A compound containing a fused ring structure and applications thereof

Abstract

The present disclosure provides a compound containing a fused ring structure and applications thereof. Specifically, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the functional groups are as defined in the text.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a compound containing a fused ring structure and its applications. Background Technology

[0002] STAT stands for signal transduction and transcription activator, and it was first discovered in 1994. The STAT family in mammalian cells comprises seven members: STAT1, STAT2, STAT3, STAT4, STAT5α, STAT5β, and STAT6, with homology levels ranging from 20% to 50%. These proteins regulate many genes that govern the cell cycle, cell survival, and immune responses. STAT3 has attracted particular attention due to its unique potential in creating innovative therapies and is the most extensively studied STAT protein.

[0003] Extensive clinical data demonstrate that STAT3 plays a crucial role in cancer promotion. Due to its ability to regulate cell cycle progression and inhibit apoptosis, STAT3 is also associated with chemotherapy resistance and poor prognosis. Furthermore, aberrant STAT3 activity is observed in immune cells, suppressing anti-tumor immune responses by upregulating immunosuppressive proteins and inhibiting immune activating factors. In addition, STAT3 is associated with autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, atherosclerosis, and inflammatory bowel disease. Therefore, STAT3 is considered a promising anti-cancer target, and developing effective STAT3 inhibitors remains a viable cancer treatment strategy.

[0004] Currently, there are no approved drugs targeting STAT3. Oral STAT3 small molecule inhibitors such as Tvardi's TTI-101 are in Phase II clinical trials, Otsuka Pharmaceutical's OPB-111077 and Bayer's BAY3630914 (VVD-130850) are in Phase I clinical trials, and Kymera's STAT3 PROTAC molecule KT-333 is in Phase I clinical trials. Summary of the Invention

[0005] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0006]

[0007] in,

[0008] A 1 It can be C or N;

[0009] A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1A 6 A 7 A 8 A 9 It contains at most 2 N,

[0010] Ring B is a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl;

[0011] R 1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, and heterocyclic alkyl are optionally substituents of one or more substituents. 1 Replaced;

[0012] R 2 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0013] L 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group.

[0014] Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -;

[0015] R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0016] Z is selected from , , , , and ,in

[0017] X 0 X 1 X 2 Each is independently selected from chemical bonds, -CR a R b -、-NR c - and -O-, and X 0 X 1 X 2 They are not both chemical bonds;

[0018] The ring C is a 3- to 6-membered cycloalkyl group;

[0019] R a R b Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0020] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0021] R 3 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0022] B 1 B 2 Each is independently N or CR a4 ;

[0023] Ring A is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 12-membered spirocycloalkyl, or a 5- to 12-membered spiroheterocycloalkyl;

[0024] R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0025] R 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0026] R 2b Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0027] Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl substitution;

[0028] n is an integer between 0 and 8.

[0029] p is an integer between 0 and 8.

[0030] q is an integer between 0 and 8.

[0031] r is an integer between 0 and 2.

[0032] In some embodiments, ring B in the compound shown in formula (I) is a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl is a heterocycloalkyl or heteroaryl containing 1 to 3 N atoms.

[0033] In some embodiments, ring B in the compound shown in formula (I) is

[0034]

[0035] in,

[0036] A 1 It can be C or N;

[0037] A 2 For CR a2 R b2 Or it may not exist;

[0038] A 3 For CR a2 CR a2 R b2 , N or NR c2 ;

[0039] A 4 For non-existent, CR a2 CR a2 R b2 , N or NR c2 A 2 and A 4 They do not exist simultaneously;

[0040] A 5 For CR a2 CR a2 R b2 , N or NR c2 ;

[0041] It can be a single bond or a double bond;

[0042] R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O.

[0043] In some implementation schemes, R a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Together they form = O.

[0044] In some implementations, R a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a2 R b2 Together they form = O.

[0045] In some embodiments, L in the compound shown in formula (I) 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), C 2-10 imide (or C) 2-6 imide or C 2-4 imide or C 2-3 (alkenyl) or C 2-10 Ethyne (or C) 2-6 Ethyne or C 2-4 Ethyne or C 2-3 (alkynyl), wherein one, two, or three of the -CH2- groups of the alkylene, alkenyl, or alkynyl groups may be independently replaced by Y. 1 The group replaced;

[0046] Y 1Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -

[0047] In some embodiments, L in the compound shown in formula (I) 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), C 2-10 imide (or C) 2-6 imide or C 2-4 imide or C 2-3 (alkenyl) or C 2-10 Ethyne (or C) 2-6 Ethyne or C 2-4 Ethyne or C 2-3 (alkynyl), wherein any one of the -CH2- groups of the alkylene, alkenylene, or alkynyl group can be independently converted by Y. 1 The group replaced;

[0048] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -

[0049] In some embodiments, L in the compound shown in formula (I) 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), wherein one of the -CH2- groups of the alkylene group can be independently converted by Y. 1 The group replaced;

[0050] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4-、-SO2NR 4 -

[0051] In some embodiments, L in the compound shown in formula (I) 1 is -O-, -S-, -CO-, -COO-, -NH-, -N(CH3)- , -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-, -CH2S-, -CH2NH-, -CH2N(CH3)-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH- or -CH2CH2CH2N(CH3)- .

[0052] In some embodiments, L in the compound shown in formula (I) 1 The denominators are -O-, -S-, -CO-, -COO-, -CH2-, -NH-, and -N(CH3)-.

[0053] In some embodiments, Z in the compound shown in formula (I) is selected from... and .

[0054] In some embodiments, the compound shown in formula (I) Selected from

[0055] , , and ,

[0056] in,

[0057] B 1 B 2 Each is independently N or CR a4 ;

[0058] B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0059] B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B4 B 5 They do not both exist;

[0060] B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0061] B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0062] B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0063] B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms;

[0064] R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O;

[0065] R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0066] R e4 Each is independently selected from oxo and imino groups.

[0067] In some embodiments, the compound shown in formula (I) Selected from

[0068] , , and ,

[0069] in,

[0070] B 1 B 2 Each is independently N or CR a4 ;

[0071] B 3 B 4 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0072] B 7 B 9 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0073] R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O;

[0074] Rd4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0075] R e4 Each is independently selected from oxo and imino groups.

[0076] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II).

[0077]

[0078] in,

[0079] A 1 It can be C or N;

[0080] A 2 For CR a2 R b2 Or it may not exist;

[0081] A 3 For CR a2 CR a2 R b2 , N or NR c2 ;

[0082] A 4 For non-existent, CR a2 CR a2 R b2 , N or NR c2 A 2 and A 4 They do not exist simultaneously;

[0083] A 5 For CR a2 CR a2 R b2 , N or NR c2 ;

[0084] A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N,

[0085] It can be a single bond or a double bond;

[0086] R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O;

[0087] R 1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0088] L 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group.

[0089] Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -;

[0090] R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0091] Z is selected from , , , , and ,in

[0092] X 0 X 1 X 2 Each is independently selected from chemical bonds, -CR a R b -、-NR c - and -O-, and X 0 X 1 X 2 They are not both chemical bonds;

[0093] The ring C is a 3- to 6-membered cycloalkyl group;

[0094] R a R b Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0095] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0096] R 3 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0097] Selected from

[0098] , , and ,

[0099] in,

[0100] B 1B 2 Each is independently N or CR a4 ;

[0101] B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0102] B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B 4 B 5 They do not both exist;

[0103] B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0104] B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0105] B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0106] B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms;

[0107] R b4 Rc4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O;

[0108] R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0109] R e4 Each is independently selected from oxo and imino groups;

[0110] R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0111] R 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0112] R 2b Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0113] Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl substitution;

[0114] n is an integer between 0 and 8.

[0115] p is an integer between 0 and 8.

[0116] q is an integer between 0 and 8.

[0117] r is an integer between 0 and 2.

