WO2025228383A1 - Indole derivative as ras inhibitor and use thereof - Google Patents

Abstract

A compound of formula (I) as an RAS inhibitor or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use thereof in the prevention or treatment of diseases mediated by RAS.

Description

Indole derivatives as RAS inhibitors and their uses

Cross-references to related applications

This application claims priority and benefits from the following patent applications, the entire contents of which are incorporated herein by reference:

Chinese Invention Patent Application No. 202410528786.8, filed with the State Intellectual Property Office of the People's Republic of China on April 29, 2024;

Chinese Invention Patent Application No. 202510103215.4, filed with the State Intellectual Property Office of the People's Republic of China on January 22, 2025; and

Chinese Invention Patent Application No. 202510250686.8 was filed with the State Intellectual Property Office of the People's Republic of China on March 4, 2025.

Technical Field

This disclosure pertains to the field of pharmaceutical technology and specifically relates to macrocyclic compounds containing an indole ring, stereoisomers thereof, or pharmaceutically acceptable salts thereof as RAS inhibitors, pharmaceutical compositions containing them, and their use as RAS inhibitors in the prevention or treatment of RAS-related diseases.

Background Technology

The KRAS gene (Kirsten Rat Sarcoma Viral Oncogene Homolog, a homolog of the Kirsten rat sarcoma virus oncogene) belongs to the RAS gene family (RAS was the first human tumor gene discovered; the RAS gene family also includes NRAS (Neuroblastoma-RAS) and HRAS (Harvey-RAS)). Located on chromosome 12, it participates in intracellular signal transduction. The KRAS protein encoded by the KRAS gene is a small GTPase, belonging to the RAS superprotein family. The KRAS protein has 188 amino acids and a molecular weight of 21.6 kDa. KRAS is activated by binding to GTP and deactivated by binding to GDP. The KRAS protein is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activators (GAPs) to maintain its activation and inactivation states. Activated KRAS proteins primarily activate downstream pathways such as the PI3K-AKT-mTOR signaling pathway, which controls cell production, and the RAS-RAF-MEK-ERK signaling pathway, which controls cell proliferation. Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating their activity. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. Indeed, the existence of many such drug/target interaction pairs may mislead one into believing that small molecule regulators targeting most (if not all) proteins can be discovered, thus justifying the amount of time, effort, and resources required. However, this is not the case. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. The remaining 90% are currently considered difficult to treat or manage with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” A large portion of these undruggable targets, or medically important human proteins, do not yet have a library of compounds to be studied. Therefore, there is great interest in discovering novel molecules that can modulate the function of such druggable targets. Given the importance of the RAS signaling pathway in cancer treatment, targeted therapy against the RAS signaling pathway has become a research hotspot in the field of cancer treatment in recent years.

Summary of the Invention

This disclosure relates to compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts.

in,

^X1 is selected from CHR ¹¹ and NR ¹² ;

^X2 is selected from _CH2 and NH;

L is selected from NH, NR ¹³ , or CR ¹⁴ R ¹⁵ ;

A is selected from _C3 - _C12 cycloalkylene, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-12 heterocyclic, wherein the _C3 - _C12 cycloalkylene, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-12 heterocyclic are optionally substituted by one or more ^Ra .

^R1 is selected from C3 _{- C12} cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-12 heteroaryl, wherein the _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-12 heteroaryl are optionally substituted by one or more ^R1a ;

^R2 , ^R3 , ^R7 , ^R8 and ^R9 are independently selected from hydrogen, halogen, hydroxyl, cyano, _C1 - _C10 alkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkyl and _C3 - _C7 cycloalkyl;

Alternatively, ^R7 and ^R8 and the atoms they are connected to together form a 4-10 membered heterocycle, which is optionally replaced by one or more ^Rb ;

^R4 is selected from hydrogen, halogen, hydroxyl, cyano, C2 _- C10 alkenyl, _C2 - _C10 alkynyl and _C1 - _C10 alkyl, wherein the hydroxyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl and _C1 - _{C10 alkyl} are optionally substituted by one or more ^R4a ;

^R5 is selected from _C1 - _C10 alkyl, C3-C12 cycloalkyl, 4-10 heterocyclic, C6- _C10 aryl, and 5-10 heteroaryl, wherein the _C1 - _C10 alkyl, _C3 - _C12 cycloalkyl, _4-10 heterocyclic, _{C6 - C10 aryl} , and 5-10 heteroaryl are optionally substituted by one or more ^R5a ;

Alternatively, ^R4 and ^R5 and the atoms they are connected to together form a 4-10 membered heterocycle, which is optionally replaced by one or more ^Rc atoms;

Alternatively, ^R4 and ^R7 and the atoms they are attached to together form a 4-10 membered heterocycle, which is optionally replaced by one or more ^Rds ;

^R6 , ^R10 , ^R11 and ^R12 are independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl and _C1 - _C4 alkoxy;

Alternatively, R ¹⁰ and its connected C, R ¹¹ and its connected C, and CH ₂ between the two Cs together form a C ₄ -C ₁₂ saturated carbon ring or a 4-10 membered heterocycle;

Alternatively, R ¹⁰ and its connected C and R ¹² and its connected N, as well as CH ₂ between said C and N, together form a 4-10 membered heterocycle;

^R13 , ^R14 and ^R15 are independently selected from non-existent, hydrogen, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl and _C1 - _C4 alkoxy;

Alternatively, ^R1 and ^R13 and the atoms connected to them, or ^R1 and ^R14 and the atoms connected to them, together form a 4-10 membered heterocycle or a 5-10 membered heteroaromatic ring, wherein the 4-10 membered heterocycle or the 5-10 membered heteroaromatic ring is optionally substituted by one or more ^R1a ;

Each ^Ra is independently selected from halogen, amino, hydroxyl, mercapto, cyano, and _C1 - _C4 alkyl groups;

Each R ^1a is independently selected from halogen, amino, hydroxyl, mercapto, cyano, _C2 - _C10 alkenyl, _C2 -C10 alkynyl, _C1 - _C10 alkyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl _{, and 5-10 heteroaryl, wherein the amino, hydroxyl, mercapto, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkyl , C3 - C12 cycloalkyl , 4-10} heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl are optionally substituted with ^Re ;

Each ^R4a , ^Rb , and ^Rd is independently selected from halogen, amino, hydroxyl, mercapto, cyano, _C1 - _C7 alkyl, _C1 - _C7 haloalkyl, _C3 - _C6 cycloalkyl, and C1 _{- C7} alkoxy.

Each R ^5a is independently selected from halogen, cyano, amino, hydroxyl, mercapto, oxo, _C1 - _C10 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C3 - _C12 cycloalkyl, 4-15-membered heterocyclic, _C6 - _C10 aryl, and 5-10-membered heteroaryl, wherein the amino, hydroxyl, mercapto, C1 _{- C10} alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C3 - _C12 cycloalkyl, 4-15-membered heterocyclic, _C6 - _C10 aryl, and 5-10-membered heteroaryl are optionally substituted by one or more R ^f ;

Each ^Rc is independently selected from hydroxyl, _C1 - _C10 alkyl, C3- _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl, wherein the hydroxyl, _C1 - _C10 alkyl _{, C3-C12 cycloalkyl ,} 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl are optionally substituted by one or more ^Re ;

Each ^{Re is} independently selected from halogen, cyano, amino, hydroxyl, mercapto, _C1 - _C10 alkyl, _C2 -C10 alkenyl, _C2 - _C10 alkynyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and _5-10 heteroaryl, wherein the _C1 - _C10 alkyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl are optionally substituted by one or more ^Rg ;

Each R ^g is independently selected from halogen, amino, hydroxy, mercapto, cyano, _C1 - _C7 alkyl, _C1 - _C7 haloalkyl, _C1 - _C7 alkoxy, 4-10 membered heterocyclic groups and C3- _{C10 cycloalkyl groups optionally substituted with halogen, amino, hydroxy, mercapto, cyano, C1-C4 alkyl , C1 - C4} haloalkyl, _C1 - _C4 hydroxyalkyl and _C1 - _C4 alkoxy;

Each ^Rf is independently selected from halogen, amino, hydroxyl, mercapto, cyano, _C1 - _C7 alkyl, _C1 - _C7 alkoxy, _C3 - _C10 cycloalkyl, and 4-12 membered heterocyclic groups, wherein the amino, hydroxyl, mercapto, _C1 - _C7 alkyl, _C1 - _C7 alkoxy, _C3 - _C10 cycloalkyl, and 4-12 membered heterocyclic groups are optionally substituted by one or more ^Rh ;

Each R h is independently selected from halogen, hydroxyl, mercapto, amino, =O, =CRj R  j , C<sub> 1 -C4 alkyl, cyano, C<sub> 3 -C 6  cycloalkyl, 3-6 membered heterocyclic alkyl, C<sub> 1 -C 4  hydroxyalkyl, C <sub> 1 -C 4  aminoalkyl, C<sub> 1 -C4 haloalkyl, (C<sub> 1 -C 4  alkylene)O C<sub> 1 -C 4  alkyl, C(O)R k , S(O) 2 R k , and C<sub> 1 -C 4  alkoxy, wherein the hydroxyl, mercapto, amino, C <sub>1 -C 4  alkyl, C<sub> 3 -C 6  cycloalkyl, 3-6 membered heterocyclic alkyl, C<sub> 1- C 4  hydroxyalkyl, C<sub> 1 -C 4  aminoalkyl, C <sub>1 -C4 haloalkyl, (C<sub> 1- C 4  alkylene)O C<sub> 1 -C4 alkyl, and C<sub>1-C<sub>4 alkoxy are optionally replaced by halogen, hydroxyl, cyano, and C1-C4  alkyl . 4- alkyl substitution;

^Rj and ^Rk are independently selected from H, halogen, hydroxyl, mercapto, cyano, amino, _C1 - _C4 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, and _C1 - _C10 alkoxy, wherein the hydroxyl, mercapto, amino, _C1 - _C4 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, and _C1 - _C10 alkoxy are optionally substituted with halogen, hydroxyl, mercapto, amino, =O, _C1 - _C4 alkyl, C1- _C4 alkoxy, C1 _{- C4} hydroxyalkyl, C1- _C4 aminoalkyl, _{C1 - C4} haloalkyl, _C3 - _C6 cycloalkyl, 3-6 membered heterocyclic alkyl, N( _C1 - _C4 alkyl) ₂ , and NH( _{C1 - C4} alkyl); and

One or more hydrogen atoms in the compound may be selected as deuterium atoms.

In some embodiments, each ^Rf and ^Rg is independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, _C1 - _C7 alkyl groups, _C1 - _C7 haloalkyl groups, _C1 - _C7 alkoxy groups, 4-10 membered _heterocyclic groups and C3- _{C10 cycloalkyl groups optionally substituted with halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, C1-C4 alkyl groups} , _{C1 - C4} haloalkyl groups, _C1 - _C4 hydroxyalkyl groups and C1-C4 alkoxy groups.

In some embodiments, each ^R4a , ^Rb and ^Rd is independently selected from halogen, amino, hydroxyl, mercapto, cyano, _C1 - _C7 alkyl, _C1 - _C7 haloalkyl and _C1 - _C7 alkoxy.

In some implementations, ^X1 is selected from CHR ¹¹ .

In some implementations, ^X1 is _CH2 .

In some implementations, ^R10 is hydrogen.

In some embodiments, ^X1 is selected from ^CHR11 , wherein ^R10 and its connected C, ^R11 and its connected C, and _CH2 between the two Cs together form a _C4 - _C12 saturated carbon ring.

In some embodiments, ^X1 is selected from ^CHR11 , wherein ^R10 and its connected C, ^R11 and its connected C, and _CH2 between the two Cs together form a _C4 - _C6 saturated carbon ring.

In some embodiments, ^X1 is selected from ^CHR11 , wherein ^R10 and its connected C, ^R11 and its connected C, and _CH2 between the two Cs together form a _C4 saturated carbon ring.

In some implementation schemes, Selected from Preferably, R ¹⁰ is hydrogen.

In some implementations, ^X2 is NH.

In some implementations, ^X1 is _CH2 and ^X2 is NH.

In some embodiments, A is selected from _C6 - _C10 arylene and 5-12 heteroarylene, wherein _{the C6-C10 arylene} and 5-12 heteroarylene are optionally substituted by one or more ^Ra .

In some embodiments, A is selected from 5-12-membered heteroaryl groups, wherein the 5-12-membered heteroaryl group is optionally substituted by one or more Ra ^groups .

In some embodiments, A is selected from 5-6-membered heteroaryl groups, which are optionally substituted by one or more Ra ^groups .

In some embodiments, A is selected from a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally substituted with one or more Ra ^atoms . In some embodiments, A is selected from a 6 membered heterocyclic group or a 5 membered heteroaryl group, wherein the 6 membered heterocyclic group or the 5 membered heteroaryl group is optionally substituted with one or more Ra ^atoms . In some embodiments, A is selected from a 6 membered heterocyclic group having one N atom and one O atom or a 5 membered heteroaryl group having one N atom and one S atom, wherein the 6 membered heterocyclic group or the 5 membered heteroaryl group is optionally substituted with one Ra ^atom .

In some embodiments, A is selected from imomorpholino and imidazolyl, wherein the imomorpholino and imidazolyl groups are optionally substituted with one or more ^{Ra groups} . In some embodiments, A is selected from imidazolyl, wherein the imidazolyl group is optionally substituted with one or more Ra ^groups .

In some implementation schemes, A is selected from The Optionally replaced by ^Ra . In some implementations, A is selected from... The It can be replaced by ^Ra .

In some implementations, ^Ra is independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups.

In some implementation schemes, A is

In some implementation schemes, A is

In some implementations, L is NH.

In some implementations, L is selected from NR ¹³ .

In some implementations, L is selected from CR ¹⁴ R ¹⁵ .

In some embodiments, ^R1 is selected from 4-10-membered heterocyclic groups and 5-12-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-12-membered heteroaryl group are optionally replaced by one or more ^R1a .

In some embodiments, ^R1 is selected from 6-10-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 6-10-membered heterocyclic group and the 5-6-membered heteroaryl group are optionally replaced by one or more ^R1a .

In some embodiments, ^R1 is selected from 5-9-membered heterocyclic groups and 5-6-membered heteroaryl groups, which are optionally substituted by one or more ^R1a . In some embodiments, ^R1 is selected from 5-9-membered heterocyclic groups and 5-6-membered heteroaryl groups, which have one N atom and one or two heteroatoms independently selected from N, O or S, and are optionally substituted by one or more ^R1a .

In some embodiments, ^R1 is selected from 8-9-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 8-9-membered heterocyclic group and the 5-6-membered heteroaryl group are optionally substituted by one or more ^R1a . In some embodiments, ^R1 is selected from 8-9-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 8-9-membered heterocyclic group and the 5-6-membered heteroaryl group have one N atom and one or two heteroatoms independently selected from N, O or S, and are optionally substituted by one or more ^R1a .

In some embodiments, ^R1 is selected from 9-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 9-membered heterocyclic group and the 5-6-membered heteroaryl group are optionally replaced by one or more ^R1a .

In some embodiments, ^R1 is selected from isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, etc. The isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, It can be replaced by one or more R ^1a .

In some embodiments, ^R1 is selected from isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, etc. The isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, It can be replaced by one or more R ^1a .

In some embodiments, ^R1 is selected from oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, etc. The oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, It can be replaced by one or more R ^1a .

In some embodiments, ^R1 is selected from isothiazolyl, oxadiazolyl, thiadiazolyl, ... Tetraazolyl, pyrimidinyl, triazineyl The isothiazolyl, oxadiazolyl, thiadiazolyl, Tetraazolyl, pyrimidinyl, triazineyl It can be replaced by one or more R ^1a .

In some embodiments, ^R1 is selected from oxadiazolyl, thiadiazolyl, and Tetraazolyl, pyrimidinyl, triazine and The oxadiazole group, thiadiazole group, Tetraazolyl, pyrimidinyl, triazine and It can be replaced by one or more R ^1a .

In some embodiments, ^R1 is selected from oxadiazolyl, thiadiazolyl, and Tetraazolyl, pyrimidinyl, and triazineyl, wherein the oxadiazolyl, thiadiazolyl, The tetrazolyl, pyrimidinyl, and triazine groups may be optionally substituted with one or more R ^1a groups.

In some embodiments, ^R1 is selected from oxadiazolyl, thiadiazolyl, and Tetraazolyl, pyrimidinyl, and triazineyl, wherein the oxadiazolyl, thiadiazolyl, The tetrazolyl, pyrimidinyl, and triazine groups may be optionally substituted with one or more R ^1a groups.

In some embodiments, each R ^1a is independently selected from _C1 - _C10 alkyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic and _C6 - _C10 aryl, wherein the _C1 - _C10 alkyl, _C3 - _C12 cycloalkyl and _C6 - _C10 aryl are optionally substituted by one or more ^Re .

In some embodiments, each R ^1a is independently selected from _C1 - _C5 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic groups, and phenyl, wherein the _C1 - _C5 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic groups, and phenyl are optionally substituted with one or more ^Re . In some embodiments, each R ^1a is independently selected from _C1 - _C4 alkyl, _C3 - _C7 cycloalkyl, 4-6 membered heterocyclic groups, and phenyl, wherein the _C1 - _C4 alkyl, _C3 - _C7 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with one or more ^Re .

In some embodiments, each R ^1a is independently selected from methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Optionally, it can be substituted with one or more ^Re . In some embodiments, each R ^1a is independently selected from methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclopentyl, phenyl, and The methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclopentyl, phenyl and It can be replaced by one or more ^Re .

In some embodiments, each R ^1a is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, n-butyl, The methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl It can be replaced by one or more ^Re .

In some embodiments, each R ^1a is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl It can be replaced by one or more ^Re .

In some embodiments, each R ^1a is independently selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl It can be replaced by one or more ^Re .

In some embodiments, each R ^1a is independently selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, phenyl, The methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, phenyl, It can be replaced by one or more ^Re .

In some embodiments, each ^Re is independently selected from halogen, cyano, hydroxyl, _C1 - _C3 alkyl, _C2 - _C4 alkenyl, _C3 - _C6 cycloalkyl, and _C6 - _C10 aryl, wherein the hydroxyl, _C1 - _C3 alkyl, _C2 - _C4 alkenyl, _C3 - _C6 cycloalkyl, and _C6 - _C10 aryl are optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from halogen, cyano, hydroxyl, _C1 - _C3 alkyl, _C2 alkenyl, _C3 - _C6 cycloalkyl, and _C6 aryl, wherein the hydroxyl, _C1 - _C3 alkyl, and _C6 aryl are optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from halogen, cyano, _C1 - _C10 alkyl, and _C6 - _C10 aryl, wherein the _C1 - _C10 alkyl and _C6 - _C10 aryl are optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from halogen, cyano, and _C1 - _C10 alkyl, wherein the _C1 - _C10 alkyl is optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from halogen, cyano, _C1 - _C4 alkyl, and phenyl, wherein the _C1 - _C4 alkyl and phenyl are optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from halogen, cyano, and _C1 - _C4 alkyl, wherein the _C1 - _C4 alkyl is optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from fluorine, cyano, hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl, wherein the hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl are optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from fluorine, cyano, hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl, wherein the methyl and hydroxyl groups are optionally substituted by one or more ^Rgs .

In some embodiments, each ^Re is independently selected from fluorine, cyano, methyl, ethyl, isopropyl, and phenyl, wherein the methyl, ethyl, isopropyl, and phenyl are optionally substituted by one or more ^Rg .

In some embodiments, each ^Re is independently selected from fluorine, cyano, methyl, ethyl, and isopropyl, wherein the methyl, ethyl, and isopropyl groups are optionally substituted by one or more Rg ^groups .

In some embodiments, each ^Rg is independently selected from halogens, _C1 - _C6 alkyl groups, and _C1 - _C6 alkoxy groups.

In some embodiments, each ^Rg is independently selected from halogens, _C1 - _C3 alkyl groups, and _C1 - _C3 alkoxy groups.

In some implementations, each ^Rg is independently selected from halogens and _C1 - _C7 alkoxy groups.

In some implementations, each R ^g is independently selected from fluorine, methyl, and methoxy.

In some implementations, each R ^g is independently selected from fluorine and methoxy groups.

In some embodiments, each ^Re is independently selected from fluorine, cyano, methyl, ethyl, isopropyl, _-CF3 , _-CH2 -O- _CH3 , phenyl, -O- _CH3 , cyclopropyl, cyclopentyl, and vinyl.

In some implementations, ^R1 is selected from

In some embodiments, L is NR ¹³ , and R ¹ and R ¹³ and the atoms connected to them together form a 5-6 membered heteroaromatic ring, which is optionally substituted by one or more R ^1a .

In some embodiments, L is NR ¹³ , and R ¹ and R ¹³ and the atoms they are connected to together form a triazole ring, which is optionally substituted by one or more R ^1a .

In some embodiments, L is CR ¹⁴ R ¹⁵ , and R ¹ and R ¹⁴ and the atoms they are attached to together form a 5-6 membered heteroaromatic ring, which is optionally replaced by one or more R ^1a , and R ¹⁵ is not present.

In some embodiments, L is CR ¹⁴ R ¹⁵ , R ¹ and R ¹⁴ and the atoms they are attached to together form a triazole ring, which is optionally replaced by one or more R ^1a , and R ¹⁵ is not present.

In some embodiments, L is NR ¹³ , and R ¹ and R ^13, together with the atoms they are attached to, form a 6-10 membered heterocycle, which optionally contains N, -C(=O)-, or -C(=O)NH- as heteroatoms or heterogroups, and is optionally substituted by one or more R ^1a or by one R ^1a , wherein R ^1a is independently selected from C ₁ -C ₆ alkyl groups, such as isopropyl. In some embodiments, the -NH- in the heterogroup "-C(=O)NH-" can serve as a linking site to the rest of the molecule.

In some implementations, L is NR ¹³ , and R ¹ and R ¹³ together with the atoms they are connected to form the structure. It can be replaced by one or more R ^1a .

In some implementations, L is NR ¹³ , and R ¹ and R ¹³ together with the atoms they are connected to form the structure.

In some implementations, L is CR ¹⁴ R ¹⁵ , and R ¹ and R ^14, along with the atoms they are bonded to, are formed together. The It can be replaced by one or more R ^1a , and R ¹⁵ does not exist.

In some implementations, L is CR ¹⁴ R ¹⁵ , and R ¹ and R ^14, along with the atoms they are bonded to, are formed together.

In some embodiments, ^R2 and ^R3 are independently selected from hydrogen, halogen, hydroxyl, cyano and _C1 - _C10 alkyl.

In some embodiments, ^R2 and ^R3 are independently selected from _C1 - _C4 alkyl groups, such as methyl.

In some implementations, both ^R2 and ^R3 are methyl groups.

In some embodiments, ^R4 is selected from hydrogen, halogen, hydroxyl, cyano, and _C1 - _C10 alkyl, wherein the hydroxyl or _C1 - _C10 alkyl is optionally substituted by one or more ^R4a , ^{and R5} is selected from _C6 - _C10 aryl and 5-10 heteroaryl, wherein the _C6 - _C10 aryl and 5-10 heteroaryl is optionally substituted by one or more ^R5a . Alternatively, ^R4 and ^R5 and the atoms attached to them together form a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle is optionally substituted by one or more ^Rc .

