TW202333678A - A sulfonylurea compound - Google Patents

Abstract

The present disclosure provides a sulfonylurea compound. Specifically, the present disclosure provides a compound represented by formula I or the pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising the same, and its use in the preparation of medicaments for the treatment of NLRP3 activity associated diseases. The definition of each group in formula I is as shown in the description.

Description

A sulfonyl urea compound

This disclosure relates to the field of medicine, specifically to a sulfonyl urea compound and its use and preparation method.

NOD-like receptor protein 3 (NLRP3) is a protein-coding gene that belongs to nucleotide-binding and oligomerization domain-like receptors (NLRs). family, also known as "pyocin domain-containing protein 3" (Inoue et al, Immunology, 2013, 139, 11-18). This gene encodes a protein that contains a pyridine domain, a nucleotide binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with adapter proteins, apoptosis-associated speck-like protein (ASC), and zymogen-1 to form the NLRP3 inflammasome. Subsequently, the activation of the NLRP3 inflammasome leads to the release of the inflammatory cytokines IL-1b and IL-18, and when the activation of the NLRP3 inflammasome is dysregulated, it drives the occurrence of many diseases.

Research shows that the activation of NLRP3 inflammasome is related to many types of diseases, including: inflammasome-related diseases, immune diseases such as autoimmune diseases, and inflammatory diseases such as autoinflammatory diseases. Therefore, there is a need to provide new NLRP3 inflammasome pathway inhibitors to provide new options for the treatment of the above diseases.

In a first aspect, the present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof,

或

； where R ₁ is

or

;

； R ₂ is

;

X ₁ is selected from S and O;

X ₂ is CR ₅ or N;

A and B are each independently selected from NR ₇ , C(R _4a ) ₂ and O;

E and D are each independently selected from NR _7b , C(R _6a ) ₂ and O;

R ₃ is selected from hydrogen, C _1-6 alkyl, and 3-6 membered cycloalkyl; the C _1-6 alkyl and 3-6 membered cycloalkyl are optionally selected from one or more C _1-6 alkyl groups. Substituted with substituents of base, 3-6 membered cycloalkyl, halogen, cyano group, and hydroxyl;

、

、

和

；該C_1-6烷基、-O-C_1-6烷基、-O-3-6員環 烷基、-O-3-6員雜環烷基、3-6員環烷基、3-6員雜環烷基、5-6員雜芳基、苯基、胺基、-CONH₂、-CO-C_1-6烷基如-COCH₃、-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂-3-6員雜環烷基視需要被一個或多個選自R_7c的取代基所取代； R ₇ or R _7b is independently selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH ₂ , -CO-C _1-6 alkyl Groups such as -COCH ₃ , -SO ₂ CH ₃ , -C _1-6 (alkylene)alkylene -SO ₂ CH ₃ , -C _1-6 (alkylene)alkylene -SO ₂ -3-6 membered heterocycle alkyl,

,

,

and

;The C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino group, -CONH ₂ , -CO-C _1-6 alkyl such as -COCH ₃ , -SO ₂ CH ₃ , -C _1-6 Alkylene-SO ₂ CH ₃ , -C _1-6 alkyl-SO ₂ -3-6-membered heterocycloalkyl is optionally replaced by one or more substituents selected from R _7c replace;

R _7a is selected from hydrogen, cyano, hydroxyl, halogen and nitro; preferably R _7a is cyano or hydroxyl;

R _7c is independently selected from C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl Substituted with substituents of base, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, amino, cyano, nitro, and hydroxyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered The heteroaryl group is optionally substituted with one or more substituents selected from halogen, amine, cyano, nitro, and hydroxyl;

Each R _4a , R _4b , R _4c , R _4d , R _4e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5- 6-membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl Base, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl are optionally substituted by one or more R _4f ;

Or R _4a forms =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl with each other; the 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally replaced by a or more selected from halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3 -Substituted by substituents of -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl;

Or R _4b and R _4c , R _4d and R _4e together with the atoms to which they are connected form =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl; the 3-8-membered cycloalkyl or The 3-8-membered heterocycloalkyl group is optionally substituted by one or more members selected from halogen, cyano group, amine group, nitro group, -CONH ₂ , C _1-6 alkyl group, -OC _1-6 alkyl group, -O- Substituents of 3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl replaced;

R ₅ is selected from hydrogen, halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O- 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 The heteroaryl and phenyl groups are optionally substituted by one or more R _5a ;

Each R _6a , R _6b , R _6c , R _6d , R _6e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH ₂ , C _1-6 alkane base, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by one or more R _6f ;

Or R _6a forms =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl with each other; the 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally replaced by a or more selected from halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3 -Substituted by substituents of -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl;

Or R _6b and R _6c , R _6d and R _6e together with the atoms to which they are connected form =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl; the 3-8-membered cycloalkyl or The 3-8-membered heterocycloalkyl group is optionally substituted by one or more members selected from halogen, cyano group, amine group, nitro group, -CONH ₂ , C _1-6 alkyl group, -OC _1-6 alkyl group, -O- Substituents of 3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl replaced;

Z is N or CR ₁₂ ;

R ₁₂ is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen , cyano group, amino group, -CONH ₂ , -SO ₂ R _12a , -CH ₂ -SO ₂ R _12a ; the C _1-6 alkyl group, -OC _1-6 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino group, -CONH ₂ is optionally substituted by one or more R _12b ;

R _12b is selected from halogen, cyano group, hydroxyl, amine group, C _1-6 alkyl group, -OC _1-6 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered Heteroaryl and phenyl; the C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl Replaced by one or more R _12c as necessary;

R _12a is selected from C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino group; the C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 The membered heterocycloalkyl group and the amino group are optionally substituted by one or more members selected from halogen, cyano group, hydroxyl, amino group, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycle Substituted by alkyl, 5-6 membered heteroaryl, phenyl substituents;

R ₈ , R ₉ , R ₁₀ , R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3- 6-membered heterocycloalkyl, 3-6-membered cycloalkyl, fused ring formed by 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 3-6-membered heterocycloalkyl, 5-6-membered hetero Aryl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, The fused ring formed by a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl group, and a 3-6-membered heterocycloalkyl group are optionally substituted by one or more R _13a ;

Or R ₈ and R ₉ together with the atoms to which they are connected form a 4-7-membered cycloalkyl group or a 5-6-membered heterocycloalkyl group, which is optionally replaced by a or more selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, - O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ - C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ substituent; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, - O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted by one or more R _13b ;

Or R ₁₀ and R ₁₁ together with the atoms to which they are connected form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, which is optionally replaced by a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group. or more selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, - O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ substituent; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, - O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted by one or more R _13c ;

Each R _13b and R _13c is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O- 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (ethylene) alkyl group -SO ₂ CH ₃ ; the C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 membered cycloalkyl group, -O-3- 6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , - C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted with one or more substituents selected from halogen, hydroxyl, and cyano;

Each R _13a is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, C _1-6 alkyl Amino group, di-C _1-6 alkylamino group, -O-3-6 membered heterocycloalkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, -OC _1-6 sub-(extension group) )alkyl-3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -CONH ₂ , -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 sub(extension) )Alkyl -SO ₂ CH ₃ ; the amino group, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, -OC _1-6 (alkylene)-3-6-membered heterocycloalkyl, 5-6-membered heteroaryl , -CONH ₂ , -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ optionally be one or more selected from C _{1- 6} alkyl, cyano, hydroxyl, halogen, -OC _1-6 alkyl, halo C _1-6 alkyl, cyano substituted C _1-6 alkyl substituted C _1-6 alkyl substituent ;

Each R _7c , R _4f , R _5a , R _6f , R _12c is independently selected from C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, amine, cyano, nitro, hydroxyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered Heterocycloalkyl and 5-6-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, and hydroxyl;

The conditions are:

時，R₁不選自

、

、

、

、視需要取代的

和視需要取代的 When R ₂ is substituted as necessary

When , R ₁ is not selected from

,

,

,

, replaced as necessary

and substituted as necessary

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

； R ₁ is

;

R ₅ is as defined in formula 1, preferably R ₅ is selected from hydrogen, halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O- 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the - CONH ₂ , C _1-6 alkyl, -O- C _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by 1-3 halogens, hydroxyl groups, and cyano groups; more preferably, R ₅ is selected from hydrogen, methyl, ethyl, Halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; optimal R ₅ is hydrogen;

、

、

和

；該C_1-6 烷基、-O-C_1-6烷基、-O-3-6員環烷基、-O-3-6員雜環烷基、3-6員環烷基、3-6員雜環烷基、5-6員雜芳基、苯基、胺基、-CONH₂、-CO-C_1-6烷基如-COCH₃、-SO₂-C_1-6烷基如-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂-3-6員雜環烷基視需要被1-3個選自鹵素、氰基、羥基的取代基所取代；更佳R_7b選自氫、C_1-6烷基、3-6員雜環烷基、-C_1-6亞(伸)烷基-3-6員雜環烷基、-C_1-6亞(伸)烷基-3-6員環烷基、羥基取代的C_1-6烷基、鹵 素取代的C_1-6烷基、

； R _7b is as defined in formula I, preferably R _7b is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH ₂ , -CO -C _1-6 alkyl group such as -COCH ₃ , -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (exylene)alkyl group -SO ₂ CH ₃ , -C _{1- 6} (ethylene)alkylene-SO ₂ -3-6-membered heterocycloalkyl,

,

,

and

;The C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino group, -CONH ₂ , -CO-C _1-6 alkyl such as -COCH ₃ , -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene)alkyl group -SO ₂ CH ₃ , -C _1-6 (alkylene)alkyl group -SO ₂ -3-6 membered heterocycloalkyl group is optionally replaced by 1 -Substituted with 3 substituents selected from halogen, cyano, and hydroxyl; more preferably, R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 sub(extension) Alkyl-3-6-membered heterocycloalkyl, -C _1-6 (alkylene)-3-6-membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl base,

;

R _7a is as defined in claim 1, preferably R _7a is cyano;

R _6a , R _6b , R _6c , R _6d , R _6e are as defined in Formula I.

；R₅如式1中所定義，較佳R₅選自氫、鹵素、氰基、胺 基、硝基、-CONH₂、C_1-6烷基、-O-C_1-6烷基、-O-3-6員環烷基、-O-3-6員雜環烷基、3-6員環烷基、3-6員雜環烷基、5-6員雜芳基、苯基；該-CONH₂、 C_1-6烷基、-O-C_1-6烷基、-O-3-6員環烷基、-O-3-6員雜環烷基、3-6員環烷基、3-6員雜環烷基、5-6員雜芳基、苯基視需要被1-3個鹵素、羥基、氰基所取代；更佳R₅選自氫、甲基、乙基、鹵素、氰基、環丙基、亞甲基環丙基、鹵甲基、鹵乙基、鹵環丙基、鹵甲基環丙基；最佳R₅為氫； In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₁ is

; R ₅ is as defined in formula 1, preferably R ₅ is selected from hydrogen, halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by 1-3 halogens, hydroxyl groups, and cyano groups; more preferably, R ₅ is selected from hydrogen, methyl, ethyl, and halogen , cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; the best R ₅ is hydrogen;

、

、

和

；該C_1-6烷基、-O-C_1-6烷基、 -O-3-6員環烷基、-O-3-6員雜環烷基、3-6員環烷基、3-6員雜環烷基、5-6員雜芳基、苯基、胺基、-CONH₂、-CO-C_1-6烷基如-COCH₃、-SO₂-C_1-6烷基如-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂-3-6員雜環烷基視需要被1-3個選自鹵素、氰基、羥基的取代基所取代；更佳R_7b選自氫、C_1-6烷基、3-6員雜環烷基、-C_1-6亞(伸)烷基-3-6員雜環烷基、-C_1-6亞(伸)烷基-3-6員環烷基、羥基取代的C_1-6烷基、鹵素取代的C_1-6烷基、

；R_7a如請求項1中所定義，較佳地R_7a為氰基； R _7b is as defined in formula I, preferably R _7b is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH ₂ , -CO -C _1-6 alkyl group such as -COCH ₃ , -SO ₂ CH ₃ , -C _1-6 (exylene)alkyl group -SO ₂ CH ₃ , -C _1-6 (exylene)alkyl group -SO ₂ - 3-6 membered heterocycloalkyl,

,

,

and

;The C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino group, -CONH ₂ , -CO-C _1-6 alkyl such as -COCH ₃ , -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene)alkyl group -SO ₂ CH ₃ , -C _1-6 (alkylene)alkyl group -SO ₂ -3-6 membered heterocycloalkyl group is optionally replaced by 1 -Substituted with 3 substituents selected from halogen, cyano, and hydroxyl; more preferably, R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 sub(extension) Alkyl-3-6-membered heterocycloalkyl, -C _1-6 (alkylene)-3-6-membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl base,

; R _7a is as defined in claim 1, preferably R _7a is cyano;

R _6a , R _6b , R _6c , R _6d , R _6e are as defined in Formula I.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

； R ₁ is

;

E and D are each independently selected from C(R _6a ) ₂ and O, and one and only one of E and D is O;

R ₅ is as defined in formula 1, preferably R ₅ is selected from hydrogen, halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O- 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the - CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3 -6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by 1-3 halogens, hydroxyl groups, and cyano groups; more preferably, R ₅ is selected from hydrogen, methyl, ethyl, halogen, Cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; optimal R ₅ is hydrogen;

R _6a , R _6b , R _6c , R _6d , R _6e are as defined in Formula I.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

； R ₁ is

;

E and D are each independently selected from NR _7b , C(R _6a ) ₂ and O, and one and only one of E and D is O;

R ₅ is as defined in formula 1, preferably R ₅ is selected from hydrogen, halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O- 3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the - CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3 -6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by 1-3 halogens, hydroxyl groups, and cyano groups; more preferably, R ₅ is selected from hydrogen, methyl, ethyl, halogen, Cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; optimal R ₅ is hydrogen;

R _7b is as defined in claim 1, preferably R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered Heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl, -CO-C _{1 -6} alkyl such as -COCH ₃ ;

R _6a , R _6b , R _6c , R _6d , R _6e are as defined in Formula I.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

或

； R ₁ is selected from

or

;

E and D are each independently selected from NR _7b , C(R _6a ) ₂ and O,

、

、

和

；該C_1-6 烷基、-O-C_1-6烷基、-O-3-6員環烷基、-O-3-6員雜環烷基、3-6員環烷基、3-6員雜環烷基、5-6員雜芳基、苯基、胺基、-CONH₂、-CO-C_1-6烷基如-COCH₃、-SO₂-C_1-6烷基如-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂CH₃、-C_1-6亞(伸)烷基-SO₂-3-6員雜環烷基視需要被1-3個選自鹵素、氰基、羥基的取代基所取代；更佳R_7b選自氫、C_1-6烷基、3-6員雜環烷基、-C_1-6亞(伸)烷基-3-6員雜環烷基、-C_1-6亞(伸)烷基-3-6員環烷基、羥基取代的C_1-6烷基、鹵 素取代的C_1-6烷基、

； R _7b is as defined in formula I, preferably R _7b is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH ₂ , -CO -C _1-6 alkyl group such as -COCH ₃ , -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (exylene)alkyl group -SO ₂ CH ₃ , -C _{1- 6} (ethylene)alkylene-SO ₂ -3-6-membered heterocycloalkyl,

,

,

and

;The C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino group, -CONH ₂ , -CO-C _1-6 alkyl such as -COCH ₃ , -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene)alkyl group -SO ₂ CH ₃ , -C _1-6 (alkylene)alkyl group -SO ₂ -3-6 membered heterocycloalkyl group is optionally replaced by 1 -Substituted with 3 substituents selected from halogen, cyano, and hydroxyl; more preferably, R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 sub(extension) Alkyl-3-6-membered heterocycloalkyl, -C _1-6 (alkylene)-3-6-membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl base,

;

R _6a , R _6b , R _6c , R _6d , R _6e are as defined in Formula I.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

或

， R ₁ is selected from

or

,

R _6a , R _6b , R _6c , R _6d , R _6e are as defined in Formula I.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _6a , R _6b , R _6c , R _6d , and R _6e are the same or different, and each is independently selected from hydrogen, halogen, Cyano group, amine group, nitro group, hydroxyl group, -CONH ₂ , C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 membered cycloalkyl group, -O-3-6 membered heterocycle Alkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl , -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, benzene The base is replaced by one or more R _6f as necessary;

R _6f is as defined in Equation 1.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _6a , R _6b , R _6c , R _6d , and R _6e are the same or different, and each is independently selected from hydrogen, halogen, Cyano group, amine group, nitro group, hydroxyl group, -CONH ₂ ; the -CONH ₂ is optionally replaced by one or more R _6f ;

R _6f is as defined in Equation 1.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _6a , R _6b , R _6c , R _6d , and R _6e are the same or different, and each is independently selected from C _1-6 Alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by one or more R _6f ; R _6f is as defined in Formula 1.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _6a , R _6b , R _6c , R _6d , and R _6e are the same or different, and each is independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _6f ; R _6f is as defined in Formula 1 .

