Substituted phenyl compounds, and pharmaceutical compositions and uses thereof

Abstract

The invention relates to a substituted phenyl compound as well as a pharmaceutical composition and application thereof, and particularly provides a substituted phenyl compound shown in a formula (I) which can be used for preparing medicines, especially medicines for preventing and / or treating Kv1.3 channel mediated diseases or symptoms. Each group in the formula (I) is as defined in the specification.

Description

[0001] This application claims priority to Chinese Patent Application No. 2024110836155, filed on August 8, 2024, Chinese Patent Application No. 2024115751577, filed on November 6, 2024, Chinese Patent Application No. 2024116809912, filed on November 22, 2024, Chinese Patent Application No. 202510042388X, filed on January 10, 2025, Chinese Patent Application No. 2025103170816, filed on March 18, 2025, Chinese Patent Application No. 2025108003576, filed on June 16, 2025, and Chinese Patent Application No. 2025110819864, filed on August 1, 2025. This application incorporates the entire contents of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to a substituted phenyl compound, a pharmaceutical composition thereof and use thereof, which can be used as a Kv1.3 channel inhibitor. BACKGROUND

[0003] Kv1.3 channel is one of the members of Kv family, which was first discovered in human T lymphocytes, and is expressed in the immune system, nervous system and vascular smooth muscle cells. Kv1.3 is one of the main potassium ion channels found in T cells, and its main function is to regulate the membrane potential. In the process of antigen presentation, Kv1.3 channels gather on the synapses of immune cells and promote Ca 2+ signaling.

[0004] Studies have shown that Kv1.3 is mainly involved in the activation process of effector T cells, so different subtypes of T cells have different sensitivities to Kv1.3 inhibitors. Selective inhibition of Kv1.3 channels can selectively inhibit the activation process of effector T cells, which provides a new idea for the treatment of autoimmune diseases related to effector T cells. Kv1.3 has thus become a new target protein for the treatment of autoimmune diseases such as multiple sclerosis, type I diabetes, psoriasis, contact dermatitis, rheumatoid arthritis and myasthenia gravis.

[0005] Kv1.3 channels also play a role in gastrointestinal disorders, including inflammatory bowel diseases (“IBD”) such as ulcerative colitis (“UC”) and Crohn’s disease. UC is a chronic IBD characterized by excessive T-cell infiltration and cytokine production. UC can impair quality of life and can lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8-positive T cells in the inflamed mucosa of UC patients have been associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are considered a biomarker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy for UC.

[0006] Peptide toxins with Kv1.3 inhibitory activity have been isolated from scorpions and sea anemones. Dalazatide (ShK-186), derived from non-natural amino acids, showed some therapeutic effect in a phase Ib clinical trial for psoriasis. However, its application is limited by poor subtype selectivity and the inability to orally administer peptide molecules. Therefore, the development of highly selective, orally administered small-molecule Kv1.3 inhibitors is of great value.

[0007] Currently, publicly disclosed patents related to Kv1.3 channel inhibitors (blockers) include WO2022076285A1, WO2022251561A2, WO2021071821A1, and WO2021071812A1. Summary of the Invention

[0008] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

[0010] in:

[0011] T is C 3-10 cycloalkyl, C 3-10 Cycloalkenyl or 3-10 membered heterocyclic groups, wherein the C 3-10 cycloalkyl, C 3-10 Cycloalkenyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace;

[0012] Ring A is a 5-10 member heteroaryl group;

[0013] Z is OH;

[0014] R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl, cyano and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cycloalkyl groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 The alkoxy, cyano, and amino groups are substituted;

[0015] R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 5-8 membered heteroaryl, 3-12 membered heterocyclic oxy group, 3-12 membered heterocyclic mercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 heterocyclic, 5-8 heteroaryl, 3-12 heterocyclic hydroxyl, and 3-12 heterocyclic mercapto are optionally surrounded by one or more R g replace;

[0016] R j and R k They may be the same or different, and each is independently selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0017] Or, Rj and R k Together with the atoms attached thereto, they form a 3-6 membered carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered carbon ring and the 3-6 membered heterocycle are optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0018] R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c NR b R c -S(O)2R e C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic and 3-6 membered heterocyclic oxy groups are optionally selected from halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0019] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl, 3-6 membered heterocyclic and 5-8 membered heteroaryl;