[0118] In some embodiments, L in the compound shown in formula (II) 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), C 2-10 imide (or C) 2-6 imide or C 2-4 imide or C 2-3 (alkenyl) or C 2-10 Ethyne (or C) 2-6 Ethyne or C 2-4 Ethyne or C 2-3 (alkynyl), wherein one, two, or three of the -CH2- groups of the alkylene, alkenyl, or alkynyl groups may be independently replaced by Y. 1 The group replaced;

[0119] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR4 -、-SO2NR 4 -

[0120] In some embodiments, L in the compound shown in formula (II) 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), C 2-10 imide (or C) 2-6 imide or C 2-4 imide or C 2-3 (alkenyl) or C 2-10 Ethyne (or C) 2-6 Ethyne or C 2-4 Ethyne or C 2-3 (alkynyl), wherein any one of the -CH2- groups of the alkylene, alkenylene, or alkynyl group can be independently converted by Y. 1 The group replaced;

[0121] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -

[0122] In some embodiments, L in the compound shown in formula (II) 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), wherein one of the -CH2- groups of the alkylene group can be independently converted by Y. 1 The group replaced;

[0123] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -

[0124] In some embodiments, L in the compound shown in formula (II)1 The ...

[0125] In some embodiments, L in the compound shown in formula (II) 1 The denominators are -O-, -S-, -CO-, -COO-, -CH2-, -NH-, and -N(CH3)-.

[0126] In some embodiments, the compound represented by formula (I) is the compound represented by formula (III).

[0127]

[0128] in,

[0129] A 1 It can be C or N;

[0130] A 3 A 4 A 5 Each independently for CR a2 CR a2 R b2 , N or NR c2 ;

[0131] A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N,

[0132] It can be a single bond or a double bond;

[0133] R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O;

[0134] R 1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0135] L 1 Selected from -CR a1 R b1 -、-NR c1 -、-O- and -S-;

[0136] R a1 R b1 R c1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a1 R b1 Together form = O;

[0137] L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group.

[0138] Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -;

[0139] R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0140] Z is selected from , , , , and ,in

[0141] X 0 X 1 X 2 Each is independently selected from chemical bonds, -CR a R b -、-NR c - and -O-, and X 0 X 1 X 2 They are not both chemical bonds;

[0142] The ring C is a 3- to 6-membered cycloalkyl group;

[0143] R a R b and R c Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0144] R 3 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0145] Selected from

[0146] , , and ,

[0147] in,

[0148] B 1 B 2 Each is independently N or CR a4 ;

[0149] B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0150] B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B 4 B 5 They do not both exist;

[0151] B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0152] B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0153] B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0154] B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms;

[0155] R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O;

[0156] R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0157] R e4 Each is independently selected from oxo and imino groups;

[0158] R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0159] R 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0160] R 2b Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0161] Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl substitution;

[0162] n is an integer between 0 and 8.

[0163] p is an integer between 0 and 8.

[0164] q is an integer between 0 and 8.

[0165] r is an integer between 0 and 2.

[0166] In some embodiments, R in the compound shown in formula (III) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Together they form = O.

[0167] In some embodiments, R in the compound shown in formula (III) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a2 R b2 Together they form = O.

[0168] In some embodiments, R in the compound shown in formula (III) a1 R b1 R c1 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a1 R b1 Together they form = O.

[0169] In some embodiments, R in the compound shown in formula (III) a1 R b1 R c1 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a1 R b1 Together they form = O.

[0170] In some embodiments, the compound represented by formula (I) is the compound represented by formula (IV).

[0171]

[0172] in,

[0173] A 1 It can be C or N;

[0174] A 3 A 4 A 5 Each independently for CR a2 CR a2 R b2 , N or NR c2 ;

[0175] A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N,

[0176] It can be a single bond or a double bond;

[0177] R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O;

[0178] R 1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0179] L 1 Selected from -CR a1 R b1 -、-NR c1 -、-O- and -S-;

[0180] R a1 R b1 R c1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a1 R b1 Together form = O;

[0181] L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group.

[0182] Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -;

[0183] R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0184] Z is selected from , , , , and ,in

[0185] X 0 X 1 X 2 Each is independently selected from chemical bonds, -CR a R b -、-NR c - and -O-, and X 0 X 1 X 2 They are not both chemical bonds;

[0186] The ring C is a 3- to 6-membered cycloalkyl group;

[0187] R a R b Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0188] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0189] R 3 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0190] Selected from

[0191] , , and ,

[0192] in,

[0193] B 1 B 2 Each is independently N or CR a4 ;

[0194] B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S;

[0195] B 1 B 2 Each is independently N or CR a4 ;

[0196] B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0197] B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B 4 B 5 They do not both exist;

[0198] B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 )0-2 Or it may not exist;

[0199] B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0200] B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0201] B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms;

[0202] R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O;

[0203] R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0204] R e4 Each is independently selected from oxo and imino groups;

[0205] R a4Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0206] R 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0207] R 2b Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0208] Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl substitution;

[0209] n is an integer between 0 and 8.

[0210] p is an integer between 0 and 8.

[0211] q is an integer between 0 and 8.

[0212] r is an integer between 0 and 2.

[0213] In some embodiments, R in the compound shown in formula (IV) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Together they form = O.

[0214] In some embodiments, R in the compound shown in formula (IV) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a2 R b2 Together they form = O.

[0215] In some embodiments, R in the compound shown in formula (IV) a1 R b1 R c1 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a1 R b1 Together they form = O.

[0216] In some embodiments, R in the compound shown in formula (IV) a1 R b1 R c1 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a1 R b1 Together they form = O.

[0217] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene (or C 1-6 Alkylene or C 1-4 Alkylene or C 1-3 Alkylene), C 2-10 imide (or C) 2-6 imide or C 2-4 imide or C 2-3 (alkenyl) or C 2-10 Ethyne (or C) 2-6 Ethyne or C 2-4 Ethyne or C 2-3 (alkynyl), wherein one, two, or three of the -CH2- groups of the alkylene, alkenyl, or alkynyl groups may be independently replaced by Y. 1 The group replaced;

[0218] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -

[0219] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-6 Alkylene (or C 1-4 Alkylene or C 1-3 Alkylene), C 2-6 imide (or C) 2-4 imide or C 2-3 (alkenyl) or C 2-6 Ethyne (or C) 2-4 Ethyne or C 2-3 (alkynyl), wherein any one of the -CH2- groups of the alkylene, alkenylene, or alkynyl group can be independently converted by Y. 1 The group replaced;

[0220] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -

[0221] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-6 Alkylene (or C 1-4 Alkylene or C 1-3 Alkylene), wherein one of the -CH2- groups of the alkylene group can be independently converted by Y. 1 The group replaced;

[0222] Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -and-CONR 4 -

[0223] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2 -(CR) a3 R b3 ) x -Y 1 -,

[0224] R a3 R b3 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced

[0225] Y 1 Selected from -O-, -S-, -COO-, -CO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -,

[0226] x is an integer between 0 and 6.

[0227] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2 -(CR) a3 R b3 ) x -Y 1 -,

[0228] R a3 R b3Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced

[0229] Y 1 Selected from -O-, -S-, -COO-, -CO-, -NR 4 -and-CONR 4 -,

[0230] x is an integer between 0 and 6.

[0231] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2 is -O-, -S-, -CO-, -COO-, -NH-, -N(CH3)- , -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-, -CH2S-, -CH2NH-, -CH2N(CH3)-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH- or -CH2CH2CH2N(CH3)- .

[0232] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 2 It can be -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH-, or -CH2CH2CH2N(CH3)-.

[0233] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 1 It can be -O-, -S-, -CO-, -COO-, -CH2-, -NH- or -N(CH3)-.

[0234] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 1 It can be -O-, -S-, -CO-, -COO-, -CH2-, -NH-, or -N(CH3)-.

[0235] L 2 -(CR) a3 R b3 ) x -Y 1 -,

[0236] R a3 R b3 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced

[0237] Y 1 Selected from -O-, -S-, -COO-, -CO-, -NR 4 -and-CONR 4 -,

[0238] x is an integer between 0 and 6.

[0239] In some embodiments, L in the compounds shown in formulas (I), (II), (III), and (IV) 1 It can be -O-, -S-, -CO-, -COO-, -CH2-, -NH-, or -N(CH3)-.

[0240] L 2 It can be -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH-, or -CH2CH2CH2N(CH3)-.

[0241] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 What it replaced.

[0242] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, and cycloalkyl are optionally substituents of one or more substituents. 1 What it replaced.

[0243] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups.