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _6f is independently selected from C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl base, 5-6 membered heteroaryl, phenyl; the C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl is optionally replaced by one or Substituted with multiple substituents selected from halogen, amine, cyano, nitro, and hydroxyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6f is independently selected from halogen, amine, cyano, nitro, and hydroxyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6f is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl, -OC _1-6 alkyl, -O -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O -3-6-membered heterocycloalkyl and 3-6-membered cycloalkyl are optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, and hydroxyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6a forms =S, =O with each other.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6b and R _6c form =S, =O.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6d and R _6e form =S, =O.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6d and R _6e together with the atoms to which they are connected are 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3 -8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally substituted by one or more selected from halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _{1- 6-} alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl Substituted with substituents of base and phenyl.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R _6a forms a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group; the 3-8 membered cycloalkyl group Or the 3-8 membered heterocycloalkyl group is optionally selected from one or more halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl replaced by base.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6b and R _6c form a 3-8-membered cycloalkyl group or a 3-8-membered heterocycloalkyl group; the 3-8-membered cycloalkyl group The base or 3-8-membered heterocycloalkyl group is optionally selected from one or more halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, - O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl substituted by substituents.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6d and R _6e form a 3-8-membered cycloalkyl group or a 3-8-membered heterocycloalkyl group; the 3-8-membered cycloalkyl group Or the 3-8 membered heterocycloalkyl group is optionally selected from one or more halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl replaced by base.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _6d and R _6e form a 3-8-membered cycloalkyl group or a 3-8-membered heterocycloalkyl group; the 3-8-membered cycloalkyl group Or the 3-8 membered heterocycloalkyl group is optionally selected from one or more halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O Substitution of -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl substituted with a group; preferably R _6d and R _6e form a 3-8-membered heterocycloalkyl group; the 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl group is optionally replaced by one or more members selected from halogen, cyano Substituted with substituents such as amine group, nitro group, -CONH ₂ and C _1-6 alkyl group.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

或

； R ₁ is

or

;

R ₇ is as defined in formula I, preferably R ₇ is methyl;

R ₃ is as defined in formula I, preferably R ₃ is methyl, propyl, isopropyl, or hydroxyethyl;

R _4a , R _4b , R _4c , R _4d , and R _4e are as defined in Formula I. Preferably, R _4a , R _4b , R _4c , R _4d , and R _4e are hydrogen.

On the basis of the implementable solutions provided above, this disclosure also provides the following technical solutions for _R2 .

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂

；R₈、R₉、R₁₀、R₁₁如式I中所定義。 for

; R ₈ , R ₉ , R ₁₀ , R ₁₁ are as defined in formula I.

； In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂ is

;

R ₈ and R ₉ form a 4-7-membered cycloalkyl or 5-6-membered heterocycloalkyl group, which is optionally replaced by one or more halogens. , hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _{1 -6} (ethylene)alkyl-SO ₂ CH ₃ substituent; the C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 member Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl Groups such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ are optionally substituted by one or more R _13b ; preferably R ₈ and R ₉ form a 4-membered cycloalkyl group, The 4-membered cycloalkyl group is optionally replaced by 1-3 members selected from halogen, hydroxyl, cyano group, amino group, C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O -3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl;

R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , a fused ring formed by a 3-6-membered cycloalkyl group, a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, a 3-6-membered heterocycloalkyl group, and a 5-6-membered heteroaryl group; the C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle The fused ring formed by the alkyl group and the 5-6-membered heteroaryl group, the 5-6-membered heteroaryl group, and the 3-6-membered heterocycloalkyl group are optionally substituted by one or more R _13a ;

R ₁₂ , R _13a , R _13b are as defined in Formula I.

； In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂ is

;

R ₈ and R ₉ form a 4-7-membered cycloalkyl or 5-6-membered heterocycloalkyl group, which is optionally replaced by one or more halogens. , hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _{1 -6} (ethylene)alkyl-SO ₂ CH ₃ substituent; the C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 member Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl Groups such as -SO ₂ CH ₃ and -C _1-6 (alkylene) -SO ₂ CH ₃ are optionally substituted by one or more R _13b ;

R ₁₀ and R ₁₁ form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, which is optionally replaced by one or more halogens. , hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _{1 -6} (ethylene)alkyl-SO ₂ CH ₃ substituent; the C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 member Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl Groups such as -SO ₂ CH ₃ and -C _1-6 (alkylene) -SO ₂ CH ₃ are optionally substituted by one or more R _13c ;

R ₁₂ , R _13b , R _13c are as defined in Formula I.

； In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂ is

;

Z is N or CR ₁₂ ;

R ₈ and R ₉ form a 4-7 membered cycloalkyl group, which is optionally replaced by one or more members selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered hetero Cycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl, such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ substituents substituted ;The C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 alkylene The base -SO ₂ CH ₃ is optionally substituted with one or more R _13b ;

R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , a fused ring formed by a 3-6-membered cycloalkyl group, a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, a 3-6-membered heterocycloalkyl group, and a 5-6-membered heteroaryl group; the C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle The fused ring formed by the alkyl group and the 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group, and the 3-6 membered heterocycloalkyl group are optionally substituted by one or more R _13a ; R ₁₂ , R _13a , R _13b , as defined in formula I;

R ¹⁰ , R ¹¹ , R ₁₂ , R _13a , R _13b are as defined in Formula I.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

； R ₂ is

;

Z is N or CR ₁₂ ;

R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halogen C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 Member heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ ; the C _1-6 alkyl, halogen C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle Alkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (exylene) alkyl -SO ₂ CH ₃ optionally replaced by one or more Replaced by R _13b ;

R ₁₀ is selected from the fused ring formed by a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, and a 5-6-membered heteroaryl group; the 3-6-membered heterocycloalkyl group and the 5-6-membered heteroaryl group The resulting fused ring, 5-6 membered heteroaryl group is optionally substituted with one or more R _13a .

R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ;

R ₁₂ , R _13a , R _13b are as defined in Formula I.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

； R ₂ is

;

Z is N or CR ₁₂ ;

R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halogen C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 Member heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ ; the C _1-6 alkyl, halogen C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle Alkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (exylene) alkyl -SO ₂ CH ₃ optionally replaced by one or more Replaced by R _13b ;

R ₁₀ is selected from 5-6 membered heteroaryl optionally substituted by one or more R _13a ;

R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ;

R ₁₂ , R _13a , R _13b are as defined in Formula I.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R ₂ is selected from

Z is N or CR ₁₂ ;

R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ;

R _10a is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ substituent; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO _2- C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted by one or more R _13c ; R _10b is selected from C _{1- 6} alkyl, the C _1-6 alkyl is optionally substituted by C _3-6 cycloalkyl;

n and m are independently selected from the integer of 0-3; preferably n and m are independently selected from the integer of 0-2;

R ₈ , R ₉ , R ₁₂ , R _13a , R _13c are as defined in formula I;

R _9a , R _9b , R _9c , R _9d , R _9e and R _9f are as defined above.

In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

； R ₂ is

;

Z is N or CR ₁₂ ;

R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ;

n is an integer selected from 0-3;

R ₁₂ , R _13a , R _13c , R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are as defined above.

In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, Z is N.

In other embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, Z is CR ₁₂ ; R ₁₂ is as defined in Formula I.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₁₂ is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3 -6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amine, -CONH ₂ , -SO ₂ R _12a , -CH ₂ -SO ₂ R _12a ; the C _{1- 6} alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino group, -CONH ₂ optionally replaced by 1 -3 R _12b replaced;

R _12a and R _12b are as defined in Formula I.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₁₂ is selected from hydrogen, halo C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl, cyano substituted C _1-6 Alkyl, -OC _1-6 alkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano group, amino group, -CONH ₂ , -SO ₂ R _12a , -CH ₂ -SO ₂ R _12a , R _12a is as defined in formula I;

Preferred R ₁₂ is selected from hydrogen, halogen, C _1-6 alkyl, halo C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, -OC _1-6 alkyl base.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _12a is selected from the group consisting of C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino. ; The C _1-6 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group and amino group are optionally substituted by one or more substituents selected from halogen, cyano group, hydroxyl group and amino group. replaced;

Preferred R _12a is selected from C _1-6 alkyl, halo C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, and 3-6 membered heterocycloalkyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _12b is selected from halogen, cyano, hydroxyl, amino, C _1-6 alkyl, -OC _1-6 alkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl; the C _1-6 alkyl, -OC _1-6 alkyl, 3-6-membered cycloalkyl , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl are optionally substituted by 1-3 R _{12c, R 12c is as defined in formula 1; preferably 12b is selected} from halogen, cyano , hydroxyl, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 Member heterocycloalkyl, 5-6 membered heteroaryl and phenyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _12c is independently selected from halogen, amine, cyano, nitro, hydroxyl, C _1-6 alkyl, -OC _{1- 6} alkyl; the C _1-6 alkyl and -OC _1-6 alkyl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, and hydroxyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are independently selected from hydrogen, halogen, hydroxyl, cyano, Amino group, C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group; the C _1-6 alkyl group, halo C _1-6 alkyl group and -OC _1-6 alkyl group are regarded as Need to be replaced by one or more R _13b , R _13b is as defined in formula I; preferably R _9a , R _9b , R _9c , R _9d , R _9e , R _9f are independently selected from hydrogen, halogen, hydroxyl, cyanide group, amino group, C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group; more preferably R _9a , R _9b , R _9c , R _9d , R _9e , R _9f are independently selected From hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl; optimal R _9a , R _9b , R _9c , R _9d , R _9e , R _9f is hydrogen.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _13b is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, -OC _1-6 alkyl , halo C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl , -OC _1-6 alkyl is optionally substituted by one or more R _13a , R _13a is as defined in Formula I.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₁₁ is selected from hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, and hydroxyl-substituted C _1-6 alkyl. ; Preferably R ₁₁ is selected from hydrogen and methyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _13a is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkylamino, di-C _{1 -6} alkylamino group, C _1-6 alkyl group, -OC _1-6 alkyl group; the amino group, C _1-6 alkyl group, -OC _1-6 alkyl group are optionally selected from 1 to 3 C _1-6 alkyl, cyano, hydroxy, halogen, -OC _1-6 alkyl, halo C _1-6 alkyl, cyano-substituted C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl substituted by substituents.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _13a is independently selected from cyano, halogen, hydroxyl, C _1-6 alkyl, -OC _1-6 alkyl, Methanesulfonyl group, -CONH ₂ , -CH ₂ -SO ₂ CH ₃ , 3-6 membered heterocyclic group, and amino group.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _13a is independently selected from C _1-6 alkyl, -OC _1-6 alkyl, -O-5-6 alkyl. Heteroaryl, -O-3-6-membered heterocycloalkyl, -OC _1-6 (alkylene)-3-6-membered heterocycloalkyl; the C _1-6 alkyl, -OC _1-6 Alkyl, -O-5-6-membered heteroaryl, -O-3-6-membered heterocycloalkyl, -OC _1-6 (alkylene)-3-6-membered heterocycloalkyl as needed 1- Substituted with 3 substituents selected from halogen, cyano group, hydroxyl group, and C _1-6 alkyl group.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, each R _13a is independently selected from the group consisting of 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heterocycloalkyl. Aryl; the 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, and 5-6-membered heteroaryl are optionally substituted by one or more C _1-6 alkyl groups, cyano groups, hydroxyl groups, and halogen groups. , -OC _1-6 alkyl, halo C _1-6 alkyl, cyano substituted C _1-6 alkyl.

In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R _10a is independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl , -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, halo 3-6 membered cycloalkyl, halo 3-6 membered heterocycloalkyl.

時，R₁不為

。 In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂ is optionally substituted

When , R ₁ is not

.

。 In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂ is not

.

。 In some embodiments, in the compound represented by Formula I or a pharmaceutically acceptable salt thereof, R ₂ is not optionally substituted

.

In a second aspect, the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

For third parties, the present disclosure also provides an isotope substitution of the compound described in the first aspect or the second aspect. Preferably, the isotope substitution is deuterium atom substitution.

In a fourth aspect, the present disclosure also provides a pharmaceutical composition, including at least a therapeutically effective amount of a compound as described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or an isotope substitute as described by a third party. , and pharmaceutically acceptable excipients.

In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof.

In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

In the fifth aspect, the present disclosure also provides compounds described in the first and second aspects or pharmaceutically acceptable salts thereof, or isotope substitutes described by cooperating manufacturers, or pharmaceutical compositions described in the fourth aspect in the preparation of treatments and Use in drugs for diseases related to NLRP3 activity.

The present disclosure also provides a method for preventing and/or treating diseases related to NLRP3 activity, which includes administering to a patient in need a therapeutically effective amount of the compound described in the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof, or The isotope substitutes described in the third aspect, or the pharmaceutical compositions described in the fourth aspect.

The present disclosure also provides a compound described in the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or an isotope substitute described above by a third party, or a pharmaceutical composition described in the fourth aspect, which is used for prevention or treatment Diseases associated with NLRP3 activity.

Diseases related to NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.

The present disclosure also provides the compounds described in the first and second aspects or pharmaceutically acceptable salts thereof, or the isotope substitutes described above or the pharmaceutical compositions described in the fourth aspect for the preparation and treatment of inflammasome-related diseases, Use in medicines for immune, inflammatory, autoimmune and/or autoinflammatory diseases.

The present disclosure also provides compounds described in the first and second aspects or pharmaceutically acceptable salts thereof, or isotope substitutes described above by a third party, or pharmaceutical compositions described in the fourth aspect, which are used For the treatment of inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.

The present disclosure also provides a method of treating and/or preventing inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and/or autoinflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of The compounds described in the first and second aspects, or pharmaceutically acceptable salts thereof, or the isotope substitutes described above by a cooperating manufacturer, or the pharmaceutical compositions described in the fourth aspect.

In some embodiments, the inflammasome-related disease, immune disease, inflammatory disease, autoimmune disease and/or autoinflammatory disease can be specifically selected from: autoinflammatory febrile syndrome (such as cryopyrin-related periodic syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis Related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, Type I or type II diabetes and its complications (such as nephropathy, retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), Cardiovascular and metabolic related disorders or diseases (such as cardiovascular disease risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure and hypertension), Wound healing, scarring, inflammatory skin diseases (e.g., acne, hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, cancer-related diseases/conditions (e.g., myeloproliferative neoplasms, leukemias, myelodysplasia syndrome (MDS), myelofibrosis, lung cancer, colon cancer).

Pharmaceutically acceptable salts of the compounds described in this disclosure can be selected from inorganic salts or organic salts.

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

The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can form a diastereomeric salt with an appropriate optically active acid or base, and then use conventional methods known in the art to The method performs diastereoisomer resolution and then recovers the pure enantiomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally combined with chemical derivatization methods (e.g., generation of amines from amines). formate).

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。本揭露所述化合物的化學結構中，鍵“

”並未指定構型，即鍵“

”的構型可以為E型或Z型，或者同時包含E和Z兩種構型。 In the chemical structure of the compounds described in this disclosure, the bond "

"Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond"

"can be"

"or"

”, or both “

"and"

"Two configurations. In the chemical structures of the compounds described in this disclosure, bonds"

"No configuration, i.e. key, was specified"

"The configuration can be E -type or Z -type, or contain both E and Z configurations.

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

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

The present disclosure also includes some isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc.

Unless otherwise stated, when a position is specifically designated as deuterium (D), that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10 % deuterium incorporation). Examples of compounds having a natural abundance greater than deuterium may be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. The present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. A person with ordinary skill in the art can synthesize the deuterated form of the compound of formula (I) with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of compounds of formula (I), or they may be prepared using conventional techniques. The technique is synthesized using deuterated reagents, which include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, deuterated iodide methane, etc.

"Optionally" or "as appropriate" is meant to mean that the subsequently described event or circumstances may but need not occur, and that the description includes instances where the event or circumstances do or do not occur. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but does not have to be present. This description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. and the case of cyano substitution.

Terminology explanation

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, as well as other ingredients such as physiologically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

"Pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent approved for human or livestock animal use Agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

As used in this disclosure, an "effective amount" or a "therapeutically effective amount" includes an amount sufficient to ameliorate or prevent symptoms or symptoms of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of the side effects. An effective amount may be the maximum dosage or dosage regimen that avoids significant side effects or toxic effects.

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxyl, pendant oxygen , cyano group, amino group, C _1-6 alkyl group, C _1-6 alkoxy group, 3 to 6 membered cycloalkyl group or 3 to 6 membered heterocycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group Or the heterocycloalkyl group is optionally substituted by halogen, hydroxyl, nitro, cyano or amine group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spiro Cycloalkyl groups of rings, bridged rings and bridged rings. The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxyl, pendant Oxygen, cyano group, amino group, C _1-6 alkyl group, C _1-6 alkoxy group, 3 to 6 membered cycloalkyl group or 3 to 6 membered heterocycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group group or heterocycloalkyl group optionally substituted by halogen, hydroxyl, nitro, cyano or amine group.

The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:

，等等。

,etc.

The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, where the ring connected to the parent structure is a heterocycloalkyl group. Non-limiting examples include:

和

等。

and

wait.

The heterocycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, hydroxyl, pendant oxygen, cyano group, and amine group. , C _1-6 alkyl group, C _1-6 alkoxy group, 3 to 6 membered cycloalkyl group or 3 to 6 membered heterocycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group shall be regarded as Needs to be substituted by halogen, hydroxyl, nitro, cyano or amine group.

The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. The alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, hydroxyl, pendant oxygen, cyano group, amine group, C _1-6 alkyl, C _1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl group is optional Substituted by halogen, hydroxyl, nitro, cyano or amine.

In the same way, "cycloalkoxy" and "heterocycloalkoxy" are the same as the above-mentioned "alkoxy".