[0020] Or, R 5And one of the R 6 Or two Rs 6 The atoms bonded to it form a 3-12 membered carbon ring or a 3-12 membered heterocycle, wherein the 3-12 membered carbon ring or 3-12 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0021] R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0022] Or, two Rs 7 The atoms bonded to it form a 3-6 membered carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered carbon ring or 3-6 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0023] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms a 3-12 membered carbon ring or a 3-12 membered heterocycle, wherein the 3-12 membered carbon ring or 3-12 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0024] R a and R d The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, OH, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0025] R b and R c They are the same or different, and each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0026] Or R b and R c Together with the nitrogen atom attached thereto, they form a 4-8 membered heterocycle, wherein the 4-8 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0027] R e Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, amino, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0028] n is 0, 1, or 2;

[0029] r is 0, 1, 2, 3, 4, 5, and 6.

[0030] In some embodiments, the heteroatoms in the heteroaryl, heterocyclic, heterocyclic, heterocyclic oxy, and heterocyclic thiol groups are independently selected from O, N, and S, and the number is 1, 2, 3, 4, or 5.

[0031] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0032] T is C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace;

[0033] Ring A is a 5-10 member heteroaryl group;

[0034] Z is OH;

[0035] R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cycloalkyl groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 The alkoxy, cyano, and amino groups are substituted;

[0036] R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, 3-12 membered heterocyclic mercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace;

[0037] Rj and R k They may be the same or different, and each is independently selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0038] Or, R j and R k Together with the atoms it is attached to, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl groups and 3-6-membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0039] R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c -S(O)2R e C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic and 3-6 membered heterocyclic oxy groups are optionally selected from halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0040] R 6They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0041] Or, R 5 And one of the R 6 Two Rs 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0042] R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0043] Or, two Rs 7 The atoms bonded to it form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0044] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0045] R a and R d The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, OH, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0046] R b and R c They are the same or different, and each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0047] Or R b and R c Together with the nitrogen atom attached thereto, a 4-8 membered heterocyclic group is formed, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0048] R e Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, amino, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0049] n is 0, 1, or 2;

[0050] r is 0, 1, 2, 3, 4, 5, and 6.

[0051] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0052] Or, two Rs 7 The atoms bonded to it form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0053] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

[0054] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, 3-12 membered heterocyclic mercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace;

[0055] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0056] Or, R 5 And one of the R 6 Two Rs 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0057] R a R b R c R d Re R j R k And r are as defined above.

[0058] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-6 cycloalkyl and C 3-6 Halogenated cycloalkyl groups.

[0059] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 Replace, R 7 As defined above.

[0060] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace;

[0061] R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0062] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

[0063] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group.

[0064] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxygen group, 3-12 membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace;

[0065] R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups.

[0066] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0067] Or, R 5 And one of the R 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

[0068] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, OH, cyano, and amino groups;

[0069] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

[0070] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0071] T is C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace;

[0072] Ring A is a 5-membered heteroaryl group;

[0073] R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxygen group, 3-12 membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace;

[0074] R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups;

[0075] R 6They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0076] Or, R 5 And one of the R 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0077] R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, OH, cyano, and amino groups;

[0078] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0079] R a R b R c and R d As defined above.

[0080] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0081] (1) Each of the "C" mentioned 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 aminoalkyl and C 1-6 The alkyl group in "cyanoalkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl or sec-butyl, for example methyl;

[0082] (2) Each of the "C" mentioned above 1-6 Alkyl and C 1-6 The halogen in "halogenated alkyl" is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, for example fluorine;

[0083] (3) Each of the "C" mentioned 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-12 Cycloalkyloxy and C 3-12 The cycloalkyl group in "cycloalkyl mercapto" is independently C10. 3-8 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, or cyclopentyl, and again, cyclopentyl or cyclopropyl;

[0084] Each of the "C" mentioned 3-6 cycloalkyl and C 3-6 The cycloalkyl group in "cycloalkyloxy" is independently cyclopentyl or cyclopropyl;

[0085] (4) The heteroatom in each of the 3-12-membered heterocyclic oxygen group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group and 3-6-membered heterocyclic oxygen group is independently N, O or S, for example N or O; the number of heteroatoms can be independently 1 or 2;

[0086] The heterocyclic group in the "3-12-membered heterocyclic oxygen group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group and 3-10-membered heterocyclic group" is preferably a 3-8-membered heterocyclic group, more preferably a 4-8-membered heterocyclic group;

[0087] The heterocyclic groups in the "3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group, and 3-6-membered heterocyclic oxy group" can independently be saturated or partially unsaturated monocyclic, bridged, fused, or spirocyclic, such as aza-heterobutyl, oxo-heterobutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydrothiaranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, etc.

