Triazole compound as well as preparation method and medical application thereof

Abstract

The invention relates to a triazole compound, a preparation method thereof and application of the triazole compound in medicine. Specifically, the invention relates to a triazole compound as shown in a general formula (I), a preparation method of the triazole compound, a pharmaceutical composition containing the triazole compound and application of the triazole compound as a therapeutic agent. The invention also relates to a use thereof, in particular as an IL-17 inhibitor and a use thereof in the preparation of medicaments for the treatment and / or prevention of cancers, inflammations or autoimmune diseases or sarcopenia. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a triazole compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a triazole compound represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, as well as its use as an IL-17 inhibitor and its use in the preparation of a drug for treating and / or preventing cancer, inflammatory or autoimmune diseases, or sarcopenia. Background Art

[0002] IL-17 is a proinflammatory cytokine primarily produced by Th17 cells. IL-17 can act on epithelial cells, prompting them to secrete antimicrobial peptides and cytokines and promoting wound repair. Therefore, IL-17 plays a crucial role in the body's defense against foreign pathogens. However, excessive or abnormal IL-17 levels can induce chronic inflammation, leading to the development of various autoimmune diseases, such as psoriasis, psoriatic arthritis, axial spondyloarthritis, and hidradenitis suppurativa. The IL-17 family includes six members, IL-17A-F. IL-17A and IL-17F are Th17-associated cytokines. IL-17A and IL-17F can form three active dimers: IL-17AA, IL-17AF, and IL-17FF. IL-17AA exhibits the strongest proinflammatory activity. Compared to IL-17AA, IL-17AF is 10-fold less active, and IL-17FF is 100-fold less active. In addition, IL-17AA is the most important IL-17 cytokine mediating the occurrence of psoriasis, and the IL-17AA content in psoriasis patients is positively correlated with the severity of the disease.

[0003] Currently, the FDA has approved three IL-17 drugs. Novartis's Secukinumab is the first approved IL-17 (IL-17A) drug, with indications including psoriasis, psoriatic arthritis, axial spondyloarthritis, and juvenile atopic arthritis. Eli Lilly's Ixekizumab (IL-17A) is approved for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis. Valeant's Brodalumab (IL 17RA) is approved for the treatment of psoriasis, but patients taking the drug are at risk of suicide, and the FDA has added a black box warning. UCB's Bimekizumab (dual inhibition of IL-17A and F) has been approved for the treatment of psoriasis in the European Union and Japan, and is awaiting FDA approval in the United States.

[0004] IL-17 biological agents have differentiated designs. Secukinumab and Ixekizumab are traditional antibodies that are selective for IL-17A; Bimekizumab is a traditional antibody that dually inhibits IL-17A and F; Sonelokimab is a nanobody that dually inhibits IL-17A and F, with a molecular weight of 40kD and a human albumin-binding domain; Izokibep is an IL-17A-selective Affibody fusion protein with a molecular weight of 18.6kD and a human albumin-binding domain.

[0005] Overall, IL-17 antibodies have demonstrated excellent efficacy in psoriasis, with PASI 75 response rates reaching 75-90% after 12 weeks of treatment. The IL-17A-selective drugs secukinumab and ixekizumab have similar safety and efficacy profiles. In a head-to-head Phase 3 clinical trial of IL17A / F versus IL-17A antibodies, both IL17A / F antibodies demonstrated superior efficacy compared to IL-17A antibodies, but the side effect of oral Candida infections was significantly higher in IL17A / F than in IL-17A antibodies. Gene knockout studies in mice and human genetic studies have also demonstrated that both IL-17A and IL-17F play important roles in the body's defense against fungal infections such as Candida albicans, and that complete inhibition of IL-17A and IL-17F can increase Candida infection. Furthermore, psoriasis disease characteristics differ between Asians and Westerners: Westerners have larger lesions, while Asians have smaller lesions. However, Asian lesions contain higher concentrations of IL-17A. IL-17A antibodies are more effective in treating psoriasis in Asians. Therefore, selective inhibition of IL-17A is the most appropriate option for psoriasis.

[0006] Hidradenitis suppurativa is a difficult-to-treat autoimmune disease. Currently, only adalimumab is approved. Tissue damage and inflammation in hidradenitis suppurativa occur more deeply, requiring therapeutic agents with good tissue penetration. Furthermore, studies have shown that both IL-17A and IL-17F are enriched to a certain extent in hidradenitis suppurativa lesions, suggesting that both IL-17A and IL-17F play a role in disease pathogenesis. In a Phase 3 clinical trial for hidradenitis suppurativa, secukinumab increased HiSCR50 by 11% compared to placebo, while bimekizumab increased it by 26%, and sonelokimab by 38%. Izokibep, with a HiSCR50 of 71%, is currently the most effective IL-17 drug, but lacks a placebo control. For hidradenitis suppurativa, sonelokimab and izokibep, with their smaller molecular weight and better permeability, are more effective.

[0007] Targeting the combination of IL-17A and IL-17RA is an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases. Currently approved IL-17A neutralizing antibodies, secukinumab and ixekizulmab, can effectively treat IL-17A-mediated autoimmune inflammatory diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0008] Although there are many IL-17A antibodies, due to the cost of producing antibodies and the limitation of administration route (injection), the development of oral small molecule inhibitor drugs specific for IL-17A has good research and development prospects.

[0009] Patent applications for disclosed IL-17 inhibitor compounds include WO2021255174A1, WO2022091056A1, WO2021239743A1, WO2021239745A1, WO2021055376A1, WO2020163554A1, WO2020146194, WO2023283453A1, WO2023049886A1, WO2023202664A1, and the like. Summary of the Invention

[0010] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in:

[0013] R 1 is selected from the group consisting of a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -CHR 1a R 1b 、-OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 7 replace;

[0014] R 1a and R 1b the same or different, and each independently a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group; wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, the heteroaryl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the arylalkyl group and the heteroarylalkyl group are each independently optionally replaced by one or more R 7a Replacement; condition is, R 1a and R 1b Not all hydrogen atoms at the same time;

[0015] R 2a is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group;

[0016] Q is N or CR 2b ;

[0017] R 2 and R 2b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 9 、-NR 10 R 11、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 8 replace;

[0018] Each R 3 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a 6- to 14-membered heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-C(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, 6 to 14 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl groups are each independently optionally substituted by one or more R B replace;

[0019] Each R B are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v R 9 、-NR 12 S(O)v NR 10 R 11 , oxo, =S, =NR 13 Sum = CR 14 R 15 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R b replace;

[0020] R 4 =O or =S;

[0021] Or, R 4 connected to ring A to form a heterocyclic group or heteroaryl group fused to ring A; the heterocyclic group and heteroaryl group are each independently optionally substituted by one or more R 6 replace;

[0022] R 5 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; or R 5 does not exist;

[0023] Each R b 、R 6 、R 7 、R 7a and R 8 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxy, amino, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v R 9 、-NR 12 S(O) v NR 10 R 11 , oxo, =S, =NR 13 Sum = CR 14 R 15 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replace;

[0024] R 9 、R 10 、R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxyalkyl group, the cycloalkyl group, the heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group are each independently optionally replaced by one or more R c replace;

[0025] Or, R 10 and R 11 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R c replace;

[0026] R 13 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group;

[0027] R 14 and R 15are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl, a heteroarylalkyl, -C(O)alkyl, -C(O)Oalkyl and a cyano group; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl and a heteroarylalkyl are each independently optionally replaced by one or more R c replace;

[0028] Or, R 14 and R 15 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R c replace;

[0029] Each R c are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 16 、-NR 17 R 18 、-C(O)R 16 、-C(O)OR 16 、-C(O)NR 17 R 18 、-OC(O)R 16 、-OC(O)OR 16 、-OC(O)NR 17 R 18 、-NR 19 C(O)R 16 、-NR 19 C(O)OR 16 、-NR 19 C(O)NR 17 R 18 、-S(O) v R 16 、-S(O) v OR 16 、-S(O) v NR 17 R 18 、-NR 19 S(O) v R 16 、-NR 19 S(O)v NR 17 R 18 , oxo, =S, =NR 20 Sum = CR 21 R 22 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replace;

[0030] Or, two R's on a ring c Together with the ring atoms to which it is attached, it forms a cycloalkyl or heterocyclyl group; the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more R 0 replace;

[0031] Each R 0 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 16 、-NR 17 R 18 、-C(O)R 16 、-C(O)OR 16 、-C(O)NR 17 R 18 、-OC(O)R 16 、-OC(O)OR 16 、-OC(O)NR 17 R 18 、-NR 19 C(O)R 16 、-NR 19 C(O)OR 16 、-NR 19 C(O)NR 17 R 18 、-S(O) v R 16 、-S(O) v OR 16 、-S(O) v NR 17 R 18 、-NR 19 S(O) v R 16 、-NR 19 S(O) v NR 17 R 18, oxo, =S, =NR 20 Sum = CR 21 R 22 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R t replace;

[0032] R 16 、R 17 、R 18 and R 19 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxyalkyl group, the cycloalkyl group, the heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group are each independently optionally replaced by one or more R t replace;

[0033] Or, R 17 and R 18 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R t replace;

[0034] R 20 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group;

[0035] R 21 and R 22 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl, a heteroarylalkyl, -C(O)alkyl, -C(O)Oalkyl and a cyano group; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl and a heteroarylalkyl are each independently optionally replaced by one or more R t replace;

[0036] Each R tare the same or different and are each independently selected from the group consisting of a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, -NH(alkyl), -N(alkyl), -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)NH, -C(O)NH(alkyl), -C(O)N(alkyl), -S-alkyl, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, an oxo group, =S, =NH, =N(OH), =N(alkyl), =N(alkoxy), =CH, =CH(halogen), and =C(halogen);

[0037] n1 is 0, 1, 2, 3, 4, or 5;

[0038] n2 is 0, 1, 2, 3, 4, or 5;

[0039] v is 0, 1, or 2.

[0040] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or the general formula (I-2) or a pharmaceutically acceptable salt thereof:

[0041]

[0042] in:

[0043] Q, Ring A, R 1 、R 2 、R 2a 、R 3 、R 4 、R 5 、R 6 , n1 and n2 are as defined in the general formula (I).

[0044] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof:

[0045]

[0046] in:

[0047] R 1 Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and -CHR 1a R 1b wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 7 replace;

[0048] X 1 、X 2 、X 3 and X 4 are the same or different and are each independently selected from N, CH and CR 6 ;

[0049] Q, R 1a 、R 1b 、R 2 、R 3 、R 6 and R 7 As defined in general formula (I).

[0050] In some embodiments of the present disclosure, the compound is not

[0051] In some embodiments of the present disclosure, R 1 Not benzyl.

[0052] In some embodiments of the present disclosure, R 2 is selected from hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxy, amino, cyano, nitro, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v NR 10 R11 and -NR 12 S(O) v R 9 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 8 Replacement; R 8 、R 9 、R 10 、R 11 、R 12 and v are as defined in general formula (I).

[0053] In some embodiments of the present disclosure, R 2 Not for

[0054] In some embodiments of the present disclosure, each R 3 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a 6- to 14-membered heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, 6 to 14 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl groups are each independently optionally substituted by one or more R B Replacement; R B 、R 9 、R 10 、R 11 、R 12 and v are as defined in general formula (I).

[0055] In some embodiments of the present disclosure, R 3 Not -C(O)NH2.

[0056] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] in:

[0059] q is 0, 1, 2, 3, 4, or 5;

[0060] Ring C is a nitrogen-containing heterocyclic group;

[0061] R 3b is a hydrogen atom or R B ;

[0062] R 3c is a hydrogen atom or R B ;

[0063] Q, Ring A, R 1 、R 2 、R B 、R c 、R 6 and n2 are as defined in the general formula (I).

[0064] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof:

[0065]

[0066] in:

[0067] R 3d is a hydrogen atom or R B ;

[0068] R 3ddis a hydrogen atom or R B ;

[0069] Q, Ring A, R 1 、R 2 、R B 、R 6 、n2、R 10 and R 11 As defined in general formula (I).

[0070] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof:

[0071]

[0072] in:

[0073] Indicates that the ring where G2 is located is aromatic;

[0074] G2 is selected from O, S, N, NR 5a and CR 6a ;

[0075] R 5a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group;

[0076] R 6a is a hydrogen atom or R 6 ;

[0077] Q, Ring A, R 1 、R 2 、R 3 、R 5 、R 6 and n2 are as defined in the general formula (I).

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VI), general formula (VI-1) or general formula (VI-2) or a pharmaceutically acceptable salt thereof:

[0079]

[0080] in:

[0081] R 5ais selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group;

[0082] A, B and D are the same or different and are each independently selected from N, CH and CR 6 ;

[0083] Q, R 1 、R 2 、R 3 and R 6 As defined in general formula (I).

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VII), general formula (VII-1) or general formula (VII-2) or a pharmaceutically acceptable salt thereof:

[0085]

[0086] in:

[0087] n2 is 0, 1, or 2;

[0088] R 6a is a hydrogen atom or R 6 ;

[0089] Q, R 1 、R 2 、R 3 and R 6 As defined in general formula (I).

[0090] In some embodiments of the present disclosure, ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; in some embodiments of the present disclosure, ring A is a phenyl group or a 5- or 6-membered heteroaryl group; in some embodiments of the present disclosure, ring A is a phenyl group or a 5-membered heteroaryl group; in some embodiments of the present disclosure, ring A is a 6-membered heteroaryl group; in some embodiments of the present disclosure, ring A is selected from phenyl, pyridyl and pyrazolyl; in some embodiments of the present disclosure, ring A is phenyl or pyridyl; in some embodiments of the present disclosure, ring A is phenyl; in some embodiments of the present disclosure, ring A is pyridyl.

[0091] In some embodiments of the present disclosure, ring A is a 5- or 6-membered heteroaryl; in some embodiments of the present disclosure, ring A is a 5-membered heteroaryl; in some embodiments of the present disclosure, ring A is a pyridyl or pyrazolyl; in some embodiments of the present disclosure, ring A is a pyrazolyl.

[0092] In some embodiments of the present disclosure, for X 1 、X 2 、X 3 and X 4 are the same or different and are each independently selected from N, CH and CR 6 ; R 3 and R 6 As defined in formula (I);

[0093] In some embodiments of the present disclosure, for n2 is 0, 1, 2, 3 or 4; R 3 and R 6 As defined in formula (I);

[0094] In some embodiments of the present disclosure, for R 6x is a hydrogen atom or R 6 ; R 3 and R 6 As defined in formula (I);

[0095] In some embodiments of the present disclosure, for R 3 As defined in general formula (I).