The term "alkylthio" refers to -S-(alkyl), where alkyl is as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propylthio, butylthio. The alkylthio group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from C _1-6 alkoxy, 3 to 6 membered rings Alkyl, 3 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _1-6 alkylthio, 3 to 6 membered cycloalkylthio, 3 to 6 6-membered heterocycloalkylthio group, the alkoxy group, cycloalkyl group, heterocycloalkyl group, cycloalkoxy group, heterocyclic oxy group, alkylthio group, cycloalkylthio group, heterocycloalkylthio group is optionally replaced by halogen , hydroxyl, cyano or amine substituted.

In the same way, "cycloalkylthio group" and "heterocycloalkylthio group" have the same definitions as the above-mentioned "alkylthio group".

"Monovalent group" refers to a compound that "formally" eliminates a monovalent atom or group. "Subunit" or "bivalent group" refers to the "formal" elimination of two monovalent or one bivalent atoms or atomic groups in a compound.

The term "alkylene" refers to the remaining part of an alkane molecule after removing 2 hydrogen atoms, including straight-chain and branched chain (alkylene) groups of 1 to 20 carbon atoms. Alkylene groups containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH ₂ -), ethylene (such as -CH ₂ CH ₂ - or -CH(CH ₃ )-). Unless otherwise specified, the (alkylene) group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available connection point, preferably one or more of the following groups, independently is selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl or C _1-6 alkoxy.

In the same way, "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene", "heterocycloalkylene" "Group" is defined as "(alkylene) group".

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6 to 12 members, e.g. phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, hydroxyl, pendant oxygen, nitro, cyano, C _{1- 6} alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _{3- 8} cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, 3 to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 3- to 8-membered cycloalkenoxy, 5- to 6-membered aryl or heteroaryl, optionally one or more selected from halogen, hydroxyl, Cyano group, amine group, C _1-6 alkyl group or C _1-6 alkoxy group.

，

、

等。 The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group preferably has 6 to 12 members, more preferably 5 or 6 members. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl,

,

,

wait.

The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, hydroxyl, cyano, amine, C _{1- 6} alkyl or C _1-6 alkoxy.

The term "spiro" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyl groups include:

The term "ring ring" refers to a compound in which two or more rings are joined by sharing two adjacent atoms. Non-limiting examples of cycloalkyl groups include:

The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The term "heterocycle" refers to atoms other than carbon atoms that make up the ring, and includes heterocycloalkyl and heteroaromatic rings.

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

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

The term "cyano" refers to -CN.

The term "amine" refers to _-NH2 .

The term "nitro" refers to _-NO2 .

The term "pendant oxygen" refers to an =O substituent.

"Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. When the substituent is a ketone or a pendant oxygen (ie, =O), then two (2) hydrogens on the atom are replaced.

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl styrene (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was tetrahydrofuran. Methylsilane (TMS).

MS was measured using Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.

HPLC determination uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatography column or Xtimate C18 2.1*30mm chromatography column or Gilson-281 Waters Xbridge 150*25mm chromatography column or Gilson-281 Waters Xbridge 150*25mm chromatography column or Gilson-281 Phenomenex luna C18 250*50mm chromatography column).

Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm I.D.,3um,Chiralpak AS-3 100×4.6mm I.D.,3μm,ChiralCel OD-3 150×4.6mm I.D.,3um,Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um chromatography column.

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin layer chromatography (TLC) are 0.15mm~0.2mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 100~200 mesh, 200~300 mesh or 300~400 mesh silica gel as the carrier.

Chiral preparation columns use DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).

The average kinase inhibition rate and IC ₅₀ value were measured using NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

There are no special instructions in the examples, and the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.

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

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses CEM Discover-S 908860 microwave reactor.

There is no special explanation in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of column chromatography and the developing agent system of thin layer chromatography used to purify the compound, the solvent The volume ratio is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example

Example 1

((3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl) ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)aminoformyl)amine sodium salt

first step

At room temperature, add compound 1a (50g, 214mmol), ethanol (500mL), malononitrile (9.20g, 139mmol), diethylamine (16.6mL, 160.8mmol), and elemental sulfur (5.48g, 161mmol). Under nitrogen atmosphere, raise the temperature to 70°C and stir for 2 hours. Cool to room temperature, filter, collect the filter cake and dry it under vacuum to obtain compound 1b (33g, yield: 75.8%). LC-MS m/z(ESI): 314.1(M+H) ⁺ .

Step 2

At room temperature, add copper bromide (4.28g, 19.1mmol), tert-butyl nitrite (1.65g, 16.0mmol), and acetonitrile (50mL) in sequence to a 500mL reaction bottle. Under nitrogen atmosphere, the temperature was raised to 65°C, compound 1b (5.0g, 16.0mmol) was added, and stirred for 2 hours. Cool to room temperature, add water (100 mL), filter, and extract the filtrate with ethyl acetate (20 mL × 3). The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 10% ethyl acetate/petroleum ether) to obtain compound 1c (2.6g, yield: 36%). LC-MS m/z(ESI): 378.0(M+H) ⁺ .

third step

At room temperature, add compound 1c (23.0g, 61.0mmol), tris(dibenzylideneacetone)dipalladium (2.79g, 3.05mmol), and N,N-diisopropylethylamine (20.2 mL, 122mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (3.53g, 6.10mmol), dioxane (300mL) and benzylthiol (15.1g, 121.9mmol) . Under a nitrogen atmosphere, the temperature was raised to 100°C and stirred for 2 hours. Cool to room temperature, add dichloromethane (500mL) and water (300mL), extract the aqueous phase with dichloromethane (200mL×3), collect the organic phase, concentrate under reduced pressure, and rinse the residue with silica gel column chromatography. The system (SiO ₂ , 10% ethyl acetate/petroleum ether) was purified to obtain compound 1d (25g, yield: 97%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 7.42-7.21(m,10H),5.12(s,2H),4.59(s,2H),4.24(s,2H),3.68(s,2H),2.65 (t,2H).

the fourth step

At room temperature, compound 1d (25.0g, 59.4mmol) and acetonitrile (250mL) were added in sequence to a 500mL single-neck bottle. The temperature was lowered to 0°C, and 1,3-dichloro-5,5-dimethylhydantoin (23.4g, 118.9mmol), water (6mL) and acetic acid (6mL) were added. Stir for 2 hours, concentrate under reduced pressure, add ethyl acetate (200 mL) and water (100 mL), dry the organic phase, filter, and concentrate under reduced pressure to obtain compound 1f (25 g, crude product), which is directly used in the next step.

the fifth step

At room temperature, compound 1f (10.0g, 25.2mmol) and 7M ammonia methanol solution (100mL, 700mmol) were added to a 500mL three-necked flask. Stir for 12 hours and concentrate under reduced pressure. Add methanol (100 mL) to beat, filter, wash the filter cake with methanol (200 mL), collect the filter cake, and obtain 1 g of compound (4.4 g, yield: 46.3%). LC-MS m/z(ESI): 378.2(M+H) ⁺ .

Step 6

At room temperature, compound 1g (4.00g, 10.6mmol), hydrogen bromide acetic acid solution (5mL, 33%), and acetic acid (15mL) were added in sequence to a 100mL single-mouth bottle, and stirred for 2 hours. Concentrate under reduced pressure, add methanol (100 mL), slowly add sodium carbonate solid to pH=9, filter, and concentrate the filtrate under reduced pressure, and purify through reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 1h (600 mg, product rate: 23.3%). LC-MS m/z(ESI): 244.0(M+H) ⁺ .

Step 7

Add compound 1h (2.00g, 8.22mmol), methanol (20mL), acetic acid (2.4mL, 41.1mmol) to a 100mL single-neck bottle, stir for 10 minutes, add paraformaldehyde (50mg) and sodium cyanoborohydride (1.55g ,24.7mmol), stirred at room temperature for 1 hour. 7M ammonia in methanol solution (2 mL) was added, concentrated under reduced pressure, and the residue was purified by reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 1i (80 mg, yield: 3.8%). LC-MS m/z(ESI): 258.0(M+H) ⁺ .

Step 8

At 0°C, add compound 1i (30 mg, 0.12 mmol), tetrahydrofuran (2 mL), and sodium tert-butoxide (11.76 mg, 0.122 mmol) into a 10 mL single-neck bottle. Warm to room temperature, stir for 30 minutes, add 1j (23 mg, 0.12 mmol), and stir for 4 hours. Concentrate under reduced pressure, and the residue is subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 50-70% B; flow 25ml/min) was purified to obtain a crude product. After the crude product was exchanged with sodium ion exchange resin, compound 1 (13.63mg, yield: 23.7%) was obtained.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.53 (s, 1H), 6.78 (s, 1H), 3.50 (s, 2H), 2.75 (t, 4H), 2.70-2.62 (m, 8H), 2.35 (s,3H),1.94-1.87(m,4H).

LC-MS m/z (ESI): 479.0 (M+Na) ⁺ .

Example 2

((1,2,3,5,6,7-hexahydro-s-indenen-4-yl)aminomethyl)((6-methyl-4,5,6,7-tetrahydrothiophene And[2,3-c]pyridin-2-yl)sulfonyl)amine sodium salt

first step

At room temperature, add compound 2a (31.0g, 251.7mmol), tetrahydrofuran (80mL), and borane dimethyl sulfide complex (252mL, 504mmol) into a 1L one-neck bottle. Under nitrogen atmosphere, raise the temperature to 80°C and stir overnight. Cool to room temperature, add 6M hydrochloric acid methanol solution (150 mL, 900 mmol) dropwise, and concentrate under reduced pressure. The residue is filtered by beating with methylene chloride (300 mL). The filter cake is concentrated under reduced pressure to obtain compound 2b (35 g, 213.8 mmol, yield :84.9%). LC-MS: MS(ESI): m/z 128.2(M+H) ⁺

Step 2

At room temperature, compound 2b (32.0g, 251.6mmol), dichloromethane (300mL), triethylamine (88mL, 633mmol) and di-tert-butyl dicarbonate (64mL, 279mmol) were added to a 1L single-neck bottle. Stir for 5 hours. Pour into water (400mL), extract with dichloromethane (250mL×3), combine the organic phases, wash with saturated brine (300mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2c (41g, yield: 72%). LC-MS: MS(ESI): m/z 213.2(M-55+CH ₃ CN) ⁺ .

third step

At room temperature, compound 2c (82.0g, 360.8mmol), paraformaldehyde (20.0g, 190.4mmol), p-toluenesulfonic acid monohydrate (1.04g, 5.46mmol) and toluene (200mL) were added in sequence to a 500mL single-neck bottle. . Then connect the reflux pipe of the water distributor and stir at 120°C for 2 hours under a nitrogen atmosphere. Concentrate under reduced pressure, add ethyl acetate (200 mL), filter, pour the filtrate into water (500 mL), and extract with ethyl acetate (400 mL × 3). The organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The residue was subjected to silica gel chromatography with an elution system (SiO ₂ , 0-10% ethyl acetate/petroleum ether) to obtain compound 2d (70 g, yield: 81.1%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 7.36(d,1H),6.85(d,1H),4.54(s,2H),3.58(t,2H),2.63(t,2H),1.42(m ,9H).

the fourth step

At room temperature, compound 2d (35g, 117mmol) and 4M hydrochloric acid 1,4-dioxane solution (250mL) were sequentially added to a 500mL single-neck bottle, and stirred for 2 hours. Concentrate under reduced pressure. The residue was slurried with ethyl acetate (400 mL) and filtered to obtain compound 2e (20.5 g, yield: 99.7%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.71 (s, 2H), 7.48 (d, 1H), 6.93 (d, 1H), 4.31 (s, 2H), 3.35-3.32 (m, 2H), 2.88 (t,2H).

LC-MS: MS(ESI): m/z 140.2(M+H) ⁺ .

the fifth step

At room temperature, compound 2e (1.00g, 5.69mmol) and triethylamine (632mg, 6.26mmol) were sequentially added to a 50mL single-neck bottle, and dissolved in tetrahydrofuran (17mL). After cooling to 0°C, acetyl chloride (491 mg, 6.26 mmol) was slowly added and stirred at room temperature for 1 hour. Filter, add ethyl acetate (30mL) and water (15mL) to the filtrate, dry the organic phase, filter, concentrate the filtrate under reduced pressure, and use silica gel chromatography to rinse the residue with the system (SiO ₂ , 0-10% ethyl acetate/petroleum) Ether) was purified to obtain compound 2f (1.03g, yield: 99.8%). LC-MS: MS(ESI): m/z 182.1(M+H) ⁺ .

Step 6

Compound 2f (2.4g, 13.241mmol) was dissolved in dichloromethane (60mL) in a 250mL single-neck bottle at room temperature, and acetic anhydride (3.8mL, 40.1mmol) was added. The temperature dropped to 0°C, concentrated sulfuric acid (0.7 mL, 14 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Concentrate under reduced pressure, add diethyl ether (100 mL), filter, and purify the filter cake with reverse column C18 (water/acetonitrile, hydrochloric acid system) to obtain 2 g of compound (3.42 g, yield: 98.8%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 6.84-6.83(m,1H),4.62-4.58(m,2H),3.68-3.63(m,2H),2.68-2.52(m,2H),2.09- 2.06(m,3H).

Step 7

At room temperature, compound 2g (8.00g, 30.6mmol) was sequentially added to a 250mL single-neck bottle, and dissolved in dichloromethane (80mL). Under nitrogen atmosphere, phosphorus pentachloride (8.67g, 41.6mmol) was added, and the mixture was stirred at room temperature for 20 hours. Pour into ice. After returning to room temperature, add dichloromethane (200 mL). The organic phase is dried and filtered. The filtrate is concentrated under reduced pressure to obtain product 2h (8.56g, crude product), which is directly used in the next step.

Step 8

Compound 2h (12g, 42.9mmol) was dissolved in dichloromethane (10mL) at room temperature, and slowly added dropwise to 7M ammonia methanol solution (300mL, 2100mmol), and stirred for 1 hour. Filter, wash the filter cake with methanol (10 mL), and collect the filter cake to obtain product 2i (10 g, yield: 89.6%). LC-MS: MS(ESI): m/z 261.0(M+H) ⁺ .

Step 9

At room temperature, compound 2i (2.00g, 7.68mmol) and 20% sodium hydroxide aqueous solution (10mL) were added in sequence to a 100mL single-neck bottle, stirred at 80°C for 3 hours. Adjust pH=7 with 2M dilute hydrochloric acid solution. A mixed solution of dichloromethane/methanol (10/1, 20 mL) was added to the reaction solution for extraction. The organic phase was dried and concentrated under reduced pressure to obtain product 2j (1.4 g, yield: 83.6%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.59 (s, 2H), 7.30 (s, 1H), 3.91 (s, 2H), 3.23 (s, 2H), 2.95 (t, 2H), 2.60-2.59 (m,1H).

Step 10

At room temperature, add compound 2j (375 mg, 1.72 mmol), methanol (3 mL), paraformaldehyde (63 mg, 0.17 mmol), acetic acid (0.2 mL, 3.4 mmol) and sodium cyanoborohydride (324 mg, 5.15mmol), stir for 2 hours. 7M ammonia methanol solution (2 mL) was added and concentrated under reduced pressure. The residue was purified by reverse phase C18 (water/acetonitrile, ammonia water system) to obtain compound 2k (180 mg, yield: 45.1%). LC-MS: MS(ESI): m/z 233.0(M+H) ⁺ .

Step 11

At room temperature, add compound 2k (150 mg, 0.646 mmol) and tetrahydrofuran (5 mL) into a 50 mL single-neck bottle, cool to 0°C, add sodium tert-butoxide (65 mg, 0.68 mmol), and stir at room temperature for 40 minutes. Then add 1j (128mg, 0.646mmol) and stir for 3 hours. Concentrate under reduced pressure, and the residue is subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 40-65 % B; flow 25ml/min) to obtain a crude product. After the crude product was exchanged with sodium ion exchange resin, compound 2 (114mg, yield: 38.9%) was obtained.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.06 (s, 1H), 6.77 (s, 1H), 3.47 (s, 2H), 2.76 (m, 4H), 2.67 (m, 4H), 2.58 (m ,4H),2.34(s,3H),2.03-1.81(m,4H).

LC-MS: MS(ESI): m/z 432.0(M+H) ⁺ .

Example 3

N-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)-5-methyl-4,5,6, 7-Tetrahydrofura[3,2-c]pyridine-2-sulfonamide

first step

At -78°C, add compound 3a (10g, 65.12mmol) and tetrahydrofuran (100mL) into the reaction bottle, add 2.5M n-butyllithium (28.6mL, 71.63mmol) dropwise, and stir for 1 hour. After connecting the buffer device and tail gas absorption device to the reaction system, pass SO ₂ gas into the reaction solution, keep the temperature below -30°C, and stir for 0.5 hours. The reaction solution was slowly warmed to room temperature, filtered, and the filter cake was collected. Dissolve the filter cake with dichloromethane (100 mL) and then cool it to 0°C. Add N-chlorosuccinimide (9.56 g, 71.63 mmol) and stir at room temperature for 1 hour. Add water (50 mL) to the reaction solution. Methyl chloride extraction (30mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3b (11 g, yield: 67%). LC-MS m/z(ESI): 251.8(M+H) ⁺ .

Step 2

At room temperature, compound 3b (15g, 59.51mmol) and pyridine (150mL) were added to the reaction flask, the temperature was cooled to 0°C, and bis-(4-methoxybenzyl)-amine (16.84g, 65.46mmol) was added. Return to room temperature and stir for 12 hours. Concentrate under reduced pressure, and the residue was purified by silica gel chromatography with an elution system (SiO ₂ , 10-50% ethyl acetate/petroleum ether) to obtain compound 3c (5g, yield: 17.7%).

