Spiro heterocyclic compound, preparation method therefor, and intermediate and use thereof

Abstract

Disclosed in the present invention are a spiro heterocyclic compound, a preparation method therefor, and an intermediate and use thereof. Specifically provided is a spiro heterocyclic compound represented by formula (IG) or a pharmaceutically acceptable salt thereof; the spiro heterocyclic compound can be used in the preparation of a drug, particularly in the preparation of a drug for preventing and / or treating CCR4 factor-mediated diseases or illnesses. All groups in formula (IG) are as defined in the description.

Description

Spiroheterocyclic compound, preparation method, intermediate and use thereof

[0001] This application claims the benefit of priority to Chinese Patent Application No. 2023115139533, filed on November 14, 2023; Chinese Patent Application No. 2024100626574, filed on January 16, 2024; Chinese Patent Application No. 2024105029090, filed on April 25, 2024; and Chinese Patent Application No. 2024115262640, filed on October 29, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to the field of medicine, and specifically relates to spiroheterocyclic compounds, preparation methods, intermediates and uses thereof. Background Art

[0003] The successful operation of the host defense system is the result that several processes jointly eliminate foreign pathogens. The innate immune response and acquired immune response of coordination are needed, and many secretory factors and cell-related factors have been confirmed as important mediators for coordinating and regulating these two host defense weapons. Chemokine is a family of cytokines that guide leukocytes to move as chemical attractants. They are secreted by various cells and can be divided into two categories functionally: hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are produced in certain tissues as a composition and control the cells of the immune system during the immune surveillance process, such as lymphocytes are directed to lymph nodes so that they can screen for invasion of pathogens. Inflammatory chemokines are released by cell response pathological events (for example, proinflammatory stimulants, such as IL-1 or viruses). It mainly works as a chemical attractant of a part for inflammatory response and is used to guide the cells of the innate immune system and the adaptive immune system to the site of inflammation.

[0004] CC chemokine receptor type 4 (CCR4), primarily expressed on Th2 cells, plays a key role in the progression of many allergic and inflammatory conditions by regulating downstream cytokines such as IL4, IL5, and IL13. While CCR4 has garnered widespread interest as a promising drug development target, developing small molecule compounds that modulate CCR4 function remains an ongoing challenge. To date, no small molecule drug has reached the market, necessitating the active exploration of new, superior, and selective CCR4 small molecule antagonists.

[0005] The CCR4-related patents that have been applied for so far include WO2019090272A1 and WO2019147862A1.

[0006] Summary of the Invention

[0007] To overcome the drawback of the single structure of CCR4 inhibitors in the prior art, the present application provides a small molecule compound with a spiroheterocyclic structure that can be used as a CCR4 inhibitor. This compound has a potent antagonistic effect on the CCR4 receptor and has excellent pharmacokinetic effects, and can be used to effectively treat or prevent CCR4-mediated diseases.

[0008] The present application provides a compound represented by formula (IG) or a pharmaceutically acceptable salt thereof,

[0009] in:

[0010] T is

[0011] G 1 CR 8 or N;

[0012] G 2 CR 9 or N;

[0013] G 3 CR 10 or N;

[0014] Z is O, S, Se, -S(O)2- or NR a ;

[0015] X and Y are the same or different and are each independently O, S, Se, -S(O)2-, NR a or CR c R d ;

[0016] R 1 For LR 12 ;

[0017] L is a chemical bond, O, S, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R 13 )-、C 1-6 Alkylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Aryl and 5-10 membered heteroaryl are optionally selected from hydroxy, amino, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 One or more substitutions selected from cycloalkyl and 3-12 membered heterocyclic groups;

[0018] R 12 Selected from H, halogen, cyano, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0019] R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from halogen, hydroxy, C1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, amino and C 3-12 substituted by one or more substituents in the cycloalkyl group;

[0020] Or, when L is NR 13 When R 12 and R 13 Optionally, the nitrogen atom to which it is connected forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g replaced by;

[0021] R 2 and R 3 are the same or different and are each independently selected from H, halogen, cyano, C 2-6 Alkynyl, -N3, hydroxyl, amino, oxo, C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0022] R 4 H, D, halogen or C 1-6 alkyl;

[0023] R 5 and R 6 are the same or different and are independently selected from H, halogen, cyano, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0024] Each R 7 are the same or different and are each independently selected from halogen, hydroxyl, cyano, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0025] R 8 、R 9 and R 10 are the same or different and are each independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0026] R 11Selected from H, halogen, cyano, amino, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、 -SF5, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0027] R a Selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0028] R c and Rd The same or different, each independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0029] Or, R c and R d Together with the atoms it is connected to form C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-8 Cycloalkyl and 3-12 membered heterocyclyl are each optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12 membered heterocyclic groups;

[0030] Or, R 4 and R 11 Together with the atoms it is connected to form C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl, the C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl and 5-6 membered heteroaryl are optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12 membered heterocyclic groups;

[0031] Or, when G 3 CR 10 When R 10 and R 11 Together with the atoms it is connected to form C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl, the C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl is optionally selected from cyano, C 2-6 Alkynyl, halogen, sulfone, oxo, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12 membered heterocyclic groups;

[0032] Each R g The same or different, and each independently is halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, -NHC(O)R g1 、-NHS(O)2R g2 、-S(O)2R g2 、-C(O)NR g3 R g4 、-S(O)2NR g3 R g4 、-NR g3 R g4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl and C 3-12 substituted by one or more substituents in the cycloalkyl group;

[0033] R k1 、R k2 、R k3 、R k4 、R k5 、R g1 、R g2 、R g3 and R g4 The same or different, each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, carboxyl, -CONH2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl and C 3-12 substituted by one or more substituents in the cycloalkyl group;

[0034] t is 0, 1, or 2;

[0035] p is 0, 1, 2, or 3;

[0036] q is 0, 1, 2, or 3;

[0037] m is 0, 1, 2, 3, 4, 5 or 6;

[0038] n is 0, 1, or 2;

[0039] k is 1, 2, 3, 4, or 5;

[0040] x is 1 or 2;

[0041] y is 1 or 2;

[0042] Wherein, the heteroatoms in the heterocyclylene group, heterocyclyl group and heteroaryl group are selected from O, N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0043] In some embodiments, T is X and Y are the same or different and are each independently O, S, Se, -S(O)2-, NR a or CR c R d .

[0044] In some embodiments, T is Z is O, S, Se, -S(O)2- or NR a .

[0045] In some embodiments, T is Z is O, S, Se, -S(O)2- or NR a ; R 11 Selected from -SF5 or

[0046] In some embodiments, T is Z is O, S, Se or NR a ; R 11 Selected from H, halogen, cyano, amino, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、 C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace.

[0047] In some embodiments, the compound represented by formula (IG) is a compound represented by formula (I),

[0048] in:

[0049] G 1 CR 8 or N;

[0050] G 2 CR 9 or N;

[0051] G 3 CR 10 or N;

[0052] Z is O, S, Se or NR a R b ;

[0053] R 1 For LR 12 ;

[0054] L is a chemical bond, O, S, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R 13 )-、C 1-6 Alkylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Aryl and 5-10 membered heteroaryl are optionally selected from hydroxy, amino, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 One or more substitutions selected from cycloalkyl and 3-12 membered heterocyclic groups;

[0055] R 12 Selected from H, halogen, cyano, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2Rk1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0056] R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, amino and C 3-12 substituted by one or more substituents in the cycloalkyl group;

[0057] Or, when L is NR 13 When R 12 and R 13 Optionally, the nitrogen atom to which it is connected forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g replaced by;

[0058] R 2 and R 3 are the same or different and are each independently selected from H, halogen, cyano, C 2-6 Alkynyl, -N3, hydroxyl, amino, oxo, C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0059] R 4 H, D, halogen or C 1-6 alkyl;

[0060] R 5 and R 6 are the same or different and are independently selected from H, halogen, cyano, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0061] Each R 7 are the same or different and are each independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 、C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0062] R 8 、R 9 and R 10 are the same or different and are each independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0063] R 11 Selected from H, halogen, cyano, amino, -N3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 ORk4 、 C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R g replace;

[0064] R a and R b are the same or different and are independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0065] Or, R a and R b Together with the nitrogen atom to which it is connected, it forms a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12 membered heterocyclic groups;

[0066] Or, R 4 and R 11 Together with the atoms it is connected to form C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl, the C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl and 5-6 membered heteroaryl are optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12 membered heterocyclic groups;

[0067] Or, when G 3 CR 10When R 10 and R 11 Together with the atoms it is connected to form C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl, the C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl is optionally selected from cyano, C 2-6 Alkynyl, halogen, sulfone, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12 membered heterocyclic groups;

[0068] Each R g The same or different, and each independently is halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, -NHC(O)R g1 、-NHS(O)2R g2 、-S(O)2R g2 、-C(O)NR g3 R g4 、-S(O)2NR g3 R g4 、-NR g3 R g4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl and C 3-12 substituted by one or more substituents in the cycloalkyl group;

[0069] R k1 、R k2 、R k3 、R k4 、R k5 、R g1 、R g2 、Rg3 and R g4 The same or different, each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, carboxyl, -CONH2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl and C 3-12 substituted by one or more substituents in the cycloalkyl group;

[0070] t is 0, 1, or 2;

[0071] m is 0, 1, 2, 3, 4, 5 or 6;

[0072] n is 0, 1, or 2;

[0073] k is 1, 2, 3, 4, or 5;

[0074] x is 1 or 2;

[0075] y is 1 or 2;

[0076] Wherein, the heteroatoms in the heterocyclylene group, heterocyclyl group and heteroaryl group are selected from O, N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0077] In some embodiments, the compound represented by formula (IG) or formula (I), or a pharmaceutically acceptable salt thereof, wherein G 1 is N.

[0078] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein G 1 is N.

[0079] In some embodiments, the compound represented by Formula (IG) or Formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is O.

[0080] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is O.

[0081] In some embodiments, the compound represented by Formula (IG) or Formula (I), or a pharmaceutically acceptable salt thereof, wherein k is 2.

[0082] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein k is 2.

[0083] In some embodiments, the compound represented by formula (IG) or formula (I), or a pharmaceutically acceptable salt thereof, wherein for

[0084] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein for

[0085] In some embodiments, in L, the 3-12 membered heterocyclylene group may be a 3-8 membered heterocyclylene group, preferably a 4-6 membered heterocyclylene group.

[0086] In some embodiments, in L, the 3-12 membered heterocyclylene group may be a "3-12 membered heterocyclylene group wherein the heteroatom is O and / or N, and the number of heteroatoms is 1 or 2"; preferably, a "3-12 membered heterocyclylene group wherein the heteroatom is O or N, and the number of heteroatoms is 1".

[0087] In some embodiments, in L, the 3-12 membered heterocyclyl group may be a "3-8 membered heterocyclyl group wherein the heteroatom is O or N"; preferably a 4-6 membered heterocyclyl group containing an aza or oxa group; more preferably a 4-6 membered azaheterocyclyl group, for example, an azetidinyl group. Azacyclopentyl or azacyclohexyl

[0088] In some embodiments, R 12 、R 13 、R g 、R k2 、R k3 and R k4 In the C 1-6 The alkyl group can be C 1-4 The alkyl group is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group or an isobutyl group.

[0089] In some embodiments, R 5 、R 12 、R 13 、R g 、R k2 、R k3 and R k4 In the C 3-12 Cycloalkyl can be C 3-8 Cycloalkyl, more preferably C 3-6 The cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0090] In some embodiments, R 10 and R 11 Together with the atoms it is connected to form C 4-8 In the cycloalkyl group, the C 4-8 Cycloalkyl can be C 4-6 The cycloalkyl group is preferably a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0091] In some embodiments, R 12 、R 13 、R k2 、R k3 and R k4 In the above, the 3-12 membered heterocyclic group may be a "3-12 membered heterocyclic group wherein the heteroatom is O and / or N, and the number of heteroatoms is 1 or 2"; preferably, a "3-12 membered heterocyclic group wherein the heteroatom is O or N".

[0092] In some embodiments, R 12 、R 13 、R k2 、R k3 and R k4 In the embodiment, the 3-12 membered heterocyclic group may be a 3-8 membered heterocyclic group, and is preferably a 4-6 membered heterocyclic group.

[0093] In some embodiments, R 12 、R 13 、R k2 、R k3 and R k4 In the embodiment, the 3-12 membered heterocyclic group may be a "3-8 membered heterocyclic group wherein the heteroatom is O or N"; preferably a 4-6 membered heterocyclic group containing an aza or oxa group; more preferably an azetidinyl group (e.g., ), azacyclopentyl (e.g., ) or azacyclohexyl

[0094] In some embodiments, R 12 and R 13 The 4-8 membered heterocyclic group formed together with the nitrogen atom to which it is connected may be a 4-8 membered heterocyclic group wherein the heteroatom is O or N; preferably a 4-6 membered azoheterocyclic group, more preferably an azetidinyl group (e.g., ), azacyclopentyl (e.g., ) or an azacyclohexyl group (e.g., ).

[0095] In some embodiments, the compound represented by formula (IG) is a compound represented by formula (IG-1), formula (IG-2) or formula (IG-3),

[0096] Among them, T, R 4 、R 5 、R 6 、R 7 、R 10 、R 11 and k are as defined in formula (IG).

[0097] In some embodiments, the compound represented by formula (IG) is a compound represented by formula (IIG-1), formula (IIG-2) or formula (IIG-3),

[0098] Among them, R 4 H or C 1-6 alkyl;

[0099] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-12 Cycloalkyl;

[0100] R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0101] R 11 Selected from H, halogen, cyano and C 1-6 alkyl;

[0102] Or, R 4 and R 11 The atoms to which it is attached together form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0103] Or, R 10 and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heteroaryl, C 4-8 Cycloalkyl or C 6-8 Aryl, the 5-6 membered heteroaryl, C 4-8 Cycloalkyl or C 6-8 Aryl is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0104] R 7A and R 7B The same or different, each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0105] T is as defined in formula (IG);

[0106] The heteroaryl group is a heteroatom selected from O, N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0107] In some embodiments, the compound represented by formula (IG) is a compound represented by formula (IIG-1a), formula (IIG-2a), formula (IIG-3a), formula (IIG-1b), formula (IIG-2b) or formula (IIG-3b),

[0108] Among them, T, R 4 、R 5 、R 7A 、R 7B 、R 10 and R 11 As defined in Formula (IIG-1), Formula (IIG-2) or Formula (IIG-3).