[0096] In some embodiments of the present disclosure, for n2 is 0, 1 or 2; R 3 and R 6 As defined in formula (I);

[0097] In some embodiments of the present disclosure, for R 6x is a hydrogen atom or R 6 ; R 3 and R 6 As defined in general formula (I).

[0098] In some embodiments of the present disclosure, for X 1 、X 2 、X 3 and X 4 are the same or different and are each independently selected from N, CH and CR 6 ; R 6 As defined in formula (I);

[0099] In some embodiments of the present disclosure, for n2 is 0, 1, 2, 3 or 4; R 6 As defined in formula (I); In some embodiments of the present disclosure, for R 6x is a hydrogen atom or R 6 ; R 6 As defined in general formula (I).

[0100] In some embodiments of the present disclosure, for n2 is 0, 1 or 2; R 6 As defined in formula (I); In some embodiments of the present disclosure, for R 6x is a hydrogen atom or R 6 ; R 6 As defined in formula (I); In some embodiments of the present disclosure, for In the above schemes, the * end is connected to NH or NR 5 connected.

[0101] In some embodiments of the present disclosure, for n2 is 0, 1, 2, 3 or 4; R 6 As defined in formula (I); In some embodiments of the present disclosure, for R 6x is a hydrogen atom or R 6 ; R 6 As defined in formula (I); In some embodiments of the present disclosure, for In the above schemes, the * end is connected to NH or NR 5 connected.

[0102] In some embodiments of the present disclosure, R 1 Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and -CHR 1a R 1b wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 7 Replacement; R 1a 、R 1b and R 7 As defined in general formula (I).

[0103] In some embodiments of the present disclosure, R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl; R 7As defined in formula (I); in some embodiments of the present disclosure, R 1 is optionally replaced by one or more R 7 Substituted 5- to 7-membered cycloalkyl; R 7 As defined in formula (I); in some embodiments of the present disclosure, R 1 is optionally replaced by one or more R 7 Substituted cyclohexyl; R 7 As defined in formula (I); in some embodiments of the present disclosure, R 1 is optionally replaced by one or more R 7 Substituted with the following groups:

[0104] R 7 As defined in formula (I); in some embodiments of the present disclosure, R 1 Selected from

[0105]

[0106] In some embodiments of the present disclosure, R 1 Selected from

[0107] In some embodiments of the present disclosure, R 1 -CHR 1a R 1b ; R 1a and R 1b The same or different, and each independently is optionally replaced by one or more R 7a Substituted 3 to 6 membered cycloalkyl; R 7a As defined in formula (I); in some embodiments of the present disclosure, R 1 -CHR 1a R 1b ; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; in some embodiments of the present disclosure, R 1 for

[0108] In some embodiments of the present disclosure, R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; R 7 、R 1a and R1b As defined in formula (I); in some embodiments of the present disclosure, R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; In some embodiments of the present disclosure, R 1 Selected from

[0109]

[0110] In some embodiments of the present disclosure, R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a phenyl group and a 3 to 6-membered cycloalkyl group; wherein the phenyl group and the 3 to 6-membered cycloalkyl group are each independently optionally substituted by one or more R 7a Replacement; R 7a As defined in formula (I); in some embodiments of the present disclosure, R 1a and R 1b The same or different, and each independently is optionally replaced by one or more R 7a Substituted 3 to 6 membered cycloalkyl; R 7a As defined in formula (I); in some embodiments of the present disclosure, R 1a and R 1b are the same or different and are each independently a 3- to 6-membered heterocyclic group; in some embodiments of the present disclosure, R 1a and R 1b are cyclopropyl; in some embodiments of the present disclosure, R 1a and R 1b All are cyclobutyl.

[0111] In some embodiments of the present disclosure, R 2 is a 5- or 6-membered heteroaryl or phenyl group; the 5- or 6-membered heteroaryl group and the phenyl group are each independently optionally substituted by one or more R 8 Replacement; R 8As defined in formula (I); in some embodiments of the present disclosure, R 2 is optionally replaced by one or more R 8 Substituted phenyl; R 8 As defined in general formula (I).

[0112] In some embodiments of the present disclosure, R 2 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclic group; the 5- or 6-membered heteroaryl and the 5- or 6-membered heterocyclic group are each independently optionally substituted by one or more R 8 Replacement; R 8 As defined in formula (I); in some embodiments of the present disclosure, R 2 is optionally replaced by one or more R 8 substituted 5- to 10-membered heteroaryl; R 8 As defined in formula (I); in some embodiments of the present disclosure, R 2 is optionally replaced by one or more R 8 Substituted 5-membered heteroaryl; R 8 As defined in formula (I);

[0113] In some embodiments of the present disclosure, R 2 is optionally replaced by one or more R 8 substituted 5- or 6-membered heteroaryl; each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3 to 6 membered cycloalkyl and cyano; in some embodiments of the present disclosure, R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and cyano;

[0114] In some embodiments of the present disclosure, R 2 is selected from the group consisting of pyrazolyl, pyrrolyl, oxadiazolyl, oxazolyl, furanyl, triazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrazinyl and phenyl; and R 2 Optionally one or more R 8 Replacement; R 8 As defined in formula (I); in some embodiments of the present disclosure, R 2 is selected from pyrazolyl, pyrrolyl and oxadiazolyl; and the pyrazolyl, pyrrolyl and oxadiazolyl are each independently optionally substituted by one or more R 8 Replacement; R 8As defined in formula (I); in some embodiments of the present disclosure, R 2 Selected from

[0115] In some embodiments of the present disclosure, R 2 Selected from In some embodiments of the present disclosure, R 2 for R Z Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; in some embodiments of the present disclosure, R 2 for

[0116] In some embodiments of the present disclosure, R Z C 1-6 Alkyl; In some embodiments of the present disclosure, R Z is selected from methyl, ethyl and isopropyl; R Z It is methyl or ethyl.

[0117] In some embodiments of the present disclosure, Q is N or CR 2b ; R 2b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; In some embodiments of the present disclosure, Q is N; In some embodiments of the present disclosure, Q is CR 2b ; R 2b As defined in formula (I); in some embodiments of the present disclosure, Q is N or CH; in some embodiments of the present disclosure, Q is CH.

[0118] In some embodiments of the present disclosure, R 2a A hydrogen atom or C 1-6 Alkyl; In some embodiments of the present disclosure, R 2a A hydrogen atom.

[0119] In some embodiments of the present disclosure, R 2b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3 to 6 membered cycloalkyl and cyano; in some embodiments of the present disclosure, R 2b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; In some embodiments of the present disclosure, R 2bis a hydrogen atom or a halogen; in some embodiments of the present disclosure, R 2b A hydrogen atom.

[0120] In some embodiments of the present disclosure, R 3 C 1-6 Alkyl or 6-membered heteroaryl; the C 1-6 The alkyl and 6-membered heteroaryl groups are each independently optionally substituted with one or more R B Replace; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 9 、-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent;

[0121] R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent;

[0122] R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 alkyl halide;

[0123] R 12 is a hydrogen atom;

[0124] In some embodiments of the present disclosure, R 3 Selected from

[0125]

[0126] In some embodiments of the present disclosure, R 3 Selected from

[0127]

[0128] In some embodiments of the present disclosure, R 3 is optionally replaced by one or more R B Substituted C 1-6 Alkyl; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkoxy, -C(O)R 9 、-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent;

[0129] R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl; R 12 is a hydrogen atom;

[0130] In some embodiments of the present disclosure, R 3 Selected from

[0131]

[0132] In some embodiments of the present disclosure, R 3 for q is 0, 1, 2, 3, 4 or 5; Ring C is a nitrogen-containing heterocyclic group; R 3b is a hydrogen atom or RB ; R 3c is a hydrogen atom or R B ; R B and R c As defined in formula (I);

[0133] In some embodiments of the present disclosure, R 3 for q is 0, 1, 2, or 3; R c Halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 Alkyl; Ring C is a 6-membered nitrogen-containing heterocyclic group; R 3b C 1-6 Alkyl; R 3c -NHC(O)R 9 ; R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 alkyl;

[0134] In some embodiments of the present disclosure, R 3 for q is 0, 1, or 2; R c C 1-6 Alkyl; R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 Alkyl; R 3b C 1-6 Alkyl; R 3c -NHC(O)R 9 ; R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 alkyl;

[0135] In some embodiments of the present disclosure, R 3 Selected from

[0136] In some embodiments of the present disclosure, R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 Alkyl; In some embodiments of the present disclosure, R is selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R is C 1-6 Alkyl; in some embodiments of the present disclosure, R is methyl.

[0137] In some embodiments of the present disclosure, R 3 Selected from R 3d is a hydrogen atom or R B ; R 3e is a hydrogen atom or R B ; R B As defined in formula (I); in some embodiments of the present disclosure, R 3 Selected from R 3d Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 3e Selected from-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heterocyclic radicals and 5 or 6 membered heteroaryls; wherein the 5 or 6 membered heteroaryls and 5 or 6 membered heterocyclic radicals are each independently optionally substituted by one or more radicals selected from oxo, halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent;

[0138] R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 8 membered cycloalkyl C 1-6 Alkyl; wherein the 3 to 8 membered cycloalkyl C 1-6 The alkyl group is optionally substituted by one or more radicals selected from halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent;

[0139] R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6Alkyl and C 1-6 alkyl halide;

[0140] R 12 is a hydrogen atom;

[0141] In some embodiments of the present disclosure, R 3 Selected from R 3d Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 3e wherein the 5 or 6 membered heterocyclic group is optionally substituted by one or more oxo groups, halogen groups, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent;

[0142] In some embodiments, R 3 Selected from

[0143]

[0144] In some embodiments, R 3 Selected from

[0145] In some embodiments, R 3 Selected from

[0146] In some embodiments of the present disclosure, R 3b Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 3b C 1-6 Alkyl; In some embodiments of the present disclosure, R 3b It is a methyl group.

[0147] In some embodiments of the present disclosure, R 3c -NHC(O)R 9 ; R9 As defined in formula (I); in some embodiments of the present disclosure, R 3c -NHC(O)R 9 ; R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 3c -NHC(O)R 9 ; R 9 C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 3c -NHC(O)R 9 ; R 9 C 1-6 Alkyl; In some embodiments of the present disclosure, R 3c for In some embodiments of the present disclosure, R 3c for In some embodiments of the present disclosure, R 3c for

[0148] In some embodiments of the present disclosure, R 3d Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 3d Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 3d Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 3d C 1-6 Alkyl; In some embodiments of the present disclosure, R 3d Selected from methyl, isopropyl, methoxymethyl and In some embodiments of the present disclosure, R 3d It is a methyl group.

[0149] In some embodiments of the present disclosure, R 3dd Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 3dd Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 3dd A hydrogen atom.

[0150] In some embodiments of the present disclosure, R 3e Selected from-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heterocyclic radicals and 5 or 6 membered heteroaryls; wherein the 5 or 6 membered heteroaryls and 5 or 6 membered heterocyclic radicals are each independently optionally substituted by one or more radicals selected from oxo, halogen, C 1-6 Alkyl and C 1-6 In some embodiments of the present disclosure, R 3e Selected from

[0151] In some embodiments of the present disclosure, R 3e -C(O)NR 10 R 11 ; R 10 and R 11 As defined in formula (I); in some embodiments of the present disclosure, R 3e Selected from -C(O)NH2,

[0152]

[0153] In some embodiments of the present disclosure, R 3e for In some embodiments of the present disclosure, R 3e for

[0154] In some embodiments of the present disclosure, R 3e is a 3- to 8-membered heterocyclic group; wherein the 3- to 8-membered heterocyclic group is optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl, C 1-6is substituted with a haloalkyl, cyano, and 3- to 6-membered cycloalkyl substituent; in some embodiments of the present disclosure, R 3e is a 5- or 6-membered heterocyclic group; wherein the 5- or 6-membered heterocyclic group is optionally substituted by one or more oxo groups, halogen groups, C 1-6 Alkyl and C 1-6 In some embodiments, R 3e Selected from

[0155] In some embodiments of the present disclosure, R 3e Selected from In some embodiments of the present disclosure, R 3e Selected from

[0156] In some embodiments of the present disclosure, R 3 is optionally replaced by one or more R B Substituted 6-membered heteroaryl; R B As defined in general formula (I); in some embodiments of the present disclosure, R 3 for R 30 、R 31 、R 32 、R 33 、R 34 and R 35 are the same or different and are each independently a hydrogen atom or R B ; R B As defined in formula (I); in some embodiments, R 3 for R 32 、R 33 、R 34 and R 35 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 3 for R 30 、R 31 and R 32 are the same or different and are each independently a hydrogen atom or R B ; R B As defined in formula (I); in some embodiments, R 3 for R30 、R 31 and R 32 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; In some embodiments of the present disclosure, R 3 for

[0157] In some embodiments of the present disclosure, R 3 for R 30 、R 31 and R 32 are the same or different and are each independently a hydrogen atom or R B ; R B As defined in formula (I); in some embodiments of the present disclosure, R 3 for R 30 、R 31 and R 32 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 3 for R 30 and R 31 are the same or different and are each independently a hydrogen atom or R B ; R B As defined in formula (I); in some embodiments of the present disclosure, R 3 for R 30 and R 31 The same or different, and each independently is C 1-6 Alkyl; In some embodiments of the present disclosure, R 3 for

[0158] In some embodiments of the present disclosure, R 30 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; In some embodiments of the present disclosure, R 30 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 30 Selected from hydrogen atoms, halogens and C 1-6Alkyl; In some embodiments of the present disclosure, R 30 Halogen or C 1-6 Alkyl; In some embodiments of the present disclosure, R 30 C 1-6 Alkyl; In some embodiments of the present disclosure, R 30 It is a methyl group.

[0159] In some embodiments of the present disclosure, R 31 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; In some embodiments of the present disclosure, R 31 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 31 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; In some embodiments of the present disclosure, R 31 Halogen or C 1-6 Alkyl; In some embodiments of the present disclosure, R 31 C 1-6 Alkyl; In some embodiments of the present disclosure, R 31 It is a methyl group.

[0160] In some embodiments of the present disclosure, R 32 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; In some embodiments of the present disclosure, R 32 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 32 is a hydrogen atom or a halogen; in some embodiments of the present disclosure, R 32 A hydrogen atom.

[0161] In some embodiments of the present disclosure, R 33 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6Haloalkoxy; In some embodiments of the present disclosure, R 33 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 33 A hydrogen atom.

[0162] In some embodiments of the present disclosure, R 34 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; In some embodiments of the present disclosure, R 34 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 34 A hydrogen atom.

[0163] In some embodiments of the present disclosure, R 35 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; In some embodiments of the present disclosure, R 35 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R 35 A hydrogen atom.