[0244] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkyl groups.

[0245] In some embodiments, A in the compounds shown in formulas (I), (II), (III), and (IV) 1 The answer is C.

[0246] In some embodiments, A in the compounds shown in formulas (I), (II), (III), and (IV) 1 A 6 A 7 A 8 For CR 1 A 9 Let N be the number of elements in the array.

[0247] In some embodiments, A in the compounds shown in formulas (I), (II), (III), and (IV) 1 A 6 A 7 A 9 For CR 1 A 8 Let N be the number of elements in the array.

[0248] In some embodiments, A in the compounds shown in formulas (I), (II), (III), and (IV) 1 A 6 A 8 A9 For CR 1 A 7 Let N be the number of elements in the array.

[0249] In some embodiments, A in the compounds shown in formulas (I), (II), (III), and (IV) 1 A 7 A 8 A 9 For CR 1 A 6 Let N be the number of elements in the array.

[0250] In some embodiments, R in the compounds shown in formulas (II), (III), and (IV) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Together they form = O.

[0251] In some embodiments, R in the compounds shown in formulas (II), (III), and (IV) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a2 R b2 Together they form = O.

[0252] In some embodiments, R in the compounds shown in formulas (II), (III), and (IV) a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, amino groups, and C atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl, or R a2 R b2 Together they form = O.

[0253] In some embodiments, R in the compounds shown in formulas (II), (III), and (IV) c2 Each is independently selected from hydrogen atoms, C atoms1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0254] In some embodiments, X in the compounds shown in formulas (I), (II), (III), and (IV) 1 Selected from chemical bonds, -CH2- and -O-, X 0 X 2 Each is independently selected from chemical bonds and -CH2-; the ring C is a 3- to 6-membered cycloalkyl group; R 3 Each is independently selected from halogens and C. 1-6 alkyl.

[0255] In some embodiments, Z in the compounds shown in formulas (I), (II), (III), and (IV) is selected from... , , , and .

[0256] In some embodiments, Z in the compounds shown in formulas (I), (II), (III), and (IV) is selected from... and .

[0257] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 3 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0258] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 3 Each is independently selected from halogen, hydroxyl, amino, imino, oxo, C 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0259] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV)3 Each is independently selected from halogen, hydroxyl, amino, imino, oxo, C 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, amino groups, C4 groups, and cycloalkyl groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0260] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 3 Each is independently selected from halogen, amino, imino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3 to 10-membered cycloalkyl groups.

[0261] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 3 Each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3 to 10-membered cycloalkyl groups.

[0262] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 3 Each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0263] In some embodiments, B in the compounds shown in formulas (I), (II), (III), and (IV) 1 For N, B 2 For N or CR a4 .

[0264] In some embodiments, B in the compounds shown in formulas (I), (II), (III), and (IV) 1 B 2 All are CR a4 .

[0265] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) a4 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0266] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) a4 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, amino groups, C4 groups, and cycloalkyl groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0267] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) a4 Each is independently selected from hydrogen atoms, halogens, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0268] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2b Each is independently selected from halogens, hydroxyl groups, amino groups, and C. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0269] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2b Each is independently selected from halogens, hydroxyl groups, amino groups, and C. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, amino groups, C4 groups, and cycloalkyl groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0270] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2b Each is independently selected from halogens, amino groups, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3 to 10-membered cycloalkyl groups.

[0271] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2b Each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0272] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 What it replaced.

[0273] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl may optionally be substituented by one or more substituents. 1 What it replaced.

[0274] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, imino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and 3 to 10-membered cycloalkyl groups.

[0275] In some embodiments, the compounds shown in formulas (I), (II), (III), and (IV) Selected from

[0276] , , and ,

[0277] in,

[0278] B 1 B 2 Each is independently N or CR a4 ;

[0279] B 3 B 4 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 )0-2 ;

[0280] B 7 B 9 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0281] R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O;

[0282] R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0283] R e4 Each is independently selected from oxo and imino groups.

[0284] In some embodiments, the compounds shown in formulas (I), (II), (III), and (IV) Selected from

[0285] , , and ,

[0286] in,

[0287] B 1 B 2 Each is independently N or CR a4 ;

[0288] B 3 B 4 B 6 Each independently for CRb4 R c4 NR d4 , O or S(R) e4 ) 0-2 ;

[0289] B 7 B 9 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist;

[0290] R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R b4 R c4 Together form = O;

[0291] R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0292] R e4 Each is independently selected from oxo and imino groups.

[0293] In some implementations, the B described in this disclosure 3 B 6 Each independently for CR b4 R c4 or NR d4 .

[0294] In some implementations, the B described in this disclosure 7 B 9 B 11 Each independently for CR b4 R c4 NR d4 0 or not present.

[0295] In some implementations, the R described in this disclosure b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R b4 R c4 Together they form = O.

[0296] In some implementations, the R described in this disclosure d4 Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Alkyl group.

[0297] In some embodiments, the compounds shown in formulas (I), (II), (III), and (IV) Selected from

[0298] .

[0299] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 4 Selected from hydrogen atom, hydroxyl group, amino group, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or cycloalkoxy group is optionally substituented by one or more substituents. 1 What it replaced.

[0300] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 4 Selected from hydrogen atom, hydroxyl group, amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl.

[0301] In some embodiments, R in the compounds shown in formulas (I), (II), (III), and (IV) 4 Selected from hydrogen atom, amino group, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0302] In some implementations, n in the compounds shown in formulas (I), (II), (III), and (IV) is an integer from 0 to 6, or an integer from 0 to 4, or an integer from 0 to 2.

[0303] In some embodiments, p in the compounds shown in formulas (I), (II), (III), and (IV) is an integer from 0 to 3, or an integer from 0 to 2, or is 0.

[0304] In some implementations, q in the compounds shown in formulas (I), (II), (III), and (IV) is an integer from 0 to 6, or an integer from 0 to 4, or an integer from 0 to 2.

[0305] In some embodiments, Q in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, amino, C 1-6 Alkyl and C 1-6 Alkyl-substituted.

[0306] In some embodiments, Q in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl and 3- to 10-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0307] In some embodiments, Q in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more halogens, oxo, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Alkyl-substituted.

[0308] In some embodiments, Q in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl and 5- to 12-membered heteroaryl.

[0309] In some embodiments, Q in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, 6- to 12-membered aryl and 5- to 12-membered heteroaryl.

[0310] In some embodiments, Q in the compounds shown in formulas (I), (II), (III), and (IV) 1 Each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl and C 1-6 Alkyl group.

[0311] The compounds disclosed herein include, but are not limited to:

[0312]

[0313] This disclosure also provides isotopic substitutes of the aforementioned compounds or their pharmaceutically acceptable salts. In some embodiments, the isotopic substitutes are deuterated derivatives.

[0314] This disclosure also provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotopic substitute thereof, and a pharmaceutically acceptable excipient.

[0315] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitute, based on the total weight of the composition.

[0316] In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0317] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0318] This disclosure also provides a combination comprising the aforementioned pharmaceutical composition and instructions for use of the pharmaceutical composition.

[0319] This disclosure also provides a method for using the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition to regulate STAT3. In some embodiments, the method includes inhibiting STAT3.

[0320] This disclosure also provides a method for treating a STAT3-mediated disease or condition using the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition. In some embodiments, the method includes administering a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, to a subject in need. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is an immunological condition.

[0321] This disclosure also provides the use of the aforementioned compounds or their pharmaceutically acceptable salts or pharmaceutical compositions in the preparation of medicaments for STAT3 inhibitors.

[0322] This disclosure also provides the use of the aforementioned compounds or their pharmaceutically acceptable salts or pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of cancer.

[0323] In some implementations, the aforementioned cancers include solid tumors such as bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, lung cancer, cervical cancer, colorectal cancer, bile duct cancer, gastric cancer, kidney cancer, and pancreatic cancer. The cancers also include hematologic malignancies such as acute myeloid leukemia (AML), T-cell large granular lymphoblastic leukemia (T-LGLL), non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphomas (PTCLs, including cutaneous T-cell lymphoma), classical Hodgkin lymphoma (cHL), and diffuse large B-cell lymphoma (DLBCL). The immune disorders include psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus (including systemic lupus erythematosus, cutaneous lupus, and lupus nephritis), rheumatoid arthritis, juvenile idiopathic arthritis, Still's disease, spondyloarthritis, scleroderma, and acute cytokine release syndromes associated with viral infection, such as COVID.