[0109] In some embodiments, the compound represented by Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b) or Formula (IIG-3b), or a pharmaceutically acceptable salt thereof, wherein R 10 is H, halogen or C 1-6 alkyl.

[0110] In some embodiments, the compound represented by Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b) or Formula (IIG-3b), or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from H, halogen, cyano and C 1-6 alkyl.

[0111] In some embodiments, the compound represented by Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b) or Formula (IIG-3b), or a pharmaceutically acceptable salt thereof, wherein R 10 is H, halogen or C 1-6 Alkyl; R 11 Selected from H, halogen, cyano and C 1-6 alkyl.

[0112] In some embodiments, the compound represented by Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b) or Formula (IIG-3b), or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

[0113] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IIA) or formula (IIB),

[0114] in,

[0115] R 4 H or C 1-6 alkyl;

[0116] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-12 Cycloalkyl;

[0117] R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0118] R 11 Selected from H, halogen, cyano and C 1-6 alkyl;

[0119] Or, R 4 and R 11 The atoms to which it is attached together form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0120] Or, R 10 and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heteroaryl, C 4-8 Cycloalkyl or C 6-8 Aryl, the 5-6 membered heteroaryl, C 4-8 Cycloalkyl or C 6-8 Aryl is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0121] R 7A and R 7B The same or different, each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0122] R 1 、R 2 、R 3 , m, n and t are as defined in formula (I);

[0123] The heteroaryl group is a heteroatom selected from O, N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0124] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IIA-1), formula (IIA-2), formula (IIB-1) or formula (IIB-2),

[0125] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 7A 、R 7B 、R 10 、R 11 , m, n and t are as defined in Formula (IIA) or Formula (IIB).

[0126] In some embodiments, the compound represented by Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1) or Formula (IIB-2) or a pharmaceutically acceptable salt thereof, wherein R 10 is H, halogen or C 1-6 alkyl.

[0127] In some embodiments, the compound represented by Formula (IIA), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1) or Formula (IIB-2) or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from H, halogen, cyano and C 1-6 alkyl.

[0128] In some embodiments, the compound represented by Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1) or Formula (IIB-2) or a pharmaceutically acceptable salt thereof, wherein R 10 is H, halogen or C 1-6 Alkyl; R 11 Selected from H, halogen, cyano and C 1-6 alkyl.

[0129] In some embodiments, the compound represented by Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1) or Formula (IIB-2) or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

[0130] In some embodiments, the compound represented by Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1) or Formula (IIB-2) or a pharmaceutically acceptable salt thereof, wherein R 4 and R 11 The atoms to which it is attached together form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The halogenated alkoxy group is substituted by one or more substituents; the 5-6 membered heteroaryl group is a 5-6 membered heteroaryl group having one or more heteroatoms selected from O, N and S.

[0131] In some embodiments, the compound represented by Formula (IIA), Formula (IIA-1) or Formula (IIA-2) or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heteroaryl or C 4-8Cycloalkyl, the 5-6 membered heteroaryl or C 4-8 Cycloalkyl is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 The halogenated alkoxy group is substituted by one or more substituents; the 5-6 membered heteroaryl group is a 5-6 membered heteroaryl group having one or more heteroatoms selected from O, N and S.

[0132] In some embodiments, the compound represented by Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b) or Formula (IIG-3b), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 11 The atoms to which it is attached together form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy and C 1-6 The halogenated alkoxy group is substituted by one or more substituents; the 5-6 membered heteroaryl group is a 5-6 membered heteroaryl group having one or more heteroatoms selected from O, N and S.

[0133] In some embodiments, the compound represented by Formula (IIG-1), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-1b), Formula (IIG-3a) or Formula (IIG-3b), Formula (IIA), Formula (IIA-1) or Formula (IIA-2), or a pharmaceutically acceptable salt thereof, wherein for Preferably

[0134] In some embodiments, the compound represented by formula (IG) is a compound represented by formula (IIIG),

[0135] Among them, R 17 For cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; T, R 5 、R 7A 、R 7B As defined in formula (IG).

[0136] In some embodiments, the compound represented by formula (IIIG) is a compound represented by formula (IIIG-1) or formula (IIIG-2),

[0137] Among them, T, R 5 、R 7A 、R 7B and R 17 As defined for the compound represented by formula (IIIG).

[0138] In some embodiments, the compound represented by formula (IG) or formula (I) is a compound represented by formula (IIIA1), formula (IIIA2) or formula (IIIA3),

[0139] Among them, R 10 H or C 1-6 Alkyl; R 14 、R 15 and R 16 The same or different, each independently H, cyano, C 1-6 Alkyl and halogenated C 1- 6 alkyl; R 1 、R 2 、R 3 、R 5 、R 7A 、R 7B , m, n and t are as defined in formula (I) or formula (IG).

[0140] In some embodiments, the compound represented by Formula (IG) or Formula (I) is a compound represented by Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1) or Formula (IIIA3-2),

[0141] where R 1 、R 2 、R 3 、R 5 、R 7A 、R 7B 、R 10 、R 14 、R 15 、R 16 , m, n and t are as defined in Formula (IIIA1), Formula (IIIA2) or Formula (IIIA3).

[0142] In some embodiments, the compound represented by formula (IG) or formula (I) is a compound represented by formula (IIIB1), formula (IIIB2) or formula (IIIB3),

[0143] Among them, R17 For cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R 18 and R 19 are the same or different and are each independently H, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1 、R 2 、R 3 、R 5 、R 7A 、R 7B , m, n and t are as defined in formula (I).

[0144] In some embodiments, the compound represented by formula (IG) or formula (I) is a compound represented by formula (IIIB1-1), formula (IIIB1-2), formula (IIIB2-1), formula (IIIB2-2), formula (IIIB3-1) or formula (IIIB3-2),

[0145] where R 1 、R 2 、R 3 、R 5 、R 7A 、R 7B 、R 17 、R 18 、R 19 , m, n and t are as defined in Formula (IIIB1), Formula (IIIB2) or Formula (IIIB3).

[0146] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, wherein T is Preferably, T is

[0147] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, for Preferably More preferably

[0148] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, for Preferably More preferably

[0149] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, for Preferably More preferably

[0150] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, wherein T is Preferably, T is More preferably, T is

[0151] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein t is 0.

[0152] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein t is 0.

[0153] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2, p is 1, and q is 1; t is 0, 1 or 2, p is 1, and q is 2; t is 0, 1 or 2, p is 2, and q is 2; preferably, t is 0, 1 or 2, p is 1, and q is 1.

[0154] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2, p is 0, and q is 1; t is 0, 1 or 2, p is 1, and q is 0.

[0155] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein t is 1.

[0156] In some embodiments, for the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, m is 0 and n is 0.

[0157] In some embodiments, for the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, m is 0 and n is 0.

[0158] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein t is 1, m is 0, and n is 0.

[0159] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein t is 0, m is 0, and n is 0.

[0160] In some embodiments, for the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, t is 0, 1 or 2, m is 0, n is 0, p is 1, and q is 1.

[0161] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2) or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond, -N(R 13)- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S;

[0162] Preferably, L is a chemical bond or -N(R 13 )-.

[0163] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S;

[0164] Preferably, L is a chemical bond or -N(R 13 )-.

[0165] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and -NR k2 R k3 , wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0166] Preferably, R 12 Selected from C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and -NR k2 R k3 , wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group in which the heteroatom is selected from O, N and S, and the number of heteroatoms is 1 or more.

[0167] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and -NR k2 R k3 , the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0168] Preferably, R 12 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and -NR k2 R k3 , wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group in which the heteroatom is selected from O, N and S, and the number of heteroatoms is 1 or more.

[0169] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from halogen, hydroxy, cyano, amino and C 3-12 The cycloalkyl group is substituted by one or more substituents; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0170] Preferably, R 13 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 The alkyl group and the 3-12 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, and amino; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N, and S;

[0171] More preferably, R 13 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0172] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; the C 1-6 Alkyl, C 3-12Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from halogen, hydroxy, cyano, amino and C 3-12 The cycloalkyl group is substituted by one or more substituents; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0173] Preferably, R 13 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 The alkyl group and the 3-12 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, and amino; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N, and S;

[0174] More preferably, R 13 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0175] In some embodiments, the compounds represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or pharmaceutically acceptable salts thereof, wherein when L is NR 13 When R 12 and R 13 Optionally, the nitrogen atom to which it is connected forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g substituted; the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group in which the heteroatom is selected from O, N and S, and the number of heteroatoms is 1 or more.

[0176] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, wherein when L is NR 13 When R12 and R 13 Optionally, the nitrogen atom to which it is connected forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g substituted; the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group in which the heteroatom is selected from O, N and S, and the number of heteroatoms is 1 or more.

[0177] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein each R g are the same or different and are each independently selected from halogen, cyano, carboxyl, hydroxyl, oxo, C 1-6 Alkyl and C 3-12 Cycloalkyl, the C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently selected from carboxyl, hydroxyl, cyano, halogen, oxo and C 1-6 The alkyl group is substituted by one or more substituents;

[0178] Preferably, the R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently selected from the group consisting of carboxyl, hydroxyl and C 1-6 The alkyl group is substituted by one or more substituents.

[0179] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein each R g are the same or different and are each independently selected from halogen, cyano, carboxyl, hydroxyl, oxo, C 1-6 Alkyl and C 3- 12 Cycloalkyl, the C 1-6 Alkyl and C 3-12The cycloalkyl groups are each independently selected from carboxyl, hydroxyl, cyano, halogen, oxo and C 1-6 The alkyl group is substituted by one or more substituents;

[0180] Preferably, the R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently selected from the group consisting of carboxyl, hydroxyl and C 1-6 The alkyl group is substituted by one or more substituents.

[0181] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R k2 and R k3 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from hydroxy, C 1-6 The 3- to 12-membered heterocyclic group is substituted by one or more substituents selected from alkyl, oxo, cyano and carboxyl groups; the 3- to 12-membered heterocyclic group is a 3- to 12-membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0182] Preferably, R k2 and R k3 Each independently is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0183] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R k2 and R k3 Each independently selected from C1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from hydroxy, C 1-6 The 3- to 12-membered heterocyclic group is substituted by one or more substituents selected from alkyl, oxo, cyano and carboxyl groups; the 3- to 12-membered heterocyclic group is a 3- to 12-membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0184] Preferably, R k2 and R k3 Each independently is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0185] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0186] Preferably, R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by a hydroxyl group; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S.

[0187] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0188] Preferably, R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by a hydroxyl group; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S.

[0189] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 1 NR 12 R 13 ;

[0190] R 12 Selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and -C(O)R k4 , wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g replace;

[0191] R 13 Selected from H, C1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0192] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g replaced by;

[0193] Each R g are the same or different and are each independently selected from halogen, cyano, carboxyl, hydroxyl, oxo, C 1-6 Alkyl and C 3-12 Cycloalkyl, the C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently selected from carboxyl, hydroxyl, cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0194] R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group or C 1-6 The alkyl group is optionally substituted with one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo.

[0195] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 1 NR 12 R 13 ;

[0196] R 12 Selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and -C(O)R k4 , wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g replace;

[0197] R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0198] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g replaced by;

[0199] Each R g are the same or different and are each independently selected from halogen, cyano, carboxyl, hydroxyl, oxo, C 1-6 Alkyl and C 3-12 Cycloalkyl, the C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently selected from carboxyl, hydroxyl, cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0200] R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group or C 1-6 The alkyl group is optionally substituted with one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo.

[0201] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S;

[0202] R 12 Selected from C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and -NR k2 R k3 ; wherein, the C 1-6 Alkyl, C 3- 12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0203] R 13 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 The alkyl group and the 3-12 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, and amino; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N, and S;

[0204] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g substituted; the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0205] The R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently selected from the group consisting of carboxyl, hydroxyl and C 1-6 The alkyl group is substituted by one or more substituents;

[0206] R k2 and R k3 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from hydroxy, C 1-6 The 3- to 12-membered heterocyclic group is substituted by one or more substituents selected from alkyl, oxo, cyano and carboxyl groups; the 3- to 12-membered heterocyclic group is a 3- to 12-membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0207] R k4 is a 3-12 membered heterocyclic group or a C1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S.

[0208] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S;

[0209] R 12 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and -NR k2 R k3 ; wherein, the C 1-6 Alkyl, C 3- 12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0210] R 13 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 The alkyl group and the 3-12 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, and amino; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N, and S;

[0211] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R gsubstituted; the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0212] The R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently selected from the group consisting of carboxyl, hydroxyl and C 1-6 The alkyl group is substituted by one or more substituents;

[0213] R k2 and R k3 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from hydroxy, C 1-6 The 3- to 12-membered heterocyclic group is substituted by one or more substituents selected from alkyl, oxo, cyano and carboxyl groups; the 3- to 12-membered heterocyclic group is a 3- to 12-membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0214] R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S.

[0215] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S;

[0216] R 12 For carboxyl, C 1-6Alkyl, 3-12 membered heterocyclic group or -NR k2 R k3 ; wherein, the C 1-6 The alkyl group is optionally substituted with one or more R g replace;

[0217] R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group;

[0218] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g substituted; the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0219] The R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxy group;

[0220] R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0221] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein T is

[0222] L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S;

[0223] R 12 For carboxyl, C 1-6 Alkyl, 3-12 membered heterocyclic group or -NR k2 R k3 ; wherein, the C 1-6 The alkyl group is optionally substituted with one or more Rg replace;

[0224] R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group;

[0225] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g substituted; the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S;

[0226] The R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxy group;

[0227] R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0228] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond, -N(R 13 )-, azacyclopentyl or azacyclohexyl;

[0229] R 12 For carboxyl, C 1-6 Alkyl or -NR k2 R k3 ; wherein, the C 1-6 The alkyl group is optionally substituted with one or more R g replace;

[0230] R 13 C 1-6 Alkyl; wherein the C1-6 The alkyl group is optionally substituted with a hydroxy group;

[0231] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms an azacyclopentyl or azacyclohexyl group;

[0232] The R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxy group;

[0233] R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0234] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein T is

[0235] L is a chemical bond, -N(R 13 )-, azacyclopentyl or azacyclohexyl;

[0236] R 12 For carboxyl, C 1-6 Alkyl or -NR k2 R k3 ; wherein, the C 1-6 The alkyl group is optionally substituted with one or more R g replace;

[0237] R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group;

[0238] Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms an azacyclopentyl or azacyclohexyl group;

[0239] The R g Each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxy group;

[0240] R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

[0241] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 1 for

[0242] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 1 for

[0243] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 1 for

[0244] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 1 for

[0245] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same, each independently H, halogen or C 1-6 alkyl.