In some embodiments _, ^R4 is selected from _C1 - _C10 alkyl groups, _which are optionally substituted with one or more ^R4a .

In some embodiments _, ^R4 is selected from _C1 - _C4 alkyl groups, _which are optionally substituted with one or more ^R4a .

In some embodiments, ^R4 is selected from methyl and ethyl, wherein the methyl and ethyl are optionally substituted by one or more ^R4a .

In some embodiments, ^R4 is an ethyl group, which is optionally substituted with one or more ^{R4a groups} .

In some embodiments, R ^4a is independently selected from cyclopropyl, halogen, amino, hydroxyl, mercapto, and cyano, or R ^4a is independently selected from halogen, amino, hydroxyl, mercapto, and cyano.

In some embodiments, R ^4a is independently selected from cyclopropyl and halogen, or R ^4a is independently selected from halogen.

In some embodiments, ^R4a is fluorine. In some embodiments, ^R4 is selected from ethyl, methyl substituted with one cyclopropyl group, or ethyl substituted with one or more halogens. In some embodiments, ^R4 is ethyl, methyl substituted with one cyclopropyl group, or ethyl substituted with one or more fluorines. In some embodiments, ^R4 is ethyl, _-CH2 -cyclopropyl, or _-CH2 - _CF3 .

In some embodiments, ^R4 and ^R7, and the atoms connected to them, together form a 6-7 membered heterocycle, which is optionally substituted with one or more ^Rd atoms. In some embodiments, ^R4 and ^R7, and the atoms connected to them, together form a 6-7 membered heterocyclic alkyl group. In some embodiments, ^R4 and ^R7, and the atoms connected to them, together form a 6-7 membered heterocyclic alkyl group having one N atom and optionally one O atom.

In some embodiments, ^R5 is selected from 4-10-membered heterocyclic groups, _C6 - _C10 aryl groups, and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group, _C6 - _C10 aryl group, and 5-10-membered heteroaryl group are optionally substituted by one or more ^R5a .

In some embodiments, ^R5 is selected from _C6 - _C10 aryl and 5-10 heteroaryl groups, wherein the C6- _{C10 aryl} and 5-10 heteroaryl groups are optionally replaced by one or more ^R5a .

In some embodiments, ^R5 is selected from 4-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally replaced by one or more ^R5a .

In some embodiments, ^R5 is selected from 9-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 9-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally substituted by one or more ^R5a . In some embodiments, ^R5 is selected from 9-10-membered heterocyclic groups and 6-10-membered heteroaryl groups, wherein the 9-10-membered heterocyclic group and the 6-10-membered heteroaryl group are optionally substituted by one or more ^R5a .

In some embodiments, ^R5 is selected from 5-10 heteroaryl groups, which are optionally replaced by one or more ^R5a groups.

In some embodiments, R ⁵ is selected from 5-6 heteroaryl groups, which are optionally replaced by one or more R ^5a groups.

In some embodiments, ^R5 is selected from pyridinyl, which is optionally replaced by one or more ^R5a .

In some implementations, ^R5 is selected from... The Optionally, it is substituted with one or more ^R5a . In some embodiments, the position adjacent to the site where ^R5 is attached to the rest of the molecule is substituted with -CH( _CH3 )-O- _CH3 or -(S)-CH( _CH3 )-O- _CH3 . In some embodiments, ^R5 is selected from pyridinyl groups, and the position adjacent to the site where the pyridinyl group is attached to the rest of the molecule is substituted with -CH( _CH3 )-O- _CH3 or -(S)-CH( _CH3 )-O- _CH3 .

In some implementations, ^R5 is selected from... The It may be optionally replaced by one or more R ^5a .

In some implementations, ^R5 is The Optionally replaced by one or more R ^5a . In some embodiments, R ⁵ is

In some embodiments, each R ^5a is independently selected from halogen, cyano, amino, hydroxyl, mercapto, oxo, C1- _C10 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl, wherein the amino, hydroxyl, mercapto, _{C1 - C10} alkyl, _C2 - _C10 alkenyl, _{C2-C10 alkynyl, C3 - C12 cycloalkyl} , 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl are optionally substituted by one or more R ^f .

In some embodiments, each R ^5a is independently selected from halogen, cyano, amino, hydroxyl, mercapto, _C1 - _C10 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl, wherein the amino, hydroxyl, mercapto, _C1 - _C10 alkyl, _C2 - _C10 alkenyl, _C2 - _C10 alkynyl, _C3 - _C12 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, and 5-10 heteroaryl are optionally substituted by one or more R ^f .

In some embodiments, ^R5a is independently selected from halogen, cyano, oxo, _C1 - _C10 alkyl, _C2 - _C10 alkynyl, and 4-10 membered heterocyclic groups, wherein the _C1 - _C10 alkyl, _C2 - _C10 alkynyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more ^Rf .

In some embodiments, ^R5a is independently selected from halogen, cyano, _C1 - _C10 alkyl, _C2 - _C10 alkynyl, and 4-10 membered heterocyclic groups, wherein the _C1 - _C10 alkyl, _C2 - _C10 alkynyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more ^Rf .

In some embodiments, ^R5a is independently selected from _C1 - _C10 alkyl, _C2 - _C10 alkynyl, and 4-10 membered heterocyclic groups, wherein the _C1 - _C10 alkyl, _C2 - _C10 alkynyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more ^Rf .

In some embodiments, ^R5a is independently selected from halogen, cyano, oxo, C1 _{- C4} alkyl, _C2 - _C4 ynyl, and 6-13 membered heterocyclic groups, wherein the _C1 - _C4 alkyl, _C2 - _C4 ynyl, and 6-13 membered heterocyclic groups are optionally substituted by one or more ^Rf .

In some embodiments, ^R5a is independently selected from halogen, cyano, oxo, _C1 - _C4 alkyl, _C2 - _C4 ynyl, and 4-7 membered heterocyclic groups, wherein the _C1 - _C4 alkyl, _C2 - _C4 ynyl, and 4-7 membered heterocyclic groups are optionally substituted by one or more ^Rf .

In some embodiments, ^R5a is independently selected from _C1 - _C4 alkyl, _C2 - _C4 ynyl, and 4-7 membered heterocyclic groups, wherein the _C1 - _C4 alkyl, _C2 - _C4 ynyl, and 4-7 membered heterocyclic groups are optionally substituted by one or more ^Rf .

In some embodiments, R ^5a is independently selected from fluorine, hydroxyl, cyano, oxo, methyl, piperidinyl, propynyl, piperazine, Ethyl, ethynyl, The hydroxyl, methyl, piperidinyl, propynyl, piperazineyl, Ethyl, ethynyl, It can be optionally replaced by one or more R ^f .

In some embodiments, R ^5a is independently selected from fluorine, cyano, oxo, methyl, piperidinyl, propynyl, piperazine, And ethyl, the methyl, piperidinyl, propynyl, piperazineyl, The ethyl group is optionally substituted with one or more R ^f .

In some embodiments, R ^5a is independently selected from fluorine, cyano, propynyl, piperazine, And ethyl, the propynyl, piperazine, The ethyl group is optionally substituted with one or more R ^f .

In some embodiments, R ^5a is independently selected from propynyl, piperazine, And ethyl, the propynyl, piperazine, The ethyl group is optionally substituted with one or more R ^f .

In some implementations, R ^5a is independently selected from fluorine, cyano, oxo, methyl, and ethyl, the methyl, The ethyl group is optionally substituted with one or more R ^f .

In some implementations, R ^5a is independently selected from fluorine, cyano, and ethyl, the The ethyl group is optionally substituted with one or more R ^f .

In some implementations, R ^5a is independently selected from and ethyl, the The ethyl group is optionally substituted with one or more R ^f .

In some embodiments, each ^Rf is independently selected from C1 _{- C4} alkyl, _C1 - _C4 alkoxy, _C3 - _C6 cycloalkyl, and 4-12 membered heterocyclic groups, wherein the _C1 - _C4 alkyl, _C1 - _C4 alkoxy, _C3 - _C6 cycloalkyl, and 4-12 membered heterocyclic groups are optionally substituted by one or more ^Rh ; optionally, the 4-12 membered heterocyclic group contains one, two, or three heteroatoms or heterogroups selected from N, O, S, -S(=O) _2- , -P(=O)-, -PH(=O)-, -S(=O)(=NH)-, -C(=O)-, or -C(=O)NH-.

Each ^Rh is independently selected from halogen, hydroxyl, =O, = ^CRjRj , _C1 - _C4 ^alkyl , cyano, _C3 - _C6 cycloalkyl, 3-6 membered heterocyclic alkyl, _C1 - _C4 hydroxyalkyl, _C1 - _{C4 aminoalkyl, C1-C4 haloalkyl ,} C(O) ^Rk , S(O) _2Rk and _C1 - _C4 alkoxy, wherein the hydroxyl, _C1 - _C4 alkyl, _C3 - _C6 ^cycloalkyl , 3-6 membered heterocyclic alkyl, _C1 - _C4 hydroxyalkyl, _C1 - _C4 aminoalkyl, _C1 - _C4 haloalkyl and _C1 - _C4 alkoxy are optionally substituted with halogen, hydroxyl, cyano and _C1 - _C4 alkyl;

^Rj is independently selected from H, halogen, and ^Rk is independently selected from H, halogen, or _C1 - _C4 alkyl, wherein the _C1 - _C4 alkyl is optionally substituted with hydroxyl, _C1 - _C4 alkoxy, 3-6 membered heterocyclic alkyl, N( _C1 - _C4 alkyl) ₂ , and NH( _C1 - _C4 alkyl).

In some embodiments, ^Rf is independently selected from C1 _{- C4} alkyl, _C1 - _C4 alkoxy, _C3 - _C5 cycloalkyl and optional 4-10 membered heterocyclic groups substituted with _C1 - _C4 hydroxyalkyl, cyano, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl and halogen.

In some embodiments, ^Rf is independently selected from _C1 - _C7 alkyl, _C1 - _C7 alkoxy, _C3 - _C10 cycloalkyl and optional 4-10 membered heterocyclic groups substituted with _C1 - _C4 hydroxyalkyl.

In some embodiments, ^Rf is independently selected from _C1 - _C4 alkyl, _C1 - _C4 alkoxy, _C3 - _C5 cycloalkyl and optionally 5-7 membered heterocyclic groups substituted with hydroxymethyl.

In some embodiments, ^Rf is independently selected from _C1 - _C4 alkyl, _C1 - _C4 alkoxy, _C3 - _C5 cycloalkyl and optionally 5-6 membered heterocyclic groups substituted with hydroxymethyl.

In some embodiments, R ^5a is independently selected from fluorine, cyano, oxo, methyl, ethynyl, ethyl, Or R ^5a is ethynyl or Or R ^5a is Or, when ^R5 is At that time, R ^5a is independently selected from acetylene group, The methyl, ethynyl, ethyl, Each is optionally substituted by one or more ^Rf , ^{wherein Rf is} independently selected from methoxy, -CH ₃ 、

In some embodiments, ^Rf is independently selected from methyl, methoxy, cyclopropyl, morpholino, oxecyclobutyl,

In some embodiments, ^Rf is independently selected from methyl, methoxy, cyclopropyl, morpholino, and

In some implementations, ^R5 is selected from

In some implementations, ^R5 is selected from

In some implementations, ^R5 is selected from...

In some implementations, ^R5 is selected from

In some embodiments, ^R6 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, and _C1 - _C4 alkyl.

In some implementations, ^R6 is hydrogen.

In some implementations, ^R7 is selected from hydrogen, halogen, hydroxyl and cyano.

In some implementations, ^R7 is hydrogen.

In some embodiments, ^R8 is selected from hydrogen, halogen, hydroxyl, cyano, and _C1 - _C10 alkyl.

In some implementations, ^R8 is hydrogen.

In some implementations, ^R9 is selected from hydrogen, halogen, hydroxyl and cyano.

In some implementations, ^R9 is selected from hydrogen and halogens.

In some implementations, ^R9 is selected from hydrogen and fluorine.

In some embodiments, each ^Rf and ^Rg is independently selected from halogen, amino, hydroxy, mercapto, cyano, _C1 - _C7 alkyl, _C1 - _C7 haloalkyl, _C1 - _C7 alkoxy, 4-10 membered heterocyclic groups optionally substituted with halogen, amino, hydroxy, mercapto, cyano, _C1 - _C4 alkyl, C1 _{- C4} haloalkyl, C1 _{- C4} hydroxyalkyl and C1- _C4 alkoxy, and _C3 -C10 cycloalkyl groups optionally substituted with halogen, amino, hydroxy, mercapto, cyano, _C1 - _C4 alkyl, _C1 - _{C4 haloalkyl} , _{C1 - C4} hydroxyalkyl and _C1 - _C4 alkoxy.

In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof.

Among them, ^X2 , A, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 are as defined in compound (I).

In some embodiments of compounds of formula (II), ^X2 is NH; A is an imidazolyl; ^R1 is a 5-membered heteroaryl containing at least one N atom, or ^R1 is an oxadiazolyl or thiadiazolyl group, wherein the 5-membered heteroaryl, oxadiazolyl, or thiadiazolyl group is substituted by one ^R1a ; ^R1a is a group substituted by two Re ^atoms . ^Re is fluorine; ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of compounds of formula (II), ^X2 is NH; A is... ^R1 is an oxadiazole group or a thiadiazole group, wherein the oxadiazole group or thiadiazole group is substituted by one ^R1a ; ^R1a is ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or its stereoisomer or a pharmaceutically acceptable salt thereof.

Among them, ^X2 , A, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 are as defined in compound (I).

In some embodiments of the compound of formula (III), ^X2 is NH; A is thiazolyl; ^R1 is a 5-membered heteroaryl containing at least one N atom, or ^R1 is oxadiazolyl or thiadiazolyl, said 5-membered heteroaryl, oxadiazolyl or thiadiazolyl is substituted by one ^R1a ; ^R1a is selected from methyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclobutyl or cyclopentyl, each optionally substituted by one or two ^Re ; ^Re is independently fluorine, methyl, ethyl or cyclopropyl; ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is ^R5a is selected from piperazinyl and propynyl groups, each substituted by one ^Rf ; ^Rf is selected from methyl, oxecyclobutyl, ... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of the compound of formula (III), ^X2 is NH; A is thiazolyl; ^R1 is a 5-membered heteroaryl containing at least one N atom, or ^R1 is oxadiazolyl or thiadiazolyl, said 5-membered heteroaryl, oxadiazolyl or thiadiazolyl is substituted by one ^R1a ; ^R1a is selected from methyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclobutyl or cyclopentyl, each optionally substituted by one or two ^Re ; ^Re is independently fluorine, methyl, ethyl or cyclopropyl; ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of compounds of formula (III), ^X2 is NH; A is... ^R1 is oxadiazolyl or thiadiazolyl, wherein the oxadiazolyl or thiadiazolyl group is substituted by one ^R1a ; ^R1a is selected from methyl, _C3 alkyl, _C4 alkyl, _C5 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl groups, each optionally substituted by two cyclopropyl groups, one fluorine group, two methyl groups, or two fluorine groups; ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of compounds of formula (III), ^X2 is NH; A is... ^R1 is an oxadiazolyl or thiadiazolyl group, wherein the oxadiazolyl or thiadiazolyl group is substituted by one ^R1a ; ^R1a is selected from methyl, n-propyl, isopropyl, and propyl groups, each optionally substituted by two cyclopropyl groups, one fluorine group, two methyl groups, or two fluorine groups. Cyclopropyl or cyclopentyl; ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of compounds of formula (III), ^X2 is NH; A is... ^R1 is an oxadiazole or thiadiazole group, wherein the oxadiazole or thiadiazole group is substituted by one ^R1a ; ^R1a is selected from isopropyl, cyclopentyl, ... Or a cyclopropyl group substituted with two methyl groups; ^R2 and ^R3 are both methyl; ^R4 is ethyl; R5 is ^{... R6} , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of compounds of formula (III), ^X2 is NH; A is an imidazolyl group; L is ^NR13 , and ^R1 and ^R13 and the atoms they are attached to together form ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments of the compound of formula (III), ^X2 is NH; A is an imidazolyl group; L is ^NR13 , and ^R1 and ^R13 and the atoms they are attached to together form ^R2 and ^R3 are both methyl; ^R4 is ethyl; ^R5 is... ^R6 , ^R7 , ^R8 and ^R9 are all hydrogen.

In some embodiments, the compounds disclosed herein, or their stereoisomers, or pharmaceutically acceptable salts thereof, are selected from the following compounds, or their stereoisomers, or pharmaceutically acceptable salts thereof.

On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), formula (II) or formula (III) of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

On the other hand, this disclosure provides a method for treating an individual (e.g., a mammal) with a disease mediated by RAS, comprising administering to an individual (e.g., a mammal, preferably a human) a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

On the other hand, this disclosure provides the use of compounds of formula (I), formula (II) or formula (III) or their stereoisomers or pharmaceutically acceptable salts or their pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of RAS-mediated diseases.

On the other hand, this disclosure provides the use of compounds of formula (I), formula (II) or formula (III) or their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the prevention or treatment of RAS-mediated diseases.

On the other hand, this disclosure provides compounds of formula (I), formula (II) or formula (III) for the prevention or treatment of RAS-mediated diseases, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

In some implementations, the RAS-mediated disease is a tumor.

The compounds of formula (I), formula (II) or formula (III) disclosed herein, or their stereoisomers or pharmaceutically acceptable salts thereof, can selectively inhibit RAS proteins, prevent or treat RAS-mediated diseases, have a killing effect on RAS protein-associated tumor cells, and can treat tumors mediated by RAS protein mutations.

Terminology Definitions and Explanations

Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

In this article Indicates the connection site.

Some of the compounds disclosed herein can exist as trans-restricted isomers, which are conformational isomers that occur when rotation around a single bond in the molecule is prevented or significantly slowed down due to steric interactions with other parts of the molecule. The compounds disclosed herein include all trans-restricted isomers, which can be pure, single trans-restricted isomers, trans-restricted isomers enriched in one of them, or nonspecific mixtures of each. Separation of isomers is permitted if the rotational potential around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow. For example, (or )and (or ) is a pair of transisomers, wherein the pyridyl group is an inhibitor of transisomers. This indicates that the orientation of this three-dimensional object is outward. This indicates that the orientation of this three-dimensional object is inward.

The diagrammatic representation of racemic or enantiomerically pure compounds in this article is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge-shaped real and wedge-shaped imaginary bonds are used. The absolute configuration of a solid center is represented by direct real keys and direct virtual keys. It indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

When one of the variables is selected as a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L represents a bond in A-L-Z, it means that the structure is actually A-Z.

If the linking group mentioned in this article does not specify its linking direction, then its linking direction is arbitrary. For example, when the structural unit... When ^L1 is selected from " _C1 - _C3 alkylene-O", ^L1 can either connect ring Q and ^R1 in a left-to-right direction to form "Cyclo- _QC1 - _C3 alkylene- ^OR1 ", or connect ring Q and ^R1 in a right-to-left direction to form "Cyclo- _QOC1 - _C3 alkylene- ^R1 ".

The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds, and therefore may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups or other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents, and mixtures thereof, are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally _” substituted with one or more halogens means that the ethyl group can be unsubstituted ( _CH₂CH₃ ), monosubstituted ( _CH₂CH₂F , _CH₂CH₂Cl , etc. ₎ , polysubstituted ( _{CHFCH₂F, CH₂CHF₂ , CHFCH₂Cl , CH₂CHCl₂} , _etc. ), or fully substituted ( _{CF₂CF₃ , CF₂CCl₃} , _{CCl₂CCl₃ , etc.} ). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and/or cannot be synthesized is _introduced .

When any variable (e.g., ^Ra , ^Rb ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is replaced by two ^Rb , then each ^Rb has an independent option.

In this article, C_{_m}-C_{_n} refers to a group having an integer number of carbon atoms within the range of mn. For example, "C _₁-C_₁₀" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

The term "alkyl" refers to a hydrocarbon group with the general formula _{CnH2n +1} , which can be straight-chain or branched. The term " _C1 - _C10 alkyl" can be understood as representing a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc.; the term " _C1 -C1" is also mentioned. " _7- alkyl" can be understood as referring to an alkyl group having 1 to 7 carbon atoms, specific examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term " _C1 - _C5 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 5 carbon atoms. The term " _C1 - _C4 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms. The term " _C1 - _C3 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The term " _C5 - _C10 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 5 to 10 carbon atoms. The term " _C1 - _C10 alkyl" may include ranges such as " _C1 - _C6 alkyl", " _C1 - _C4 alkyl", " _C1 - _C3 alkyl", or " _C5 - _C10 alkyl", and " _C1 - _C6 alkyl" may further include " _C1 - _C4 alkyl" or " _C1 - _C3 alkyl". The term "halogenated alkyl" is intended to include both monohalogenated and polyhalogenated alkyl. For example, the term " _C1 - _C10 haloalkyl" means a _C1 - _C10 alkyl group as defined above that is substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols, and can be understood as "alkyloxy" or "alkyl-O-", where alkyl is as defined above. The term " _C1 - _C10 alkoxy" can be understood as " _C1 - _C10 alkyloxy" or " _C1 - _C10 alkyl-O-"; the term " _C1 - _C7 alkoxy" can be understood as " _C1 - _C7 alkyloxy" or " _C1 - _C7 alkyl-O-". The " _C1 - _C10 alkoxy" may include the ranges of "C1- _C7 alkoxy" and " _C1 - _C3 alkoxy", and the " _C1 - _C7 alkoxy" may _further include " _C1 - _C3 alkoxy".

The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. The term " _C2 - _C10 alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, ₉ , or 10 carbon atoms. The term " _C6 - _C10 alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 6, 7, 8, 9, or 10 carbon atoms. "C2- _C10 alkenyl" can include " _C2 - _C6 alkenyl,"" _C2 - _C4 alkenyl,"" _C6 - _C10 alkenyl," _C2 , or _C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds can be separable or conjugated. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, etc.

The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having at least one triple bond, consisting of carbon and hydrogen atoms. The term " _C2 - _C10 alkynyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of " _C2 - _C10 alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH3 _{, -CH2C≡CH} ), but-1-alkynyl, but-2-alkynyl, or but-3-alkynyl. " _C2 - _C10 alkynyl" can include " _C2 - _C3 alkynyl," and examples of " _C2 - _C3 alkynyl" include ethynyl (-C≡CH), propynyl ( _-C≡CCH3 ), and propynyl ( _-CH2C≡CH ).

The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term " _C3 - _C12 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. The term " _C3 - _C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms. The term "cycloalkylene" is a residue derived from a cycloalkyl group by further removing a hydrogen atom.