[0088] (5) The 5-10-membered heteroaryl, 5-8-membered heteroaryl and 5-membered heteroaryl are preferably 5-membered heteroaryl, wherein the heteroatom is N, O or S, preferably N and O, for example N; the number of heteroatoms can be 1, 2, 3 or 4, for example 2 or 3, for example triazolyl, tetrazolyl, thiazolyl, pyrazolyl, imidazole and oxazolyl;

[0089] (6) Each of the C's descriptions 3-10 The cycloalkenyl group is independently C 5-6 Cycloalkenyl;

[0090] (7) Each of the C's descriptions 2-6 The alkenyl group is independently C 2-4 Alkenyl groups, such as vinyl groups; and

[0091] (8) Each of the C's descriptions 2-6 The alkynyl group is independently C 2-4 Alkyne group, such as ethynyl group.

[0092] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from... The a-terminus is connected to a phenyl group; m is 0, 1, 2, 3, 4, 5, and 6; h is 0, 1, 2, 3, and 4; j is 0, 1, 2, 3, and 4; R 8 Selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, and oxo; R 7 As defined by compound (I);

[0093] Preferably, j is 0, h is 0, m is 0, 1, or 2, and R 7 For deuterium, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, -C 1-6 Alkylene-3-6-membered heterocyclic group or 3-6-membered heterocyclic group.

[0094] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from... m represents 0, 1, 2, 3, and 4; the a-terminus is connected to a phenyl group; R 7 As defined by compound (I).

[0095] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from... m represents 0, 1, 2, 3, and 4; the a-terminus is connected to a phenyl group; R 7 As defined by compound (I).

[0096] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a T of

[0097] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a T of m is 0, 1, 2, 3, and 4; R 7 As defined above.

[0098] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a T of Preferred

[0099] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (IIG):

[0100]

[0101] in,

[0102] G is selected from non-existent, CR 7b R 7c NR 7e O and S;

[0103] u is 1 and 2;

[0104] v is 0, 1, or 2;

[0105] R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0106] R 7e Selected from H, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0107] Or, R 7b and R 7c The atoms bonded to it form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0108] Or, R 7a and R 5 、or R 7a And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group;

[0109] R 1 R 2 R 3 R 4 R 5 R 6 R 7 The rings A, m, and n are as defined in compound (I).

[0110] In some embodiments, the compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof, wherein G is a CR 7b R 7c R 7b and R 7c For H.

[0111] In some embodiments, the compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof, wherein v and m are independently 0, 1, or 2. In some embodiments, the compound represented by formula (IIG) is the compound represented by formula (II).

[0112]

[0113] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7a R 7b R 7c R 7d The ring A and n are as defined in compounds of formula (IIG).

[0114] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II), wherein R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0115] Or R 7a and R 5 、or R 7a And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group;

[0116] R 1 R 2 R 3 R4 R 5 R 6 The ring A and n are as defined in compound (I).

[0117] In some embodiments, the compound represented by formula (I), formula (IIG), or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from triazole groups (e.g., ), imidazole group (e.g.) ), pyrazolyl (e.g.) ), oxazolyl, thiazolyl, isoxazolyl (e.g.) ), tetrazolium (e.g.) ), pyridyl (e.g.) ),

[0118] In some embodiments, the compound represented by formula (I), formula (IIG) or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from triazolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl.

[0119] In some embodiments, the compound represented by formula (I), formula (IIG), or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from triazole, imidazolyl, pyrazolyl, isoxazolyl, tetrazolyl, and pyridinyl, preferably selected from triazole (e.g., ) and imidazole groups (e.g. ).

[0120] In some embodiments, the compound represented by formula (I), formula (IIG), or formula (II), or a pharmaceutically acceptable salt thereof, wherein Selected from R 5 and R 6 As defined by compound (I).