[0246] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same, each independently H, halogen or C 1-6 alkyl.

[0247] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Same, both are H.

[0248] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Same, both are H.

[0249] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 5 H or C 1-6 alkyl.

[0250] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 5 H or C 1-6 alkyl.

[0251] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 5 It is a methyl group.

[0252] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 5 It is a methyl group.

[0253] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 6 H or C 1-6 alkyl.

[0254] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 6 H or C 1-6 alkyl.

[0255] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 6 For H.

[0256] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 6 For H.

[0257] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 7A and R 7B The same or different, each independently halogen, C 1-6 Alkyl or C 1- 6-halogenated alkyl.

[0258] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 7A and R 7B The same or different, each independently halogen, C1-6 Alkyl or C 1-6 Halogenated alkyl.

[0259] In some embodiments, the compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a pharmaceutically acceptable salt thereof, wherein R 7A and R 7B The same or different, each independently a halogen; preferably Cl.

[0260] In some embodiments, the compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, wherein R 7A and R 7B The same or different, each independently a halogen; preferably Cl.

[0261] In some embodiments, exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table A below:

[0262] Table A

[0263] In some embodiments, exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table B below:

[0264] Table B

[0265] Another aspect of the present application provides an isotope-labeled compound of Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0266] Another aspect of the present application provides an isotope-labeled compound of Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a compound shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0267] Another aspect of the present application provides a method for preparing a compound represented by formula (IG), wherein a compound represented by formula (Y) reacts with a compound represented by formula (XI) to obtain a compound represented by formula (IG):

[0268] wherein X is Cl, Br or I;

[0269] T, R 4 、R 5 、R 6 、R 7 、R 11 , G 1 , G 2 , G 3 and k is as described in any one of the present invention.

[0270] Another aspect of the present application provides a method for preparing a compound represented by formula (I), wherein a compound represented by formula (X) reacts with a compound represented by formula (XI) to obtain a compound represented by formula (I);

[0271] Wherein, X is Cl, Br or I;

[0272] R1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 11 , G 1 , G 2 , G 3 , Z, m, n, k and t are as described in any one of the present invention.

[0273] Another aspect of the present application provides a compound represented by formula (X),

[0274] Among them, R 1 、R 2 、R 3 , Z, m, n and t are as described in any one of the present invention.

[0275] In some embodiments, the compound represented by formula (X) is selected from the following compounds,

[0276] In some embodiments, the compound represented by formula (X) is selected from the following compounds,

[0277] Another aspect of the present application provides a compound represented by formula (Y), TH (Y)

[0278] Where T is

[0279] R 1 、R 2 、R 3 , Z, X, Y, m, n, p, q and t are as described in any one of the present invention.

[0280] In some embodiments, the compound represented by formula (Y) is selected from the following compounds,

[0281] Another aspect of the present application provides a compound represented by formula (Z),

[0282] Where M is

[0283] R t NHR 0 ; R 0 C 1-6 alkyl;

[0284] R 2 、R 3 、R 4 、R5 、R 7 , G 1 , G 2 , G 3 , m, n, p, q, k and t are as described in any one of the present invention.

[0285] In some embodiments, the compound represented by formula (Z) is a compound represented by formula (Z1),

[0286] Where M is R t 、R 2 、R 3 , m, n, p, q and t are as described in any one of the present invention.

[0287] In some embodiments, the compound represented by formula (Z) or formula (Z1) is

[0288] for Preferably

[0289] In some embodiments, the compound represented by formula (Z) or formula (Z1) is

[0290] for Preferably

[0291] In some embodiments, the compound represented by formula (Z) or formula (Z1) is

[0292] for Preferably

[0293] In some embodiments, the compound represented by formula (Z) or formula (Z1) is

[0294] for Preferably

[0295] In some embodiments, the compound represented by formula (Z1) is selected from the following compounds,

[0296] In another aspect, the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0297] On the other hand, the present application also provides the use of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for regulating CCR4.

[0298] On the other hand, the present application also provides the use of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a drug for regulating CCR4.

[0299] On the other hand, the present application also provides the use of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for inhibiting CCR4.

[0300] On the other hand, the present application also provides the use of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for antagonizing CCR4.

[0301] The present application also provides the use of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and / or treating CCR4-mediated diseases or conditions; preferably, the diseases and conditions are diseases or conditions in which CCR4 is overexpressed.

[0302] The present application also provides the use of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating CCR4-mediated diseases or conditions; preferably, the diseases and conditions are diseases or conditions in which CCR4 is overexpressed.

[0303] The present application also provides formula (I), formula (IIA), formula (IIB), formula (IIA-1), formula (IIA-2), formula (IIB-1), formula (IIB-2), formula (IIIA1), formula (IIIA2), formula (IIIA3), formula (IIIB1), formula (IIIB2), formula (IIIB3), formula (IIIA1-1), formula (IIIA1-2), formula (IIIA2-1), formula (IIIA2-2), formula (IIIA3-1), formula (IIIA3-2), formula (IIIB1 -1), a compound shown in Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer; preferably, in the preparation of a medicament for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0304] The present application also provides the use of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer; preferably, in the preparation of a medicament for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0305] The present application also provides a method for inhibiting CCR4, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0306] The present application also provides a method for inhibiting CCR4, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1), or Formula (IIIG-2).

[0307] The compound, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0308] The present application also provides a method for preventing and / or treating a CCR4-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0309] The present application also provides a method for preventing and / or treating a CCR4-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0310] The present application also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0311] The present application also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0312] The present application also provides a method for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0313] The present application also provides a method for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0314] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a drug.

[0315] The present application also provides a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a medicine.

[0316] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a CCR4 modulator.

[0317] The present application also provides a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 modulator.

[0318] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 inhibitor.

[0319] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 antagonist.

[0320] The present application also provides a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 antagonist.

[0321] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and / or treating CCR4-mediated diseases or conditions; preferably, the diseases and conditions are diseases or conditions in which CCR4 is overexpressed.

[0322] The present application also provides a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and / or treating CCR4-mediated diseases or conditions; preferably, the diseases and conditions are diseases or conditions in which CCR4 is overexpressed.

[0323] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer.

[0324] The present application also provides a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a drug for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer.

[0325] The present application also provides a compound represented by Formula (I), Formula (IIA), Formula (IIB), Formula (IIA-1), Formula (IIA-2), Formula (IIB-1), Formula (IIB-2), Formula (IIIA1), Formula (IIIA2), Formula (IIIA3), Formula (IIIB1), Formula (IIIB2), Formula (IIIB3), Formula (IIIA1-1), Formula (IIIA1-2), Formula (IIIA2-1), Formula (IIIA2-2), Formula (IIIA3-1), Formula (IIIA3-2), Formula (IIIB1-1), Formula (IIIB1-2), Formula (IIIB2-1), Formula (IIIB2-2), Formula (IIIB3-1) or Formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0326] The present application also provides a compound represented by Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0327] In some embodiments, the CCR4-mediated disease is selected from the group consisting of an autoimmune disease, an inflammatory disease, and cancer.

[0328] In some embodiments, the CCR4-mediated disease is selected from arthritis, psoriasis, systemic lupus erythematosus, and inflammatory bowel disease.

[0329] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0330] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the compound represented by the aforementioned formula (I), formula (IIA), formula (IIB), formula (IIA-1), formula (IIA-2), formula (IIB-1), formula (IIB-2), formula (IIIA1), formula (IIIA2), formula (IIIA3), formula (IIIB1), formula (IIIB2), formula (IIIB3), formula (IIIA1-1), formula (IIIA1-2), formula (IIIA2-1), formula (IIIA2-2), formula (IIIA3-1), formula (IIIA3-2), formula (IIIB1-1), formula (IIIB1-2), formula (IIIB2-1), formula (IIIB2-2), formula (IIIB3-1), formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotopically labeled compound thereof, based on the total weight of the composition.

[0331] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the compound represented by the aforementioned Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof, based on the total weight of the composition.

[0332] In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the compound represented by the aforementioned formula (I), formula (IIA), formula (IIB), formula (IIA-1), formula (IIA-2), formula (IIB-1), formula (IIB-2), formula (IIIA1), formula (IIIA2), formula (IIIA3), formula (IIIB1), formula (IIIB2), formula (IIIB3), formula (IIIA1-1), formula (IIIA1-2), formula (IIIA2-1), formula (IIIA2-2), formula (IIIA3-1), formula (IIIA3-2), formula (IIIB1-1), formula (IIIB1-2), formula (IIIB2-1), formula (IIIB2-2), formula (IIIB3-1), formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotopically labeled substance thereof.

[0333] In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the compound represented by the aforementioned Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.

[0334] In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound represented by the aforementioned formula (I), formula (IIA), formula (IIB), formula (IIA-1), formula (IIA-2), formula (IIB-1), formula (IIB-2), formula (IIIA1), formula (IIIA2), formula (IIIA3), formula (IIIB1), formula (IIIB2), formula (IIIB3), formula (IIIA1-1), formula (IIIA1-2), formula (IIIA2-1), formula (IIIA2-2), formula (IIIA3-1), formula (IIIA3-2), formula (IIIB1-1), formula (IIIB1-2), formula (IIIB2-1), formula (IIIB2-2), formula (IIIB3-1), formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotopically labeled substance thereof.

[0335] In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound represented by the aforementioned Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.

[0336] In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound represented by the aforementioned formula (I), formula (IIA), formula (IIB), formula (IIA-1), formula (IIA-2), formula (IIB-1), formula (IIB-2), formula (IIIA1), formula (IIIA2), formula (IIIA3), formula (IIIB1), formula (IIIB2), formula (IIIB3), formula (IIIA1-1), formula (IIIA1-2), formula (IIIA2-1), formula (IIIA2-2), formula (IIIA3-1), formula (IIIA3-2), formula (IIIB1-1), formula (IIIB1-2), formula (IIIB2-1), formula (IIIB2-2), formula (IIIB3-1), formula (IIIB3-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotopically labeled substance thereof.

[0337] In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound represented by the aforementioned Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IIG-1a), Formula (IIG-2a), Formula (IIG-3a), Formula (IIG-1b), Formula (IIG-2b), Formula (IIG-3b), Formula (IIIG), Formula (IIIG-1) or Formula (IIIG-2), or represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.

[0338] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of one or more pharmaceutically acceptable excipients.

[0339] When used as a drug, the compounds of the present application can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be local (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal, oral or parenteral). Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus, or can be administered, for example, by a continuous infusion pump.

[0340] In preparing the compositions of the present application, the active ingredient is typically mixed with excipients and the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0341] The "excipient" mentioned in this application refers to ingredients other than the active ingredient, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants and lubricants.

[0342] On the other hand, the pharmaceutically acceptable salts of the compounds described in the present application may be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amino group), they can also form internal salts.

[0343] On the other hand, the compounds of the present invention may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present application.

[0344] The term "plurality" used herein to indicate the number of substituents or heteroatoms means two, three, four or five.

[0345] In the chemical structure of the compounds described in this application, the bond Indicates that the configuration is not specified. Indicates the absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.

[0346] key indicates unspecified configuration, including cis (E) or trans (Z) configuration.

[0347] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the application. "Tautomers" refer to structural isomers of different energies that can be interconverted via low energy barriers. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present application are within the scope of the present application. The name of the compound named in a single manner does not exclude any tautomer.

[0348] The present application also includes isotopically labeled compounds of the present application having the same structure as described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as2 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 All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0349] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to be deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium or more. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. In preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0350] As used herein, a "therapeutically effective amount" refers to the amount of an active compound or drug that is sought by researchers, veterinarians, physicians, or other clinicians to elicit a biological or medical response in a tissue, system, animal, individual, or human, including one or more of the following: (1) preventing disease: for example, preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) inhibiting disease: for example, inhibiting a disease, disorder, or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviating disease: for example, alleviating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. For drugs or pharmacologically active agents, a "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of an effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0351] The term "pharmaceutically acceptable" in this application means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0352] The term "patient" as used herein refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0353] Definitions and Explanations of Terms

[0354] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0355] In this application means that the corresponding group passes through the Connect with other fragments and groups in the compound.

[0356] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof. The alkyl group can be substituted or unsubstituted.

[0357] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred alkoxy groups (C 1-12 Alkoxy), more preferably an alkoxy containing 1 to 6 carbon atoms (C 1- 6 alkoxy groups). Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0358] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0359] The term " spiroalkyl " refers to 5 to 20 yuan, a polycyclic group sharing a carbon atom (claiming spiral atom) between each monocycle in the system, which can contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiral atoms between ring and ring, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0360] Term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares the full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, and wherein one or more rings can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).Can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of composition ring, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic alkyl.Non-limiting examples of fused cycloalkyl include:

[0361] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0362] The cycloalkyl ring includes a cycloalkyl group as described herein (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0363] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclyls.

[0364] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of shared spiral atoms between rings, spiro heterocyclic radicals are divided into monospiro heterocyclic radicals, dispiro heterocyclic radicals or polyspiro heterocyclic radicals, preferably monospiro heterocyclic radicals and dispiro heterocyclic radicals. It is more preferably 3 / 5 members, 3 / 6 members, 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members monospiro heterocyclic radicals. Non-limiting examples of spiro heterocyclic radicals include:

[0365] The term "fused heterocyclic radical" refers to 5 to 20 yuan, and each ring in the system shares a polycyclic heterocyclic group of a pair of atoms adjacent to other rings in the system, and one or more rings can contain one or more double bonds, wherein one or more annular atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulphur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining annular atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radicals, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radicals. The limiting examples of fused heterocyclic radicals include:

[0366] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0367] The heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0368] The heterocyclic group may be substituted or unsubstituted.