The term "heterocyclic group" or "heterocycle" refers to a fully saturated or partially saturated (not aromatic as a whole) monocyclic, fused-ring, spirocyclic, or bridged-ring group whose ring atoms contain 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3 or 1-2) heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). The "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O) _2- , -S(=O)-, -P(=O) _2- , -P(=O)-, -PH(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=O)N=, or -NHC(=O)NH-, etc. The term "4-10 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and whose ring atoms contain 1, 2, 3, 4, or 5 independently selected heteroatoms or heterogroups as described above. "4-10 membered heterocyclic group" can include "4-7 membered heterocyclic group". The term "4-7 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, or 7 ring atoms, and whose ring atoms contain 1, 2, 3, 4, or 5 independently selected heteroatoms or heterogroups as described above. Specific examples of 4-membered heterocyclic groups include, but are not limited to, azirrocyclobutane or oxocyclobutane; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, trithiaalkyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazacycloheptane. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group can be a benzofused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl, etc. The term "4-10 membered heterocyclic group" can include the ranges of "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocyclic alkyl group", "5-10 membered heterocyclic alkyl group", "4-7 membered heterocyclic alkyl group", "5-6 membered heterocyclic alkyl group", and "6-8 membered heterocyclic alkyl group". "4-7 membered heterocyclic group" can further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocyclic alkyl group", "4-6 membered heterocyclic alkyl group", and "5-6 membered heterocyclic alkyl group". Although some bicyclic heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is non-aromatic. The term "hypo-heterocyclic group" refers to a residue derived by further removing a hydrogen atom from a heterocyclic group.

The term "heterocyclic alkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O) _2- , -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "4-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4, or 5 independently selected heteroatoms or heteroatom groups as described above. The term "5-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heterogroups independently selected from those described above. "4-10-membered heterocyclic alkyl" and "5-10-membered heterocyclic alkyl" include "4-7-membered heterocyclic alkyl", wherein specific examples of 4-membered heterocyclic alkyl include, but are not limited to, acridine, oxadiazolyl, or thiobutylcycloyl; specific examples of 5-membered heterocyclic alkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocyclic alkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and specific examples of 7-membered heterocyclic alkyl include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term " _C6 - _C10 aryl" can be understood as an aryl group having 6 to 10 carbon atoms. The term " _C6 - _C7 aryl" can be understood as an aryl group having 6 to 7 carbon atoms. Examples include a ring with 6 carbon atoms (" _C6 aryl"), such as phenyl; or a ring with 9 carbon atoms (" _C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms (" _C10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. The term "aryl derivative" refers to a residue derived from an aryl group by further removing a hydrogen atom.

The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system that is aromatic in nature as a whole, containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C. The term "5-12-membered heteroaryl" can be understood to include monocyclic or bicyclic aromatic ring systems that have 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, for example, 5, 6, 9, 10, 11, or 12 ring atoms, and contain 1, 2, 3, 4, or 5 heteroatoms, for example, 1, 2, or 3 independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, or 1,2,5-thiadiazolyl, as well as their benzo[a] derivatives, such as benzofuranyl, benzothienyl, and benzothiazolyl. Benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, or isoquinolinyl, etc.; or acridineyl, indazinyl, purine, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthidyl, pteridineyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, or phenotoxazinyl, etc. The term "6-10-membered heteroaryl" can be understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9, or 10 ring atoms, for example, 6, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5, for example 1, 2, or 3 heteroatoms independently selected from N, O, and S. The term "5-6 heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1, 2, or 3 heteroatoms, for example 1-2, independently selected from N, O, and S. The term "hybrid aryl" refers to a residue derived from a heteroaryl by further removing a hydrogen atom.

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

The term "hydroxyl group" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "amino" refers to the _-NH2 group.

The term "nitro" refers to the _-NO2 group.

The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

(i) Suppress the disease or disease state, that is, curb its development;

(ii) To alleviate the disease or disease state, that is, to make the disease or disease state disappear.

The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, and (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in an individual (e.g., a mammal), particularly when such an individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed with the disease state.

The term "individual" includes both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and/or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid or base salt of the compounds of this disclosure, including salts formed by the compounds of this disclosure with inorganic or organic acids, and salts formed by the compounds of this disclosure with inorganic or organic bases.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word “comprise” or “include” and its English variants such as comprises or comprising can be understood as having an open, non-exclusive meaning, that is, “including but not limited to”.

This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^31P , ^32P , ^35S , ^18F , ^123I , ^125I , and ^36Cl , respectively.

Certain isotopically labeled compounds of this disclosure (e.g., labeled with ^3H and ^14C ) can be used in the analysis of compound and/or substrate tissue distribution. Tritium (i.e., ^3H ) and carbon-14 (i.e., ^14C ) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emission isotopes, such as ^15O , ^13N , ^11C , and ^18F , can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of this disclosure can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents using a procedure similar to those disclosed in the schemes and/or examples below.

The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

The dosage is determined based on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), and the specific circumstances of the case, including, for example, the specific formulation administered, the route of administration, the condition being treated, and the subject or host being treated.

In all methods of administration of the compounds of general formula (I) described herein, in the case of oral administration, the daily dose is from 0.001 mg/kg to 5000 mg/kg body weight, preferably from 0.01 mg/kg to 100 mg/kg body weight, in the form of single or separate doses. The daily dose and unit dose may vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the route of administration, the individual subject's requirements, the severity of the disease or condition to be treated, and the practitioner's judgment.

The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

Abbreviations:

EA represents ethyl acetate; TMSCHN ₂ represents trimethylsilyl diazomethane; DMAP represents 4-dimethylaminopyridine; NMP represents N-methylpyrrolidone; LDA represents lithium diisopropylaminoacetate; DTBA represents di-tert-butyl azodicarbonate; DMPUN represents N,N-dimethylpropenylurea; BPMPO represents _N1 , _N2 -bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide; TBDPSCl represents tert-butyldiphenylchlorosilane; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; MeOH represents methanol; TsOH ^· _H2O represents p-toluenesulfonic acid monohydrate; n-BuLi represents n-butyllithium; Boc _2O represents di-tert-butyl dicarbonate; TFA: trifluoroacetic acid; DIEA or DIPEA represents N,N-diisopropylethylamine; Pd(dppf)Cl ₂ represents [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; Pd(dtbpf)Cl ₂ represents 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate); Et ₃ N or TEA represents triethylamine; PPh ₃ represents triphenylphosphine; Pd(PPh ₃ ) ₂ Cl ₂ represents bis(triphenylphosphine)palladium dichloride; Ru-L(S,S) represents (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride; [Ir(cod)Cl ₂ represents 1,5-cyclooctadiene iridium chloride dimer; B ₂ Pin ₂ represents bis-pinacol borate or 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane); COMU represents (2-oxime-cyanoethyl acetate)-N,N-dimethyl-morpholinourea hexafluorophosphate; ACN/MeCN represents acetonitrile; NIS represents N-iodosuccinimide; KOAc represents potassium acetate; DME represents ethylene glycol dimethyl ether; EtI represents iodoethane; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT represents 1-hydroxybenzotriazole; AcOH represents acetic acid; Boc represents tert-butyloxycarbonyl; toluene represents toluene; TBAF represents tetrabutylammonium fluoride; DMSO represents dimethyl sulfoxide; NMM represents N-methylmorpholine; (CH ₂ O)n represents paraformaldehyde; dioxane represents 1,4-dioxane; CDI represents 1,1-carbonyldiimidazole; Oxone represents potassium peroxymonosulfonate; Piperidine represents piperidine; t-BuOH represents tert-butanol; tBuXPhos Pd G3 represents methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); PE represents petroleum ether; TLC represents thin-layer chromatography; FA represents formic acid; mCPBA represents m-chloroperoxybenzoic acid; TMSCN represents trimethylcyanosilane; Pyridine represents pyridine; DCE represents 1,2-dichloroethane; NMI represents N-methylimidazole; Ac ₂ O represents acetic anhydride; TCFH represents N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate; Pd ₂ (dba) ₃ represents tris(dibenzylacetone)palladium; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry; ^1H NMR represents proton nuclear magnetic resonance spectroscopy; ESI represents electrospray ionization; PBS represents phosphate buffer; _IC50 represents half-maximum inhibitory concentration, which is the concentration at which half of the maximum inhibition effect is achieved.

Example

The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed herein, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation thereof. The present disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

Unless otherwise stated, the proportions of mixed solvents are volume-based.

Unless otherwise stated, % refers to weight percentage (wt%).

Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

The structure of the compounds was determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The NMR shift was expressed in units of ^10⁻⁶ (ppm). The solvents used for NMR measurements included deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol, with tetramethylsilane (TMS) as the internal standard.

The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

Preparation Example

Preparation Example 1: Synthesis of intermediate compound Int-1

Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionic acid (compound A2)

tert-butyldiphenylchlorosilane (76.82 g, 279.35 mmol), imidazole (19.02 g, 279.35 mmol), and compound A1 (30 g, 253.96 mmol) were added to dichloromethane (1000 mL). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH 5 with 2N HCl. The solution was extracted three times with dichloromethane (100 mL). The resulting organic phases were combined, washed twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound A2 (88 g, 246.82 mmol, yield: 97.19%). The product was used directly in the next step without purification.

Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (compound A3)

Compound A2 (88 g, 246.82 mmol) was dissolved in dichloromethane (1000 mL) at 0 °C. Under nitrogen protection, N,N-dimethylformamide (1.80 g, 24.68 mmol, 1.91 mL) was added to the solution, followed by dropwise addition of oxaloyl chloride (62.69 g, 493.65 mmol, 42.13 mL). The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by LC-MS until complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound A3 (80 g, 213.35 mmol, yield: 86.44%). The product was used directly in the next step without purification.

Step 3: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (compound A4)

Compound A3 (80 g, 213.35 mmol) was dissolved in dichloromethane (1.5 L) at 0 °C. Under nitrogen protection, tin tetrachloride solution (1 M, 213.35 mL) and 5-bromo-1H-indole (41.83 g, 213.35 mmol) were added. The reaction mixture was reacted at 0 °C for 10 hours. LC-MS showed complete consumption of the starting material and detection of the product. The reaction mixture was diluted with ethyl acetate (600 mL), washed four times with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel chromatography (ethyl acetate/tetrahydrofuran = 5/1 to 3/1) to give compound A4 (8 g, 14.97 mmol, yield: 7.01%).

MS(ESI ⁺ )m/z=534.0[M+H] ⁺ .

Step 4: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-ol (compound A5)

Compound A4 (8 g, 14.97 mmol) was dissolved in tetrahydrofuran (71.30 mL) at 0 °C. Under nitrogen protection, a 2 M lithium borohydride tetrahydrofuran solution (2 M, 18.71 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was then heated to 60 °C and reacted for 16 hours. LC-MS showed complete consumption of the starting material, and the desired compound was detected. The reaction mixture was quenched with methanol (20 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound A5 (8 g, 14.91 mmol, yield: 99.62%). No further purification was performed; it was used directly in the next step.

Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indole (compound A6)

Compound A5 (8 g, 14.91 mmol), dihydropyridine (4.37 g, 17.25 mmol), and p-toluenesulfonic acid monohydrate (2.84 g, 14.91 mmol) were dissolved in dichloromethane (150 mL) and stirred at 0 °C for 2 hours under nitrogen protection. LC-MS showed complete consumption of the reactants and detection of the desired compound. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was washed three times with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give compound A6 (7 g, 13.45 mmol, yield: 90.19%).

MS(ESI ⁺ )m/z=520.0[M+H] ⁺ .

Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (compound Int-1)

Compound A6 (3 g, 5.76 mmol) was dissolved in tetrahydrofuran (10 mL), and _I₂ (1.46 g, 5.76 mmol) and silver trifluoromethanesulfonate (1.78 g, 6.92 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed complete consumption of the reactants, and the desired compound was detected. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated _{Na₂S₂O₃ aqueous solution} (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 10/1) to give compound Int-1 (973 mg, 1.51 mmol, yield: 26.12%).

MS(ESI ⁺ )m/z=646.1[M+H] ⁺ .

Preparation Example 2: Synthesis of intermediate compound Int-2

The first step is the synthesis of (4-bromothiazol-2-yl)methanol (compound B2).

Compound B1 (10 g, 52 mmol) was added to methanol (15 mL) with sodium borohydride (2.95 g, 78.11 mmol), and the mixture was stirred at 0 °C for 0.5 h. Thin-layer chromatography showed that compound B1 reacted completely. The reaction was quenched by adding 10 mL of dilute hydrochloric acid (1 M). The reaction mixture was concentrated under reduced pressure to remove the solvent, giving compound B2 (9 g, 46.38 mmol, yield 89.07%).

MS(ESI ⁺ )m/z=194.3[M+H] ⁺ .

Step 2: Synthesis of 4-bromo-2-(bromomethyl)thiazole (compound B3)

Carbon tetrabromide (23.07 g, 69.57 mmol), compound B2 (9 g, 46.38 mmol), and triphenylphosphine (18.25 g, 69.57 mmol) were added to 120 mL of dichloromethane at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0-10%) to give compound B3 (9.0 g, 35.20 mmol, yield: 75.9%). MS (ESI ⁺ ) m/z = 255.7 [M+H] ⁺ .

Step 3: Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5)

(R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B4, 7.10 g, 38.53 mmol) was added to tetrahydrofuran (100 mL), and n-butyllithium (16.81 mL, 42.03 mmol, 2.5 M) was slowly added at -78 °C. After addition, the mixture was stirred at -78 °C for 0.5 h. Compound B3 (9.0 g, 35.20 mmol) was added to the mixture, and the mixture was stirred at -78 °C for 1 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (100 mL × 2), and the organic layer was evaporated to dryness and purified by silica gel column chromatography (0-15% petroleum ether/ethyl acetate) to give compound B5 (10.5 g, 29.14 mmol, yield: 83%).

MS(ESI ⁺ )m/z=360.2[M+H] ⁺ .

Step 4: Synthesis of (S)-2-amino-3-(4-bromothiazol-2-yl)propionate (B6)

Hydrochloric acid (195 mL, 0.3 M) was added to an acetonitrile solution (60 mL) of compound B5 (10.5 g, 29.14 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS until complete. The mixture was alkalized to pH 8 with saturated sodium bicarbonate solution. It was then extracted with ethyl acetate (100 mL × 6), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum to give compound B6 (6.8 g, 25.65 mmol, yield: 88%).

MS(ESI ⁺ )m/z=264.9[M+H] ⁺ .

Step 5: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propionate (compound B7)

Triethylamine (8.94 mL, 64.12 mmol) and di-tert-butyl dicarbonate (8.4 g, 38.47 mmol) were added separately to a solution of compound B6 (6.8 g, 25.65 mmol) in dichloromethane (80 mL). The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The reaction was quenched with water (75 mL) and extracted with dichloromethane (75 mL × 2). The organic layer was evaporated to dryness and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0-30%) to give compound B7 (6.5 g, yield: 68%).

MS(ESI ⁺ )m/z=364.9[M+H] ⁺ .

Step 6: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid (compound B8)

Compound B7 (6.5 g, 17.44 mmol) and lithium hydroxide monohydrate (2.93 g, 69.76 mmol) were added to a mixed solvent of tetrahydrofuran (60 mL), methanol (5 mL), and water (20 mL). The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was acidified to pH 5 with 1 M hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound B8 (6 g, 17.08 mmol, yield: 98%).

MS(ESI ⁺ )m/z=351.2[M+H] ⁺ .

Step 7: Synthesis of (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (compound Int-2)

(S)-hexahydropyridazine-3-carboxylic acid methyl ester (trifluoroacetate) (compound B9, 757.75 mg, 2.04 mmol), compound B8 (550 mg, 1.57 mmol), N-methylmorpholine (956 mg, 9.45 mmol), 1-hydroxybenzotriazole (639 mg, 4.73 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (906 mg, 4.73 mmol) were added to a solution of dichloromethane (4 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS until complete. The reaction was quenched with water (15 mL) and extracted with dichloromethane (15 mL × 2). The organic layer was dried, filtered, and the filtrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0-50%) to give compound Int-2 (600 mg, 1.26 mmol, yield: 80.12%).

MS(ESI ⁺ )m/z=477.1[M+H] ⁺ .

Preparation Example 3: Synthesis of intermediate compound Int-3

Step 1: Synthesis of (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (compound C2)

Under _N2 protection, a solution of formic acid (6.63 g, 143.98 mmol, 5.43 mL) in triethylamine (72.84 g, 719.88 mmol, 100.41 mL) was cooled to 0 °C. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (379 mg, 599.90 μmol) was added. The reaction solution was heated to 40 °C and stirred for 15 min, then cooled to room temperature. Compound C1 (12 g, 59.99 mmol) was added, and the reaction solution was heated to 40 °C and stirred for 2 h. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure and purified by column chromatography to give compound C2 (12 g, 59.41 mmol, yield: 99%).

MS(ESI ⁺ )m/z=202.1[M+H] ⁺ .

Step 2: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)pyridine (compound C3)

Under _N2 protection, a solution of compound C2 (12.00 g, 59.41 mmol) in N,N-dimethylformamide (75 mL) was cooled to 0 °C, and sodium hydride (2.85 g, 71.27 mmol, 60% purity) was added. The mixture was stirred at 0 °C for 15 min, then iodomethane (16.86 g, 118.78 mmol) was added, and the mixture was allowed to warm to room temperature naturally and stirred for 2 h. The reaction solution was slowly added to ice water (750 mL), and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound C3 (11 g, 50.9 mmol, yield: 86%). MS (ESI ⁺ ) m/z = 216.1 [M+H] ⁺ .

Step 3: Synthesis of 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-ylboronic acid (compound C4)

4,4'-di-tert-butyl-2,2'-bipyridine (931.61 mg, 3.47 mmol) and 1,5-cyclooctadiene iridium chloride dimer (466.30 mg, 694.20 mmol) were added to a tetrahydrofuran (50 mL) solution of compound C3 (5.0 g, 23.14 mmol) and bis-pinacol boronic acid ester (8.81 g, 34.71 mmol) under _a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS until complete, with no starting material remaining. The mixture was concentrated under reduced pressure. The resulting mixture was dissolved in ethyl acetate (30 mL), and the pH was adjusted to 10 with a solution of water (600 mL) containing sodium carbonate (40 g) and sodium hydroxide (10 g). Extraction was performed with ethyl acetate (100 mL). The aqueous phase was acidified to pH 6 with hydrochloric acid (6M) to give compound C4 (4.5 g, 17.3 mmol, yield: 75%).

MS(ESI ⁺ )m/z=260.0[M+H] ⁺ .

Step 4: Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (compound C5)

Compound C4 (4.5 g, 17.3 mmol) and N-iodosuccinimide (36.70 g, 163.14 mmol) were added to acetonitrile (50 mL) under _N2 protection. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LC-MS until complete. The resulting mixture was dissolved in dichloromethane (80 mL), washed with saturated sodium thiosulfate aqueous solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 0-15%) to give compound C5 (4.3 g, 12.6 mmol, yield: 73%). MS (ESI ⁺ ) m/z = 341.8 [M+H] ⁺ .

Step 5: Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound C7)

Under _N2 protection, compounds C5 (4.3 g, 12.6 mmol), C6 (2.77 g, 12.57 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP) (156.59 mg, 251.48 μmol), palladium acetate (141.15 mg, 628.71 μmol), _Cs₂CO₃ (10.24 g, 31.44 mmol), and toluene (50 mL ₎ were mixed in a sealed tube. The resulting solution was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LC-MS to ensure complete reaction. After the reaction was complete, the reaction mixture was cooled to 25 °C. The mixture was extracted with ethyl acetate (80 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified the crude product by silica gel column chromatography (petroleum ether/ethyl acetate: 0-45%) to give compound C7 (3.6 g, 8.29 mmol, yield: 65.92%).

MS(ESI ⁺ )m/z=434.2[M+H] ⁺ .

Step 6: Synthesis of (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound Int-3)

Compound C7 (9.6 g, 22.10 mmol), _B2Pin2 (28.06 g, 110.52 mmol), and potassium acetate (6.51 g, 66.31 mmol) were dissolved in 1,4-dioxane ₍ 100 mL). Under nitrogen protection, Pd(dppf) _Cl2 (1.62 g, 2.21 mmol) was added to the reaction solution, and the nitrogen atmosphere was purged five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored for completeness. The mixture was then filtered and concentrated under reduced pressure. Ethyl acetate (100 mL) and 6N HCl (100 mL) were added, and the mixture was stirred for 16 hours. The mixture was then filtered, concentrated under reduced pressure, and purified by reverse-phase silica gel column chromatography (water/acetonitrile = 1/0 to 1/1) to give compound Int-3 (4.6 g, 9.52 mmol, yield: 43.06%).

MS(ESI ⁺ )m/z=482.2[M+H] ⁺ .

Preparation Example 4: Synthesis of intermediate compound Int-4

The first step was the synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D1).

Compounds Int-1 (4 g, 6.19 mmol), Int-3 (4.47 g, 9.28 mmol), and potassium carbonate (2.57 g, 18.56 mmol) were dissolved in a solution of ethylene glycol dimethyl ether (40 mL) and water (8 mL). Under nitrogen protection, Pd(dppf) _Cl₂ (452.74 mg, 618.74 μmol) was added to the reaction solution, and the nitrogen atmosphere was purged five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored for completeness by LC-MS. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0–1/5) to give compound D1 (2.3 g, 2.63 mmol, yield: 42.49%).

MS(ESI ⁺ )m/z=873.3[M+H] ⁺ .

The second step involves the synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D2).

Compound D1 (2.3 g, 2.63 mmol) was dissolved in DMF (30 mL), and cesium carbonate (2.57 g, 7.89 mmol) and iodoethane (820.88 mg, 5.26 mmol) were added in portions. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound D2 (2.0 g, crude product). This was used directly in the next step.

MS(ESI ⁺ )m/z=901.3[M+H] ⁺ .

The third step is the synthesis of (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D3).

Compound D2 (2.0 g, crude) was dissolved in tetrahydrofuran (30 mL), and TBAF (1 M, 22.17 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was concentrated under reduced pressure and purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1) to give the less polar isomer, compound D3 (0.5 g, 753.42 μmol, yield: 33.4%).

MS(ESI ⁺ )m/z=663.3[M+H] ⁺ .

Step 4: Synthesis of (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D4)

Compound D3 (0.5 g, 753.42 μmol), bis-pinacol boronic acid ester (573.96 mg, 2.26 mmol), and potassium acetate (184.86 mg, 1.88 mmol) were dissolved in toluene (10 mL). Under nitrogen protection, Pd(dppf) _Cl₂ (55.13 mg, 75.34 μmol) was added to the reaction solution, and the nitrogen atmosphere was purged five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored for completeness by LC-MS. The solution was filtered and concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0–1/3) to give compound D4 (0.4 g, 562.82 μmol, yield: 74.7%).

MS(ESI ⁺ )m/z=711.4[M+H] ⁺ .

Step 5: Synthesis of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (compound D5).

Compound D4 (260 mg, 365.83 μmol), compound Int-2 (174.64 mg, 365.83 μmol), and potassium phosphate (232.96 mg, 1.10 mmol) were dissolved in a mixed solution of dioxane (1 mL), toluene (3 mL), and water (1 mL). Under nitrogen protection, Pd(dtbpf) _Cl₂ (23.84 mg, 36.58 μmol) was added to the reaction solution, and nitrogen was purged five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored by LC-MS to ensure complete reaction. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/3) to give compound D5 (270 mg, 275.17 μmol, yield: 75.22%).

MS(ESI ⁺ )m/z=981.4[M+H] ⁺ .

Step 6: Synthesis of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid (compound D6).