[0121] In some embodiments, the compound represented by formula (I), formula (IIG), or formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group -S(O)2R e -C(O)R a -CH2-N(R)b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxy group and 3-8 membered heterocyclic thiol group are optionally surrounded by one or more R g replace;

[0122] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0123] Or, R 5 And one of the R 6 Two Rs 6 The atoms bonded to it form 4-12 membered heterocyclic groups, wherein the 4-12 membered heterocyclic groups are optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 Substituted by one or more substituents in the cycloalkyl group and the 3-6 membered heterocyclic group; R g R a R b R c R d R e R j R k and R g As defined above.

[0124] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (II-1).

[0125]

[0126] Among them, R 7a R 7b R7c and R 7d They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, F, CH3, CH2NH2, CH2CN, aziridine, piperidinyl, and

[0127] R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group -S(O)2R e C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxy group and 3-8 membered heterocyclic thiol group are optionally surrounded by one or more R g replace;

[0128] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocyclic and 5-8 membered heteroaryl;

[0129] Or R 7a and R 5The atoms bonded to it form 4-12 membered heterocyclic groups, wherein the 4-12 membered heterocyclic groups are optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group;

[0130] R 1 R 2 R 3 R 4 R a R b R c R d R e R j R k and R g As defined by compound (I).

[0131] In some embodiments, the compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof, wherein Selected from R 5 R 6 R 7 R 7b R 7c R 7d And m are as defined above.

[0132] In some embodiments, the compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 5 R 6 R 7b R 7c and R 7d As defined above.

[0133] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (II-2).

[0134]

[0135] R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, deuterium, halogen, and C.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, F, CH3, CH2OH, CH2CN, aziridine, piperidinyl, and

[0136] R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl mercapto, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxy group and 3-8 membered heterocyclic mercapto group are optionally surrounded by one or more R g replace;

[0137] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocyclic and 5-8 membered heteroaryl;

[0138] Or, R 7a and R 5 、or R 5 and its adjacent R 6 Any group of atoms connected to it forms C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-12 Cycloalkyl or 4-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group;

[0139] R 1 R 2 R 3 R 4 R a R b R c R d and R g As defined by compound (I).

[0140] In some embodiments, the compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 5 and its adjacent R 6 The atoms bonded to it form 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic groups are optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents among cycloalkyl and 3-6 membered heterocyclic groups.

[0141] In some embodiments, the compounds represented by formulas (I), (II), and (II-2), or their pharmaceutically acceptable salts, wherein Selected from

[0142] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (II-3).

[0143]

[0144] R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, F, CH3, CH2OH, CH2CN, aziridine, piperidinyl, and

[0145] R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxygen group and 3-8 membered heterocyclic thiol group are optionally surrounded by one or more R g replace;

[0146] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocyclic and 5-8 membered heteroaryl;

[0147] Or, R 7a and R 6 、or R 5 and R 6 Any group of atoms bonded to it forms a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group;

[0148] R 1 R 2 R 3 R 4 R a R b R c R d and R g As defined by compound (I).

[0149] In some embodiments, the compound represented by formula (II-3) or a pharmaceutically acceptable salt thereof, wherein R 7a and R 6 、or R 5 and R 6 Any group of atoms bonded to it forms a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents among cycloalkyl and 3-6 membered heterocyclic groups.

[0150] In some embodiments, the compound represented by formula (II-3) or a pharmaceutically acceptable salt thereof, wherein Selected from R v Whether the elements are the same or different, they are each independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups; p is 0, 1, 2, 3 and 4.

[0151] In some embodiments, the compounds represented by formulas (II), (II-1), (II-2), and (II-3), or pharmaceutically acceptable salts thereof, wherein R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, OH, cyano, and amino.

[0152] In some implementation schemes, where Selected from R u Selected from H, C 1-6 Alkyl and C(O)R a ;R 6 and R a As defined above.

[0153] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (III).

[0154]

[0155] R 1 R 2 R 3 R 4 R 5 R 6 And T is as defined above.