[0369] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0370] Aryl groups can be substituted or unsubstituted.

[0371] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0372] Heteroaryl groups can be substituted or unsubstituted.

[0373] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" and the like herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0374] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heterocyclylene" and "heteroarylene".

[0375] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.

[0376] The term "heterocyclyloxy" refers to a heterocyclyl-O- group wherein heterocyclyl is as defined herein.

[0377] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

[0378] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

[0379] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0380] The term "halogen" refers to F, Cl, Br or I.

[0381] The term "hydroxy" refers to -OH.

[0382] The term "amino" refers to -NH2.

[0383] The term "cyano" refers to -CN.

[0384] The term "nitro" refers to -NO2.

[0385] The term "oxo" or "oxo" refers to "=0".

[0386] The term "carbonyl" refers to C=O.

[0387] The term "carboxy" refers to -C(O)OH.

[0388] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined herein.

[0389] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0390] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0391] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0392] The reagents and raw materials used in the present invention are commercially available. Beneficial effects:

[0393] The present application provides a small molecule compound having a spiroheterocyclic structure, which can be used as a CCR4 inhibitor. Such compound or pharmaceutical composition has a potent antagonistic effect on the CCR4 receptor and has excellent pharmacokinetic effects, and can be used to effectively treat or prevent CCR4-mediated diseases. DETAILED DESCRIPTION

[0394] The technical solutions of the present invention will be described in further detail below with reference to specific examples. It should be understood that the following examples are merely illustrative of and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above-mentioned contents of the present invention are encompassed within the scope of protection intended by the present invention. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0395] In the following examples, the experimental methods without specific conditions were carried out according to conventional methods and conditions, or selected according to the product instructions.

[0396] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker Avance III 400 MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0397] Mass spectra (MS) were measured by Waters 2767 HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0398] Chiral HPLC analysis was performed using Shimadzu LC-20AD.

[0399] The thin layer chromatography silica gel plate used was GF254 silica gel plate produced by Chenghua (Shanghai) Co., Ltd. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.2-0.25 mm, and the specification used for thin layer chromatography separation and purification products was 0.4-0.5 mm.

[0400] Column chromatography generally uses 100-200 mesh silica gel as a carrier produced by Chenghua (Shanghai) Co., Ltd.

[0401] Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatography were used for high performance liquid chromatography.

[0402] Gilson GX-281 preparative HPLC was used for chiral separation column chromatography.

[0403] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0404] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1 liter.

[0405] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0406] Unless otherwise specified in the examples, the reaction temperature is room temperature, which ranges from 20°C to 30°C.

[0407] Those skilled in the art will understand that the chiral compounds that have been separated can be distinguished by the order of their retention times in a chiral chromatographic column. Therefore, the chiral compounds separated according to the order of their retention times are distinguished by numbering suffixes such as P1 and P2. That is, suffix P1 corresponds to the chiral structure separated first, and suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of a compound is listed in the structural formula, it does not mean a one-to-one correspondence with the compounds with numbering suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with numbering suffixes P1 and P2 is based on the absolute configuration objectively corresponding to the specific retention time.

[0408] English abbreviations and corresponding Chinese names:

[0409] Synthesis of intermediate A

[0410] Under nitrogen, triethylamine (4.60 g, 45.54 mmol) was added to a solution of Compound A-1 (3.00 g, 15.19 mmol) and Compound A-2 (3.04 g, 15.99 mmol) in ethanol (140 mL). The resulting reaction solution was stirred at room temperature for 16 hours. The reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using a silica gel column (petroleum ether:ethyl acetate = 1:0-10:1) to obtain Compound A (4.70 g).

[0411] MS m / z(ESI):351.9(M+1) + .

[0412] Example 1 (Compound 1)

[0413] first step

[0414] n-Butyl lithium (46.5 mL, 116 mmol, 2.50 mol / L) was added to THF (100 mL). The temperature was lowered to 0°C, and 3-methyl-3-buten-1-ol (5.02 g, 580 mmol) and N,N,N',N'-tetramethylethylenediamine (6.72 g, 580 mmol) were added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at 0°C for 2 h. Compound 1-1 (10.0 g, 580 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at 0°C for 2 h. After the reaction, 100 mL of aqueous NH4Cl was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified on a silica gel column (petroleum ether:ethyl acetate = 3:1 to 0:1) to obtain compound 1-2 (10.0 g).

[0415] Step 2

[0416] Compound 1-2 (5.00 g, 19.0 mmol) was added to THF (50.0 mL). Under nitrogen, the temperature was lowered to -40°C, and n-butyllithium (7.60 mL, 19.0 mmol, 2.50 mol / L) was added to the reaction mixture. The reaction mixture was stirred at -40°C for 30 minutes. TsCl (3.72 g, 19.0 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at -40°C for 2 hours. The temperature was raised to 0°C, and n-butyllithium (7.60 mL, 19.0 mmol, 2.50 mol / L) was added to the reaction mixture, and the reaction mixture was stirred at 0°C for 4 hours. After the reaction, 100 mL of aqueous NH4Cl solution was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases after extraction were combined and dried, filtered and concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate=20:1-5:1) to obtain compound 1-3 (2.00 g).

[0417] Step 3

[0418] Compound 1-3 (1.90 g, 8.00 mmol) was added to THF (10.0 mL) and H₂O (10.0 mL). Potassium osmate dihydrate (585 mg, 1.50 mmol) and NaIO₄ (3.42 g, 16.0 mmol) were then slowly added to the reaction solution, and the reaction solution was stirred at 25°C for 2 h. After the reaction, the reaction mixture was added to 20.0 mL of sodium sulfite water and extracted with EA (20.0 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified on a silica gel column (petroleum ether:ethyl acetate = 8:1-3:1) to obtain compound 1-4 (1.50 g).

[0419] Step 4

[0420] Compound 1-4 (300 mg, 1.24 mmol) and methylamine (46.3 mg, 1.49 mmol) were added to MeOH (10 mL). NaBH3CN (156 mg, 2.48 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was added to 20 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 1-5 (250 mg).

[0421] MS m / z(ESI):257.1(M+H) + .

[0422] Step 5

[0423] Compound 1-5 (250 mg, 0.976 mmol), iodoethanol (201 mg, 1.17 mmol), and K2CO3 (404 mg, 2.93 mmol) were added to DMF (10.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 10 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 1-6 (200 mg).

[0424] MS m / z(ESI):301.1(M+H) + .

[0425] Step 6

[0426] Compound 1-6 (140 mg, 0.466 mmol) was added to 1,4-dioxane (5.0 mL). Hydrogen chloride-1,4-dioxane (5.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 1-7 (100 mg).

[0427] MS m / z(ESI):201.1(M+H) + .

[0428] Step 7

[0429] Intermediate A (133 mg, 0.381 mmol), compound 1-7 (100 mg, 0.571 mmol), and CS2CO3 (372 mg, 1.14 mmol) were added to CH3CN (5.0 mL) and DMSO (5.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 1 (104.9 mg).

[0430] 1 H NMR (400MHz, CD3OD) δ7.45–7.34(m,2H),7.25(d,J=8.6Hz,1H),5.52–5.42(m,1H),3.91–3.80(m,3H),3.77–3.40(m,4H),3.3 1–3.29(m,1H),2.79–2.72(m,3H),2.40(s,3H),2.11(s,3H),2.11–2.08(m,1H),1.91–1.75(m,1H),1.63–1.54(m,2H),1.50(d J=1.5Hz,3H).

[0431] MS m / z(ESI):514.1(M+H) + .

[0432] Example 2 (Compound 2)

[0433] first step

[0434] Compound 1-4 (250 mg, 1.04 mmol) and 3-azetidinecarboxylic acid (125 mg, 1.24 mmol) were added to MeOH (10.0 mL). NaBH3CN (194 mg, 3.09 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then separated and purified by reverse phase column chromatography (H2O:MeOH = 1:1) to afford compound 2-1 (130 mg).

[0435] MS m / z(ESI):327.1(M+H) + .

[0436] Step 2

[0437] Compound 2-1 (100 mg, 0.307 mmol) was added to 1,4-dioxane (3.0 mL). Hydrogen chloride-1,4-dioxane (5.0 mL) was then added to the reaction mixture, and the reaction mixture was stirred at 25°C for 3 hours. After the reaction was completed, the reaction mixture was directly concentrated to obtain crude compound 2-2 (80.0 mg).

[0438] MS m / z(ESI):227.1(M+H) + .

[0439] Step 3

[0440] Compound 2-2 (80.0 mg, 0.353 mmol), intermediate A (123 mg, 0.353 mmol), and CS2CO3 (344 mg, 1.05 mmol) were added to DMSO (10.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water, the pH of the reaction mixture was adjusted to 5 with citric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (H2O:MeOH = 1:1) to afford compound 2 (34.5 mg).

[0441] 1 H NMR (400MHz, CD3OD) δ7.43 (d, J=2.1Hz, 1H), 7.37 (d J=3.4Hz, 1H), 7.25 (d J=1.8Hz,1H),5.51–5.48(m,1H),4.18–4.10(m,4H),3.97–3.88(m,2H),3.88–3.78(m,2H),3. 75–3.58(m,2H),3.52–3.41(m,1H),3.37–3.33(m,1H),2.28(s,3H),1.91–1.72(m,1H),1.50(d J=1.2Hz,3H),1.45–1.23(m,3H).

[0442] MS m / z(ESI):540.1(M+H) + .

[0443] Example 3 (Compound 3)

[0444] first step

[0445] Compound 3-1 (300 mg, 1.39 mmol) was added to 1,4-dioxane (2.0 mL). Hydrogen chloride-1,4-dioxane (10.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 3-2 (250 mg).

[0446] Step 2

[0447] Compound 3-2 (250 mg, 2.11 mmol) and compound 1-4 (300 mg, 1.24 mmol) were added to MeOH (10.0 mL). NaBH3CN (234 mg, 3.72 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then separated and purified by reverse phase column chromatography (H2O:MeOH = 2:1) to afford compound 3-3 (150 mg).

[0448] MS m / z(ESI):341.1(M+H) + .

[0449] Step 3

[0450] Compound 3-3 (150 mg, 0.441 mmol) was added to 1,4-dioxane (3.0 mL). Hydrogen chloride-1,4-dioxane (7.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 3-4 (110 mg).

[0451] MS m / z(ESI):241.1(M+H) + .

[0452] Step 4

[0453] Compound 3-4 (80.0 mg, 0.333 mmol), intermediate A (116 mg, 0.333 mmol), and CS2CO3 (324 mg, 0.999 mmol) were added to DMSO (10.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water, the pH of the reaction mixture was adjusted to 5 with citric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (H2O:MeOH = 1:1) to afford compound 3 (25.0 mg).

[0454] 1H NMR (400MHz, CD3OD) δ7.42 (d, J=2.3Hz, 1H), 7.37 (d J=3.4Hz, 1H), 7.25 (d J=1.7Hz,1H),5.53–5.46(m,1H),4.29–4.26(m,2H),3.98–3.75(m,6H),3.71–3.61 (m,2H),3.50–3.38(m,1H),2.28(s,3H),1.90(d,J=12.5Hz,1H),1.65–1.26(m,9H).

[0455] MS m / z(ESI):554.1(M+H) + .

[0456] Example 4 (Compound 5)

[0457] first step

[0458] Compound 5-1 (300 mg, 1.39 mmol) was added to 1,4-dioxane (2.0 mL). Hydrogen chloride-1,4-dioxane (10.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 5-2 (250 mg).

[0459] Step 2

[0460] Compound 5-2 (192 mg, 1.49 mmol) and compound 1-4 (300 mg, 1.24 mmol) were added to MeOH (10.0 mL). NaBH3CN (234 mg, 3.72 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then separated and purified by reverse phase column chromatography (H2O:MeOH = 1:1) to afford compound 5-3 (100 mg).

[0461] MS m / z(ESI):355.1(M+H) + .

[0462] Step 3

[0463] Compound 5-3 (70.0 mg, 0.197 mmol) was added to DCM (6.0 mL). TFA (2.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 3 h. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 5-4 (60.0 mg).

[0464] MS m / z(ESI):255.1(M+H) + .

[0465] Step 4

[0466] Compound 5-4 (60.0 mg, 0.228 mmol), intermediate A (50.0 mg, 0.143 mmol), and Cs2CO3 (139 mg, 0.429 mmol) were added to DMSO (10.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water, the pH of the reaction mixture was adjusted to 5 with citric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (H2O:MeOH = 1:1) to afford compound 5 (12.5 mg).

[0467] 1 H NMR (400MHz, CD3OD) δ7.42(t,J=2.2Hz,1H),7.37(d,J=3.2Hz,1H),7.25(d,J=2.1Hz,1H),5.4 9(d,J=2.4Hz,1H),3.97–3.76(m,4H),3.69(d,J=24.0Hz,1H),3.53–3.35(m,3H),3.21(d,J=9 .2Hz,1H),3.10–2.99(m,1H),2.68(d,J=6.4Hz,1H),2.46–2.36(m,2H),2.28(s,4H),2.01(d, J=12.7Hz,1H),1.69(dt,J=19.5,12.6Hz,3H),1.50(dd,J=7.1,0.9Hz,3H),1.36–1.29(m,2H).

[0468] MS m / z(ESI):568.1(M+H) + .

[0469] Example 5 (Compound 6)

[0470] first step

[0471] Compound 1-4 (300 mg, 1.24 mmol) and 4-piperidinic acid (192 mg, 1.49 mmol) were added to MeOH (10.0 mL). NaBH3CN (234 mg, 3.72 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then separated and purified by reverse phase column chromatography (H2O:MeOH = 1:1) to afford compound 6-1 (100 mg).

[0472] MS m / z(ESI):355.1(M+H) + .

