TW202317510A - 3-phenylpropionic acid compounds, their preparation methods and their medical use - Google Patents

Abstract

The present disclosure relates to 3-phenylpropionic acid compounds, their preparation methods and their medical use. Specifically, the present disclosure relates to a 3-phenylpropionic acid compound represented by the general formula (M), a preparation method thereof, a pharmaceutical composition containing the same, and the use thereof as a therapeutic agent, especially in the preparation of soluble guanylate cyclase (sGC) agonists and/or activators and in the preparation of a medicament for the treatment and/or prevention of a disease, condition or disorder mediated by sGC.

Description

3-phenylpropionic acid compound, its preparation method and its application in medicine

The disclosure belongs to the field of medicine, and relates to a 3-phenylpropionic acid compound, its preparation method and its application in medicine. In particular, this disclosure relates to 3-phenylpropionic acid compounds represented by general formula (M), their preparation methods, pharmaceutical compositions containing such compounds and their use as therapeutic agents, especially in the preparation of soluble guanylic acid Use of a cyclase (sGC) agonist and/or promoter and use in the manufacture of a medicament for the treatment and/or prevention of a disease, condition or disorder mediated by sGC.

With the acceleration of population aging and the rising incidence of cardiovascular diseases such as hypertension, coronary heart disease, and atherosclerosis, the prevalence of myocardial infarction and heart failure is gradually increasing. Myocardial infarction is when the blood flow of the coronary artery is sharply reduced or interrupted during coronary artery disease, resulting in severe and persistent ischemia and necrosis of the myocardium. Heart failure, referred to as heart failure, is due to cardiac systolic or diastolic dysfunction, which causes cardiac circulation disorder syndrome. Heart failure is not an independent disease, but the end stage of various cardiovascular diseases, and almost all cardiovascular diseases will eventually lead to heart failure. Patients with heart failure are facing the threat of high mortality, which seriously affects the quality of life of patients. The huge patient population and relatively high mortality pose a huge challenge to the treatment of heart failure.

Over the years, advances have been made in the field of drug therapy for heart failure, including diuretics, beta-blockers to slow the heart rate, and angiotensin receptor blockers, among others. In heart failure patients, impairment of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway can be observed, leading to decreased myocardial and vascular function , causing left ventricular remodeling, fibrosis and inflammation, and ultimately lead to the occurrence and development of heart failure.

NO is an important signaling molecule in various systems such as cardiovascular, nervous, digestive, metabolic, and immune systems, especially the cardiovascular system and nervous system. As the receptor of NO, sGC is a key metalloenzyme in the NO signal transduction pathway. After NO activates sGC, it catalyzes the conversion of guanosine triphosphate (GTP) into cGMP. cGMP is an important secondary messenger molecule, which can activate a variety of downstream effector molecules, such as cyclic nucleotide-gated ion channel (CNG), phosphodiesterase (PDE) and cGMP-dependent protein kinase (PKG), etc. A series of cascade reactions play important physiological functions in the blood circulation system and nervous system, such as promoting the relaxation of blood vessels and smooth muscles, inhibiting platelet aggregation, vascular remodeling and inflammation. In mammals, NO is synthesized by nitric oxide synthase (NOS), and then diffuses into cells through the lipid bilayer and binds to its receptor protein sGC, thereby producing a large amount of cGMP. However, when the NO-sGC-cGMP signaling pathway is abnormal, it will lead to the dysfunction of vascular endothelial cells, and then lead to a series of cardiovascular diseases, such as pulmonary hypertension and heart failure. As a key enzyme in the NO signaling pathway, sGC has received more and more attention as a drug target for various diseases.

sGC is distributed throughout the cytosol of mammals and is a heterodimer containing a heme prosthetic group consisting of an α subunit and a β subunit, each of which contains an amino-terminal HNOX-binding domain (Heme NO /Oxygen binding domain), the α-helical coiled-coil domain and the catalytic domain at the carboxy-terminus, the expression of a single subunit does not have catalytic activity, and the αβ heterodimer is necessary for the catalytic activity of sGC. sGC has two isomers of α1β1 and α2β1, and α2β1 only exists in limited organization. While α1β1 is widely expressed in tissues, the activity of sGC in blood vessels is mainly due to the high abundance expression of α1β1.

Compounds found to act directly on sGC can be divided into two categories: agonists and promoters. The initiation of sGC is due to the combination of NO and heme in the HNOX binding domain on the β1 subunit, which changes the conformation of sGC and activates the catalytic domain, thereby converting GTP into cGMP. The sGC agonist is dependent on the heme of the HNOX binding domain and cooperates with NO gas to activate sGC. It can enhance the sensitivity of sGC to NO and plays an important role in the development of cardiovascular drugs. However, oxidative stress in the human body can promote the conversion of sGC hemoglobin from a reduced state to an oxidized state, and the content of oxidized hemoglobin in humans with cardiovascular diseases such as hypertension and hyperlipidemia and type II diabetes will also increase, or genetically The mutation of sGC will lead to desensitization of sGC to NO. At this time, sGC agonists cannot cooperate with NO to start sGC, and sGC promoters emerge as the times require. sGC promoters are a class of compounds that can act on oxidized or deheme sGC. It does not rely on reduced heme, but mainly activates sGC by binding to the sGC heme cavity, and then catalyzes the conversion of GTP into cGMP, thereby improving Myocardium and blood vessel function, reduce ventricular remodeling, myocardial hypertrophy, inflammation and fibrosis, and delay the progression of heart failure.

Published sGC-related patent applications include WO2012139888A1, US20140309307A1, US20160264515A1, WO2019105881 A1, WO2020020790 A1, WO2020020789A1, WO2020148379A1, CN112794848A, CN112384214A, CN111712247A and CN106459017B.

The purpose of this disclosure is to provide a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof:

in,

；較佳地，R⁰為氫原子或

； R ⁰ is a hydrogen atom or

; Preferably, R ⁰ is a hydrogen atom or

;

Z is N or ^CR4 ;

G is N or CR ^4a ;

R ¹ and R ² and the connected carbon atoms form ring A', or R ² and R ³ and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl, Aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl , alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cyano, pendant oxy, alkenyl, alkynyl, -NR ^12a R ^12b , -MHC(O)R ¹³ , -C( One or more identical or different substituents in O) R ¹³ and -C(O)OR ¹³ are substituted;

When R ¹ and R ² and the attached carbon atom form ring A', R ³ is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine and nitro;

When ^R2 and ^R3 and the attached carbon atom form ring A, ^R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano group, amine group and nitro group;

R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;

R ⁵ and R ⁶ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; Wherein the alkyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group and heterocyclic group are each independently selected from one or more of alkenyl, alkynyl, cyano, amino, nitro and ^R Substituting with the same or different substituents; or R ⁵ and R ⁶ and the connected carbon atoms form a cycloalkyl or heterocyclic group;

R ^b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro Substitution by one or more identical or different substituents;

Each ^R is the same or different, and is independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine, and nitro;

^R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;

^R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or ^R8 and ^R9 and the connected carbon atom form cycloalkyl or heterocyclyl;

R ¹⁰ and R ¹¹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;

R ^12a and R ^12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R ^12a and R ^12b form a heterocyclic group together with a connected nitrogen atom;

^R is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

n is 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

in,

G is N or CR ^4a ;

R ¹ and R ² and the connected carbon atoms form ring A', or R ² and R ³ and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl, Aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy In radical, hydroxyalkyl, cyano, pendant oxy, alkenyl, alkynyl, -NR ^12a R ^12b , -NHC(O)R ¹³ , -C(O)R ¹³ and -C(O)OR ¹³ Substitution by one or more identical or different substituents;

When R ¹ and R ² and the attached carbon atom form ring A', R ³ is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine and nitro;

When ^R2 and ^R3 and the attached carbon atom form ring A, ^R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano group, amine group and nitro group;

R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;

R ⁵ and R ⁶ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; Wherein the alkyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group and heterocyclic group are each independently selected from one or more of alkenyl, alkynyl, cyano, amino, nitro and ^R Substituting with the same or different substituents; or R ⁵ and R ⁶ and the connected carbon atoms form a cycloalkyl or heterocyclic group;

R ^b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro Substitution by one or more identical or different substituents;

Each ^R is the same or different, and is independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine, and nitro;

^R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;

^R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or ^R8 and ^R9 and the connected carbon atom form cycloalkyl or heterocyclyl;

R ¹⁰ and R ¹¹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;

R ^12a and R ^12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R ^12a and R ^12b form a heterocyclic group together with a connected nitrogen atom;

^R is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

n is 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound represented by the general formula (M), the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof Salt:

in,

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ^2a is the same or different and is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, pendant oxy, alkenyl, alkynyl, -NR ^12a R ^12b , -NHC(O)R ¹³ , -C(O)R ¹³ and -C(O)OR ¹³ ;

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

G, R ¹ , R ⁴ to R ¹¹ , R ^12a , R ^12b , R ¹³ and n are as defined in general formula (M) or general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ⁶ , R ⁹ and R ¹¹ are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group; preferably, R ⁶ , R ⁹ and R ¹¹ are all hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or its pharmaceutically acceptable salts:

in,

G is CR ^4a ;

Ring A, R ^2a , R ^4a , R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in the general formula (II).

In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein, R ¹⁰ is selected from from a hydrogen atom, halogen and C _1-6 alkyl; preferably, R ¹⁰ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof:

in,

；較佳地，R⁰為氫原子或

； R ⁰ is a hydrogen atom or

; Preferably, R ⁰ is a hydrogen atom or

;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ^2a is the same or different, and each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, side oxygen radical, alkenyl, alkynyl, -NR ^12a R ^12b , -NHC(O)R ¹³ , -C(O)R ¹³ and -C(O)OR ¹³ :

R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in the group, amino group and nitro group;

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

Z, G, R ¹ , R ⁷ , R ⁸ , R ^12a , R ^12b , R ¹³ and n are as defined in the general formula (M).

In some embodiments of the present disclosure, the compound represented by the general formula (M) or the general formula (G) or a pharmaceutically acceptable salt thereof is the general formula (G-1) or the general formula (G-2) The indicated compound or its pharmaceutically acceptable salt:

in,

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G).

In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (G), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof , which is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof:

in,

R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in the group, amino group and nitro group;

G is CR ^4a ;

Ring A, R ^2a , R ^4a , R ¹ , R ⁴ , R ⁷ , R ⁸ , m and n are as defined in general formula (II) or general formula (III).

In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (G), general formula (I), general formula (II), general formula (III) or general formula (IV) or Its pharmaceutically acceptable salt, which is a compound represented by general formula (IV-1) or general formula (IV-2) or its pharmaceutically acceptable salt:

in,

R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in the group, amino group and nitro group;

G is CR ^4a ;

Ring A, R ^2a , R ^4a , R ¹ , R ⁴ , R ⁷ , R ⁸ , m and n are as defined in general formula (II), general formula (III) or general formula (IV).

；更佳地，R⁵為

。 In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein, R ⁵ is Halogen C _1-6 alkyl; preferably, R ⁵ is

; More preferably, R ⁵ is

.

In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (IV), general formula (IV-1) or general formula (IV -2) the compound or its pharmaceutically acceptable salt, wherein, R ^5a and R ^5b are different, and each independently selected from halogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _{1- 6} alkoxy, halogen C _1-6 alkoxy, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic; wherein the C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkane Oxygen, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxyl, cyano, amino and nitro are substituted by one or more of the same or different substituents; preferably, R ^5a Different from R ^5b , and each independently is C _1-6 alkyl or halogen C _1-6 alkyl; further preferably, R ^5a is C _1-6 alkyl, R ^5b is halogen C _1-6 alkyl; More preferably, R ^5a is methyl and R ^5b is trifluoromethyl.

In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV), A compound represented by general formula (IV-1) or general formula (IV-2), wherein m is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the compound represented by general formula (G), general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, wherein each R ^2a is the same or different , and each independently selected from a deuterium atom, a halogen, and a C _1-6 alkyl group; preferably, each R ^2a is the same or different, and each independently selected from a deuterium atom, a fluorine atom, a chlorine atom, and a methyl group.

In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV), A compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R ^2a is the same or different, and is independently halogen or C _1-6 alkyl; Preferably, each R ^2a is the same or different, and each is independently selected from a fluorine atom, a chlorine atom and a methyl group.

In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV), A compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R ^2a is the same or different, and is independently halogen or C _1-6 alkyl, And m is 1, 2, 3 or 4; or m is 0; preferably, m is 0.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), Compounds represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or pharmaceutically acceptable salts thereof, wherein ring A is selected from 6 to 10 membered aryl groups , 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, ring A is selected from phenyl, 5 or 6 membered heteroaryl and 5 or 6 membered cycloalkane base.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), Shown in general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic; preferably, Ring A is selected from phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclic; more preferably, ring A is selected from phenyl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclyl.

In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV), A compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 10 membered heteroaryl, 8-membered cycloalkyl and 3 to 8-membered heterocyclyl; each R ^2a is the same or different, and each independently is halogen or C _1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; Preferably, ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered cycloalkyl and 5 or 6-membered heterocyclyl; each R ^2a is the same or different, and is independently halogen or C _1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; more preferably, ring A is selected from phenyl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclic group; each R ^2a are the same or different, and are independently halogen or C _1-6 alkyl, m is 1, 2, 3 or 4; or m is 0.

選自

、

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

,

,

選自

、

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

,

,

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

,

選自

、

、

、

、

In some embodiments of the present disclosure, the compound represented by general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

選自

、

、

、

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

選自

、

、

、

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

選自

、

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

,

,

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

,

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

,

,

,

選自

、

、

、

和

。 In some embodiments of the present disclosure, the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein,

selected from

,

,

,

and

.

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein,

selected from

,

,

,

,

,

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein,

selected from

,

,

,

,

,

選自

、

、

、

和

。 In some embodiments of the present disclosure, the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein,

selected from

,

,

,

and

.

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein,

selected from

,

,

,

,

,

選自

、

、

、

、

、

In some embodiments of the present disclosure, the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein,

selected from

,

,

,

,

,

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), A compound represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is the same or different, and each are independently halogen or C _1-6 alkyl; preferably, each R ⁷ is the same or different, and each independently is a halogen; more preferably, each R ⁷ is independently a chlorine atom.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), A compound represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is the same or different, and each independently selected from chlorine atom, bromine atom and methyl group.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), A compound represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; preferably , n is 1.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), A compound represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is the same or different, and each independently halogen or C _1-6 alkyl, and n is 1, 2, 3 or 4; or n is 0;

Preferably, R ⁷ is halogen or C _1-6 alkyl, and n is 1;

More preferably, R ⁷ is halogen, and n is 1.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), A compound represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ^R is selected from C _1-6 alkane Base, halogen C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkoxy, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably; R ⁸ is C _1-6 alkyl or 3 to 8 membered cycloalkyl; more preferably; R ⁸ is 3 to 8 membered cycloalkyl; most preferably, R ⁸ is cyclopropyl.