¹ H NMR(400MHz, CDCl ₃ )δ 8.40(d,1H),7.39(dd,1H),7.23(d,1H),7.12-7.06(m,4H),6.78-6.72(m,4H),4.41 (s,4H),3.76(s,6H).LC-MS m/z(ESI): 472.9(M+H) ⁺ .

third step

At room temperature, add compound 3c (5g, 10.57mmol) and N,N-dimethylformamide (50mL) into the reaction bottle, stir evenly, and then add triethylamine (7.4mL, 52.86mmol), formic acid ( 2.43g, 52.86mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.43g, 0.53mmol). Stir at 70°C for 3 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 40-50% ethyl acetate/petroleum ether) to obtain product 3d (3g, yield: 64.7%). LC-MS m/z(ESI): 439.1(M+H) ⁺ .

the fourth step

Compound 3d (100 mg, 0.23 mol), trimethyloxonium tetrafluoroborate (34 mg, 0.23 mmol), and dichloromethane (5 mL) were added to the reaction bottle at room temperature, and the reaction solution was stirred at room temperature for 3 hours. Concentrate under reduced pressure, and the crude product was purified by silica gel chromatography with an elution system (SiO ₂ , 0-15% ethyl acetate/petroleum ether) to obtain compound 3e (123 mg, yield: 99.8%). LC-MS m/z(ESI): 453.3(M) ⁺ .

the fifth step

At room temperature, compound 3e (123 mg, 0.27 mmol) and methanol (2 mL) were added to the reaction flask. Stir until dissolved, cool down to 0°C in ice-water bath, and add sodium borohydride (51 mg, 1.36 mmol). Raise the temperature to 50°C and stir for 2 hours. The reaction solution was brought to room temperature, added to a saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an elution system (SiO ₂ , 0-15% ethyl acetate/petroleum ether) to obtain compound 3f (50 mg, yield: 40.4%). LC-MS m/z(ESI): 457.3(M+H) ⁺ .

Step 6

At room temperature, compound 3f (200 mg, 0.44 mmol), dichloromethane (5 mL), and trifluoroacetic acid (50 mg, 0.44 mmol) were added to the reaction bottle. Stir until dissolved. The mixture was stirred at room temperature for 48 hours, and the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by reverse phase column C18 (acetonitrile/water) to obtain compound 3g (50 mg, yield: 52.8%). LC-MS m/z(ESI): 217.1(M+H) ⁺ .

Step 7

At room temperature, add compound 3h (2.00g, 9.43mmol), compound 3i (2.17g, 9.43mmol), K ₂ CO ₃ (3.91mg, 28.3mmol), dioxane (20mL), and H ₂ into the reaction bottle. O (4 mL), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (385 mg, 0.471 mmol), replaced with nitrogen three times, and stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an elution system (SiO ₂ , 40%-50% ethyl acetate/petroleum ether) to obtain product 3j (1.2g, yield: 54.1%). LC-MS m/z(ESI): 236.2(M+H) ⁺ .

Step 8

At room temperature, add compound 3j (30 mg, 0.13 mmol), tetrahydrofuran (1 mL), and triethylamine (13 mg, 0.13 mmol) into the reaction bottle. Under a nitrogen atmosphere, lower the temperature to 0°C and add triphosgene (89 mg, 0.30 mmol). ), the reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was concentrated to obtain compound 3k (33 mg crude product).

Step 9

At room temperature, compound 3g (30 mg, 0.12 mmol) and tetrahydrofuran (1 mL) were added to the reaction flask. After the mixture was cooled to 0°C in an ice-water bath, sodium tert-butoxide (12 mg, 0.13 mmol) was added. The reaction solution was then stirred at room temperature for 0.5 hours, and then compound 3k (33 mg, 0.13 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. Concentrate under reduced pressure, and the residue is subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 30-50 % B; flow 25ml/min) was purified to obtain compound 3 (8mg, 14.5%).

¹ H NMR (400MHz, DMSO- d ₆ )δ 8.64(d,1H),7.93(s,1H),7.64(d,1H),7.14(s,2H),6.34(s,1H),3.28(s ,2H),2.86(m,8H),2.67(s,3H),2.04-1.97(m,2H).

LC-MS: MS(ESI): m/z 478.2(M+H) ⁺ .

Example 4

((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)aminoformyl)((5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)sulfonyl)amine sodium salt

first step

At room temperature, add compound 4a (9.00g, 28.2mmol), tris(dibenzylideneacetone)dipalladium (1.29g, 1.41mmol), and 4,5-bis(diphenylphosphine)-9 into the reaction bottle. , 9-dimethylxanthene (1.63g, 2.82mmol), dioxane (100mL), N,N-diisopropylethylamine (9mL, 56.4mmol), under nitrogen atmosphere, add benzylthiol ( 6mL, 56.4mmol), stir at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, then water (100 mL) was added, and extracted with ethyl acetate (100 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 20-40% ethyl acetate/petroleum ether) to obtain the target product 4b (9g, yield: 88.1%). LC-MS m/z(ESI): 363.5(M+H) ⁺ .

Step 2

At room temperature, compound 4b (8.00g, 22.1mmol), acetonitrile (100mL), acetic acid (8mL), and H ₂ O (4mL) were added to the reaction bottle. After stirring evenly, cool down to 0°C, slowly add dichlorohydantoin (15.2g, 77.2mmol), and stir for 2 hours. Add water (200mL), extract with dichloromethane (300mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 4c (6.5g), which can be used directly in the next step without purification. reaction. LC-MS m/z(ESI): 380.0(M+H+CH ₃ CN) ⁺ .

third step

At room temperature, add ammonia methanol solution (120 mL) to the reaction bottle, add compound 4c (6.5 g) in portions while stirring, and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography with an elution system (SiO ₂ , 0-40% ethyl acetate/petroleum ether) to obtain compound 4d (5.5g, yield: 89.8%). LC-MS m/z(ESI): 320.1(M+H) ⁺ .

the fourth step

Compound 4d (1.00g, 3.13mmol) and dioxane hydrochloride solution (13mL) were added to the reaction bottle at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 4e (600 mg, yield: 87.4%). LC-MS m/z(ESI): 219.9(M+H) ⁺ .

the fifth step

At room temperature, compound 4e (500 mg, 1.96 mmol) and methanol (10 mL) were added to the reaction flask. After stirring until dissolved, add sodium acetate (1.33g, 9.78mmol) and a small amount of acetic acid to adjust the pH of the system to 3-5, then add paraformaldehyde (579mg, 1.56mmol) and 2-methylpyridineborane (209mg, 1.96 mmol) and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product which was purified by reversed-phase column chromatography (system: 0.1% ammonia/acetonitrile/water to obtain the target product 4f (100 mg, yield: 30%); LC-MS m/z (ESI): 233.9(M+H) ⁺ .

Step 6

Add compound 4f (40 mg, 0.17 mmol) and tetrahydrofuran (1 mL) to the reaction flask at room temperature. After the mixture cools to 0°C in an ice-water bath, add sodium tert-butoxide (20 mg, 0.21 mmol) and stir at room temperature for 0.5 hours. , then slowly add a solution of compound 1j (41 mg, 0.21 mmol) in tetrahydrofuran (1 mL), and stir at room temperature for 4 hours. The reaction solution was subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 50-70% B; flow 25ml/ min) was purified to obtain compound 4g (1.5mg, yield: 2%). LC-MS: MS(ESI): m/z 474.2(M+H+CH ₃ CN) ⁺ .

Step 7

After filling the IR120 cation exchange resin-sodium column, rinse the column with acetonitrile and water respectively. After rinsing, dissolve 4g of compound (25.6mg, 0.06mmol) in acetonitrile (2mL) and add it dropwise to the column. Rinse the column with a rinsing system (0:1-1:0, acetonitrile/water), add the rinsed fractions to the second column, combine the fractions after rinsing twice and freeze-dry to obtain compound 4 ( 14.03 mg, yield: 52.1%).

1H NMR(400MHz,DMSO-d6)δ 7.63(br s,1H),6.78(s,1H),3.71(s,2H),2.85-2.73(m,8H),2.68-2.64(m,4H), 2.44(s,3H),1.94-1.84(m,4H). LC-MS m/z(ESI): 433.3(M+H)+.

Example 5

((4-Hydroxy-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)sulfonyl)((5-(2-methoxypyridine-4- (yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)amine sodium salt

first step

To the 250mL reaction bottle, add 6,7-dihydro-4(5H)-benzothiophenone ( 5a ) (9.5g, 62.4mmol) and dichloromethane (100mL), and slowly add chlorosulfonate dropwise at -10°C. Acid (10.2g, 87.4mmol). After the dropwise addition was completed, the temperature was raised to room temperature and stirred for 72 hours. Pour off the supernatant, dissolve the precipitated viscous material in water, and freeze-dry. The residue was purified by reverse phase C18 (0.225% formic acid/acetonitrile/water system) to obtain compound 5b (2.6 g, yield: 12.6%). LC-MS m/z: 230.9[MH] ^- .

Step 2

To the 100 mL reaction flask, add compound 5b (1.3 g, 81.2% purity, 5.59 mmol) and dichloromethane (10 mL). Cool to 0°C, add phosphorus pentachloride (10.5g, 50.4mmol) and pyridine (4.05mL, 50.4mmol). Stir at room temperature for 16 hours. Phosphorus pentachloride (10.5g, 50.4mmol) and pyridine (4.1mL, 50.4mmol) were added, and the mixture was stirred for 2 hours. Phosphorus pentachloride (10.5g, 50.4mmol) and pyridine (4.1mL, 50.4mmol) were added again, and the reaction was completed after stirring for 2 hours. Add dichloromethane (10 mL) to the reaction flask, add the reaction solution to ammonia gas in tetrahydrofuran solution (10 mL, 5 mol/L) under ice bath, and add ammonia water (10 mL, 25%). Stir at room temperature for 0.5 hours, filter, wash the filter cake with dichloromethane (10 mL), and concentrate the filtrate under reduced pressure. The residue was separated by column chromatography (SiO2, 30% ethyl acetate/petroleum ether). Compound 5c (40 mg) was obtained. ¹ HNMR (400MHz, DMSO- d ₆ ) δ 7.77 (s, 2H), 7.60 (s, 1H), 3.07 (t, 2H), 2.26-2.19 (m, 2H), 2.17-2.10 (m, 2H). LC-MS m/z: 230.0(MH) ^- .

third step

To a 50 mL reaction flask, add compound 5c (90 mg, 0.39 mmol) and tetrahydrofuran (3 mL), cool to 0°C, add 3M methylmagnesium bromide in THF solution (1.9 mL, 5.7 mmol), and stir at room temperature for 1 hour. Add saturated aqueous sodium bicarbonate solution (2 mL), extract with ethyl acetate (5 mL × 3), wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by thin layer chromatography with a developing system (petroleum ether: ethyl acetate = 1:1) to obtain compound 5d (55 mg, yield: 57%). LC-MS m/z: 246.1(MH) ^- .

the fourth step

To a 10mL reaction flask, add compound 5d (65mg, 74.1% purity, 0.19mmol), tetrahydrofuran (1mL), compound 6n ’s tetrahydrofuran solution (2mL, 0.52mmol, 0.26M tetrahydrofuran solution) and 1,8-diazabicyclo Undec-7-ene (148 mg, 0.97 mmol). Stir at room temperature for 1 hour, add water (5 mL), and extract with ethyl acetate (1 mL). The aqueous phase was directly purified by reversed-phase column C18 (water/acetonitrile), lyophilized, and the residue was purified by high-performance liquid chromatography (chromatography column: Gilson-281, Xbridge 150*25mm, 5μm; mobile phase: aqueous phase (10mM Ammonia) and acetonitrile, gradient ratio: 0-9min 6-36% B; flow 25ml/min) was purified to obtain compound 5e (18mg, yield: 18.4%).

¹ HNMR (400MHz, DMSO- d ₆ ) δ 9.48 (s, 1H), 8.05 (d, 1H), 7.33-7.29 (m, 2H), 7.11-7.09 (m, 1H), 7.06-7.01 (m, 1H) ),6.91(d,1H),6.75(s,1H),4.86(s,1H),3.85(s,3H),2.88(t,2H),2.80-2.70(m,2H),2.64-2.61( m,2H),1.99-1.92(m,3H),1.76-1.73(m,1H),1.69-1.64(m,2H),1.34(s,3H).

LC-MS m/z: 512.1(MH) ^- .

the fifth step

To an 8 mL reaction flask, add compound 5e (16 mg, 0.03 mmol) and tetrahydrofuran (1 mL). Cool the temperature to 0°C, add sodium tert-butoxide solid (2.99 mg, 0.03 mmol), and stir for 5 minutes. Concentration and purification gave product 5 (7 mg, yield: 43.6%).

¹ H NMR(400MHz,DMSO)δ 8.06(d,1H),7.26(s,1H),7.22(s,1H),7.06(m,2H),6.95(s,1H),6.78(s,1H) ,4.82(s,1H),3.86(s,3H),3.31(s,2H),2.89(t,2H),2.78(d,2H),2.65(m,2H),1.98-1.93(m,2H ),1.74(d,2H),1.35(s,3H).

LC-MS m/z: 512.1(MH) ^- .

Example 6

((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)((5-methyl-4,5,6 ,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt

first step

At room temperature, compound 6a (45g, 323mmol) and tetrahydrofuran (500mL) were added to a 1L three-necked flask. The temperature was lowered to 0°C, and N,N-diisopropylethylamine (112 mL, 679 mmol) and benzyl chloroformate (50 mL, 356 mmol) were added dropwise. Raise the temperature to 20°C and stir for 12 hours. The reaction solution was slowly poured into water (500 mL), and then extracted three times with ethyl acetate (200 mL × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 20%-25% ethyl acetate/petroleum ether) to obtain compound 6b (72g, yield: 80.5%).

¹ HNMR(400MHz, CDCl ₃ )δ 7.40-7.36(m,5H),7.14(d,1H),6.78(s,1H),5.20(s,2H),4.61(s,2H),3.83(s, 2H),2.89(s,2H).

LC-MS: m/z (ESI): 274.0 (M+H) ⁺ .

Step 2

Add compound 6b (24g, 87.8mmol) and anhydrous dichloromethane (250mL) to a 500mL three-necked flask, cool to 0°C, add chlorosulfonic acid (6mL, 92.2mmol), and react for 5 minutes. Add water (150 mL), concentrate under reduced pressure to remove methylene chloride, extract the aqueous phase with ethyl acetate (300 mL × 3), combine the organic phases, dry and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column C18 (0.2% formic acid/acetonitrile/water) to obtain compound 6c (20g, yield: 61.9%).

¹ HNMR(400MHz, DMSO- d ₆ )δ 7.39-7.32(m,5H),6.89(s,1H),5.13(s,2H),4.45-4.41(m,2H),3.68(s,2H), 2.76-2.75(m,2H).

LC-MS: m/z (ESI): 351.9 (M+H) ⁺ .

third step

Add compound 6c (20g, 56.6mmol) and dichloromethane (200mL) to a 1L three-necked flask, cool to 0°C, and slowly add pyridine (13.7mL, 170mmol) and phosphorus pentachloride (35.4g, 170mmol). Warm up to room temperature and stir for 2 hours. Add ice water (300 mL) to quench, stir for 5 minutes, let stand for liquid separation, extract the aqueous phase with dichloromethane (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 6d ( 37g, crude product), used directly in the next step.

the fourth step

Add compound 6d (37g, 99.5mmol) and tetrahydrofuran (250mL) to a 1L three-necked flask, then slowly add amine gas/tetrahydrofuran solution (99.5mL, 199mmol, 2M) at 0°C, raise to room temperature, and stir for 12 hours. Concentrate under reduced pressure, and the residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 45%-70% ethyl acetate/petroleum ether) to obtain the product compound 6e (16g, yield: 45.6%).

¹ HNMR (400MHz, DMSO- d ₆ ) δ 7.61 (s, 2H), 7.39-7.32 (m, 6H), 5.13 (s, 2H), 4.52-4.49 (m, 2H), 3.71 (s, 2H), 2.85(t,2H).

the fifth step

At 10°C, compound 6e (7g, 19.9mmol) and anhydrous dichloromethane (70mL) were added to a 250mL three-necked flask, hydrobromic acid/acetic acid (15mL, 33%) was slowly added dropwise, and stirred at room temperature for 2 hours. Filter, dissolve the filter cake in methanol (80 mL), slowly add sodium carbonate solid to pH=10, filter, and concentrate the filtrate under reduced pressure to obtain compound 6f (5g, crude product), which is directly used in the next step.

Step 6

At room temperature, add compound 6f (2.20g, 10.1mmol), methanol (20mL), acetic acid (2.88mL, 50.4mmol), paraformaldehyde (300mg, 10.1mmol) and sodium cyanoborohydride (1.27 g, 20.2mmol), stir for 10 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an elution system (SiO ₂ , 10-30% methanol/dichloromethane) to obtain compound 6g (2.2g, yield: 81.4%).

¹ HNMR (400MHz, CD ₃ OD) δ 7.33 (s, 1H), 3.88 (s, 2H), 3.35-3.31 (m, 2H), 3.25-3.21 (m, 2H), 2.72 (s, 3H). LC-MS m/z(ESI): 233.0(M+H) ⁺ .