Compound D5 (270 mg, 275.17 μmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (32.95 mg, 1.38 mmol) was added to the reaction solution, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The solution was diluted with ethyl acetate (30 mL) and water (30 mL). The aqueous phase was adjusted to pH 6 with 1 M HCl aqueous solution, and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid compound D6 (220 mg, 227.47 μmol, yield: 82.66%).

MS(ESI ⁺ )m/z=967.5[M+H] ⁺ .

Step 7: Synthesis of compound D7

Compound D6 (210 mg, 217.13 μmol), DIEA (1.12 g, 8.69 mmol, 1.51 mL), EDCI (1.25 g, 6.51 mmol), and HOBt (293.39 mg, 2.17 mmol) were dissolved in acetonitrile (5 mL). The mixture was stirred at 25 °C for 16 hours, and the reaction was monitored by LC-MS until complete. The solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/4) to give compound D7 (130 mg, 136.96 μmol, yield: 63.08%).

MS(ESI ⁺ )m/z=949.3[M+H] ⁺ .

Step 8: Synthesis of compound D8

Compound D7 (130 mg, 136.96 μmol) was dissolved in methanol (10 mL). Pd(OH) _₂ /C (64.11 mg, 273.92 μmol, 60% purity) was added to the reaction solution under nitrogen protection. The nitrogen was then replaced five times with hydrogen. The mixture was stirred at 25 °C for 16 hours under one atmosphere of pressure. The reaction was monitored for completeness by LC-MS. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound D8 (0.1 g, 122.69 μmol, yield: 89.58%).

MS(ESI ⁺ )m/z=815.5[M+H] ⁺ .

Step 9: Synthesis of compound D9

Compound D8 (100 mg, 122.69 μmol) and acetic acid (22.10 mg, 368.08 μmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 1 hour. Then, paraformaldehyde (36.85 mg, 1.23 mmol) and _NaBH3CN (23.13 mg, 368.08 μmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was filtered and concentrated under reduced pressure to give compound D9 (80 mg, 96.49 μmol, yield: 78.65%).

MS(ESI ⁺ )m/z=829.5[M+H] ⁺ .

Step 10: Synthesis of compound Int-4

Compound D9 (80 mg, 96.49 μmol) was dissolved in methanol (10 mL). Under nitrogen protection, 4N dioxane hydrochloride solution (5 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 5 hours. The reaction was monitored by LC-MS until it was complete. The solution was concentrated by rotary evaporation to give a white solid compound Int-4 (60 mg, 82.3 μmol, yield: 85.3%).

MS(ESI ⁺ )m/z=729.4[M+H] ⁺ .

Preparation Example 5: Synthesis of intermediate compound Int-5

The first step was the synthesis of 3-(2-diazoacetyl)cyclobutane-1-one (compound E2).

Under ice bath conditions, thionyl chloride (89.12 mL, 1.23 mol) was added dropwise to a solution of compound E1 (70.0 g, 613.5 mmol) in ethyl acetate (700.0 mL). The mixture was heated to 60 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was concentrated to dryness and azeotropically treated with toluene. The crude product was dissolved in a mixed solution of tetrahydrofuran (250.0 mL) and acetonitrile (250.0 mL). At 0 °C, a 2.0 M solution of trimethylsilyl diazomethane in hexane (460.1 mL, 920.2 mmol) was added dropwise to the crude product solution, and the mixture was slowly heated to room temperature and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, and the reaction was quenched with acetic acid (50.0 mL) and water (200.0 mL). The solution was then concentrated to obtain a residue, which was diluted with a saturated aqueous sodium bicarbonate solution (200.0 mL). The obtained mixture was extracted three times with ethyl acetate (300 mL). The combined organic layers were washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound E2 (45.0 g, 325.77 mmol, yield: 53.1%).

MS m/z(ESI): 139.0[M+H] ⁺ .

Step 2: Preparation of 2-(3-oxocyclobutyl)acetic acid (compound E3)

Silver nitrate (59.0 g, 347.5 mmol) was added in portions to a mixture of water (360.0 mL) and tetrahydrofuran (720.0 mL) containing compound E2 (40.0 g, 289.6 mmol), and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated to obtain a residue. Water (1000.0 mL) was added to the residue, and the pH was adjusted to 1-2 with dilute hydrochloric acid (1.0 M). The resulting mixture was extracted five times with ethyl acetate (300 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound E3 (36.0 g, 280.91 mmol, yield: 97.0%), which was used directly in the next step without further purification.

MS m/z(ESI): 127.0 [MH] ^- .

Step 3: Preparation of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (compound E4)

Compound E3 (36 g, 280.91 mmol), (S)-4-benzyloxazolidin-2-one (49.8 g, 281.0 mmol), 4-dimethylaminopyridine (3.8 g, 31.2 mmol), and triethylamine (130.6 mL, 936.6 mmol) were sequentially added to dichloromethane (800.0 mL), followed by the addition of 2-chloro-1-methylpyridine iodide (87.7 g, 343.4 mmol) in portions. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water, and the organic phase was washed twice with water (1000.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound E4 (49.43 g, 171.64 mmol, yield: 61.1%).

MS m/z(ESI): 288.1[M+H] ⁺ .

Step 4: Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (compound E5)

Compound E4 (49.43 g, 171.64 mmol) and acetic acid (22.9 g, 381.4 mmol) were added sequentially to tetrahydrofuran (550.0 mL). The mixture was cooled to 0 °C, and sodium borohydride (5.77 g, 152.6 mmol) was added in portions. After the addition was complete, the mixture was stirred for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (150.0 mL) was slowly added dropwise to quench the reaction. The mixture was concentrated under reduced pressure to the residue. The residue was extracted three times with ethyl acetate (300.0 mL). The organic phase was washed with a saturated sodium bicarbonate aqueous solution, and the pH was adjusted to 8. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound E5 (48.68 g, 167.86 mmol, yield: 97.8%), which was used directly in the next step without further purification. MS m/z (ESI): 290.2 [M+H] ⁺ .

Step 5: Preparation of (S)-3-(2-(4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)cyclobutyl-4-methylbenzenesulfonate (compound E6)

Compound E5 (48.68 g, 167.86 mmol), 4-dimethylaminopyridine (18.2 g, 149.3 mmol), and N,N-diisopropylethylamine (48.8 mL, 280.0 mmol) were added to anhydrous dichloromethane (500.0 mL). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (39.1 g, 205.3 mmol) was added in portions. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred overnight. After the reaction was complete, the mixture was washed with water (500.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound E6 (49.8 g, 112.14 mmol, yield: 66.8%).

MS m/z(ESI): 444.1[M+H] ⁺ .

Step 6: Preparation of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (compound E7)

Compound E6 (49.8 g, 112.14 mmol) and lithium bromide (19.0 g, 219.2 mmol) were added to N-methylpyrrolidone (500.0 mL), and the reaction mixture was heated to 90 °C and stirred for 12 hours. After the reaction was completed, the mixture was diluted with saturated sodium chloride aqueous solution (1.0 L), extracted three times with ethyl acetate (300.0 mL), and the organic phase was washed once with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound E7 (34.74 g, 98.68 mmol, yield: 88.0%).

MS m/z(ESI): 352.2[M+H] ⁺ .

Step 7: Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (compound E8)

Under an argon atmosphere, compound E7 (10.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (100.0 mL), cooled to -78 °C, and then a mixture of lithium diisopropylaminocarbonate in tetrahydrofuran and n-heptane (18.5 mL, 2.0 M) was slowly added dropwise, with stirring for 0.5 h. Then, a solution of di-tert-butyl azodicarbonate (7.84 g, 34.0 mmol) in anhydrous dichloromethane (20.0 mL) was added to the above solution, and stirring continued for 0.5 h. Next, N,N-dimethylpropenylurea (109.2 g, 851.7 mmol) was slowly added to the above reaction solution, the temperature was slowly raised to room temperature, and stirring continued for 13 h. After the reaction was complete, water (100.0 mL) was added to quench the reaction, followed by the addition of lithium hydroxide monohydrate (3.58 g, 85.1 mmol), and stirring was continued at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and then diluted with saturated sodium chloride aqueous solution (200.0 mL). The solution was extracted three times with ethyl acetate (200.0 mL), and the organic phase was discarded. The aqueous phase was adjusted to pH 5 with dilute hydrochloric acid (1.0 M) and extracted three more times with ethyl acetate (200.0 mL). The organic phase was washed once with saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound E8 (1.0 g, 2.91 mmol, yield: 10.2%).

MS m/z(ESI): 343.1[M+H] ⁺ .

Step 8: Preparation of 2,3-di-tert-butyl-4-methyl(S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylic acid ester (compound E9)

At room temperature, a solution of trimethylsilyldiazomethane in n-hexane (7.3 mL, 2.0 M) was slowly added dropwise to a methanol (10.0 mL) solution of compound E8 (1.0 g, 2.91 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, a few drops of acetic acid were added to quench the reaction. The reaction solution was concentrated to give the title compound E9 (1.0 g, 2.8 mmol, yield: 96.2%).

MS m/z(ESI): 357.2[M+H] ⁺ .

Step 9: Preparation of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (compound Int-5)

At room temperature, trifluoroacetic acid (2.0 mL) was slowly added dropwise to a solution of compound E9 (706.0 mg, 1.98 mmol) in dichloromethane (6.0 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to give the title compound Int-5 (312 mg, 1.98 mmol, yield: 100.0%).

MS m/z(ESI): 157.0[M+H] ⁺ .

Preparation Example 6: Synthesis of intermediate compound Int-6

Compound Int-5 (309 mg, 1.98 mmol) and N,N-diisopropylethylamine (3.45 mL, 19.8 mmol) were added sequentially to a solution of compound B8 (695.4 mg, 1.98 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (896.3 mg, 2.38 mmol) in N,N-dimethylformamide (7.0 mL). The mixture was stirred at room temperature for 2 hours. After purification by reversed-phase silica gel column chromatography (water:acetonitrile, gradient: 95/5 to 5/95), compound Int-6 (600.0 mg, yield: 61.9%) was obtained.

MS m/z(ESI): 489.2[M+H] ⁺ .

Preparation Example 7: Synthesis of intermediate compound Int-7

Synthesis of compound F1 in the first step

Compound D4 (117.6 mg, 165.5 μmol), compound Int-6 (89 mg, 182.05 μmol), and potassium phosphate (232.96 mg, 1.10 mmol) were dissolved in a mixed solution of dioxane (1 mL), toluene (3 mL), and water (1 mL). Under nitrogen protection, Pd(dtbpf) _Cl₂ (23.84 mg, 36.58 μmol) was added to the reaction solution, and nitrogen was purged five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored by LC-MS until complete. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/3) to give compound F1 (142.2 mg, 143.16 μmol, yield: 86.5%).

MS(ESI ⁺ )m/z=993.4[M+H] ⁺ .

The second step involves the synthesis of compound F2.

Compound F1 (142.2 mg, 143.16 μmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (32.95 mg, 1.37 mmol) was added to the reaction solution, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The solution was diluted with ethyl acetate (30 mL) and water (30 mL). The pH of the aqueous phase was adjusted to approximately 6 with 1 M HCl aqueous solution. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid compound F2 (120 mg, 122.83 μmol, yield: 85.8%).

MS(ESI ⁺ )m/z=979.5[M+H] ⁺ .

The third step involves the synthesis of compound F3.

Compound F2 (120 mg, 122.83 μmol), DIEA (1.12 g, 8.69 mmol, 1.51 mL), EDCI (1.25 g, 6.51 mmol), and HOBt (293.39 mg, 2.17 mmol) were dissolved in acetonitrile (5 mL). The mixture was stirred at 25 °C for 16 hours, and the reaction was monitored by LC-MS until complete. The solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/4) to give compound F3 (35.4 mg, 36.85 μmol, yield: 30.4%).

MS(ESI ⁺ )m/z=961.1[M+H] ⁺ .

The fourth step is the synthesis of compound F4.

Compound F3 (35.4 mg, 36.85 μmol) was dissolved in methanol (10 mL). Pd(OH) _₂ /C (64.11 mg, 273.92 μmol, 20% purity) was added to the reaction solution under nitrogen protection. The nitrogen was then replaced five times with hydrogen. The mixture was stirred at 25°C for 16 hours under one atmosphere of pressure. The reaction was monitored for completeness by LC-MS. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound F4 (28 mg, 33.9 μmol, yield: 92%).

MS(ESI ⁺ )m/z=827.2[M+H] ⁺ .

Step 5: Synthesis of compound F5

Compound F4 (40.0 mg, 48.37 μmol), 3-oxetane (7.0 mg, 97 μmol), sodium cyanoborohydride (6.0 mg, 97 μmol), and acetic acid (9.0 mg, 150 μmol) were added to isopropanol (3 mL). The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound F5 (38.0 mg, 43 μmol, yield 89%).

MS(ESI ⁺ )m/z=883.4[M+H] ⁺ .

Step 6: Synthesis of compound Int-7

Compound F5 (38.0 mg, 43 μmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added dropwise to the solution at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into a saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound Int-7 (32.0 mg, 40.85 μmol, yield 95%). MS: m/z (ESI) = 783.4 [M+H] ⁺ .

Preparation Example 8: Synthesis of intermediate compound Int-8

Synthesis of compound G2 (Step 1)

Compound G1 (1.05 g, 9.08 mmol) and tert-butyl hydrazine carbamate (1.00 g, 7.57 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.74 g, 9.08 mmol), 1-hydroxybenzotriazole (1.23 g, 9.08 mmol), and N,N-diisopropylethylamine (1.96 g, 15.13 mmol, 2.64 mL). The reaction mixture was then reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give compound G2 (1.30 g, 5.64 mmol, yield: 74.5%).

MS(ESI ⁺ )m/z=231.1[M+H] ⁺ .

The second step involves the synthesis of compound Int-8.

Compound G2 (200.0 mg, 868.42 μmol) was dissolved in dioxane hydrochloride (4 mL). The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was poured into an excess of saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound Int-8 (108.5 mg, 833.39 μmol, yield: 96.0%).

MS(ESI ⁺ )m/z=131.1[M+H] ⁺ .

Preparation Example 9: Synthesis of intermediate compound Int-9

Synthesis of compound H1 in the first step

Compound F4 (100 mg, 120.91 μmol) and acetic acid (22.10 mg, 368.08 μmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 1 hour. Then, paraformaldehyde (36.85 mg, 1.23 mmol) and _NaBH3CN (23.13 mg, 368.08 μmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was filtered and concentrated under reduced pressure to give compound H1 (84 mg, 99.85 μmol, yield: 82.58%).

MS(ESI ⁺ )m/z=841.3[M+H] ⁺ .

The second step involves the synthesis of compound Int-9.

Compound H1 (84 mg, 99.85 μmol) was dissolved in methanol (10 mL). Under nitrogen protection, 4N hydrochloric acid 1,4-dioxane solution (5 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 5 hours. The reaction was monitored by LC-MS until it was complete. The solution was concentrated by rotary evaporation to give a white solid compound Int-9 (66 mg, 89.0 μmol, yield: 89.1%).

MS(ESI ⁺ )m/z=741.3[M+H] ⁺ .

Preparation Example 10: Synthesis of intermediate compound Int-10

The first step is the synthesis of compound I2.

Compound I1 (1.05 g, 11.92 mmol) and tert-butyl hydrazine carbamate (1.00 g, 7.57 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.28 g, 11.92 mmol), 1-hydroxybenzotriazole (1.61 g, 11.92 mmol), and N,N-diisopropylethylamine (1.96 g, 15.13 mmol, 2.64 mL). The reaction mixture was then reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give compound I2 (0.96 g, 4.72 mmol, yield: 62.3%).

MS(ESI ⁺ )m/z=203.1[M+H] ⁺ .

The second step involves the synthesis of compound Int-10.

Compound I2 (203.1 mg, 1000.0 μmol) was dissolved in 1,4-dioxane hydrochloric acid solution (4 mL). The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was poured into an excess of saturated sodium bicarbonate solution. The residue was then extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound Int-10 (93.8 mg, 918.4 μmol, yield: 91.0%).

MS(ESI ⁺ )m/z=103.1[M+H] ⁺ .

Preparation Example 11: Synthesis of intermediate compound Int-11

Synthesis of compound J3 in the first step

Compound J1 (40 g, 184.95 mmol) was dissolved in N,N-dimethylformamide (800 mL) and cooled to 0 °C. Sodium hydride (18.49 g, 462.38 mmol, 60%) was slowly added under nitrogen protection and stirred at 0 °C for 0.5 h. Then, J2 (58.70 g, 462.38 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C under nitrogen protection for 16 h. The reaction was monitored for completeness by LC-MS. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound J3 (45 g, 145.54 mmol, yield: 78.69%).

MS(ESI ⁺ )m/z=309.2[M+H] ⁺ .

The second step involves the synthesis of compound J4.

Compound J3 (45 g, 145.54 mmol) was dissolved in a solution of trifluoroacetic acid (120 mL) and dichloromethane (480 mL), and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was filtered and concentrated under reduced pressure to give compound J4 (14.8 g, 75.09 mmol, yield: 51.59%). MS (ESI ⁺ ) m/z = 197.1 [M+H] ⁺ .

The third step involves the synthesis of compound Int-11.

Compound J4 (14.8 g, 75.09 mmol) was dissolved in tetrahydrofuran (200 mL), and 1,1-carbonyldiimidazole (13.46 g, 83.00 mmol) was added in portions. The mixture was stirred at 25 °C for 16 hours. Then, sodium hydroxide (5 M, 45.27 mL) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to ensure complete reaction. The mixture was adjusted to pH 1 with 6N hydrochloric acid, extracted first with ethyl acetate (100 mL * 2), then with dichloromethane (100 mL * 2), and washed with brine (100 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-11 (10.6 g, 69.24 mmol, yield: 92.21%).

MS(ESI ⁺ )m/z=153.1[M+H] ⁺ .

Preparation Example 12: Synthesis of intermediate compound Int-12

The first step is the synthesis of compound K2.

Under nitrogen protection, diethyl 2-oxomalactone (23.1 g, 132.5 mmol, 20.2 mL) was added to a tetrahydrofuran (200 mL) solution of compound K1 (50.0 g, 132.5 mmol), and the mixture was reacted overnight at 70 °C. The reaction was monitored by TLC until complete. The reaction solvent was removed by vacuum distillation, and the residue was dissolved in toluene (300 mL). Then, n-heptane (60 mL) was added dropwise, and a solid precipitated. The solid was filtered, and the filtrate was concentrated to give compound K2 (25.0 g, 91.2 mmol, yield: 68.8%).

MS(ESI ⁺ )m/z=274.1[M+H] ⁺ .

The second step involves the synthesis of compound K3.

Compound K2 (10.0 g, 36.5 mmol) was dissolved in a mixed solvent of acetonitrile (80 mL) and water (60 mL). A mixture of potassium peroxymonosulfonate (53.9 g, 87.82 mmol) and sodium bicarbonate (11.4 g, 135.39 mmol) was added in portions, and the mixture was reacted at room temperature for 5 hours. The reaction was monitored by TLC until complete. The reaction solution was added to water, extracted with dichloromethane (100 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-70:30) to give compound K3 (5.2 g, 17.9 mmol, yield: 49.0%).

MS(ESI ⁺ )m/z=290.1[M+H] ⁺ .

The third step involves the synthesis of compound Int-12.

Compound K3 (4.0 g, 13.8 mmol) and compound B6 (3.7 g, 13.8 mmol) were dissolved in toluene (80 mL) and stirred overnight at room temperature under nitrogen protection. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give compound Int-12 (3.5 g, 9.2 mmol, yield: 66.7%).

MS(ESI ⁺ )m/z=380.2[M+H] ⁺ .

Preparation Example 13: Synthesis of intermediate compound Int-13

Synthesis of compound L2 in the first step

Compound L1 (128 mg, 1.0 mmol) was dissolved in sulfone dichloromethyl (5.0 mL), and zinc chloride (27.3 mg, 0.2 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give compound L2 (183 mg, 1.0 mmol, yield: 99%), which was used directly in the next step without purification.

The second step involves the synthesis of compound Int-13.

Compound Int-12 (76 mg, 0.2 mmol) was dissolved in acetone (1.0 mL) at 0 °C. Under nitrogen protection, potassium carbonate (138 mg, 1.0 mmol) and compound L2 (183 mg, 1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at 25 °C for 16 hours. LC-MS was used to monitor complete reaction, and the reaction mixture was then heated to 60 °C and stirred for 24 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography (Water/NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound Int-13 (31 mg, 0.063 mmol, yield: 31.6%).

MS(ESI+)m/z＝490.3[M+H] ⁺ .

Preparation Example 14: Synthesis of intermediate compound Int-14

Synthesis of compound M1 (Step 1)

Compound Int-11 (210.0 mg, 1.4 mmol) was added to thionyl chloride (2 mL), and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated to give compound M1 (235.0 mg, 1.4 mmol, yield: 100%).

The second step involves the synthesis of compound Int-14.

(Trimethylsilyl)diazomethane (2M, 1.5 mL) was added to a reaction flask, followed by the dropwise addition of a solution of anhydrous tetrahydrofuran (2 mL) and anhydrous acetonitrile (2 mL) of compound M1 (235.0 mg, 1.4 mmol) under ice bath conditions. The reaction was allowed to proceed at room temperature for 5 hours. Then, an aqueous solution of hydrobromic acid (40%, 2 mL) was added dropwise under ice bath conditions, and the reaction was allowed to proceed at room temperature for 18 hours. Water and ethyl acetate were added to the reaction solution, and after separation, the organic layer was washed successively with water, saturated sodium bicarbonate solution, and water, and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-85:15) to give compound Int-14 (165.0 mg, 0.72 mmol, yield: 51.4%). This compound was used directly in the next step.

Preparation Example 15: Synthesis of intermediate compound Int-15

The first step is the synthesis of compound N2.

3-Bromopropyne N1 (10.0 g, 84.06 mmol) was added dropwise to a solution of 1,4-oxazacycloheptane (8.93 g, 88.27 mmol) and potassium carbonate (29.05 g, 210.16 mmol) in N,N-dimethylformamide (100 mL), and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was poured into ethyl acetate (500 mL), washed with saturated brine (100 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to give compound N2 (6.10 g, 43.71 mmol, yield: 52%).

MS(ESI ⁺ )m/z=140.1[M+H] ⁺ .

The second step involves the synthesis of compound Int-15.

Under nitrogen protection, compound N2 (307.5 mg, 2.21 mmol), bis(triphenylphosphine)palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol), and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a 5 mL solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was poured into 50 mL of ethyl acetate, washed with 20 mL of saturated brine (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to give compound Int-15 (609.2 mg, 1.72 mmol, yield: 99%).

MS(ESI ⁺ )m/z=354.2[M+H] ⁺ .

Preparation Example 16: Synthesis of intermediate compound Int-16

Under nitrogen protection, compound O2 (450 mg, 2.6 mmol), bis(triphenylphosphine)palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol), and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a 5 mL solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was poured into 50 mL of ethyl acetate, washed with 20 mL of saturated brine (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to give compound Int-16 (561.4 mg, 1.45 mmol, yield: 83%).

MS(ESI ⁺ )m/z=387.2[M+H] ⁺ .

Preparation Example 17: Synthesis of intermediate compound Int-17

The first step is the synthesis of compound P2.