[0164] In some embodiments of the present disclosure, R 4 =0; In some embodiments of the present disclosure, R 4 is connected to ring A to form a 5-membered heteroaryl group fused to ring A; the 5-membered heteroaryl group is optionally replaced by an R 6 Replacement; R 6 As defined in general formula (I).

[0165] In some embodiments of the present disclosure, R 5 A hydrogen atom or C 1-6 Alkyl; In some embodiments of the present disclosure, R 5 is a hydrogen atom; in some embodiments of the present disclosure, R 5 Does not exist.

[0166] In some embodiments of the present disclosure, X 1 N; X 2 、X 3 and X 4 The same or different, and each independently CH or CR 6 ; R 6 As defined in formula (I); in some embodiments of the present disclosure, X 2 N; X 1 、X 3 and X 4 The same or different, and each independently CH or CR 6 ; R 6 As defined in formula (I); in some embodiments of the present disclosure, X 1 CH or CR 6 , R 6 As defined in general formula (I); X 2 、X 3 and X 4 are CH; in some embodiments of the present disclosure, X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 、X 3 and X 4 are CH; in some embodiments of the present disclosure, X 1 is CH or CF; X 2 、X 3 and X 4 are CH; in some embodiments of the present disclosure, X 1 CF;X 2 、X 3 and X 4 are CH; in some embodiments of the present disclosure, X 1 、X 2 、X 3 and X 4 All are CH.

[0167] In some embodiments of the present disclosure, each R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and cyano; In some embodiments of the present disclosure, each R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6Haloalkyl; In some embodiments of the present disclosure, R 6 is halogen; in some embodiments of the present disclosure, R 6 For F.

[0168] In some embodiments of the present disclosure, R 6x Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and cyano; In some embodiments of the present disclosure, R 6x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; In some embodiments of the present disclosure, R 6x is a hydrogen atom or a halogen; in some embodiments of the present disclosure, R 6x is halogen; in some embodiments of the present disclosure, R 6x is a hydrogen atom or F; in some embodiments of the present disclosure, R 6x is F; in some embodiments of the present disclosure, R 6x For H.

[0169] In some embodiments of the present disclosure, each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, hydroxy and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; In some embodiments of the present disclosure, each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; In some embodiments of the present disclosure, each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments of the present disclosure, each R 7 are the same or different and are each independently selected from F, methyl, trifluoromethyl and =CF2.

[0170] In some embodiments of the present disclosure, each R 7a are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, cyano, and hydroxy; in some embodiments of the present disclosure, each R 7a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0171] In some embodiments of the present disclosure, each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3 to 6 membered cycloalkyl and cyano; in some embodiments of the present disclosure, each R 8 The same or different, and each independently selected from C 1-6 alkyl, 3 to 6 membered cycloalkyl and cyano; in some embodiments of the present disclosure, each R 8 The same or different, and each independently is C 1-6 Alkyl; In some embodiments of the present disclosure, each R 8 are the same or different and are each independently selected from methyl, ethyl, isopropyl, cyclopropyl and cyano; in some embodiments of the present disclosure, each R 8 are the same or different and are each independently methyl or ethyl.

[0172] In some embodiments of the present disclosure, R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 8 membered heterocyclic group, 3 to 8 membered heterocyclic group C 1-6 Alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8-membered heterocyclic group, the 3 to 8-membered heterocyclic group C 1-6 Alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered cycloalkyl C 1-6The alkyl groups are each independently optionally substituted with one or more R c Substitution; In some embodiments of the present disclosure, R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 8 membered heterocyclic and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 The alkyl groups are each independently optionally substituted with one or more R c Replacement; In the above schemes, R c As defined in formula (I); in some embodiments of the present disclosure, R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments of the present disclosure, R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 9 C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 8 membered cycloalkyl C 1-6 Alkyl; wherein the 3 to 8 membered cycloalkyl C 1-6 The alkyl group is optionally substituted by one or more radicals selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments of the present disclosure, R 9 Selected from ethyl, methoxymethyl, In some embodiments of the present disclosure, R 9 is ethyl or methoxymethyl.

[0173] In some embodiments of the present disclosure, R 9 is optionally replaced by one or more R c substituted 3 to 8 membered heterocyclyl; in some embodiments of the present disclosure, R 9 is optionally replaced by one or more R c substituted 3 to 8 membered nitrogen-containing heterocyclic group; in some embodiments, R 9 is optionally replaced by one or more R c substituted 5- or 6-membered heterocyclyl; in some embodiments, R 9 is optionally replaced by one or more R c substituted 5- or 6-membered nitrogen-containing heterocyclic group; in some embodiments, R 9 is optionally replaced by one or more R c substituted 6-membered heterocyclyl; in some embodiments, R 9 is optionally replaced by one or more R c substituted 6-membered nitrogen-containing heterocyclic group; in some embodiments, R 9 is optionally replaced by one or more R c substituted piperazinyl or optionally substituted with one or more R c substituted piperidinyl; in some embodiments, R 9 is optionally replaced by one or more R c substituted piperazinyl; in some embodiments, R 9 is selected from the group consisting of azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, azaspiro[3,3]heptane, and 4,7-diazaspiro[2.5]octane; and R 9 Optionally one or more R c Replacement; In the above schemes, R c As defined in general formula (I).

[0174] In some embodiments of the present disclosure, R 9 for Ring C is a nitrogen-containing heterocyclic group; q is 0, 1, 2, 3, 4 or 5; R c As defined in formula (I); in some embodiments of the present disclosure, R 9 for q is 0, 1, or 2; R c C 1-6 Alkyl; R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 alkyl.

[0175] In some embodiments, R 9 Selected from

[0176] In some embodiments, R 9 Selected from

[0177] In some embodiments of the present disclosure, ring C is a 3- to 8-membered nitrogen-containing heterocyclic group; in some embodiments, ring C is a 5- or 6-membered nitrogen-containing heterocyclic group; in some embodiments, ring C is a 6-membered nitrogen-containing heterocyclic group; in some embodiments, ring C is a piperazinyl or piperidinyl; in some embodiments, ring C is a piperazinyl; in some embodiments, ring C is selected from azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, azaspiro[3,3]heptane and 4,7-diazaspiro[2.5]octane.

[0178] In some embodiments of the present disclosure, for q is 0, 1, or 2; R c C 1-6 Alkyl; R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 Alkyl; In some embodiments of the present disclosure, Selected from

[0179] In some embodiments, Selected from

[0180] In some embodiments of the present disclosure, Selected from In some embodiments of the present disclosure, Selected from

[0181]

[0182] In some embodiments of the present disclosure, R c are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C1-6 Alkyl, hydroxyl, -N(CH3)2, -C(O)C 1-6 Alkyl, benzyl, phenoxy, 6-membered heteroaryl C 1-6 Alkyl, -C 1-6 Alkylene -COOH and -C 1-6 Alkylene-C(O)OC 1-6 Alkyl; In some embodiments of the present disclosure, R c are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and hydroxyl; In some embodiments of the present disclosure, R c The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 Alkyl; In some embodiments of the present disclosure, R c The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; In some embodiments of the present disclosure, R c C 1-6 Alkyl; In some embodiments of the present disclosure, R c It is a methyl group.

[0183] In some embodiments of the present disclosure, two R c Together with the attached ring atoms, they form a 3- to 8-membered cycloalkyl group; the 3- to 8-membered cycloalkyl group is optionally substituted with one or more R 0 Replacement; R 0 As defined in formula (I); In some embodiments of the present disclosure, two R c Together with the attached carbon atom it forms a cyclopropyl group.

[0184] In some embodiments of the present disclosure, each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 9 、-NR12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally replaced by one or more R b Replacement; R b 、R 9 、R 10 、R 11 and R 12 As defined in formula (I);

[0185] In some embodiments of the present disclosure, each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 9 、-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl; R 12 A hydrogen atom.

[0186] In some embodiments of the present disclosure, each R b are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, oxo, cyano and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, each R b are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments of the present disclosure, each R b The same or different, and each independently halogen or C 1-6 haloalkyl; in some embodiments of the present disclosure, each R b The same or different, and each independently is oxo or C 1-6 haloalkyl; in some embodiments of the present disclosure, each R b are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano and C 1-6 Hydroxyalkyl; In some embodiments of the present disclosure, R b C 1-6 Alkyl; In some embodiments of the present disclosure, R b It is a methyl group.

[0187] In some embodiments of the present disclosure, R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C 1-6 Alkylene-N(C 1-6 alkyl)2; or, R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally substituted by one or more R c Replacement; R c As defined in formula (I); in some embodiments, R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 10 and R 11are the same or different and are each independently selected from hydrogen atoms, methyl groups and

[0188] In some embodiments of the present disclosure, R 12 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 12 is a hydrogen atom or a methyl group; in some embodiments, R 12 A hydrogen atom.

[0189] In some embodiments of the present disclosure, R 13 Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; In some embodiments of the present disclosure, R 13 is hydroxy or methoxy.

[0190] In some embodiments of the present disclosure, R 14 and R 15 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; In some embodiments of the present disclosure, R 14 and R 15 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 14 and R 15 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 14 and R 15 are all hydrogen atoms; in some embodiments, R 14 and R 15 All are F.

[0191] In some embodiments of the present disclosure, R 16 Selected from hydrogen atoms, C 1-6 Alkyl or phenyl.

[0192] In some embodiments of the present disclosure, R 17 and R 18 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; In some embodiments of the present disclosure, R 17 and R 18 are all methyl groups; in some embodiments of the present disclosure, R 17 and R 18 All are hydrogen atoms.

[0193] In some embodiments of the present disclosure, R 19 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 19 C 1-6 Alkyl; in some embodiments, R 19is a hydrogen atom or a methyl group; in some embodiments, R 19 A hydrogen atom.

[0194] In some embodiments of the present disclosure, R 20 Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; In some embodiments of the present disclosure, R 20 is a hydroxyl or methoxy group.

[0195] In some embodiments of the present disclosure, R 21 and R 22 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 21 and R 22 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 21 and R 22 are all hydrogen atoms; in some embodiments, R 21 and R 22 All are F.

[0196] In some embodiments of the present disclosure, each R 0 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, cyano, hydroxy, and oxo; in some embodiments, each R 0 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0197] In some embodiments of the present disclosure, each R t are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, cyano, hydroxy, and oxo; in some embodiments, each R t are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0198] In some embodiments of the present disclosure, v is 0; in some embodiments of the present disclosure, v is 1; in some embodiments of the present disclosure, v is 2.

[0199] In some embodiments of the present disclosure, n1 is 0 or 1; in some embodiments of the present disclosure, n1 is 1; in some embodiments of the present disclosure, n1 is 0.

[0200] In some embodiments of the present disclosure, n2 is 0, 1, 2, 3 or 4; in some embodiments of the present disclosure, n2 is 0, 1 or 2; in some embodiments of the present disclosure, n2 is 0 or 1; in some embodiments of the present disclosure, n2 is 0; in some embodiments of the present disclosure, n2 is 1.

[0201] In some embodiments of the present disclosure, q is 0, 1, 2 or 3; in some embodiments of the present disclosure, q is 0, 1 or 2; in some embodiments of the present disclosure, q is 1 or 2; in some embodiments of the present disclosure, q is 1; in some embodiments of the present disclosure, q is 2.

[0202] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; Each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from a hydrogen atom or a halogen; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3 to 6-membered cycloalkyl and cyano; R 2a is a hydrogen atom; R 4 =O; R 5 is a hydrogen atom; R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; n2 is 0, 1 or 2; ring A is phenyl or 5- or 6-membered heteroaryl; n1 is 1; R 3 C 1-6 Alkyl or 6-membered heteroaryl; the C 1-6 Alkyl or 6-membered heteroaryl are each independently optionally substituted by one or more R B Replace; each RB are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 9 、-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl; R 12 A hydrogen atom.

[0203] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 substituted 4- to 10-membered cycloalkyl; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from a hydrogen atom or a halogen; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6Alkyl, 3 to 6-membered cycloalkyl and cyano; R 2a is a hydrogen atom; R 4 =O; R 5 is a hydrogen atom; R 6 is halogen; n2 is 0 or 1; Ring A is phenyl or 5- or 6-membered heteroaryl; n1 is 1; R 3 for q is 0, 1, 2, or 3; R c Halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and -C(O)C 1-6 Alkyl; Ring C is a 6-membered nitrogen-containing heterocyclic group; R 3b C 1-6 Alkyl; R 3c -NHC(O)R 9 ; R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 alkyl.

[0204] In some embodiments of the present disclosure, the compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; Each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from a hydrogen atom or a halogen; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3 to 6 membered cycloalkyl and cyano; X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6Haloalkyl; X 2 、X 3 and X 4 All are CH; R 3 C 1-6 Alkyl or 6-membered heteroaryl; the C 1-6 Alkyl or 6-membered heteroaryl are each independently optionally substituted by one or more R B Replace; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 9 、-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl; R 12 A hydrogen atom.

[0205] In some embodiments of the present disclosure, the compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 substituted 4- to 10-membered cycloalkyl; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15; R 14 and R 15 are the same or different and are each independently a hydrogen atom or a halogen; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3 to 6 membered cycloalkyl and cyano; X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 、X 3 and X 4 All are CH; R 3 for R 30 、R 31 and R 32 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl.

[0206] In some embodiments of the present disclosure, the compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 substituted 4- to 10-membered cycloalkyl; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently a hydrogen atom or a halogen; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3 to 6 membered cycloalkyl and cyano; X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 、X 3 and X 4 All are CH; R 3 for q is 0, 1, or 2; R c C 1-6Alkyl; Ring C is a 6-membered nitrogen-containing heterocyclic group; R 3b C 1-6 Alkyl; R 3c -NHC(O)R 9 ; R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 alkyl.

[0207] In some embodiments of the present disclosure, the compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 substituted 4- to 10-membered cycloalkyl; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently a hydrogen atom or a halogen; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3 to 6 membered cycloalkyl and cyano; X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 、X 3 and X 4 All are CH; R 3 Selected from R 3d Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 3e Selected from-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heterocyclic radicals and 5 or 6 membered heteroaryls; wherein the 5 or 6 membered heteroaryls and 5 or 6 membered heterocyclic radicals are each independently optionally substituted by one or more radicals selected from oxo, halogen, C 1-6 Alkyl and C 1-6Substituted by a haloalkyl substituent; R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 8 membered cycloalkyl C 1-6 Alkyl; wherein the 3 to 8 membered cycloalkyl C 1-6 The alkyl group is optionally substituted by one or more radicals selected from halogen, C 1-6 Alkyl and C 1-6 Substituted by a haloalkyl substituent; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl; R 12 A hydrogen atom.