In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), A compound represented by general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ¹ , R4 and R ^4a are all hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered cycloalkane and 5 or 6-membered heterocyclyl; G is N or CR ^4a ; each R ^2a is the same or different, and each independently is halogen or C _1-6 alkyl; m is 0, 1 or 2; R ¹ , R ⁴ and R ^4a are both hydrogen atoms; R ⁵ is halogen C _1-6 alkyl; R ⁶ , R ⁹ and R ¹¹ are all hydrogen atoms; R ¹⁰ is hydrogen atom; R ⁷ is halogen or C _1-6 alkyl ; n is 1; R ⁸ is 3 to 8 membered cycloalkyl groups.

In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered cycloalkane and 5 or 6-membered heterocyclyl; G is CR ^4a ; each R ^2a is the same or different, and each independently is halogen or C _1-6 alkyl; m is 0, 1 or 2; R ¹ , R ⁴ and R ^4a are all hydrogen atoms; R ⁵ is halogen C _1-6 alkyl; R ¹⁰ is hydrogen atom; R ⁷ is halogen or C _1-6 alkyl; n is 1; R ⁸ is cyclopropyl.

In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein, R ^5a and R ^5b are different, and each independently Selected from halogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkoxy, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkane and 3 to 8 membered heterocyclic groups; wherein the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups Each is independently selected from halogen, C _1-6 alkyl, C 1-6 alkoxy, halogen C _1-6 alkyl, halogen _{C 1-6 alkoxy} , hydroxyl, cyano, amino and One or more of the same or different substituents in the nitro group are substituted; G is CR ^4a ; R ¹ , R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; each R ^2a is the same or different, and each independently is halogen or C _1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; each R ⁷ is the same or different, and each independently is halogen or C _1-6 alkyl, n is 1, 2, 3 or 4; or n is 0; R is ^selected from C _1-6 alkyl, halogen C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkoxy, C _1-6 hydroxyalkane and 3 to 8 membered cycloalkyl groups.

In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or general formula (TV-2) or a pharmaceutically acceptable salt thereof, wherein, R ^5a and R ^5b are different, and each independently is C _1-6 alkyl or halogen C _1-6 alkyl; G is CR ^4a ; R ¹ , R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl ; Ring A is selected from phenyl, 5 or 6-membered heterocyclyl and 5 or 6-membered cycloalkyl; each R ^2a is the same or different, and each independently is halogen or C _1-6 alkyl, m is 1, 2 , 3 or 4; or m is 0; R ⁷ is halogen, n is 1; R ⁸ is C _1-6 alkyl or 3 to 8 membered cycloalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein, R ^5a is C _{1 -6} alkyl, R ^5b is halogen C _1-6 alkyl; G is CR ^4a ; R ¹ , R ⁴ and R ^4a are all hydrogen atoms; ring A is selected from phenyl, 5 or 6 membered heteroaryl, 5 or 6-membered cycloalkyl and 5 or 6-membered heterocyclyl; each R ^2a is the same or different, and is independently halogen or C _1-6 alkyl; m is 0, 1 or 2; R ⁷ is halogen or C _1-6 alkyl; n is 0 or 1; R ⁸ is C _1-6 alkyl or 3 to 8 membered cycloalkyl.

；各個 R^2a相同或不同，且各自獨立地選自氘原子、鹵素和C_1-6烷基；m為0、1或2；R⁷為鹵素或C_1-6烷基；n為1；R⁸為3至8員環烷基。 In some embodiments of the present disclosure, the compound represented by general formula (G), general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, wherein, R ^5a is C _{1 -6} alkyl, R ^5b is halogen C _1-6 alkyl; ring A is selected from phenyl, 5 or 6 member heteroaryl, 5 or 6 member cycloalkyl and 5 or 6 member heterocyclyl; Z is N Or CR ⁴ ; G is N or CR4 ^a ; R ¹ , R ⁴ and R ^4a are all hydrogen atoms; R ⁰ is a hydrogen atom or

; Each R ^2a is the same or different, and is independently selected from deuterium atom, halogen and C _1-6 alkyl; m is 0, 1 or 2; R ⁷ is halogen or C _1-6 alkyl; n is 1; R ⁸ is 3 to 8 membered cycloalkyl.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to compounds represented by general formula (MA) or salts thereof:

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

Z, G, R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (M).

Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

G, R ¹ to R ¹¹ and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to compounds represented by general formula (IIA) or salts thereof:

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (II).

Another aspect of the present disclosure relates to the compound represented by general formula (IIIA) or a salt thereof:

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in the general formula (III).

Another aspect of the present disclosure relates to compounds represented by general formula (GA) or salts thereof:

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

Rings A, Z, G, R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G).

Another aspect of the present disclosure relates to a compound represented by general formula (G-1A) or general formula (G-2A) or a salt thereof:

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

Rings A, Z, G, R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (G-1) or general formula (G-2).

Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof:

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV).

Another aspect of the present disclosure relates to a compound represented by general formula (IV-1A) or general formula (IV-2A) or a salt thereof:

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1) or general formula (IV-2).

Typical intermediate compounds or salts thereof disclosed in Table B include but are not limited to:

Another aspect of the present disclosure relates to a compound represented by general formula (Ga-A), general formula (Ga-A1) or general formula (Ga-A2) or a salt thereof:

in,

R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy The radical, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, Amino and nitro are substituted by one or more identical or different substituents; wherein when one of R ^5a and R ^5b is methyl, the other is not ethyl or propyl;

Rings A, Z, G, R ^2a , m and R ¹ are as defined in general formula (G), general formula (G-1) or general formula (G-2).

Another aspect of the present disclosure relates to a compound represented by general formula (IVa-A), general formula (IVa-A1) or general formula (IVa-A2) or a salt thereof:

in,

R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy The radical, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, Amino and nitro are substituted by one or more identical or different substituents; wherein when one of R ^5a and R ^5b is methyl, the other is not ethyl or propyl;

G is CR ^4a ;

Ring A, R ^2a , m, R ^4a , R ¹ and R ⁴ are as defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

Table C Typical intermediate compounds or salts thereof disclosed in the present disclosure, including but not limited to:

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

A compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is selected from an alkyl group, the compound represented by the general formula (MA) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (M) whose ^R is a hydrogen atom or its pharmaceutically acceptable Salt;

時，通式(MA)所示的化合物或其鹽脫去R^w，得到R⁰ 為

的通式(M)所示的化合物或其可藥用的鹽；較佳地，當R為

時，通式(MA)所示的化合物或其鹽脫去R^w，得到R⁰為

的通式(M)所示的化合物或其可藥用的鹽； when R is

When , the compound represented by the general formula (MA) or its salt removes R ^w , and R ⁰ is obtained as

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is

When , the compound represented by the general formula (MA) or its salt removes R ^w , and R ⁰ is obtained as

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof;

Z, G, R ⁰ , R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (M).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (MA) or a salt thereof, the method comprising the following steps:

The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (Ib-A) or its salt are condensed and acylated to obtain the compound represented by the general formula (MA) or its salt;

in,

Z, G, R, R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (MA).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

G, R ¹ to R ¹¹ and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IA) or a salt thereof, the method comprising the following steps:

The compound represented by the general formula (Ia-A) or a salt thereof and the compound represented by the general formula (Ib-A) or a salt thereof undergo a condensation acylation reaction to obtain a compound represented by the general formula (IA) or a salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

G, R ¹ to R ¹¹ and n are as defined in general formula (IA).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IIA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof with the following steps;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (II).

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (IIA) or a salt thereof, the method comprising the following steps:

The compound represented by the general formula (IIa-A) or a salt thereof and the compound represented by the general formula (Ib-A) or a salt thereof undergo a condensation acylation reaction to obtain a compound represented by the general formula (IIA) or a salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (IIA).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by general formula (IIIA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in the general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or a salt thereof, the method comprising the following steps:

The compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIb-A) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (IIIA) or its salt;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in general formula (IIIA).

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (G) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

A compound represented by the general formula (GA) or a salt thereof is reacted to obtain a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is an alkyl group, the compound represented by the general formula (GA) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (G) whose ^R is a hydrogen atom or a pharmaceutically acceptable salt thereof ;

時，通式(GA)所示的化合物或其鹽脫去R^w，得到R⁰ 為

的通式(G)所示的化合物或其可藥用的鹽；較佳地，當R為

時，通式(GA)所示的化合物或其鹽脫去R^w，得到R⁰為

的通式(G)所示的化合物或其可藥用的鹽； when R is

When, the compound represented by the general formula (GA) or its salt removes R ^w , and R ⁰ is obtained as

A compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by the general formula (GA) or its salt removes R ^w , and R ⁰ is obtained as

A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof;

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

A compound represented by general formula (G-IA) or a salt thereof is reacted to obtain a compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is an alkyl group, the compound represented by the general formula (G-1A) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (G-1) whose ^R is a hydrogen atom or its alternative medicinal salts;

時，通式(G-1A)所示的化合物或其鹽脫去R^w，得到 R⁰為

的通式(G-1)所示的化合物或其可藥用的鹽；較佳地，當R為

時，通式(G-1A)所示的化合物或其鹽脫去R^w，得到R⁰為

的通式(G-1)所示的化合物或其可藥用的鹽； when R is

When, the compound represented by the general formula (G-1A) or its salt removes R ^w , and obtains R ⁰ as

A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by the general formula (G-1A) or its salt removes R ^w , and obtains R ⁰ as

A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof;

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

A compound represented by general formula (G-2A) or a salt thereof is reacted to obtain a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is an alkyl group, the compound represented by the general formula (G-2A) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (G-2) whose ^R is a hydrogen atom or its alternative medicinal salts;

傳，通式(G-2A)所示的化合物或其鹽脫去R^w，得到 R⁰為

的通式(G-2)所示的化合物或其可藥用的鹽；較佳地，當R為

時，通式(G-2A)所示的化合物或其鹽脫去R^w，得到R⁰為

的通式(G-2)所示的化合物或其可藥用的鹽； when R is

Pass, the compound shown in general formula (G-2A) or its salt removes R ^w , obtains R ⁰ as

A compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by the general formula (G-2A) or its salt removes R ^w , and obtains R ⁰ as

A compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;

Rings A, Z, G, R ⁰ , R ¹ , R2 ^a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1A) or general formula (G-2A) or a salt thereof, the method comprising the following steps:

The compound shown in general formula (Ga-A) or its salt and the compound shown in general formula (IVb-A) or its salt generation condensation acylation reaction, obtain general formula (G-1A) or general formula (G-2A ) or a salt thereof;

in,

Rings A, Z, G, R, R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (G-1A) or general formula (G-2A).

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IVA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV).

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV-2).

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (IV-1A) or general formula (IV-2A) or a salt thereof, the method comprising the following steps:

The compound shown in general formula (IVa-A) or its salt and the compound shown in general formula (IVb-A) or its salt generation condensation acylation reaction, obtain general formula (IV-1A) or general formula (IV-2A ) or a salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1A) or general formula (IV-2A).

Another aspect of the disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt are condensed and acylated to obtain the compound represented by the general formula (M) or its pharmaceutically acceptable salt ;

in,

Z, G, R ⁰ , R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (M).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (IB) or its salt are condensed and acylated to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt ;

in,

G, R ¹ to R ¹¹ and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IIa-A) or its salt and the compound represented by the general formula (IB) or its salt are condensed and acylated to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt ;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by general formula (IIIa-A) or its salt and the compound represented by general formula (IIIB) or its salt are condensed and acylated to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt ;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in the general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (Ga-A) or its salt and the compound represented by the general formula (GB) or its salt are condensed and acylated to obtain the compound represented by the general formula (G-1) or the general formula (G-2). The indicated compound or its pharmaceutically acceptable salt;

in,

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G-1) or (G-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by the general formula (IVa-A) or its salt and the compound represented by the general formula (IVB) or its salt are condensed and acylated to obtain the compound represented by the general formula (IV-1) or the general formula (IV-2). The indicated compound or its pharmaceutically acceptable salt;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1) or general formula (IV-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) and general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by general formula (G) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (G-1) and general formula (G-2) or its pharmaceutically acceptable salt;

in,

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) and general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

The compound represented by general formula (IV) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (IV-1) and general formula (IV-2) or its pharmaceutically acceptable salt;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1) or general formula (IV-2).

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective amount of the general formula (M), general formula (G), general formula (G-1), general formula (G-2) of the present disclosure , general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in table A or its can A pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it are in the preparation of sGC agonist and/or Use in starters.

The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (TV), general formula (IV-1), general formula (IV-2) and Table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it is used in the preparation for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoarthritis Loose, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, the disease, The condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, the renal disease is chronic renal failure or chronic renal insufficiency.

The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it is used for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoarthritis Loose, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral artery disease, intermittent claudication, severe Lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, the cardiovascular disease selected from hypertension, myocardial infarction and heart failure.

The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it is used for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoarthritis Loose, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the fibrotic disease is selected from fibrosis of the skin, liver, kidney and lung; the urinary system disease is selected from overactive bladder, benign prostatic hyperplasia and erectile dysfunction; the neurological disease is selected from Alzheimer's disease, Parkinson's disease, and neuropathic pain; the inflammatory disease is selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crowe's Engel's disease and chronic obstructive pulmonary disease.

The disclosure further relates to a method for activating and/or activating sGC, which comprises administering a therapeutically effective amount of general formula (M), general formula (G), general formula (G-1), general formula (G-2) to a patient in need ), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its A pharmaceutically acceptable salt, or a pharmaceutical composition comprising it.

The disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by activating and/or activating sGC, which comprises administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general Formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it, wherein the disease, condition or disease is selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, Diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction. Preferably, the disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, the renal disease For chronic renal failure or chronic renal insufficiency.

The disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by activating and/or activating sGC, which comprises administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general The compound shown in formula (IV-2) and Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, the disease, condition or disease is that the disease, condition or disease is selected from cardiovascular disease, kidney disease, Pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spine Vascular stenosis, peripheral arterial disease, intermittent claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral hemorrhage Vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, the cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.

The disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by activating and/or activating sGC, which comprises administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general Compounds shown in formula (IV-2) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, wherein the disease, condition or disease is selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease , diabetes, glaucoma, obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction; wherein the fibrosis is selected from fibrosis of the skin, liver, kidney and lung; the urinary system disease is selected from Overactive bladder, benign prostatic hyperplasia, and erectile dysfunction; the neurological disease selected from Alzheimer's disease, Parkinson's disease, and neuropathic pain; the inflammatory disease selected from psoriasis, multiple sclerosis, arthritis, asthma , ulcerative colitis, Crohn's disease and chronic obstructive pulmonary disease.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , the compound shown in the general formula (IV), the general formula (IV-1), the general formula (IV-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicine.