[0473] Step 2

[0474] Compound 6-1 (70.0 mg, 0.508 mmol) was added to DCM (4.0 mL). TFA (2.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 3 h. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 6-2 (60.0 mg).

[0475] MS m / z(ESI):255.1(M+H) + .

[0476] Step 3

[0477] Compound 6-2 (58.2 mg, 0.229 mmol), intermediate A (50.0 mg, 0.143 mmol), and Cs2CO3 (139 mg, 0.429 mmol) were added to DMSO (10.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water, the pH of the reaction mixture was adjusted to 5 with citric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (H2O:MeOH = 1:1) to afford compound 6 (6.5 mg).

[0478] 1H NMR (400MHz, CD3OD) δ7.42(d,J=2.2Hz,1H),7.37(d,J=2.6Hz,1H),7.25(d,J=2.1Hz,1H), 5.56–5.45(m,1H),3.96(d,J=4.2Hz,1H),3.90–3.74(m,3H),3.72–3.58(m,1H),3.47(dt,J =26.5,11.5Hz,3H),2.97(s,1H),2.39(d,J=23.5Hz,1H),2.28(s,3H),2.22–2.08(m,2H),1 .97(dd,J=29.0,16.4Hz,3H),1.81–1.64(m,2H),1.50(dd,J=7.1,0.8Hz,3H),1.33(s,3H).

[0479] MS m / z(ESI):568.1(M+H) + .

[0480] Example 6 (Compounds 7, 7R, 7S, 7R-P1, 7R-P2, 7S-P1, 7S-P2)

[0481] first step

[0482] Compound 1 (300 mg, 1.24 mmol) and 3-piperidinic acid (192 mg, 1.49 mmol) were added to MeOH (10.0 mL). NaBH3CN (234 mg, 3.72 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then separated and purified by reverse phase column chromatography (H2O:MeOH = 1:1) to afford compound 7-1 (100 mg).

[0483] MS m / z(ESI):355.1(M+H) + .

[0484] Step 2

[0485] Compound 7-1 (80.0 mg, 0.225 mmol) was added to DCM (4.0 mL). TFA (2.0 mL) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 3 h. After the reaction was completed, the reaction solution was directly concentrated to obtain crude compound 7-2 (70 mg).

[0486] MS m / z(ESI):255.1(M+H) + .

[0487] Step 3

[0488] Compound 7-2 (70.0 mg, 0.272 mmol), intermediate A (50.0 mg, 0.143 mmol), and Cs2CO3 (139 mg, 0.429 mmol) were added to DMSO (5.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was added to 30 mL of water, the pH of the reaction mixture was adjusted to 5 with citric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (H2O:MeOH = 1:1) to afford compound 7 (28.5 mg).

[0489] 1 H NMR (400MHz, CD3OD) δ7.42(q,J=2.0Hz,1H),7.37(dd,J=8.4,2.9Hz,1H),7.26(dt,J=8.4,1.9Hz,1H),5.55–5.44(m,1H),4.04–3.78(m,4H),3.69( d,J=25.0Hz,2H),3.50(q,J=12.2Hz,1H),3.36(s,2H),3.16(d,J=24.2Hz ,2H),2.67(s,1H),2.28(s,4H),2.05–1.70(m,7H),1.50(d,J=7.0Hz,3H).

[0490] MS m / z(ESI):568.1(M+H) + .

[0491] The raw material 3-piperidinic acid in the first step is replaced with R-configured 3-piperidinic acid to obtain compound 7R; further chiral resolution is performed to obtain 7R-P1 and 7R-P2.

[0492] SFC conditions:

[0493] Chiral column: Daicel OJ 25*250mm, 10μm;

[0494] Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 70 / 30;

[0495] Flow rate: 100 mL / min

[0496] 7R-P1 (retention time: 0.900 minutes):

[0497] 1H NMR (400MHz, DMSO-d6) δ7.54(d,J=4.0Hz,1H),7.48(d,J=12Hz,1H),7.39–7.36(m,2H),5.43–5.40(m,1H),3.75–3.72(m,5H),2 .86(d,J=8.0Hz,1H),2.70(d,J=12.0Hz,1H),2.34–2.19(m,7H),1.97–1.85(m,1H),1.77(d,J=12.0Hz,1H),1.62–1.23(m,10H).

[0498] MS m / z(ESI):498.2(M+1) + .

[0499] 7R-P2 (retention time: 1.430 minutes):

[0500] 1 H NMR (400MHz, DMSO-d6) δ7.56–7.54(m,1H),7.48(d,J=8Hz,1H),7.39–7.36(m,2H),5.43–5.40(m,1H),3.78–3.65(m,5H),2.87(d,J=8.0Hz ,1H),2.68–2.67(m,1H),2.34–2.33(m,3H),2.19(s,4H),1.97–1.85(m,1H),1.77(d,J=12.0Hz,1H),1.62–1.59(m,2H),1.45–1.23(m,8H).

[0501] MS m / z(ESI):498.2(M+1) + .

[0502] The raw material 3-piperidinic acid in the first step is replaced with S-configured 3-piperidinic acid to obtain compound 7S; further chiral resolution is performed to obtain 7S-P1 and 7S-P2.

[0503] SFC conditions:

[0504] Chiral column: Daicel IG 25*250mm, 10μm;

[0505] Mobile phase: CO2 / EtOH [0.5% NH3 (7M in MeOH)] = 45 / 55;

[0506] Flow rate: 100 mL / min

[0507] 7S-P1 (retention time: 0.935 minutes):

[0508] 1 H NMR (400MHz, DMSO-d6) δ7.55(d,J=4.0Hz,1H),7.48(d,J=8Hz,1H),7.39–7.36(m,2H),5.43–5.40(m,1H),3.78–3.65(m,5H),2.88(d,J=12.0Hz,1H ),2.70(d,J=12.0Hz,1H),2.31–2.29(m,3H),2.19–2.15(m,4H),1.97–1. 85(m,1H),1.78(d,J=12.0Hz,1H),1.62–1.59(m,2H),1.45–1.23(m,8H).

[0509] MS m / z(ESI):498.2(M+1) + .

[0510] 7S-P2 (retention time: 1.359 minutes):

[0511] 1 H NMR (400MHz, DMSO-d6) δ7.55(d,J=4.0Hz,1H),7.48(d,J=8Hz,1H),7.39–7.36(m,2H),5.43–5.40(m,1H),3.78–3.65(m,5H),2.87(d,J=12.0 Hz,1H),2.68–2.67(m,1H),2.34–2.33(m,3H),2.19(s,4H),1.97–1.85 (m,1H),1.78(d,J=12.0Hz,1H),1.62–1.58(m,2H),1.48–1.23(m,8H).

[0512] MS m / z(ESI):498.2(M+1) + .

[0513] Example 7 (Compound 85S)

[0514] first step

[0515] Compound 85-1 (10.0 g, 52.8 mmol) and 3-buten-1-ol (4.19 g, 58.1 mmol) were dissolved in a reaction flask. The reaction mixture was cooled to 0°C and H2SO4 (18 mL, 70%) was added dropwise at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 16 h. The reaction mixture was poured into an ice-water solution to quench the mixture. The pH was adjusted to approximately 8 with 10% NaOH solution, and the mixture was dissolved in water. The aqueous phase was washed with EA (200 x 3 mL). The combined organic layers were washed with saturated NaCl solution (200 x 3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (DCM:MeOH = 5:1) to yield compound 85-2 (6.0 g).

[0516] MS m / z(ESI):262.1(M+1) + .

[0517] Step 2

[0518] Compound 85-2 (3.0 g, 11.4 mmol) was dissolved in EtOH (50 mL). Pd / C (300.0 mg, 2.82 mmol) and HCOONH4 (5.07 g, 80.3 mmol) were then added, and the reaction mixture was stirred at 80°C for 16 h. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to obtain compound 85-3 (1.0 g).

[0519] MS m / z(ESI):172.1(M+1) + .

[0520] Step 3

[0521] Intermediate A (1.25 g, 3.56 mmol), compound 85-3 (914 mg, 5.34 mmol), and DIEA (2.30 g, 17.8 mmol) were added to DMSO (10.0 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was added to 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified on a silica gel column (EA:PE = 3:1) to afford compound 85-4 (1.5 g).

[0522] MS m / z(ESI):485.1(M+1) + .

[0523] Step 4

[0524] Compound 85-4 (1.45 g, 2.98 mmol) was added to DCM (15.0 mL). The reaction mixture was cooled to 0°C and Dess-Martin (7.58 g, 17.8 mmol) was added at 0°C. Under nitrogen, the reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was quenched by pouring into an aqueous solution of sodium sulfite and then dissolved in water. The aqueous phase was washed with EA (3 x 30 mL). The combined organic layers were washed with saturated NaHCO₃ solution (3 x 30 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to yield crude compound 85-5 (1.4 g).

[0525] MS m / z(ESI):483.1(M+1) + .

[0526] Step 5

[0527] Compound 85-5 (120 mg, 0.25 mmol), compound (S)-pyrrolidine-3-carboxylic acid (58 mg, 0.5 mmol), and methanol (8 mL) were added to a 50 mL single-necked vial at room temperature and stirred for 1 hour. Sodium cyanoborohydride (47 mg, 0.75 mmol) was added to the mixture and stirred for 20 hours. After completion, the reaction was quenched with water (10 mL), extracted three times with EA (25 mL), and the organic phase was washed three times with water (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (DCM:MeOH = 5:1) and then by reverse phase preparative chromatography (Prep-HPLC waters XB-C18 19x250 mm, 10 μm; ACN:H2O (10 mM NH4HCO3) = 45-60%, UV: 214 nm) to afford compound 85S (22.2 mg).

[0528] 1 H NMR(400MHz,DMSO-d6)δ7.55(d,J=2.4Hz,1H),7.47–7.31(m,2H),7.25(d,J=6.8Hz,1H ),5.35(q,J=6.6Hz,1H),3.95(t,J=10.6Hz,2H),3.73–3.59(m,1H),3.49(t,J=11.8Hz, 1H),3.23–2.53(m,6H),2.34(d,J=12.9Hz,2H),2.18(s,3H),1.89(q,J=7.3Hz,3H),1. 78–1.53(m,2H),1.44(d,J=7.1Hz,3H),1.29(d,J=24.6Hz,3H),1.04(q,J=11.7Hz,2H).

[0529] MS m / z(ESI):582.2(M+1) + .

[0530] Example 8 (Compound 86R)

[0531] first step

[0532] Compound 85-5 (120 mg, 0.25 mmol) and (R)-piperidine-3-carboxylic acid (48.4 mg, 0.37 mmol) were added to MeOH (8 mL), and NaBH3CN (47.1 mg, 0.75 mmol) was added to the reaction mixture. The reaction mixture was stirred at 50°C for 16 h. After completion of the reaction, the reaction mixture was added to 20 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified on a silica gel column (DCM:MeOH = 5:1) to afford compound 86R (43.8 mg).

[0533] 1 H NMR (400MHz, DMSO-d6) δ7.56 (dd, J=3.3, 2.1Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 7.36 (dt, J=8.4, 2.1 Hz,1H),7.26(d,J=6.6Hz,1H),5.45–5.23(m,1H),3.95(s,2H),3.68(d,J=11.2Hz,1H),3.49(t, J=11.7Hz,3H),2.85(d,J=9.0Hz,2H),2.66(d,J=12.0Hz,2H),2.36–2.25(m,2H),2.18(s,4H),1.89(s,1H), 1.75(d,J=12.0Hz,1H), 1.61(d,J=12.0Hz,3H), 1.44(d,J=7.1Hz,3H), 1.32(s,4H), 1.14(t,J=12.3Hz,2H).

[0534] MS m / z(ESI):596.1(M+1) + .

[0535] Example 9 (Compounds 74R, 74-P1, 74-P2)

[0536] first step

[0537] Compound 74-1 (270 mg 2.09 mmol) and compound 2-BOC-5-oxa-7-oxo-2-azaspiro[3.4]octane (470 mg 2.09 mmol) were added to methanol (4 ml), followed by sodium cyanoborohydride (260 mg 4.81 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%-10%) to obtain compound 74-2 (301 mg).

[0538] MS m / z(ESI):341.1(M+1) + .

[0539] Step 2

[0540] Compound 74-2 (301 mg, 0.88 mmol) was added to DCM (2 ml), followed by trifluoroacetic acid (2 ml). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain compound 74-3 (200 mg), which was then used for the next step.

[0541] MS m / z(ESI):241.1(M+1) + .

[0542] Step 3

[0543] Compound 74-3 (200 mg 0.83 mmol) and intermediate A (87 mg 0.25 mmol) were added to DMSO (4 ml), followed by the addition of cesium carbonate (540 mg 1.62 mmol). The reaction mixture was heated and stirred at 80°C for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature and extracted with EA (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 7 / 1) to obtain compound 74R.

[0544] MS m / z(ESI):554.1(M+1) + .

[0545] Step 4

[0546] Compound 74R was purified by SFC (chromatographic column: Daicel OZ (25*250 mm, 10.0 um); mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 50 / 50; column temperature: 30°C; flow rate: 100 mL / min; detection wavelength: 214 nm; column pressure: 100 bar) to give compounds 74-P1 (31.16 mg) and 74-P2 (25.50 mg).

[0547] MS m / z(ESI):554.1(M+1) + .

[0548] Compound 74-P1 (retention time: 1.423 minutes):

[0549] 1 H NMR (400MHz, DMSO-d6): δ12.23(s,1H),7.54(d,J=2.1Hz,1H),7.48(d,J=8.4Hz,1H),7.37(dd,J=8.3, 1.9Hz,2H),5.42(p,J=7.0Hz,1H),3.85(dt,J=11.6,5.4Hz,4H),3.66–3.51(m,2H),2.95(dd,J=14.0,7 .1Hz,1H),2.81(d,J=9.7Hz,1H),2.47–2.35(m,2H),2.24(dd,J=12.5,7.5Hz,1H),2.18(s,3H),2.14– 2.01(m,2H),1.91(d,J=6.5Hz,1H),1.76(d,J=11.0Hz,1H),1.60(s,1H),1.40(dd,J=24.4,8.9Hz,5H).

[0550] MS m / z(ESI):554.1(M+1) + .