Step 7

At room temperature, compound 6h (23.5g, 176.440mmol), triethylamine (31.9mL, 229.37mmol) and dichloromethane (150mL) were added to a 250mL reaction flask. Stir until dissolved, add acetic anhydride (19.1 mL, 202.91 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 0.1 hour, and then stir at room temperature for 1.4 hours. Add water (25 mL) to the filtrate, extract with dichloromethane (10 mL × 3), wash with saturated brine (20 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is subjected to column chromatography (SiO ₂ , 20-40% ethyl acetate/petroleum ether) purification to obtain compound 6i (24.2g).

¹ H NMR(400MHz, CDCl ₃ )δ 7.73(d, J =8.0Hz,1H),7.15(t, J =7.6Hz,1H),7.03(d, J =7.6Hz,1H),2.96(t, J =7.2Hz,2H),2.82(t, J =7.2Hz,2H),2.19(s,3 H)2.08-2.15(m,2 H). LC-MS: m/z 176.3(M+H) ⁺ .

Step 8

At room temperature, add compound 6i (5g, 28.534mmol), toluene (40mL), p-toluenesulfonic acid (2.99g, 15.694mmol), and palladium acetate (0.30g, 1.341mmol) into a 100mL single-neck bottle, and stir for 0.5 hours. Add N-bromosuccinimide (4.32g, 24.254mmol) and stir at room temperature for 2 hours. Sodium thiosulfate aqueous solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 10%-50% ethyl acetate/petroleum ether) to obtain compound 6j (4g). LC-MS: m/z: 254.1(M+H) ⁺ .

Step 9

At room temperature, add compound 6j (16g, 62.960mmol), ethanol (60mL) and 36%~38% hydrochloric acid (90mL, 2912.781mmol) into a 500mL reaction bottle. Stir until dissolved, and stir the reaction solution at 80°C for 36 hours. Concentrate under reduced pressure to obtain compound 6k (18g). The crude product did not require purification and was used directly in the next reaction. LC-MS: m/z 212.2(M+H) ⁺ .

Step 10

At room temperature, add compound 6k (6g, 19.803mol), 2-methoxypyridine-4-boronic acid ( 6l ) (3.63g, 23.763mmol), potassium carbonate (8.76g, 63.369mmol), Dioxane (10 mL) and water (10 mL) were stirred under nitrogen atmosphere for 15 minutes. [1,1-Bis(diphenylphosphine)ferrocene]palladium dichloride (0.81g, 0.990mmol) was added, and the reaction solution was stirred at 80°C for 36 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL × 3), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 15% ethyl acetate/petroleum ether) to obtain compound 6m (3.08g).

¹ H NMR (400MHz, CDCl ₃ )δ 8.22(dd,1H),7.01(dd,1H),6.98(d,1H),6.87-6.86(m,1H),6.77(d,1H),3.99(s ,3H),3.50-3.91(m,2H),2.97(t,2H),2.77(t,2H),2.13-2.21(m,2H).

LC-MS: m/z: 241.3(M+H) ⁺ .

Step 11

At room temperature, add compound 6m (1g, 4.161mmol) and tetrahydrofuran (15mL) to a 50mL single-neck bottle, stir until dissolved, cool to 0°C in an ice-water bath, add triethylamine (1.23g, 4.161mmol) and triphosgene ( 1.23g, 4.161mmol). Stir at room temperature for 0.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6n (800 mg). The crude product did not require purification and was used directly in the next reaction. LC-MS: m/z: 267.2(M+H) ⁺ .

Step 12

At 0°C, add compound 6g (300mg, 1.29mmol), N,N -dimethylformamide (5mL), compound 6n (378mg, 1.42mmol) and 1,8-diazabicyclo to a 50mL reaction bottle. [5.4.0] Undec-7-ene (2.95g, 19.4mmol), warmed to room temperature, and stirred for 1 hour. Add water (10 mL) and ethyl acetate (10 mL), stir and let stand for liquid separation. The aqueous phase is purified with reversed-phase column C18 (system: water/acetonitrile, gradient: acetonitrile 20%~30%) to obtain compound 6o (100 mg , yield: 15.4%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.49 (s, 1H), 8.03 (d, 1H), 7.21 (s, 1H), 7.07 (d, 1H), 7.02 (d, 1H), 6.91 (d ,1H),6.88(s,1H),6.75(s,1H), 3.85(s,3H),3.56-3.54(m,2H),2.76-2.74(m,4H),2.64-2.60(m,4H ),2.34(s,3H),1.98-1.94(m,2H).

LC-MS m/z(ESI): 499.0(M+H) ⁺ .

Step 13

Compound 6o (97.7mg, 0.20mmol) was dissolved in 2-methyltetrahydrofuran (5mL), washed with saturated sodium chloride solution (2mL×3), dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (0.3 mL), cooled to 0°C, added 1 M sodium tert-butoxide solution in tetrahydrofuran (0.2 mL, 0.2 mmol), stirred for 30 minutes, and concentrated under reduced pressure to obtain compound 6 (55 mg, yield 51.1%).

¹ H NMR (400MHz, DMSO- d ₆ )δ 8.02(d,1H),7.22(s,1H),7.06(d,1H),7.02(d,1H),6.92(d,1H),6.89(s ,1H),6.75(s,1H),3.85(s,3H),2.88(t,2H),2.76-2.74(m,4H),2.67-2.60(m,4H),2.34(s,3H), 1.99-1.94(m,2H).

LC-MS m/z(ESI): 499.1(M+H) ⁺ .

Example 7

N-((1,2,3,5,6.7-hexahydro-s-indacen-4-yl)aminomethanoyl)-1-isopropyl-5-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-sulfonamide

first step

At room temperature, compound 7a (4.4g, 19.7mmol), acetonitrile (50mL) and N-iodosuccinimide (8.87g, 39.41mmol) were added to a 250mL reaction flask. The temperature was raised to 60°C and stirred for 16 hours. Add saturated aqueous sodium sulfite solution (50 mL) to quench. Extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 0%-100% ethyl acetate/petroleum ether) to obtain the product compound 7b (2.4g, yield: 35%).

¹ HNMR (400MHz, DMSO- d ₆ ) δ 12.97 (s, 1H), 4.11 (s, 2H), 3.58 (t, 2H), 2.68-2.60 (m, 2H), 1.42 (s, 9H). LC-MS m/z(ESI): 350.0(M+H) ⁺ .

Step 2

To a 100 mL reaction flask, add compound 7b (2.10 g, 6.01 mmol) and N,N-dimethylformamide (20 mL). Cool the temperature to 0°C, add sodium hydride (0.31g, 7.82mmol, 60%) and iodoisopropane (1.53g, 9.02mmol), and stir at room temperature for 1 hour. Water (40 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of compounds 7c and 7c-1 (2.05 g, yield: 87.2%). LC-MS m/z(ESI): 392.0(M+H) ⁺ .

third step

Add a mixture of compounds 7c and 7c-1 (2.05g, 5.24mmol), p-methoxybenzylthiol (1.21g, 7.86mmol), and tris(dibenzylideneacetone) dipalladium (0.96g) into a 50mL reaction bottle. ,1.05mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (961mg, 1.05mmol), dioxane (20mL) and N,N-diisopropylethylamine ( 1.30mL,7.86mmol). Under a nitrogen atmosphere, the temperature was raised to 100°C and stirred for 16 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 25% ethyl acetate/petroleum ether) to obtain a mixture of compounds 7d and 7d-1 (1.6 g, yield: 73%). LC-MS m/z(ESI): 418.1(M+H) ⁺ .

the fourth step

A mixture of compounds 7d and 7d-1 (1.2g, 2.67mmol), acetic acid (15mL) and water (5mL) were added to a 50mL reaction flask. Cool the temperature to 0°C, slowly add N-chlorobutanilimide (2.50g, 18.7mmol), and stir at room temperature for 3 hours. The reaction solution was added to ammonia water (20 mL, 25%) at 0°C. Concentrate under reduced pressure, and the residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 50% ethyl acetate/petroleum ether) to obtain compounds 7e (90 mg, yield: 9.8%) and 7e-1 (240 mg, Yield: 26.1%).

¹ H NMR(400MHz, CDCl ₃ )δ 8.04(br s,2H),4.59(s,2H),4.46-4.35(m,1H),3.81-3.67(m,2H),2.72-2.70(m,2H ),1.50-1.49(m,15H).

LC-MS m/z(ESI): 345.2(M+H) ⁺ .

the fifth step

Compound 7e (180 mg, 0.52 mmol), dioxane (10 mL) and 6M hydrochloric acid (5 mL, 30 mmol) were added to a 50 mL reaction flask, and stirred for 1 hour. Concentrate under reduced pressure to obtain compound 7f (160 mg, crude product), which was used directly in the next step.

Step 6

Add compound 7f (160 mg, 0.48 mmol), methanol (10 mL), paraformaldehyde (16.0 mg, 0.18 mmol), triethylamine (0.1 mL, 0.48 mmol) and palladium on carbon (51 mg, 0.048 mmol) into a 25 mL reaction flask. ,10%), stirred in a hydrogen atmosphere and room temperature for 5 hours. Filter, and the filtrate is concentrated under reduced pressure. The residue was analyzed by high performance liquid chromatography (chromatography column: Waters min) was purified to obtain compound 7g (60mg, yield: 48.4%).

¹ HNMR(400MHz, DMSO- d ₆ )δ 7.31(s,1H),4.50-4.46(m,1H),3.40(s,2H),2.74-2.71(m,2H),2.63-2.62(m,2H ),2.36(s,3H),1.37(d,6H). LC-MS m/z(ESI): 259.1(M+H) ⁺ .

Step 7

Add compound 7g (60mg, 0.23mmol), tetrahydrofuran (5mL), compound 1j (69mg, 0.35mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene ( 106 mg, 0.70 mmol), stirred at room temperature for 1 hour. Concentrate under reduced pressure, and the residue is purified by reverse phase C18 (system: water/acetonitrile, 30% acetonitrile). The crude product obtained is purified by high performance liquid chromatography (chromatography column: Waters Xbridge 150*25mm*5μm; mobile phase: water phase ( 10mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-10min 21-51% B; flow 25ml/min) was separated and purified to obtain compound 7 (12mg, yield: 10.9%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.85 (s, 1H), 6.89 (s, 1H), 4.55-4.45 (m, 1H), 3.64-3.56 (m, 2H), 2.81-2.74 (m, 6H),2.63-2.55(m,6H),2.46-2.37(m,3H),1.98-1.81(m,4H),1.35(d,6H).

LC-MS m/z(ESI): 458.2(M+H) ⁺ .

Example 8

N-((5-(2-Fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminomethanoyl)-5-methyl-4,5,6,7 -Tetrahydrothieno[3,2-c]pyridine-2-sulfonamide

Adopting the synthetic route of Example 6, replacing the raw material 2-methoxypyridine-4-boronic acid ( 6l ) in the tenth step with 2-fluoro-4-pyridineboronic acid, compound 8 (18 mg, yield: 12.5%) was obtained. .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.10 (d, 1H), 7.75 (br s, 1H), 7.23 (s, 1H), 7.18-7.05 (m, 4H), 3.83 (s, 2H), 3.12(s,3H),2.96-2.92(m,4H),2.77(s,2H),2.66(s,2H),2.02-1.95(m,2H).

LC-MS m/z(ESI): 487.0(M+H) ⁺ .

Example 9

5-Methyl-N-((5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)aminomethanoyl)-4,5,6,7-tetrahydro Thieno[3,2-c]pyridine-2-sulfonamide

The synthetic route of Example 6 was adopted, and the raw material 2-methoxypyridine-4-boronic acid ( 6l ) in the tenth step was replaced with pyridine-3-boronic acid to prepare compound 9 (15 mg, yield: 8.6%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.48-8.47(m,2H),7.66-7.64(m,1H),7.32-7.29(m,1H),7.17-7.13(m,2H),7.07( d,1H),3.67(s,2H),2.93-2.89(m,6H),2.73(t,2H),2.52(s,3H),1.99(m2H).

LC-MS m/z(ESI): 469.1(M+H) ⁺ .

Example 10

N-((5-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)-5-methyl-4,5,6, 7-Tetrahydrothiophene[3,2-c]pyridine-2-sulfonamide

Adopting the synthetic route of Example 6, replacing the raw material 2-methoxypyridine-4-boronic acid ( 6l ) in the tenth step with 5-fluoro-3-pyridineboronic acid, compound 10 (6 mg, yield: 3.2%) was obtained. .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.45 (d, 1H), 8.36 (s, 1H), 7.61-7.60 (m, 1H), 7.15-7.09 (m, 2H), 7.01 (s, 1H) ,3.43(s,2H),2.92-2.87(m,6H),2.76(t,2H),2.52(s,3H),2.02-1.95(m,2H).

LC-MS m/z(ESI): 487.2(M+H) ⁺ .

Example 11

N-((5-(2-cyanopyrimidin-5-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)-5-methyl-4,5,6 ,7-Tetrahydrothieno[3,2-c]pyridine-2-sulfonamide

Adopting the synthetic route of Example 6, the tenth step raw material 2-methoxypyridine-4-boronic acid ( 6l ) was replaced with 2-cyanopyrimidine-5-boronic acid pinacol ester to prepare compound 11 (9 mg, product rate: 6.3%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.88 (s, 2H), 7.75 (s, 1H), 7.17 (m, 2H), 6.91 (s, 1H), 3.58 (s, 2H), 2.92 (t ,2H),2.89-2.83(m,4H),2.81(t,2H),2.52(s,3H),2.04-1.96(m,2H).

LC-MS m/z(ESI): 495.3(M+H) ⁺ .

Example 12

((5-(3,6-Dihydro-2H-pyran-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)-5-methyl-4 ,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt

Adopt the synthetic route of Example 6, replace the raw material 2-methoxypyridine-4-boric acid ( 6l ) in the tenth step with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to prepare Compound 12 (57 mg, yield: 81.1%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.49 (s, 1 H), 7.23 (s, 1H), 7.01-6.98 (m, 1H), 6.89-6.86 (m, 1H), 5.52 (s, 1H) ),4.07-4.05(m,2H),3.69-3.65(m,2H),3.52-3.51(m,2H),2.84-2.80(m,6H),2.68-2.63(m,2H),2.51(s ,3H),2.14-2.13(m,2H),1.94-1.89(m,2H).

LC-MS m/z(ESI): 474.1(M+H) ⁺ .

Example 13

N-((5-(6-cyanopyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)-5-methyl- 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine-2-sulfonamide

Adopting the synthetic route of Example 6, replacing the raw material 2-methoxypyridine-4-boronic acid ( 6l ) in the tenth step with 2-cyano-5-pyridineboronic acid, compound 13 (7mg, yield: 6.2% ).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.66 (s, 1H), 7.91 (s, 2H), 7.55 (s, 1H), 7.12 (dd, 2H), 6.89 (s, 1H), 3.45 (s ,2H),2.91(t,2H),2.81-2.75(m,6H),2.42(s,3H),2.02-1.95(m,2H).

LC-MS m/z(ESI): 494.1(M+H) ⁺ .

Example 14

5-(4-(3-((5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)ureido)-2, 3-Dihydro-1H-inden-5-yl)pyridinamide

Adopt the synthetic route of Example 6, replace the raw material 2-methoxypyridin-4-boronic acid ( 6l ) in the tenth step with (6-aminomethoxypyridin-3-yl)boronic acid, and prepare compound 14 (10 mg , yield: 12.2%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.56(d,1H),8.13(s,1H),7.92(d,1H),7.83(dd,1H),7.59(s,1H),7.42(br s,1H),7.11(dd,2H),6.93(s,1H),3.43(s,2H),2.91(t,2H),2.81-2.74(m,6H),2.41(s,3H),2.02 -1.94(m,2H).

LC-MS m/z(ESI): 512.3(M+H) ⁺ .

Example 15

((5-(2-Fluoropyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)((5-methyl-4,5,6,7 -Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt

The synthetic route of Example 6 was adopted, and the raw material 2-methoxypyridine-4-boronic acid ( 6l ) in the tenth step was replaced with 2-fluoro-3-pyridineboronic acid to prepare compound 15 (11 mg, yield: 56.8%) .

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.12(d,1H),7.73-7.71(m,1H),7.29(s,1H),7.22-7.17(m,1H),7.06(d,1H) ,7.00(d,1H),6.84(s,1H),3.32(s,2H),2.90(t,2H),2.82-2.73(m,4H),2.62(t,2H),2.35(s,3H ),2.03-1.93(m,2H).

LC-MS m/z(ESI): 487.2(M+H) ⁺ .

Example 16

((5-(5-cyanopyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)((5-methyl-4,5,6, 7-Tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt

Adopting the synthetic route of Example 6, replacing the raw material 2-methoxypyridine-4-boronic acid ( 6l ) in the tenth step with 5-cyano-3-pyridineboronic acid, compound 16 (16.93mg, yield: 57.7 %).

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.80(d,1H),8.73(d,1H),8.12(t,1H),7.51(br s,1H),7.09(dd,2H),6.77( s,1H),3.31(s,2H),2.90(t,2H),2.81-2.74(m,4H),2.62(t,2H),2.35(s,3H),2.02-1.94(m,2H) .

LC-MS m/z(ESI): 494.1(M+H) ⁺ .

Example 17

((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)((5-(2-(methanesulfonyl) Ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt

first step

At room temperature, add compound 6f (300mg, 1.0mmol), absolute ethanol (4mL), triethylamine (0.6mL, 4.0mmol) and compound 17a (128mg, 1.2mmol) into a 10mL reaction bottle, and heat it to 80°C , stir for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 100% ethyl acetate/petroleum ether) to obtain compound 17b (200 mg, yield 61.5%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.56 (s, 2H), 7.23 (s, 1H), 3.54 (s, 2H), 3.37 (t, 2H), 3.00 (s, 3H), 3.91 (t ,2H),2.85-2.82(m,2H),2.80-2.77(m,2H).