The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as agonist and/or Or drugs that initiate sGC.

The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for stimulating and/or Or start sGC.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as treatment and / or a medicament for preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein the disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, the disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, the renal disease is chronic renal failure or chronic renal insufficiency.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used for the treatment and and/or prevention of a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein the disease, condition or disorder is selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis , fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, the disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, the renal disease is chronic renal failure or chronic Renal insufficiency.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as treatment and / or a medicament for preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein the disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; where the cardiovascular Disease selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, intermittent claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke , coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, the cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used for the treatment and and/or prevention of a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein the disease, condition or disorder is selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis , fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral artery disease, intermittent claudication, severe lower extremity Ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, the cardiovascular disease is selected from from hypertension, myocardial infarction and heart failure.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as treatment and / or a medicament for preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein the disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the fibrotic disease is selected from fibrosis of the skin, liver, kidney and lung; the urinary system disease is selected from overactive bladder, benign prostate Proliferative and erectile dysfunction; the neurological disease selected from Alzheimer's disease, Parkinson's disease and Neuropathic pain; the inflammatory disease is selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease and chronic obstructive pulmonary disease.

The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) , general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used for the treatment and and/or prevention of a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein the disease, condition or disorder is selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis , fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the fibrotic disease is selected from fibrosis of the skin, liver, kidney and lung; the urinary system disease is selected from overactive bladder, benign prostatic hyperplasia and Erectile dysfunction; the neurological disease selected from Alzheimer's disease, Parkinson's disease, and neuropathic pain; the inflammatory disease selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease disease and chronic obstructive pulmonary disease. Preferably, the peripheral arterial disease disclosed in the present disclosure is selected from thromboangiitis obliterans, peripheral arterial occlusive disease and Raynaud's disease or Raynaud's syndrome.

The active compounds may be prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compound is preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose. Expression of Unit Dose of Compounds or Compositions of the Disclosure The form may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period of time.

Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injection or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

Compounds of the disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the state of the patient's health, the patient's behavior, patient’s diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable The type of salt can be verified according to the traditional treatment plan.

[term explanation]

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) carbon atoms straight or branched (i.e. C _1-20 alkyl), preferably an alkyl group containing 1 to 12 carbon atoms (i.e. C _1-12 Alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (ie C _1-6 alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as above, preferably having 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkenyl), more preferably alkenyl containing 2 to 6 carbon atoms (ie C _2-6 alkenyl). Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxy One or more of alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms alkynyl (ie C _2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring has 3 to 20 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably with 3 to 12 (eg 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms (ie 3 to 12 membered cycloalkanes group), preferably containing 3 to 8 carbon atoms, more preferably having 3 to 6 carbon atoms (i.e. 3 to 6 membered cycloalkyl), most preferably having 5 or 6 carbon atoms (i.e. 5 or 6 membered cycloalkane base). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members, sharing one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds (that is, 5 to 20 membered spirocycloalkane base). It is preferably 6 to 14 members (ie 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members) (ie 7 to 10 membered spirocycloalkyl). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is divided into multiple spirocycloalkyl groups such as single spirocycloalkyl, double spirocycloalkyl, etc., preferably single spirocycloalkyl and double spirocycloalkyl . More preferably 3 members/5 members, 3 members/6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members, 5 members/6 members, 6 members/6 members , 6-membered/4-membered or 6-membered/5-membered single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds (ie 5 to 20 membered fused cycloalkyl). It is preferably 6 to 14 members (ie 6 to 14 membered fused cycloalkyl), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members) (ie 7 to 10 membered fused cycloalkyl). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members /3 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people/3 people, 6 people/4 people, 6 people/5 people, 6 people/6 people, 6 people/7 people member, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 membered bridge Cycloalkyl). It is preferably 6 to 14 members (ie, 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members) (ie, 7 to 10 membered bridged cycloalkyl). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic and other tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

、

和

等；較佳

和

。 The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl On the ring, where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include

,

and

etc; better

and

.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo Alkoxy One or more of radical, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent comprising 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur can be optionally oxidized (i.e., to form argon or argon), but excluding the -O-O-, -O-S- or -S-S- ring portion, the remaining ring atoms are carbon (i.e., 3 to 20 membered heterocyclyl). Preferably comprising 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g. 1, 2, 3 and 4) are Heteroatoms (ie 3 to 12 membered heterocyclyl); more preferably contain 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 (eg 1, 2 and 3 ) is a heteroatom (ie 3 to 12 membered heterocyclyl); more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms (ie 3 to 6 membered heterocyclyl); optimally contains 5 or 6 ring atoms, 1-3 of which are heteroatoms (ie 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,3-dioxolyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperidine Azinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a multicyclic heterocyclic group with 5 to 20 members sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, the sulfur can be oxidized (ie to form argon or sulfur) if desired, and the remaining ring atoms are carbon. It may contain one or more double bonds (ie 5 to 20 membered spiroheterocyclyl). It is preferably 6 to 14 members (ie 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members) (ie 7 to 10 membered spiroheterocyclyl). According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is divided into multiple spiro heterocyclic groups such as single spiro heterocyclic group and double spiro heterocyclic group, preferably single spiro heterocyclic group and double spiro heterocyclic group . More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclyls include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (i.e. forming argon or argon) and the remaining ring atoms being carbon (i.e. 5 to 20 membered fused Cyclo). It is preferably 6 to 14 members, more preferably 7 to 10 members (such as 7, 8, 9 or 10 members) (ie 6 to 14 membered fused heterocyclic group). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/3 members, 5 members/4 members, 5 members/5 members, 5 members/6 members, 6 members/3 members, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclyl" refers to a 5 to 14-membered polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (ie to form argon or thionium) and the remaining ring atoms are carbon (ie 5 to 14 membered bridged heterocyclyl). It is preferably 6 to 14 members (ie, 6 to 14 membered bridged heterocyclic group), more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members) (ie, 7 to 10 membered bridged heterocyclic group). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic heterocyclyl, spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl) fused to an aryl, heteroaryl or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

、

、

和

等。

,

,

and

wait.

The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (a fused polycyclic ring is a ring sharing adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6 to 10 members such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered heteroaryl (5 or 6 membered heteroaryl), eg furyl , Thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent The residues from which the atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroaryl".

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structure of the compound described in this disclosure, the bond "/" indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond "/" can be "

"or"

, or both "

"and"

"Two configurations.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxyl" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "side oxy" or "side oxygen" refers to "=0".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically derivative" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, hydrogen is replaced by "deuterium" or "tritium", or fluorine is replaced by ¹⁸ F-fluorine label ( ¹⁸ F isotope), or ¹¹ C-, ¹³ C-, or ¹⁴ C-enriched Compounds in which carbon atoms are replaced by carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

Various deuterated forms of compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.

When a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium (i.e., at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium (i.e. at least 15% deuterium incorporation), at least 2000 times more abundant deuterium (i.e. at least 30% deuterium incorporation) , deuterium at least 3000 times the abundance (i.e. at least 45% deuterium incorporation), at least 3340 times the abundance of deuterium (i.e. at least 50.1% deuterium incorporation), at least 3500 times the abundance of deuterium (i.e. at least 52.5% deuterium incorporation), at least 4000 times more abundant deuterium (i.e. at least 60% deuterium incorporation), at least 4500 times more abundant deuterium (i.e. at least 67.5% deuterium incorporation), at least 5000 times more Deuterium in abundance (i.e. at least 75% deuterium incorporation), deuterium in at least 5500 times abundance (i.e. at least 82.5% deuterium incorporation), deuterium in at least 6000 times abundance (i.e. at least 90% deuterium incorporation) deuterium incorporation), at least 6333.3 times the abundance of deuterium (i.e. at least 95% deuterium incorporation), at least 6466.7 times the abundance of deuterium (i.e. at least 97% deuterium incorporation), at least 6600 times the abundance of deuterium ( i.e. at least 99% deuterium incorporation), at least 6633.3 times more abundant deuterium (i.e. at least 99.5% deuterium incorporation), or higher abundance of deuterium.

Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers isomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures , all of these mixtures fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine, lactam-lactimine isomerizations. An example of a lactam-lactimine equilibrium is between A and B shown below.

All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

"Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. And the case of cyano substitution.

"Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. Those skilled in the art are able to determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

For a drug or a pharmacologically active agent, the term "therapeutically effective amount" refers to the amount of the drug or agent that is sufficient to achieve or partially achieve the desired effect. The determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the subject, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine experiments.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue medical judgment. Toxicity, irritation, allergic reaction or other problems or complications that have a reasonable benefit/risk ratio and are effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes preferably within ±5%. As will be understood by those of ordinary skill in the art, when a parameter is not critical, the digits are generally given for illustrative purposes only, and not for limitation.

The synthetic method of the disclosed compound

In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

Option One

The preparation method of the compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

A compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is selected from an alkyl group, the compound represented by the general formula (MA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (M) whose ^R is a hydrogen atom or its pharmaceutically acceptable salts;

時，通式(MA)所示的化合物或其鹽在金屬催化劑(較佳四(三苯基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w，得到 R⁰為

的通式(M)所示的化合物或其可藥用的鹽；較佳地，當R為

時，通式(MA)所示的化合物或其鹽在金屬催化劑(較佳四(三苯 基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w，得到R⁰為

的通式(M)所示的化合物或其可藥用的鹽； when R is

When, the compound represented by general formula (MA) or its salt removes R under the action of metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and nucleophile (preferably diethylamine or tetrahydropyrrole) ^w , getting R ⁰ as

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by general formula (MA) or its salt removes R under the action of metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and nucleophile (preferably diethylamine or tetrahydropyrrole) ^w , getting R ⁰ as

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof;

Z, G, R ⁰ , R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (M).

Option II

The preparation method of the compound represented by the general formula (MA) or its salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (Ib-A) or its salt are condensed and acylated under alkaline conditions to obtain the compound represented by the general formula (MA) or its salts;

in,

Z, G, R, R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (MA).

third solution

The preparation method of the compound represented by the general formula (I) or its pharmaceutically acceptable salt disclosed in this disclosure comprises the following steps:

A compound represented by general formula (IA) or a salt thereof undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; wherein,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

G, R ¹ to R ¹¹ and n are as defined in the general formula (I).

Option four

The preparation method of the compound represented by general formula (IA) or its salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (Ib-A) or its salt are condensed and acylated under alkaline conditions to obtain the compound represented by the general formula (IA) or its salts;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

G, R ¹ to R ¹¹ and n are as defined in general formula (IA).

Option five

The preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

A compound represented by general formula (IIA) or a salt thereof undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof; wherein,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (II).

Option six

The preparation method of the compound represented by general formula (IIA) or its salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (IIa-A) or its salt and the compound represented by the general formula (Ib-A) or its salt are condensed and acylated under alkaline conditions to obtain the compound represented by the general formula (IIA) or its salts;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (IIA).

Option seven

The preparation method of the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by the general formula (IIIA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in the general formula (III).

Option eight

The preparation method of the compound represented by the general formula (IIIA) or its salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIb-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (IIIA) or its salts;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in general formula (IIIA).

Option nine

The preparation method of the compound represented by the general formula (G) or its pharmaceutically acceptable salt disclosed in this disclosure comprises the following steps:

A compound represented by the general formula (GA) or a salt thereof is reacted to obtain a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is an alkyl group, the compound represented by the general formula (GA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (G) whose ^R is a hydrogen atom or its alternative medicinal salts;

時，通式(GA)所示的化合物或其鹽在金屬催化劑(較 佳四(三苯基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w，得到 R⁰為

的通式(G)所示的化合物或其可藥用的鹽；較佳地，當R為

時，通式(GA)所示的化合物或其鹽在金屬催化劑(較佳四(三苯基 膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w，得到R⁰為

的通式(G)所示的化合物或其可藥用的鹽； when R is

When, the compound represented by general formula (GA) or its salt removes R under the action of metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and nucleophile (preferably diethylamine or tetrahydropyrrole) ^w , getting R ⁰ as

A compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by general formula (GA) or its salt removes R under the action of metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and nucleophile (preferably diethylamine or tetrahydropyrrole) ^w , getting R ⁰ as

A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof;

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G).

Plan ten

The preparation method of the compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by the general formula (G-1A) or its salt is reacted to obtain the compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is an alkyl group, the compound represented by the general formula (G-1A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain ^{R as} represented by the general formula (G-1) of a hydrogen atom. A compound or a pharmaceutically acceptable salt thereof;

時，通式(G-1A)所示的化合物或其鹽在金屬催化劑(較佳四(三苯基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w， 得到R⁰為

的通式(G-1)所示的化合物或其可藥用的鹽；較佳地，當 R為

時，通式(G-1A)所示的化合物或其鹽在金屬催化劑(較佳四(三苯基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w，得到R⁰ 為

的通式(G-1)所示的化合物或其可藥用的鹽； when R is

When, the compound represented by the general formula (G-1A) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) to R ^w , get R ⁰ as

A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by the general formula (G-1A) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) to R ^w , to get R ⁰ as

A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof;

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G-1).

Plan Eleven

The preparation method of the compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

A compound represented by general formula (G-2A) or a salt thereof is reacted to obtain a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;

in,

；較佳地，R為烷基或

； R is alkyl or

; Preferably, R is an alkyl group or

;

R ^w is alkyl or allyl; preferably, R ^w is allyl;

The condition is that when R is an alkyl group, the compound represented by the general formula (G-2A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain R ⁰ as represented by the general formula (G-2) of a hydrogen atom. A compound or a pharmaceutically acceptable salt thereof;

時，通式(G-2A)所示的化合物或其鹽在金屬催化劑(較佳四(三苯基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w， 得到R⁰為

的通式(G-2)所示的化合物或其可藥用的鹽；較佳地，當 R為

時，通式(G-2A)所示的化合物或其鹽在金屬催化劑(較佳四(三苯基膦)鈀)和親核試劑(較佳二乙胺或四氫吡咯)的作用下脫去R^w，得到R⁰ 為

的通式(G-2)所示的化合物或其可藥用的鹽； when R is

When, the compound represented by the general formula (G-2A) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) to R ^w , get R ⁰ as

A compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof; preferably, when R is

When, the compound represented by the general formula (G-2A) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) to R ^w , to get R ⁰ as

A compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G-2).