[0551] Compound 74-P2 (retention time: 2.053 minutes):

[0552] 1 H NMR (400MHz, DMSO-d6): δ12.22(s,1H),7.54(d,J=2.1Hz,1H),7.48(d,J=8.4Hz,1H),7.38(dd,J= 8.4,2.2Hz,2H),5.41(p,J=7.0Hz,1H),3.93(d,J=9.5Hz,1H),3.89–3.82(m,1H),3.74(d,J=8.6Hz ,3H),3.55(dd,J=8.5,6.9Hz,1H),3.00–2.91(m,1H),2.69–2.58(m,2H),2.38(dd,J=11.4,7.6Hz, 1H), 2.18 (s, 5H), 2.02–1.90 (m, 2H), 1.76 (d, J = 10.1Hz, 1H), 1.62 (s, 1H), 1.41 (t, J = 12.5Hz, 5H).

[0553] MS m / z(ESI):554.1(M+1) + .

[0554] Example 10 (Compounds 90R, 90-P1, 90-P2)

[0555] first step

[0556] At room temperature, compound 85-5 (1.20 g, 2.48 mmol) was added to a solution of compound (R)-3-pyrrolidineacetic acid hydrochloride (1.48 g, 7.44 mmol) in methanol (50 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0°C, and then sodium cyanoborohydride (0.47 g, 7.44 mmol) was slowly added to the reaction solution. The mixture was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 20 hours. LCMS monitored the completion of the reaction. Water (10 ml) was first added to the reaction solution to quench the reaction, and then concentrated until solid precipitated. DMF (8 ml) was added to the mixture until it dissolved and clarified. After reverse phase purification (H2O:MeOH=65%-68%), compound 90R (550.0 mg) was obtained.

[0557] MS m / z(ESI):596.2(M+1) + .

[0558] Step 2

[0559] Compound 90 (550.0 mg, 0.84 mmol) was separated by SFC (chromatographic column: Daicel AS; 25×250 mm, 10 μm; mobile phase: CO2 / EtOH [0.5% NH3 (7 M in MeOH)] = 75 / 25; column temperature: 30°C; flow rate: 100 mL / min) to give compound 90-P1 (146.9 mg) and compound 90-P2 (169.7 mg).

[0560] 90-P1 (retention time: 1.688 minutes):

[0561] 1H NMR (400MHz, DMSO-d6): δ7.55(d,J=2.1Hz,1H),7.43(d,J=8.4Hz,1H),7.37(dd,J=8.4,2.1Hz,1H),7.2 6(d,J=6.8Hz,1H),5.36(p,J=6.9Hz,1H),3.95(d,J=12.8Hz,2H),3.66(dd,J=11.7,3.4Hz,1H),3.49(t ,J=11.3Hz,1H),3.12(s,1H),2.91(t,J=11.0Hz,1H),2.72(t,J=7.9Hz,1H),2.52(s,2H),2.46–2.30(m ,2H),2.30–2.13(m,6H),1.91(m,2H),1.69(t,J=22.0Hz,2H),1.44(d,J=7.1Hz,3H),1.38–0.98(m,6H).

[0562] MS m / z(ESI):596.2(M+1) + .

[0563] 90-P2 (retention time: 2.987 minutes):

[0564] 1 H NMR (400MHz, DMSO-d6): δ7.56(d,J=2.1Hz,1H),7.43(d,J=8.4Hz,1H),7.36(dd,J=8.4,2.1Hz,1H),7.26(d,J=6.7Hz ,1H),5.40–5.30(m,1H),3.97(d,J=13.2Hz,2H),3.66(dd,J=11.6,3.3Hz,1H),3.49(t,J=11.3Hz,1H),3.08–2.97(m, 1H),2.91(t,J=11.6Hz,1H),2.74(t,J=8.0Hz,1H),2.55(d,J=7.2Hz,2H),2.46–2.22(m,5H),2.22–2.09(m,4H),1.98 –1.79(m,2H),1.72(d,J=11.4Hz,1H),1.59(s,1H),1.44(d,J=7.1Hz,3H),1.39–1.18(m,4H),1.06(t,J=12.0Hz,1H).

[0565] MS m / z(ESI):596.2(M+1) + .

[0566] Example 11 (Compound 91R)

[0567] first step

[0568] At room temperature, compound 91-1 (500 mg, 1.48 mmol) was dissolved in DMSO (6 mL), and 1-oxa-9-azaspiro[5.5]undecane-4-ol (380.15 mg, 2.22 mmol) and cesium carbonate (1.45 g, 4.44 mmol) were added thereto. The reaction mixture was stirred at 80 ° C for 16 hours. The reaction solution was poured into water (30 mL), extracted with dichloromethane (30 mL × 3), washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain compound 91-2 (514 mg). The synthesis of 91-1 refers to patent WO2023196432A1 page 264.

[0569] MS m / z(ESI):471.1(M+H) + .

[0570] Step 2

[0571] In an ice-water bath, compound 91-2 (200 mg, 0.42 mmol) was dissolved in dichloromethane (3 mL), and Dess-Martin periodinane (445.35 mg, 1.05 mmol) was added. The mixture was then stirred at room temperature for 16 hours. The reaction solution was poured into saturated sodium sulfite (50 mL), extracted with dichloromethane (30 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 91-3 (240 mg).

[0572] MS m / z(ESI):469.1(M+H) + .

[0573] Step 3

[0574] Compound 91-3 (240 mg, 0.41 mmol) and (R)-(-)-piperidine-3-carboxylic acid (52.96 mg, 0.41 mmol) were dissolved in methanol (3 mL) at room temperature and stirred for 30 minutes. Sodium cyanoborohydride (77.29 mg, 1.23 mmol) was then added and stirred for 16 hours. After completion of the reaction, the reaction solution was poured into water (30 mL), extracted with dichloromethane (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (dichloromethane:methanol = 5:4) to obtain crude compound 91 (180 mg). The crude product was purified by preparative HPLC (column: XBridge-C18 19x250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 35-50%; wavelength: 214 nm) to give compound 91R (67.9 mg).

[0575] 1 H NMR (400MHz, DMSO-d6): δ12.32(s,1H),7.82(s,1H),7.57(m,1H),7.47–7.41(m, 2H),7.38(m,1H),5.44–5.35(m,1H),4.03–3.90(m,2H),3.73–3.65(m,1H),3.49( t,J=12.0Hz,1H),3.20–2.77(m,4H),2.33(m,3H),2.19(s,1H),1.90(d,J=13.6Hz ,1H),1.77(s,1H),1.60(s,2H),1.45(d,J=7.2Hz,3H),1.34(m,4H),1.16(m,1H).

[0576] MS m / z(ESI):582.2(M+H) + .

[0577] Example 12 (Compound 92R)

[0578] Compound (R)-pyrrolidine-2-acetic acid (320 mg, 2.47 mmol) and sodium cyanoborohydride (207 mg, 3.3 mmol) were added sequentially to a solution of compound 85-5 (800 mg, 1.65 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred at 60°C for 16 h. After completion of the reaction, the reaction solution was concentrated and then purified using a Combi-Flash rapid preparative column (C18 reverse phase column, mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), gradient: 35%-40%) to obtain the crude product. The crude product was then purified by high-performance liquid chromatography (Prep-HPLC: Kromasil 100-5-C18 21.2 x 150 mm; ACN:H2O (0.1% FA) = 8-35%, UV: 214 nm) to obtain compound 92R (460 mg).

[0579] 1 H NMR (400MHz, DMSO-d6): δ7.55(d,J=2.1Hz,1H),7.43(d,J=8.4Hz,1H),7.37(dd,J=8.4,2.1Hz,1H), 7.28(d,J=6.8Hz,1H),5.44–5.31(m,1H),3.96(d,J=12.8Hz,2H),3.72(dd,J=11.8,3.8Hz,1H),3.5 9–3.51(m,1H),3.32(s,1H),3.12(s,2H),2.98–2.83(m,2H),2.74(t,J=8.3Hz,1H),2.39–2.22(m,2 H), 2.19 (s, 3H), 1.94 (m, 2H), 1.77–1.66 (m, 3H), 1.46 (m, 4H), 1.35 (s, 2H), 1.19 (q, J = 12.5Hz, 1H).

[0580] MS m / z(ESI):596.2(M+1) + .

[0581] Example 13 (Compounds 105-P1, 105-P2, 105-P3, 105-P4)

[0582] first step

[0583] Compound 105-1 (600 mg, 3.72 mmol) was dissolved in dimethyl sulfoxide (10 mL) at room temperature, and intermediate A (1.31 g, 3.72 mmol) and cesium carbonate (3.64 g, 11.16 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (100 mL), extracted with dichloromethane (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was separated on a silica gel column (petroleum ether:ethyl acetate = 5:3) to obtain compound 105-2 (1.02 g).

[0584] MS m / z(ESI):443.1(M+H) + .

[0585] Step 2

[0586] Compound 105-2 (1.02 g, 2.30 mmol) was dissolved in anhydrous dichloromethane (10 mL) under an ice-water bath, and Dess-Martin reagent (2.93 g, 6.90 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of sodium sulfite (100 mL), extracted with dichloromethane (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate = 5:2) to obtain compound 105-3 (400 mg).

[0587] MS m / z(ESI):441.1(M+H) + .

[0588] Step 3

[0589] Compound 105-3 (370 mg, 0.67 mmol) was dissolved in methanol (5 mL) at room temperature, followed by the addition of ethylamine hydrochloride (163.90 mg, 2.01 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (126.31 mg, 2.01 mmol) and continued stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water (20 mL), extracted with dichloromethane (10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford compound 105-4 (210 mg).

[0590] MS m / z(ESI):470.2(M+H) + .

[0591] Step 4

[0592] Compound 105-4 (284 mg, 0.54 mmol) and 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (97.56 mg, 0.76 mmol) were dissolved in toluene (3 mL) at room temperature. The reaction mixture was stirred at 140°C for 2 hours, and then diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (192.86 mg, 0.76 mmol) was slowly added portionwise at 140°C. The reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 2:3) to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: YMC-Actus Triart-C18 150x20 mml, 12 nm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 35-50%; wavelength: 214 nm) to afford 105P1 (46.03 mg) and 105P2 (23.37 mg). 105P1 and 105P2 may contain a mixture of two, three, or four isomers of 105-P1, 105-P2, 105-P3, and 105-P4.

[0593] 105P1:

[0594] MS m / z(ESI):582.17[M+1] + .

[0595] 1 H NMR (400MHz, DMSO-d6): δ12.18(s,1H),7.60–7.41(m,2H),7.40–7.25(m,2H),5.42(m,1H),4.00–3.49(m,5H),3.44(m,1H),3.2 9–3.20(m,1H),3.12(m,1H),2.44(m,4H),2.18(s,4H),1.79(m,3H),1.43(d,J=7.2Hz,3H),1.25(s,3H),0.89(t,J=7.2Hz,3H).

[0596] 105P2:

[0597] MS m / z(ESI):582.17[M+1] + .

[0598] 1H NMR (400MHz, DMSO-d6): δ12.08(s,1H),7.57–7.43(m,2H),7.41–7.30(m,2H),5.42(m,1H),4.00–3.54(m,5H),3.45(m,1H), 3.29–3.18(m,3H),2.47(s,1H),2.27–2.07(m,6H),1.88(m,3H),1.43(d,J=7.2Hz,3H),1.31(s,3H),0.90(t,J=7.2Hz,3H).

[0599] Example 14 (Compounds 106P1, 106P2)

[0600] Compound 105-4 (100 mg, 0.21 mmol) was dissolved in methanol (1 mL) at room temperature, and 3-oxocyclobutanecarboxylic acid (71.88 mg, 0.63 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours, followed by the addition of sodium cyanoborohydride (39.59 mg, 0.63 mmol) and continued stirring at 60°C for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified on a silica gel column (dichloromethane:methanol = 2:1) to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters XB-C18 19x250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-45%; wavelength: 214 nm) to obtain 106P1 (5.9 mg) and 106P2 (53.7 mg). 106P1 and 106P2 may contain a mixture of 2, 3 or 4 isomers among 106-P1, 106-P2, 106-P3 and 106-P4.

[0601] 106P1:

[0602] MS m / z(ESI):568.17[M+1] + .

[0603] 1H NMR (400MHz, DMSO-d6): δ12.12(s,1H),7.55–7.53(m,1H),7.48(d,J=8.4Hz,1H),7.40–7.35(m, 2H),5.45–5.39(m,1H),3.94(d,J=9.6Hz,1H),3.84(d,J=9.2Hz,1H),3.77(t,J=7.6Hz,2H),3.71 (m,1H),3.59(m,1H),3.43(m,1H),3.37(m,1H),3.27(m,1H),2.76(t,J=9.6Hz,1H),2.47(m,1H), 2.18(m,3H),2.16–2.06(m,4H),1.99–1.76(m,2H),1.43(d,J=7.2Hz,3H),0.90(t,J=7.2Hz,3H).

[0604] 106P2:

[0605] MS m / z(ESI):568.17[M+1] + .

[0606] 1 H NMR (400MHz, DMSO-d6): δ7.54(d,J=2.4Hz,1H),7.48(d,J=8.4Hz,1H),7.40–7.35 (m,2H),5.42(m,1H),3.94(d,J=9.6Hz,1H),3.88–3.75(m,3H),3.71(s,1H),3.49 –3.41(m,2H),3.26(m,1H),3.04(m,1H),2.66–2.55(m,1H),2.46(m,1H),2.21(m, 2H), 2.18 (s, 3H), 2.01–1.79 (m, 4H), 1.43 (d, J = 7.2Hz, 3H), 0.90 (t, J = 7.2Hz, 3H).

[0607] Example 15 (Compounds 108P1 and 108P2)

[0608] At room temperature, compound (R) 3-oxocyclopentanecarboxylic acid (80.72 mg, 0.63 mmol) was added to a solution of compound 105-4 (100 mg, 0.21 mmol) in methanol (1 mL). The reaction mixture was stirred at room temperature for 16 hours. Then, sodium cyanoborohydride (39.59 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure and purified by reverse phase separation (water:methanol = 5:3) to obtain the crude product. The crude product was purified by preparative HPLC (column: YMC-Actus Triart-C18 150x20mml.DS-5um, 12um; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-55%; wavelength: 214 nm) to obtain compound 108P1 (8.0 mg) and compound 108P2 (18.1 mg). Compound 108P1 and Compound 108P2 may contain a mixture of 2, 3, or 4 isomers among 108-P1, 108-P2, 108-P3, and 108-P4.