LC-MS m/z(ESI): 324.9(M+H) ⁺ .

Step 2

At room temperature, compound 17b (80 mg, 0.25 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a 25 mL reaction flask. Cool to 0°C, and slowly add 1M sodium tert-butoxide/tetrahydrofuran solution (0.4 mL, 0.4 mmol) dropwise. The reaction was carried out at 0°C for 0.5 hours, and compound 3k (156 mg, 0.296 mmol) was added. React at room temperature for 1 hour. Water (2 mL) and methyl tert-butyl ether (10 mL) were added. The aqueous phase was lyophilized and subjected to preparative liquid chromatography (chromatography column: Waters Xbridge 150*25mm* 5um; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-9min 3-33% B; flow 25ml/min) to obtain compound 17c (40.48mg, yield: 27.9%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.56 (d, 1H), 7.90 (s, 1H), 7.76 (br s, 1H), 7.61-7.59 (m, 1H), 7.13 (s, 2H), 6.89(s,1H),3.48(s,2H),3.37(s,2H),3.02(s,3H),2.91(m,4H),2.80(m,6H),2.02-1.99(m,2H) . LC-MS m/z(ESI): 586.3(M+H) ⁺ .

third step

Compound 17c (38 mg) was dissolved in acetonitrile (1 mL), and added dropwise into the IR120 cation exchange resin-Na type column, using acetonitrile: water = 0: 1-20: 80-40: 60-50: 50-1 :0 system withdrawal. The fractions were combined and lyophilized to obtain compound 17 (40 mg, yield: 93.1%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.55 (d, 1H), 7.90 (s, 1H), 7.61-7.59 (m, 2H), 7.10 (s, 2H), 6.80 (s, 1H), 3.47 (s,2H),3.38(s,2H),3.01(s,3H),2.91(t,4H),2.83-2.77(m,6H),2.03-1.95(m,2H).

LC-MS m/z(ESI): 586.1(M+H) ⁺ .

Example 18

N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)-5-(2-(methanesulfonyl) (ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide

Compound 18 (20 mg, yield: 3.6%) was prepared by reacting compound 17b with compound 6n using a synthetic method similar to Example 6.

¹ H NMR (400MHz, DMSO- d ₆ )δ 8.04(d,1H),7.74(s,1H),7.21(s,1H),7.17(d,1H),7.08(d,1H),6.83(d ,1H),6.70(s,1H),3.85(s,3H), 3.52(s,2H),3.37-3.30(m,2H),3.00(s,3H),2.93-2.89(m,4H), 2.84-2.80(m,4H),2.71-2.67(m,2H),2.02-1.94(m,2H).

LC-MS m/z(ESI): 591.4(M+H) ⁺ .

Example 19

((5-((3-(hydroxymethyl)oxetan-3-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- yl)sulfonyl)((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)amine sodium salt

first step

At room temperature, compound 19a (1.21g, 6.68mmol), compound 6f (2.00g, 6.68mmol), triethylamine (2.80mL, 20.1mmol) and N,N-dimethylformamide were added in sequence to a 50mL single-neck bottle. Amine (10 mL), react at 100°C for 16 hours. Cool to room temperature and concentrate under reduced pressure. The crude product was subjected to preparative liquid chromatography (chromatography column: Kromasil Eternity XT 250*80mm*10μm; mobile phase: aqueous phase (10mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-20min 5-30% B; flow 140mL /min) to obtain compound 19b (600 mg, yield: 24.7%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.46 (s, 2H), 7.23 (s, 1H), 4.82 (s, 1H), 4.36-4.28 (m, 4H), 3.64 (s, 2H), 3.42 (s,2H),2.80(t,2H),2.77(s,2H),2.66(t,2H). LC-MS m/z(ESI): 319.1(M+H) ⁺ .

Step 2

Compound 19 (93 mg, yield: 69.1%) was prepared by reacting compound 19b with compound 6n using a synthetic method similar to that in Example 6.

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.03(d,1H),7.26(s,1H),7.07(d,1H),7.02(d,1H),6.92-6.89(m,2H),6.76 (s,1H),4.82(s,1H),4.35-4.30(m,4H),3.85(s,3H),3.65(s,2H),3.35(s,2H),2.88(t,2H), 2.77-2.72(m,6H),2.65-2.62(m,2H),2.00-1.92(m,2H). LC-MS m/z(ESI): 585.1(M+H) ⁺ .

Example 20

((5-(2-(oxetan-3-yloxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)(( 5-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)amine sodium salt

first step

At room temperature, add 60% sodium hydrogen (32.9 mg, 0.822 mmol) and tetrahydrofuran (5 mL) into a 25 mL reaction flask. Cool to 0°C and add compound 20a (45.7 mg, 0.617 mmol). Stirring was continued at 0°C for 0.5 hours, and compound 8 (200 mg, 0.411 mmol) was added. Stir at room temperature for 8 hours, pour the reaction solution into ice water (5 mL), and extract with ethyl acetate (3 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution (5mL×1), and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and the crude product is subjected to preparative liquid chromatography (chromatography column: Waters Xbridge 150*50mm* 10um; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-11min 15-45% B ; flow 60mL/min) and purified to obtain compound 20b (37mg, yield: 16.7%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.01 (d, 1H), 7.75 (br s, 1H), 7.17-7.14 (m, 2H), 7.08 (d, 1H), 6.91 (d, 1H), 6.82(s,1H),5.59-5.53(m,1H),4.91(t,2H),4.58(dd,2H),3.74(s,2H),2.95-2.89(m,6H),2.73(t, 2H),2.60(s,3H),2.02-1.95(m,2H). LC-MS m/z(ESI): 541.1(M+H) ⁺ .

Step 2

Compound 20b (37 mg, 0.068 mmol) was dissolved in acetonitrile (1 mL), dropped into the IR120 cation exchange resin-Na type column, and eluted with acetonitrile: water = 1:0-0:1 system. The fractions were combined and lyophilized to obtain compound 20 (32 mg, yield: 86.8%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.98 (d, 1H), 7.44 (br s, 1H), 7.10 (d, 1H), 7.06-7.02 (m, 2H), 6.93 (d, 1H), 6.82(s,1H),5.58-5.53(m,1H),4.89(t,2H),4.58(dd,2H),3.49(s,2H),2.89(t,2H),2.83-2.72(m, 6H),2.44(s,3H),1.99-1.95(m,2H).

LC-MS m/z(ESI): 541.2(M+H) ⁺ .

Example 21

((4-Hydroxy-4-methyl-4,,5,6,7-tetrahydrobenzofuran-2-yl)sulfonyl)((5-(2-methoxypyridin-4-yl)- 2,3-Dihydro-1H-inden-4-yl)aminoformyl)amine sodium salt

The synthesis route of Example 5 was adopted, and the first step raw material 6,7-dihydro-4(5H)-benzothiophenone ( 5a ) was replaced by 6,7-dihydro-4(5H)-benzofuranone. , Compound 21 (17 mg, yield: 55%) was obtained.

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.07(d,1H),7.36(s,1H),7.12-7.01(m,2H),6.98-6.90(m,1H),6.77(s,1H) ,6.51(s,1H),4.71(s,1H),3.86(s,3H),3.62-3.51(m,2H),2.88(t,2H),2.77(t,2H),2.05-1.89(m ,3),1.79-1.64(m,2H),1.62-1.53(m,1H),1.31(s,3H).

LC-MS m/z(ESI): 498.2(M+H) ⁺ .

Example 22

3-cyano-N-((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminomethyl)-6-methyl-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-2-sulfonamide

At room temperature, compound 1i (50 mg, 0.19 mmol) and tetrahydrofuran (1 mL) were added sequentially to the reaction flask. After the ice-water bath dropped to 0°C, sodium tert-butoxide (22 mg, 0.23 mmol) was added, and the temperature was raised to room temperature and stirred for 0.5 hours. Then, a solution of compound 3k (60 mg, 0.23 mmol) in tetrahydrofuran (1 mL) was slowly added, and the solution was stirred at room temperature. Stir for 3 hours. After the reaction is completed, the reaction solution is subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B; flow 25ml/min) was purified to obtain compound 22 (19mg, 18.5%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.60 (d, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 7.12 (s, 2H), 3.10 (s, 2H), 2.91 (t ,4H),2.82(d,4H),2.67(s,3H),2.06-1.97(m,2H).

LC-MS m/z(ESI): 519.1(M+H) ⁺ .

Example 23

N-((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminomethyl)-6-methyl-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-2-sulfonamide

Using a synthetic method similar to Example 22, compound 2k and compound 3k were reacted to prepare compound 23 (11 mg, 19.5%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.59(d,1H),7.90(s,1H),7.60(d,1H),7.16(d,2H),7.02(s,1H),3.93(s ,2H),3.02(s,2H),2.92(t,2H),2.80(t,2H),2.76-2.70(m,2H),2.62(s,3H),2.08-1.93(m,2H). LC-MS m/z(ESI): 494.2(M+H) ⁺ .

Example 24

N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminomethyl)-5-methyl-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridine-2-sulfonamide

The synthetic route of Example 4 was adopted, and compound 1j in the sixth step was replaced with compound 6n to prepare compound 24 (5 mg, 7.7%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.09(d,1H),7.11(d,1H),7.05(d,1H),6.95(d,1H),6.76(s,1H),3.87(s ,3H),2.97(s,2H),2.89(t,2H),2.84-2.71(m,4H),2.62-2.53(m,5H),2.03-1.92(m,2H).

LC-MS m/z(ESI): 500.1(M+H) ⁺ .

Example 25

N-((5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminomethyl)-5-methyl-4,5,6, 7-Tetrahydrothiazolo[5,4-c]pyridine-2-sulfonamide

The synthetic route of Example 4 was adopted, and compound 1j in the sixth step was replaced with compound 3k to obtain compound 25 (20 mg, 31.8%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.63(d,1H),7.93(s,1H),7.64(s,1H),7.13(s,2H),4.09(s,2H),3.21(s ,2H),2.92(m,4H),2.81(dd,2H),2.70(s,3H),2.04-1.95(m,2H). LC-MS m/z(ESI): 495.2(M+H) ⁺ .

Example 26

((3-cyano-6-(oxetan-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)aminoformyl)amine sodium salt

The synthetic route of Example 1 was adopted, and the raw material paraformaldehyde in the seventh step was replaced with oxetane-3-carbaldehyde to prepare compound 26 (14 mg, yield: 37.4%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.50 (s, 1H), 6.77 (s, 1H), 4.63 (dd, 2H), 4.26 (t, 2H), 3.53 (s, 2H), 3.27-3.23 (m,2H),2.81-2.66(m,11H),2.05-1.99(m,2H),1.93-1.88(m,4H). LC-MS m/z(ESI): 513.1(M+H) ⁺ .

Example 27

((3-cyano-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5 ,6,7-Hexahydro-s-indacen-4-yl)aminoformyl)amine sodium salt

The synthetic route of Example 1 was adopted, and the raw material paraformaldehyde in the seventh step was replaced with acetaldehyde to prepare compound 27 (42 mg, yield: 56.2%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 7.52(s,1H),6.77(s,1H),3.56(s,2H),2.75-2.53(m,14H),1.98-1.83(m,4H) ,1.06(t,3H). LC-MS m/z(ESI): 471.2(M+H) ⁺ .

Example 28

((6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5,6,7 -Hexahydro-s-indacen-4-yl)aminoformyl)amine sodium salt

At 0°C, add compound 2i (100 mg, 0.384 mmol), tetrahydrofuran (2 mL), and sodium tert-butoxide (37 mg, 0.38 mmol) into a 25 mL single-neck bottle, and stir at room temperature for 40 minutes. Compound 1j (76 mg, 0.38 mmol) was added and stirred for 3 hours. Concentrate under reduced pressure, and the residue is subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 30-65% B; flow 25ml/min) was purified to obtain a crude product. After the crude product was exchanged with sodium ion exchange resin, compound 28 (48mg, yield: 26.0%) was obtained.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.43 (s, 1H), 7.09 (d, 1H), 6.77 (s, 1H), 4.62 (d, 2H), 3.75-3.57 (m, 2H), 2.76 (t,4H),2.68(t,6H),2.07(m,3H),1.94-1.87(m,4H).

LC-MS m/z(ESI): 460.1(M+H) ⁺ .

Example 29

((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)aminoformyl)((6-methyl-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridin-2-yl)sulfonyl)amine sodium salt

The synthetic route of Example 2 was adopted, and compound 1j in the eleventh step was replaced with compound 6n to prepare compound 29 (16 mg, yield: 14.1%).

¹ H NMR (400MHz, DMSO- d ₆ )δ 8.03(d,1H),7.25(s,1H),7.08(d,1H),7.03(d,1H),6.94(s,1H),6.92(d ,1H),6.76(s,1H),3.85(s,3H),3.48(s,2H),2.89(t,2H),2.77(t,2H),2.59(s,4H),2.35(s, 3H),2.03-1.88(m,2H). LC-MS m/z(ESI): 499.2(M+H).

Example 30

((6-acetyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)sulfonyl)((1,2,3,5,6,7-hexahydrofuro[2,3-c]pyridin-2-yl) Hydrogen-s-indacen-4-yl)aminoformyl)amine sodium salt

first step

Add compound 30a (8.00g, 83.3mmol), ethanol (100mL), and nitromethane (4.4mL, 83mmol) to the single-neck bottle in sequence, add 10N sodium hydroxide aqueous solution (8.3mL, 83mmol) at 0°C, and stir for 1 hour. The reaction solution was poured into 15% hydrochloric acid aqueous solution (100 mL), the solid was precipitated, filtered, and the filter cake was decompressed and dried to obtain product 30b (6 g, yield: 51.8%). used directly in the next step.

Step 2

Add 2.5M tetrahydrofuran solution of lithium aluminum tetrahydrogen (6.4mL, 16mmol) and 2mL tetrahydrofuran to the one-neck bottle, add sulfuric acid (0.4mL, 8mmol) dropwise at 0°C, and stir for 20 minutes. A solution of compound 30b (500 mg, 3.59 mmol) in tetrahydrofuran (2 mL) was added and stirred for 10 minutes. Heat to reflux and stir for 5 minutes. Lower to 0°C, add isopropanol (1.7mL, 21.6mmol) and sodium hydroxide (1.29g, 32.3mmol), filter, wash the filter cake with ethyl acetate, collect the filtrate, and concentrate under reduced pressure to obtain crude product 30c ( 380 mg, crude product), which was directly used in the next reaction.

LC-MS m/z(ESI): 112.1.

third step

At room temperature, add compound 30c (380mg, 3.42mmol), dichloromethane (2mL), triethylamine (0.8mL, 5.4mmol), and di-tert-butyl dicarbonate (0.9mL, 3.76 mmol) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an elution system (SiO ₂ , 10% ethyl acetate/petroleum ether) to obtain compound 30d (480 mg, yield: 55.4%).

¹ H NMR (400MHz, CDCl ₃ )δ 7.37(t,1H),7.27(s,1H),6.29(s,1H),4.59(s,1H),3.32-3.31(m,2H),2.61(t ,2H),1.44(m,9H).

the fourth step

At room temperature, add compound 30d (380 mg, 1.80 mmol), toluene (8 mL), paraformaldehyde (34 mg, 0.95 mmol), and p-toluenesulfonic acid (6 mg, 0.04 mmol) in sequence to a 100 mL single-neck bottle, and stir under reflux. 2 hours. Water (10 mL) and ethyl acetate (20 mL) were added, and the organic phase was washed with brine (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to elute the system (SiO ₂ , 10% ethyl acetate/petroleum ether) and purified to obtain compound 30e (200 mg, yield: 49.8%).

¹ H NMR (400MHz, CDCl ₃ )δ 7.28(d,1H),6.24(d,1H),4.44(s,2H),3.63(s,2H),2.53-2.51(m,2H),1.48(s ,9H).

the fifth step

At room temperature, compound 30e (3.93g, 17.5mmol), dichloromethane (24mL), and trifluoroacetic acid (8mL) were added in sequence to a 100mL single-neck bottle, and stirred for 2 hours. Concentration gave compound 30f (3.2g, crude product), which was used directly in the next step.

LC-MS m/z(ESI): 124.4(M+H) ⁺ .

Step 6

At room temperature, in a 250mL single-neck bottle, add compound 30f (3.20g, 16.3mmol), tetrahydrofuran (90mL), and triethylamine (4mL, 28.6mmol), lower to 0°C, and add acetyl chloride (2mL, 28.6 mmol), raised to room temperature, and stirred for 1 hour. Filter, add water (30 mL) to the filtrate, extract with ethyl acetate (30 mL × 3), and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with an elution system (SiO ₂ , 15% ethyl acetate/petroleum ether). , 30g of compound (1.69g, yield: 62.8%) was obtained.

LC-MS m/z(ESI): 166.0(M+H) ⁺ .

Step 7

At room temperature, compound 30g (1.69g, 10.2mmol) and dichloromethane (10mL) were added in sequence to a 50mL single-neck bottle. Cool the temperature to 0°C, add chlorosulfonic acid (1.79g, 15.3mmol), and stir at room temperature for 10 minutes. Ice water (20 mL) was added to quench, and the aqueous phase was purified using reverse column C18 (water/acetonitrile, HCl system) to obtain compound 30h (2.3 g, yield: 92.0%).