[0324] This disclosure also provides a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (I-1) or a salt thereof with the compound of formula (I-2) or a salt thereof.

[0325]

[0326] Z' is selected from , , , , and ;

[0327] P is an aldehyde group or -OMs;

[0328] A 1 A 6 A 7 A 8 A 9 Ring B, R 2 L 1 L 2 Z, ring A, B 1 B 2 R 2a R 2b , q, r, n are as described above.

[0329] This disclosure also provides a method for preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (II-1) or a salt thereof with the compound of formula (II-2) or a salt thereof.

[0330]

[0331] Z' is selected from , , , , and ;

[0332] P is an aldehyde group or -OMs;

[0333] A 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 L 1 L 2 Z, ring A, B 1 B 2 R 2a R 2b As mentioned above, q and r are used in this context.

[0334] This disclosure also provides a method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (III-1) or a salt thereof with the compound of formula (III-2) or a salt thereof.

[0335]

[0336] Z' is selected from , , , , and ;

[0337] P is an aldehyde group or -OMs;

[0338] A 1 A 3 A 4 A 5 A 6 A 7 A 8 A 9 L 1 L 2 Z, ring A, B 1 B 2 R 2a R 2b As mentioned above, q and r are used in this context.

[0339] This disclosure also provides a method for preparing the compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (IV-1) or a salt thereof with the compound of formula (IV-2) or a salt thereof.

[0340]

[0341] Z' is selected from , , , , and ;

[0342] P is an aldehyde group or -OMs;

[0343] A 1 A 3 A 4 A 5 A 6 A 7 A 8 A 9 L 1 L 2 Z, ring A, B 1 B 2 R 2a R 2b As mentioned above, q and r are used in this context.

[0344] This disclosure also provides a compound of formula (I-A1) or a salt thereof.

[0345]

[0346] in,

[0347] P is an aldehyde group or -OMs;

[0348] L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group.

[0349] Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -;

[0350] R 4 Selected from hydrogen, C 1-6 Alkyl, C1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced;

[0351] Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl-substituted.

[0352] In some implementations, L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one, two, or three of the selected alkylene, alkenyl, or alkynyl groups can each be independently converted by Y. 1 Replaced by the group; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -. In some implementations, L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-6 Alkylene, C 2-6 imide or C 2-6 The alkynyl group, wherein one of the -CH2- groups of the alkylene, alkenylene, or alkynyl group can be independently converted by Y. 1 Replaced by the group; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -. In some implementations, L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced1-6 Alkylene, wherein one of the -CH2- groups of the alkylene group can be independently converted by Y. 1 Replaced by the group; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -and-CONR 4 -

[0353] In some implementations, L 2 -(CR) a3 R b3 ) x -Y 1 -, R a3 R b3 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced by, Y 1 Selected from -O-, -S-, -COO-, -CO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 - where x is an integer between 0 and 6.

[0354] In some implementations, L 2 It can be -O-, -S-, -CO-, -COO-, -NH-, -N(CH3)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH-, or -CH2CH2CH2N(CH3)-. In some embodiments, L 2 It can be -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH-, or -CH2CH2CH2N(CH3)-.

[0355] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0356] The compound salts described in this disclosure may be selected from inorganic or organic salts.

[0357] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0358] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0359] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations."

[0360] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. An example of a lactam-lactamimide equilibrium is between A and B as shown below:

[0361] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0362] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 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.

[0363] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0364] "Optionally" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0365] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0366] "Pharmaceutical excipients" include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0367] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions 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 to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0368] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 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 their various branched isomers. The alkyl group may be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, and C6 groups. 1-6 Alkyl or C 1-6 Alkyl group.

[0369] "Alkenyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C6, C2-C4, and C3 alkenyl groups. These include, but are not limited to, vinyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotonyl), etc. Alkenyl groups used in any context herein may optionally be substituted in the same manner as alkyl groups.

[0370] "Alynyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C2-C6, C2-C4, and C3 alkynyl groups. These include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, pentynyl-4-alkynyl, and pentynyl-1,4-diynyl. In any context herein, alkynyl groups may optionally be substituted in the same manner as alkyl groups.

[0371] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms, or 3 to 6 carbon atoms, such as 4 or 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl group.

[0372] The term "cycloalkoxy" refers to -O-cycloalkyl, wherein the cycloalkyl group is as defined above. Non-limiting examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0373] The term "heterocycloalkyl" or "alicyclic heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 14 ring atoms, such as 4 or 5 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m Heteroatoms (where m is an integer from 0 to 2), excluding the ring moiety of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Non-limiting examples of "heterocyclic alkyl" include: , or ,etc.

[0374] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl group.

[0375] In some embodiments, the heterocyclic alkyl group may be fused to an aryl or heteroaryl ring, wherein the ring connected to the parent structure is a heterocyclic alkyl group.

[0376] In some embodiments, the heterocyclic alkyl group exists in a polycyclic cyclic form, including "spirocyclic", "fused-ring", or "bridged ring".

[0377] The term "spirocyclic" refers to a compound in which two rings share a single atom. "Spirocyclic alkyl" refers to a polycyclic carbocyclic group consisting of 5 to 20 quintillary rings sharing a single atom (called a spiro atom), preferably 6 to 14 quintillary, and more preferably 7 to 10 quintillary. Non-limiting examples of spirocyclic alkyl groups include:

[0378] , , , and .

[0379] The term "spiroheteroalkyl" refers to a polycyclic heteroalkyl group consisting of 5 to 20 membered monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quinary, more preferably 7 to 10 quinary. Spiroheteroalkyl groups are classified as monospiroheteroalkyl, bispiroheteroalkyl, or polyspiroheteroalkyl groups based on the number of shared spiro atoms between rings, preferably monospiroheteroalkyl and bispiroheteroalkyl. More preferably, they are 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, or 6 / 6 monospiroheteroalkyl groups. "Spirohetero" refers to the ring system in a spiroheteroalkyl group. Non-limiting examples of spiroheteroalkyl groups include:

[0380] .

[0381] The term "cyclic" refers to a compound in which two or more rings are fused together by sharing two adjacent atoms. Non-limiting examples of cyclic alkyl groups include:

[0382] , , , , and .

[0383] The term "bridged ring" refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms. Depending on the number of rings, bridged alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged alkyl groups include:

[0384] , , , and .

[0385] In polycyclic ring systems such as "spirocyclic," "fused ring," and "bridged ring," if there are substituents with no specific substitution position, unless otherwise stated, the substituents can exist in any monocyclic ring system. For example, In, substituent R 3 Since it is a substituent without positional limitation, therefore R 3 It can exist on the piperidine ring above, or on the ring C below.

[0386] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy. The alkoxy group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, and C- groups.1-6 Alkyl or C 1-6 Alkyl group.

[0387] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0388] , , , , , , , , , , , and .

[0389] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl group.

[0390] The term "heteroaryl" or "heteroary ring" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, such as 7-, 8-, or 9-membered, and more preferably 5- or 6-membered. For example, non-limiting examples include: , , or .

[0391] The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl group, and non-limiting examples include:

[0392] , , , , , , and .

[0393] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C1-6 Alkyl group.

[0394] The term "heterocyclic" refers to a ring composed of atoms other than carbon atoms, including heterocyclic alkyl and heteroaryl groups. "Heterocyclic alkyl" and "heteroaryl" are as defined above.

[0395] A "monovalent group" refers to a compound in which one monovalent atom or group is "formally" removed. A "divalent group" refers to a compound in which two monovalent or one divalent atom or group is "formally" removed. For example, "methylene" represents the part remaining after removing two hydrogen atoms from an alkane molecule.

[0396] In some implementations, the heterocyclic alkyl and heteroaryl groups can be monovalent, divalent, or polyvalent, and those skilled in the art will recognize from the context the number of available valences.