Plan twelve

The preparation method of the compound represented by general formula (G-1A) or general formula (G-2A) or its salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (Ga-A) or its salt and the compound represented by the general formula (IVb-A) or its salt undergo condensation acylation reaction under alkaline conditions to obtain the general formula (G-1A) or the general formula A compound represented by formula (G-2A) or a salt thereof;

in,

Rings A, Z, G, R, R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (G-1A) or general formula (G-2A).

Plan Thirteen

The preparation method of the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by the general formula (IVA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV).

Plan Fourteen

The preparation method of the compound represented by the general formula (IV-1) or its pharmaceutically acceptable salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV-1).

Plan fifteen

The preparation method of the compound represented by the general formula (IV-2) or its pharmaceutically acceptable salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (IV-2).

Plan sixteen

The preparation method of the compound represented by general formula (IV-1A) or general formula (IV-2A) or its salt disclosed in this disclosure comprises the following steps:

The compound represented by general formula (IVa-A) or its salt and the compound represented by general formula (IVb-A) or its salt occur condensation acylation reaction under alkaline condition, obtain general formula (IV-1A) or general formula (IV-1A) or its salt A compound represented by formula (IV-2A) or a salt thereof;

in,

R is an alkyl group; preferably, R is a C _1-6 alkyl group; more preferably, R is a tertiary butyl group;

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1A) or general formula (IV-2A).

Plan seventeen

The preparation method of the compound represented by the general formula (M) or its pharmaceutically acceptable salt disclosed in this disclosure comprises the following steps:

The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (M) or its salt. pharmaceutically acceptable salts;

in,

Z, G, R ⁰ , R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in the general formula (M).

Plan eighteen

The preparation method of the compound represented by the general formula (I) or its pharmaceutically acceptable salt disclosed in this disclosure comprises the following steps:

The compound represented by general formula (Ia-A) or its salt and the compound represented by general formula (IB) or its salt occur condensation acylation reaction under alkaline condition, obtain the compound represented by general formula (I) or its salt pharmaceutically acceptable salts;

in,

G, R ¹ to R ¹¹ and n are as defined in the general formula (I).

Plan nineteen

The preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by the general formula (IIa-A) or its salt and the compound represented by the general formula (IB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound of the general formula (II) or its pharmaceutical the salt used;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ to R ¹¹ , m and n are as defined in the general formula (II).

Program twenty

The preparation method of the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (III) or its salt pharmaceutically acceptable salts;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in the general formula (III).

Program 21

The preparation method of the compound represented by general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by general formula (Ga-A) or its salt and the compound represented by general formula (GB) or its salt occur condensation acylation reaction under basic condition, obtain general formula (G-1) or general formula ( G-2) compound or pharmaceutically acceptable salt thereof;

in,

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G-1) or (G-2).

Program twenty-two

The preparation method of the compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof disclosed in the present disclosure comprises the following steps:

The compound represented by general formula (IVa-A) or its salt and the compound represented by general formula (IVB) or its salt occur condensation acylation reaction under basic condition, obtain general formula (IV-1) or general formula ( IV-2) compound or a pharmaceutically acceptable salt thereof;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1) or general formula (IV-2).

Program twenty-three

The preparation method of the compound represented by the general formula (G-1) and the general formula (G-2) or the pharmaceutically acceptable salt thereof disclosed in this disclosure comprises the following steps:

The compound represented by general formula (G) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (G-1) and general formula (G-2) or its pharmaceutically acceptable salt;

in,

Rings A, Z, G, R ⁰ , R ¹ , R ^2a , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in the general formula (G).

Program twenty-four

The preparation method of the compound represented by the general formula (IV-1) and the general formula (IV-2) or the pharmaceutically acceptable salt thereof disclosed in this disclosure comprises the following steps:

The compound represented by general formula (IV) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (IV-1) and general formula (IV-2) or its pharmaceutically acceptable salt;

in,

Ring A, R ^2a , G, R ¹ , R ⁴ , R ^5a , R ^5b , R ⁷ , R ⁸ , m and n are as defined in general formula (IV-1) or general formula (IV-2).

The reagents providing basic conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but not limited to triethylamine, pyridine, N,N -diisopropylethylamine, n-butyl lithium, diiso Lithium propylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the reagent providing basic conditions is pyridine.

The acids described in the above synthesis schemes include but are not limited to mellitic acid, thiosulfuric acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; preferably, the acid is tri Fluoroacetic acid.

The condensation and acylation reaction mentioned in the above synthesis scheme is preferably carried out in the presence of a condensation reagent, and the condensation reagent is preferably 1-chloro- N,N ,2-trimethylacrylamine.

The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, isopropanol, acetone, acetonitrile, n-butanol, toluene, tetrahydrofuran, Dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfide, toluene, 1,4-dioxane, water, N, N-dimethylformamide, N,N -dimethyl Acetamide, 1,2-dibromoethane and mixtures thereof.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR was carried out with a Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvents were deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

The determination of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high-performance liquid chromatography.

Chiral HPLC analysis and determination using Agilent 1260 DAD high performance liquid chromatography.

High performance liquid phase preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparative chromatography A Shimadzu LC-20AP preparative chromatograph was used.

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm~0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

Kinase average inhibition rate and IC ₅₀ value were measured with NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals, Adamas Reagent Co., Ltd., Sigma-Aldrich (Shanghai) Trading Co., Ltd., Shanghai Pide Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., Thermo Fisher Scientific (China) Technology Co., Ltd. Companies and other companies.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the system of the eluting agent of the column chromatography adopted by the purified compound and the developing agent system of the thin-layer chromatography include: A : dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-2

first step

( R )-4,4,4-trifluoro-3-methylbutyric acid benzyl ester 1b

Compound ( R )-4,4,4-trifluoro-3-methylbutanoic acid 1a (11.5g, 73.7mmol, prepared by the method disclosed in Example 18A of the patent application "US2012115863A1") and benzyl alcohol (8g, 73.9mmol) was dissolved in dichloromethane (300mL), diisopropylethylamine (29g, 224.4mmol) was added, cooled to 0°C, ethyl 2-oxime cyanoacetate (13.6g, 95.7mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (18.4g, 96.0mmol), then naturally warmed to room temperature and stirred for 10 hours. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (11 g, yield: 61%).

second step

(3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro-3-methylbutyric acid benzyl ester 1d (diastereoisomer mixture)

Solution A: Compound 1b (80mg, 0.324mmol) was dissolved in toluene (5mL), cooled to -20°C with a dry-ice acetone bath, and a tetrahydrofuran solution (1M, 974.14μL) of lithium bistrimethylsilylamide was added to the - Stir at 10°C for 15 minutes. Solution B: Compound 5-bromo-2,3-dihydro-1 H -indene 1c (64mg, 0.324mmol, Shanghai Pide Pharmaceutical Technology Co., Ltd.) was dissolved in toluene (5mL), and palladium acetate (8mg, 0.324mmol), 2-(2-dicyclohexylphosphinephenyl) -N , N -dimethylaniline (25mg, 0.063mmol), stirred at room temperature for 10 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, raise to room temperature and stir for 1 hour, heat to 85°C and stir for 3 hours, cool to room temperature and stir for 16 hours. After concentration, the residue was purified by silica gel column chromatography with eluent system C to obtain the title product 1d (mixture of diastereomers, 50 mg, yield: 42%).

third step

( 3R )-2-(2,3-dihydro- 1H -inden-5-yl)-4,4,4-trifluoro-3-methylbutanoic acid 1e (mixture of diastereoisomers)

Compound 1d (50 mg, 0.137 μmol) was dissolved in water (1 mL) and dioxane (5 mL), added with sodium hydroxide (20 mg, 0.50 mmol), and stirred at 50° C. for 16 hours. Concentrate, add 10 mL of water and 10 mL of dichloromethane, extract, and acidify the aqueous phase to pH 3 with 1M hydrochloric acid. Add 10 mL of ethyl acetate for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude title product 1e (diastereoisomer mixture, 37 mg), which was directly subjected to the next reaction without purification.

MS m/z (ESI): 271.2 [M-1].

the fourth step

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid tert-butyl ester 1g-1

or

( S )-3-(4-chloro-3-(( 2R ,3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro- 3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid tert-butyl ester 1g-2

Compound 1e (37mg, 0.135mmol), dissolved in dichloromethane (5mL), added 1-chloro- N , N , 2-trimethylacrylamine (27mg, 0.202mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) at room temperature , and stirred for 30 minutes. Add pyridine (32 mg, 0.404 mmol) and ( S )-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid tert-butyl ester 1f (39 mg, 0.131 mmol, using patent application "US20130079412A1" prepared by the method disclosed in Example 30A of the description)) dissolved in dichloromethane (1 mL) solution. Stir at room temperature for 30 minutes. After concentration, it was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g-1 or 1g-2 (70 mg, yield: 93%).

MS m/z (ESI): 572.0 [M+23].

the fifth step

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,3-dihydro-1 H -inden-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-2

Compound 1g-1 or 1g-2 (50 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), and 2 mL of trifluoroacetic acid was added at room temperature, and stirred for 1 hour. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid); acetonitrile; 15 minutes gradient: 65% -80%) was purified to obtain the title compound 1-1 or 1-2 (17 mg, yield: 38%).

MS m/z (ESI): 494.1 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 12.02(s,1H),9.70(s,1H),7.46(d,1H),7.34(dd,1H),7.30(s,1H),7.20(s ,2H),7.11-7.05(m,1H),4.05(d,1H),2.84(q,4H),2.67-2.53(m,3H),2.24(q,1H),2.06-1.94(m,2H ),0.93(s,1H),0.88-0.76(m,3H),0.49(s,1H),0.26(d,2H),0.06(s,1H).

Example 2

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyramide) Phenyl)-3-cyclopropylpropionic acid 2-1

or

( S )-3-(4-Chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyramide) Phenyl)-3-cyclopropylpropionic acid 2-2

first step

Benzyl ( 3R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butanoate 2b (mixture of diastereoisomers)

Solution A: Compound 1b (86mg, 0.349mmol), dissolved in toluene (5mL), cooled to -20°C with a dry ice acetone bath, added a tetrahydrofuran solution of lithium bistrimethylsilylamide (1M, 1mL), in- Stir at 10°C for 15 minutes. Solution B: Compound 2-bromonaphthalene 2a (71mg, 0.342mmol, Shanghai Pide Pharmaceutical Technology Co., Ltd.) was dissolved in toluene (5mL), and palladium acetate (8mg, 0.324mmol) and 2-(2-bicyclo Hexylphosphinephenyl)-N ,N -dimethylaniline (27mg, 0.068mmol), stirred at room temperature for 10 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, stir at room temperature for 1 hour, stir at 85 °C for 3 hours, and stir at room temperature for 16 hours. After concentration, the residue was purified by silica gel column chromatography with eluent system C to obtain the title product 2b (mixture of diastereomers, 50 mg, yield: 38%).

second step

(3 R )-4,4,4-Trifluoro-3-methyl-2-(naphthalen-2-yl)butanoic acid 2c (mixture of diastereomers)

Compound 2b (50 mg, 0.137 μmol) was dissolved in water (1 mL) and dioxane (5 mL), added with sodium hydroxide (40 mg, 1 mmol), and stirred at 50° C. for 16 hours. Concentrate, add 10 mL of water, 10 mL of dichloromethane, extract, and acidify the aqueous phase to pH 3 with 1M hydrochloric acid. Add 10 mL of ethyl acetate for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude title product 2c (mixture of diastereoisomers, 37 mg). The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 281.1 [M-1].

third step

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyramide) Phenyl)-3-cyclopropyl propanoic acid tert-butyl ester 2d-1

or

( S )-3-(4-Chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyramide) Phenyl)-3-cyclopropyl propanoic acid tert-butyl ester 2d-2

Compound 2c (37mg, 0.131mmol) was dissolved in dichloromethane (5mL), and 1-chloro- N , N ,2-trimethylacrylamine (26mg, 0.194mmol) was added at room temperature, and stirred for 30 minutes. A solution of pyridine (31 mg, 0.391 mmol) and compound If (38 mg, 0.128 mmol) dissolved in dichloromethane (1 mL) was added. Stir at room temperature for 30 minutes. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d-1 or 2d-2 (50 mg, yield: 68%).

MS m/z (ESI): 582.0 [M+23].

the fourth step

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyramide) Phenyl)-3-cyclopropylpropionic acid 2-1

or

( S )-3-(4-Chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyramide) Phenyl)-3-cyclopropylpropionic acid 2-2

Compound 2d-1 or 2d-2 (50 mg, 0.89 mmol) was dissolved in dichloromethane (5 mL), and 2 mL of trifluoroacetic acid was added at room temperature, and stirred for 1 hour. After concentration, use high-performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 67%-77 %) was purified to obtain the title compound 2-1 or 2-2 (40 mg, yield: 89%).

MS m/z (ESI): 504.1 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 12.01(s,1H),9.89(s,1H),8.05-7.84(m,4H),7.62(d,1H),7.57-7.48(m,2H) ,7.42(d,1H),7.33(dd,1H),7.08(dd,1H),4.28(d,1H),3.49(d,1H),2.66-2.54(m,2H),2.23(d,1H ),0.97-0.90(m,1H),0.84(dd,3H),0.52-0.42(m,1H),0.32-0.16(m,2H),0.04(q,1H).

Example 3

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl )-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 3-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl )-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 3-2

first step

(3 R )-2-(2,2-Difluorobenzo[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutanoic acid Benzyl ester 3b (mixture of diastereomers)

Solution A: Compound 1b (3.50 g, 14.21 mmol) was dissolved in toluene (100 mL). Cool to -20°C with a dry ice acetone bath, add 1M tetrahydrofuran solution (21.3 mL) of lithium bistrimethylsilylamide, and stir at -10°C for 15 minutes. Solution B: Compound 5-bromo-2,2-difluorobenzo[ d ][1,3]dioxolane 3a (3.68g, 15.53mmol) was dissolved in toluene (20mL), and acetic acid was added under nitrogen atmosphere Palladium (319 mg, 1.42 mmol), 2-(2-dicyclohexylphosphinephenyl) -N , N -dimethylaniline (1.12 g, 2.85 mmol), stirred at room temperature for 20 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, raise to room temperature and stir for 1 hour, heat to 80°C and stir for 3 hours, cool to room temperature and stir for 2 hours. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (mixture of diastereomers, 2.3 g, yield: 40.2%).

second step

(3 R )-2-(2,2-Difluorobenzo[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutanoic acid 3c (mixture of diastereoisomers)

Compound 3b (2.30g, 5.71mmol) was dissolved in water (6mL) and dioxane (30mL), added with sodium hydroxide (1.83g, 45.75mmol), and stirred at 60°C for 16 hours. Concentrate, add water (10mL), extract with dichloromethane (30mL), acidify the aqueous phase with 1M hydrochloric acid to pH 1~2, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, and wash with anhydrous sulfuric acid After drying over sodium, after filtration, the filtrate was concentrated to obtain the crude title product 3c (mixture of diastereomers, 888 mg), and the product was directly carried on to the next reaction without purification.