LC-MS m/z(ESI): 246.3(M+H) ⁺ .

Step 8

At room temperature, compound 30h (600mg, 2.45mmol) and dichloromethane (12mL) were added sequentially to a 50mL single-neck bottle, then pyridine (0.2mL, 2.7mmol) was added, and phosphorus pentachloride (764mg, 764mg, was added under a nitrogen atmosphere. 3.67mmol), stir for 12 hours, pour the reaction solution into ice water (15mL), rise to room temperature, extract with dichloromethane (20mL), dry the organic phase, filter, and concentrate the filtrate under reduced pressure to obtain product 30i (500mg , yield: 77.4%).

LC-MS m/z(ESI): 264.2(M+H) ⁺ .

Step 9

At room temperature, compound 30i (500mg, 1.90mmol) was dissolved in dichloromethane (2mL), and a solution of compound 30i (500mg, 1.90mmol) in dichloromethane (2mL) was added dropwise to 7M ammonia methanol solution (20mL). Stir for 1 hour. Concentrate under reduced pressure and purify using reverse column C18 (water/acetonitrile, ammonia water system) to obtain compound 30j (150 mg, yield: 32.3%).

LC-MS m/z(ESI): 245.3(M+H).

Step 10

At 0°C, add compound 30j (100 mg, 0.384 mmol), tetrahydrofuran (2 mL), and sodium tert-butoxide (19.7 mg, 0.205 mmol) into a 50 mL single-neck bottle. Stir at room temperature for 40 minutes. Compound 1j (40.8 mg, 0.205 mmol) in tetrahydrofuran (2 mL) was added. Stir for 3 hours. The reaction solution was subjected to preparative liquid chromatography (chromatography column: Waters, Xbridge 250*19mm, 10μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 45-60% B; flow 25ml/ min) to obtain a crude product, which was exchanged with sodium ion exchange resin to obtain compound 30 (42 mg, yield: 23.5%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 7.45(s,1H),6.77(s,1H),6.45(s,1H),4.51-4.46(m,2H),3.67-3.60(m,2H) ,2.75(m,4H),2.69-2.63(m,4H),2.39-2.33(m,2H),2.09-2.06(m,3H),1.98-1.81(m,4H).

LC-MS m/z(ESI): 444.2(M+H) ⁺ .

Example 31

((5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H-cyclo Butano[f]inden-3-yl)aminoformyl)amine sodium salt

first step

Dissolve compound 3g (104mg, 0.481mmol) in anhydrous tetrahydrofuran (5mL), cool to 0°C, add dropwise sodium tert-butoxide solution (0.5mL, 0.5mmol, 1M tetrahydrofuran solution), stir at 0°C for half an hour, Compound 31a (81 mg, 0.437 mmol, prepared by the method disclosed in the patent application "WO2020018975, Example 141 on page 339 of the specification") was added, and the reaction was continued at 0°C for half an hour. After the reaction solution was concentrated, the crude product was purified by a reversed-phase column (0-23.5%, acetonitrile/0.2% ammonia) to obtain compound 31b (70 mg, yield: 39.87%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.69 (s, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 3.76 (s, 2H), 3.06-3.00 (m, 2H), 2.84 -2.83(m,4H),2.78(t,2H),2.69-2.66(m,4H),2.49(s,3H),1.96-1.88(m,2H).

LC-MS m/z: 402.2(M+H) ⁺ .

Step 2

After filling two IR120 cation exchange resin-sodium columns (about 15 cm high), rinse the columns with deionized water (20mL), acetonitrile (20mL), and deionized water (20mL) respectively. After rinsing, Compound 31b (70 mg, 0.174 mmol) was dissolved in acetonitrile (2 mL) and added dropwise to the column. The column was rinsed with the elution system (0:1-1:0, acetonitrile/water), and the rinsed fraction was added to On the second column, the fractions washed twice were combined and freeze-dried to obtain compound 31 (49 mg, yield: 66.15%) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.54 (s, 1H) ,6.52 (s,1H),6.43(s,1H),3.22(s,2H),3.05-3.03(m,2H),2.82-2.75(m,4H),2.69-2.62(m,6H),2.33 (s,3H),1.97-1.87(m,2H).

LC-MS m/z(ESI): 402.1(M+H) ⁺ .

Example 32

((5-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H -cyclobutano[f]inden-3-yl)aminoformyl)amine sodium salt

The synthetic route of Example 31 was adopted, and compound 3g in the first step was replaced by compound 6g to prepare compound 32 (9 mg, yield: 6.3%).

¹ H NMR (400MHz, DMSO- d ₆ )δ 7.42 (s, 1H) 7.02 (s, 1H) 6.51 (s, 1H) 3.29 (s, 2H) 3.03-3.09 (m, 2H) 2.81 (t, 2H) 2.77(t,2H)2.74(t,2H)2.67(t,2H)2.56(t,2H)2.32(s,3H)1.90(m,2H).

LC-MS m/z: 418.0(M+H) ⁺ .

Example 33

((5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H -cyclobutano[f]inden-3-yl)aminoformyl)amine sodium salt

first step

Add compound 6f (1g, 3.34mmol) to dimethylsulfoxide (15mL), cool to 0°C in an ice-water bath, slowly add cesium fluoride (0.76g, 5.01mmol), and then add ethyl iodide (0.63g, 4.01 mmol), warmed to room temperature naturally, and stirred at 20°C for 1 hour. The reaction solution was directly purified by reverse column chromatography (C18, 30%, acetonitrile/0.2% ammonia) to obtain compound 1b (220 mg, yield 26.7%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.55 (s, 2H), 7.24 (s, 1H), 3.43 (s, 2H), 2.82 (t, J =5.6Hz, 2H), 2.70 (t, J =5.6Hz,2H),2.52(q, J =7.2Hz,2H),1.07(t, J =7.2Hz,3H).

LC-MS m/z(ESI): 247.1(M+H) ⁺ .

Step 2

Using the synthetic route of Example 31, compound 3g in the first step was replaced by compound 33a to prepare compound 33 (55.91 mg, yield 14.4%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 10.19(s,1H),7.71(s,1H),7.30(s,1H),6.60(s,1H),3.93(s,2H),3.21-3.13 (m,2H),3.08-3.03(m,2H),2.99-2.93(m,4H),2.85-2.80(m,2H),2.76(t, J =7.6Hz,2H),2.65(t, J =7.6Hz,2H),1.95-1.88(m,2H),1.18(t, J =7.2Hz,3H).

LC-MS m/z(ESI): 432.2(M+H) ⁺ .

Example 34

((5-isopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro- 1H-cyclobutano[f]inden-3-yl)aminoformyl)amine sodium salt

The synthetic route of Example 33 was adopted, and the raw material ethyl iodide was replaced by isopropane iodide to obtain compound 34 (86.82 mg, yield 12%) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.58 (s, 1H ),7.17(s,1H),6.56(s,1H),3.77(s,2H),3.17-3.14(m,1H),3.06-3.00(m,4H),2.87-2.83(m,4H), 2.77(t, J =7.2Hz,2H), 2.67(t, J =7.2Hz,2H), 1.94-1.87(m,2H), 1.13(d, J =6.4Hz,6H).

LC-MS m/z(ESI): 446.2(M+H) ⁺ .

Example 35

((5-cyanomethyl-4,5,6,7-tetrahydrothio[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro -1H-cyclobutano[f]inden-3-yl)aminoformyl)amine sodium salt

The synthetic route of Example 33 was adopted, and the raw material iodoethane was replaced by bromoacetonitrile to prepare compound 35 (18.61 mg, yield 39.85%).

¹ H NMR(400MHz, DMSO- d ₆ )δ 7.45(s,1H),7.08(s,1H),6.52(s,1H),3.90(s,2H),3.51(s,2H),3.08-3.03 (m,2H),2.82-2.75(m,8H),2.67(t, J =7.2Hz,2H),1.93-1.86(m,2H).

LC-MS m/z (ESI): 465.2 (M+Na) ⁺ .

Example 36

((5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H-cyclo Butano[f]inden-3-yl)aminoformyl)amine sodium salt

Adopt the synthetic route of Example 3, replace the raw material trimethyloxonium tetrafluoroborate with triethyloxonium tetrafluoroborate in the fourth step, replace the raw material 3k with compound 31a in the ninth step, and prepare compound 36 (18.61 mg, yield 39.85%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 7.60 (br s, 1H), 6.54 (s, 2H), 3.53-3.44 (m, 2H), 3.07-3.02 (m, 2H), 2.96-2.86 ( m,2H),2.82-2.76(m,4H),2.69-2.65(m,6H),1.91(quint, J =7.2Hz,2H),1.10(t, J =7.2Hz,3H).

LC-MS m/z(ESI): 416.0(M+H) ⁺ .

Example 37

((6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)sulfonyl)((2,4,5,6-tetrahydro-1H-cyclo Butano[f]inden-3-yl)aminoformyl)amine sodium salt

The synthetic route of Example 3 was adopted, the raw material 3a was replaced with furo[2,3-C]pyridine, and the raw material 3k in the ninth step was replaced with 31a to obtain compound 37 (38.36 mg, yield: 99.23%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.54 (s, 1H), 6.52 (s, 1H), 6.46-6.45 (m, 1H), 3.37 (s, 2H), 3.04-3.03 (m, 2H) ,2.81-2.80(m,2H),2.77(t,2H),2.67(t,2H),2.57-2.54(m,2H),2.43-2.41(m,2H),2.35(s,3H),1.94 -1.86(m,2H).

LC-MS m/z(ESI): 402.3(M+H) ⁺ .

Example 38

((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)aminoformyl)((6-methyl-4,5,6,7-tetrahydrofuro[2 ,3-c]pyridin-2-yl)sulfonyl)amine sodium salt

The synthetic route of Example 37 was adopted, the raw material 31a was replaced with compound 1j , and compound 38 (110 mg, yield: 95.4%) was obtained.

¹ H NMR (400MHz, DMSO- d ₆ )δ 7.53(s,1H),6.77(s,1H),6.44(s,1H),3.36(s,2H),2.75(t,4H),2.65(t ,4H),2.57-2.54(m,2H),2.43-2.40(m,2H),2.35(s,3H),1.94-1.87(m,4H).

LC-MS m/z(ESI): 416.2(M+H) ⁺ .

biological evaluation

Test Example 1: NLRP3 inflammasome activity inhibition experiment in THP-1 cells

1) Experimental materials

2) Experimental steps

THP-1 cells were resuspended in cell culture medium of RPMI1640, 10% FBS, and 1% P/S, and the cell density was adjusted to 1×10 ⁶ cells/mL. Plate 10 mL of THP-1 cells in a cell culture dish with a diameter of 10 cm, and add PMA for differentiation treatment. The final concentration of PMA is 10 ng/mL. After the cells were incubated for 24 hours in a cell culture incubator at 37°C and 5% carbon dioxide, take out the culture dish, remove the supernatant and non-adherent cells, digest the cells and resuspend them, and seed them in 96 cells at 10 ⁵ cells/well. in the orifice plate. Place the cell plate in the incubator and incubate overnight. Take it out after 12 hours, remove the medium, add 50uL of fresh medium containing 200ng/mL LPS, and place it in a cell incubator at 37°C and 5% carbon dioxide for 3.5 hours. At the same time, prepare a compound stock solution with a concentration of 30mM in DMSO in a test tube, then use DMSO as a solvent to dilute the sample gradiently as needed, and finally dilute it 333 times into the culture medium. Transfer 50uL of the sample to be tested into each well of a 96-well plate and incubate it in a cell culture incubator at 37°C and 5% carbon dioxide for 0.5 hours. Take out the 96-well plate, add 50uL medium containing 15uM Negericin to each well, and incubate for 1 hour in a cell culture incubator at 37°C and 5% carbon dioxide. Take out the cell plate, centrifuge and take the supernatant, follow the instructions of the ELISA kit to detect IL-1β. Add reagents to the cells in the cell plate and follow the instructions of the CellTiter-Glo Luminescent Cell Viability Assay Kit to detect cell viability.

Table 1 shows the IC ₅₀ values of the compounds of the present invention for inhibiting the activity of NLRP3 inflammasome in THP-1 cells.

Conclusion:

Test Example 2: Pharmacokinetic evaluation of the compound of the present invention

1) Evaluation of pharmacokinetics in mice

In male CD-1 mice (n=3, 6/compound, purchased from Spefford (Beijing) Biotechnology Co., Ltd.), the test compound was dissolved to obtain a clear solution, which was administered via tail vein injection and intragastric administration respectively. Plasma samples were collected within 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. The intravenous administration dose was 1 mg/kg, and the intragastric administration dose was 3 mg. /kg, the intravenous vehicle is 5% DMSO, 5% Solutol and 90% water, and the oral vehicle is 0.5% HPMC, 0.1% TW80 aqueous solution. Blood was collected from the saphenous vein and centrifuged to obtain plasma. LC-MS/MS was used to determine blood drug concentrations, and Phoenix WinNonlin was used for non-compartmental analysis to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration ( C _max ), half-life (T _1/2 ), area under the drug-time curve (AUC _0-t ), bioavailability (F), etc.

Table 2 shows the pharmacokinetic parameters of the compounds of the present invention in mice.

Conclusion: The disclosed compound has good drug metabolism and absorption activity in mice and has pharmacokinetic advantages.

2) Evaluation of pharmacokinetics in SD rats

In male SD rats (n=3, 6/compound, purchased from Spefford (Beijing) Biotechnology Co., Ltd.), the test compound was dissolved to obtain a clear solution, which was administered via tail vein injection and intragastric administration. Plasma samples were collected within 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. The intravenous administration dose was 1 mg/kg, and the intragastric administration dose was 3 mg. /kg, the intravenous vehicle is 5% DMSO, 5% Solutol and 90% water, and the oral vehicle is 0.5% HPMC, 0.1% TW80 aqueous solution. Blood was collected from the saphenous vein and centrifuged to obtain plasma. LC-MS/MS was used to determine blood drug concentrations, and Phoenix WinNonlin was used for non-compartmental analysis to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration ( C _max ), half-life (T _1/2 ), area under the drug-time curve (AUC _0-t ), bioavailability (F), etc.

Table 3 shows the pharmacokinetic parameters of the compounds of the present invention in rats.

Conclusion: The disclosed compound has good drug metabolism and absorption activity in rats and has pharmacokinetic advantages.

Claims (47)

A compound represented by formula I or a pharmaceutically acceptable salt thereof,

in, R ₁ is

or

; R ₂ is

; X ₁ is selected from S and O; X ₂ is CR ₅ or N; A and B are each independently selected from NR ₇ , C(R _4a ) ₂ and O; E and D are each independently selected from NR _7b , C(R _6a ) ₂ and O; R ₃ is selected from hydrogen, C _1-6 alkyl, and 3-6 membered cycloalkyl; the C _1-6 alkyl and 3-6 membered cycloalkyl are optionally selected from one or more C _1-6 alkyl groups. Substituted with substituents of base, 3-6 membered cycloalkyl, halogen, cyano group, and hydroxyl; R ₇ or R _7b is independently selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH ₂ , -CO-C _1-6 alkyl Such as -COCH ₃ , -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ , -C _1-6 (alkylene) Base -SO ₂ -3-6 membered heterocycloalkyl,