[0208] In some embodiments of the present disclosure, the compound represented by formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; Each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 Alkyl, 3 to 6-membered cycloalkyl and cyano; R c C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; q is 0, 1, 2 or 3; Ring C is a 6-membered nitrogen-containing heterocyclic group; R 3b C 1-6 Alkyl; R 3c -NHC(O)R 9 ; R 9 Selected from C 1-6Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; Ring A is phenyl; n2 is 0, 1 or 2; each R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0209] In some embodiments of the present disclosure, the compound represented by formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 substituted 4- to 10-membered cycloalkyl; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from a hydrogen atom or a halogen; Q is N; R 2 for R Z Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 hydroxyalkyl and 3 to 8-membered cycloalkyl; Ring A is phenyl; n2 is 0 or 1; R 6 is halogen; R 3b C 1-6 Alkyl; R 3c -NHC(O)R 9 ; R 9 C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl; Ring C is a 6-membered nitrogen-containing heterocyclic group; R c C 1-6 Alkyl; q is 0, 1, 2 or 3.

[0210] In some embodiments of the present disclosure, the compound represented by formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; Each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14R 15 ; R 14 and R 15 are the same or different and are each independently selected from a hydrogen atom or a halogen; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; Q is N; R 2 is optionally replaced by one or more R 8 substituted 5-membered heteroaryl; each R 8 The same or different, and each independently selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, and cyano; Ring A is phenyl; n2 is 0 or 1; R 6 is halogen; R 3d Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 3dd is a hydrogen atom; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0211] Table A Typical compounds of the present disclosure include, but are not limited to:

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221] Another aspect of the present disclosure relates to a compound represented by formula (IA) or a salt thereof,

[0222]

[0223] in:

[0224] X is a halogen, preferably Br;

[0225] Q, Ring A, R 1 、R 2a 、R 3 、R 4 、R 5 、R 6 , n1 and n2 are as defined in the general formula (I).

[0226] Another aspect of the present disclosure relates to a compound represented by general formula (I-1A) or general formula (I-2A) or a salt thereof,

[0227]

[0228] in:

[0229] X is a halogen, preferably Br;

[0230] Q, Ring A, R 1 、R 2a 、R 3 、R 4 、R 5 、R 6 , n1 and n2 are as defined in the general formula (I-1) or the general formula (I-2).

[0231] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof,

[0232]

[0233] in:

[0234] X is a halogen, preferably Br;

[0235] Q, R 1 、R 3 、X 1 、X 2 、X 3 and X 4 As defined in general formula (II).

[0236] Another aspect of the present disclosure relates to a compound represented by formula (II-1A) or formula (II-2A) or a salt thereof,

[0237]

[0238] in:

[0239] X is a halogen, preferably Br;

[0240] Q, R 1 、R 3 、X 1 、X2 、X 3 and X 4 As defined in general formula (II-1) or general formula (II-2).

[0241] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,

[0242]

[0243] in:

[0244] X is a halogen, preferably Br;

[0245] Ring A, Ring C, Q, R 1 、R 3b 、R 3c 、R c 、R 6 , n2 and q are as defined in the general formula (III).

[0246] Another aspect of the present disclosure relates to a compound represented by formula (III-1A) or formula (III-2A) or a salt thereof,

[0247]

[0248] in:

[0249] X is a halogen, preferably Br;

[0250] Ring A, Ring C, Q, R 1 、R 3b 、R 3c 、R c 、R 6 , n2 and q are as defined in the general formula (III-1) or the general formula (III-2).

[0251] Another aspect of the present disclosure relates to a compound represented by formula (IVA), formula (IV-1A) or formula (IV-2A) or a salt thereof,

[0252]

[0253] in:

[0254] X is a halogen, preferably Br;

[0255] Q, Ring A, R 1 、R 3d 、R 3dd 、R 6 、n2、R 10 and R 11 As defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0256] Another aspect of the present disclosure relates to a compound represented by formula (Ia), formula (I-1a) or formula (I-2a) or a salt thereof,

[0257] in:

[0258] PG is an amino protecting group, preferably SEM;

[0259] Q, Ring A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , n1 and n2 are as defined in the general formula (I), the general formula (I-1) or the general formula (I-2).

[0260] Another aspect of the present disclosure relates to a compound represented by formula (IIa), formula (II-1a) or formula (II-2a) or a salt thereof,

[0261]

[0262] in:

[0263] PG is an amino protecting group, preferably SEM;

[0264] Q, R 1 、R 2 、R 3 、X 1 、X 2 、X 3 and X 4 As defined in general formula (II), general formula (II-1) or general formula (II-2).

[0265] Another aspect of the present disclosure relates to a compound represented by formula (IIIa), formula (III-1a) or formula (III-2a) or a salt thereof,

[0266]

[0267] in:

[0268] PG is an amino protecting group, preferably SEM;

[0269] Ring A, Ring C, Q, R 1 、R 2 、R 3b 、R 3c 、R c 、R 6 , n2 and q are as defined in general formula (III), general formula (III-1) or general formula (III-2).

[0270] Another aspect of the present disclosure relates to a compound represented by formula (IVa), formula (IV-1a) or formula (IV-2a) or a salt thereof,

[0271]

[0272] in:

[0273] PG is an amino protecting group, preferably SEM;

[0274] Q, Ring A, R 1 、R 2 、R 3d 、R 3dd 、R 6 、n2、R 10 and R 11 As defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0275] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0276]

[0277]

[0278]

[0279] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0280]

[0281] The compound represented by the general formula (IA) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0282] in:

[0283] X is a halogen, preferably Br;

[0284] R w -B(OH)2 or

[0285] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0286] Q, Ring A, R 1 、R 2a 、R 3 、R4 、R 5 、R 6 、R 8 , n1 and n2 are as defined in the general formula (I).

[0287] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0288]

[0289] The compound represented by the general formula (I-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt to obtain the compound represented by the general formula (I-1) or its pharmaceutically acceptable salt; or

[0290] The compound represented by the general formula (I-2A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof to obtain the compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

[0291] in:

[0292] X is a halogen, preferably Br;

[0293] R w -B(OH)2 or

[0294] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0295] Q, Ring A, R 1 、R 2a 、R 3 、R 4 、R 5 、R 6 、R 8 , n1 and n2 are as defined in the general formula (I-1) or the general formula (I-2).

[0296] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0297]

[0298] The compound represented by general formula (IIA) or its salt undergoes a coupling reaction with the compound represented by general formula (M) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0299] in:

[0300] X is a halogen, preferably Br;

[0301] R w -B(OH)2 or

[0302] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0303] Q, R 1 、R 3 、R 8 、X 1 、X 2 、X 3 and X 4 As defined in formula (II)

[0304] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0305]

[0306] The compound represented by the general formula (II-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt; or

[0307] The compound represented by the general formula (II-2A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

[0308] in:

[0309] X is a halogen, preferably Br;

[0310] R w -B(OH)2 or

[0311] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0312] Q, R 1 、R 3 、R 8 、X 1 、X 2 、X 3 and X 4 As defined in general formula (II-1) or general formula (II-2).

[0313] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0314]

[0315] The compound represented by general formula (IIIA) or its salt undergoes a coupling reaction with the compound represented by general formula (M) or its salt to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0316] in:

[0317] X is a halogen, preferably Br;

[0318] R w -B(OH)2 or

[0319] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0320] Ring A, Ring C, Q, R 1 、R 3b 、R 3c 、R c 、R 6 、R 8 , n2 and q are as defined in the general formula (III).

[0321] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0322]

[0323]

[0324] The compound represented by the general formula (III-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt to obtain the compound represented by the general formula (III-1) or its pharmaceutically acceptable salt; or

[0325] The compound represented by the general formula (III-2A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0326] in:

[0327] X is a halogen, preferably Br;

[0328] R w -B(OH)2 or

[0329] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0330] Ring A, Ring C, Q, R 1 、R 3b 、R 3c 、R c 、R 6 、R 8 , n2 and q are as defined in the general formula (III-1) or the general formula (III-2).

[0331] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0332]

[0333] The compound represented by the general formula (IVA) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt to obtain the compound represented by the general formula (IV) or its pharmaceutically acceptable salt; or

[0334] The compound represented by the general formula (IV-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt to obtain the compound represented by the general formula (IV-1) or its pharmaceutically acceptable salt; or

[0335] The compound represented by the general formula (IV-2A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0336] in:

[0337] X is a halogen, preferably Br;

[0338] R w -B(OH)2 or

[0339] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0340] Q, Ring A, R 1 、R 3d 、R 3dd 、R 6 、n2、R 8 、R 10 and R 11As defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0341] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (I), general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0342]

[0343] The compound represented by general formula (Ia) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt; or

[0344] The compound represented by the general formula (I-1a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (I-1) or its pharmaceutically acceptable salt; or

[0345] The compound represented by the general formula (I-2a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (I-2) or its pharmaceutically acceptable salt;

[0346] in:

[0347] PG is an amino protecting group, preferably SEM;

[0348] R 2a is H;

[0349] Q, Ring A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , n1 and n2 are as defined in the general formula (I), the general formula (I-1) or the general formula (I-2).

[0350] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0351]

[0352] The compound represented by general formula (IIa) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt; or

[0353] The compound represented by the general formula (II-1a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt; or

[0354] The compound represented by the general formula (II-2a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (II-2) or its pharmaceutically acceptable salt;

[0355] in:

[0356] PG is an amino protecting group, preferably SEM;

[0357] Q, R 1 、R 2 、R 3 、X 1 、X 2 、X 3 and X 4 As defined in general formula (II), general formula (II-1) or general formula (II-2).

[0358] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0359]

[0360] The compound represented by general formula (IIIa) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt; or

[0361] The compound represented by the general formula (III-1a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (III-1) or its pharmaceutically acceptable salt; or

[0362] The compound represented by the general formula (III-2a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (III-2) or its pharmaceutically acceptable salt;

[0363] in:

[0364] PG is an amino protecting group, preferably SEM;

[0365] Ring A, Ring C, Q, R 1 、R 2 、R 3b 、R 3c 、R c 、R 6 , n2 and q are as defined in general formula (III), general formula (III-1) or general formula (III-2).

[0366] Another aspect of the present disclosure relates to a method for preparing a compound represented by the above-mentioned general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0367]

[0368]

[0369] The compound represented by general formula (IVa) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt; or

[0370] The compound represented by the general formula (IV-1a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (IV-1) or its pharmaceutically acceptable salt; or

[0371] The compound represented by the general formula (IV-2a) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (IV-2) or its pharmaceutically acceptable salt;

[0372] in:

[0373] PG is an amino protecting group, preferably SEM;

[0374] Q, Ring A, R 1 、R 2 、R 3d 、R 3dd 、R 6 、n2、R 10 and R 11 As defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0375] Another aspect of the present disclosure relates to a pharmaceutical composition, comprising a compound of the present disclosure of general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2), general formula (VI), general formula (VI-1), general formula (VI-2), general formula (VII), general formula (VII-1), general formula (VII-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0376] The present disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by IL-17; preferably, wherein the IL-17 is IL-17A.

[0377] The present disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2), or a pharmaceutical composition comprising the compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2), or a pharmaceutical composition comprising the compound of formula (I), formula (I-1), formula (I-2), or a pharmaceutical composition comprising the compound of formula (I), formula (I-1), formula (VI-2), or a pharmaceutical composition comprising the compound of formula (I), formula (I-2), or a pharmaceutical composition comprising the compound of formula (I), formula (I-1), formula (II-2), The present invention relates to a group of diseases comprising the following: arthritis, spondyloarthritis (e.g., axial spondyloarthritis), uveitis (e.g., non-infectious uveitis), bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, allograft rejection (e.g., kidney), psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behçet's disease, ulcerative colitis, Behçet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD), and Helicobacter pylori-associated gastritis, preferably selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, more preferably psoriasis.

[0378] The present disclosure further relates to a method for inhibiting IL-17, comprising administering to a patient in need thereof a compound of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, wherein the IL-17 is IL-17A.

[0379] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by IL-17, comprising administering to a patient in need thereof a compound of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, wherein the IL-17 is IL-17A.

[0380] The present disclosure further relates to a method for treating and / or preventing cancer, inflammation or autoimmune disease or sarcopenia, which comprises administering to a patient in need thereof a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, juvenile atopic dermatitis, The present invention relates to a group of diseases comprising the following: arthritis, spondyloarthritis (e.g., axial spondyloarthritis), uveitis (e.g., non-infectious uveitis), bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, allograft rejection (e.g., kidney), psoriasis, psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behçet's disease, ulcerative colitis, Behçet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD) and Helicobacter pylori-associated gastritis, preferably selected from psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, more preferably psoriasis.

[0381] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug.

[0382] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an IL-17 inhibitor; preferably, wherein the IL-17 is IL-17A.

[0383] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting IL-17; preferably, wherein the IL-17 is IL-17A.

[0384] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for treating and / or preventing a disease or condition mediated by IL-17; preferably, wherein the IL-17 is IL-17A.

[0385] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), formula (VI), formula (VI-1), formula (VI-2), formula (VII), formula (VII-1), formula (VII-2) or shown in Table A, or a pharmaceutical composition comprising the same, for treating and / or preventing cancer, inflammation or autoimmune disease or sarcopenia; preferably, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Hidradenitis suppurativa, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis (e.g., axial spondyloarthritis), uveitis (e.g., non-infectious uveitis), bone erosions, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, allograft rejection (e.g., renal), psoriasis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behçet's disease, ulcerative colitis, Behçet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD), and Helicobacter pylori. pylori)-related gastritis, preferably selected from psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, more preferably psoriasis.

[0386] The IL-17-mediated disease or condition of the present disclosure is preferably selected from cancer, inflammatory or autoimmune disease or sarcopenia; more preferably inflammatory or autoimmune disease; further preferably inflammation; preferably, the inflammatory or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis (e.g., axial spondyloarthritis), uveitis (e.g., non-infectious uveitis), bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), Crohn's disease, The present invention relates to a disease of the present invention which is selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis, angiogenesis, atherosclerosis, asthma (e.g., bronchial asthma), multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD) and Helicobacter pylori-associated gastritis, preferably selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, more preferably psoriasis.

[0387] The psoriasis of the present disclosure is preferably selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis and palmoplantar psoriasis.

[0388] The spondyloarthritis described in the present disclosure is preferably axial spondyloarthritis.

[0389] The uveitis described in the present disclosure is preferably non-infectious uveitis.

[0390] The asthma described in the present disclosure is preferably bronchial asthma.

[0391] The IL-17 described in the present disclosure is preferably IL-17A or IL-17F, more preferably IL-17A.