MS m/z (ESI): 311.2 [M-1].

third step

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl )-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanoic acid tert-butyl ester 3d-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl )-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropyl propanoic acid tert-butyl ester 3d-2

Compound 3c (888mg, 2.84mmol) was dissolved in dichloromethane (50mL), 1-chloro- N , N ,2-trimethylacrylamine (608mg, 4.55mmol) was added at room temperature, and stirred at room temperature for 30 minutes. A solution of pyridine (562 mg, 7.10 mmol) and compound If (841 mg, 2.84 mmol) in dichloromethane (5 mL) was added. Stir at room temperature for 30 minutes. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3d-1 or 3d-2 (1.22 g, yield: 72.7%).

MS m/z (ESI): 588.4 [M-1].

the fourth step

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl )-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 3-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl )-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 3-2

Compound 3d-1 or 3d-2 (280 mg, 0.47 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added at room temperature, and stirred for 2 hours. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid); acetonitrile, 15 minutes gradient: 65% -80%) to obtain the title compound 3-1 or 3-2 (105 mg, yield: 41.4%).

MS m/z (ESI): 534.1 [M+1].

¹ H NMR (500MHz, DMSO- d ₆ )δ 12.1-11.9(brs,1H),9.82(s,1H),7.51-7.48(m,1H),7.45-7.39(m,2H),7.38-7.33( m,1H),7.32-7.26(m,1H),7.13-7.04(m,1H),4.15(d,1H),3.37-3.32(m,1H),2.65-2.56(m,2H),2.29- 2.20(m,1H),0.99-0.90(m,1H),0.82(d,3H),0.53-0.44(m,1H),0.32-0.25(m,1H),0.24-0.18(m,1H), 0.10-0.02(m,1H).

Example 4

( S )-3-cyclopropyl-3-(3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5 -yl)-4,4,4-trifluoro-3-methylbutyrylamino)-4-methylphenyl)propionic acid 4-1

or

( S )-3-cyclopropyl-3-(3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5 -yl)-4,4,4-trifluoro-3-methylbutyrylamino)-4-methylphenyl)propionic acid 4-2

Compound 3-1 or 3-2 (30mg, 0.056mmol), trimethylboroxine (3M, 189μL, 0.565mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride ( 8mg, 0.012mmol), potassium phosphate (36mg, 0.169mmol) were mixed in a reaction flask, and xylene (2mL) and water (0.7mL) were added. Under nitrogen atmosphere, microwave heating to 150° C., stirring for 0.5 hours. After cooling and concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15-minute gradient: 65%-80%) to obtain the title compound 4-1 or 4-2 (13 mg, yield: 45%).

MS m/z (ESI): 512.1 [M-1].

¹ H NMR (500MHz, DMSO- d ₆ )δ 12.47-11.64(brs,1H),9.61(s,1H),7.51-7.45(m,1H),7.44-7.38(m,1H),7.30-7.24( m,1H),7.22-7.16(m,1H),7.11-7.06(m,1H),7.00-6.94(m,1H),4.00(d,1H),2.68-2.51(m,3H),2.25- 2.18(m,1H),1.97(s,3H),0.99-0.88(m,1H),0.82(d,3H),0.52-0.42(m,1H),0.30-0.24(m,1H),0.23- 0.14(m,1H),0.09-0.01(m,1H).

Example 5

( S )-3-(3-((2 S ,3 R )-2-(benzo[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 5-1

or

( S )-3-(3-((2 R ,3 R )-2-(benzo[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro -3-methylbutyrylamino (4-chlorophenyl)-3-cyclopropylpropionic acid 5-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by 4-bromo-1,2-methylenedioxybenzene to obtain the title compound 5-1 or 5-2 (5mg, yield 40% ).

MS m/z (ESI): 498.1 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 12.04(s,1H),9.72(s,1H),7.50-7.31(m,2H),7.22-7.08(m,2H),7.00(d,1H) ,6.92(s,1H),6.02(d,2H),4.03(d,1H),2.68-2.56(m,2H),2.29-2.22(m,1H),0.99-0.90(m,1H),0.83 (d,3H), 0.53-0.47(m,1H), 0.34-0.27(m,1H), 0.27-0.21(m,1H), 0.10-0.04(m,1H).

Example 6

3-(4-bromo-3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)-4, 4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 6-1

or

3-(4-bromo-3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)-4, 4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 6-2

first step

(4-Bromo-3-nitrophenyl)(cyclopropyl)methyl ketone 6b

(4-Bromophenyl) (cyclopropyl) methyl ketone 6a (5g, 22.2mmol), weighed in a reaction flask, cooled to -20°C, added fuming nitric acid (7.81g, 118mmol, 95%) to recover slowly Stir the reaction at 5-10°C for 2.5 hours, pour the reaction system into ice water, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (30mL×2), dry over anhydrous sodium sulfate, and filter. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6b (2.95 g, yield: 49%).

second step

tert-butyl 3-(4-bromo-3-nitrophenyl)-3-cyclopropylacrylate 6c (mixture of cis and trans isomers)

Under a nitrogen atmosphere, sodium hydride (309mg, 8.06mmol, purity 60%) was dispersed in dry tetrahydrofuran (6mL), cooled to 0°C, and then slowly added dropwise with tert-butyl diethylphosphonoacetate (1.82g , 7.22mmol) in tetrahydrofuran (10mL) and stirred at room temperature for 1 hour. Cool to 0°C again, slowly add compound 6b (1.5g, 5.56mmol) in tetrahydrofuran (10mL) solution dropwise, stir at room temperature for 8 hours, quench the reaction with saturated ammonium chloride aqueous solution (30mL), ethyl acetate (50mL× 3) Extraction, after merging the organic phases, washing with saturated brine (30mL), drying over anhydrous sodium sulfate, filtering, and concentrating, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6c (cis-trans isomers mixture, 1.62 g, yield: 79%).

third step

(±)-3-(3-Amino-4-bromophenyl)-3-cyclopropylpropionic acid tert-butyl ester 6d

Compound 6c (1.1 g, 2.98 mmol) was dissolved in ethyl acetate (50 mL), 10% palladium on carbon (233 mg, 0.119 mmol) was added, and the reaction was stirred for 18 hours under hydrogen atmosphere. After filtration and concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% ammonium bicarbonate); acetonitrile; 25 minutes Gradient: 65 %-80%) to obtain the title compound 6d (100 mg, yield: 10%).

the fourth step

3-(4-bromo-3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)-4, tert-butyl 4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanoate 6e-1 (mixture of diastereoisomers)

or

3-(4-bromo-3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)-4, tert-butyl 4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanoate 6e-2 (mixture of diastereoisomers)

Compound 3c (62mg, 0.197mmol) was dissolved in dichloromethane (2mL), 1-chloro- N , N ,2-trimethylacrylamine (29mg, 0.22mmol) was added at room temperature, and stirred at room temperature for 30 minutes. A solution of pyridine (57 mg, 0.72 mmol) and compound 6d (67 mg, 0.197 mmol) in dichloromethane (2 mL) was added and stirred at room temperature for 30 minutes. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6e-1 or 6e-2 (mixture of diastereomers, 45 mg, yield: 36%).

MS m/z (ESI): 634.3 [M-1].

the fifth step

3-(4-bromo-3-((2 S ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)-4, 4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 6-1 (mixture of diastereoisomers)

or

3-(4-bromo-3-((2 R ,3 R )-2-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)-4, 4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanoic acid 6-2 (mixture of diastereoisomers)

Compound 6e-1 or 6e-2 (55 mg, 0.086 mmol) was dissolved in dichloromethane (10 mL), and 1 mL of trifluoroacetic acid was added at room temperature, and stirred for 2 hours. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65% -80%)) to obtain the title product 6-1 or 6-2 (mixture of diastereomers, 15 mg, yield: 30%).

MS m/z (ESI): 578.0 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.47(d,1H),7.42-7.32(m,2H),7.30-7.24(m,1H),7.23-7.18(m,1H),7.12-7.02(m ,1H),3.99(d,1H),3.44-3.32(m,1H),2.72-2.61(m,1H),2.61-2.52(m,1H),2.41-2.22(m,1H),1.03-0.95 (m,1H),0.91(d,3H),0.61-0.49(m,1H),0.42-0.35(m,1H),0.35-0.28(m,1H),0.17-0.04(m,1H).

Example 7

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-dimethylbenzo[ d ][1,3]dioxol-5- Base)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 7-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-dimethylbenzo[ d ][1,3]dioxol-5- Base)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 7-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 5-bromo-2,2-dimethylbenzo[ d ][1,3]dioxolane to obtain the title compound 7- 1 or 7-2 (20 mg, yield: 45%).

MS m/z (ESI): 526.1 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.54(s,1H),7.33(d,1H),7.10(d,1H),6.88(s,1H),6.87(d,1H),6.73(d, 1H),3.88(d,1H),3.30-3.22(m,1H),2.79-2.65(m,2H),2.38-2.29(m,1H),1.67(s,3H),1.66(s,3H) ,1.08-0.99(m,1H),0.93(d,3H),0.64-0.56(m,1H),0.46-0.38(m,1H),0.36-0.29(m,1H),0.20-0.12(m, 1H).

Example 8

( S )-3-(3-((2 S ,3 R )-2-(benzo[ d ][1,3]dioxol-5-yl-2,2- d ₂ )-4 ,4,4-Trifluoro-3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 8-1

or

( S )-3-(3-((2 R ,3 R )-2-(benzo[ d ][1,3]dioxol-5-yl-2,2- d ₂ )-4 ,4,4-Trifluoro-3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 8-2

Using the synthetic route of Example 3, the raw material 3a of the first step is replaced by the compound 5-bromobenzo[ d ][1,3]dioxolane-2,2- d ₂ (which can be obtained from the compound 4-bromo-1 , 2-methylenedioxybenzene and deuterated dibromomethane hydrogen deuterium replacement) to obtain the title compound 8-1 or 8-2 (35mg, yield: 67%).

MS m/z (ESI): 500.1 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.53(s,1H),7.33(d,1H),7.10(d,1H),6.99(s,1H),6.93(d,1H),6.82(d, 1H),3.91(d,1H),3.31-3.27(m,1H),2.79-2.64(m,2H),2.37-2.29(m,1H),1.05-1.01(m,1H),0.92(d, 3H), 0.63-0.56(m, 1H), 0.45-0.38(m, 1H), 0.35-0.29(m, 1H), 0.18-0.11(m, 1H).

Example 9

( S )-3-(3-((2 R ,3 R )-2-(benzo[ b ]thiophen-2-yl)-4,4,4-trifluoro-3-methylbutyramide )-4-chlorophenyl)-3-cyclopropylpropionic acid 9-1

or

( S )-3-(3-((2 S ,3 R )-2-(benzo[ b ]thiophen-2-yl)-4,4,4-trifluoro-3-methylbutyramide )-4-chlorophenyl)-3-cyclopropylpropionic acid 9-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromobenzo[ b ]thiophene to obtain the title compound 9-1 or 9-2 (40 mg, yield: 40%).

MS m/z (ESI): 510.4 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 10.02(s,1H),7.95(d,1H),7.86(d,1H),7.50(d,1H),7.44(s,1H),7.41-7.33 (m,3H),7.13(dd,1H),4.62(d,1H),2.71-2.53(m,3H),2.30-2.23(m,1H),0.98(d,3H),0.96-0.91(m ,1H),0.53-0.47(m,1H),0.33-0.21(m,2H),0.08(m,1H).

Example 10

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(5-chlorothien-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 10-1

or

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(5-chlorothien-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 10-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-5-chlorothiophene to obtain the title compound 10-1 or 10-2 (15 mg, yield: 32%).

MS m/z (ESI): 492.2 [M-1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.58(d,1H),7.37(d,1H),7.14(dd,1H),6.95(d,1H),6.91(d,1H),4.32(d, 1H),3.21-3.12(m,1H),2.80-2.66(m,2H),2.40-2.32(m,1H),1.09-1.01(m,1H),1.04(d,3H),0.65-0.58( m, 1H), 0.48-0.40(m, 1H), 0.37-0.30(m, 1H), 0.21-0.13(m, 1H).

Example 11

( S )-3-(4-chloro-3-((2 S, 3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indole- 6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 11-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indole- 6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 11-2

first step

( 3R )-4,4,4-Trifluoro-3-methyl-2-(1-methyl- 1H -indol-6-yl)butanoic acid benzyl ester 11b (mixture of diastereoisomers )

Compound 1b (120mg, 0.487mmol), 6-bromo-1-methyl-1 H -indole 11a (102mg, 0.49mmol), palladium acetate (11mg, 0.049mmol) and 2-(2-dicyclohexylphosphine Phenyl) -N,N -dimethylaniline (29mg, 0.073mmol) was added to the reaction flask, under a nitrogen atmosphere, dry toluene (4mL) was added, stirred and dissolved for 10min, cooled to -20°C with a dry ice acetone bath, added A toluene solution (1 mL, 1 M) of lithium bistrimethylsilylamide was stirred at low temperature for 15 minutes, then heated to 85° C. and stirred for 5 hours. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 11b (mixture of diastereomers, 146 mg, yield: 80%).

second step

( 3R )-4,4,4-Trifluoro-3-methyl-2-(1-methyl- 1H -indol-6-yl)butanoic acid 11c (mixture of diastereoisomers)

Compound 11b (146mg, 0.389mmol) was dissolved in water (1mL) and dioxane (5mL), sodium hydroxide (78mg, 1.95mmol) was added, and the reaction was stirred at 60°C for 10 hours. Cool to room temperature, concentrate, add 10 mL of water, wash with dichloromethane (30 mL×3), acidify the aqueous phase with 1M hydrochloric acid to pH about 3, and extract with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product 11c (mixture of diastereomers, 102 mg).

third step

( S )-3-(4-chloro-3-((2 S, 3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indole- 6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 11-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indole- 6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 11-2

Compound 11c (50mg, 0.175mmol) was dissolved in dichloromethane (3mL), 1-chloro- N , N ,2-trimethylacrylamine (23mg, 0.175mmol) was added at room temperature, and stirred at room temperature for 30 minutes. Add pyridine (28mg, 0.35mmol) and ( S )-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropionic acid 11d (42mg, 0.175mmol, which can be desorbed from compound 1f via trifluoroacetic acid tertiary butyl acetate) in dichloromethane (2 mL) and stirred at room temperature for 1 hour. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65% -80%) was purified to obtain the title compound 11-1 or 11-2 (55 mg, yield: 62%).