[0397] The term "amino" refers to -N(R) a )2, where R a Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups, wherein the alkyl, cycloalkyl, or heterocyclic alkyl group is optionally selected from one or more elements selected from halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, the "amino" can be an unsubstituted amino group (i.e., -NH2) or a substituted amino group (-N(R)). a )2, R a (Not all of it is hydrogen).

[0398] The term "hydroxyl group" refers to the -OH group.

[0399] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0400] The term "cyano" refers to -CN.

[0401] The term "nitro" refers to -NO2.

[0402] The term "oxo" refers to =O.

[0403] The term "imino" refers to =NH.

[0404] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0405] The "substituents" disclosed herein include, but are not limited to, halogens (such as chlorine and fluorine), hydroxyl groups, cyano groups, nitro groups, amino groups, and C groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy and 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic alkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy and 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic alkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -OC 2-6 Alkenyl groups may be optionally replaced by one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, or C groups. 1-6 Alkyl or C 1-6 Alkyl-substituted. Detailed Implementation

[0406] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0407] Example

[0408] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0409] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0410] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0411] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0412] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0413] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0414] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0415] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0416] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0417] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0418] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0419] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0420] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0421] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0422] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0423] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0424] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0425] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0426] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0427] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0428] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0429] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate system, C: n-hexane / ethyl acetate system, D: acetone, E: dichloromethane / acetone system, F: ethyl acetate / dichloromethane system, G: ethyl acetate / dichloromethane / n-hexane, H: ethyl acetate / dichloromethane / acetone. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0430] Example 1

[0431] 8-chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-2-methylphthalazin-1(2H)-one

[0432] 8-Chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hepta-6-yl)methyl)-2-methylphthalazine-1(2H)-one

[0433]

[0434]

[0435] first step

[0436] (E)-5-(3,3-diethoxyprop-1-en-1-yl)-6-fluoro-1,3-dihydroisobenzofuran

[0437] (E)-5-(3,3-diethoxypropyl-1-en-1-yl)-6-fluoro-1,3-dihydroisobenzofuran 1c

[0438] 5-Bromo-6-fluoro-1,3-dihydroisobenzofuran 1a (132 mg, 608 μmol, prepared by the method disclosed in the literature "Journal of Medicinal Chemistry, 2020, vol. 63, # 2, p. 638 - 655"), (E)-2-(3,3-diethoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane 1b (156 mg, 608 μmol, Shanghai Bide) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (85 mg, 116 μmol) and cesium carbonate (594 mg, 1.82 mmol) were added, nitrogen was purged, and the reaction was carried out at 100°C for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (140 mg, yield: 86.4%).

[0439] Step 2

[0440] 5-(3,3-diethoxypropyl)-6-fluoro-1,3-dihydroisobenzofuran

[0441] 5-(3,3-diethoxypropyl)-6-fluoro-1,3-dihydroisobenzofuran 1d

[0442] Compound 1c (140 mg, 526 μmol) was dissolved in ethyl acetate (5 mL), and palladium carbon hydrogenation catalyst (10%) (22 mg) was added. The mixture was purged with hydrogen and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1d (100 mg), which was used directly in the next reaction without purification.

[0443] Step 3

[0444] 3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propanal

[0445] 3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propionaldehyde 1e

[0446] The crude compound 1d (50 mg, 186 μmol) was dissolved in acetone (2 mL) and water (5 mL), and concentrated hydrochloric acid (0.6 mL) was added. The mixture was then purged with hydrogen and stirred at 30°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 1e (36 mg), which was used directly in the next step of the reaction without purification.

[0447] Step 4

[0448] 8-chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-2-methylphthalazin-1(2H)-one

[0449] 8-Chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hepta-6-yl)methyl)-2-methylphthalazine-1(2H)-one

[0450] 5-((2-azaspiro[3.3]hept-6-yl)methyl)-8-chloro-2-methylphthalazine-1(2H)-one 4-methylbenzenesulfonate 1f (55 mg, 115 μmol, prepared by the method disclosed in Example 90 on page 183 of patent application "WO2024182693") and crude compound 1e (25 mg, 165 μmol) were dissolved in tetrahydrofuran (5 mL), ethanol (1 mL) and dichloromethane (1 mL), acetic acid (23 mg, 386 μmol) and sodium acetate (21 mg, 257 μmol) were added. After stirring for 0.5 hours, sodium triacetoxyborohydride (109 mg, 515 μmol) was added and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150). mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to obtain title compound 1 (5 mg, yield: 8%).

[0451] MS m / z (ESI): 482.5 [M+1].

[0452] 1H NMR (500 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.75 (d, 1H), 7.62 (d, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 5.03 – 4.88 (m, 4H), 3.67 (s, 3H), 3.08 – 2.98(m, 6H), 2.55 (t, 2H), 2.39 (dd, 1H), 2.28 (t, 2H), 2.13 – 2.03 (m, 2H), 1.86– 1.79 (m, 2H), 1.48 (p, 2H).

[0453] Example 2

[0454] 8-chloro-5-((2-(2-((6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)ethyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-2-methylphthalazin-1(2H)-one

[0455] 8-Chloro-5-((2-(2-((6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)ethyl)-2-azaspiro[3.3]hepta-6-yl)methyl)-2-methylphthalazine-1(2H)-one 2

[0456]

[0457] MS m / z (ESI): 483.4 [M+1].

[0458] Example 3

[0459] 8-chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-2-methylphthalazin-1(2H)-one

[0460] 8-Chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hept-6-yl)oxy)-2-methylphthalazine-1(2H)-one 3

[0461]

[0462] MS m / z (ESI): 484.4 [M+1].

[0463] Example 4

[0464] 8-chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)(methyl)amino)-2-methylphthalazin-1(2H)-one

[0465] 8-Chloro-5-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hepta-6-yl)(methyl)amino)-2-methylphthalazine-1(2H)-one 4

[0466]

[0467] MS m / z (ESI): 497.4 [M+1].

[0468] Example 5

[0469] 8-chloro-5-((2-(2-((6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)ethyl)-2-azaspiro[3.3]heptan-6-yl)(methyl)amino)-2-methylphthalazin-1(2H)-one

[0470] 8-Chloro-5-((2-(2-((6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)ethyl)-2-azaspiro[3.3]hepta-6-yl)(methyl)amino)-2-methylphthalazine-1(2H)-one 5

[0471]

[0472] MS m / z (ESI): 498.4 [M+1].

[0473] Example 6

[0474] 6-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-1,7-dimethyl-1H-indazole

[0475] 6-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hept-6-yl)methyl)-1,7-dimethyl-1H-indazole 6

[0476]

[0477]

[0478] first step

[0479] tert-butyl 6-((1,7-dimethyl-1H-indazol-6-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylate

[0480] 6-((1,7-dimethyl-1H-indazol-6-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6c

[0481] 6-Bromo-1,7-dimethyl-1H-indazole 6a (93 mg, 413 μmol, prepared by the method disclosed in M18 on page 111 of patent application "WO2024182693"), 6-((4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)methylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6b (166 mg, 496 μmol, Shanghai Bide) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (30 mg, 41 μmol) and potassium phosphate (263 mg, 1.2 mmol) were added, nitrogen was purged, and the reaction was carried out at 80°C for 3 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6c (140 mg, yield: 95.9%).

[0482] MS m / z (ESI): 354.2 [M+1].

[0483] Step 2

[0484] tert-butyl 6-((1,7-dimethyl-1H-indazol-6-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0485] 6-((1,7-dimethyl-1H-indazol-6-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6d

[0486] Compound 6c (140 mg, 396 μmol) was dissolved in ethyl acetate (5 mL), palladium on carbon (10%) (84 mg, 79 μmol) was added, hydrogen was purged, and the mixture was stirred for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 6d (138 mg), which was used directly in the next step of the reaction without purification.

[0487] MS m / z (ESI): 356.3 [M+1].

[0488] Step 3

[0489] 6-((2-azaspiro[3.3]heptan-6-yl)methyl)-1,7-dimethyl-1H-indazole 2,2,2-trifluoroacetate

[0490] 6-((2-azaspiro[3.3]hept-6-yl)methyl)-1,7-dimethyl-1H-indazole 2,2,2-trifluoroacetate 6e

[0491] The crude compound 6d (138 mg, 388 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the title compound 6e (140 mg). The product was used directly in the next reaction without purification.