[0156] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, 3-12-membered heterocyclic, 5-8-membered heteroaryl, 3-12-membered heterocyclic oxy, 3-12-membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkenyl, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy groups and 3-12-membered heterocyclic groups are optionally separated by one or more R groups. g replace;

[0157] R j and R k Together with the atoms it is attached to, they form 3-6 membered heterocycles;

[0158] R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, amino, oxo, =NH, C(O)R a NR b R c 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxygen groups, wherein the C 1-6 Alkyl groups and 3-6-membered heterocyclic groups are optionally selected from halogens and C. 1-6 One or more substituents in the alkoxy group are substituted;

[0159] R a and R d The same or different, and each independently selected from C 1-6 Alkyl groups and 3-6 membered heterocyclic groups;

[0160] R b and R c Selected from H and C 1-6 Alkyl, or R b and R c Together with the nitrogen atom attached thereto, they form a 4-8 membered heterocycle; the 4-8 membered heterocycle is optionally selected from OH and C. 1-6 One or more substituents in the alkyl group are substituted;

[0161] r is 0 or 1.

[0162] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 Selected from H, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic, 5-8 membered heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 The cycloalkenyl and 3-12 membered heterocyclic groups are optionally separated by one or more R g replace;

[0163] R g They may be the same or different, and each is independently selected from -NH2, halogen, OH, C. 1-6 Alkyl, C1-6 Halogenated alkyl groups and oxo groups.

[0164] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl mercapto, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxy group and 3-8 membered heterocyclic mercapto group are optionally surrounded by one or more R g Replace; R a R b R c R d and R g As defined above; and / or, R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups.

[0165] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 6 They may be the same or different, and each is independently selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, -S(O)2R e and C 3-6 cycloalkyl;

[0166] R e Selected from C 1-6 alkyl;

[0167] n is 0 or 1.

[0168] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 6 They may be the same or different, and each is independently selected from deuterium, halogens, and C. 1-6 alkyl;

[0169] n is 0 or 1.

[0170] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 6 Selected from CH3, CN, (CH2)3OH, CHF2, CF3, Cl, S(O)2CH3, Br, D, F or cyclopropyl;

[0171] n is 0 or 1. In some embodiments, the compounds shown in formula (I), formula (IIG), formula (II), formula (II-2), and formula (II-3), or pharmaceutically acceptable salts thereof, wherein R 5 and its adjacent R 6 Or two adjacent R 6 The atoms bonded to them form 5-10 membered heterocycles, wherein the 5-10 membered heterocycles are optionally selected from C. 1-6 Alkyl, C 1-6 Hydroxyalkyl and -C(O)-C 1-6 It is replaced by one or more substituents in the alkyl group.

[0172] In some embodiments, the compounds represented by formulas (I), (IIG), (II), (II-2), and (II-3), or pharmaceutically acceptable salts thereof, wherein R 5 and one of its adjacent R 6 Or two adjacent R 6 and the formation of atoms connected to them. ( (Indicates the key shared with ring A).

[0173] In some embodiments, the compounds represented by formulas (I) and (III) or their pharmaceutically acceptable salts, wherein R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C.1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-3-6-membered heterocyclic groups and 3-6-membered heterocyclic groups; preferably H.

[0174] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 5 、or R 7 and R 6 And the atoms connected to them form 5-10 membered heterocycles.

[0175] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 5 、or R 7 and R 6 and the formation of atoms connected to them. (* indicates a site shared with T) (Indicates the key shared with ring A).

[0176] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 Selected from H, (CH2) t NH2, O-(CH2) t NH2, (CH2) t OH, cyclopropyl,

[0177] t is 1, 2, 3, 4, 5, and 6;

[0178] And / or, R 6 They are the same or different, and each is independently selected from H, deuterium, and C. 1-3 Alkyl, cyano and S(O)2CH3.

[0179] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 for

[0180] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, cyano and C 2-6 Alkyne group.

[0181] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 For Cl, R 3 For H, R 4 Selected from H, CN and acetylene groups.

[0182] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

[0183] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen and cyano groups.

[0184] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 Both are Cl, R 3 and R 4 For H; or R 2 and R 3 Whether the two are the same or different, and each is independently Cl or methyl, R 1 and R 4 All are H.

[0185] In some embodiments, the compounds represented by formulas (I), (IIG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein for

[0186] In some embodiments, the compounds represented by formulas (I) and (III) or their pharmaceutically acceptable salts, wherein R 7 They may be the same or different, and each is independently selected from H, deuterium, F, CH3, CH2OH, CH2CN, aziridine, piperidinyl, and

[0187] In some embodiments, the compounds represented by formulas (I) and (III) or their pharmaceutically acceptable salts, wherein R 7 They may be the same or different, and each is independently selected from H, F, CH3, CH2OH and CH2CN.