MS m/z (ESI): 507.1 [M-1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.57(d,1H),7.53(s,1H),7.49(s,1H),7.30(d,1H),7.19(s,1H),7.15(d, 1H),7.08(d,1H),6.44(s,1H),4.07(d,1H),3.84(s,3H),3.46-3.38(m,1H),2.75-2.60(m,2H),2.37 -2.29(m,1H),1.06-0.97(m,1H),0.91(d,3H),0.63-0.55(m,1H),0.44-0.36(m,1H),0.35-0.29(m,1H) ,0.17-0.10(m,1H).

Example 12

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indazole- 6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 12-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indazole- 6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 12-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 6-bromo-1-methyl- 1H -indazole to obtain the title compound 12-1 or 12-2 (25mg, yield: 36%).

MS m/z (ESI): 506.1 [M-1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 9.84(s,1H),8.02(s,1H),7.74(d,1H),7.69(s,1H),7.42(d,1H),7.34(d ,1H),7.24(d,1H),7.08(dd,1H),4.24(d,1H),4.04(s,3H),3.53-3.43(m,1H),2.67-2.53(m,2H), 2.27-2.20(m,1H),0.97-0.89(m,1H),0.82(d,3H),0.51-0.44(m,1H),0.31-0.19(m,2H),0.08-0.02(m,1H ).

Example 13

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indazole- 5-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 13-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(1-methyl-1 H -indazole- 5-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 13-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 5-bromo-1-methyl- 1H -indazole to obtain the title compound 13-1 or 13-2 (40mg, yield: 27%).

MS m/z (ESI): 506.1 [M-1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 9.79(s,1H),8.07(s,1H),7.82(s,1H),7.64(d,1H),7.49(d,1H),7.43(s ,1H),7.34(d,1H),7.08(d,1H),4.21(d,1H),4.04(s,3H),3.46-3.38(m,1H),2.67-2.54(m,2H),2.28 -2.20(m,1H),0.97-0.89(m,1H),0.79(d,3H),0.52-0.45(m,1H),0.32-0.19(m,2H),0.09-0.02(m,1H) .

Example 14

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(5-chloropyridin-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 14-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(5-chloropyridin-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 14-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-5-chloropyridine to obtain the title compound 14-1 or 14-2 (18 mg, yield: 22%).

MS m/z (ESI): 489.1 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 9.94(s,1H),8.67(d,1H),8.00(dd,1H),7.64(d,1H),7.44(d,1H),7.36(d ,1H),7.11(dd,1H),4.33(d,1H),3.54-3.42(m,1H),2.65(dd,1H),2.58(dd,1H),2.29-2.22(m,1H), 0.99-0.90(m,1H),0.86(d,3H),0.53-0.46(m,1H),0.33-0.21(m,2H),0.10-0.04(m,1H).

Example 15

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(5-chloropyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 15-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(5-chloropyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 15-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-5-chloropyrimidine to obtain the title compound 15-1 or 15-2 (19 mg, yield: 26%).

MS m/z (ESI): 490.1 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 9.95(s,1H),9.02(s,2H),7.43(s,1H),7.36(d,1H),7.12(d,1H),4.48(d ,1H),3.54-3.46(m,1H),2.70-2.55(m,2H),2.29-2.22(m,1H),0.99(d,3H),0.88-0.84(m,1H),0.54-0.46 (m,1H), 0.35-0.21(m,2H), 0.10-0.04(m,1H).

Example 16

( S )-3-(3-((2 S ,3 R )-2-([1,1'-biphenyl]-4-yl)-4,4,4-trifluoro-3-methyl Butymidylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 16-1

or

( S )-3-(3-((2 R ,3 R )-2-([1,1'-biphenyl]-4-yl)-4,4,4-trifluoro-3-methyl Butymidylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 16-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 4-bromo-1,1'-biphenyl to obtain the title compound 16-1 or 16-2 (59 mg, yield: 46%) .

MS m/z (ESI): 530.2 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 12.02(s,1H),9.81(s,1H),7.70-7.65(m,3H),7.56-7.52(m,2H),7.48-7.43(m, 3H),7.37-7.33(m,2H),7.08(dd,1H),4.17(d,1H),3.44-3.35(m,1H),2.63(dd,1H),2.55(dd,1H),2.27 -2.20(m,1H),0.98-0.89(m,1H),0.84(d,3H),0.51-0.45(m,1H),0.31-0.19(m,2H),0.08-0.02(m,1H) .

Example 17

( S )-3-(3-((2 S ,3 R )-2-(4-(2 H -1,2,3-triazol-2-yl)phenyl)-4,4,4- Trifluoro-3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 17-1

or

( S )-3-(3-((2 R ,3 R )-2-(4-(2 H -1,2,3-triazol-2-yl)phenyl)-4,4,4- Trifluoro-3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 17-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-(4-bromophenyl)-2 H -1,2,3-triazole to obtain the title compound 17-1 or 17- 2 (39 mg, yield: 42%).

MS m/z (ESI): 521.1 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 9.89(s,1H),8.14(s,2H),8.07-8.02(m,2H),7.68-7.62(m,2H),7.44(d,1H) ,7.36(d,1H),7.11(dd,1H),4.21(d,1H),3.44-3.35(m,1H),2.68-2.54(m,2H),2.29-2.21(m,1H),0.99 -0.91(m,1H),0.85(d,3H),0.53-0.46(m,1H),0.33-0.20(m,2H),0.10-0.07(m,1H).

Example 18

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(8-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 18-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(8-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 18-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 7-bromo-1-chloronaphthalene to obtain the title compound 18-1 or 18-2 (50 mg, yield: 43%).

MS m/z (ESI): 536.0 [M-1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 12.02(s,1H),9.97(s,1H),8.31(s,1H),8.06(d,1H),7.96(d,1H),7.77-7.72 (m,2H),7.53(dd,1H),7.41(d,1H),7.35(d,1H),7.10(d,1H),4.40(d,1H),3.55-3.46(m,1H), 2.64(dd,1H),2.57(dd,1H),2.28-2.20(m,1H),0.98-0.90(m,1H),0.83(d,3H),0.52-0.45(m,1H),0.32- 0.19(m,2H),0.08-0.02(m,1H).

Example 19

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(7-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 19-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(7-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 19-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-7-chloronaphthalene to obtain the title compound 19-1 or 19-2 (40 mg, yield: 36%).

MS m/z (ESI): 538.2 [M+1].

¹ H NMR (500MHz, CDCl ₃ )δ 8.17(s,1H),7.89-7.68(m,4H),7.54(d,1H),7.45(d,1H),7.20(d,1H),6.90(s ,1H),3.89(d,1H),3.60-3.49(m,1H),2.88-2.56(m,2H),2.40-2.25(m,1H),0.98(d,3H),0.94-0.82(m ,1H),0.62-0.47(m,1H),0.46-0.34(m,1H),0.32-0.18(m,1H),0.15-0.04(m,1H).

Example 20

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(6-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 20-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(6-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 20-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-6-chloronaphthalene to obtain the title compound 20-1 or 20-2 (45 mg, yield: 35%).

MS m/z (ESI): 538.2 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 12.02(s,1H),9.92(s,1H),8.06(s,1H),8.02(s,1H),7.99(d,1H),7.94(d ,1H),7.69(d,1H),7.55(d,1H),7.42(s,1H),7.34(d,1H),7.10(d,1H),4.29(d,1H),3.55-3.45( m,1H),2.64(dd,1H),2.56(dd,1H),2.28-2.20(m,1H),0.96-0.92(m,1H),0.82(d,3H),0.52-0.45(m, 1H), 0.32-0.19(m, 2H), 0.08-0.02(m, 1H).

Example 21

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(5-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 21-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(5-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutyryl Amino)phenyl)-3-cyclopropylpropionic acid 21-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 6-bromo-1-chloronaphthalene to obtain the title compound 21-1 or 21-2 (60 mg, yield: 52%).

MS m/z (ESI): 536.2 [M-1].

¹ H NMR (500MHz, CD ₃ OD) δ 8.28(d,1H),8.03(d 1H),7.87(d,1H),7.77(dd,1H),7.63(d,1H),7.51-7.46(m ,2H),7.31(d,1H),7.09(dd,1H),4.22(d,1H),3.56-3.46(m,1H),2.73(dd,1H),2.66(dd,1H),2.34- 2.28(m,1H),1.06-0.96(m,1H),0.92(d,3H),0.62-0.54(m,1H),0.43-0.35(m,1H),0.33-0.27(m,1H), 0.17-0.10(m,1H).

Example 22

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,3-dihydro-1 H -inden-2-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 22-1

or

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydro-1 H -inden-2-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 22-2

first step

Benzyl (3R)-4,4,4-trifluoro-2-( 1H -inden-2-yl)-3-methylbutyrate 22b (mixture of diastereoisomers)

Compound 1b (100mg, 0.406mmol), 2-bromo-1 H -indene 22a (195mg, 0.425mmol), palladium acetate (9mg, 0.040mmol) and 2-(2-dicyclohexylphosphinephenyl) -N, Add N -dimethylaniline (31mg, 0.078mmol) into the reaction flask, under nitrogen atmosphere, add dry toluene (4mL), stir and dissolve for 10 minutes, cool to -20°C with dry ice acetone bath, add bistrimethylsilane A toluene solution of lithium amide (0.6 mL, 1 M) was stirred at low temperature for 15 minutes, then heated to 85° C. and stirred for 5 hours. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 22b (mixture of diastereomers, 109 mg, yield: 75%).

second step

( 3R )-2-(2,3-dihydro- 1H -inden-2-yl)-4,4,4-trifluoro-3-methylbutanoic acid 22c (mixture of diastereomers)

Compound 22b (109 mg, 0.302 mmol) was dissolved in ethyl acetate (5 mL) and methanol (5 mL), 10% palladium on carbon (32 mg, 0.032 mmol) was added, and the reaction was stirred for 8 hours under hydrogen atmosphere. Concentration by filtration afforded crude product 22c (mixture of diastereoisomers, 46 mg, yield: 56%).

third step

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,3-dihydro-1 H -inden-2-yl)-4,4,4-trifluoro -3-Methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid tert-butyl ester 22d-1

or

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydro-1 H -inden-2-yl)-4,4,4-trifluoro -3-Methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid tert-butyl ester 22d-2

Compound 22c (46mg, 0.169mmol) was dissolved in dichloromethane (2mL), 1-chloro- N , N ,2-trimethylacrylamine (23mg, 0.175mmol) was added at room temperature, and stirred at room temperature for 30 minutes. A solution of pyridine (40 mg, 0.505 mmol) and compound 1f (50 mg, 0.169 mmol) in dichloromethane (2 mL) was added and stirred at room temperature for 1 hour. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% ammonium bicarbonate), acetonitrile; 15 minutes gradient: 65% -80%) was purified to obtain the title compound 22d-1 or 22d-2 (10 mg, yield: 11%).

the fourth step

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,3-dihydro-1 H -inden-2-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 22-1

or

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydro-1 H -inden-2-yl)-4,4,4-trifluoro -3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 22-2

Compound 22d-1 or 22d-2 (10 mg, 0.018 mmol) was dissolved in dichloromethane (4 mL), and 2 mL of trifluoroacetic acid was added at room temperature, and stirred for 2 hours. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65% -80%) to obtain the title compound 22-1 or 22-2 (3 mg, yield: 33%).

MS m/z (ESI): 494.2 [M+1].

¹ H NMR (500MHz,DMSO- d ₆ )δ 9.75(s,1H),7.74-7.65(m,1H),7.35(d,1H),7.24-7.14(m,2H),7.12-7.05(m, 2H),6.65(s,1H),4.13(d,1H),3.13-3.05(m,2H),3.04-2.79(m,4H),2.29-2.23(m,1H),2.00-1.94(m, 1H),1.48-1.41(m,1H),0.92-0.88(m,1H),0.86(d,3H),0.49-0.42(m,1H),0.30-0.19(m,2H),0.06-0.01( m, 1H).

Example 23

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(quinolin-7-yl)butyramide )Phenyl)-3-cyclopropylpropionic acid 23-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(quinolin-7-yl)butyramide )Phenyl)-3-cyclopropylpropionic acid 23-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 7-bromoquinoline to obtain the title compound 23-1 or 23-2 (25 mg, yield: 29%).

MS m/z (ESI): 505.1 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 9.16(d,1H),9.02(d,1H),8.40(s,1H),8.31(d,1H),8.07(d,1H),7.98(s, 1H),7.50(s,1H),7.31(d,1H),7.11(d,1H),4.41(d,1H),3.60-3.50(m,1H),2.74(dd,1H),2.66(dd ,1H),2.34-2.27(m,1H),1.05-0.98(m,1H),0.95(d,3H),0.63-0.53(m,1H),0.44-0.24(m,2H),0.18-0.07 (m,1H).

Example 24

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-2-(isoquinolin-3-yl)-3-methylbutanamide Base) phenyl) -3-cyclopropylpropionic acid 24-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-2-(isoquinolin-3-yl)-3-methylbutanamide Base) phenyl) -3-cyclopropylpropionic acid 24-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 3-bromoisoquinoline to obtain the title compound 24-1 or 24-2 (15 mg, yield: 31%).

MS m/z (ESI): 505.4 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 9.42(s,1H),8.22(d,1H),8.06(s,1H),8.03(d,1H),7.93-7.89(m,1H),7.81- 7.77(m,1H),7.75(s,1H),7.32(d,1H),7.08(d,1H),4.33(d,1H),3.68-3.57(m,1H),2.75(dd,1H) ,2.67(dd,1H),2.36-2.28(m,1H),1.00(d,3H),0.95-0.88(m,1H),0.63-0.55(m,1H),0.44-0.28(m,2H) ,0.17-0.11(m,1H).

Example 25

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(quinolin-3-yl)butyramide )Phenyl)-3-cyclopropylpropionic acid 25-1

or

( S )-3-(4-Chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(quinolin-3-yl)butyramide )Phenyl)-3-cyclopropylpropionic acid 25-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 3-bromoquinoline to obtain the title compound 25-1 or 25-2 (30 mg, yield: 33%).

MS m/z (ESI): 505.5 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 9.15(s,1H),8.83(s,1H),8.20-8.14(m,2H),8.02-7.97(m,1H),7.86-7.81(m,1H ),7.53(s,1H),7.34(d,1H),7.13(d,1H),4.40(d,1H),3.66-3.55(m,1H),2.79-2.63(m,2H),2.36- 2.27(m,1H),1.02(d,3H),0.95-0.88(m,1H),0.63-0.55(m,1H),0.44-0.27(m,2H),0.17-0.10(m,1H).

Example 26

( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,3-dihydrobenzo[ b ][1,4]dioxan-6-yl)- 4,4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 26-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,3-dihydrobenzo[ b ][1,4]dioxan-6-yl)- 4,4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 26-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by 6-bromo-1,4-benzodioxane to obtain the title compound 26-1 or 26-2 (30mg, yield: 25% ).