[0492] MS m / z (ESI): 256.2 [M+1].

[0493] Step 4

[0494] 6-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-1,7-dimethyl-1H-indazole

[0495] 6-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hept-6-yl)methyl)-1,7-dimethyl-1H-indazole 6

[0496] Crude compound 6e (30 mg, 81 μmol) and crude compound 1e (16 mg, 81 μmol) were dissolved in ethanol (1 mL) and dichloromethane (1 mL). Acetic acid (15 mg, 244 μmol) and sodium acetate (14 mg, 162 μmol) were added, and the mixture was stirred for 0.5 hours. Then, sodium triacetoxyborohydride (69 mg, 325 μmol) was added and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Boston phlex prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 6 (10 mg, yield: 29.3%).

[0497] MS m / z (ESI): 434.5 [M+1].

[0498] 1 H NMR (500 MHz, CDCl3): δ 7.86 (s, 1H), 7.44 (d, 1H), 7.03 (d, 1H), 6.88 (dd, 2H), 5.13 – 5.01 (m, 4H), 4.35 (s, 3H), 3.25 (d, 3H), 2.83 (d, 2H), 2.69 (s, 3H), 2.65 (t, 2H), 2.45 (dt, 3H), 2.24 (ddd, 2H), 1.94 – 1.88 (m, 2H), 1.67 (p, 3H).

[0499] Example 7

[0500] 8-chloro-5-((1-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)piperidin-4-yl)methyl)-2-methylphthalazin-1(2H)-one

[0501] 8-Chloro-5-((1-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)piperidin-4-yl)methyl)-2-methylphthalazine-1(2H)-one 7

[0502]

[0503]

[0504] first step

[0505] tert-butyl 4-((8-chloro-2-methyl-1-oxo-1,2-dihydrophthalazin-5-yl)methylene)piperidine-1-carboxylate

[0506] 4-((8-chloro-2-methyl-1-oxo-1,2-dihydrophthalazine-5-yl)methylene)piperidine-1-carboxylic acid tert-butyl ester 7c

[0507] 8-Chloro-5-iodo-2-methylphthalazine-1(2H)-one 7a (600 mg, 1.9 mmol, prepared by the method disclosed in M14 on page 107 of patent application "WO2024182693"), 4-((4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)methylene)piperidine-1-carboxylic acid tert-butyl ester 7b (786 mg, 2.4 mmol, Shanghai Titan) were dissolved in 1,4-dioxane (15 mL) and water (3 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (68 mg, 93 μmol) and potassium phosphate (1.2 g, 5.6 mmol) were added, nitrogen was purged, and the reaction was carried out at 80°C for 3 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 7c (240 mg, yield: 32.9%).

[0508] MS m / z (ESI): 390.3 [M+1].

[0509] Step 2

[0510] tert-butyl 4-((8-chloro-2-methyl-1-oxo-1,2-dihydrophthalazin-5-yl)methyl)piperidine-1-carboxylate

[0511] 4-((8-chloro-2-methyl-1-oxo-1,2-dihydrophthalazine-5-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester 7d

[0512] Compound 7c (240 mg, 616 μmol) was dissolved in ethyl acetate (5 mL), and rhodium / alumina (5%) (126 mg, 61 μmol) was added. The mixture was purged with hydrogen and stirred for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 7d (241 mg), which was used directly in the next step of the reaction without purification.

[0513] MS m / z (ESI): 392.3 [M+1].

[0514] Step 3

[0515] 8-chloro-2-methyl-5-(piperidin-4-ylmethyl)phthalazin-1(2H)-one 2,2,2-trifluoroacetate

[0516] 8-Chloro-2-methyl-5-(piperidin-4-ylmethyl)phthalazine-1(2H)-one 2,2,2-trifluoroacetate 7e

[0517] The crude compound 7d (80 mg, 204 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the title compound 7e (59 mg). The product was used directly in the next reaction without purification.

[0518] MS m / z (ESI): 292.2 [M+1].

[0519] Step 4

[0520] 8-chloro-5-((1-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)piperidin-4-yl)methyl)-2-methylphthalazin-1(2H)-one

[0521] 8-Chloro-5-((1-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)piperidin-4-yl)methyl)-2-methylphthalazine-1(2H)-one 7

[0522] Crude compound 7e (60 mg, 206 μmol) and crude compound 1e (40 mg, 206 μmol) were dissolved in ethanol (2 mL) and dichloromethane (2 mL). Acetic acid (37 mg, 616 μmol) and sodium acetate (33 mg, 402 μmol) were added, and the mixture was stirred for 0.5 hours. Then, sodium triacetoxyborohydride (131 mg, 618 μmol) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Boston phlex prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 7 (8 mg, yield: 7.9%).

[0523] MS m / z (ESI): 470.5 [M+1].

[0524] 1 H NMR (500 MHz, DMSO-d6): δ 8.52 (s, 1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.20 (d, 1H), 7.10 (d, 1H), 4.94 (d, 4H), 3.68 (s, 3H), 3.31 (s, 4H), 2.92(d, 2H), 2.68 – 2.62 (m, 1H), 2.59 (t, 2H), 2.39 – 2.35 (m, 1H), 1.68 (s,3H), 1.57 – 1.41 (m, 4H).

[0525] Example 8

[0526] 6-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hept-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-b]pyridine

[0527] 6-((2-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)-2-azaspiro[3.3]hept-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-b]pyridine 8

[0528]

[0529] MS m / z (ESI): 435.4 [M+1].

[0530] Example 9

[0531] 6-((1-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)piperidin-4-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-b]pyridine

[0532] 6-((1-(3-(6-fluoro-1,3-dihydroisobenzofuran-5-yl)propyl)piperidin-4-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-b]pyridine 9

[0533]

[0534] MS m / z (ESI): 423.2 [M+1].

[0535] Example 10

[0536] 8-chloro-5-((2-(3-(6'-fluoro-3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-2-methylphthalazin-1(2H)-one

[0537] 8-Chloro-5-((2-(3-(6'-fluoro-3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)propyl)-2-azaspiro[3.3]hept-6-yl)methyl)-2-methylphthalazine-1(2H)-one 10

[0538]

[0539]

[0540] first step

[0541] 5-bromo-6-fluoroisobenzofuran-1(3H)-one

[0542] 5-Bromo-6-fluoroisobenzofuran-1(3H)-one 10b

[0543] 10a (10 g, 42.9 mmol) of 4-bromo-5-fluoro-2-methylbenzoic acid was dissolved in acetonitrile (200 mL), and sodium persulfate (31 g, 130.2 mmol) and tetrabutylammonium bromide (41.5 g, 128.7 mmol) were added. The reaction was carried out at 80°C for 3 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 10b (9 g, yield: 90.1%).

[0544] Step 2

[0545] 1-(4-bromo-5-fluoro-2-(hydroxymethyl)phenyl)cyclopropan-1-ol

[0546] 1-(4-bromo-5-fluoro-2-(hydroxymethyl)phenyl)cycloprop-1-ol 10c

[0547] Compound 10b (1 g, 4.3 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen protection. Tetraisopropyl titanate (1.36 g, 4.8 mmol) was added at 0°C. After reacting at 0°C for 0.5 hours, ethyl magnesium bromide solution (10.4 mmol, 5.2 mL, 2 M in THF) was added dropwise. The reaction was continued at 0°C for 1 hour, and then quenched with water. The solid was filtered, and the filtrate was extracted with ethyl acetate (40 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 10c (900 mg, yield: 79.6%).

[0548] Step 3

[0549] 5'-bromo-6'-fluoro-3'H-spiro[cyclopropane-1,1'-isobenzofuran]

[0550] 5'-Bromo-6'-Fluoro-3'H-spiro[cyclopropane-1,1'-isobenzofuran] 10d

[0551] Triphenylphosphine (2.4 g, 9.2 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection. Diisopropyl azodicarbonate (1.86 g, 9.2 mmol, Shanghai Shaoyuan) was added at 0°C. After reacting at 0°C for 1 hour, a tetrahydrofuran solution of compound 10c (800 mg, 3.1 mmol) (20 mL) was added dropwise, and the reaction was continued at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 10d (426 mg, yield: 57.2%).

