration, and the animals were euthanized according to the KCI standard protocol. The animals were dissected according to the KCI animal anatomy experimental procedure. After the animals were perfused through the low temperature PBS, the liver was collected, and the liquid nitrogen of some animal livers (fixed selection of the same liver lobe on the left side of each animal) was rapidly frozen and stored at -80 ° C. The remaining animal liver was fixed after formalin (the volume ratio of liver to fixative was 1:10), and relevant pathological correlation tests were performed.

2.5 hematoxylin-eosin staining

The left lobe of the liver was fixed with 10% formalin, embedded in paraffin, and made into 5 μm sections for hematoxylin-eosin (H&E) staining. Hematoxylin-eosin staining reflects the extent of tissue inflammation, fat deposition, vacuolar degeneration and tissue fibrosis. The semi-quantitative analysis criteria for lesion severity are shown in Table 6.

Table 6 Pathological scoring criteria for liver fibrosis

2.6 Sirius red staining

The liver tissue was made into 5 μm sections, dried for 2 h, and re-watered and stained with Sirius Red (Beijing Hyde Venture, Cat. No. 26357) for 30 min at room temperature, and then dehydrated and sealed for image analysis. Aperio ScanScope CS2 (Leica) was used to scan the pathological sections at 200× magnification, and then the scanned images were opened in the Aperio ImageScope program to remove the blood vessels, and the target image was analyzed by Color Deconvolution v9. The fibrotic portion stained red was identified as a positive signal using software and the percentage of fibrosis was calculated.

3. Statistical analysis

Data are expressed as mean ± standard error. Significant analysis was performed using the student t-test, one way ANOVA or two way ANOVA and post-hoc Dunnett's test.

4. Experimental results

4.1 Hepatocyte necrosis

Compared with the normal control group, the degree of hepatocyte necrosis in the model group was significantly increased; after treatment in each compound group, the degree of hepatocyte necrosis was significantly reduced compared with the model group. The degree of hepatocyte necrosis reduction in the compound group of Example 5 and Example 29 (3 mg/kg/d) was significantly higher than or similar to the GS-4997 group (30 mg/kg/d). The experimental results are shown in Table 7.

Table 7 Hepatocyte necrosis

. ** P <0.01vs normal control group;. ^# P <0.05vs model group;. ^## P <0.01vs model group;. ^### P <0.001vs model group

4.2 Liver fibrosis score

After induction of CCL4 and high-fat diet, the liver fibrosis area was significantly increased in the model group compared with the normal control group; the compound group of Example 5 and Example 29 (3 mg/kg/d) significantly reduced liver fibrosis compared with the model group. The area, the improvement of fibrosis is significantly better than the GS-4997 group (30mg/kg/d). The experimental results are shown in Table 8.

Table 8 Liver fibrosis score

It can be seen that the compound of the present invention has a certain therapeutic effect on the HFD-CCL4-induced mouse NASH model; in histopathology, it can effectively reduce hepatic steatosis, hepatocyte injury and reduce liver fibrosis compared with the model group. .

While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims

a compound of the formula A or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug,

among them,

Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, Alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, dialkylamino, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;

Ring B is selected from the group consisting of a monocyclic aryl group, a bicyclic aryl group, a bicyclic heteroaryl group, and a bicyclic heterocyclic group, wherein the monocyclic aryl group, the bicyclic aryl group, the bicyclic heteroaryl group, and the bicyclic heterocyclic ring are described. The group is optionally selected from one or more of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, Alkynoylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or oxo group;

Ring C is a monocyclic heteroaryl group wherein the heteroaryl group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, Nitro, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic Or a heteroaryl group;

Ring D is selected from
And tetrazole, wherein the group is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano a base, an amino group, a monoalkylamino group, an alkylacylamino group, an alkyl acyl group, an aminoacyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group or a heteroaryl group;

Z 1 is an acyl group, an alkylene group or is absent;

Z 2 is -CONH-, -NHCO- or does not exist;

R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl An acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

With the proviso that when Z 1 is absent, ring A is heteroaryl and is optionally substituted by one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitrate Base, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl or oxo group Replace

When ring B is a monocyclic aryl group, ring D is tetrazolium.
A compound according to claim 1 or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

Ring A is selected from the group consisting of C 3-12 cycloalkyl, C 6-18 aryl and 5-20 membered heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted by one or more halogens, Hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkane Oxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl , Bi C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic, 6-12 membered aryl, 5-12 Substituted aryl or oxo group;

Ring B is selected from the group consisting of a 10-18 membered bicyclic aryl group, a 9- or 10-membered bicyclic heteroaryl group, a 9- or 10-membered bicyclic heterocyclic group, wherein the bicyclic aryl group and the bicyclic heteroaryl group are described. And the bicyclic heterocyclic group are optionally substituted by one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1- 6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- a 12-membered heterocyclic group, a 6-12 membered aryl group, a 5-12 membered heteroaryl group or an oxo group;

Ring C is a 5-12 membered monocyclic heteroaryl group optionally substituted by one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkane Aminoacylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3- a 12 cycloalkyl group, a 3-12 membered heterocyclic group or a 5-12 membered heteroaryl group;

Ring D is selected from
And tetrazolium;

Z 1 is an acyl group, a C 1-6 alkyl acyl group or is absent;