[0609] 108P1:

[0610] MS m / z(ESI):582.17[M+1] + .

[0611] 1 H NMR (400MHz, DMSO-d6): δ7.53(t,J=2.0Hz,1H),7.48(m,1H),7.41–7.35( m,2H),5.48–5.36(m,2H),3.90(m,2H),3.74(m,3H),3.47(m,2H),3.11(m, 1H),2.74(m,1H),2.43(m,2H),2.18(s,3H),1.88(m,3H),1.75(s,2H),1.6 2–1.53(m,2H),1.43(d,J=7.2Hz,3H),1.36(m,1H),0.95(t,J=7.2Hz,3H).

[0612] 108P2:

[0613] MS m / z(ESI):582.17[M+1] + .

[0614] 1H NMR (400MHz, DMSO-d6): δ7.57–7.44(m,2H),7.41–7.33(m,2H),5.42(m,3.0H z,1H),3.89(m,2H),3.79–3.60(m,3H),3.48(m,2H),3.09–3.01(m,1H),2.61( m,1H),2.47–2.39(m,2H),2.18(s,3H),1.93(m,2H),1.78–1.63(m,3H),1.56– 1.47(m,1H),1.43(d,J=7.2Hz,3H),1.40–1.27(m,1H),0.95(t,J=7.2Hz,3H).

[0615] Example 16 (Compound 107)

[0616] first step

[0617] Compound 105-3 (697 mg, 1.58 mmol) was dissolved in methanol (10 mL), and methylamine hydrochloride (320.04 mg, 4.74 mmol) and sodium cyanoborohydride (297.86 mg, 4.74 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated to obtain a residue. The residue was separated by silica gel column chromatography (dichloromethane / methanol = 0% to 8%) to obtain compound 107-1 (346 mg).

[0618] MS m / z(ESI):456.1(M+H) + .

[0619] Step 2

[0620] At 25°C, 3-carbonyl-1-cyclohexanecarboxylic acid (63.97 mg, 0.45 mmol) was added to a solution of compound 107-1 (70 mg, 0.15 mmol) in methanol (2 mL). One drop of acetic acid was added to the reaction mixture. The reaction mixture was stirred at 60°C for 2 hours, then cooled to 25°C. Sodium cyanoborohydride (28.28 mg, 0.45 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 60°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (Waters XB-C18 19x250mm, 10 μm; ACN:H2O (10 mM NH4HCO3) = 50-65%, UV: 214 nm) to obtain compound 107 (16.6 mg).

[0621] Compound 107:

[0622] 1 H NMR (400MHz, DMSO-d6): δ12.12(s,1H),7.54(d,J=2.0Hz,1H),7.49(d,J=8 .4Hz,1H),7.40–7.34(m,2H),5.50–5.35(m,1H),4.01–3.57(m,6H),3.52– 3.45(m,1H),2.74–2.62(m,1H),2.19(s,3H),2.06(d,J=5.5Hz,3H),1.97– 1.72(m,4H),1.65–1.52(m,2H),1.43(d,J=7.1Hz,4H),1.34–1.13(m,4H).

[0623] MS m / z(ESI):582.2(M+H) + .

[0624] Comparative Example (Synthesis of Compounds B-P1 and B-P2)

[0625] first step

[0626] Triethylamine (4.6 g, 45.6 mmol) was added to a solution of B-1 (3 g, 15.2 mmol) and (R)-1-(2,4-dichlorophenyl)ethanamine (3.04 g, 16 mmol) in ethanol (140 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether:ethyl acetate = 1:0-10:1) to obtain product B-2 (4.7 g).

[0627] MS m / z(ESI):350.1(M+1).

[0628] Step 2

[0629] Cesium carbonate (1.6 g, 11.4 mmol) was added to a solution of B-2 (1.2 g, 3.4 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (620 mg, 2.7 mmol) in acetonitrile (20 mL). The reaction mixture was heated to 80°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The resulting residue was purified by silica gel column chromatography using an eluent system (petroleum ether:ethyl acetate = 1:0-5:1) to obtain product B-3 (1 g).

[0630] MS m / z(ESI):540.2(M+1).

[0631] Step 3

[0632] B-3 (300 mg, 0.56 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (5 mL), and the reaction system was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product B-4 (300 mg), which was used directly in the next step without purification.

[0633] MS m / z(ESI):440.2(M+1).

[0634] Step 4

[0635] Sodium cyanoborohydride (140 mg, 2.2 mmol) was added to a solution of B-4 (200 mg, 0.37 mmol) and 1-methyl-3-oxocyclobutane-1-carboxylic acid (142 mg, 1.11 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified using reverse phase preparative chromatography to obtain pure products B-P1 (63.2 mg) and B-P2 (52.3 mg).

[0636] B-P1:

[0637] 1 H NMR (400MHz, DMSO) δ12.18(s,1H),8.07–7.44(m,2H),7.38(dd,J=8.4,2.1Hz,1H),7.30(d,J=7.3Hz,1H),5.51–5.37(m,1H),3.58– 3.40(m,2H),3.30(s,1H),2.73–2.53(m,2H),2.46–2.37(m,3H),2.37–2.25(m,2H),2.18(s,3H),1.72–1.37(m,10H),1.28(s,3H).

[0638] MS m / z(ESI):552.2(M+1).

[0639] B-P2:

[0640] 1H NMR (400MHz, DMSO) δ7.51(dd,J=18.3,5.3Hz,2H),7.37(dd,J=8.4,2.1Hz,1H),7.29(d,J=7.3Hz,1H),5.88–5.23(m,1H),3.59–3.43(m ,3H),2.81–2.60(m,2H),2.40–2.24(m,1H),2.21–2.12(m,5H),2.14–1.99(m,3H),1.94–1.81(m,2H),1.55–1.39(m,7H),1.30(s,3H).

[0641] MS m / z(ESI):552.2(M+1).

[0642] Biological testing

[0643] Test Example 1 Calcium flux assay of HEK293-CCR4 cells using the compounds of the present invention

[0644] 20 μL of 50 μg / mL coating solution (containing poly-lysine) was added to a 384-well cell plate (Greiner, 781090). After pre-incubation at 37°C for 2 hours or at 4°C overnight, the coating solution was discarded and the cells were washed with sterile water. HEK293-CCR4 cells (see Li G, Li GY, etc. The chemokine-like factor 1 induces asthmatic pathological change by activating nuclear factor-κB signaling pathway. Int Immunopharmacol. 2014, 20(1):81-88) were diluted to 1×10 with culture medium (DMEM+10% FBS+300 μg / mL G418+BS (Blasticidin) 2 μg / mL+1% PS (Penicillin-Streptomycin)). 6cells / mL, 20μL / well was added to the 384-well cell plate after washing as above; after incubation in a 5% CO2, 37℃ incubator overnight, the cell culture medium was removed, and 20L of experimental buffer (20mM HEPES, 1×HBSS, 0.5% BSA) and 20μL of 2×Fluo-4 detection reagent (Invitrogen, F10471, final concentration 4μM, containing 2.5mM Probenecid) were added to each well in sequence, incubated in a 37℃ incubator for 50min, and then allowed to stand at room temperature for 10min. The agonist working solution CCL17 (final concentration of 1μM, 4-fold dilution, 10 concentrations) after serial dilution of the experimental buffer and the above cell plate were placed in the FLIPR instrument, the instrument was started, 10μL of agonist was transferred to the cell plate, the reading was read, and the EC was calculated. 80 .

[0645] The test compound was prepared with laboratory buffer to a final concentration of 3 μM, with 10 concentrations, 3-fold dilutions, and duplicate wells. The final DMSO concentration was 0.5%. 20 μL of experimental buffer was added to the cell culture plate after removing the culture medium. Then, 20 μL of 2×Fluo-4 detection reagent and 10 μL of the test compound were added. The plate was incubated at 37°C for 50 minutes, and then allowed to stand at room temperature for 10 minutes. The FLIPR instrument was started, and 10 μL of 6×EC80 agonist working solution was transferred to the cell plate. The plate was read, and the inhibition rate of each compound was calculated according to the following formula:

[0646] Antagonist inhibition rate: inhibition rate % = 100-(RLU-LC) / (DMSO-LC)*100

[0647] RLU: fluorescence signal value, 1 to the maximum allowed reading;

[0648] DMSO: average fluorescence signal of DMSO group; LC: average fluorescence signal of the highest antagonist concentration.

[0649] The experimental test results are shown in Table 1 below.

[0650] Table 1

[0651] The above data show that the compound of the present invention has a potent antagonistic effect on CCR4 receptor.

[0652] Test Example 2 CCR4-mediated CCRF-CEM chemokine inhibition experiment

[0653] Experimental procedures

[0654] CCRF-CEM cells (ATCC, CCL-119) were centrifuged, the supernatant was removed, and the cells were resuspended in human serum to adjust the cell density to 2.5 × 10 6 / mL, plate the cells into 96-well cell plates, 100 μL per well. Dissolve the test compound in DMSO to a 10 mM stock solution and store at -20°C for use. The starting concentration of the compound is 5 μM, 0.4% DMSO, 4-fold dilution, 7 concentrations, two replicates. Transfer 25 μL of the test compound to each well of the cells in a 96-well plate (Corning, 3599) and incubate in a cell culture incubator at 37°C and 5% carbon dioxide for 0.5 hours. Prepare a 1 nM hCCL22 (PROSPEC, chm-250-b) solution in HBSS (gibco, 14175-09 500 ml) buffer containing 0.1% BSA (Biyuntian, ST025-5g), and remove Transport Receiver Plate (Millpore, MATRNPS50) was added with 330 μL of hCCL22 solution and placed Remove the cells from the incubator and transfer 100 μL of cells to each well of the filter plates (Millpore, MAMIC5S10). Cover the well and incubate in a cell culture incubator at 37°C and 5% carbon dioxide for 1 hour. Aspirate the liquid in the upper chamber, remove the upper chamber, and place it in another Millpore plate with 330 μL of Cell / Tissue Dissociation Solution (Accumax, AM-105) added. The Transport Receiver Plate was placed in a cell culture incubator at 37°C and 5% carbon dioxide together with the previous lower chamber receiving solution for another 0.5 hour. The lower chamber receiving solution was removed. 50 μL of the lower chamber receiving solution from each well was mixed in a white opaque 96-well plate. 50 μL of CellTiter-Glo (Promega, G7571) reagent was added. After incubation in the dark for 30 minutes, the luminescence signal was read using a Molecular Device SpectraMax i3x microplate reader. The inhibition rate of the compound on cell migration was obtained by fitting with Graphpad software, and the IC was calculated. 50 .

[0655] The compounds of the present application have good activity in inhibiting CCR4-mediated CCRF-CEM chemokines.

[0656] Test Example 3 Evaluation of Pharmacokinetic Properties in Mice

[0657] 3.1 Experimental methods

[0658] A certain amount of the test compound 7R-P2 was weighed and dissolved in 10% DMAC (N,N-dimethylacetamide) + 10% Solutol (polyethylene glycol-15 hydroxystearate) + 80% PBS. The mixture was vortexed and heated and sonicated to prepare a clear solution of the appropriate concentration. Male ICR mice were administered the test compound solution intravenously at a dose of 1 mg / kg. A certain amount of the test compound 7R-P2 was weighed and dissolved in 10% DMAC (N,N-dimethylacetamide) + 10% Solutol (polyethylene glycol-15 hydroxystearate) + 80% PBS. The mixture was vortexed and heated and sonicated to prepare a clear solution of the appropriate concentration. Male ICR mice were administered the test compound solution orally at a dose of 5 mg / kg. Whole blood was collected at specific time points, and plasma was prepared. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0659] The experimental test results are shown in Table 2 below.

[0660] Table 2

[0661] The compound of the present application has good pharmacokinetic properties in mice.

[0662] Test Example 4 Evaluation of Pharmacokinetic Properties in Rats

[0663] 4.1 Experimental methods

[0664] A certain amount of the test compound was weighed and dissolved in 10% DMAC (N,N-dimethylacetamide) + 10% Solutol (polyethylene glycol-15 hydroxystearate) + 80% PBS. The mixture was vortexed and heated and sonicated to prepare a clear solution of the appropriate concentration. Male SD rats were selected and administered the test compound solution intravenously at a dose of 1 mg / kg. A certain amount of the test compound was weighed and dissolved in 10% DMAC (N,N-dimethylacetamide) + 10% Solutol (polyethylene glycol-15 hydroxystearate) + 80% PBS. The mixture was vortexed and sonicated to prepare a clear solution of the appropriate concentration. Male SD rats were orally administered the test compound solution at a dose of 5 mg / kg. Whole blood was collected at specific time points, and plasma was prepared. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0665] The experimental test results are shown in Table 3 below.

[0666] Table 3

[0667] The compound of the present application has good pharmacokinetic properties in rats.

[0668] The above is a description of specific embodiments of the present invention. It should be understood that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for the purpose of illustrating the principles of the present invention. Those skilled in the art may make various non-substantial changes and improvements to the present invention without departing from the scope of the present invention, and all of these fall within the scope of protection claimed in the present invention.