2-Amino-5-bromobenzaldehyde (5.0 g, 25.0 mmol) and ethyl nitrate (6.65 g, 49.99 mmol) were added to a mixture of acetic acid (20.0 mL) and water (20.0 mL), followed by the addition of piperidine (1.23 mL, 12.5 mmol). The mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the mixture was added dropwise to ice water, and the precipitated solid was filtered off, washed with pure water, and dried to give compound P2 (6.0 g, 22.3 mmol, yield: 89.2%). MS (ESI ⁺ ) m/z = 269.0 [MH] ^- .

The second step involves the synthesis of compound P3.

Compound P2 (2.0 g, 7.43 mmol) and benzyl piperazine-1-carboxylate (2.46 g, 11.15 mmol) were added to tert-butanol (20.0 mL), followed by the addition of methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (590.2 mg, 743.3 μmol) and potassium tert-butoxide (2.5 g, 22.3 mmol). The mixture was stirred at 90 °C under argon protection for 16 hours, and the reaction was monitored for completeness by LC-MS. The mixture was filtered, and the filtrate was extracted with water (50 mL) and concentrated to obtain the crude product. The crude product was purified by reverse-phase (Water/ _NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound P3 (1.2 g, 2.94 mmol, yield: 39.5%).

MS(ESI ⁺ )m/z=409.1[M+H] ⁺ .

The third step involves the synthesis of compound P4.

Compound P3 (1.2 g, 2.94 mmol) was added to phosphorus oxychloride (20.0 mL), and the mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the mixture was added dropwise to ice water to quench the reaction, and then extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain compound P4 (500.0 mg, 1.17 mmol, yield: 39.8%).

MS(ESI ⁺ )m/z=427.1[M+H] ⁺ .

The fourth step is the synthesis of compound P5.

Compound P4 (500.0 mg, 1.17 mmol) was added to N,N-dimethylformamide (10.0 mL), followed by bis(triphenylphosphine)palladium dichloride (82.1 mg, 117.1 μmol) and (1-ethoxyethylene)trimethylstanane (846.0 mg, 3.58 mmol). The mixture was stirred at 110 °C under nitrogen protection for 1 hour. After the reaction was complete, 1,4-dioxane hydrochloride solution (10.0 mL, 4.0 M) was added to the reaction mixture, and the mixture was stirred for 30 minutes. After the reaction was completed by TLC monitoring, the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to give compound P5 (380.0 mg, 874.7 μmol, yield: 74.7%).

MS(ESI ⁺ )m/z=435.1[M+H] ⁺ .

Step 5: Synthesis of compound P6

Compound P5 (330.0 mg, 759.5 μmol) and iron powder (849.4 mg, 15.19 mmol) were added to acetic acid ( _{10.0 mL) and stirred in an oil bath at 60 °C for 1 hour. After the reaction was completed, the residue was filtered off, the filtrate was washed with an aqueous solution of saturated ammonium chloride, extracted with ethyl acetate, and the crude product obtained by concentration of the organic phase was purified by reverse-phase reaction (Water/NH4OH} (0.5%):MeCN = 95:5 to 5:95) to give compound P6 (280.0 mg, 692.2 μmol, yield: 91.1%).

MS(ESI ⁺ )m/z=405.1[M+H] ⁺ .

Step 6: Synthesis of compound P7

Under an argon atmosphere and ice bath conditions, triethylamine (744.5 mg, 7.36 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (39.0 mg, 61.3 μmol) were added to formic acid (67.7 mg, 1.47 mmol), heated to 40 °C, and stirred for 15 minutes. The reaction solution was cooled to room temperature, and compound P6 (248.0 mg, 613.1 μmol) was added. The mixture was then heated to 40 °C and stirred for 2 hours. After the reaction was complete, the crude product obtained by concentration was purified by reverse-phase chromatography (Water/ _NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound P7 (196.0 mg, 482.1 μmol, yield: 78.6%).

MS(ESI ⁺ )m/z=407.1[M+H] ⁺ .

Step 7: Synthesis of compound P8

Under ice bath conditions, p-toluenesulfonic acid (360.0 mg, 2.09 mmol) and compound P7 (170.0 mg, 418.23 μmol) were added to acetonitrile (10.0 mL), followed by the addition of an aqueous solution of sodium nitrite (144.3 mg, 2.09 mmol) and potassium iodide (347.1 mg, 2.09 mmol). The mixture was stirred for 10 minutes under ice bath conditions, then transferred to room temperature and stirred for another hour. After the reaction was complete, a saturated aqueous solution of sodium sulfite was added to quench the reaction, and the mixture was extracted with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to give compound P8 (132.0 mg, 255.1 μmol, yield: 61.0%).

MS(ESI ⁺ )m/z=518.0[M+H] ⁺ .

Step 8: Synthesis of compound Int-17

Under an argon atmosphere and ice bath conditions, compound P8 (150.0 mg, 289.9 μmol) was added to N,N-dimethylformamide (5.0 mL) containing sodium hydride (23.2 mg, 579.9 μmol, dispersed at 60% concentration in liquid paraffin). After stirring for 10 minutes, iodomethane (82.3 mg, 579.9 μmol) was added, and the mixture was then transferred to room temperature and stirred for another hour. After the reaction was complete, the reaction solution was added dropwise to 0.5 M dilute hydrochloric acid, and then extracted with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to give compound Int-17 (132.0 mg, 248.1 μmol, yield: 85.6%).

MS(ESI ⁺ )m/z=532.0[M+H] ⁺ .

Preparation Example 18: Synthesis of intermediate compound Int-18

Synthesis of compound Q2 (Step 1)

Compound Q1 (6.00 g, 30.30 mmol) was dissolved in anhydrous ethyl acetate (80 mL), and then m-chloroperoxybenzoic acid (10.46 g, 60.60 mmol) was added. The mixture was reacted at room temperature for 30 minutes, then heated to 50 °C and reacted for another 5 hours. The reaction mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate. The filter cake was dried to give compound Q2 (5.60 g, 26.17 mmol, yield: 86.4%).

MS(ESI ⁺ )m/z=213.9[M+H] ⁺ .

The second step involves the synthesis of compound Q3.

Compound Q2 (5.40 g, 25.23 mmol) was dissolved in acetonitrile (100 mL), and then trimethylcyanosilane (5.01 g, 50.46 mmol) and triethylamine (7.66 g, 75.69 mmol, 10.55 mL) were added. The mixture was heated to 80 °C and reacted for 12 hours. The reaction solution was concentrated, and ethyl acetate (20 mL) was added to the residue and stirred. The reaction solution was filtered, and the filter cake was washed with a small amount of ethyl acetate. The filter cake was dried to give compound Q3 (4.10 g, 18.39 mmol, yield: 73%).

MS(ESI ⁺ )m/z=222.9[M+H] ⁺ .

The third step involves the synthesis of compound Q4.

At 0 °C, methyl magnesium bromide (3 M, 18 mL) was added dropwise to a tetrahydrofuran (20 mL) solution of compound Q3 (4.00 g, 17.93 mmol). The mixture was heated to room temperature and stirred for 3 hours. The reaction solution was poured into dilute hydrochloric acid (6 M, 20 mL), and the tetrahydrofuran was removed by concentration under reduced pressure. Water (60 mL) was added to the residue, and the mixture was extracted with dichloromethane (80 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound Q4 (2.80 g, 11.66 mmol, yield: 65%).

MS(ESI ⁺ )m/z=240.2[M+H] ⁺ .

Step 4: Synthesis of compound Q5

Compound Q4 (1.4 g, 5.83 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of potassium carbonate (2.4 g, 17.50 mmol) and 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (2.92 g, 9.33 mmol). The mixture was reacted at 100 °C for 8 hours. The reaction solution was filtered, and water (100 mL) was added to the filtrate. The filtrate was extracted with ethyl acetate (80 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give compound Q5 (640.0 mg, 1.40 mmol, yield: 24%).

MS(ESI ⁺ )m/z=457.0[M+H] ⁺ .

Step 5: Synthesis of compound Q6

Formic acid (130.2 mg, 2.83 mmol) was added to triethylamine (1.43 g, 14.17 mmol, 1.97 mL) at 0 °C, and nitrogen was exchanged three times. Then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (7.5 mg, 11.81 μmol) was added, and the mixture was reacted at 40 °C for 30 minutes. After cooling to room temperature, compound Q5 (540.0 mg, 1.18 mmol) was added, and the mixture was reacted at 40 °C for another 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Q6 (480.0 mg, 1.04 mmol, yield: 89%).

MS(ESI ⁺ )m/z=459.2[M+H] ⁺ .

Step 6: Synthesis of compound Q7

At 0 °C, sodium hydride (51.5 mg, 1.25 mmol, dispersed in paraffin liquid at 60% concentration) was added in portions to a solution of compound Q6 (480.0 mg, 1.04 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 0 °C for 1 hour, followed by the addition of iodomethane (296.7 mg, 2.09 mmol). The reaction was continued at 0 °C for 1 hour. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (10 mL), and then water (10 mL) was added. The mixture was extracted with ethyl acetate (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain compound Q7 (480.0 mg, 1.01 mmol, yield: 97%).

MS(ESI ⁺ )m/z=473.0[M+H] ⁺ .

Step 7: Synthesis of compound Q8

At room temperature, trifluoroacetic acid (72.3 mg, 633.76 μmol, 48.8 μL) and N-iodosuccinimide (784.2 mg, 3.49 mmol) were added sequentially to a dichloromethane (5 mL) solution of compound Q7 (1.5 g, 3.17 mmol). The mixture was heated to 40 °C and stirred for 4 hours. After the reaction solution cooled to room temperature, it was added dropwise to a saturated sodium bicarbonate solution (20 mL), followed by the addition of water (20 mL) and extraction with ethyl acetate (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:00 - 70:30) to give compound Q8 (1.40 g, 2.34 mmol, yield: 74%).

MS(ESI ⁺ )m/z=599.0[M+H] ⁺ .

The second step involves the synthesis of compound Int-18.

At room temperature, cuprous cyanide (56.2 mg, 627.51 μmol) was added to a pyridine (2 mL) solution of compound Q8 (300.0 mg, 500.62 μmol), and the mixture was heated to 100 °C and stirred for 8 hours. After the reaction was completed, the reaction solution was directly evaporated to dryness, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Int-18 (180.0 mg, 361.18 μmol, yield: 72%).

MS(ESI ⁺ )m/z=498.0[M+H] ⁺ .

Preparation Example 19: Synthesis of intermediate compound Int-19

The first step is the synthesis of compound R2.

Compound R1 (1.1 g, 10.0 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of potassium carbonate (2.4 g, 17.50 mmol) and 3-bromopropyne (1.77 g, 15.0 mmol). The mixture was reacted at 25 °C for 4 hours. The reaction solution was filtered, and water (50 mL) was added to the filtrate. The filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-30:70) to give compound R2 (940.0 mg, 6.3 mmol, yield: 63%).

MS(ESI ⁺ )m/z=149.2[M+H] ⁺ .

The second step involves the synthesis of compound Int-19.

Under nitrogen protection, compound R2 (388.0 mg, 2.6 mmol), bis(triphenylphosphine)palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol), and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a 5 mL solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was poured into 50 mL of ethyl acetate, washed with 20 mL of saturated brine (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to give compound Int-16 (450.0 mg, 1.24 mmol, yield: 71%).

MS(ESI ⁺ )m/z=362.2[M+H] ⁺ .

Example 1: Synthesis of Compound 1

Compound Int-4 (10 mg, 13.72 μmol) and compound 1A (6.71 mg, 41.16 μmol) were dissolved in DMF (2 mL), and TEA (5.69 mg, 56.21 μmol, 7.84 μL) was added in portions. The mixture was stirred at 80 °C for 20 hours. The reaction was monitored by LC-MS to ensure complete reaction. Extracted with ethyl acetate (5 mL) and water (5 mL), the organic phase was washed with saturated brine ( ₁₀ mL ₎ , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (Boston Prime C18 column; 150 _* 30 mm*5 μm; mobile phase A: _H₂O- ( _NH₃H₂O - _NH₄HCO₃ ), _NH₃H₂O concentration was 0.05%, _NH₄HCO₃ concentration was ₂ mM; mobile phase B: MeCN; MeCN ratio 40%-60%) to obtain compound 1 (1 mg, 1.23 μmol, yield: 8.99%).

MS(ESI ⁺ )m/z=811.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ＝8.52-8.40(m,2H),8.05-7.97(m,1H),7.81(s,1H),7.77-7.69(m,1H),7.55(d,J＝8.4Hz,1H) ,7.22(d,J＝2.8Hz,1H),5.29-5.14(m,2H),4.40-4.10(m,5H),3.66-3.52(m,2H),3.22-3.16(m,8 H),2.98-2.88(m,2H),2.84-2.77(m,1H),2.43-2.41(m,4H),2.31(s,3H),2.24-2.20(m,4H),2.1 0(s,1H),1.81(s,2H),1.57-1.48(m,1H),1.33(d,J＝6.0Hz,3H),0.96-0.87(m,6H),0.35(s,3H).

Example 2: Synthesis of Compound 2

Compounds Int-4 (10 mg, 13.72 μmol), 2A (2.59 mg, 13.72 μmol), and potassium phosphate (8.74 mg, 41.16 μmol) were dissolved in tert-butanol (1 mL) and stirred. Cuprous oxide (196.30 μg, 1.37 μmol) and N <sub>₁ ,N_₂-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide (576.86 μg, 1.37 μmol) were added to the reaction mixture under a nitrogen atmosphere. The nitrogen atmosphere was purged three times, and the reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LC-MS until completion. Add water (5 mL), extract with ethyl acetate (5 mL), wash the organic phase with saturated brine (10 mL ₎ , dry with anhydrous sodium sulfate, filter, concentrate the filtrate _under reduced pressure, and purify the crude product by reversed-phase column chromatography (Boston Prime C18 column; 150*30 mm*5 μm; mobile phase A: _H₂O- ( _NH₃H₂O - _{NH₄HCO₃), NH₃H₂O concentration} 0.05%, _NH₄HCO₃ concentration ₂ mM; mobile phase _B : MeCN; MeCN ratio 50%-70%, flow rate: 15 mL/min) to obtain a white solid compound 2 (1 mg, 1.2 μmol, yield: 8.7%).

MS(ESI ⁺ )m/z=837.5[M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ＝8.49(s,1H),8.45(d,J＝3.2Hz,1H),7.79(s,1H),7.76-7.70(m,1H),7.5 5(d,J＝8.4Hz,1H),7.27-7.17(m,2H),5.20-5.04(m,2H),4.38-4.07(m,5H), 3.63-3.52(m,2H),3.21(s,6H),2.22(s,3H),2.15-2.05(m,3H),2.04-1.94( m,2H),1.85-1.72(m,3H),1.60-1.43(m,2H),1.34(d,J＝6.0Hz,3H),1.24(br s,4H),1.18-1.13(m,2H),1.03-0.99(m,2H),0.94-0.84(m,7H),0.36(s,3H)

Example 3: Synthesis of Compound 3

Step 1: Synthesis of Compound 3-1

At 0 °C, cyclopentylformyl chloride (25.40 mg, 191.57 μmol) was added dropwise to a tetrahydrofuran (3 mL) solution of ammonium thiocyanate (14.39 mg, 191.57 μmol), and the mixture was stirred at room temperature for 2 hours. The above reaction solution was then added dropwise to a tetrahydrofuran (10 mL) solution of compound Int-7 (150 mg, 191.57 μmol), and the mixture was stirred at room temperature for another 2 hours. The reaction solution was concentrated, and the residue was poured into water (20 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-80:20) to give compound 3-1 (166.0 mg, 176.90 μmol, yield: 92.3%).

MS(ESI ⁺ )m/z＝938.4[M+H] ⁺

Step 2: Synthesis of Compound 3-2

Compound 3-1 (60.0 mg, 63.95 μmol) was dissolved in a mixed solvent of N,N-dimethylformamide (1 mL) and tetrahydrofuran (2 mL), followed by the addition of potassium carbonate (26.5 mg, 191.85 μmol). The mixture was stirred at room temperature for 10 minutes, and then iodomethane (18.2 mg, 127.90 μmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction solution was filtered, and the filtrate was poured into water (20 mL). The solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-70:30) to give compound 3-2 (59.5 mg, 62.47 μmol, yield: 97.7%).

MS(ESI ⁺ )m/z=952.4[M+H] ⁺ .

Step 3: Synthesis of Compound 3

Sodium acetate (12.9 mg, 157.52 μmol) was added to a methanol (2 mL) solution of hydroxylamine hydrochloride (11.0 mg, 157.52 μmol). The mixture was stirred at room temperature for 30 minutes. Then, compound 3-2 (50.0 mg, 52.51 μmol) was added, and stirring was continued at room temperature for 2 hours. The reaction solution was poured into water (20 mL), and extracted with dichloromethane (10 mL * 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative chromatography (XBridge Prep C18 column; 150 * 19 mm * 5 μm; mobile phase A: _H₂O- ( _NH₃H₂O ), _{NH₃H₂ ) .} O concentration 0.05%; mobile phase B: MeCN; MeCN ratio 50%-70%; time: 10 min; flow rate: 15 mL/min) to obtain compound 3 (12.0 mg, 13.05 μmol, yield: 24.85%).

MS(ESI ⁺ )m/z=919.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ＝8.50(d,J＝2.9Hz,1H),8.48(d,J＝1.6Hz,1H),7.62(dd,J＝8.6,1.6Hz,1H),7.35(d,J＝8.6Hz,1H),7.32(s,1H),7.11(s,1H),5.37(d,J＝10.9 Hz,1H),5.32-5.27(m,1H),5.18(d,J＝11.0Hz,1H),4.86(d,J＝10.9Hz, 1H),4.79-4.69(m,4H),4.34-4.24(m,2H),4.21-4.14(m,1H),3.75-3.6 2(m,3H),3.47-3.43(m,2H),3.38(s,3H),3.22-3.11(m,3H),2.77-2.7 0(m,2H),2.62-2.54(m,2H),2.49-2.39(m,2H),2.25-2.13(m,2H),2.12 -1.99(m,3H),1.95-1.87(m,2H),1.83-1.77(m,2H),1.70-1.64(m,4H) ,1.47-1.44(m,3H),1.33-1.30(m,2H),0.98-0.93(m,6H),0.42(s,3H).

Example 4: Synthesis of Compound 4

Synthesis of compound 4-2 (Step 1)

Compound Int-7 (100.0 mg, 127.72 μmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (33.0 mg, 255.43 μmol, 44.49 μL) was added. Then, compound 4-1 (35.6 mg, 153.26 μmol) was slowly added at 0 °C, and the mixture was reacted at 0 °C for 5 minutes. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-10:1) to give compound 4-2 (40.0 mg, 48.46 μmol, yield: 37.94%).

MS(ESI ⁺ )m/z=825.4[M+H] ⁺ .

The second step involves the synthesis of compound 4-3.

Compound Int-8 (8.0 mg, 61.45 μmol) and compound 4-2 (50.7 mg, 61.45 μmol) were dissolved in acetonitrile (1 _mL ). The mixture was reacted at 80 °C for 15 min. The reaction solution was then directly processed by high performance liquid chromatography (HPLC) column (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: _H₂O- ( _NH₃H₂O ), _NH₃H₂O concentration 0.05%; mobile phase B: MeCN; MeCN ratio 60%-70%, time: 10 min, flow rate: 15 mL _/ min) to obtain compound 4-3 (15.0 mg, 15.70 μmol, yield: 25.5%).

MS(ESI ⁺ )m/z=955.4[M+H] ⁺ .

Step 3: Synthesis of Compound 4

Compound 4-3 (10.0 mg, 10.47 μmol) was dissolved in acetonitrile (0.3 mL), followed by the addition of triphenylphosphine (5.5 mg, 20.94 μmol), N,N-diisopropylethylamine (10.8 mg, 83.75 μmol, 14.59 μL), and then hexachloroethane (5.0 mg, 20.94 μmol). The reaction was then carried out at room temperature for 12 hours. The reaction solution was concentrated, and the residue was subjected to high-performance liquid chromatography (HPLC) (XBridge Prep C18 column; 150*19 mm* _{5 μm; mobile phase A: H₂O-(NH₃H₂O ) , NH₃H₂O} concentration 0.05%; mobile phase B: MeCN; MeCN ratio 45%-70%, time: 10 min, flow rate: 15 mL _/ min) to obtain compound 4 (3.0 mg, 3.26 μmol, yield: 31.14%).

MS(ESI ⁺ )m/z=921.4[M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ＝8.45(d,J＝2.9Hz,1H),8.43(d,J＝1.6Hz,1H),8.03(d,J＝9.8Hz,1H),7.84 (s,1H),7.74(dd,J＝8.6,1.6Hz,1H),7.56(d,J＝8.7Hz,1H),7.25(d,J＝2.9Hz, 1H),6.03(d,J＝11.0Hz,1H),5.09(t,J＝8.7Hz,1H),4.72(d,J＝11.0Hz,1H),4 .56(t,J＝6.5Hz,2H),4.53-4.48(m,1H),4.48-4.43(m,2H),4.32-4.24(m,1H) ,4.18-4.12(m,2H),3.62-3.50(m,2H),3.48-3.41(m,1H),3.31-3.27(m,4H) ,3.23-3.19(m,3H),2.93(d,J＝14.4Hz,1H),2.68-2.64(m,2H),2.47-2.44(m, 2H),2.43-2.39(m,4H),2.34-2.32(m,1H),2.21-2.16(m,1H),1.69-1.54(m,6 H),1.34(d,J=6.1Hz,3H),0.93-0.86(m,6H),0.85-0.79(m,6H),0.33(s,3H).

Example 5: Synthesis of compounds 5-P1 and 5-P2

Synthesis of compound 5-1 in step one

Compound 4-1 (34.5 mg, 148.46 μmol) was slowly added to a 2 mL solution of compound Int-9 (100.0 mg, 134.96 μmol) and N,N-diisopropylethylamine (34.9 mg, 269.92 μmol, 47.01 μL) in dichloromethane at -5 °C. The mixture was reacted at -5 °C for 5 minutes. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-50:1) to give compound 5-1 (80.0 mg, 102.17 μmol, yield: 76%).

The second step involves the synthesis of compound 5-2.

Under nitrogen protection, compound 5-1 (80.0 mg, 102.17 μmol) and compound Int-10 (20.8 mg, 204.34 μmol) were dissolved in acetonitrile (1 mL). The mixture was reacted at 90 °C for 30 min. The reaction solution was then directly passed through a high-performance liquid chromatography column (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: _{H₂O- ( NH₄HCO₃} ), _NH₄HCO₃ concentration ₅ mmol/L; mobile phase B: MeCN; MeCN ratio 40%-75%, time: 15 min, flow rate: 25 mL/min) to obtain compound 5-2 (15.0 mg, 16.95 μmol, yield: 16%).

MS(ESI ⁺ )m/z=885.4[M+H] ⁺ .