[0392] The compounds disclosed herein have good inhibitory activity against the binding of human IL-17A:IL-17RA.

[0393] The disclosed compounds have good inhibitory activity on the secretion of chemokine CXCL1 induced by human IL-17A on HaCaT cells.

[0394] As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0395] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0396] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0397] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0398] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0399] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0400] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0401] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0402] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0403] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0404] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0405] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0406] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0407] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0408] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0409] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0410] Terminology

[0411] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0412] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0413] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0414] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0415] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0416] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0417] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl) and 3 to 10 ring atoms (i.e., 3 to 10-membered cycloalkyl); in some embodiments, it has 4 to 10 ring atoms (i.e., 4 to 10-membered cycloalkyl); more preferably, it has 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), more preferably, it has 5 to 7 ring atoms (i.e., 5 to 7-membered cycloalkyl), more preferably, it has 5 or 6 ring atoms (i.e., 5 or 6-membered cycloalkyl), and most preferably, it has 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl); in some embodiments, "cycloalkyl" refers to cycloalkyl with 4 to 10 ring atoms (i.e., 4 to 10-membered cycloalkyl); in some embodiments, "cycloalkyl" refers to cycloalkyl with 5 to 7 ring atoms (i.e., 5 to 7-membered cycloalkyl).

[0418] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0419] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0420] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0421] Its connection point can be at any position;

[0422] wait.

[0423] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include:

[0424] Its connection point can be at any position;

[0425]

[0426] wait.

[0427] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0428] Its connection point can be at any position.

[0429] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0430] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclyl group); further preferred are a heterocyclyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered heterocyclyl group) and a heterocyclyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 4 to 10 ring atoms (i.e., a 4- to 10-membered heterocyclyl group); more preferably a heterocyclyl group having 5 to 7 ring atoms (i.e., a 5- to 7-membered heterocyclyl group); more preferably a heterocyclyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclyl group); most preferably a heterocyclyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 6 ring atoms (i.e., a 6-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 5 ring atoms (i.e., a 5-membered heterocyclyl group).

[0431] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0432] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0433] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, 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 / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0434] wait.

[0435] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, 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 / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0436]

[0437] wait.

[0438] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0439] wait.

[0440] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0441] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, a phenyl group. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0442] wait.

[0443] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0444] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl group preferably has 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group); in some embodiments, a heteroaryl group having 5 ring atoms (i.e., a 5-membered heteroaryl group); in some embodiments, a heteroaryl group having 6 ring atoms (i.e., a 6-membered heteroaryl group).

[0445] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, pyridine nitrogen oxide, etc.

[0446] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0447]

[0448] wait.

[0449] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0450] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), tert-butylsulfinyl, trifluoroacetyl (Tfa), trichloroacetyl, trityl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0451] The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0452] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0453] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0454] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0455] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0456] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkoxy and alkyl are as defined above. The term "cycloalkyloxy" refers to a cycloalkyl-O- group, wherein cycloalkyl is as defined above.

[0457] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0458] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0459] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0460] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0461] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein alkyl is as defined above. The term "deuteratedalkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0462] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

[0463] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0464] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0465] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0466] The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

[0467] The term "methylidene" refers to =CH2.

[0468] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0469] The term "hydroxy" refers to -OH.

[0470] The term "mercapto" refers to -SH.

[0471] The term "amino" refers to -NH2.

[0472] The term "cyano" refers to -CN.

[0473] The term "nitro" refers to -NO2.

[0474] The term "oxo" or "oxo" refers to "=0".

[0475] The term "carbonyl" refers to C=O.

[0476] The term "acetyl" refers to -C(O)CH3.

[0477] The term "amido" refers to -C(O)NH2.

[0478] The term "carboxy" refers to -C(O)OH.

[0479] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above. The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein amino and alkyl are as defined above.

[0480] "Substituted or unsubstituted" refers to both the cases where the group is substituted and the cases where it is not substituted; when substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0481] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0482] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z or E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E are included; The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0483] In the chemical structures of the compounds described herein, the bond to the stereogenic center of the compound is , indicating the relative configuration of the stereogenic center.

[0484] In the chemical structures of the compounds disclosed herein, "rac" is short for racemate (also known as raceme), which refers to an equimolar mixture of a pair of enantiomers. For example, when the compound has only one chiral center, "rac" refers to an equimolar mixture of the (R) configuration and the (S) configuration; when the compound has two chiral centers, "rac" refers to an equimolar mixture of the (R,R) configuration and the (S,S) configuration; or an equimolar mixture of the (R,S) configuration and the (S,R) configuration. Specifically, "rac-(1R,2R)" means that the compound is a racemate, which is an equimolar mixture of the (1R,2R) configuration and the (1S,2S) configuration.

[0485] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of an enamine-imine equilibrium is shown below:

[0486]

[0487] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0488]

[0489] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0490] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S.36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0491] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0492] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0493] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0494] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not 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 bond (such as an alkene).

[0495] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0496] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0497] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0498] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0499] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustrative purposes only and are not limiting.

[0500] Synthesis method of the disclosed compound

[0501] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0502] Option 1

[0503] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0504]

[0505] The compound represented by the general formula (IA) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0506] in:

[0507] X is a halogen, preferably Br;

[0508] R w -B(OH)2 or

[0509] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0510] Q, Ring A, R 1 、R 2a 、R 3 、R 4 、R 5 、R 6 、R 8 , n1 and n2 are as defined in the general formula (I).

[0511] Option 2

[0512] The present disclosure provides a method for preparing a compound represented by general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0513]

[0514] The compound represented by the general formula (I-1A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof under alkaline conditions and a catalyst to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof;

[0515] or

[0516] The compound represented by the general formula (I-2A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof under alkaline conditions and a catalyst to obtain the compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

[0517] in:

[0518] X is a halogen, preferably Br;

[0519] R w -B(OH)2 or

[0520] R2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0521] Q, Ring A, R 1 、R 2a 、R 3 、R 4 、R 5 、R 6 、R 8 , n1 and n2 are as defined in the general formula (I-1) or the general formula (I-2).

[0522] Option 3

[0523] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0524]

[0525] The compound represented by the general formula (IIA) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof under alkaline conditions and a catalyst to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

[0526] in:

[0527] X is a halogen, preferably Br;

[0528] R w -B(OH)2 or

[0529] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0530] Q, R 1 、R 3 、R 8 、X 1 、X 2 、X 3 and X 4 As defined in general formula (II).

[0531] Option 4

[0532] The present disclosure provides a method for preparing a compound represented by general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0533]

[0534] The compound represented by the general formula (II-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt; or,

[0535] The compound represented by the general formula (II-2A) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof under alkaline conditions and a catalyst to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

[0536] in:

[0537] X is a halogen, preferably Br;

[0538] R w -B(OH)2 or

[0539] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0540] Q, R 1 、R 3 、R 8 、X 1 、X 2 、X 3 and X 4 As defined in general formula (II-1) or general formula (II-2).

[0541] Plan 5

[0542] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0543]

[0544] The compound represented by the general formula (IIIA) or a salt thereof undergoes a coupling reaction with the compound represented by the general formula (M) or a salt thereof under alkaline conditions and a catalyst to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

[0545] in:

[0546] X is a halogen, preferably Br;

[0547] R w -B(OH)2 or

[0548] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0549] Ring A, Ring C, Q, R 1 、R 3b 、R 3c 、R c 、R 6 、R 8 , n2 and q are as defined in the general formula (III).

[0550] Plan 6

[0551] The present disclosure provides a method for preparing a compound represented by general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0552]

[0553] The compound represented by the general formula (III-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (III-1) or its pharmaceutically acceptable salt; or,

[0554] The compound represented by the general formula (III-2A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (III-2) or its pharmaceutically acceptable salt;

[0555] in:

[0556] X is a halogen, preferably Br;

[0557] R w -B(OH)2 or

[0558] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0559] Ring A, Ring C, Q, R 1 、R 3b 、R 3c 、R c 、R 6 、R 8 , n2 and q are as defined in the general formula (III-1) or the general formula (III-2).

[0560] Plan 7

[0561] The present disclosure provides a method for preparing a compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0562]

[0563] The compound represented by the general formula (IVA) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (IV) or its pharmaceutically acceptable salt; or,

[0564] The compound represented by the general formula (IV-1A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (IV-1) or its pharmaceutically acceptable salt; or,

[0565] The compound represented by the general formula (IV-2A) or its salt undergoes a coupling reaction with the compound represented by the general formula (M) or its salt under alkaline conditions and the action of a catalyst to obtain the compound represented by the general formula (IV-2) or its pharmaceutically acceptable salt;

[0566] in:

[0567] X is a halogen, preferably Br;

[0568] R w -B(OH)2 or

[0569] R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace;

[0570] Q, Ring A, R 1 、R 3d 、R 3dd 、R 6 、n2、R 8 、R 10 and R 11 As defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0571] Plan 8

[0572] The present disclosure provides a method for preparing a compound represented by general formula (I), general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0573]

[0574] The compound represented by general formula (Ia) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt; or

[0575] The compound represented by the general formula (I-1a) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof; or

[0576] The compound represented by the general formula (I-2a) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (I-2) or its pharmaceutically acceptable salt;

[0577] in:

[0578] PG is an amino protecting group, preferably SEM;

[0579] R 2a is H;

[0580] Q, Ring A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , n1 and n2 are as defined in the general formula (I), the general formula (I-1) or the general formula (I-2).

[0581] Plan 9

[0582] The present disclosure provides a method for preparing a compound represented by general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0583]

[0584]

[0585] The compound represented by general formula (IIa) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt; or

[0586] The compound represented by the general formula (II-1a) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof; or

[0587] The compound represented by the general formula (II-2a) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (II-2) or its pharmaceutically acceptable salt;

[0588] in:

[0589] PG is an amino protecting group, preferably SEM;

[0590] Q, R 1 、R 2 、R 3 、X 1 、X 2 、X 3 and X 4As defined in general formula (II), general formula (II-1) or general formula (II-2).

[0591] Plan 10

[0592] The present disclosure provides a method for preparing a compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0593]

[0594]

[0595] The compound represented by general formula (IIIa) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt; or

[0596] The compound represented by the general formula (III-1a) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof; or

[0597] The compound represented by the general formula (III-2a) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (III-2) or its pharmaceutically acceptable salt;

[0598] in:

[0599] PG is an amino protecting group, preferably SEM;

[0600] Ring A, Ring C, Q, R 1 、R 2 、R 3b 、R 3c 、R c 、R 6 , n2 and q are as defined in general formula (III), general formula (III-1) or general formula (III-2).

[0601] Plan 11

[0602] The present disclosure provides a method for preparing a compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0603]

[0604] The compound represented by general formula (IVa) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt; or

[0605] The compound represented by the general formula (IV-1a) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IV-1) or its pharmaceutically acceptable salt; or

[0606] The compound represented by the general formula (IV-2a) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0607] in:

[0608] PG is an amino protecting group, preferably SEM;

[0609] Q, Ring A, R 1 、R 2 、R 3d 、R 3dd 、R 6 、n2、R 10 and R 11 As defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0610] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; preferably, the reagent providing alkaline conditions is potassium carbonate.

[0611] The catalyst described in the above synthesis scheme includes but is not limited to tetrakis(triphenylphosphine)palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II), 1,1'-bis(dibenzylphosphine)dichlorodipentaferropalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, tris(dibenzylideneacetone)dipalladium, etc., preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex.

[0612] The reagents providing acidic conditions in the above scheme include but are not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf; preferably trifluoroacetic acid.

[0613] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0614] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0615] Example

[0616] 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-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0617] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0618] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0619] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMOQExactive)

[0620] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0621] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0622] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0623] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0624] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0625] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0626] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0627] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0628] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0629] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0630] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0631] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0632] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0633] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0634] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0635] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0636] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0637] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0638] Example 1

[0639] 2-(4-(2-cycloheptyl-2-(5-(1-ethyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide 1 (a mixture of four isomers)

[0640]

[0641] first step

[0642] Diethyl 2-cycloheptylmalonate 1c

[0643] Diethyl malonate 1b (4.75 g, 29.66 mmol, Shanghai Titan) was dissolved in anhydrous ethanol (30 mL), and sodium ethoxide (2.02 g, 29.68 mmol) and bromocycloheptane 1a (5 g, 28.24 mmol, Acros) were added sequentially. The mixture was stirred at 90°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added and the mixture was extracted with petroleum ether (10 mL × 3). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 1c (4.39 g), which was used directly in the next reaction without purification.

[0644] MS m / z(ESI):257.0[M+1].

[0645] Step 2

[0646] (±)-2-Cycloheptyl-3-ethoxy-3-oxopropanoic acid 1d

[0647] The crude compound 1c (1.5 g, 5.85 mmol) was dissolved in ethanol (30 mL) and water (20 mL). Potassium hydroxide (328 mg, 5.85 mmol) was added under ice-bath, and the mixture was stirred and allowed to return to room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added. The pH was adjusted to 1-2 with 5 M hydrochloric acid, and the mixture was extracted with ether (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 1d (1.33 g), which was used directly in the next reaction without purification.

[0648] Step 3

[0649] (±)-2-(3-Fluoro-4-nitrophenyl)propionic acid 1f

[0650] Ethyl (±)-2-(3-fluoro-4-nitrobenzene)propionate 1e (1 g, 4.15 mmol, Shanghai Bidex) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (522 mg, 12.44 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. The pH of the reaction solution was adjusted to about 4 with 1 M hydrochloric acid and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1f (880 mg), which was used directly in the next reaction without purification.

[0651] Step 4

[0652] (±)-2-(3-Fluoro-4-nitrophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide 1g

[0653] The crude compound 1f (880 mg, 3.30 mmol) and N-methyl-2,2,2-trifluoroethylamine hydrochloride (494 mg, 3.30 mmol, Shanghai Leyan) were dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (2.14 g, 16.56 mmol) was added under ice bath and stirred for 30 minutes. Propylphosphonic tricyclic anhydride (3.42 g, 5.37 mmol, Shanghai Titan) was added and stirred for 5 hours. Water was added to the reaction solution to quench the reaction. The solution was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g (1 g, yield: 98.2%).

[0654] MS m / z(ESI):309.0[M+1].

[0655] Step 5

[0656] (±)-2-(4-amino-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide 1h

[0657] Compound 1g (1 g, 3.24 mmol) was dissolved in anhydrous ethanol (15 mL) and tetrahydrofuran (15 mL), and 10% palladium / carbon catalyst (880 mg, 826.9 mmol) was added. The gas was replaced with a hydrogen balloon, and the reaction was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1h (890 mg), which was used directly in the next reaction without purification.