MS m/z (ESI): 512.2 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.53(s,1H),7.33(d,1H),7.10(d,1H),6.97(s,1H),6.91(d,1H),6.84(d, 1H),4.26(s,4H),3.86(d,1H),3.30-3.21(m,1H),2.75(dd,1H),2.68(dd,1H),2.36-2.30(m,1H),1.07 -0.99(m,1H),0.91(d,3H),0.64-0.56(m,1H),0.46-0.38(m,1H),0.36-0.28(m,1H),0.19-0.12(m,1H) .

Example 27

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro -2H -Benzo[ b ][1,4]oxazin-7-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 27-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro -2 H -benzo[ b ][1,4]oxazin-7-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 27-2

Using the synthetic route of Example 3, replace the raw material 3a of the first step with 7-bromo-4-methyl-3,4-dihydro- 2H -1,4-benzo[ b ][1,4] Oxazine, the title compound 27-1 or 27-2 (30 mg, yield: 27%) was obtained.

MS m/z (ESI): 525.1 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.54(s,1H),7.33(d,1H),7.09(d,1H),6.88(d,1H),6.81(s,1H),6.72(d, 1H),4.32-4.29(m,2H),3.79(d,1H),3.44-3.37(m,1H),3.28-3.24(m,2H),2.90(s,3H),2.75(dd,1H) ,2.68(dd,1H),2.36-2.30(m,1H),1.07-1.00(m,1H),0.91(d,3H),0.63-0.56(m,1H),0.46-0.38(s,1H) ,0.37-0.29(m,1H),0.19-0.12(s,1H).

Example 28

( S )-3-(4-chloro-3-((2 S ,3 R )-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro -2H -Benzo[ b ][1,4]oxazin-6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 28-1

or

( S )-3-(4-chloro-3-((2 R ,3 R )-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro -2 H -benzo[ b ][1,4]oxazin-6-yl)butyrylamino)phenyl)-3-cyclopropylpropionic acid 28-2

Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 6-bromo-4-methyl-3,4-dihydro- 2H -benzo[ b ][1,4]oxazine, The title compound 28-1 or 28-2 (20 mg, yield: 32%) was obtained.

MS m/z (ESI): 525.6 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.54(s,1H),7.33(d,1H),7.10(d,1H),6.81(s,1H),6.71-6.60(m,2H),4.30- 4.24(m,2H),3.83(d,1H),3.38-3.34(m,1H),3.29-3.24(m,2H),2.91(s,3H),2.75(dd,1H),2.68(dd, 1H),2.37-2.30(m,1H),1.08-0.99(m,1H),0.92(d,3H),0.65-0.56(m,1H),0.46-0.38(m,1H),0.36-0.29( m,1H), 0.19-0.12(m,1H).

Example 29

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-difluorobenzene And[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanyl )oxy)-3,4,5-trihydroxytetrahydro- 2H -pyran-2-carboxylic acid 29-1

or

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-difluorobenzene And[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanyl )oxy)-3,4,5-trihydroxytetrahydro- 2H -pyran-2-carboxylic acid 29-2

first step

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-difluorobenzene And[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanyl )oxy)-3,4,5-trihydroxytetrahydro- 2H -pyran-2-carboxylic acid allyl ester 29b-1

or

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-difluorobenzene And[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanyl )oxy)-3,4,5-trihydroxytetrahydro- 2H -pyran-2-carboxylic acid allyl ester 29b-2

Compound 3-1 or 3-2 (90 mg, 0.169 mmol) and (2 S ,3 S ,4 S ,5 R )-3,4,5,6-tetrahydroxytetrahydro-2 H -pyran-2 - allyl carboxylate 29a (40mg, 0.169mmol, prepared by the synthesis method of compound 2 in " Journal of Organic Chemistry 2006, 71(26), 9628-9636") was dissolved in acetonitrile (8mL), followed by Add N -methylmorpholine (60mg, 0.591mmol), O- (7-azabenzotriazol-1-yl) -N , N , N ', N' -tetramethyluronium hexafluorophosphate ( 77mg, 0.202mmol), stirred at room temperature for 10 hours, added acetic acid (41mg, 0.676mmol) to quench the reaction, concentrated directly, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 29b-1 or 29b-2 (57 mg, yield: 45%).

second step

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 S ,3 R )-2-(2,2-difluorobenzene And[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanyl )oxy)-3,4,5-trihydroxytetrahydro- 2H -pyran-2-carboxylic acid 29-1

or

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 R ,3 R )-2-(2,2-difluorobenzene And[ d ][1,3]dioxol-5-yl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanyl )oxy)-3,4,5-trihydroxytetrahydro- 2H -pyran-2-carboxylic acid 29-2

Compound 29b-1 or 29b-2 (15 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), cooled to 0° C., tetrakis(triphenylphosphine) palladium (4 mg, 0.004 mmol) and tetrahydropyrrole (4 mg, 0.04 mmol), stirred and reacted for 1 hour, concentrated the residue with high performance liquid chromatography (Waters SQD2, chromatographic column: Welch Xtimate C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile ; 17 minutes gradient: 35%-95%) and purified to obtain the title compound 29-1 or 29-2 (5 mg, yield: 35%).

MS m/z (ESI): 708.0 [M-1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.50-7.44(m,1H),7.40-7.37(m,1H),7.36-7.27(m,2H),7.25-7.20(m,1H),7.18-7.12 (m,1H),5.40-5.34(m,1H),4.07-3.99(m,1H),3.66-3.54(m,1H),3.52-3.37(m,4H),2.92-2.74(m,2H) ,2.46-2.37(m,1H),1.11-1.00(m,1H),0.92(d,3H),0.64-0.55(m,1H),0.46-0.32(m,2H),0.19-0.11(m, 1H).

Example 30

(2 S ,3 S ,4 S ,5 R )-6-((( S )-3-(4-chloro-3-((2 S ,3 R )-2-(4-chlorophenyl)- 4,4,4-Trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropionyl)oxy)-3,4,5-trihydroxytetrahydro- 2H -pyridine Fran-2-carboxylic acid 30

Using the synthetic route of Example 29, the raw material 3-1 or 3-2 of the first step is replaced by ( S )-3-(4-chloro-3-((2 S ,3 R )-2-(4- Chlorophenyl)-4,4,4-trifluoro-3-methylbutyrylamino)phenyl)-3-cyclopropylpropanoic acid (Runcaciguat, reference " Journal of Medicinal Chemistry 2021, 64(9) , 5323-5344" by the synthesis method of compound 45), and the title compound 30 (20 mg, yield: 30%) was obtained.

MS m/z (ESI): 662.0 [M-1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.54-7.44(m,3H),7.44-7.37(m,2H),7.34-7.27(m,1H),7.16-7.08(m,1H),5.48-5.38 (m,1H),4.08-3.83(m,2H),3.61-3.50(m,1H),3.48-3.37(m,3H),2.96-2.76(m,2H),2.46-2.32(m,1H) ,1.10-0.98(m,1H),0.90(d,3H),0.66-0.56(m,1H),0.47-0.30(m,2H),0.19-0.09(m,1H).

biological evaluation

Test Example 1. The Compounds of the Present Disclosure have the Stimulating and/or Initiating Effects of cGMP on CHO-K1 Cells Overexpressing sGC

The following method is used to determine the reaction of the disclosed compounds in the presence of heme-dependent sGC inhibitor 1H-1,2,4-oxadiazolo-(4,3a)-quinoxalin-1-one (ODQ) CHO-K1 cells expressing sGC produce agonistic and/or priming effects of cGMP. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1. CHO-K1/sGC (Shanghai Hengrui Pharmaceutical Co., Ltd., NA)

2. cGMP kit (cisbio, 62GM2PEH)

3. 384-well plate (Corning, 4513)

4. U-bottom 96-well plate (Corning, 3795)

5. Earle's Balanced Salt Solution (EBSS) (Shanghai Yuanpei Biotechnology Co., Ltd., B610KJ)

6. 3-isobutyl-1-methylxanthine (IBMX) (sigma, I7018-1G)

7. BSA (Sangon Bioengineering Co., Ltd., 9048-46-8)

8. MgCl ₂ (sigma, 68475-100ML-F)

9. HEPES (Gibco, 15630-080)

10. DMEM/F12 medium (GE, SH30023.01)

11. G418. Sulfate (ENZO, ALX-380-013-G005)

12. Hygromycin B (Thermo, 10687-010)

13. Microplate reader (BMG, PHERAsta)

14. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

2. Experimental steps

CHO-K1/sGC cells were cultured in complete medium (DMEM/F12 medium containing 10% FBS, 1 mg/mL G418, 200 μg/mL Hygromycin B), passaged 2 to 3 times a week, and the passage ratio was 1:8 or 1:15. For subculture, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200rpm for 3 minutes, discard the supernatant medium residue, and resuspend the cells with complete medium.

During the experiment, digest the cells with trypsin, centrifuge to discard the supernatant, wash the cells once with the experimental buffer (EBSS contains 5mM MgCl ₂ , 10mM HEPES, 0.05%BSA, 500μM IBMX), centrifuge and discard the residual liquid, and use the experimental buffer to resuspend the cells. After counting with a cell counter, adjust the density to 2×10 ⁶ cells/mL, and add 5 μL/well into a 384-well plate. Then, 2 μL/well of ODQ diluted to 0.5 mM with experimental buffer was added to the ODQ experimental wells, and incubated in a 37° C. incubator for 30 minutes. The sample to be tested was diluted to 1.11mM with DMSO, then 3-fold serially diluted to 10 concentrations, and blank wells were set. Take 3 μL of the test compound solution prepared in gradient concentration and add it to 97 μL of the test buffer to prepare the compound-containing test buffer. Take 3 μL of the above compound-containing experimental buffer and add it to a 384-well plate, and incubate in a 37° C. incubator for 30 minutes. Then the experiments were carried out according to the instructions of the cGMP kit. The signal value was read with the HTRF program of the PHERAstar microplate reader, and the data was processed with GraphPad software. The test results are shown in Table 1.

Table 1 The agonistic and/or initiating effects of the disclosed compounds on cGMP produced by CHO-K1 cells overexpressing sGC

Conclusion: The compounds disclosed in this disclosure have a strong cGMP agonistic and/or initiating effect on CHO-K1 cells overexpressing sGC.

Test Example 2. Induction activity of the compound disclosed in this disclosure on cytochrome P450 isoenzyme CYP3A4 in the recombinant human liver cell line HepG2.

Pregnane X receptor (PXR), a member of the nuclear receptor family, is the main transcriptional regulator that induces the expression of cytochrome P450 isoenzyme CYP3A4, which can be activated by a variety of exogenous substances. PXR functions by combining with the retinoid X receptor (RXR) to form a heterodimer. PXR-RXR combines with the upstream regulatory sequence of the CYP3A4 gene to up-regulate the expression of CYP3A4. The two promoters of the CYP3A4 gene were selected and cloned upstream of the luciferase gene, and the human liver cancer cell line HepG2 was co-transfected with a plasmid containing the human PXR gene to construct a luciferase reporter gene system. The light signal detects the CYP3A4-inducing activity of the compound.

The experimental method is briefly described as follows:

1. Reagents and instruments

(1) pcDNA3.1-hPXR plasmid and pGL4.17-CYP3A4-5'promoter-luc plasmid (internal construction, reference is "Biochemical Pharmacology 2004, 68(12), 2347-2358")

(2) Fetal Bovine Serum (FBS) (Thermo Fisher Scientific, 10099-141)

(3) 0.25% Trypsin-EDTA (1x), phenol red (Thermo Fisher Scientific, 25200-072)

(4) HepatoZYME-SFM (Thermo Fisher Scientific, 17705-021)

(5) MEM (EBSS) (GE Healthcare Life Sciences, SH30024.01)

(6) Lipofectamine® 3000 transfection reagent (Thermo Fisher Scientific, L3000001)

(7) ONE-Glo ^TM Luciferase Assay System (Promega, E6110)

(8) DMSO (Shanghai titanchem, G75927B)

(9) HepG2 (ATCC, HB8065)

(10) Poly-D-Lysine 96-well microplate, black/clear (BD, 356692)

(11) 96-well U-bottom plate (Corning, 3795)

(12) Opti-MEM ^TM I reduced serum medium (Thermo Fisher Scientific, 31985070)

(13) Microplate reader (PerkinElmer, VICTOR3)

(14) Rifampicin (Sigma, R3501)

2. Experimental steps

(1) Cell culture and plating

On the first day of the experiment, HepG2 cells were fully digested with 0.25% Trypsin-EDTA, resuspended into a single cell suspension after centrifugation, and the viable cell density was adjusted to 2×10 ⁵ cells/mL with cell culture medium (EMEM+10%FBS) , add 100 μL/well to a 96-well cell culture plate (BD, 356692), and culture overnight in an incubator (37°C, 5% CO ₂ ).

(2) Cell transfection

Cells were co-transfected with a CYP3A4 plasmid (pGL4.17-CYP3A4-5'promoter-luc) and a PXR plasmid (pcDNA3.1-hPXR) with Lipofectamine® 3000 transfection reagent. Take a centrifuge tube, add 400 μL Opti-MEM, then add 6.4 μg of CYP3A4 plasmid and 1.6 μg of PXR plasmid, add 16 μL of P3000 reagent, and gently pipette up and down to mix. Take another centrifuge tube, add 400 μL Opti-MEM, then add 24 μL Lipofectamine® 3000 transfection reagent, mix thoroughly, and place at room temperature for 5 minutes, mix the liquids in the two centrifuge tubes, and place at room temperature for 10 minutes. Take out the cell culture plate, replace with 100 μL/well of fresh culture medium (EMEM+10%FBS), then add 10 μL/well of the above plasmid mixture, and culture at 37°C, 5% CO ₂ for 24 hours.

(3) Sample preparation and dosing

Positive control Rifampicin and test compound solution were prepared with 20mM concentration in DMSO;

Take 10 μL of the positive control Rifampicin and the test compound solution at a concentration of 20 mM, add them to a 96-well U-bottom plate, then add 40 μL DMSO, mix well, dilute to 4 mM, then take 10 μL of the 4 mM solution into 90 μL DMSO, mix well, Dilute to 0.4mM, take 5μL of the above 4mM and 0.4mM solutions into 195μL HepatoZYME-SFM medium, and prepare 10× compound solutions with concentrations of 100μM and 10μM. In addition, take 5 μL DMSO to a 96-well U-bottom plate, add 195 μL HepatoZYME-SFM medium, and dilute to 2.5% DMSO.