Step 5: Synthesis of compounds 5-P1 and 5-P2

Compound 5-2 (10.0 mg, 11.30 μmol) was dissolved in acetonitrile (0.2 mL), followed by the addition of triphenylphosphine (5.9 mg, 22.60 μmol), N,N-diisopropylethylamine (11.6 mg, 90.38 μmol, 15.74 μL), and hexachloroethane (5.4 mg, 22.60 μmol, 2.56 μL). The mixture was reacted at room temperature for 2 hours. The reaction solution was directly passed through a high-performance liquid chromatography column (YMC TA-C18, 30*150mm, _5μm ; mobile phase A: _H₂O- ( _NH₄HCO₃ ), _NH₄HCO₃ concentration _5mmol /L; mobile phase B: MeCN; MeCN ratio 60%-90%, time: 15min, flow rate: 25mL/min) to prepare compounds 5-P1 (2.0mg, 2.33μmol, yield: 20.6%, retention time: 10.25min) and 5-P2 (1.5mg, 1.69μmol, yield: 15.0%, retention time: 11.50min).

Compound 5-P1 MS(ESI ⁺ ) m/z = 851.4 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ8.45(d,J＝2.8Hz,1H),8.43(d,J＝1.6Hz,1H),8.05(d,J＝9.8Hz,1H),7.84(s ,1H),7.76-7.71(m,1H),7.56(d,J＝8.7Hz,1H),7.24(d,J＝2.8Hz,1H),6.04(d, J＝11.0Hz,1H),5.11-5.00(m,1H),4.73(d,J＝11.0Hz,1H),4.54-4.46(m,1H),4 .34-4.23(m,1H),4.20-4.08(m,2H),3.62-3.50(m,2H),3.39-3.36(m,1H),3.3 2-3.24(m,4H),3.21(s,3H),3.20-3.15(m,1H),3.06-2.97(m,1H),2.97-2.90 (m,1H),2.71-2.60(m,2H),2.56-2.52(m,2H),2.48-2.46(m,2H),2.45-2.40(m ,1H),2.38-2.32(m,2H),2.27(s,2H),2.22-2.17(m,1H),1.69-1.61(m,1H),1. 34(d,J＝6.0Hz,3H),1.25(s,3H),1.23(s,3H),0.94-0.83(m,6H),0.33(s,3H).

Compound 5-P2 MS(ESI ⁺ ) m/z = 867.3 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ8.45(d,J＝2.9Hz,1H),8.43(d,J＝1.5Hz,1H),8.20(d,J＝9.4Hz,1H),7.83(s ,1H),7.77-7.72(m,1H),7.56(d,J＝8.6Hz,1H),7.25(s,1H),6.02(d,J＝11.0H z,1H),5.32-5.23(m,1H),4.71(d,J＝11.0Hz,1H),4.52-4.47(m,1H),4.33-4. 24(m,1H),4.20-4.09(m,2H),3.61-3.52(m,2H),3.40-3.36(m,1H),3.32-3.23 (m,4H),3.21(s,3H),3.18-3.11(m,2H),2.94(d,J＝14.4Hz,1H),2.69-2.62(m ,2H),2.55-2.52(m,2H),2.49-2.47(m,2H),2.46-2.43(m,1H),2.38-2.31(m, 2H),2.28(s,2H),2.21-2.16(m,1H),1.68-1.61(m,1H),1.34(d,J＝6.1Hz,3H) ,1.26(d,J＝2.0Hz,3H),1.25(d,J＝2.0Hz,3H),0.94-0.82(m,6H),0.33(s,3H).

Example 6: Synthesis of compounds 6-P1 and 6-P2

Synthesis of compound 6-2 in step one

At room temperature, compound 6-1 (70.0 mg, 613.27 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (349.7 mg, 919.91 μmol), and N,N-diisopropylethylamine (198.1 mg, 1.53 mmol) were added to N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 15 minutes, and then a solution of hydrazine hydrate (1.44 g, 28.8 mmol, 85%) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was poured into ethyl acetate (30 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 6-2 (70.0 mg, 546.14 μmol, yield: 89%).

MS(ESI ⁺ )m/z=129.1[M+H] ⁺ .

The second step involves the synthesis of compound 6-3.

Compound 4-2 (50.0 mg, 61.65 μmol) and compound 6-2 (15.8 mg, 123.29 μmol) were added to acetonitrile (0.5 mL), and the mixture was reacted at 90 °C for 30 min under nitrogen protection. After the reaction was complete, the reaction solution was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:methanol = 98:2) to give compound 6-3 (40.0 mg, 41.96 μmol, yield: 68.06%).

MS(ESI ⁺ )m/z=953.4[M+H] ⁺ .

The third step involves the synthesis of compounds 6-P1 and 6-P2.

Compound 6-3 (40.0 mg, 41.96 μmol) was dissolved in acetonitrile (2 mL), and then triphenylphosphine (22.0 mg, 83.93 μmol), N,N-diisopropylethylamine (43.3 mg, 335.70 μmol, 58.4 μL) and hexachloroethane (19.8 mg, 83.93 μmol, 9.6 μL) were added. The mixture was reacted at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (YMC TA-C18 column, 30 * 150 mm, 5 μm; mobile phase A: _H₂O- ( ₅ mmol _NH₄HCO₃ ); mobile phase B: MeCN; MeCN ratio 55%-85%, time: 15 min, flow rate: 25 mL/min) to obtain 6-P1 (3.0 mg, 3.26 μmol, yield: 7.76%, retention time: 9.50 min) and 6-P2 (1.0 mg, 1.07 μmol, yield: 2.55%, retention time: 11.0 min).

Compound 6-P1 MS(ESI ⁺ ) m/z = 919.4 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ8.38(d,J＝2.9Hz,1H),8.36(d,J＝1.6Hz,1H),7.88(d,J＝9.9Hz,1H),7.77(s ,1H),7.68(dd,J＝8.7,1.6Hz,1H),7.49(d,J＝8.6Hz,1H),7.18(d,J＝2.9Hz,1H ),5.96(d,J＝10.9Hz,1H),4.97(t,J＝8.6Hz,1H),4.64(d,J＝11.0Hz,1H),4.50 (t,J＝6.5Hz,2H),4.46-4.36(m,3H),4.26-4.20(m,1H),4.13-4.04(m,2H),3.5 4-3.45(m,2H),3.41-3.34(m,2H),3.25-3.21(m,4H),3.19-3.08(m,4H),2.87 (d,J＝14.4Hz,1H),2.59-2.55(m,2H),2.38-2.31(m,4H),2.30-2.22(m,2H),2 .11(t,J＝9.7Hz,1H),1.58(t,J＝9.4Hz,1H),1.38(t,J＝4.8Hz,1H),1.30-1.25 (m,4H),1.21-1.14(m,1H),1.10-0.97(m,6H),0.87-0.75(m,6H),0.26(s,3H).

Compound 6-P2 MS(ESI ⁺ ) m/z = 935.4 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(s,1H),8.41(d,J＝10.2Hz,1H),8.10(d,J＝9.4Hz,1H),7.83(d,J＝1.9Hz,1H ),7.73(t,J＝8.1Hz,1H),7.57(dd,J＝8.6,4.2Hz,1H),7.25(s,1H),6.00(d,J＝10.6 Hz,1H),5.29-5.23(m,1H),4.70(d,J＝11.2Hz,1H),4.59-4.54(m,2H),4.54-4.43( m,3H),4.38-4.33(m,1H),4.33-4.26(m,1H),4.20-4.08(m,3H),3.91-3.81(m,2H) ,3.58-3.50(m,2H),3.47-3.42(m,2H),3.32-3.27(m,4H),3.26-3.17(m,3H),2.99 -2.92(m,1H),2.44-2.38(m,4H),2.20-2.15(m,1H),1.64-1.59(m,1H),1.53-1.48 (m,1H),1.38-1.31(m,4H),1.28-1.25(m,1H),1.15-1.10(m,3H),1.08-1.05(m,2H ),0.95-0.92(m,1H),0.92-0.86(m,3H),0.86-0.78(m,4H),0.32(d,J＝4.5Hz,3H).

Example 7 Synthesis of compounds 7-P1 and 7-P2

Synthesis of compound 7-1 (Step 1)

At room temperature, compound Int-11 (121.6 mg, 800.0 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (349.7 mg, 919.91 μmol), and N,N-diisopropylethylamine (198.1 mg, 1.53 mmol) were added to N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 15 minutes, and then a solution of hydrazine hydrate (1.44 g, 24.53 mmol, 85%) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was poured into ethyl acetate (30 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 7-1 (113 mg, 676.24 μmol, yield: 84.53%).

MS(ESI ⁺ )m/z=167.1[M+H] ⁺ .

The second step involves the synthesis of compound 7-2.

Compound 4-2 (150.0 mg, 181.81 μmol) and compound 7-1 (60.4 mg, 363.61 μmol) were added to acetonitrile (0.5 mL), and the mixture was reacted at 90 °C for 30 min under nitrogen protection. The reaction solution was then directly subjected to high-performance liquid chromatography (HPLC) (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: _{H₂O- (NH₄HCO₃ )} , _NH₄HCO₃ concentration 5 mmol/L; mobile phase B: MeCN; MeCN ratio 40%-75%, time: 15 min, flow rate: 25 mL _/ min) to obtain compound 7-2 (40.0 mg, 40.35 μmol, yield: 22%).

MS(ESI ⁺ )m/z=991.4[M+H] ⁺ .

The third step involves the synthesis of compounds 7-P1 and 7-P2.

Compound 7-2 (35.0 mg, 35.31 μmol) was dissolved in acetonitrile (0.5 mL), followed by the addition of triphenylphosphine (18.5 mg, 70.62 μmol), N,N-diisopropylethylamine (36.5 mg, 282.48 μmol, 49.2 μL), and hexachloroethane (16.7 mg, 70.62 μmol, 8.0 μL). The mixture was reacted at room temperature for 2 hours. The reaction solution was directly passed through a high-performance liquid chromatography column (YMC TA-C18, 30*150mm, _5μm ; mobile phase A: _H₂O- ( _NH₄HCO₃ ), _NH₄HCO₃ concentration 5mmol/L; mobile phase B: MeCN; MeCN ratio 70% _-95 %, time: 15min, flow rate: 25mL/min) to prepare compounds 7-P1 (5.0mg, 5.21μmol, yield: 15%, retention time: 8.50min) and 7-P2 (8.0mg, 8.11μmol, yield: 23%, retention time: 9.50min).

Compound 7-P1 MS(ESI ⁺ ) m/z = 957.4 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(d,J＝2.9Hz,1H),8.43(d,J＝1.5Hz,1H),8.13(d,J＝9.6Hz,1H),7.84(s,1H), 7.74(dd,J＝8.6,1.6Hz,1H),7.56(d,J＝8.7Hz,1H),7.25(d,J＝2.9Hz,1H),6.05(d,J＝ 11.0Hz,1H),5.12-5.06(m,1H),4.71(d,J＝11.0Hz,1H),4.61-4.53(m,3H),4.54-4. 42(m,5H),4.40-4.32(m,1H),4.32-4.24(m,1H),4.19-4.09(m,2H),3.63-3.51(m,2H ),3.47-3.42(m,1H),3.41-3.35(m,2H),3.31-3.27(m,4H),3.27-3.22(m,1H),3.20 (s,3H),3.17-3.12(m,1H),2.96-2.89(m,1H),2.68-2.64(m,1H),2.47-2.44(m,1H), 2.44-2.37(m,4H),2.35-2.30(m,1H),2.20-2.14(m,1H),2.12-2.06(m,2H),2.06-1. 96(m,2H),1.69-1.60(m,1H),1.34(d,J＝6.1Hz,3H),0.98-0.84(m,6H),0.33(s,3H).

Compound 7-P2 MS(ESI ⁺ ) m/z = 973.4 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(d,J＝2.9Hz,1H),8.43(d,J＝1.6Hz,1H),8.31(d,J＝9.3Hz,1H),7.83(s,1H),7.7 7-7.71(m,1H),7.56(d,J＝8.7Hz,1H),7.25(d,J＝2.9Hz,1H),6.03(d,J＝11.0Hz,1H),5.3 8-5.28(m,1H),4.71(d,J＝11.0Hz,1H),4.59-4.53(m,3H),4.53-4.49(m,1H),4.49-4.4 0(m,4H),4.37-4.24(m,2H),4.20-4.09(m,2H),3.63-3.51(m,2H),3.47-3.41(m,1H),3. 41-3.36(m,1H),3.36-3.34(m,1H),3.32-3.27(m,4H),3.27-3.23(m,1H),3.20(s,3H), 3.19-3.15(m,1H),2.96-2.88(m,1H),2.69-2.63(m,1H),2.48-2.44(m,1H),2.45-2.38( m,4H),2.37-2.31(m,1H),2.22-2.15(m,1H),2.14-2.08(m,1H),2.09-2.00(m,2H),2.00 -1.91(m,1H),1.68-1.58(m,1H),1.34(d,J＝6.1Hz,3H),0.96-0.80(m,6H),0.34(s,3H).

Example 8: Synthesis of Compound 8

Synthesis of compound 8-1 in step one

At 0 °C, 2-ethylbutyryl chloride (163.3 mg, 1.21 mmol) was added dropwise to a tetrahydrofuran (1 mL) solution of ammonium thiocyanate (118.5 mg, 1.58 mmol), and the mixture was reacted at room temperature for 2 hours. Then, it was added to a tetrahydrofuran (1 mL) solution of compound Int-7 (95.0 mg, 121.33 μmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was prepared by high performance liquid chromatography (YMC TA-C18 column, 30 * 150 mm, 5 μm; mobile phase A: H ₂ O - (NH ₄ HCO ₃ ), NH ₄ HCO ₃ concentration was 5 mmol/L; mobile phase B: MeCN; MeCN ratio 65%-95%, time: 15 min, flow rate: 25 mL/min) to obtain compound 8-1 (20.0 mg, 21.27 μmol, yield: 17.6%).

MS(ESI ⁺ )m/z=940.4[M+H] ⁺ .

The second step involves the synthesis of compound 8-2.

Compound 8-1 (20.0 mg, 21.27 μmol) was dissolved in N,N-dimethylformamide (0.2 mL) and tetrahydrofuran (0.2 mL), followed by the addition of potassium carbonate (11.8 mg, 85.09 μmol). Iodomethane (15.1 mg, 106.36 μmol) was then added at 0 °C, and the mixture was reacted at room temperature for 4 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 8-2 (15.0 mg, 15.72 μmol, yield: 73.9%).

MS(ESI ⁺ )m/z=954.4[M+H] ⁺ .

Step 3: Synthesis of Compound 8

Sodium acetate (5.2 mg, 62.88 μmol) was added to a methanol (0.5 mL) solution of hydroxylamine hydrochloride (4.4 mg, 62.88 μmol). The mixture was stirred at room temperature for 30 minutes, and then compound 8-2 (15.0 mg, 15.72 μmol) was added. The mixture was stirred at room temperature for another 4 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to high-performance liquid chromatography (HPLC) (YMC TA-C18 column, 30 * ₁₅₀ mm, 5 μm; mobile phase A: _H₂O- ( _NH₄HCO₃ ), _NH₄HCO₃ concentration ₅ mmol/L; mobile phase B: MeCN; MeCN ratio 60%-95%, time: 15 min, flow rate: 25 mL/min) to obtain compound 8 (1.5 mg, 1.57 μmol, yield 10%).

MS(ESI ⁺ )m/z=921.4[M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ8.45(d,J＝2.9Hz,1H),8.43(d,J＝1.7Hz,1H),7.82(s,1H),7.74(dd,J＝8.7,1 .6Hz,1H),7.56(d,J＝8.7Hz,1H),7.35(d,J＝10.0Hz,1H),7.25(d,J＝2.9Hz,1H) ,5.94(d,J＝11.1Hz,1H),4.98(t,J＝8.4Hz,1H),4.73(d,J＝11.1Hz,1H),4.56(t ,J＝6.5Hz,2H),4.53-4.42(m,3H),4.33-4.24(m,1H),4.20-4.09(m,2H),3.62- 3.51(m,2H),3.48-3.41(m,1H),3.28-3.25(m,2H),3.21(s,3H),2.94(d,J=14. 3Hz,1H),2.79-2.70(m,1H),2.70-2.62(m,2H),2.45-2.37(m,5H),2.35-2.30( m,2H),2.18(t,J＝9.8Hz,1H),2.03-1.95(m,1H),1.71-1.60(m,4H),1.37-1.31 (m,3H),1.28-1.19(m,4H),0.94-0.88(m,4H),0.88-0.78(m,6H),0.33(s,3H).

Example 9: Synthesis of Compound 9

Synthesis of compound 9-1 (Step 1)

At 0°C, oxalyl chloride (325.4 mg, 2.56 mmol, 223.6 μL) was slowly added dropwise to a solution of Int-11 (300.0 mg, 1.97 mmol) in dichloromethane (3 mL), followed by the addition of 1 drop of N,N-dimethylformamide. The mixture was reacted at room temperature for 1 hour. The reaction solution was then concentrated directly to dryness to obtain crude compound 9-1 (360.0 mg), which was used directly in the next step.

The second step involves the synthesis of compound 9-2.

At 0 °C, compound 9-1 (130.7 mg, 766.29 μmol) was added dropwise to a tetrahydrofuran (1 mL) solution of ammonium thiocyanate (74.8 mg, 996.18 μmol), and the mixture was reacted at room temperature for 2 hours. Then, it was added to a tetrahydrofuran (1 mL) solution of compound Int-7 (60 mg, 76.63 μmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 95:5) to give compound 9-2 (63.0 mg, 64.54 μmol, yield: 84%).

MS(ESI ⁺ )m/z=976.4[M+H] ⁺ .

The third step involves the synthesis of compound 9-3.

Compound 9-2 (58.0 mg, 59.41 μmol) was dissolved in N,N-dimethylformamide (1 mL) and tetrahydrofuran (1 mL), followed by the addition of potassium carbonate (24.6 mg, 178.23 μmol). Iodomethane (25.3 mg, 178.23 μmol, 11.10 μL) was then added at 0 °C, and the mixture was reacted at room temperature for 4 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 9-3 (55.0 mg, 55.53 μmol, yield: 93.45%).

MS(ESI ⁺ )m/z=990.4[M+H] ⁺ .

Step 4: Synthesis of Compound 9

Sodium acetate (17.9 mg, 218.13 μmol) was added to a methanol (0.5 mL) solution of hydroxylamine hydrochloride (15.2 mg, 218.13 μmol). The mixture was stirred at room temperature for 30 minutes, and then compound 9-3 (55.0 mg, 55.53 μmol) was added. The mixture was stirred at room temperature for another 4 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was prepared by high performance liquid chromatography (YMC TA-C18 column, 30 * 150 mm, 5 μm; mobile phase A: H ₂ O - (NH ₄ HCO ₃ ), NH ₄ HCO ₃ concentration was 5 mmol/L; mobile phase B: MeCN; MeCN ratio 50%-80%, time: 15 min, flow rate: 25 mL/min) to obtain compound 9 (2.2 mg, 2.3 μmol, yield: 4.1%).

MS(ESI ⁺ )m/z=957.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(d,J＝2.8Hz,1H),8.43(s,1H),7.83(s,1H),7.74(d,J＝8.5Hz,1H) ,7.56(d,J＝8.6Hz,1H),7.44(d,J＝9.8Hz,1H),7.28-7.23(m,1H),5.96(d, J＝11.1Hz,1H),5.35-5.31(m,1H),5.00-4.94(m,1H),4.75-4.71(m,1H),4 .63-4.43(m,8H),4.40-4.35(m,1H),4.35-4.26(m,2H),4.18-4.12(m,2H) ,3.59-3.51(m,2H),3.48-3.41(m,2H),3.31-3.25(m,4H),3.23-3.17(m, 3H),2.97-2.89(m,1H),2.66-2.61(m,1H),2.45-2.38(m,4H),2.21-2.12( m,3H),2.11-2.04(m,2H),2.02-1.97(m,2H),1.67-1.61(m,1H),1.48-1.4 2(m,1H),1.34(d,3H),0.93-0.89(m,3H),0.88-0.81(m,3H),0.32(s,3H).

Example 10: Synthesis of Compound 10

Synthesis of compound 10-1 in the first step

Compound D4 (44.7 mg, 0.063 mmol) and Int-13 (37.2 mg, 0.076 mmol) were dissolved in a mixed solution of dioxane (0.3 mL), toluene (0.3 mL), and water (0.1 mL). Under nitrogen protection, Pd(dtbpf) _Cl₂ (9.8 mg, 0.015 mmol) and potassium phosphate (48.8 mg, 0.23 mmol) were added to the reaction solution, and nitrogen was purged five times. The mixture was stirred at 70 °C for 4 hours, and the reaction was monitored by LC-MS to ensure complete reaction. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography (Water (containing 0.5% _NH₄OH ):MeCN = 95:5 to 5:95) to give compound 10⁻¹ (40.0 mg, 0.040 mmol, yield: 63.5%).

MS(ESI ⁺ )m/z=994.3[M+H] ⁺ .

The second step involves the synthesis of compound 10-2.

Compound 10⁻¹ (34.8 mg, 0.035 mmol) was dissolved in DCE (0.6 mL), and trimethyltin hydroxide (63.3 mg, 0.35 mmol) was added. The reaction was then carried out at 70 °C for 24 hours. After the reaction was complete, dilute HCl (2 mL, 1 M) was added to the reaction solution to quench the reaction. The organic phase was extracted with ethyl acetate (5.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10⁻² (33.3 mg, 0.034 mmol, yield: 97.1%). The product was used directly in the next step without further purification.

MS(ESI ⁺ )m/z=980.3[M+H] ⁺ .

The third step involves the synthesis of compound 10⁻³.

Compound 10-2 (33.3 mg, 0.034 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), and the solution was heated to 0 °C. Compound Int-5 (10.9 mg, 0.070 mmol) and N,N-diisopropylethylamine (13.6 mg, 0.11 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 10 minutes, followed by the addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.8 mg, 0.070 mmol). The reaction mixture was then cooled to room temperature and stirred for 30 minutes. After the reaction was complete, the solution was filtered through diatomaceous earth, concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography (Water (containing 0.5% _NH₄OH ):MeCN = 95:5 to 5:95) to give compound 10-3 (16.8 mg, 0.015 mmol, yield: 44.1%).

MS(ESI ⁺ )m/z=1118.4[M+H] ⁺ .

Step 4: Synthesis of compound 10⁻⁴

Compound 10⁻³ (16.8 mg, 0.015 mmol) was dissolved in DCE (0.6 mL), and trimethyltin hydroxide (63.3 mg, 0.35 mmol) was added. The reaction was then carried out at 70 °C for 12 hours. After the reaction was complete, dilute HCl (2 mL, 1 M) was added to quench the reaction mixture. The organic phase was extracted with ethyl acetate (5.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10⁻⁴ (15.5 mg, 0.014 mmol, yield: 93.3%). The product was used directly in the next step without further purification.

MS(ESI ⁺ )m/z=1104.3[M+H] ⁺ .

Step 5: Synthesis of compound 10⁻⁵

N,N,N',N'-Tetramethylchloromethanemid hexafluorophosphate (42.1 mg, 0.15 mmol) and N-methylimidazole (24.6 mg, 0.30 mmol) were dissolved in anhydrous acetonitrile (1.00 mL) and stirred at 0 °C for 10 min. Then, compound 10⁻⁴ (15.5 mg, 0.014 mmol) was dissolved in anhydrous acetonitrile (0.5 mL) and added dropwise to the above reaction solution at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for another 10 min. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-50:1) to give compound 10⁻⁵ (10.9 mg, 0.010 mmol, yield: 71.4%). MS ( ^ESI⁺ ) m/z = 1086.3 [M + H] ^⁺ .