,

,

and

;The C _1-6 alkyl group, -O- C _1-6 alkyl group, -O-3-6 membered cycloalkyl group, -O-3-6 membered heterocycloalkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino group, -CONH ₂ , -CO-C _1-6 alkyl such as -COCH ₃ , -SO ₂ -C _1-6 alkyl group, -C _1-6 (alkylene)-SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ -3-6-membered heterocycloalkyl, optionally selected from one or more Substituted from the substituent of R _7c ; R _7a is selected from hydrogen, cyano, hydroxyl, halogen and nitro; preferably R _7a is cyano or hydroxyl; R _7c is independently selected from C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl Substituted with substituents of base, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, amino, cyano, nitro, and hydroxyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered The heteroaryl group is optionally substituted with one or more substituents selected from halogen, amine, cyano, nitro, and hydroxyl; Each R _4a , R _4b , R _4c , R _4d , R _4e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5- 6-membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl Base, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl are optionally substituted by one or more R _4f ; Or R _4a forms =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl with each other; the 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally replaced by a or more selected from halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3 -Substituted by substituents of -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl; Or R _4b and R _4c , R _4d and R _4e together with the atoms to which they are connected form =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl; the 3-8-membered cycloalkyl or The 3-8-membered heterocycloalkyl group is optionally selected from one or more halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O- Substituents of 3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl replaced; R ₅ is selected from hydrogen, halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O- 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 The heteroaryl and phenyl groups are optionally substituted by one or more R _5a ; Each R _6a , R _6b , R _6c , R _6d , R _6e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH ₂ , C _1-6 alkane base, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by one or more R _6f ; Or R _6a forms =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl with each other; the 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally replaced by a or more selected from halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3 -Substituted by substituents of -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl; Or R _6b and R _6c , R _6d and R _6e together with the atoms to which they are connected form =S, =O, 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl; the 3-8-membered cycloalkyl or The 3-8-membered heterocycloalkyl group is optionally substituted by one or more members selected from halogen, cyano group, amine group, nitro group, -CONH ₂ , C _1-6 alkyl group, -OC _1-6 alkyl group, -O- Substituents of 3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl replaced; Z is N or CR ₁₂ ; R ₁₂ is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen , cyano group, amino group, -CONH ₂ , -SO ₂ R _12a , -CH ₂ -SO ₂ R _12a ; the C _1-6 alkyl group, -OC _1-6 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino group, -CONH ₂ is optionally substituted by one or more R _12b ; R _12b is selected from halogen, cyano group, hydroxyl, amine group, C _1-6 alkyl group, -OC _1-6 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered Heteroaryl and phenyl; the C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl Replaced by one or more R _12c as necessary; R _12a is selected from C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino group; the C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 The membered heterocycloalkyl group and the amino group are optionally substituted by one or more members selected from halogen, cyano group, hydroxyl, amino group, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycle Substituted by alkyl, 5-6 membered heteroaryl, phenyl substituents; R ₈ , R ₉ , R ₁₀ , R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3- Condensed ring formed by 6-membered heterocycloalkyl, 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered hetero Aryl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkyl The fused ring formed by the 5-6 membered heteroaryl group, the 3-6 membered cycloalkyl group, the 5-6 membered heteroaryl group, and the 3-6 membered heterocycloalkyl group are optionally substituted by one or more R _13a ; Or R ₈ and R ₉ together with the atoms to which they are connected form a 4-7-membered cycloalkyl group or a 5-6-membered heterocycloalkyl group, which is optionally replaced by a or more selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, - O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ substituent; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, - O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted by one or more R _13b ; Or R ₁₀ and R ₁₁ together with the atoms to which they are connected form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, which is optionally replaced by a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group. or more selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, - O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ substituent; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, - O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted by one or more R _13c ; Each R _13b and R _13c is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O- 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (ethylene) alkyl group -SO ₂ CH ₃ ; the C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 membered cycloalkyl group, -O-3- 6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , - C _1-6 (alkylene)-SO ₂ CH ₃ is optionally substituted with one or more substituents selected from halogen, hydroxyl, and cyano; Each R _13a is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, C _1-6 alkyl Amino group, di-C _1-6 alkylamino group, -O-3-6 membered heterocycloalkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, -OC _1-6 sub-(extension group) )alkyl-3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -CONH ₂ , -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 sub(extension) )Alkyl -SO ₂ CH ₃ ; the amino group, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, -OC _1-6 (alkylene)-3-6-membered heterocycloalkyl, 5-6-membered heteroaryl , -CONH ₂ , -SO ₂ -C _1-6 alkyl group such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ optionally be _one or more selected from C _{1- 6} alkyl, cyano, hydroxyl, halogen, -OC _1-6 alkyl, halo C _1-6 alkyl, cyano substituted C _1-6 alkyl substituted C _1-6 alkyl substituent ; Each R _7c , R _4f , R _5a , R _6f , R _12c is independently selected from C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3 -6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, amine, cyano, nitro, hydroxyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered Heterocycloalkyl and 5-6-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, and hydroxyl; The conditions are: When R ₂ is substituted as necessary

Hour, R ₁ is not selected from

,

,

,

, replaced as necessary

and substituted as necessary

. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is

; R ₅ is as defined in claim 1, preferably R ₅ is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclic Propyl, halomethylcyclopropyl; more preferably R ₅ is hydrogen; R _7b is as defined in claim 1, preferably R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered Heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl, -C _1-6 Alkylene-SO ₂ CH ₃ ,

,

; R _7a , R _6a , R _6b , R _6c , R _6d , R _6e are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is

; R ₅ is as defined in claim 1, preferably R ₅ is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclic Propyl, halomethylcyclopropyl; more preferably R ₅ is hydrogen; R _7b is as defined in claim 1, preferably R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered Heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl, -C _1-6 Alkylene-SO ₂ CH ₃ ,

,

;More preferably, R _7b is selected from C _1-6 alkyl; R _7a is as defined in claim 1, preferably R _7a is cyano; R _6a , R _6b , R _6c , R _6d , R _6e are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is

; E and D are each independently selected from C(R _6a ) ₂ and O, and one and only one of E and D is O; R ₅ is as defined in claim 1, preferably R ₅ is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclic Propyl, halomethylcyclopropyl; more preferably R ₅ is hydrogen; R _6a , R _6b , R _6c , R _6d , R _6e are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is

; E and D are each independently selected from NR _7b , C(R _6a ) ₂ and O, and one and only one of E and D is O; R ₅ is as defined in claim 1, preferably R ₅ is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclic Propyl, halomethylcyclopropyl; more preferably R ₅ is hydrogen; R _7b is as defined in claim 1, preferably R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered Heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl, -CO-C _{1 -6} alkyl such as -COCH ₃ ; R _6a , R _6b , R _6c , R _6d , R _6e are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is selected from

or

; E and D are each independently selected from NR _7b , C(R _6a ) ₂ and O, R _7b is as defined in claim 1, preferably R _7b is selected from hydrogen, C _1-6 alkyl, 3-6 membered heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered Heterocycloalkyl, -C _1-6 (alkylene)-3-6 membered cycloalkyl, hydroxyl-substituted C _1-6 alkyl, halogen-substituted C _1-6 alkyl, -CO-C _{1 -6} alkyl such as -COCH ₃ ; R _6a , R _6b , R _6c , R _6d , R _6e are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is selected from

or

, R _6a , R _6b , R _6c , R _6d , R _6e are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, Each R _6a , R _6b , R _6c , R _6d , R _6e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, -CONH ₂ , C _1-6 alkane base, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered hetero Cycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are optionally substituted by one or more R _6f ; R _6f is as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, Each R _6a , R _6b , R _6c , R _6d , R _6e is the same or different, and each is independently selected from hydrogen, halogen, cyano, amine, nitro, hydroxyl, -CONH ₂ ; the -CONH ₂ is regarded as Needs to be replaced by one or more R _6f ; R _6f is as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, Each R _6a , R _6b , R _6c , R _6d , R _6e is the same or different, and each is independently selected from C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl base, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5- The 6-membered heteroaryl and phenyl groups are optionally substituted by one or more R _6f ; R _6f is as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein each R _6a , R _6b , R _6c , R _6d , and R _6e are the same or different, and each Independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally replaced by one or more R _6f replace; R _6f is as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, wherein each R _6f is independently selected from C _1-6 alkyl, 3-6 membered cycloalkyl , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered The heteroaryl group is optionally substituted with one or more substituents selected from halogen, amine, cyano, nitro, and hydroxyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R _6f is independently selected from halogen, amine, cyano, nitro, and hydroxyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R _6f is independently selected from halogen, cyano, hydroxyl, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl; the C _1-6 alkyl, -OC _1-6 alkyl, -O-3- 6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, and 3-6-membered cycloalkyl are optionally substituted by one or more substituents selected from halogen, amino, cyano, nitro, and hydroxyl. replace. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein R _6d and R _6e together with the atoms to which they are connected are 3-8-membered cycloalkyl or 3-8-membered cycloalkyl Heterocycloalkyl; the 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally selected from one or more halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 Alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl , 5-6 membered heteroaryl, phenyl substituent substituted. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein R _6a forms a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group with each other, Or R _6b and R _6c , R _6d and R _6e form a 3-8-membered cycloalkyl group or a 3-8-membered heterocycloalkyl group; the 3-8-membered cycloalkyl group or 3-8-membered heterocycloalkyl group is optionally One or more are selected from halogen, cyano, amine, nitro, -CONH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O- Substituted with substituents of 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R _6d and R _6e form a 3-8-membered cycloalkyl group or a 3-8-membered heterocycloalkyl group ; The 3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl is optionally selected from one or more halogen, cyano, amino, nitro, -CONH ₂ , C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 Substituted with heteroaryl or phenyl substituents; Preferably, R _6d and R _6e form a 3-8-membered heterocycloalkyl group; the 3-8-membered cycloalkyl group or 3-8-membered heterocycloalkyl group is optionally replaced by one or more members selected from halogen, cyano, and amino groups. , nitro, -CONH ₂ , C _1-6 alkyl substituents. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, R ₁ is

or

; R ₇ is as defined in claim 1, preferably R ₇ is methyl; R ₃ is as defined in claim 1, preferably R ₃ is methyl, propyl, isopropyl, or hydroxyethyl; R _4a , R _4b , R _4c , R _{4d ,} and R _4e are as defined in claim 1. Preferably, R _4a , R _4b , R _4c , R _4d , and R _4e are hydrogen. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

; R ₈ , R ₉ , R ₁₀ , R ₁₁ are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

; R ₈ and R ₉ form a 4-7-membered cycloalkyl or 5-6-membered heterocycloalkyl group, which is optionally replaced by one or more halogens. , hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _{1 -6} (ethylene)alkyl-SO ₂ CH ₃ substituent; the C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 member Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl Groups such as -SO ₂ CH ₃ and -C _1-6 (alkylene) -SO ₂ CH ₃ are optionally substituted by one or more R _13b ; R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , a fused ring formed by a 3-6-membered cycloalkyl group, a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, a 3-6-membered heterocycloalkyl group, and a 5-6-membered heteroaryl group; the C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle The fused ring formed by the alkyl group and the 5-6-membered heteroaryl group, the 5-6-membered heteroaryl group, and the 3-6-membered heterocycloalkyl group are optionally substituted by one or more R _13a ; R ₁₂ , R _13a , R _13b are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

; R ₈ and R ₉ form a 4-7-membered cycloalkyl or 5-6-membered heterocycloalkyl group, which is optionally replaced by one or more halogens. , hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _{1 -6} (ethylene)alkyl-SO ₂ CH ₃ substituent; the C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 member Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl Groups such as -SO ₂ CH ₃ and -C _1-6 (alkylene) -SO ₂ CH ₃ are optionally substituted by one or more R _13b ; R ₁₀ and R ₁₁ form a 4-7 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, which is optionally replaced by one or more halogens. , hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered Heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _{1 -6} (ethylene)alkyl-SO ₂ CH ₃ substituent; the C _1-6 alkyl group, halo C _1-6 alkyl group, -OC _1-6 alkyl group, -O-3-6 member Cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl Groups such as -SO ₂ CH ₃ and -C _1-6 (alkylene) -SO ₂ CH ₃ are optionally substituted by one or more R _13c ; R ₁₂ , R _13b , R _13c are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

; Z is N or CR ₁₂ ; R ₈ and R ₉ form a 4-7 membered cycloalkyl group, which is optionally replaced by one or more members selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered hetero Cycloalkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl, such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ substituents substituted ;The C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 alkylene The base -SO ₂ CH ₃ is optionally substituted with one or more R _13b ; R ₁₀ and R ₁₁ are independently selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl , a fused ring formed by a 3-6-membered cycloalkyl group, a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, a 3-6-membered heterocycloalkyl group, and a 5-6-membered heteroaryl group; the C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle The fused ring formed by the alkyl group and the 5-6-membered heteroaryl group, the 5-6-membered heteroaryl group, and the 3-6-membered heterocycloalkyl group are optionally substituted by one or more R _13a ; R ¹⁰ , R ¹¹ , R ₁₂ , R _13a , R _13b are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

; Z is N or CR ₁₂ ; R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halogen C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 Member heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ ; the C _1-6 alkyl, halogen C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle Alkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (exylene) alkyl -SO ₂ CH ₃ optionally replaced by one or more Replaced by R _13b ; R ₁₀ is selected from the fused ring formed by a 3-6-membered heterocycloalkyl group and a 5-6-membered heteroaryl group, and a 5-6-membered heteroaryl group; the 3-6-membered heterocycloalkyl group and the 5-6-membered heteroaryl group The formed fused ring and 5-6 membered heteroaryl group are optionally substituted by one or more R _13a ; R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ; R ₁₂ , R _13a , R _13b are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

; Z is N or CR ₁₂ ; R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halogen C _1-6 alkyl, - OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 Member heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene) -SO ₂ CH ₃ ; the C _1-6 alkyl, halogen C _{1 -6} alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycle Alkyl, 5-6 membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (exylene) alkyl -SO ₂ CH ₃ optionally replaced by one or more Replaced by R _13b ; R ₁₀ is selected from 5-6 membered heteroaryl optionally substituted by one or more R _13a ; R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ; R ₁₂ , R _13a , R _13b are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is selected from:

Z is N or CR ₁₂ ; R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ; R _10a is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (alkylene)-SO ₂ CH ₃ substituent; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -SO ₂ -C _1-6 alkyl such as -SO ₂ CH ₃ , -C _1-6 (e)alkylene -SO ₂ CH ₃ is optionally substituted by one or more R _13c ; R _10b is selected _from C _1-6 alkyl, which is optionally substituted by C _3-6 cycloalkyl; n and m are independently selected from the integer of 0-3; preferably n and m are independently selected from the integer of 0-2; R ₈ , R ₉ , R ₁₂ , R _13a , R _13c are as defined in claim 1; R _9a , R _9b , R _9c , R _9d , R _9e , R _9f are as defined in claim 23. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, R ₂ is

Z is N or CR ₁₂ ; R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a ; n is an integer selected from 0-3; R ₁₂ , R _13a , R _13c are as defined in claim 1; R _9a , R _9b , R _9c , R _9d , R _9e , R _9f are as defined in claim 23. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein Z is N. The compound represented by Formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 26, wherein Z is CR ₁₂ ; R ₁₂ is as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein R ₁₂ is selected from hydrogen, C _1-6 alkyl, -OC _1-6 alkyl, 3 -6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, halogen, cyano, amino, -CONH ₂ , -SO ₂ R _12a , -CH ₂ -SO ₂ R _12a ; the C _1-6 alkyl, -OC _1-6 alkyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, amino group , -CONH ₂ is replaced by 1-3 R _12b as needed; R _12a , R _12b are as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein R ₁₂ is selected from hydrogen, halo C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl , cyano substituted C _1-6 alkyl, -OC _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano Group, amine group, -CONH ₂ , -SO ₂ R _12a , -CH ₂ -SO ₂ R _12a , R _12a is as defined in claim 1; Preferred R ₁₂ is selected from hydrogen, halogen, C _1-6 alkyl, halo C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, -OC _1-6 alkyl base. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 23 to 30, Among them, R _9a , R _9b , R _9c , R _9d , R _9e , and R _9f are independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, halogen C _1-6 alkyl, -OC _1-6 alkyl; the C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13b , R _13b is as in claim 1 defined; Preferably, R _9a , R _9b , R _9c , R _9d , R _9e and R _9f are hydrogen. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein R _13b is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 alkyl, -OC _1-6 alkyl, halo C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 18, wherein R ₁₁ is selected from hydrogen, halogen, C _1-6 alkyl, -OC _1-6 alkyl; The C _1-6 alkyl, -OC _1-6 alkyl is optionally substituted by one or more R _13a , and R _13a is as defined in claim 1. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 20 and 23 to 33, wherein R ₁₁ is selected from hydrogen, C _1-6 alkyl, halo C _1-6 alkyl group, hydroxyl-substituted C _1-6 alkyl group; preferably R ₁₁ is selected from hydrogen and methyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein each R _13a is independently selected from halogen, hydroxyl, cyano, amine, C _1-6 Alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkyl group, -OC _1-6 alkyl group; the amino group, C _1-6 alkyl group, -OC _1-6 alkyl group are optional Substituted by 1-3 C _1-6 alkyl, hydroxyl substituted by C 1-6 _alkyl , cyano, hydroxyl, halogen, -OC _1-6 alkyl, halo C _1-6 alkyl, cyano Substituted with C _1-6 alkyl substituents. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein each R _13a is independently selected from cyano, halogen, hydroxyl, C _1-6 alkyl, -OC _1-6 alkyl group, methanesulfonyl group, -CONH ₂ , -CH ₂ -SO ₂ CH ₃ , 3-6 membered heterocyclic group, and amino group. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein each R _13a is independently selected from C _1-6 alkyl, -OC _1-6 alkyl , -O-5-6-membered heteroaryl, -O-3-6-membered heterocycloalkyl, -OC _1-6 (alkylene)-3-6-membered heterocycloalkyl; the C _1-6 Alkyl, -OC _1-6 alkyl, -O-5-6 heteroaryl, -O-3-6 heterocycloalkyl, -OC _1-6 alkyl-3-6 The heterocycloalkyl group is optionally substituted with 1 to 3 substituents selected from halogen, cyano group, hydroxyl, and C _1-6 alkyl group. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein each R _13a is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocycle Alkyl, 5-6-membered heteroaryl; the 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl is optionally selected from one or more C _1-6 alkyl groups Substituted with radical, cyano group, hydroxyl, halogen, -OC _1-6 alkyl, halo C _1-6 alkyl, cyano-substituted C _1-6 alkyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 38, wherein R _10a is independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl , Halo C _1-6 alkyl, -OC _1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl, halogen 3-6 membered cycloalkyl, halogen 3-6 membered heterocycloalkyl. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 39, wherein R ₂ is optionally substituted

When , R ₁ is not

. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 39, wherein R ₂ is not

. The compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 39, wherein R ₂ is not optionally substituted

. The compound represented by formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, which is selected from:

An isotope substitution of the compound represented by formula I in any one of claims 1 to 43, preferably, the isotope substitution is deuterium atom substitution. A pharmaceutical composition comprising at least a therapeutically effective amount of a compound represented by formula I as described in any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in claim 44 , and pharmaceutically acceptable excipients. A compound represented by formula I as described in any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in claim 44, or a pharmaceutical composition as described in claim 45. Use in the preparation of drugs for treating diseases related to NLRP3 activity. A compound represented by formula I as described in any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in claim 44, or a pharmaceutical composition as described in claim 45. Use in preparing drugs for treating inflammasome-related diseases, immune diseases such as autoimmune diseases, and inflammatory diseases such as autoinflammatory diseases.