[0188] In some embodiments, the compounds represented by formula (IIG), formula (II), formula (II-1), formula (II-2), and formula (II-3), or pharmaceutically acceptable salts thereof, wherein R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, F, CH3, CH2OH, CH2CN, aziridine, piperidinyl, and

[0189] In some embodiments, the compounds represented by formula (IIG), formula (II), formula (II-1), formula (II-2), and formula (II-3), or pharmaceutically acceptable salts thereof, wherein R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, F, CH3, CH2OH and CH2CN.

[0190] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table A below:

[0191] Table A

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table B below:

[0203] Table B

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] Another aspect of this application provides a compound of formula (C) or a pharmaceutically acceptable salt thereof.

[0227]

[0228] Where R A The hydroxyl protecting group is, for example, methyl, -SEM ((trimethylsilyl)ethoxymethyl), -TBS (tert-butyldimethylsilyl), -MOM (methoxymethyl), -MEM (2-methoxyethoxymethyl), -THP (2-tetrahydropyran), etc.

[0229] R 1 R 2 R 3 R 4 R 5 and R 6 As defined by compound (I).

[0230] In some embodiments, the compound represented by formula (C) is selected from the following compounds:

[0231]

[0232] Another aspect of this application provides a method for preparing a compound of formula (IIIA), comprising a cyclization reaction of the compound of formula (A) with the compound of formula (B) to obtain the compound of formula (C1), followed by a deprotection reaction to obtain the compound of formula (IIIA), as shown in the following reaction formula:

[0233]

[0234] Among them, R A The hydroxyl protecting group is, for example, methyl, -SEM ((trimethylsilyl)ethoxymethyl), -TBS (tert-butyldimethylsilyl), -MOM (methoxymethyl), -MEM (2-methoxyethoxymethyl), -THP (2-tetrahydropyran), etc.

[0235] R 1R 2 R 3 R 4 and R 5 As defined by compound (I).

[0236] In another aspect, this application provides isotope labels for compounds shown in Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), as well as those shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or... 2 H) replaces hydrogen ( 1 H).

[0237] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0238] In another aspect, this application also provides the use of compounds of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for inhibiting the Kv1.3 channel.

[0239] In another aspect, this application also provides the use of compounds of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for blocking Kv1.3 channels.

[0240] In another aspect, this application also provides the use of compounds of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of Kv1.3 channel-mediated diseases.

[0241] This application also provides the use of compounds of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer, such as in the preparation of medicaments for the prevention and / or treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

[0242] This application also provides a method for inhibiting the Kv1.3 channel, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned.

[0243] This application also provides a method for blocking the Kv1.3 channel, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned.

[0244] This application also provides a method for preventing and / or treating Kv1.3 channel-mediated diseases or conditions, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned.

[0245] This application also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope label thereof, or a pharmaceutical composition comprising the aforementioned.

[0246] This application also provides a method for preventing and / or treating rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope label thereof, or a pharmaceutical composition comprising the aforementioned.

[0247] This application also provides a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the above-mentioned isotope label, or the aforementioned pharmaceutical composition, for use as a drug.

[0248] This application also provides a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the above-mentioned isotope label, or the aforementioned pharmaceutical composition, which is used as a Kv1.3 channel inhibitor.

[0249] This application also provides a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the above-mentioned isotope label, or the aforementioned pharmaceutical composition, which is used as a Kv1.3 channel blocker.

[0250] This application also provides a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a pharmaceutically acceptable salt thereof, or the above-mentioned isotope label, or the aforementioned pharmaceutical composition containing the above, for use as a medicament for the prevention and / or treatment of Kv1.3 channel-mediated diseases or conditions.

[0251] This application also provides a compound of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the above-mentioned isotope label, or the aforementioned pharmaceutical composition comprising the above, for use as a medicament for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0252] This application also provides a medicament for the prevention and / or treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

[0253] The diseases mediated by the Kv1.3 channel described in this application are selected from autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0254] The diseases mediated by the Kv1.3 channel described in this application are selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

[0255] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0256] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof.