Step 6: Synthesis of compound 10⁻⁶

Compound 10⁻⁵ (10.9 mg, 0.010 mmol) was dissolved in anhydrous methanol (2.00 mL), and palladium hydroxide/carbon (2.00 mg) and paraformaldehyde (11.0 mg, 0.37 mmol) were added. The reaction was stirred under a hydrogen atmosphere for 17 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to give compound 10⁻⁶ (7.7 mg, 0.008 mmol, yield: 80%), which was used directly in the next step.

MS(ESI ⁺ )m/z=966.3[M+H] ⁺ .

Step 7: Synthesis of Compound 10

Compound 10-6 (7.7 mg, 0.008 mmol) was dissolved in anhydrous dichloromethane (0.2 mL), and trifluoroacetic acid (7.00 mg, 0.060 mmol) was added. The reaction was carried out at 25 °C for 4 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative chromatography (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: _{H₂O- (NH₃H₂O), NH₃H₂O concentration 0.05} %; mobile phase B: MeCN; MeCN ratio 50%-70%, time: 10 min, flow rate: 15 mL _/ min) to obtain compound 10 (2.1 mg, 0.0024 mmol, yield: 30%).

MS(ESI ⁺ )m/z＝866.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ8.44(d,J＝3.0Hz,1H),8.42(s,1H),7.81(s,1H),7.75-7.70(m,1H),7.55(d,J＝8. 7Hz,1H),7.22(s,1H),5.92(d,J＝11.0Hz,1H),5.72(d,J＝7.1Hz,1H),5.35(dd,J＝10 .4,4.8Hz,1H),4.75(d,J＝11.1Hz,1H),4.50(q,J＝4.0Hz,1H),4.33-4.25(m,1H),4. 19-4.13(m,2H),3.90(dd,J＝15.4,7.3Hz,1H),3.58(d,J＝10.7Hz,1H),3.48(d,J＝10. 8Hz,1H),3.23(s,3H),3.13(d,J＝15.2Hz,1H),3.09-3.01(m,1H),2.97(d,J＝14.6Hz ,1H),2.70-2.60(m,4H),2.34-2.30(m,3H),2.27-2.19(m,5H),2.15(d,J＝9.7Hz,1H) ,2.12-2.02(m,2H),2.01-1.91(m,1H),1.69-1.59(m,2H),1.33(d,J＝6.1Hz,3H),1. 24(s,2H),0.98(d,J=6.9Hz,3H),0.95-0.92(m,5H),0.91-0.82(m,6H),0.30(s,3H).

Example 11 Synthesis of Compound 11

Synthesis of compound 11-1 in step one

Compound 4-2 (5.0 mg, 6.1 μmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), followed by the addition of ammonia (1 mL). The reaction was carried out at room temperature for 1 hour. Water and ethyl acetate were added, and the organic phase was washed with saturated brine after separation. The solution was concentrated to dryness to give compound 11-1 (5.0 mg, 5.9 μmol, yield: 96.7%).

MS(ESI ⁺ )m/z=842.4[M+H] ⁺ .

The second step involves the synthesis of compound 11.

Compound 11-1 (5.0 mg, 5.9 μmol) and compound Int-14 (1.4 mg, 6.1 μmol) were dissolved in anhydrous ethanol (1 mL) and refluxed for 2 hours. The reaction solution was concentrated to dryness, and the residue was subjected to high performance liquid chromatography (HPLC) column (YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: _H₂O ( _containing 5 mmol _NH₄HCO₃ ); mobile phase B: MeCN; MeCN ratio 50%-80%; time: 10 min; flow rate: 25 mL/min) to prepare compound 11 (0.9 mg, 0.9 μmol, yield: 16%).

MS(ESI ⁺ )m/z=972.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD)δ8.35(s,1H),8.31(d,J＝2.9Hz,1H),7.58(dd,J＝8.5,1.6Hz,1H),7.44(s,1H),7.39(d,J＝8.5Hz,1H),7.25(d,J＝2.9Hz,1H),6.18(s,1H),5. 51-5.43(m,1H),4.63(t,J＝6.6Hz,2H),4.59-4.51(m,3H),4.49(s,2H), 4.35-4.26(m,1H),4.26-4.14(m,4H),4.13-4.04(m,2H),3.67-3.60(m,1 H),3.60-3.53(m,1H),3.39-3.34(m,1H),3.31-3.26(m,4H),3.04-2.92 (m,1H),2.63-2.54(m,2H),2.51-2.43(m,4H),2.40-2.32(m,1H),2.13- 2.06(m,1H),1.96-1.80(m,4H),1.54-1.40(m,2H),1.33(d,J＝6.1Hz,3H ),1.29-1.14(m,6H),0.95-0.86(m,3H),0.86-0.77(m,3H),0.41(s,3H).

Example 12 Synthesis of Compound 12

Synthesis of compound A6-1 (Step 1)

Compound A6 (10.4 g, 20.0 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature and added to a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0 M, 50.0 mL). The mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was quenched dropwise in water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to give the title compound A6-1 (4.67 g, 16.6 mmol, yield: 83.0%).

MS(ESI ⁺ )m/z=282.1[M+H] ⁺ .

The second step involves the synthesis of compound 12-1.

Acetic anhydride (1.28 mL, 13.11 mmol) was slowly added dropwise to a solution of compound A6-1 (3.7 g, 13.11 mmol), 4-dimethylaminopyridine (80.1 mg, 655.6 μmol), and triethylamine (3.98 g, 39.34 mmol) in dichloromethane (40.0 mL) under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 6 hours. After the reaction was complete, the reaction solution was quenched dropwise in ice water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give the title compound 12-1 (4.0 g, 12.34 mmol, yield: 94.0%).

MS(ESI ⁺ )m/z=324.1[M+H] ⁺ .

The third step involves the synthesis of compound 12-2.

Compound 12-1 (4.6 g, 14.19 mmol), potassium acetate (3.48 g, 35.47 mmol), and bis-pinacolborate (9.0 g, 35.47 mmol) were added to 1,4-dioxane (46.0 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.04 g, 1.42 mmol), purging the mixture three times with argon. The resulting mixture was heated to 90 °C under argon protection and stirred for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound 12-2 (4.5 g, 12.12 mmol, yield: 85.4%).

MS(ESI ⁺ )m/z=372.1[M+H] ⁺ .

Step 4: Synthesis of compound 12-3

Compound 12-2 (2.6 g, 7.0 mmol), compound B7 (2.81 g, 7.7 mmol), and potassium phosphate (3.71 g, 17.5 mmol) were dissolved in a mixed solution of dioxane (30.0 mL) and water (3.0 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (452.2 mg, 618 μmol) was added to the reaction solution, and argon gas was purged five times. The mixture was stirred at 90 °C for 12 hours, and the reaction was monitored to be complete by LC-MS. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95/5 to 5/95) to give compound 12-3 (3.0 g, 5.66 mmol, yield: 80.9%).

MS(ESI ⁺ )m/z=530.1[M+H] ⁺ .

Step 5: Synthesis of compound 12-4

Compound 12-3 (3.7 g, 6.98 mmol) and N-iodosuccinimide (1.57 g, 6.99 mmol) were added to N,N-dimethylformamide (40.0 mL), and the mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was poured into water (400.0 mL), extracted three times with ethyl acetate (50.0 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95/5 to 5/95) to give the title compound 12-4 (2.6 g, 3.97 mmol, yield: 56.77%).

MS(ESI ⁺ )m/z=656.5[M+H] ⁺ .

Step 6: Synthesis of compound 12-5

Compound 12-4 (2.6 g, 3.97 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (5 mL). Lithium hydroxide (474.9 mg, 19.8 mmol) was added to the reaction solution. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The organic solvent was removed by vacuum distillation. The mixture was diluted with ethyl acetate and water. The pH of the aqueous phase was adjusted to approximately 6 with 1 M HCl aqueous solution. The mixture was extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-5 (2.3 g, 3.84 mmol, yield: 96.7%).

MS(ESI ⁺ )m/z=600.0[M+H] ⁺ .

Step 7: Synthesis of compound 12-6

Compound 12-5 (393.0 mg, 655.2 μmol), compound Int-5 (265.0 mg, 1.7 mmol), N,N-diisopropylethylamine (1.69 g, 13.11 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (370.8 mg, 975.3 μmol) were added to an 8.0 mL solution of N,N-dimethylformamide and stirred at room temperature for 2 hours. After the reaction was complete, the crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95/5 to 5/95) to give the title compound 12-6 (290.0 mg, 393.1 μmol, yield: 60.0%).

MS(ESI ⁺ )m/z=738.1[M+H] ⁺ .

Step 8: Synthesis of compound 12-7

Compound 12-6 (290 mg, 393.1 μmol) was dissolved in a mixed solution of tetrahydrofuran (2.0 mL) and water (2.0 mL). Lithium hydroxide (94.1 mg, 3.93 mmol) was added to the reaction solution. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS until complete. The mixture was diluted with ethyl acetate and water. The pH of the aqueous phase was adjusted to approximately 6 with 1 M HCl aqueous solution. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-7 (200.0 mg, 276.4 μmol, yield: 70.3%).

MS(ESI ⁺ )m/z=724.1[M+H] ⁺ .

Step 9: Synthesis of compound 12-8

Compound 12-7 (140.0 mg, 193.4 μmol), N-methylimidazole (794.2 mg, 9.67 mmol), and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (298.5 mg, 1.06 mmol) were added to a mixed solution of N,N-dimethylformamide (1.2 mL) and acetonitrile (12.0 mL), and stirred at room temperature for 2 hours. After the reaction was complete, the crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95/5 to 5/95) to give the title compound 12-8 (44.0 mg, 62.3 μmol, yield: 32.2%).

MS(ESI ⁺ )m/z=706.2[M+H] ⁺ .

Step 10: Synthesis of compounds 12-9

Compound 12-8 (98.0 mg, 138.0 μmol), potassium acetate (19.47 mg, 198.4 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos) (11.6 mg, 28.3 μmol), and tris(dibenzylacetone)dipalladium (10.3 mg, 11.3 μmol) were added to 1,4-dioxane (4.0 mL), and the mixture was purged with argon three times. The mixture was placed in an ice bath and cooled to 0 °C. Under an argon atmosphere, a solution of pinacol borane (58.0 mg, 453.5 μmol) and 1,4-dioxane (4.0 mL) was added dropwise to the mixture. The reaction mixture was then heated to 50 °C and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered with diatomaceous earth. The filtrate was washed with saturated sodium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reversed-phase column chromatography (water: acetonitrile, gradient: 95/5 to 5/95) to give the title compound 12-9 (25.0 mg, 35.4 μmol, yield: 25.6%).

MS(ESI ⁺ )m/z=706.1[M+H] ⁺ .

Step 11: Synthesis of Compounds 12-10

Compound 12-9 (25.0 mg, 35.4 μmol), compound Int-15 (18.7 mg, 53.1 μmol), and potassium carbonate (14.7 mg, 106.2 μmol) were added to a mixed solution of 1,4-dioxane (3.6 mL) and water (0.9 mL), and argon gas was purged. Under an argon atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.2 mg, 7.1 μmol) was added, and the resulting mixture was heated to 70 °C and stirred for 16 hours under argon protection. After the reaction was completed, the reaction solution was filtered with diatomaceous earth. The filtrate was washed with saturated sodium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reversed-phase column chromatography (water: acetonitrile, gradient: 95/5 to 5/95) to give the title compound 12-10 (19.6 mg, 23.0 μmol, yield: 65%).

MS(ESI ⁺ )m/z=852.2[M+H] ⁺ .

Step 12: Synthesis of compound 12-11

Compound 12-10 (19.6 mg, 23.0 μmol) and cesium carbonate (24.5 mg, 75.2 μmol) were added to N,N-dimethylformamide (2.0 mL), and argon was purged. Iodoethane (5.8 mg, 37.5 μmol) was added dropwise to the reaction mixture under an argon atmosphere, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the organic phase was dried and concentrated to obtain a crude product, which was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95/5 to 5/95) to separate the less polar isomer, yielding the title compound 12-11 (7.0 mg, 8.0 μmol, yield: 34.8%).

MS(ESI ⁺ )m/z=880.2[M+H] ⁺ .

Step 13: Synthesis of Compound 12-12

At room temperature, trifluoroacetic acid (0.7 mL) was slowly added dropwise to a solution of compound 12-11 (15.2 mg, 17.2 μmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness, washed with an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 12-12 (12.7 mg, 16.3 μmol, yield: 94.8%).

MS(ESI ⁺ )m/z=780.2[M+H] ⁺ .

Step Fourteen: Synthesis of Compounds 12-13

Under argon protection and in an ice-salt bath, a solution of compound 4-1 (2.6 mg, 11.28 μmol) in dichloromethane (1 mL) was added dropwise to a solution of compound 12-12 (12.7 mg, 16.3 μmol) and N,N-diisopropylethylamine (2.7 mg, 20.51 μmol, 3.57 μL) in dichloromethane (1 mL). The mixture was stirred for 5 minutes. TLC showed complete conversion of the starting material. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound 12-13 (9.0 mg, 10.9 μmol, yield: 66.9%).

MS(ESI ⁺ )m/z = 822.3

Step 15: Synthesis of compounds 12-14

Under argon protection, 4-fluoro-2-(2-fluoroethyl)butyrylhydrazide (compound 7-1, 2.7 mg, 16.42 μmol) was added to a solution of compound 12-13 (9.0 mg, 10.9 μmol) in acetonitrile (0.5 mL), and the mixture was reacted at 90 °C for 30 min. The reaction mixture was monitored by LC-MS until complete. The reaction solution was distilled under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound 12-14 (10.0 mg, 10.1 μmol, yield: 92.7%). MS (ESI ⁺ ) m/z = 988.4 [M+H] ⁺ .

Step 16: Synthesis of compounds 12-P1 and 12-P2

Triphenylphosphine (7.4 mg, 28.33 μmol), N,N-diisopropylethylamine (14.7 mg, 113.34 μmol, 19.8 μL), and hexachloroethane (6.7 mg, 28.33 μmol) were added sequentially to a 1 mL solution of compound 12-14 (10.0 mg, 10.1 μmol) in acetonitrile. The mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated to dryness, and the residue was subjected to high-performance liquid chromatography (HPLC) with an XBridge Prep C18 column (150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), _NH3H2O concentration 0.05%; mobile phase _B : MeCN; MeCN ratio 55%-75%, time: 10 min, flow rate: 15 mL/min) to prepare compounds 12-P1 (1.3 mg, 1.4 μmol, yield: 13.8%, retention time: 7.62 min) and 12-P2 (1.0 mg, 1.0 μmol, yield: 9.9%, retention time: 8.38 min).

Compound 12-P1 MS(ESI ⁺ ) m/z = 954.4 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ8.81(d,J＝2.1Hz,1H),8.45(d,J＝1.6Hz,1H),8.14(d,J＝9.7Hz,1H),8.00( d,J＝2.1Hz,1H),7.86(s,1H),7.76(dd,J＝8.6,1.6Hz,1H),7.55(d,J＝8.6Hz, 1H),6.01(d,J＝10.9Hz,1H),5.04(t,J＝8.5Hz,1H),4.77(d,J＝11.0Hz,1H),4 .62-4.53(m,1H),4.53-4.42(m,3H),4.41-4.32(m,1H),4.02-3.88(m,2H),3. 87-3.78(m,1H),3.71-3.66(m,4H),3.66-3.52(m,4H),3.25-3.22(m,1H),3. 17-3.13(m,1H),3.09(s,3H),3.07-3.02(m,1H),2.80-2.73(m,4H),2.39-2.3 4(m,2H),2.22-2.13(m,1H),2.13-1.94(m,5H),1.88-1.81(m,2H),1.72-1.6 4(m,1H),1.21(d,J＝6.3Hz,3H),1.16-1.07(m,4H),0.93(s,3H),0.49(s,3H).

Compound 12-P2 MS(ESI ⁺ ) m/z = 970.4 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d6 ₎ )δ8.80(d,J＝2.1Hz,1H),8.45(d,J＝1.6Hz,1H),8.30(d,J＝9.1Hz,1H),7.86( d,J＝2.2Hz,1H),7.85(s,1H),7.77(dd,J＝8.8,1.7Hz,1H),7.59(d,J＝8.7Hz, 1H),6.03(d,J＝11.0Hz,1H),5.33-5.32(m,1H),4.71(d,J＝11.0Hz,1H),4.56 -4.48(m,2H),4.47-4.40(m,2H),4.38-4.24(m,3H),4.12-4.03(m,1H),3.71 -3.67(m,4H),3.65-3.62(m,2H),3.60-3.54(m,2H),3.27-3.25(m,1H),3.24 (s,3H),3.20-3.16(m,1H),2.94-2.89(m,1H),2.78-2.72(m,4H),2.23-2.15 (m,2H),2.12-2.07(m,1H),1.98-1.93(m,5H),1.87-1.82(m,2H),1.66-1.59 (m,1H),1.36(d,J=6.1Hz,3H),1.32-1.29(m,4H),0.85(s,3H),0.34(s,3H).

The compounds listed in the table below can be synthesized by modifying some of the raw materials, referring to the methods in the above embodiments:

Biological tests

Test Example 1: Effect of Compounds on Tumor Cell Proliferative Activity

Experimental materials and instruments:

The materials required for this experiment include: RPMI-1640 cell culture medium (BasalMedia #L240KJ); DMEM (BasalMedia #L110KJ); fetal bovine serum (FBS) (Proteintech #PM00011); PBS phosphate buffer (BasalMedia #B320KJ); 0.25% trypsin (Gibco #25200-072); 100% DMSO (Sigma #D2650); 96-well permeable sterile culture plate (Corning #3599); 96-well plate (Corning #3610); CellTiter- 2.0 Luminescent cell viability assay kit (Vazyme#DD1101); 25 mL pipettes (Corning); 5 mL pipettes (Corning); P1000 pipette tips, P200 pipette tips and P10 pipette tips (Axygen).

The instruments and equipment required for this experiment include: Eppendorf pipettes; Eppendorf pipettes; Eppendorf centrifuges; ThermoFisher incubator; Vi-cell XR fully automated cell counter (Beckman Coulter); and Envision microplate reader (Perkin Elmer).

The cells required for this experiment include: KRAS ^G12D mutant cell line AsPC-1 (ATCC#CRL-1682 ^TM ), and the complete culture medium is RPMI-1640 medium containing 10% FBS.

Experimental methods:

AsPC-1 cells were digested from the culture flasks using 0.25% trypsin and resuspended in the corresponding fresh complete culture medium. After counting, the AsPC-1 cell density was adjusted to 2000 cells/90 μL/well. 90 μL of the solution was added to each well of a 96-well plate and incubated overnight at 37°C with 5% CO2. A 10 mM stock solution of the compound was diluted 10-fold to 1 mM with DMSO, then further diluted 100-fold to 10 μM with complete culture medium. Using this as the starting concentration, a 3-fold serial dilution was performed with complete culture medium containing 1% DMSO, resulting in nine consecutive concentration gradients. 10 μL of each serially diluted compound was then added to each well to ensure a final DMSO concentration of 0.1% in each well. The positive control group consisted of wells without cell seeding; the negative control group consisted of wells with cells but without the compound treatment. The cell culture plates were incubated at 37°C with 5% CO2 for 5 days. Add an equal volume of CellCounting-Lite 2.0 assay reagent to each well of the cell plate, vortex for 2-5 min to allow for complete cell lysis, and incubate at room temperature for 10 min to stabilize the luminescence signal. Read the luminescence value using an Envision microplate reader. Calculate the inhibition rate using the following formula: Inhibition% = (Signal _{negative control} – Signal _sample ) / (Signal _{negative control} – Signal _{positive control} ) * 100. Calculate the _IC50 value using IDBS XLfit with 4-parameter fitting. The measured _IC50 values are shown in Table 1.

Table 1

Test Example 2: Inhibitory effect of the disclosed compound on cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4

I. Test Materials and Equipment

1. Reagents

2. Liver microsomes

3. Test equipment

II. Experimental Procedure

1. Prepare a 10 mM DMSO stock solution of the test compound. Then, use DMSO to serially dilute the compound to obtain DMSO solutions of the following concentrations: 0, 4, 20, 100, 400, 2000, and 10000 μM. The concentrations of the test compound in the final incubation system are 0, 0.02, 0.1, 0.5, 2, 10, and 50 μM. The volume ratio of organic solvent introduced into the test system along with the test compound is 0.5%. The final concentration information of the positive inhibitor in the reaction system is shown in the table below.

working solution concentration of positive inhibitor

The final concentration of the positive inhibitor in the reaction system

2. Preparation of substrate stock solution

The specific preparation method for the substrate stock solution is shown in the table below. After preparation, the stock solution should be stored at -20°C. Thaw at room temperature before use.

Substrate stock solution information

3. Preparation of phosphate buffer (100mM, pH 7.4)

First, weigh 7.098 g of disodium hydrogen phosphate and dissolve it in 500 mL of pure water by sonication, as solution A. Weigh 3.400 g of potassium dihydrogen phosphate and dissolve it in 250 mL of pure water by sonication, as solution B. Slowly add solution B to solution A on a stirrer until the pH reaches 7.4. Store the phosphate buffer at 4°C for later use.

4.10mM NADPH preparation

Before the experiment, weigh an appropriate amount of NADPH and prepare a 10mM working solution with phosphate buffer. The final concentration of NADPH in the experimental system is 1mM.

5. Preparation of the incubation system

The preparation of the incubation system is shown in the table below. Before use, preheat the system in a water bath at 37°C for 15 minutes.

6. Test Methods

The entire incubation process was carried out in 96-well deep-well plates. First, 179 μL of the incubation system was added to the plate, followed by 1 μL of the compound solution or solvent (DMSO), and then 20 μL of 10 mM NADPH solution. Before initiating the reaction, the incubation system was preheated at 37°C for 15 minutes. After adding NADPH to initiate the reaction, the plate was incubated at 37°C for 45 minutes. The experimental samples were prepared in duplicate.

After incubation for 45 min, the reaction was terminated by adding 400 μL of ice-cold methanol (containing internal standards, 10 ng/mL glipizide and 10 ng/mL propranolol). After vortexing, the deep-well plate was centrifuged at 4000 rpm and 4 °C for 10 min. 100 μL of the supernatant was transferred to a new 96-well plate, and 100 μL of pure water was added and mixed. The mixture was then used for LC-MS/MS analysis.

III. Data Analysis

The generated metabolites were analyzed by LC-MS/MS. The reduction in metabolite formation in the drug-treated group compared to the blank solvent control group was compared by the peak area ratio of the sample to the internal standard, and the _IC50 value was calculated using GraphPad Prism 8.0 based on the percentage of remaining activity.

Calculate the remaining activity percentage using the following formula:

Remaining activity percentage (%) = (Ratio of peak area of metabolite to peak area of internal standard) / (Ratio of peak area of test _substance to peak area of metabolite to peak area of internal standard) × 100% of _{blank solvent} .

The experimental results are shown in Table 2.

Table 2 shows the inhibitory effects of the disclosed compounds on cytochrome P450 enzymes.

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Test Example 3: Rat Hepatocyte Stability Test

Experimental objective: To investigate the metabolic stability of the compound in cryopreserved SD rat hepatocytes.