[0658] MS m / z(ESI):279.0[M+1].

[0659] Step 6

[0660] Ethyl 2-cycloheptyl-3-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropanoate 1i (mixture of four isomers)

[0661] The crude compound 1h (267 mg, 956.6 μmol) and compound 1d (210 mg, 919.9 μmol) were dissolved in pyridine (6 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (479 mg, 2.76 mmol, Shanghai Shaoyuan) was added. The reaction was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure and dissolved in ethyl acetate (10 mL). Saturated ammonium chloride solution was added and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1i (565 mg), which was used directly in the next reaction without purification.

[0662] MS m / z(ESI):489.5[M+1].

[0663] Step 7

[0664] 2-Cycloheptyl-3-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropanoic acid 1j (mixture of four isomers)

[0665] Crude compound 1i (565 mg, 1.16 mmol) was dissolved in tetrahydrofuran (6 mL) and water (5 mL). Lithium hydroxide monohydrate (100 mg, 2.38 mmol) was added and stirred for 15 hours. The reaction solution was adjusted to pH 2-3 with 1M hydrochloric acid and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford crude title compound 1j (454 mg), which was used directly in the next step without purification. MS m / z (ESI): 461.0 [M+1].

[0666] Step 8

[0667] 2-Cycloheptyl-N 1 -(2-Fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)malonamide 1k (mixture of four isomers)

[0668] Crude compound 1j (454 mg, 986 μmol) and ammonium chloride (132 mg, 2.47 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (382 mg, 2.96 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 1.38 mmol, Shanghai Shaoyuan), and 1-hydroxybenzotriazole (210 mg, 1.38 mmol, Shanghai Bidex) were added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to obtain the title compound 1k (436 mg, 96.2% yield). MS m / z (ESI): 460.1 [M+1].

[0669] Step 9

[0670] 2-Cycloheptyl-N 1 -((dimethylamino)methylene)-N 3 -(2-Fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)

[0671] (1-(2 ...1-oxopropan-2-yl-phenyl)malonamide) 11 (mixture of eight isomers))

[0672] Compound 1k (436 mg, 948.9 μmol) was dissolved in dichloromethane (10 mL), and N,N-dimethylformamide dimethyl acetal (218 mg, 1.83 mmol, Shanghai Shaoyuan) was added. The mixture was heated to 65°C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1l (488 mg, yield: 99.9%), which was used directly in the next reaction without purification.

[0673] MS m / z(ESI):515.2[M+1].

[0674] Step 10

[0675] 2-(4-(2-cycloheptyl-2-(4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide 1m (a mixture of four isomers)

[0676] Crude compound 11 (488 mg, 948.4 μmol) was dissolved in glacial acetic acid (6 mL), and 85% hydrazine hydrate (558 mg, 9.47 mmol) was added. The mixture was stirred and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to obtain the title compound 1m (327 mg, yield: 71.3%). MS m / z (ESI): 484.4 [M+1].

[0677] Step 11

[0678] 2-(4-(2-(5-bromo-4H-1,2,4-triazol-3-yl)-2-cycloheptylacetamido)-3-fluorophenyl)-N-methyl

[0679] -N-(2,2,2-trifluoroethyl)propionamide 1n (mixture of four isomers)

[0680] Compound 1m (277 mg, 572.9 μmol) was dissolved in dichloromethane (8 mL), and a solution of phenyltrimethylammonium tribromide (248 mg, 636 μmol, Shanghai Shaoyuan) and sodium hydroxide (69 mg, 1.73 mmol) in water (0.9 mL) was added. The mixture was stirred for 16 hours. 5 mL of water was added to the reaction solution, which was then extracted with dichloromethane (15 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford the title compound 1n (298 mg, 92.5% yield).

[0681] MS m / z(ESI):562.3[M+1].

[0682] Step 12

[0683] 2-(4-(2-cycloheptyl-2-(5-(1-ethyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide 1 (a mixture of four isomers)

[0684] Compound 1n (90 mg, 160 μmol), 1-ethyl-1H-pyrazole-5-boronic acid pinacol ester (72 mg, 324.2 μmol, Shanghai Leyan), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (50 mg, 59.1 μmol) and potassium carbonate (68 mg, 488.4 μmol) were dissolved in N,N-dimethylformamide (3 mL) and water (0.5 mL), replaced with nitrogen, and stirred at 115 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 1 (8 mg, yield: 8.7%).

[0685] MS m / z(ESI):578.6[M+1].

[0686] 1 H NMR (500MHz, CD3OD): δ7.88(t,1H),7.55(s,1H),7.15-7.04(m,2H),6.83(d,1H),4.70(q,2H),4.30-4.14(m,2H),4.12-3.92(m,2H),3.06(s, 3H),2.51(s,1H),2.01-1.88(m,1H),1.80-1.72(m,1H),1.71-1.62(m, 3H),1.57(q,3H),1.48(dt,2H),1.45-1.38(m,5H),1.37-1.29(m,3H).

[0687] Example 2

[0688] 2-Cycloheptyl-2-(5-(1-ethyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-N-(2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide 2-1 (mixture of two isomers)

[0689] or

[0690] 2-Cycloheptyl-2-(5-(1-ethyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-N-(2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide 2-2 (mixture of two isomers)

[0691]

[0692]

[0693] first step

[0694] tert-Butyl (4-acetyl-2-fluorophenyl)carbamate 2b

[0695] Tert-butyl (4-bromo-2-fluorophenyl)carbamate 2a (10.2 g, 35.15 mmol, Shanghai Titan) was dissolved in tetrahydrofuran (100 mL). Under a nitrogen atmosphere, 2.5 M n-butyllithium in n-hexane (31 mL) was added dropwise at -78°C. The temperature was maintained and stirred for 1 hour. N,N-dimethylacetamide (8.2 mL) was added dropwise and the mixture was naturally restored to room temperature. The reaction was continued for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2b (4.5 g, yield: 50.5%).

[0696] MS m / z(ESI):254.2[M+1].

[0697] Step 2: Tert-Butyl (4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)ethyl)-2-fluorophenyl)carbamate 2d (mixture of two isomers)

[0698] Compound 2b (2 g, 7.9 mmol) was dissolved in tetrahydrofuran (40 mL), and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride 2c (1.9 g, 9.45 mmol, WuXi AppTec) and triethylamine (2.4 g, 23.7 mmol) were added. After stirring for 10 minutes, tetraisopropyl titanate (3.37 g, 11.86 mmol) was added. The reaction was stirred at 65°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (30 mL). Sodium borohydride (1 g, 26.4 mmol) was added under ice bath, and the reaction was allowed to return to room temperature for 2 hours. Saturated ammonium chloride solution was added to the reaction solution, and the solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2d (2.88 g). The product was used directly in the next reaction without purification.

[0699] MS m / z(ESI):366.2[M+1].

[0700] Step 3: Tert-butyl (2-fluoro-4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate 2e (mixture of two isomers)

[0701] tert-Butyl (2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate

[0702] 2e-1

[0703] tert-Butyl (2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)carbamate

[0704] 2e-2

[0705] The crude compound 2d (2.88 g, 7.88 mmol) was dissolved in dichloromethane (80 mL), and N,N-diisopropylethylamine (3.1 g, 24 mmol) and triphosgene (795 mg, 2.68 mmol) were added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to give the crude title compound 2e (3 g). The crude product was further purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound (1.44 g, yield: 46.6%), (1.1 g, yield: 35.6%).

[0706] Single configuration compound (shorter retention time): (1.44 g, yield: 46.6%)

[0707] MS m / z(ESI):392.2[M+1].

[0708] HPLC analysis: retention time 1.37 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; Mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). Single configuration compound (longer retention time): (1.1 g, yield: 35.6%)

[0709] MS m / z(ESI):392.2[M+1].

[0710] HPLC analysis: retention time 1.40 minutes, purity: 99% (chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0711] Step 4

[0712] (S)-1-((R)-1-(4-amino-3-fluorophenyl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one hydrochloride 2f-1

[0713] or

[0714] (S)-1-((S)-1-(4-amino-3-fluorophenyl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one hydrochloride 2f-2

[0715] The compound with the shorter retention time (256 mg, 910 μmol) of compounds 2e-1 and 2e-2 was dissolved in dichloromethane (3 mL). A 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (300 mg). This product was used directly in the next step without purification. MS m / z (ESI): 292.1 [M+1].

[0716] Step 5

[0717] 2-Cycloheptyl-3-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropanoic acid ethyl ester 2g-1 (mixture of two isomers)

[0718] or

[0719] Ethyl 2-cycloheptyl-3-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropanoate 2g-2 (mixture of two isomers)

[0720] The crude compound 2f-1 or 2f-2 (300 mg, 915 μmol) and compound 1d (209 mg, 915 μmol) were dissolved in pyridine (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (477 mg, 2.75 mmol) was added. The reaction was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 2g-1 or 2g-2 (419 mg, yield: 91%).

[0721] MS m / z(ESI):500.4[M-1].

[0722] Step 6

[0723] 2-Cycloheptyl-3-((2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropanoic acid 2h-1 (mixture of two isomers)

[0724] or

[0725] 2-Cycloheptyl-3-((2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)amino)-3-oxopropanoic acid 2h-2 (mixture of two isomers)

[0726] Compound 2g-1 or 2g-2 (419 mg, 835 μmol) was dissolved in tetrahydrofuran (6 mL), and an aqueous solution (5 mL) of lithium hydroxide monohydrate (70 mg, 1.67 mmol) was added. The mixture was stirred at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the pH was slowly adjusted to 2-3 with 1M hydrochloric acid. The mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 2h-1 or 2h-2 (395 mg), which was used directly in the next reaction without purification.

[0727] MS m / z(ESI):474.3[M+1].

[0728] Step 7

[0729] 2-Cycloheptyl-N 1 -(2-Fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)malonamide 2i-1 (mixture of two isomers)

[0730] or

[0731] 2-Cycloheptyl-N 1 -(2-Fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)malonamide 2i-2 (mixture of two isomers)

[0732] Compound 2h-1 or 2h-2 (395 mg, 834 μmol), ammonium chloride (112 mg, 2.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (203 mg, 1.17 mmol) and 1-hydroxybenzotriazole (177 mg, 1.17 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (323 mg, 2.5 mmol) was added. The mixture was stirred for 18 hours, and 10 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (15 mL×3), and the organic phases were combined and concentrated under reduced pressure to give the crude title compound 2i-1 or 2i-2 (392 mg), which was used directly in the next reaction without purification.

[0733] MS m / z(ESI):473.3[M+1].

[0734] Step 8

[0735] 2-Cycloheptyl-N 1 -((dimethylamino)methylene)-N 3 -(2-Fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)malonamide 2j-1 (a mixture of four isomers)

[0736] or

[0737] 2-Cycloheptyl-N 1 -((dimethylamino)methylene)-N 3 -(2-Fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)malonamide 2j-2 (a mixture of four isomers)

[0738] Crude compound 2i-1 or 2i-2 (392 mg, 829 μmol) was dissolved in dichloromethane (10 mL), and N,N-dimethylformamide dimethyl acetal (296 mg, 2.49 mmol) was added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound 2j-1 or 2j-2 (437 mg), which was used directly in the next step without purification. MS m / z (ESI): 528.3 [M+1].

[0739] Step 9

[0740] 2-Cycloheptyl-N-(2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)-2-(4H-1,2,4-triazol-3-yl)acetamide 2k-1 (mixture of two isomers)

[0741] or

[0742] 2-Cycloheptyl-N-(2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)benzene

[0743] 1-(4H-1,2,4-triazol-3-yl)acetamide 2k-2 (a mixture of two isomers)

[0744] Crude compound 2j-1 or 2j-2 (437 mg, 828 μmol) was dissolved in glacial acetic acid (6 mL). Hydrazine hydrate (732 mg, 12.4 mmol, 85% purity) was added under ice-cooling. The mixture was allowed to return to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove most of the solvent, diluted with water, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 2k-1 or 2k-2 (410 mg), which was used directly in the next reaction without purification.

[0745] MS m / z(ESI):497.3[M+1].

[0746] Step 10

[0747] 2-(5-Bromo-4H-1,2,4-triazol-3-yl)-2-cycloheptyl-N-(2-fluoro-4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide 2l-1 (mixture of two isomers)

[0748] or

[0749] 2-(5-Bromo-4H-1,2,4-triazol-3-yl)-2-cycloheptyl-N-(2-fluoro-4-((S)-1-((S)-2-oxo-4-(trifluoromethyl)

[0750] Imidazolidin-1-yl)ethyl)phenyl)acetamide 2l-2 (mixture of two isomers)

[0751] The crude compound 2k-1 or 2k-2 (410 mg, 825 μmol) was dissolved in dichloromethane (16 mL). A solution of phenyltrimethylammonium tribromide (354 mg, 908 mmol) and sodium hydroxide (99 mg, 2.48 mmol) in water (1.3 mL) was added and the mixture was stirred for 16 hours. 5 mL of water was added to the reaction solution, which was then extracted with dichloromethane (15 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford the title compound 2l-1 or 2l-2 (373 mg, 78% yield).

[0752] MS m / z(ESI):575.3[M+1].

[0753] Step 11

[0754] 2-Cycloheptyl-2-(5-(1-ethyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-N-(2-fluoro-4-((R)-1-((S)-2-

[0755] Oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide 2-1 (mixture of 2 isomers)

[0756] or

[0757] 2-Cycloheptyl-2-(5-(1-ethyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-N-(2-fluoro-4-((S)-1-((S)-2-

[0758] Oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)phenyl)acetamide 2-2 (mixture of 2 isomers)

[0759] Compound 2l-1 or 2l-2 (373 mg, 648 μmol), 1-ethyl-1H-pyrazole-5-boronic acid pinacol ester 2m (173 mg, 777 μmol, Shanghai Leyan), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (274 mg, 324 μmol) and potassium carbonate (269 mg, 1.94 mmol) were dissolved in N,N-dimethylformamide (6 mL) and water (1 mL), replaced with nitrogen, and stirred at 115 ° C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, Welch Xtimate C18 column, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40-50%, flow rate: 30 mL / min) to obtain the title compound 2-1 or 2-2 (9 mg, yield: 2%).

[0760] MS m / z(ESI):591.4[M+1].

[0761] 1H NMR (500MHz, CD3OD): δ7.91(t,1H),7.53(d,1H),7.18-7.07(m,2H),6.81(d,1H),5.11(q, 1H),4.71-4.67(m,2H),4.31-4.27(m,1H),3.98(d,1H),3.76(t,1H),3.17-3.12(m,1H),2 .56-2.44(m,1H),2.19(t,1H),2.03(d,1H),1.99-1.90(m,1H),1.78-1.70(m,1H),1.68-1 .62(m,3H),1.59-1.51(m,3H),1.52(d,3H),1.49-1.42(m,1H),1.40(t,3H),0.90(t,1H).