[0257] In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compounds of formula (I), (II), (II-1), (II-2), (II-3), (III), (IIIA), Table A or Table B, or pharmaceutically acceptable salts thereof or isotopic labels thereof.

[0258] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable one or more excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable one or more excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable one or more excipients.

[0259] When administered as a medicine, the compounds of this application may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump.

[0260] In preparing the compositions of this application, the active ingredient is typically mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0261] The term "excipients" as used in this application refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0262] On the other hand, pharmaceutically acceptable salts of the compounds described in this application may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0263] On the other hand, the compounds of this application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0264] In the chemical structure of the compound described in this application, the bond... This indicates that no configuration has been specified. Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be Or simultaneously include Two configurations, This indicates the presence of axial chirality.

[0265] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0266] Furthermore, the compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of all compounds in this application are within the scope of this application. The name of a compound named in a single manner does not exclude any tautomer.

[0267] This application also includes compounds of this application with the same structure as described herein, but with one or more atoms replaced by isotopes of atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S,18 F, 123 I, 125 I and 36 Cl, etc. All isotopic variations of the compounds in this application, regardless of radioactivity, are included within the scope of this application.

[0268] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0269] The "therapeutic effective amount" in this application refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of a drug or pharmacologically active agent, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0270] "Pharmaceutical acceptable" in this application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0271] In this application, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0272] Beneficial effects

[0273] This application provides a small molecule compound that can be used as a Kv1.3 channel inhibitor (blocker), and such compounds or pharmaceutical compositions can be used to effectively treat or prevent Kv1.3 channel-mediated diseases.

[0274] Terminology Definitions and Explanations

[0275] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0276] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted.

[0277] The term "alkenyl" should be understood to preferably refer to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C...). 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group may be substituted or unsubstituted.

[0278] The term "alkynyl" should be understood to refer to a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl, 2-methyl The alkynyl group can be pentyl-3-ynyl, 1-methylpentyl-3-ynyl, 4-methylpentyl-2-ynyl, 1-methylpentyl-2-ynyl, 4-methylpentyl-1-ynyl, 3-methylpentyl-1-ynyl, 2-ethylbutyl-3-ynyl, 1-ethylbutyl-3-ynyl, 1-ethylbutyl-2-ynyl, 1-propylpropyl-2-ynyl, 1-isopropylpropyl-2-ynyl, 2,2-dimethylbutyl-3-ynyl, 1,1-dimethylbutyl-3-ynyl, 1,1-dimethylbutyl-2-ynyl, or 3,3-dimethylbutyl-1-ynyl. Specifically, the alkynyl group is ethynyl, propyl-1-ynyl, or propyl-2-ynyl. The alkynyl group can be substituted or unsubstituted.

[0279] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, alkoxy groups (C-) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 Alkoxy groups, more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1-6 Alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0280] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkenyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl, etc.; polycyclic cycloalkenyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkenyl groups.

[0281] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0282] The term "spirocycloalkyl," or when the cycloalkyl group is spirocyclic, refers to a 5- to 20-membered polycyclic group in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 5-membered, or 5- / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0283]

[0284] The term "fused cycloalkyl," or when the cycloalkyl group is fused-ring, refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0285]

[0286] The term "bridged cycloalkyl," or when the cycloalkyl group is bridged, refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly connected (i.e., three or more) carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0287]

[0288] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic ring as described herein, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0289] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone) or substituted with =NH, but excluding the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 5, for example, 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0290] The term "spiroheterocyclic group," or when the heterocyclic group is spirocyclic, refers to a 5- to 20-membered polycyclic heterocyclic group in which each monocyclic ring in the system shares one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0291]

[0292] The term "fused heterocyclic group," or when the heterocyclic group is fused ring, refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, 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 / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0293]

[0294] The term "bridged heterocyclic group," or when the heterocyclic group is a bridged ring, refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms (i.e., sharing three or more), and may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0295]

[0296]

[0297] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0298] The heterocyclic group may be substituted or unsubstituted.

[0299] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0300] The aryl group can be substituted or unsubstituted.

[0301] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0302] The heteroaryl group can be substituted or unsubstituted.