Z 2 is -CONH-, -NHCO- or absent; and

R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy a group, a hydroxy C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl and 3-12 membered heterocyclic, 6- 12-membered aryl or 5-12-membered heteroaryl.
The compound according to claim 1 or 2, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the formula A has the structure of the following formula Ia,

among them,

Y is selected from the group consisting of an alkylene group, an alkenylene group, and a cycloalkylene group, and the alkylene group, the alkenylene group, and the cycloalkylene group are optionally one or more alkyl groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, a halogen, an oxo group, an alkoxy group, a carboxyl group, a cyano group, an amino group, a monoalkylamino group or a dialkylamino group, or when Y is an alkylene group and is substituted by two alkyl groups, the two An alkyl group may form a cycloalkyl group together with the C atom to which they are attached;

W is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl Amino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

M is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl An amino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

R 1 is as defined in formula A or claim A.
A compound according to claim 3, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

structure
Selected from
The compound according to claim 1 or 2, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the formula A has the structure of the following formula Id,

among them,

Ring B is selected from monocyclic aryl groups, which are optionally selected from one or more selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy , cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkyl amino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, Substituted with a heteroaryl group and an oxo group;

R 2 is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino , monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxygen One or more of the generation groups;

W is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl An amino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

Z 2 is -CONH-, -NHCO- or is absent.
The compound according to claim 1 or 2, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the formula A has the structure of the following formula Ib,

among them:

W is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl Amino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B, Ring C, Z 1 , Z 2 , R 1 are as defined according to Formula A in claim 1 or 2.
The compound according to claim 1 or 2, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the formula A has the structure of the following formula Ic,

among them:

W is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acyl Amino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Y is selected from the group consisting of alkylene, alkenylene and cycloalkylene, wherein the alkylene, alkenylene and cycloalkylene are optionally substituted by one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl a halogen, an oxo group, an alkoxy group, a carboxyl group, a cyano group, an amino group, a monoalkylamino group or a dialkylamino group, or when Y is an alkylene group and is substituted by two alkyl groups, the two Alkyl groups may form a cycloalkyl group together with the C atom to which they are attached;

X 1 and X 2 are each independently selected from C(R 2 ) and N, wherein R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy Base, nitro, carboxyl, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkylamino, alkenyl, alkynyl, cycloalkyl, hetero a cyclic group, an aryl group, and a heteroaryl group;

Rings C and R 1 are as defined according to formula A in claim 1 or 2.
The compound according to claim 3 or 7, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:

Y is selected from the group consisting of a C 1-6 alkyl group, a C 2-10 alkenylene group, and a C 3-10 cycloalkyl group, wherein the C 1-6 alkyl group, the C 2-10 alkenylene group, and the C 3 group -10 cycloalkylene may be one or more C 1-6 alkyl, halo C 1-6 alkyl, hydroxy, hydroxy C 1-6 alkyl, halogen, oxo, C 1-6 alkane Alkali, carboxy, cyano, amino, mono C 1-6 alkylamino or di C 1-6 alkylamino, or when Y is alkyl and substituted by two alkyl The alkyl group may form a C 3-8 cycloalkyl group together with the C atom to which they are attached; further preferably, Y is selected from the group consisting of a C 1-3 alkyl group, a C 2-6 alkenylene group, and a C 3-6 cycloalkane. a group wherein the subC 1-3 alkyl group, C 2-6 alkenylene group and C 3-6 cycloalkylene group may be one or more C 1-3 alkyl groups, halogenated C 1-3 alkyl groups Base, hydroxy, hydroxy C 1-3 alkyl, halogen, oxo group, C 1-3 alkoxy group, carboxyl group, cyano group, amino group, mono C 1-3 alkylamino group or di C 1-3 alkyl group Substituting an amino group, or when Y is an alkylene group and substituted by two alkyl groups, the two alkyl groups may form a C 3-6 cycloalkyl group together with the C atom to which they are attached; more preferably, Y Selected from methylene An ethylene group, a propylene group, a vinylidene group, a propylene group, and a cyclopropylene group, wherein the methylene group, an ethylene group, a propylene group, a vinylidene group, a propylene group, and a cyclopropylene group Optionally substituted by one or more halogen, methyl, ethyl, propyl, isopropyl, oxo groups, or when Y is an alkylene group and is substituted by two alkyl groups, the two alkyl groups A C 3 -C 6 cycloalkyl group may be formed together with the C atom to which they are attached;

W is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 a aryl group or a 5-12 membered heteroaryl group; further preferably, W is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkane Alkylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 10 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; more preferably, W is selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl , an isopropyl group, a halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy Group, a C 1-3 alkoxy group, halo, a C 1-3 alkoxy group, hydroxy, nitro, carboxy, cyano, amino, mono C 1-3 alkyl amino, acylamino C 1-3 alkyl, C 1-3 alkyl acyl group, amino acyl group, C 1-3 alkylamino acyl group, bis C 1-3 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a 6-8 membered aryl group or a 5-8 membered heteroaryl group;

R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy a group, a hydroxy C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl and 3-12 membered heterocyclic, 6- 12-membered aryl or 5-12-membered heteroaryl; further preferably, R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl , C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1- 3 alkylacylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; more preferably, R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl , propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1 -3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl Acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 a cycloalkyl group, a 3-8 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group;

M is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, 6-12 A aryl group, a 5-12 membered heteroaryl group or an oxo group.
The compound according to claim 1 or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug, and a pharmaceutically acceptable carrier.
The compound of any one of claims 1-9, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or the pharmaceutical composition of claim 10, for use in the treatment and/or Or the use of a drug that prevents apoptosis signaling in the regulation of kinase-1 associated diseases.