[0552] Step 4

[0553] 8-chloro-5-((2-(3-(6'-fluoro-3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)propyl)-2-azaspiro[3.3]heptan-6-yl)methyl)-2-methylphthalazin-1(2H)-one

[0554] 8-Chloro-5-((2-(3-(6'-fluoro-3'H-spiro[cyclopropane-1,1'-isobenzofuran]-5'-yl)propyl)-2-azaspiro[3.3]hept-6-yl)methyl)-2-methylphthalazine-1(2H)-one 10

[0555] Using the synthetic route in Example 1, the starting material compound 1a in the first step was replaced with compound 10d to obtain title compound 10 (39 mg, yield: 34.2%).

[0556] MS m / z (ESI): 508.5 [M+1].

[0557] 1H NMR (500 MHz, DMSO-d6): δ 8.47 (s, 1H), 7.76 (d, 1H), 7.62 (d, 1H), 7.14 (d, 1H), 6.76 (d, 1H), 5.02 (s, 2H), 3.67 (s, 3H), 3.11 – 3.01 (m, 4H),2.99 (s, 2H), 2.59 – 2.54 (m, 2H), 2.42 – 2.35 (m, 1H), 2.28 (t, 2H), 2.13 –2.05 (m, 2H), 1.85 – 1.79 (m, 2H), 1.48 (p, 2H), 1.19 – 1.14 (m, 2H), 0.97 –0.92 (m, 2H).

[0558] Biological evaluation

[0559] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0560] Test Example 1: Inhibitory activity test of the disclosed compound against the DNA binding function of STAT3 protein.

[0561] I. Experimental Objective

[0562] The purpose of this experiment was to test the inhibitory effect of the compound on the DNA binding function of STAT3 protein, based on IC50. 50 Evaluate the in vitro activity of the compound.

[0563] II. Experimental Principle

[0564] In HTRF interaction detection, a terbium (Tb)-labeled His-tagged monoclonal antibody recognizes the His-tagged STAT3 protein, while d2-Streptavidin recognizes a biotin-tagged DNA fragment that specifically binds to the STAT3 protein. The detection signal intensity is proportional to the STAT3:DNA binding, and the inhibition rate of the compound can be calculated from the fluorescence values ​​read.

[0565] III. Experimental Materials and Instruments

[0566] 1. STAT3 (ACROBiosystems, ST3-H5149-100ug)

[0567] 2. DNA (Platinum, Customized)

[0568] 5'-TGCATTTCCCGTAAATCTT / 3BiodT / -3' duplexed with 5'-AAGATTTACGGGAAATGC-3'

[0569] 3. DPBS (Gibco, 14190144)

[0570] 4. BSA (Biotechnology, A500023-0100)

[0571] 5. Tween-20 (Biotechnology, A100777-0500)

[0572] 6. DTT, 1M (Invitrogen, P2325)

[0573] 7. HTRF PPI Terbium detection buffer (Revvity, 61DB10RDF)

[0574] 8. HTRF MAb Anti-6HIS Tb cryptate Gold (Revvity, 61HI2TLA)

[0575] 9. HTRF Streptavidin-d2 (Revvity, 610SADLA)

[0576] 10. ProxiPlate shallow-hole non-bottom-through microporous plate (Revvity, 6008280)

[0577] 11. Dispenser (Agilent, Bravo)

[0578] 12. Microplate reader (BMG Labtech, PHERA Star)

[0579] IV. Experimental Methods

[0580] Ten concentrations of the compound were diluted 3-fold with DMSO (final concentration range: 0.5-10,000 nM), and 2.5 μL was added to each well of a 384-well plate. STAT3 protein was diluted in DPBS reaction buffer containing 0.1% BSA, 0.05% Tween-20, and 1 mM DTT to prepare a 60 nM (4×) solution, and 2.5 μL was transferred to each well of a microplate and incubated at room temperature for 60 minutes. Positive and negative controls were provided for wells with and without the enzyme, respectively. DNA was diluted in reaction buffer to prepare a 60 nM (2×) working solution, and 5 μL was transferred to each well to initiate the reaction. Immediately afterward, 10 μL of the detection antibody pair prepared in HTRF PPI buffer was added, and the plate was incubated at room temperature for 20 minutes. HTRF signals were read using a Pherastar microplate reader.

[0581] V. Data Analysis

[0582] The IC50 of the compound's inhibitory activity was calculated using Xlfit software. 50 Value. The activity IC50 of the compound disclosed herein was measured. 50 The values ​​are shown in the table below:

[0583] Table 1. Inhibitory activity of the compounds disclosed in this study against the DNA binding function of STAT3 protein.

[0584] Example number <![CDATA[STAT3 DNA Interaction IC 50 (nM)]]> 1 5.6 6 17.45 7 66.9

[0585] Conclusion: The compound disclosed herein exhibits significant inhibitory activity against STAT3 protein.

Claims

1. The compound shown in formula (I) or a pharmaceutically acceptable salt thereof, ， in, A 1 It can be C or N; A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N, Ring B is a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl; R 1 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 2 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; L 1 L 2 Each can be independently replaced by one or more substituents Q. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group. Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -; R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; Z is selected from , , , , and ,in X 0 X 1 X 2 Each is independently selected from chemical bonds, -CR a R b -、-NR c - and -O-, and X 0 X 1 X 2 They are not both chemical bonds; The ring C is a 3- to 6-membered cycloalkyl group; R a R b Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 3 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; B 1 B 2 Each is independently N or CR a4 ; Ring A is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 12-membered spirocycloalkyl, or a 5- to 12-membered spiroheterocycloalkyl; R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 2b Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl substitution; n is an integer between 0 and 8. p is an integer between 0 and 8. q is an integer between 0 and 8. r is an integer between 0 and 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one, two, or three of the selected alkylene, alkenyl, or alkynyl groups can each be independently converted by Y. 1 The group replaced; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -; Preferred L 1 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, wherein one of the -CH2- groups of the alkylene group can be independently converted by Y. 1 The group replaced; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -; More preferably L 1 is -O-, -S-, -CO-, -COO-, -NH-, -N(CH3)- , -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-, -CH2S-, -CH2NH-, -CH2N(CH3)-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH- or -CH2CH2CH2N(CH3)- ; Optimal choice L 1 It can be -O-, -S-, -CO-, -COO-, -NH-, -N(CH3)- or -CH2-.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring B is a 5- or 6-membered cycloalkyl, a 5- or 6-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl is a heterocycloalkyl or heteroaryl containing 1 to 3 N atoms.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring B is... in, A 1 It can be C or N; A 2 For CR a2 R b2 Or it may not exist; A 3 For CR a2 CR a2 R b2 , N or NR c2 ; A 4 For non-existent, CR a2 CR a2 R b2 , N or NR c2 A 2 and A 4 They do not exist simultaneously; A 5 For CR a2 CR a2 R b2 , N or NR c2 ; It can be a single bond or a double bond; R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (II). in, A 1 It can be C or N; A 2 For CR a2 R b2 Or it may not exist; A 3 For CR a2 CR a2 R b2 , N or NR c2 ; A 4 For non-existent, CR a2 CR a2 R b2 , N or NR c2 A 2 and A 4 They do not exist simultaneously; A 5 For CR a2 CR a2 R b2 , N or NR c2 ; A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N, It can be a single bond or a double bond; R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O; Selected from , , and , in, B 1 B 2 Each is independently N or CR a4 ; B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B 4 B 5 They do not both exist simultaneously; B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms; R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O; R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R e4 Each is independently selected from oxo and imino groups; R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 1 R 2a R 2b L 1 L 2 Z, q, r, Q 1 As described in claim 1.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (III). in, A 1 It can be C or N; A 3 A 4 A 5 Each independently for CR a2 CR a2 R b2 , N or NR c2 ; A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N, It can be a single bond or a double bond; R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O; Selected from , , and , in, B 1 B 2 Each is independently N or CR a4 ; B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B 4 B 5 They do not both exist simultaneously; B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms; R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O; R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R e4 Each is independently selected from oxo and imino groups; R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 1 R 2a R 2b L 1 L 2 Z, q, r, Q 1 As described in claim 1.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (IV). in, A 1 It can be C or N; A 3 A 4 A 5 Each independently for CR a2 CR a2 R b2 , N or NR c2 ; A 6 A 7 A 8 A 9 Each independently for CR 1 Or N, and A 1 A 6 A 7 A 8 A 9 It contains at most 2 N, It can be a single bond or a double bond; R a2 R b2 R c2 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Formation = O; Selected from , , and , in, B 1 B 2 Each is independently N or CR a4 ; B 3 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 4 B 5 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it does not exist, and B 4 B 5 They do not both exist simultaneously; B 7 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; B 8 B 10 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 9 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; B 3 B 4 B 5 B 6 It contains at most 3 heteroatoms, B 7 B 8 B 9 B 10 B 11 It contains at most 3 heteroatoms; R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O; R d4 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R e4 Each is independently selected from oxo and imino groups; R a4 Each is independently selected from hydrogen atom, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R 1 R 2a R 2b L 1 L 2 Z, q, r, Q 1 As described in claim 1.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4-7, wherein R a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced, or R a2 R b2 Together form = O; Preferred R a2 R b2 R c2 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy and 3- to 10-membered cycloalkyl, or R a2 R b2 Together they form = O.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein X 1 Selected from chemical bonds, -CH2- and -O-, X 0 X 2 Each is independently selected from chemical bonds and -CH2-; the ring C is a 3- to 6-membered cycloalkyl group; R 3 Each is independently selected from halogens and C. 1-6 alkyl.