[0762] Example 3

[0763] 2,4-Dimethyl-3-(4-(2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4-methylcyclohexyl)acetamido)phenyl)pyridine 1-oxide 3 (mixture of four isomers)

[0764]

[0765] first step

[0766] Diethyl 2-(4-methylcyclohexylidene)malonate 3b

[0767] Under ice, titanium tetrachloride (16.9 g, 89.15 mmol) was dissolved in tetrahydrofuran (40 mL). 4-Methylcyclohexane-1-one 3a (5.0 g, 44.57 mmol, Shanghai Titan), diethyl malonate (7.9 g, 49.19 mmol), and pyridine (14.1 g, 178.26 mmol) were added. The reaction mixture was allowed to react at room temperature for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, which was then washed sequentially with water and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to afford the title compound 3b (10.0 g, 88% yield).

[0768] Step 2

[0769] Diethyl 2-(4-methylcyclohexyl)malonate 3c (mixture of two isomers)

[0770] Compound 3b (3.0 g, 11.80 mmol) was dissolved in ethanol (20 mL), and 10% palladium-carbon hydrogenation catalyst (1.3 g) and 20% palladium hydroxide (0.8 g) were added. The atmosphere was replaced with hydrogen and the reaction was allowed to proceed at 50°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to afford the title compound 3c (2.5 g, 83% yield).

[0771] MS m / z(ESI):257.2[M+1].

[0772] Step 3

[0773] 3-Ethoxy-2-(4-methylcyclohexyl)-3-oxopropanoic acid 3d (mixture of four isomers)

[0774] Compound 3c (1.2 g, 4.68 mmol) was dissolved in ethanol (4 mL), and sodium hydroxide (190 mg, 4.75 mmol) was added. The mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and water (10 mL) and ethyl acetate (10 mL) were added to the residue. The pH was slowly adjusted to 2 with 1 M hydrochloric acid. The layers were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 3d (1.1 g), which was used directly in the next reaction without purification.

[0775] MS m / z(ESI):229.2[M+1].

[0776] Step 4

[0777] Ethyl 3-((4-(2,4-dimethylpyridin-3-yl)phenyl)amino)-2-(4-methylcyclohexyl)-3-oxopropanoate 3e (mixture of four isomers)

[0778] Crude compound 3d (400 mg, 1.75 mmol) and 4-(2,4-dimethylpyridin-3-yl)aniline (350 mg, 1.76 mmol, prepared using the method disclosed in Intermediate 1-19 on page 65 of patent application WO2022091056) were dissolved in pyridine (8 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (920 mg, 5.3 mmol) was added and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 3e (715 mg, 89% yield).

[0779] MS m / z(ESI):409.4[M+1].

[0780] Step 5

[0781] 3-((4-(2,4-dimethylpyridin-3-yl)phenyl)amino)-2-(4-methylcyclohexyl)-3-oxopropanoic acid 3f (mixture of four isomers)

[0782] Compound 3e (635 mg, 1.55 mmol) was dissolved in tetrahydrofuran (6 mL), and an aqueous solution (5 mL) of lithium hydroxide monohydrate (131 mg, 3.12 mmol) was added. The mixture was stirred at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The aqueous phase was slowly adjusted to pH 2-3 with 1M hydrochloric acid, and extracted with dichloromethane (30 mL × 3). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 3f (591 mg), which was used directly in the next reaction without purification.

[0783] MS m / z(ESI):381.4[M+1].

[0784] Step 6

[0785] N 1 -(4-(2,4-dimethylpyridin-3-yl)phenyl)-2-(4-methylcyclohexyl)malonamide 3g (mixture of four isomers)

[0786] Crude compound 3f (590 mg, 1.55 mmol), ammonium chloride (208 mg, 3.88 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377 mg, 2.17 mmol), and 1-hydroxybenzotriazole (331 mg, 2.17 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (600 mg, 4.64 mmol) was added and stirred for 18 hours. The reaction mixture was quenched by the addition of 10 mL of water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 3g (399 mg), which was used directly in the next reaction without purification.

[0787] MS m / z(ESI):380.4[M+1].

[0788] Step 7

[0789] N 1 -((dimethylamino)methylene)-N 3 -(4-(2,4-dimethylpyridin-3-yl)phenyl)-2-(4-methylcyclohexyl)malonamide 3h (mixture of eight isomers)

[0790] Dissolve the crude compound 3g (399 mg, 1.05 mmol) in dichloromethane (10 mL), add N,N-dimethylformamide dimethyl acetal (376 mg, 3.15 mmol), and stir at 65°C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 3h (456 mg), which was used directly in the next reaction without purification.

[0791] MS m / z(ESI):435.5[M+1].

[0792] Step 8

[0793] N-(4-(2,4-dimethylpyridin-3-yl)phenyl)-2-(4-methylcyclohexyl)-2-(4H-1,2,4-triazol-3-yl)acetamide 3i

[0794] (mixture of four isomers)

[0795] The crude compound 3h (456 mg, 1.05 mmol) was dissolved in glacial acetic acid (6 mL), and hydrazine hydrate (930 mg, 15.78 mmol, 85% purity) was added under ice bath. The mixture was returned to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, diluted with water, and adjusted to pH 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and concentrated under reduced pressure to give the crude title compound 3i (423 mg), which was used directly in the next reaction without purification.

[0796] MS m / z(ESI):404.5[M+1].

[0797] Step 9

[0798] 2-(5-Bromo-4H-1,2,4-triazol-3-yl)-N-(4-(2,4-dimethylpyridin-3-yl)phenyl)-2-(4-methylcyclohexyl)acetamide 3j (a mixture of four isomers)

[0799] Crude compound 3i (423 mg, 1.05 mmol) was dissolved in dichloromethane (10 mL), and a solution of phenyltrimethylammonium tribromide (450 mg, 1.15 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in water (1.6 mL) was added. The mixture was stirred for 16 hours. 5 mL of water was added to the reaction solution, which was then extracted with dichloromethane (15 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford the title compound 3j (414 mg, 82% yield).

[0800] MS m / z(ESI):482.3[M+1].

[0801] Step 10

[0802] N-(4-(2,4-dimethylpyridin-3-yl)phenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazole-3-yl)-

[0803] 4-Methylcyclohexyl)acetamide 3k (a mixture of four isomers)

[0804] Compound 3j (200 mg, 0.41 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (173 mg, 0.83 mmol, Shanghai Titan), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (170 mg, 0.21 mmol), and potassium carbonate (172 mg, 1.24 mmol) were dissolved in a mixture of N,N-dimethylformamide (6 mL) and water (1 mL). The atmosphere was replaced with nitrogen and the reaction was stirred at 115°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to provide the title compound 3k (15 mg, 8% yield).

[0805] MS m / z(ESI):484.4[M+1].

[0806] Step 11

[0807] 2,4-dimethyl-3-(4-(2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4-methylcyclohexyl)

[0808] Acetamido)phenyl)pyridine 1-oxide 3 (mixture of four isomers)

[0809] Compound 3k (8 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL), and m-chloroperbenzoic acid (4.3 mg, 0.02 mmol) was added under ice-cooling. The reaction mixture was returned to room temperature and stirred for 1 hour. A small amount of saturated aqueous sodium bicarbonate solution was added to the reaction solution and stirred until no bubbles were generated. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 25-50%, flow rate: 30 mL / min) to give the title compound 3 (4 mg, yield: 48%).

[0810] MS m / z(ESI):500.4[M+1].

[0811] 1H NMR (500MHz, CD3OD): δ8.29(d,1H),7.80(t,2H),7.53(s,1H),7.36(d,1H),7.20(d,2H),6.83(s,1H),4.23(s ,3H),3.82(d,1H),2.28(s,3H),2.11(s,3H),1.96(d,1H),1.86-1.43(m,6H),1.41-1.33(m,3H),0.93(d,3H).

[0812] Example 4

[0813] 2-Cycloheptyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide 4 (mixture of two isomers)

[0814]

[0815] Step 1: Tert-butyl ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)carbamate 4b

[0816] (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butanoic acid 4a (2 g, 5.84 mmol, using the Intermediate 74) and (2R)-1,2-dimethylpiperazine dihydrochloride (1.1 g, 5.88 mmol, Nanjing Yaoshi) were dissolved in N,N-dimethylformamide (30 mL). N,N-diisopropylethylamine (3.8 g, 29.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.33 g, 8.76 mmol) were added under ice-cooling. The mixture was stirred for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to give the title compound 4b (2.3 g, yield: 89.8%). MS m / z (ESI): 439.5 [M+1].

[0817] Step 2

[0818] (2R,3S)-2-Amino-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)butan-1-one 4c

[0819] Compound 4b (2.3 g, 5.25 mmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 4c (2.37 g), which was used directly in the next reaction without purification.

[0820] MS m / z(ESI):339.5[M+1].

[0821] Step 3

[0822] N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)-2-methoxyacetamide 4d

[0823] The crude compound 4c (2.3 g, 5.08 mmol) and methoxyacetic acid (700 mg, 7.77 mmol, Shanghai Shaoyuan) were dissolved in pyridine (25 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.65 g, 15.3 mmol, Shanghai Shaoyuan) was added. The reaction was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 4d (1.4 g, yield: 67.1%).

[0824] MS m / z(ESI):411.3[M+1].

[0825] Step 4

[0826] N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutan-2-yl)-2-methoxyacetamide 4e

[0827] Compound 4d (1.4 g, 3.41 mmol) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL). 10% palladium-on-carbon hydrogenation catalyst (700 mg, 0.66 mmol) was added, and the atmosphere was replaced with hydrogen. The reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4e (1.23 g), which was used directly in the next step without purification. MS m / z (ESI): 381.5 [M+1].

[0828] Step 5

[0829] (rac)-3-amino-2-cycloheptyl-3-oxopropionic acid ethyl ester 4f (a pair of enantiomers)

[0830] Crude compound 1d (1.68 g, 7.36 mmol), ammonium chloride (1.02 g, 19.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.80 g, 10.37 mmol), and 1-hydroxybenzotriazole (1.57 g, 10.32 mmol) were dissolved in N,N-dimethylformamide (12 mL). N,N-diisopropylethylamine (2.86 g, 22.13 mmol) was added and stirred for 18 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated under reduced pressure to afford the crude title compound 4f (1.67 g), which was used directly in the next step without purification.

[0831] MS m / z(ESI):228.3[M+1].

[0832] Step 6

[0833] 4 g of ethyl 2-cycloheptyl-3-(((dimethylamino)methylene)amino)-3-oxopropanoate (a mixture of four isomers)

[0834] Dissolve crude compound 4f (1.67 g, 7.35 mmol) in dichloromethane (40 mL), add N,N-dimethylformamide dimethyl acetal (2.62 g, 21.99 mmol), and stir at 65°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound 4g (2.07 g), which was used directly in the next step without purification.

[0835] MS m / z(ESI):283.2[M+1].

[0836] Step 7

[0837] Ethyl (rac)-2-cycloheptyl-2-(4H-1,2,4-triazol-3-yl)acetate 4h (a pair of enantiomers)

[0838] The crude compound 4g (2.07 g, 7.33 mmol) was dissolved in glacial acetic acid (40 mL), and hydrazine hydrate (864 mg, 14.67 mmol, 85% purity) was added under ice bath. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, diluted with water, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate (15 mL×3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 4h (1.58 g, yield: 85.7%).

[0839] MS m / z(ESI):252.2[M+1].

[0840] Step 8

[0841] Ethyl (rac)-2-(5-bromo-4H-1,2,4-triazol-3-yl)-2-cycloheptyl acetate 4i (a pair of enantiomers)

[0842] Compound 4h (0.86 g, 3.42 mmol) was dissolved in acetonitrile (30 mL) and added at 0°C. N -Bromosuccinimide (NBS) (914 mg, 5.13 mmol) was added and allowed to react at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, Welch Xtimate C18 column, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: 30-60% acetonitrile, flow rate: 30 mL / min) to afford the title compound 4i (116 mg, yield: 10.3%).

[0843] MS m / z(ESI):330.0[M+1].

[0844] Step 9: Ethyl (rac)-2-(5-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-2-cycloheptyl acetate 4j (a pair of enantiomers)

[0845] Compound 4i (175 mg, 0.53 mmol) was dissolved in acetonitrile (8 mL). Potassium carbonate (150 mg, 1.08 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (115 mg, 0.69 mmol) were added at 0°C and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to provide the title compound 4j (191 mg, 78.3% yield).

[0846] MS m / z(ESI):460.1[M+1].

[0847] Step 10

[0848] (rac)-2-cycloheptyl-2-(5-(1-methyl-1H-pyrazol-5-yl)-4-((2-(trimethylsilyl)ethoxy)methyl

[0849] Ethyl)-4H-1,2,4-triazol-3-yl)acetate 4k (a pair of enantiomers)

[0850] Compound 4j (30 mg, 0.065 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (28 mg, 0.13 mmol, Shanghai Titan), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (16 mg, 0.019 mmol), and potassium carbonate (28 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) and water (0.4 mL). The atmosphere was replaced with nitrogen and the reaction was stirred at 100°C for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to provide the title compound 4k (7 mg, 23.3% yield).

[0851] MS m / z(ESI):462.4[M+1].

[0852] Step 11

[0853] (rac)-2-cycloheptyl-2-(5-(1-methyl-1H-pyrazol-5-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)acetic acid 4l (a pair of enantiomers)

[0854] Compound 4k (7 mg, 0.015 mmol) was dissolved in ethanol (0.5 mL) and tetrahydrofuran (1 mL). A solution of sodium hydroxide (30 mg, 0.75 mmol) in water (0.4 mL) was added, and the mixture was stirred at 50°C for 7 hours. The reaction solution was cooled to room temperature, and 1 M hydrochloric acid was added dropwise to adjust the pH to 8. The solution was then concentrated under reduced pressure to afford the crude title compound 4l (7 mg), which was used directly in the next step without purification.

[0855] MS m / z(ESI):434.3[M+1].

[0856] Step 12

[0857] 2-Cycloheptyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4-((2-(trimethylsilyl)ethoxy)methyl

[0858] (4H-1,2,4-triazol-3-yl)acetamide 4m (a mixture of two isomers)

[0859] Crude compound 41 (7 mg, 0.016 mmol) and compound 4e (7 mg, 0.018 mmol) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (12 mg, 0.093 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10 mg, 0.026 mmol) were added and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to provide the title compound 4m (4 mg, 31.1% yield).