Experimental materials: Suspended hepatocytes from SD rats

Experimental Procedure: Frozen rat hepatocytes were removed from the liquid nitrogen tank and thawed. Cell viability was calculated using trypan blue staining. The hepatocyte suspension was added to a preheated incubation plate, followed by the addition of the test sample and control compound working solutions (preparation method: 1 mM test sample diluted to 100 μM with ACN, 3 mM control compound diluted to 300 μM with ACN). The mixture was thoroughly mixed and immediately placed in a shaker in an incubator. The timer was started to begin the reaction. Incubation time points were set at 0, 15, 30, 60, and 90 minutes. Incubation conditions were 37°C, saturated humidity, and 5% _CO₂ . The final concentration of the test sample was 1 μM, the final concentration of the control was 3 μM, and the final concentration of rat hepatocytes was 0.5 × ^10⁶ cells/mL. At the end of the incubation at the corresponding time point, remove the incubation plate and transfer an appropriate amount of cell suspension to a sample plate containing a certain volume of stop solution (acetonitrile solution containing 250 nM tolbutamide and labetalol). After sealing all sample plates, shake at 600 rpm for 10 minutes on a shaker, then centrifuge at 3220 × g for 20 minutes. Dilute the supernatant of the test sample and control sample with ultrapure water at a ratio of 1:3. After mixing all samples, analyze them by LC/MS/MS, and calculate the elimination rate constant and clearance rate of the test compound in rat hepatocytes using the following formula.

Data Analysis: The in vitro elimination rate constants k_{_e} of the test and control compounds were obtained by converting the ratio of the peak area of the compound to that of the internal standard into the residual percentage using the following formula:

when

The in vitro intrinsic clearance rate (CL _int(liver) ) is obtained by the elimination rate k _{_e} , as shown in the following formula:

CL _int(hep) = k _e / cell volume per milliliter (million cells/mL)

CL _int(liver) = CL _int(hep) × liver weight to body weight ratio × number of hepatocytes per gram of liver

Experimental results show that the compound of the present invention has excellent stability in rat hepatocytes.

The experimental results are shown in Table 3.

Table 3. Rat stability results of the compounds disclosed herein.

Claims (21)

Compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt,
in, X1 is selected from CHR 11 and NR 12 ; X2 is selected from CH2 and NH; L is selected from NH, NR 13 , or CR 14 R 15 ; A is selected from C3 - C12 cycloalkylene, 4-10 heterocyclic, C6 - C10 aryl, and 5-12 heterocyclic, wherein the C3 - C12 cycloalkylene, 4-10 heterocyclic, C6 - C10 aryl, and 5-12 heterocyclic are optionally substituted by one or more Ra . R1 is selected from C3 - C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl, and 5-12 heteroaryl, wherein the C3 - C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl, and 5-12 heteroaryl are optionally substituted by one or more R1a ; R2 , R3 , R7 , R8 and R9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1 - C10 alkyl, C1 - C10 alkoxy, C1 - C10 haloalkyl and C3 - C7 cycloalkyl; Alternatively, R7 and R8 and the atoms they are connected to together form a 4-10 membered heterocycle, which is optionally replaced by one or more Rb ; R4 is selected from hydrogen, halogen, hydroxyl, cyano, C2 - C10 alkenyl, C2 - C10 alkynyl and C1 - C10 alkyl, wherein the hydroxyl, C2- C10 alkenyl, C2 - C10 alkynyl and C1 - C10 alkyl are optionally substituted by one or more R4a ; R5 is selected from C1 - C10 alkyl, C3-C12 cycloalkyl, 4-10 heterocyclic, C6- C10 aryl, and 5-10 heteroaryl, wherein the C1 - C10 alkyl, C3 - C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl , and 5-10 heteroaryl are optionally substituted by one or more R5a ; Alternatively, R4 and R5 and the atoms they are connected to together form a 4-10 membered heterocycle, which is optionally replaced by one or more Rc atoms; Alternatively, R4 and R7 and the atoms they are connected to together form a 4-10 membered heterocycle, which is optionally replaced by one or more Rds ; R6 , R10 , R11 and R12 are independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1 - C4 alkyl, C1 - C4 haloalkyl and C1 - C4 alkoxy; Alternatively, R 10 and its connected C, R 11 and its connected C, and CH 2 between the two Cs together form a C 4 -C 12 saturated carbon ring or a 4-10 membered heterocycle; Alternatively, R 10 and its connected C and R 12 and its connected N, as well as CH 2 between said C and N, together form a 4-10 membered heterocycle; R13 , R14 and R15 are independently selected from non-existent, hydrogen, C1 - C4 alkyl, C1 - C4 haloalkyl and C1 - C4 alkoxy; Alternatively, R1 and R13 and the atoms connected to them, or R1 and R14 and the atoms connected to them, together form a 4-10 membered heterocycle or a 5-10 membered heteroaromatic ring, wherein the 4-10 membered heterocycle or the 5-10 membered heteroaromatic ring is optionally substituted by one or more R1a ; Each Ra is independently selected from halogen, amino, hydroxyl, mercapto, cyano, and C1 - C4 alkyl groups; Each R 1a is independently selected from halogen, amino, hydroxyl, mercapto, cyano, C2 - C10 alkenyl, C2 -C10 alkynyl, C1 - C10 alkyl, C3 - C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl , and 5-10 heteroaryl, wherein the amino, hydroxyl, mercapto, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkyl , C3 - C12 cycloalkyl , 4-10 heterocyclic, C6 - C10 aryl, and 5-10 heteroaryl are optionally substituted with Re ; Each R4a , Rb , and Rd is independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1 - C7 alkyl, C1 - C7 haloalkyl, C3 - C6 cycloalkyl, and C1 - C7 alkoxy. Each R 5a is independently selected from halogen, cyano, amino, hydroxyl, mercapto, oxo, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, C3 - C12 cycloalkyl, 4-15-membered heterocyclic, C6 - C10 aryl, and 5-10-membered heteroaryl, wherein the amino, hydroxyl, mercapto, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, C3 - C12 cycloalkyl, 4-15-membered heterocyclic, C6 - C10 aryl, and 5-10-membered heteroaryl are optionally substituted by one or more R f ; Each Rc is independently selected from hydroxyl, C1 - C10 alkyl, C3- C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl, and 5-10 heteroaryl, wherein the hydroxyl, C1 - C10 alkyl , C3-C12 cycloalkyl , 4-10 heterocyclic, C6 - C10 aryl, and 5-10 heteroaryl are optionally substituted by one or more Re ; Each Re is independently selected from halogen, cyano, amino, hydroxyl, mercapto, C1 - C10 alkyl, C2 -C10 alkenyl, C2 - C10 alkynyl, C3 - C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl, and 5-10 heteroaryl, wherein the C1 - C10 alkyl, C3 - C12 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl , and 5-10 heteroaryl are optionally substituted by one or more Rg ; Each R g is independently selected from halogen, amino, hydroxy, mercapto, cyano, C1 - C7 alkyl, C1 - C7 haloalkyl, C1 - C7 alkoxy, 4-10 membered heterocyclic groups and C3- C10 cycloalkyl groups optionally substituted with halogen, amino, hydroxy, mercapto, cyano, C1-C4 alkyl , C1 - C4 haloalkyl, C1 - C4 hydroxyalkyl and C1 - C4 alkoxy; Each Rf is independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1 - C7 alkyl, C1 - C7 alkoxy, C3 - C10 cycloalkyl, and 4-12 membered heterocyclic groups, wherein the amino, hydroxyl, mercapto, C1 - C7 alkyl, C1 - C7 alkoxy, C3 - C10 cycloalkyl, and 4-12 membered heterocyclic groups are optionally substituted by one or more Rh ; Each R h is independently selected from halogen, hydroxyl, mercapto, amino, =O, =CRj R  j , C<sub> 1 -C4 alkyl, cyano, C<sub> 3 -C 6  cycloalkyl, 3-6 membered heterocyclic alkyl, C<sub> 1 -C 4  hydroxyalkyl, C <sub> 1 -C 4  aminoalkyl, C<sub> 1 -C4 haloalkyl, (C<sub> 1 -C 4  alkylene)O C<sub> 1 -C 4  alkyl, C(O)R k , S(O) 2 R k , and C<sub> 1 -C 4  alkoxy, wherein the hydroxyl, mercapto, amino, C <sub>1 -C 4  alkyl, C<sub> 3 -C 6  cycloalkyl, 3-6 membered heterocyclic alkyl, C<sub> 1- C 4  hydroxyalkyl, C<sub> 1 -C 4  aminoalkyl, C <sub>1 -C4 haloalkyl, (C<sub> 1- C 4  alkylene)O C<sub> 1 -C4 alkyl, and C<sub>1-C<sub>4 alkoxy are optionally replaced by halogen, hydroxyl, cyano, and C1-C4  alkyl . 4- alkyl substitution; Rj and Rk are independently selected from H, halogen, hydroxyl, mercapto, cyano, amino, C1 - C4 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, and C1 - C10 alkoxy, wherein the hydroxyl, mercapto, amino, C1 - C4 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, and C1 - C10 alkoxy are optionally substituted with halogen, hydroxyl, mercapto, amino, =O, C1 - C4 alkyl, C1- C4 alkoxy, C1 - C4 hydroxyalkyl, C1- C4 aminoalkyl, C1 - C4 haloalkyl, C3 - C6 cycloalkyl, 3-6 membered heterocyclic alkyl, N( C1 - C4 alkyl) 2 , and NH( C1 - C4 alkyl); and One or more hydrogen atoms in the compound may be selected as deuterium atoms. The compound of formula (I) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein X1 is selected from CHR 11 ; or X1 is CH 2 ; and/or X2 is NH; and/or R 10 is hydrogen. The compound of formula (I) as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein X1 is selected from CHR 11 , wherein R 10 and its connected C, R 11 and its connected C, and CH2 between the two Cs together form a C4 - C6 saturated carbide ring; or, X1 is selected from CHR 11 , wherein R 10 and its connected C, R 11 and its connected C, and CH2 between the two Cs together form a C4 saturated carbide ring. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Selected from Optionally, R10 is hydrogen. The compound of formula (I) as claimed in any one of claims 1-4, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein A is selected from C6 - C10 arylene, 5-6-membered heterocyclic, and 5-6-membered heterocyclic, wherein the C6-C10 arylene , 5-6-membered heterocyclic, and 5-6-membered heterocyclic are optionally substituted with one or more Ra ; or, A is selected from a 6-membered heterocyclic or 5-membered heterocyclic, wherein the 6-membered heterocyclic or 5-membered heterocyclic is optionally substituted with one or more Ra ; or, A is selected from a 6-membered heterocyclic having one N atom and one O atom or a 5-membered heterocyclic having one N atom and one S atom, wherein the 6-membered heterocyclic or 5-membered heterocyclic is optionally substituted with one Ra ; or, A is selected from imomorpholino and imidazolyl, wherein the imomorpholino and imidazolyl are optionally substituted with one or more Ra ; or, A is... The Either can be replaced by R a ; or A is The compound of formula (I) as claimed in any one of claims 1-5, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R1 is selected from 6-10-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 6-10-membered heterocyclic group and the 5-6-membered heteroaryl group are optionally substituted by one or more R1a ; or, R1 is selected from 8-9-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 8-9-membered heterocyclic group and the 5-6-membered heteroaryl group are optionally substituted by one or more R1a ; or, R1 is selected from 8-9-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 8-9-membered heterocyclic group and the 5-6-membered heteroaryl group have one N atom and one or two heteroatoms independently selected from N, O or S, and are optionally substituted by one or more R1a ; or, R 1 is selected from isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, The isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazoleyl, Optionally substituted with one or more R 1a ; or, R 1 is selected from oxadiazolyl or thiadiazolyl, wherein the oxadiazolyl or thiadiazolyl is optionally substituted with one or more R 1a ; or, R 1 is selected from... The compound of formula (I) as claimed in any one of claims 1-6, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R 1a is independently selected from C1 - C5 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclic group and phenyl, wherein the C1 - C5 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclic group and phenyl are optionally substituted with one or more Re ; or, each R 1a is independently selected from methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Optionally substituted with one or more Re ; or, each R1a is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, n-butyl, The methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, n-butyl, Optional replacement by one or more Re ; and/or Each Re is independently selected from halogen, cyano, hydroxyl, C1 - C3 alkyl, C2 alkenyl, C3 - C6 cycloalkyl, and C6 aryl, wherein the hydroxyl, C1 - C3 alkyl, and C6 aryl groups are optionally substituted by one or more Rg groups ; or, each Re is independently selected from fluorine, cyano, hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl, wherein the methyl and hydroxyl groups are optionally substituted by one or more Rg groups; or, each Re is independently selected from fluorine, cyano, methyl, ethyl, isopropyl, and phenyl, wherein the methyl, ethyl, isopropyl, and phenyl groups are optionally substituted by one or more Rg groups ; or, each Re is independently selected from fluorine, cyano, methyl, ethyl, isopropyl , -CF3, -CH2 -O- CH3 phenyl, -O- CH3 , cyclopropyl, cyclopentyl, and vinyl; and/or Each R g is independently selected from halogens, C1 - C6 alkyl and C1 - C6 alkoxy; or, each R g is independently selected from halogens, C1 - C3 alkyl and C1 - C3 alkoxy; or, each R g is independently selected from fluorine, methyl and methoxy; or, each R g is independently selected from fluorine and methoxy. The compound of formula (I) as claimed in any one of claims 1-7, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein L is NH; or, L is NR 13 , R 1 and R 13 and the atoms attached to them together form a 5-6 membered heteroaromatic ring or triazole ring, said 5-6 membered heteroaromatic ring or triazole ring optionally substituted by one or more R 1a ; or, L is CR 14 R 15 , R 1 and R 14 and the atoms attached to them together form a 5-6 membered heteroaromatic ring or triazole ring, said 5-6 membered heteroaromatic ring or triazole ring optionally substituted by one or more R 1a , and R 15 is absent; or, L is NR 13 , R 1 and R 13 and the atoms attached to them together form a 6-10 membered heterocycle, said 6-10 membered heterocycle optionally containing N, -C(=O)-, -C(=O)NH- as heteroatoms or heterogroups, and optionally substituted by one or more R 1a or by one R 1a substitution, wherein R 1a is independently selected from C1 - C6 alkyl, such as isopropyl; or, L is NR 13 , and R 1 and R 13 and the atoms they are attached to together form The It can be substituted by one or more R 1a ; or, L is NR 13 , and R 1 and R 13 and the atoms they are connected to form a combination. Alternatively, L is CR 14 R 15 , formed by R 1 and R 14 and the atoms they are bonded to. The It can be substituted by one or more R 1a , and R 15 is not present; or, L is CR 14 R 15 , where R 1 and R 14 and the atoms they are connected to together form L. The compound of formula (I) as claimed in any one of claims 1-8, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R2 and R3 are independently selected from hydrogen, halogen, hydroxyl, cyano and C1 - C10 alkyl; or R2 and R3 are independently selected from C1 - C4 alkyl, such as methyl; or R2 and R3 are both methyl. The compound of formula (I) as claimed in any one of claims 1-9, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C1 - C4 alkyl, said C1 - C4 alkyl optionally substituted with one or more R4a ; or, R4 is ethyl, said ethyl optionally substituted with one or more R4a ; or, R4 is ethyl, ethyl substituted with one cyclopropyl, or ethyl substituted with one or more fluorine; or, R4 is ethyl, -CH2 -cyclopropyl, or -CH2 - CF3 ; and/or R4a is independently selected from cyclopropyl, halogen, amino, hydroxyl, mercapto, and cyano; or, R4a is independently selected from cyclopropyl and halogen; or, R4a is a halogen, such as fluorine; or, R4 and R7 and the atoms connected to them together form a 6-7 membered heterocycle, which is optionally substituted by one or more Rd ; or, R4 and R7 and the atoms connected to them together form an unsubstituted 6-7 membered heterocyclic alkyl group; or, R4 and R7 and the atoms connected to them together form an unsubstituted 6-7 membered heterocyclic alkyl group having one N atom and optionally one O atom. The compound of formula (I) as claimed in any one of claims 1-10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R5 is selected from 4-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and 5-10-membered heteroaryl group are optionally substituted by one or more R5a ; or, R5 is selected from 9-10-membered heterocyclic groups and 6-10-membered heteroaryl groups, wherein the 9-10-membered heterocyclic group and 6-10-membered heteroaryl group are optionally substituted by one or more R5a ; or, R5 is selected from The Optionally substituted with one or more R5a , optionally, the position adjacent to the site where R5 connects to the rest of the molecule is substituted with -CH( CH3 )-O- CH3 or -(S)-CH( CH3 )-O- CH3 ; or R5 is Alternatively, R5 is selected from Or R5 is selected from The compound of formula (I) as claimed in any one of claims 1-11, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R5a is independently selected from halogen, cyano, oxo, C1 - C10 alkyl, C2 - C10 ynyl, and 4-10 membered heterocyclic groups, wherein the C1 - C10 alkyl, C2 - C10 ynyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more Rf ; or, R5a is independently selected from halogen, cyano, oxo, C1 - C4 alkyl, C2 - C4 ynyl, and 6-10 membered heterocyclic groups, wherein the C1 - C4 alkyl, C2 - C4 ynyl, and 6-10 membered heterocyclic groups are optionally substituted by one or more Rf ; or, R5a is independently selected from fluorine, cyano, oxo, methyl, piperidinyl, propynyl, piperazine, Ethyl, ethynyl, The methyl, piperidinyl, propynyl, piperazineyl, Ethyl, ethynyl, Optionally substituted with one or more R f ; or, R 5a independently selected from ethyl, The ethyl, It can be optionally replaced by one or more R f . The compound of formula (I) as claimed in any one of claims 1-12, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein Rf is independently selected from C1 - C4 alkyl, C1 - C4 alkoxy, unsubstituted C3 - C5 cycloalkyl, and optionally substituted with C1 - C4 hydroxyalkyl, cyano, C1 - C4 alkyl, C1 -C4 haloalkyl, and halogen-substituted 4-10 membered heterocyclic groups; or, Rf is independently selected from C1 - C4 alkyl, C1 - C4 alkoxy, unsubstituted C3 - C5 cycloalkyl , and optionally substituted with hydroxymethyl 5, 6, or 7 membered heterocyclic groups; or, Rf is independently selected from methyl, methoxy, cyclopropyl, morpholino, oxetyl, Or R f is independently selected from methoxy groups, -CH 3 、 The compound of formula (I) as claimed in any one of claims 1-13, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R6 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, and C1 - C4 alkyl, and R7 is selected from hydrogen, halogen, hydroxyl, and cyano; or, both R6 and R7 are hydrogen; and/or, R8 is selected from hydrogen, halogen, hydroxyl, cyano, and C1 - C10 alkyl; or R8 is hydrogen; and/or, R9 is selected from hydrogen, halogen, hydroxyl, and cyano; or, R9 is selected from hydrogen and halogen; or, R9 is selected from hydrogen and fluorine. The compound of formula (I) as claimed in any one of claims 1 and 5-14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (II) as a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
X2 , A, R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 and R9 are as defined in any one of claims 1 and 5-14. The compound of formula (I) as claimed in claim 15, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein X2 is NH; A is an imidazolyl; R1 is a 5-membered heteroaryl containing at least one N atom, or R1 is an oxadiazolyl or thiadiazolyl, wherein the 5-membered heteroaryl, oxadiazolyl or thiadiazolyl is substituted by one R1a ; R1a is a compound substituted by two Re atoms . Re is fluorine; R2 and R3 are both methyl; R4 is ethyl; R5 is... And R6 , R7 , R8 , and R9 are all hydrogen, or, X 2 is NH; A is R1 is an oxadiazole group or a thiadiazole group, wherein the oxadiazole group or thiadiazole group is substituted by one R1a ; R1a is R2 and R3 are both methyl; R4 is ethyl; R5 is... R6 , R7 , R8 and R9 are all hydrogen. The compound of formula (I) as claimed in any one of claims 1 and 5-14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (III) as a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
X2 , A, R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 and R9 are as defined in any one of claims 1 and 5-14. The compound of formula (I) as claimed in claim 17, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein X2 is NH; A is thiazolyl; R1 is a 5-membered heteroaryl containing at least one N atom, or R1 is oxadiazolyl or thiadiazolyl, said 5-membered heteroaryl, oxadiazolyl or thiadiazolyl being substituted by one R1a ; R1a is selected from C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl or cyclopentyl, each optionally substituted by one or two Re ; Re is independently fluorine, methyl or ethyl; R2 and R3 are both methyl; R4 is ethyl; R5 is R1a is selected from piperazinyl and propynyl groups, each substituted by one Rf ; Rf is selected from methyl, oxecyclobutyl, ... And R6 , R7 , R8 , and R9 are all hydrogen; or, X2 is NH; A is thiazolyl; R1 is a 5-membered heteroaryl containing at least one N atom, or R1 is oxadiazolyl or thiadiazolyl, wherein the 5-membered heteroaryl, oxadiazolyl, or thiadiazolyl is substituted by one R1a ; R1a is selected from C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, each optionally substituted by one or two Re ; Re is independently fluorine, methyl, or ethyl; R2 and R3 are both methyl; R4 is ethyl; R5 is... And R6 , R7 , R8 , and R9 are all hydrogen; or, X 2 is NH; A is R1 is oxadiazolyl or thiadiazolyl, wherein the oxadiazolyl or thiadiazolyl is substituted by one R1a ; R1a is selected from C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, each optionally substituted with two methyl or two fluorine groups; R2 and R3 are both methyl; R4 is ethyl; R5 is... And R6 , R7 , R8 , and R9 are all hydrogen; or, X 2 is NH; A is R1 is an oxadiazolyl or thiadiazolyl group, wherein the oxadiazolyl or thiadiazolyl group is substituted by one R1a ; R1a is selected from isopropyl groups, each optionally substituted by two methyl groups or two fluorine groups. Cyclopropyl or cyclopentyl; R2 and R3 are both methyl; R4 is an unsubstituted ethyl; R5 is... And R6 , R7 , R8 , and R9 are all hydrogen; or, X 2 is NH; A is R1 is an oxadiazole or thiadiazole group, wherein the oxadiazole or thiadiazole group is substituted by one R1a ; R1a is selected from isopropyl, cyclopentyl, ... Or a cyclopropyl group substituted with two methyl groups; R2 and R3 are both methyl; R4 is ethyl; R5 is... And R6 , R7 , R8 , and R9 are all hydrogen; or, X2 is NH; A is thiazole group; L is NR 13 , R1 and R 13 and the atoms they are attached to together form R2 and R3 are both methyl; R4 is ethyl; R5 is... And R6 , R7 , R8 , and R9 are all hydrogen; or, X2 is NH; A is thiazole group; L is NR 13 , R1 and R 13 and the atoms they are attached to together form R2 and R3 are both methyl; R4 is ethyl; R5 is... R6 , R7 , R8 and R9 are all hydrogen. The compound or its stereoisomer or pharmaceutically acceptable salt thereof, selected from the following compounds or their pharmaceutically acceptable salts.










A pharmaceutical composition comprising any one of claims 1-19, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method for preventing or treating RAS-mediated diseases in individuals in need, comprising administering to the individual a compound of any one of claims 1-20 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.