10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein Z is selected from... and , where R 3 p is as described in claim 1.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one, two, or three of the selected alkylene, alkenyl, or alkynyl groups can each be independently converted by Y. 1 The group replaced; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -; Preferred L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-6 Alkylene, C 2-6 imide or C 2-6 The alkynyl group, wherein one of the -CH2- groups of the alkylene, alkenylene, or alkynyl group can be independently converted by Y. 1 The group replaced; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -; More preferably L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-6 Alkylene, wherein one of the -CH2- groups of the alkylene group can be independently converted by Y. 1 The group replaced; Y 1 Selected from -O-, -S-, -CO-, -COO-, -NR 4 -and-CONR 4 - 12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein L 2 -(CR) a3 R b3 ) x -Y 1 -, R a3 R b3 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced Y 1 Selected from -O-, -S-, -COO-, -CO-, -NR 4 -, -SO2-, -SONR 4 -、-CONR 4 -、-SO2NR 4 -, x is an integer between 0 and 6.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R a3 R b3 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced by Y 1 Selected from -O-, -S-, -COO-, -CO-, -NR 4 -and-CONR 4 - where x is an integer between 0 and 6.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein R 4 Selected from hydrogen atom, hydroxyl group, amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl; Preferred R 4 Selected from hydrogen atom, amino group, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein L 2 is -O-, -S-, -CO-, -COO-, -NH-, -N(CH3)- , -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-, -CH2S-, -CH2NH-, -CH2N(CH3)-, -CH2CH2O-, -CH2CH2S-, - CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH- or -CH2CH2CH2N(CH3)-; Preferably, it is -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH-, or -CH2CH2CH2N(CH3)-.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein L 1 For -O-, -S-, -CO-, -COO-, -CH2-, -NH- or -N(CH3)-, L 2 It can be -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2S-, -CH2CH2NH-, -CH2CH2N(CH3)-, -CH2CH2CH2O-, -CH2CH2CH2S-, -CH2CH2CH2NH-, or -CH2CH2CH2N(CH3)-.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R a4 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; Preferred R a4 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, amino groups, C4 groups, and cycloalkyl groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; More preferably R a4 Each is independently selected from hydrogen atoms, halogens, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein R 2b Each is independently selected from halogens, hydroxyl groups, amino groups, and C. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; Preferred R 2b Each is independently selected from halogens, hydroxyl groups, amino groups, and C. 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, amino groups, C4 groups, and cycloalkyl groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; More preferably R 2b Each is independently selected from halogens, amino groups, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3 to 10-membered cycloalkyl groups.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, wherein Selected from , , and , in, B 1 B 2 Each is independently N or CR a4 ; B 3 B 4 B 6 Each independently for CR b4 R c4 NR d4 , O or S(R) e4 ) 0-2 ; B 7 B 9 B 11 Each independently for CR b4 R c4 NR d4 、O、S(R e4 ) 0-2 Or it may not exist; R b4 R c4 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, imino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy-substituted, or R b4 R c4 Formation = O; R d4 Each independently selected from R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; R e4 Each is independently selected from oxo and imino groups.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 5-19, wherein B 3 B 6 Each independently for CR b4 R c4 or NR d4 B 7 B 9 B 11 Each independently for CR b4 R c4 NR d4 0 or not present.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein... Selected from 。 22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-21, wherein A 1 The answer is C.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein R 1 Each is independently selected from hydrogen atoms, halogens, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl is optionally substituented by one or more substituents. 1 Replaced; Preferred R 1 Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 2 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, and 3- to 10-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkoxy, or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, C7 groups, C8 groups, C9 ... 1-6 Alkyl or C 1-6 Alkoxy groups are substituted. Preferred R 2 Each is independently selected from halogen, hydroxyl, amino, oxo, C 1-6 Alkyl groups and 3- to 10-membered cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally selected from one or more halogens, hydroxyl groups, amino groups, C4 groups, and cycloalkyl groups. 1-6 Alkyl or C 1-6 Alkoxy groups are substituted. More preferably R 2 Each is independently selected from halogens, amino groups, oxo groups, and C groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3 to 10-membered cycloalkyl groups.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, amino, C 1-6 Alkyl and C 1-6 Alkoxy substitution, Preferred Q 1 Each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl and 5- to 12-membered heteroaryl.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 27. The compound of any one of claims 1-26 or an isotope-substituted product of a pharmaceutically acceptable salt thereof, preferably a deuterated product.

28. A pharmaceutical composition comprising at least a therapeutically effective amount of the compound as claimed in any one of claims 1-26 or a pharmaceutically acceptable salt thereof or an isotopic substitute as claimed in claim 27, and a pharmaceutically acceptable excipient.

29. Use of the compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or the isotope substitute of claim 27, or the pharmaceutical composition of claim 28 in the preparation of a medicament for the prevention and / or treatment of cancer and / or immune diseases, preferably the cancer being selected from bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, lung cancer, cervical cancer, colorectal cancer, bile duct cancer, gastric cancer, kidney cancer, pancreatic cancer, acute myeloid leukemia, T-cell large granular lymphoblastic leukemia, non-Hodgkin lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma, classical Hodgkin lymphoma, and diffuse large B-cell lymphoma, preferably the immune disease being selected from psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus, rheumatoid arthritis, juvenile idiopathic arthritis, Still's disease, spondyloarthritis, scleroderma, and acute cytokine release syndrome with viral infection.

30. Use of the compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or the isotope substitute of claim 27, or the pharmaceutical composition of claim 28 in the preparation of a medicament for regulating STAT3, preferably in a medicament for inhibiting STAT3.

31. A method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the step of reacting the compound of formula (I-1) or a salt thereof with the compound of formula (I-2) or a salt thereof. in, Z' is selected from , , , , and ; P is an aldehyde group or -OMs; A 1 A 6 A 7 A 8 A 9 Ring B, R 2 L 1 L 2 Z, ring A, B 1 B 2 R 2a R 2b , q, r, n as described in claim 1.

32. A compound of formula (I-A1) or a salt thereof, in, P is an aldehyde group or -OMs; L 2 Q is optionally substituted by one or more substituents. 1 The C that was replaced 1-10 Alkylene, C 2-10 imide or C 2-10 The alkynyl group, wherein one or more of the -CH2- groups selected from the alkylene, alkenyl, and alkynyl groups can be independently replaced by a Y group. Y is independently selected from -O-, -S-, -CO-, and -NR. 4 -, -SO2- and -SONR 4 -; R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, or heterocyclic alkyl is optionally substituented by one or more substituents. 1 Replaced; Q 1 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally selected from one or more of halogen, oxo, thio, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkyl-substituted.

Images