[0860] MS m / z(ESI):796.7[M+1].

[0861] Step 13

[0862] 2-Cycloheptyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamide)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide 4 (mixture of two isomers)

[0863] Compound 4m (4 mg, 0.005 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at 0°C and the mixture was allowed to react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, Welch Xtimate C18 column, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to afford the title compound 4 (1 mg, 30.0% yield).

[0864] MS m / z(ESI):666.2[M+1].

[0865] 1 H NMR (500MHz, CD3OD): δ7.99-7.93(m,1H),7.54(s,1H),7.17-7.08(m,2H),6.86-6.81(m,1H),5.03(d,1H),4.24(s,3H),4.19-4.15(m,1H),4.01 -3.92(m,3H),3.67-3.64(m,1H),3.46-3.42(m,3H),2.77-2.56(m,6H), 2.06-2.04(m,3H),1.68-1.60(m,6H),1.42-1.36(m,10H),0.92(s,3H).

[0866] Example 5

[0867] N-((2R,3S)-3-(4-(2-cycloheptyl-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)propanamide 5 (mixture of two isomers)

[0868]

[0869] MS m / z(ESI):636.2[M+1].

[0870] Example 6

[0871] N-((2R,3S)-3-(4-((R)-2-(4,4-difluorocyclohexyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)propanamide 6

[0872]

[0873] MS m / z(ESI):658.2[M+1].

[0874] Example 7

[0875] (R)-2-(4,4-difluorocyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide 7

[0876]

[0877] MS m / z(ESI):688.2[M+1].

[0878] Example 8

[0879] N-((2R,3S)-3-(3-fluoro-4-(2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4-methylcyclohexyl)acetamido)phenyl)-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)propanamide 8 (a mixture of four isomers)

[0880]

[0881] MS m / z(ESI):636.2[M+1].

[0882] Example 9

[0883] N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4-methylcyclohexyl)acetamide 9

[0884] (mixture of four isomers)

[0885]

[0886] MS m / z(ESI):666.2[M+1].

[0887] Example 10

[0888] N-((2R,3S)-3-(4-(2-(4-(difluoromethylene)cyclohexyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)propanamide 10 (mixture of two isomers)

[0889]

[0890] MS m / z(ESI):670.2[M+1].

[0891] Example 11

[0892] 2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide 11 (mixture of two isomers)

[0893]

[0894] MS m / z(ESI):700.2[M+1].

[0895] Example 12

[0896] N-((2R,3S)-3-(4-(2-(3-(difluoromethylene)cyclohexyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamido)-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)propanamide 12 (a mixture of four isomers)

[0897]

[0898] MS m / z(ESI):670.2[M+1].

[0899] Example 13

[0900] 2-(3-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutan-2-yl)-2-fluorophenyl)-2-(5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide 13 (a mixture of four isomers)

[0901]

[0902] MS m / z(ESI):700.2[M+1].

[0903] Biological evaluation

[0904] Test Example 1. Inhibitory activity of the disclosed compounds on the binding of human IL-17A:IL-17RA (IL-17AA competition assay)

[0905] IL-17A can bind to its receptor, the IL17RA / IL17RC heterodimer, in a dimerized form (IL-17AA) to exert its biological effects. It has been reported that the binding mode of IL-17AA to the IL17RA / IL17RC heterodimer is that IL-17AA preferentially binds to IL-17RA and subsequently to IL-17RC. In this study, the inhibitory effect of compounds on the binding between IL-17A and IL-17RA was assessed using homogeneous time-resolved fluorescence (HTRF) technology. IL-17A protein (MCE, HY-P70527) was diluted to a final concentration of 5 nM in reaction buffer (10 mM HEPES, 150 mM NaCl, 0.02% BSA, 0.01% Tween-20). 4 μL of IL-17A protein solution was added to each well of a 384-well plate. A negative control well was treated with 4 μL of reaction buffer. Add 2 μL of a serially diluted 10x concentration of compound to each well. Add 2 μL of 5% DMSO to negative control wells (no IL-17A or compound) and positive control wells (no compound). Seal the plate and centrifuge, mix thoroughly by vortexing for 2 minutes, and incubate at room temperature for 10 minutes. Dilute IL-17RA protein (BPS Bioscience, 91013-2) in reaction buffer to a final concentration of 12.5 nM. Add 4 μL of the IL-17RA protein solution to each well of a 384-well plate. Seal the plate and centrifuge, mix thoroughly by vortexing for 2 minutes, and incubate at room temperature for 60 minutes.

[0906] Mix 4×Streptavidin-d2 dilution and 4×MAb Anti-6HIS Tb cryptate Gold dilution at a volume ratio of 1:1, add 10 μL of Streptavidin-d2:MAb Anti-6HIS Tb cryptate Gold mixture to each well, centrifuge, shake for 2 minutes, centrifuge again, and let stand at room temperature for 2 hours before reading the plate and detecting the 665 / 620 Ratio value.

[0907] Graphpad Prism software was used to draw the inhibition curve based on the concentration of each compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, i.e., IC 50 value.

[0908] Table 1 Inhibitory activity IC of the disclosed compounds on the binding of human IL-17A:IL-17RA 50 value

[0909]

[0910] Conclusion: The disclosed compounds have good inhibitory activity against the binding of human IL-17A:IL-17RA. Test Example 2. Inhibitory activity of the disclosed compounds against the secretion of chemokine CXCL1 induced by human IL-17A on HaCaT cells (HaCaT IL-17A neutralization assay)

[0911] HaCaT cells are human epidermal cells that are a target cell for IL-17 and highly express the IL-17 receptor. IL-17A binds to the IL-17 receptor on HaCaT cells and can induce activation of downstream signaling pathways, thereby expressing and secreting the chemokine CXCL1. This experiment used enzyme-linked immunosorbent assay (ELISA) to detect the inhibitory effect of compound treatment on cell secretion of CXCL1, thereby evaluating the activity of the compound. The cells were diluted to 2×10 5 cells / mL, then plated at 50 μL / well (10,000 cells / well); the cells were placed in a 5% CO2, 37°C incubator. Afterwards, cell culture medium containing IL17A (GenScript, Z03228, final concentration 5 ng / ml) and 3-fold gradient dilutions of the compound was added to the cell culture plate at 50 μL / well or 50 ul / well of DMSO-containing dilutions were added to the corresponding wells (negative and positive controls were empty), the plate was tapped to mix, and the cells were placed in a 5% CO2, 37°C incubator for further culture for 24 hours. After collecting the cell supernatant, CXCL1 / GRO alpha ELISA test (R&D System, DY275) was performed according to the method provided by the manufacturer. Graphpad Prism software was used to draw the inhibition curve based on the concentrations of the compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, that is, the IC 50 value.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: R 1 is selected from the group consisting of a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -CHR 1a R 1b 、-OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 7 replace; R 1a and R 1b the same or different, and each independently a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group; wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, the heteroaryl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the arylalkyl group and the heteroarylalkyl group are each independently optionally replaced by one or more R 7a Replacement; condition is, R 1a and R 1b Not all hydrogen atoms at the same time; R 2a is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group; Q is N or CR 2b ; R 2 and R 2b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 8 replace; Each R 3 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a 6- to 14-membered heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-C(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-NR 12 S(O) v NR 10 R 11 and -NR 12 S(O) v R 9 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, 6 to 14 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl groups are each independently optionally substituted by one or more R B replace; Each R B are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v R 9 、-NR 12 S(O) v NR 10 R 11 , oxo, =S, =NR 13 Sum = CR 14 R 15 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R b replace; R 4 =O or =S; Or, R 4 connected to ring A to form a heterocyclic group or heteroaryl group fused to ring A; the heterocyclic group and heteroaryl group are each independently optionally substituted by one or more R 6 replace; R 5 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; or R 5 does not exist; Each R b 、R 6 、R 7 、R 7a and R 8 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxy, amino, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, -OR 9 、-NR 10 R 11 、-C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OC(O)R 9 、-OC(O)OR 9 、-OC(O)NR 10 R 11 、-NR 12 C(O)R 9 、-NR 12 C(O)OR 9 、-NR 12 C(O)NR 10 R 11 、-S(O) v R 9 、-S(O) v OR 9 、-S(O) v NR 10 R 11 、-NR 12 S(O) v R 9 、-NR 12 S(O) v NR 10 R 11 , oxo, =S, =NR 13 Sum = CR 14 R 15 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replace; R 9 、R 10 、R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxyalkyl group, the cycloalkyl group, the heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group are each independently optionally replaced by one or more R c replace; Or, R 10 and R 11 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R c replace; R 13 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; R 14 and R 15 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl, a heteroarylalkyl, -C(O)alkyl, -C(O)Oalkyl and a cyano group; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl and a heteroarylalkyl are each independently optionally replaced by one or more R c replace; Or, R 14 and R 15 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R c replace; Each R c are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 16 、-NR 17 R 18 、-C(O)R 16 、-C(O)OR 16 、-C(O)NR 17 R 18 、-OC(O)R 16 、-OC(O)OR 16 、-OC(O)NR 17 R 18 、-NR 19 C(O)R 16 、-NR 19 C(O)OR 16 、-NR 19 C(O)NR 17 R 18 、-S(O) v R 16 、-S(O) v OR 16 、-S(O) v NR 17 R 18 、-NR 19 S(O) v R 16 、-NR 19 S(O) v NR 17 R 18 , oxo, =S, =NR 20 Sum = CR 21 R 22 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R 0 replace; Or, two R's on a ring c Together with the ring atoms to which it is attached, it forms a cycloalkyl or heterocyclyl group; the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more R 0 replace; Each R 0 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a -OR 16 、-NR 17 R 18 、-C(O)R 16 、-C(O)OR 16 、-C(O)NR 17 R 18 、-OC(O)R 16 、-OC(O)OR 16 、-OC(O)NR 17 R 18 、-NR 19 C(O)R 16 、-NR 19 C(O)OR 16 、-NR 19 C(O)NR 17 R 18 、-S(O) v R 16 、-S(O) v OR 16 、-S(O) v NR 17 R 18 、-NR 19 S(O) v R 16 、-NR 19 S(O) v NR 17 R 18 , oxo, =S, =NR 20 Sum = CR 21 R 22 wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally substituted by one or more R t replace; R 16 、R 17 、R 18 and R 19 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxyalkyl group, the cycloalkyl group, the heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group and a heteroarylalkyl group are each independently optionally replaced by one or more R t replace; Or, R 17 and R 18 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R t replace; R 20 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; R 21 and R 22 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl, a heteroarylalkyl, -C(O)alkyl, -C(O)Oalkyl and a cyano group; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl and a heteroarylalkyl are each independently optionally replaced by one or more R t replace; Each R t are the same or different and are each independently selected from the group consisting of a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, -NH(alkyl), -N(alkyl), -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)NH, -C(O)NH(alkyl), -C(O)N(alkyl), -S-alkyl, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, an oxo group, =S, =NH, =N(OH), =N(alkyl), =N(alkoxy), =CH, =CH(halogen), and =C(halogen); n1 is 0, 1, 2, 3, 4, or 5; n2 is 0, 1, 2, 3, 4, or 5; v is 0, 1, or 2.

2. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of general formula (II) or a pharmaceutically acceptable salt thereof: in: R 1 Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and -CHR 1a R 1b wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 7 replace; X 1 、X 2 、X 3 and X 4 are the same or different and are each independently selected from N, CH and CR 6 Preferably, X 1 、X 2 、X 3 and X 4 The same or different, and each independently CH or CR 6 ; R 6 As defined in claim 1; More preferably, X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 、X 3 and X 4 All are CH; Q, R 1a 、R 1b 、R 2 、R 3 、R 6 and R 7 As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally replaced by one or more R 7 Substituted 4- to 10-membered cycloalkyl or -CHR 1a R 1b ; R 1a and R 1b are the same or different and are each independently a 3- to 6-membered cycloalkyl group; each R 7 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 14 R 15 ; R 14 and R 15 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; preferably, R 1 Selected from and / or R 2 is optionally replaced by one or more R 8 substituted 5- or 6-membered heteroaryl; each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3 to 6-membered cycloalkyl and cyano; preferably, R 2 Selected from and / or Q is N or CR 2b ; R 2b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, Q is N; and / or R 3 C 1-6 Alkyl or 6-membered heteroaryl; the C 1-6 The alkyl and 6-membered heteroaryl groups are each independently optionally substituted with one or more R B replace; Each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C(O)R 9 、-NR 12 C(O)R 9 、-C(O)NR 10 R 11 , 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group; wherein the 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclic group are each independently optionally substituted by one or more selected from oxo, halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent; R 9 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 8 membered heterocyclic group and 3 to 8 membered cycloalkyl C 1-6 wherein the 3 to 8 membered heterocyclic group and the 3 to 8 membered cycloalkyl C 1-6 Each alkyl group is independently optionally substituted by one or more alkyl groups selected from halogen, C 1-6 Alkyl and C 1-6 substituted by a haloalkyl substituent; R 10 and R 11 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 alkyl halide; R 12 is a hydrogen atom; Preferably, R 3 Selected from and / or X 1 、X 2 、X 3 and X 4 The same or different, and each independently CH or CR 6 ; R 6 As defined in claim 1; preferably, X 1 CH or CR 6 , R 6 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 、X 3 and X 4 All are CH.

4. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is selected from any one of the following compounds:

5. A compound represented by general formula (IIA) or a salt thereof: in: X is a halogen, preferably Br; Q, R 1 、R 3 、X 1 、X 2 、X 3 and X 4 As defined in claim 2.

6. A compound or a salt thereof, which is selected from any one of the following compounds:

7. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by general formula (IIA) or its salt undergoes a coupling reaction with the compound represented by general formula (M) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt; in: R w -B(OH)2 or R 2 is aryl or heteroaryl; wherein the aryl and heteroaryl are each independently optionally substituted by one or more R 8 replace; Q, R 1 、R 3 、R 8 、X 1 、X 2 、X 3 and X 4 As defined in claim 2.

8. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by IL-17; preferably, the IL-17 is IL-17A.

10. Use of the compound represented by general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for treating and / or preventing cancer, inflammation or autoimmune diseases or sarcopenia; preferably, the inflammation or autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, juvenile atopic arthritis, spondyloarthritis, uveitis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (I The present invention relates to a disease of the present invention which is selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis, angiogenesis, atherosclerosis, asthma, multiple sclerosis (MS), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, Behcet's disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, palmoplantar pustulosis (PPP), atopic dermatitis, chronic obstructive pulmonary disease (COPD) and Helicobacter pylori-associated gastritis, preferably selected from the group consisting of psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, more preferably psoriasis.

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