Claims

1. A compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, in: T is G 1 CR 8 or N; G 2 CR 9 or N; G 3 CR 10 or N; Z is O, S, Se, -S(O)2- or NR a ; X and Y are the same or different and are each independently O, S, Se, -S(O)2-, NR a or CR c R d ; R 1 For LR 12 ; L is a chemical bond, O, S, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R 13 )-、C 1-6 Alkylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-10 Aryl and 5-10 membered heteroaryl are optionally selected from hydroxy, amino, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 One or more of cycloalkyl and 3-12 membered heterocyclic groups are substituted; R 12 Selected from H, halogen, cyano, -N3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R g replace; R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, amino and C 3-12 The cycloalkyl group is substituted by one or more substituents; Or, when L is NR 13 When R 12 and R 13 The nitrogen atom to which it is attached optionally forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g replaced by; R 2 and R 3 are the same or different and are each independently selected from H, halogen, cyano, C 2-6 Alkynyl, -N3, hydroxyl, amino, oxo, C 1- 6 alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered hetero The aryl groups are each independently optionally substituted with one or more R g replace; R 4 H, D, halogen or C 1-6 alkyl; R 5 and R 6 are the same or different and are independently selected from H, halogen, cyano, -N3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R g replace; Each R 7 are the same or different and are each independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R g replace; R 8 , R 9 and R 10 are the same or different and are each independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; R 11 Selected from H, halogen, cyano, amino, -N3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , -SF5、 C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R g replace; R a Selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; R c and R d are the same or different and are independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; Or, R c and R d Together with the atoms it is connected to, it forms C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-12 membered heterocyclyl are each optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12-membered heterocyclic group; Or, R 4 and R 11 Together with the atoms it is connected to, it forms C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl, the C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl and 5-6 membered heteroaryl are optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12-membered heterocyclic group; Or, when G 3 CR 10 When R 10 and R 11 Together with the atoms it is connected to, it forms C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl, the C 4-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-6 membered heteroaryl is optionally selected from cyano, C 2-6 Alkynyl, halogen, sulfone, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 substituted by one or more substituents of cycloalkyl and 3-12-membered heterocyclic group; Each R g are the same or different and are each independently halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, -NHC(O)R g1 、-NHS(O)2R g2 、-S(O)2R g2 、-C(O)NR g3 R g4 、-S(O)2NR g3 R g4 、-NR g3 R g4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl and C 3-12 The cycloalkyl group is substituted by one or more substituents; R k1 , R k2 , R k3 , R k4 , R k5 , R g1 , R g2 , R g3 and R g4 are the same or different, each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, carboxyl, -CONH2, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl and C 3-12 The cycloalkyl group is substituted by one or more substituents; t is 0, 1, or 2; p is 0, 1, 2 or 3; q is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1 or 2; k is 1, 2, 3, 4 or 5; x is 1 or 2; y is 1 or 2; Wherein, the heteroatoms in the heterocyclylene group, heterocyclyl group and heteroaryl group are selected from O, N and S, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

2. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by the formula (IG) satisfies any one of the following conditions, (1) T is X and Y are the same or different and are each independently O, S, Se, -S(O)2-, NR a or CR c R d ; (2) T is Z is O, S, Se, -S(O)2- or NR a ; (3) T is Z is O, S, Se, -S(O)2- or NR a ; R 11 Selected from -SF5 or (4) T is Z is O, S, Se or NR a ; R 11 Selected from H, halogen, cyano, amino, -N3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R g replace; (5) The compound represented by formula (IG) is a compound represented by formula (I), Wherein, Z is O, S, Se or NR a R b ; R 11 Selected from H, halogen, cyano, amino, -N3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHNR k2 R k3 、-ONR k2 R k3 、-NHC(O)NHNR k2 R k3 、-NHC(O)NR k2 R k3 、-N(O) y 、-NR k2 R k3 、-C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、-NR k2 OR k4 , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more R g replace; R a and R b are the same or different and are independently selected from H, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; Or, R a and R b Together with the nitrogen atom connected thereto, a 3-12 membered heterocyclic group is formed, wherein the 3-12 membered heterocyclic group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 The cycloalkyl group and the 3- to 12-membered heterocyclic group are substituted by one or more substituents.

3. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound represented by the formula (IG) satisfies one or more of the following conditions: (1) Z is O; (2) G 1 is N; (3) k is 2; (4) for (5) In L, the 3-12 membered heterocyclylene group is a "3-8 membered heterocyclylene group wherein the heteroatom is O or N"; preferably a 4-6 membered heterocyclylene group containing an aza or oxa group; more preferably a 4-6 membered azacyclylene group, for example, an azetidinyl group, an azacyclopentyl group or an azacyclohexyl group; (6)R 12 , R 13 , R g , R k2 , R k3 and R k4 In the C 1-6 Alkyl is C 1-4 Alkyl, preferably methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl; (7)R 5 , R 12 , R 13 , R g , R k2 , R k3 and R k4 In the C 3-12 Cycloalkyl is C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8)R 10 and R 11 Together with the atoms it is connected to, it forms C 4-8 In the cycloalkyl group, the C 4-8 Cycloalkyl is C 4-6 Cycloalkyl, preferably cyclobutyl, cyclopentyl or cyclohexyl; (9)R 12 , R 13 , R k2 , R k3 and R k4 In the above, the 3-12 membered heterocyclic group is a "3-8 membered heterocyclic group wherein the heteroatom is O or N"; preferably, an aza or oxa 4-6 membered heterocyclic group; more preferably, an azetidinyl, an azacyclopentyl or an azacyclohexyl; (10)R 12 and R 13 In the 4-8 membered heterocyclic group formed together with the nitrogen atom connected thereto, the 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group whose heteroatom is O or N; preferably a 4-6 membered azacyclic group, more preferably an azetidinyl, azacyclopentyl or azacyclohexyl group.

4. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The compound represented by formula (IG) is a compound represented by formula (IIA), formula (IIB), formula (IIA-2), formula (IIB-2), formula (IIG-1), formula (IIG-2), formula (IIG-3), formula (IIG-1b), formula (IIG-2b) or formula (IIG-3b), in, R 4 H or C 1-6 alkyl; R 5 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-12 Cycloalkyl; R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; R 11 Selected from H, halogen, cyano and C 1-6 alkyl; Or, R 4 and R 11 The atoms connected thereto form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group; Or, R 10 and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heteroaryl group, C 4-8 Cycloalkyl or C 6-8 Aryl, the 5-6 membered heteroaryl, C 4-8 Cycloalkyl or C 6-8 Aryl is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1- 6 is substituted by one or more substituents in a haloalkoxy group; R 7A and R 7B are the same or different, each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; T.R 1 , R 2 , R 3 , m, n and t are as defined in any one of claims 1 to 3; The heteroaryl group is a heteroatom selected from O, N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5.

5. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: R 4 and R 11 The atoms connected thereto form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by one or more substituents in a haloalkoxy group; or, R 10 and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heteroaryl or C 4-8 Cycloalkyl, the 5-6 membered heteroaryl or C 4-8 Cycloalkyl is optionally selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkoxy group; wherein, for For example 6. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound represented by formula (IG) is a compound represented by formula (IIIA1), formula (IIIA2), formula (IIIA3), formula (IIIA1-2), formula (IIIA2-2) or formula (IIIA3-2), Among them, R 10 H or C 1-6 Alkyl; R 14 , R 15 and R 16 are the same or different and are each independently H, cyano, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 1 , R 2 , R 3 , R 5 , R 7A , R 7B , m, n and t are as defined in any one of claims 1-5.

7. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: The compound represented by formula (IG) is a compound represented by formula (IIIB1), formula (IIIB2), formula (IIIB3), formula (IIIB1-2), formula (IIIB2-2), formula (IIIB3-2), formula (IIIG) or formula (IIIG-2), Among them, R 17 For cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R 18 and R 19 are the same or different and are each independently H, C 1-6 Alkyl or C 1-6 Haloalkyl; T, R 1 , R 2 , R 3 , R 5 , R 7A , R 7B , m, n and t are as defined in any one of claims 1-7.

8. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: The compound represented by the formula (IG) satisfies one or more of the following conditions: (1) t is 0, 1 or 2; (2) m is 0, n is 0; (3) p is 0, 1 or 2; (4) q is 0, 1 or 2; (5) L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S; preferably, L is a chemical bond or -N(R 13 )-; (6)R 12 Selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and-NR k2 R k3 , where the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S; Preferably, R 12 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and-NR k2 R k3 , wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S; (7)R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 Alkyl, C 3-12 The cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from halogen, hydroxy, cyano, amino and C 3-12 The cycloalkyl group is substituted by one or more substituents; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S; Preferably, R 13 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 The alkyl group and the 3-12 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, and amino; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N, and S; More preferably, R 13 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group; (8) Each R g are the same or different and are each independently selected from halogen, cyano, carboxyl, hydroxyl, oxo, C 1-6 Alkyl and C 3-12 ring Alkyl, the C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently selected from carboxyl, hydroxyl, cyano, halogen, oxo and C 1-6 The alkyl group is substituted by one or more substituents; Preferably, the R g are each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently selected from carboxyl, hydroxyl and C 1-6 The alkyl group is substituted by one or more substituents; (9)R k2 and R k3 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from hydroxyl, C 1-6 The 3- to 12-membered heterocyclic group is a 3- to 12-membered heterocyclic group having one or more heteroatoms selected from O, N and S; Preferably, R k2 and R k3 Each independently is C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group; (10)R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxyl, carboxyl, amino and oxo; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S; Preferably, R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by a hydroxyl group; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S.

9. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: When L is NR 13 When R 12 and R 13 Optionally, the nitrogen atom to which it is connected forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g The 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S; and / or, T is in, for Preferably More preferably for Preferably More preferably for Preferably More preferably 10. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that: The compound represented by the formula (IG) satisfies any of the following schemes, Option 1: R 1 NR 12 R 13 ; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl and -C(O)R k4 , where the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g replace; R 13 Selected from H, C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g replaced by; Each R g are the same or different and are each independently selected from halogen, cyano, carboxyl, hydroxyl, oxo, C 1-6 Alkyl and C 3-12 Cycloalkyl, the C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently selected from carboxyl, hydroxyl, cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkoxy group; R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group or C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxy, carboxyl, amino and oxo; Preferably, T is Scheme 2: L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S; R 12 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(O)R k4 and-NR k2 R k3 ; wherein said C 1-6 Alkyl, C 3- 12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently optionally substituted with one or more R g Substitution; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S; R 13 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group; wherein said C 1-6 The alkyl group and the 3-12 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, and amino; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N, and S; Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g The 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S; The R g are each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently selected from carboxyl, hydroxyl and C 1-6 The alkyl group is substituted by one or more substituents; R k2 and R k3 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally selected from hydroxyl, C 1-6 The 3- to 12-membered heterocyclic group is a 3- to 12-membered heterocyclic group having one or more heteroatoms selected from O, N and S; R k4 is a 3-12 membered heterocyclic group or a C 1-6 Alkyl, the 3-12 membered heterocyclic group and C 1-6 The alkyl group is optionally substituted by one or more selected from halogen, cyano, hydroxyl, carboxyl, amino and oxo; the 3-12 membered heterocyclic group is a 3-12 membered heterocyclic group having one or more heteroatoms selected from O, N and S; Preferably, T is Scheme 3: T is L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S; R 12 For carboxyl, C 1-6 Alkyl, 3-12 membered heterocyclic group or -NR k2 R k3 ; wherein said C 1-6 The alkyl group is optionally substituted with one or more R g replace; R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g The 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S; The R g are each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxyl group; R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Scheme 4: T is L is a chemical bond, -N(R 13 )-, azacyclopentyl or azacyclohexyl; R 12 For carboxyl, C 1-6 Alkyl or -NR k2 R k3 ; wherein said C 1-6 The alkyl group is optionally substituted with one or more R g replace; R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms an azacyclopentyl or azacyclohexyl group; The R g are each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxyl group; R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Scheme 5: T is L is a chemical bond, -N(R 13 )- or 3-12 membered heterocyclylene; the 3-12 membered heterocyclylene is a 3-12 membered heterocyclylene having one or more heteroatoms selected from O, N and S; R 12 For carboxyl, C 1-6 Alkyl, 3-12 membered heterocyclic group or -NR k2 R k3 ; wherein said C 1-6 The alkyl group is optionally substituted with one or more R g replace; R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is connected, it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R g The 4-8 membered heterocyclic group is a 4-8 membered heterocyclic group having one or more heteroatoms selected from O, N and S; The R g are each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxyl group; R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Scheme 6: T is L is a chemical bond, -N(R 13 )-, azacyclopentyl or azacyclohexyl; R 12 For carboxyl, C 1-6 Alkyl or -NR k2 R k3 ; wherein said C 1-6 The alkyl group is optionally substituted with one or more R g replace; R 13 C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with a hydroxy group; Or, when L is NR 13 When R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms an azacyclopentyl or azacyclohexyl group; The R g are each independently selected from halogen, cyano, carboxyl, hydroxyl and C 1-6 Alkyl; the C 1-6 The alkyl groups are each independently substituted with a hydroxyl group; R k2 and R k3 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a hydroxy group.

11. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that: The compound represented by the formula (IG) satisfies one or more of the following conditions: (1)R 1 for (2)R 2 and R 3 are the same, each independently H, halogen or C 1-6 Alkyl, preferably H; (3)R 5 H or C 1-6 Alkyl, preferably methyl; (4)R 6 H or C 1-6 Alkyl, preferably H; (5)R 7A and R 7B are the same or different and are each independently halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably halogen, such as Cl; (6) T is Preferably, T is More preferably, T is 12. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized in that: The compound represented by the formula (IG) has any of the following structures:

13. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that: The compound represented by the formula (IG) has any of the following structures:

14. A method for preparing a compound represented by formula (IG), characterized in that: The compound represented by formula (Y) reacts with the compound represented by formula (XI) to obtain the compound represented by formula (IG); Wherein, X is Cl, Br or I; T.R 4 , R 5 , R 6 , R 7 , R 11 , G 1 , G 2 , G 3 and k as described in any one of claims 1-13.

15. A compound represented by formula (Y), TH (Y) wherein, T is R 1 , R 2 , R 3 , Z, X, Y, m, n, p, q and t as described in any one of claims 1-14; Preferably, the compound represented by formula (Y) is selected from the following compounds, 16. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound represented by formula (IG) as described in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

17. Use of a compound represented by formula (IG) according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16 in the preparation of a medicament for regulating CCR4.

18. Use of the compound represented by formula (IG) according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating a disease mediated by CCR4 factor; Preferably, the disease is a disease or disorder in which CCR4 is highly expressed.

19. Use of a compound represented by formula (IG) according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases or cancer, for example, in the preparation of a medicament for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

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