Take out the cell culture plate, replace the culture medium with 90 μL/well of HepatoZYME-SFM, then add 10 μL/well of 10× compound solution, the final concentration of the compound is 10 μM and 1 μM, the positive control is 10 μM Rifampicin, and the negative control is 0.25% DMSO. Incubate for 24 hours at 37°C, 5% CO ₂ .

(4) Plate reading

Add 50 μL/well ONE-Glo reagent to a 96-well cell culture plate, place it in a dark place at room temperature for 5 minutes, and read the chemiluminescence value on a microplate reader (PerkinElmer, VICTOR3).

(5) Data processing

The data were processed in the GraphPad Prism8 software. First, the average value of the negative control (0.25% DMSO) chemiluminescence (RLU) was calculated, and the average value of the RLU of each concentration of the test compound was divided by the average value of the negative control RLU to obtain the induction factor ( Fold of induction), the induction fold of the positive control 10 μM Rifampicin should be greater than or equal to 7, the induction fold was subtracted from 1 to obtain the induction increase fold (Fold increase above DMSO control), and the induction increase fold of each concentration of the test compound was divided by the positive control 10 μM The induction increase factor of rifampicin is multiplied by 100%, and the induction increase factor of each concentration of the test compound accounts for the percentage of the induction increase factor of 10μM rifampicin, and the induction ability of the compound is judged according to the induction increase factor percentage of the 10μM compound, and less than 15% is no Induction (Negative), greater than or equal to 15% and less than 40% are weak induction (Weak), greater than or equal to 40% and less than 69% are moderate induction (Moderate), and greater than or equal to 70% are strong induction (Strong).

3. Experimental results

Using 10 μM Rifampicin as a positive control and 0.25% DMSO as a negative control, the in vitro PXR-initiating/CYP3A4-inducing activity of the test compound was detected using the HepG2 luciferase reporter gene system.

。 Compound Runcaciguat (compound 45 in the reference " Journal of Medicinal Chemistry 2021,64(9), 5323-5344"), the structure is:

.

Table 2 In vitro PXR-initiating/CYP3A4-inducing activity of the disclosed compounds

Conclusion: The disclosed compound does not induce CYP3A4 in the HepG2 luciferase reporter gene system, while Runcaciguat induces it to a moderate degree, suggesting that the disclosed compound has no potential induction effect on CYP3A4 in the evaluation of drug interaction. Drugs metabolized by CYP3A4 have the advantage of being safer.

Test Example 3. Test of Glutathione Addition Products of Compounds of the Disclosure

1. Experimental materials and instruments

Phosphate buffer (20×PBS, purchased from Shenggong)

Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

Human liver microsomes (Corning Gentest, Lot No.9050002, Donor, 35)

ACQUITY BEH C ₁₈ column, 2.1×100mm, 1.7μm (Waters, USA)

Glutathione (hereinafter referred to as GSH, SIGMA, Lot No.: SLBW3322)

Quality Control Control Compound (Diclofenac, SIGMA, Lot No.: BCBB7312)

Dionex U3000 Q-Exactive Orbitrap Tandem High Resolution Mass Spectrometer (Thermo Fisher Scientific)

2. Experimental steps

2.1. Preparation of the test compound solution: Take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve it, and mix well to prepare a stock solution with a concentration of 30mM. The stock solution with a concentration of 30 mM was diluted 10 times with 50% acetonitrile/water ( v/v ) to obtain a working solution 1 with a concentration of 3.0 mM. Working solution 1 with a concentration of 3.0 mM was diluted 10 times with PBS to obtain working solution 2 at 300 μM.

2.2. Preparation of liver microsome solution: Take an appropriate amount of liver microsome stock solution (concentration: 20mg/mL) and dilute it to 1.43mg/mL microsome solution with 100mM phosphate buffer (pH 7.4).

2.3. Preparation of NADPH cofactor solution: Weigh an appropriate amount of NADPH and magnesium chloride and dissolve in an appropriate amount of 100mM phosphate buffer (pH 7.4), so that the concentrations of NADPH and magnesium chloride are 10mM and 30mM respectively.

2.4. Preparation of GSH solution: Weigh an appropriate amount of GSH, dissolve it in an appropriate amount of phosphate buffer (pH 7.4) with a concentration of 100 mM, and prepare a solution with a concentration of 50 mM.

2.5. In vitro incubation: Precisely pipette 40 μL of the test compound working solution 2 with a concentration of 300 μM, add it to a 1.5 mL centrifuge tube, and then add 280 μL of a liver microsome solution with a concentration of 1.43 mg/mL, so that the liver microsomes in the incubation system The protein concentration was 1 mg/mL. After adding 40 μL of NADPH solution with a concentration of 10 mM and 40 μL of GSH solution with a concentration of 50 mM, put it into a constant temperature incubator at 37° C. for shaking incubation, and start timing. After 60 minutes of incubation, the incubation samples were taken out from the incubator, and 1000 μL of ice-cold acetonitrile solution was added to terminate the reaction and left at room temperature for 10 minutes, then centrifuged at 12000 rpm for 10 minutes. Pipette all supernatants into centrifuge tubes and concentrate to dryness in vacuo at 37°C. The residue was redissolved in 200 μL of 25% acetonitrile/water solution, centrifuged at 12000 rpm for 10 min, the supernatant was transferred to a 1.5 mL centrifuge tube, and 10 μL was drawn for LC/MS analysis. For the blank sample, add 40 μL PBS instead of working solution 2 of the test compound. The positive control diclofenac (10 μM) was the same as the test compound.

Use MetWorks or Compound discoverer software to process the collected data and screen for potential GSH binders.

Table 3 Glutathione addition test results of the disclosed compounds

Conclusion: Compound 29-1 or 29-2 is the metabolite of compound 3-1 or 3-2, and 30 is the metabolite of compound Runcaciguat. The metabolites of the compounds disclosed in this disclosure do not interact with GSH in cells in vivo Covalent binding with free sulfhydryl-containing proteins is less likely to cause cytotoxicity, and it has better safety than Runcaciguat.

Claims (27)

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof,

in, R ⁰ is a hydrogen atom or

; Preferably, R ⁰ is a hydrogen atom or

; Z is N or ^CR4 ; G is N or CR ^4a ; R ¹ and R ² and the connected carbon atoms form ring A', or R ² and R ³ and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl, Aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl , alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cyano, pendant oxy, alkenyl, alkynyl, -NR ^12a R ^12b , -NHC(O)R ¹³ , -C( One or more identical or different substituents in O) R ¹³ and -C(O)OR ¹³ are substituted; When R ¹ and R ² and the attached carbon atom form ring A', R ³ is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine and nitro; When ^R2 and ^R3 and the attached carbon atom form ring A, ^R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano group, amine group and nitro group; R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro; R ⁵ and R ⁶ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; Wherein the alkyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group and heterocyclic group are each independently selected from one or more of alkenyl, alkynyl, cyano, amino, nitro and ^R Substituting with the same or different substituents; or R ⁵ and R ⁶ and the connected carbon atoms form a cycloalkyl or heterocyclic group; R ^b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro Substitution by one or more identical or different substituents; Each ^R is the same or different, and is independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine, and nitro; ^R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl; ^R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or ^R8 and ^R9 and the connected carbon atom form cycloalkyl or heterocyclyl; R ¹⁰ and R ¹¹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl; R ^12a and R ^12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R ^12a and R ^12b form a heterocyclic group together with a connected nitrogen atom; ^R is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; n is 0, 1, 2, 3 or 4. The compound represented by the general formula (M) or its pharmaceutically acceptable salt as described in Claim 1, which is the compound represented by the general formula (I) or its pharmaceutically acceptable salt:

in, G is N or CR ^4a ; R ¹ and R ² and the connected carbon atoms form ring A', or R ² and R ³ and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl, Aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy In radical, hydroxyalkyl, cyano, pendant oxy, alkenyl, alkynyl, -NR ^12a R ^12b , -NHC(O)R ¹³ , -C(O)R ¹³ and -C(O)OR ¹³ Substitution by one or more identical or different substituents; When R ¹ and R ² and the attached carbon atom form ring A', R ³ is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine and nitro; When ^R2 and ^R3 and the attached carbon atom form ring A, ^R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano group, amine group and nitro group; R ⁴ and R ^4a are the same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro; R ⁵ and R ⁶ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; Wherein the alkyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group and heterocyclic group are each independently selected from one or more of alkenyl, alkynyl, cyano, amino, nitro and ^R Substituting with the same or different substituents; or R ⁵ and R ⁶ and the connected carbon atoms form a cycloalkyl or heterocyclic group; R ^b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro Substitution by one or more identical or different substituents; Each ^R is the same or different, and is independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amine, and nitro; ^R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl; ^R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or ^R8 and ^R9 and the connected carbon atom form cycloalkyl or heterocyclyl; R ¹⁰ and R ¹¹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl; R ^12a and R ^12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R ^12a and R ^12b form a heterocyclic group together with a connected nitrogen atom; ^R is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; n is 0, 1, 2, 3 or 4. The compound represented by the general formula (M) or its pharmaceutically acceptable salt as described in Claim 1 or 2, which is the compound represented by the general formula (II) or its pharmaceutically acceptable salt:

in, Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R ^2a is the same or different and is independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, pendant oxy, alkenyl, alkynyl, -NR ^12a R ^12b , -NHC(O)R ¹³ , -C(O)R ¹³ and -C(O)OR ¹³ ; m is 0, 1, 2, 3 or 4; G, R ¹ , R ⁴ to R ¹¹ , R ^12a , R ^12b , R ¹³ and n are as defined in claim 1. The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ⁶ , R ⁹ and R ¹¹ are the same or different, and each independently represents hydrogen atom or C _1-6 alkyl. A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, which is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

in, G is CR ^4a ; Ring A, R ^2a , R ^4a , R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹⁰ , m and n are as defined in Claim 3. The compound represented by general formula (M) or its pharmaceutically acceptable salt as described in any one of claims 1 to 5, which is represented by general formula (IV-1) or general formula (IV-2) Compound or its pharmaceutically acceptable salt:

in, R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in the group, amino group and nitro group; G is CR ^4a ; Ring A, R ^2a , R ^4a , R ¹ , R ⁴ , R ⁷ , R ⁸ , m and n are as defined in claim 3. The compound represented by the general formula (M) as claimed in Claim 6 or a pharmaceutically acceptable salt thereof, wherein R ^5a and R ^5b are different and each independently selected from halogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _1-6 alkoxy, halogen C _1-6 alkoxy, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; wherein the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently selected from halogen, C _1-6 One or more of the same or different substitutions of ₆ alkyl, C _1-6 alkoxy, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, hydroxyl, cyano, amino and nitro Preferably, R ^5a and R ^5b are different, and each independently is C _1-6 alkyl or halogen C _1-6 alkyl. The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 3 to 7, wherein each R ^2a is the same or different, and each independently represents halogen or C _1-6 alkyl, and m is 1, 2, 3 or 4; or m is 0. The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl , 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl. The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, wherein each R ⁷ is the same or different, and each independently represents halogen or C _1-6 Alkyl, and n is 1, 2, 3 or 4; or n is 0; preferably, R ⁷ is halogen, and n is 1. A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10, wherein R ^is selected from C _1-6 alkyl, halogen C _1-6 alkyl , C _1-6 alkoxy, halogen C _1-6 alkoxy, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably; R ⁸ is C _1-6 alkyl or 3 to 8-membered cycloalkyl. The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, wherein R ¹ , R ⁴ and R ^4a are the same or different, and are each independently selected from Hydrogen atom, halogen and C _1-6 alkyl. A compound, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

A compound represented by general formula (MA) or a salt thereof,

in, R is alkyl or

; Preferably, R is an alkyl group or

; R ^w is alkyl or allyl; preferably, R ^w is allyl; Z, G, R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in claim 1. The compound or salt thereof represented by general formula (MA) as described in Claim 14, which is the compound or salt thereof represented by general formula (IA):

in, R is an alkyl group; preferably, R is a C _1-6 alkyl group; G, R ¹ to R ¹¹ and n are as defined in claim 2. A compound or salt thereof selected from any one of the following compounds:

A compound or salt thereof represented by general formula (IVa-A), general formula (IVa-A1) or general formula (IVa-A2),

in, R ^5a and R ^5b are different and each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein the alkyl, alkoxy The group, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, Amino and nitro are substituted by one or more identical or different substituents; wherein when one of R ^5a and R ^5b is methyl, the other is not ethyl or propyl; G is CR ^4a ; Ring A, R ^2a , m, R ^4a , R ¹ and R ⁴ are as defined in claim 6. A compound or salt thereof selected from the following structures:

A method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as claimed in claim 1, the method comprising the following steps:

A compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof; in, R is alkyl or

; Preferably, R is an alkyl group or

; R ^w is alkyl or allyl; preferably, R ^w is allyl; The condition is that when R is selected from an alkyl group, the compound represented by the general formula (MA) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (M) whose ^R is a hydrogen atom or its pharmaceutically acceptable Salt; when R is

, the compound represented by the general formula (MA) or its salt removes R ^w to obtain R ⁰ as

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is

When , the compound represented by the general formula (MA) or its salt removes R ^w , and R ⁰ is obtained as

A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof; Z, G, R ⁰ , R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in Claim 1. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 2, the method comprising the following steps:

The compound represented by the general formula (IA) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof; in, R is an alkyl group; preferably, R is a C _1-6 alkyl group; G, R ¹ to R ¹¹ and n are as defined in claim 2. A method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as claimed in claim 1, the method comprising the following steps:

The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt are condensed and acylated to obtain the compound represented by the general formula (M) or its pharmaceutically acceptable salt ; in, Z, G, R ⁰ , R ¹ to R ³ , R ⁵ to R ¹¹ and n are as defined in Claim 1. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 2, the method comprising the following steps:

The compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (IB) or its salt are condensed and acylated to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt ; in, G, R ¹ to R ¹¹ and n are as defined in claim 2. A pharmaceutical composition, which contains a therapeutically effective amount of a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 13, and one or more pharmaceutically acceptable carrier, diluent or excipient. A compound represented by general formula (M) as described in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 23 in the preparation of sGC agonists and/or initiating use in pharmaceuticals. A compound represented by general formula (M) as described in any one of claim items 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 23 is used for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoarthritis Loose, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, the disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, the renal disease is chronic renal failure or Chronic renal insufficiency. The use as described in claim 25, wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral artery disease, intermittent claudication, critical lower extremity ischemia, stable or unstable Angina pectoris, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, the cardiovascular disease is selected from hypertension, myocardial infarction and heart failure. The use as described in claim 25, wherein the fibrotic disease is selected from fibrotic diseases of the skin, liver, kidney and lung; the urinary system disease is selected from overactive bladder, benign prostatic hyperplasia and erectile dysfunction; the neurological disease selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; Diseases include psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease and chronic obstructive pulmonary disease.