[0303] The terms “alkyl,” “alkenyl,” “alkynyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0304] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing a hydrogen atom from a parent ring atom (e.g., ), or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent compound, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene", "heteroarylene" (e.g. It can also include carbon rings or heterocycles formed by the direct connection of substituents on the same atom or different atoms;

[0305] For example, in this application, when R 5 for and for At that time, it can be said that R j and R k Together with the atoms it is attached to, it forms a heterocycle, or R j and R k Together with the atoms it is attached to, it forms a heterocyclic group;

[0306] For example, in this application, when R 7 and R 5The atoms connected to it form (* indicates a site connected to T, and dashed lines indicate bonds shared with ring A) When R is mentioned, it can be said that R 7 and R 5 Together with the atoms it is attached to, it forms a heterocyclic group, or R 7 and R 5 Together with the atoms it is attached to, it forms a heterocycle.

[0307] The term "carbon ring" refers to a saturated or partially unsaturated monocyclic or polycyclic ring, which may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7 and 8 carbon atoms).

[0308] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic ring, which may contain 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1, 2, 3, 4, or 5 ring atoms are heteroatoms.

[0309] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0310] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0311] The term “cycloalkyl mercapto” refers to cycloalkyl-S-, where the cycloalkyl group is as defined herein.

[0312] The term “heterocyclic thiol” refers to the heterocyclic group -S-, where the heterocyclic group is as defined herein.

[0313] The term “halogenated alkyl” refers to an alkyl group that is substituted with one or more halogens, wherein the halogens and alkyl groups are as defined herein.

[0314] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined herein, for example -CH2NH2.

[0315] The term "cyanoalkyl" refers to an alkyl group that is substituted with one or more cyano groups, wherein the alkyl group is as defined herein, for example -CH2CN.

[0316] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the halogens and alkoxy groups are as defined herein.

[0317] The term “halogenated cycloalkyl” refers to a cycloalkyl group that is substituted with one or more halogens, wherein the halogens and the cycloalkyl group are as defined herein.

[0318] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined herein.

[0319] The term "halogen" refers to F, Cl, Br, or I.

[0320] The term "hydroxyl group" refers to -OH.

[0321] The term "amino" refers to -NH2.

[0322] The term "cyano" refers to -CN.

[0323] The term "nitro" refers to -NO2.

[0324] The term "oxo" or "oxo" refers to "=O".

[0325] The term "carbonyl" refers to C=O.

[0326] The term "carboxyl group" refers to -C(O)OH.

[0327] The term “carboxylic acid ester group” refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined herein.

[0328] "Optional" or "optionally" means that the event or circumstance described below may, but does not have to, occur. This description includes situations in which the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but does not have to, be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0329] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond. Detailed Implementation

[0330] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0331] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0332] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The measurements are given in units of ppm. NMR determinations were performed using Bruker Ascend. TM -400 NMR was used, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an Agilent 6110, Agilent 1100, Agilent 6120, or Agilent G6125B liquid chromatography-mass spectrometry system.

[0333] HPLC determinations were performed using a Shimadzu HPLC-2010C high-performance liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um column).

[0334] Chiral HPLC analysis was performed using THARSFC X5.

[0335] The silica gel plates used for thin-layer chromatography are GF254 silica gel plates from Yantai Qingdao. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0336] Column chromatography typically uses Qingdao marine silica gel 200-300 mesh as the carrier.

[0337] High-performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2545, and the innovative Hengtong LC3000 preparative chromatograph.

[0338] Chiral preparative column chromatography was performed using Shimadzu LC-20AP and THARSFC PREP 80.

[0339] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0340] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0341] The microwave reaction uses a Biotage initiator+ type microwave reactor.

[0342] Unless otherwise specified in the experimental examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0343] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of about 1 liter.

[0344] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0345] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20℃ to 30℃.

[0346] Those skilled in the art should understand that chiral compounds can be distinguished by their retention times in a chiral chromatographic column. Therefore, chiral compounds separated according to their retention times are correspondingly distinguished by suffixes such as P1, P2, etc. That is, for example, suffix P1 corresponds to a chiral compound with a certain chiral structure that was eluted earlier from the chiral chromatographic column, while suffix P2 corresponds to a chiral compound with a certain chiral structure that was eluted later from the chiral chromatographic column. If the absolute configuration of a compound is listed in the structural formula, it does not imply a direct correspondence with the compounds suffixed P1 or P2; it merely indicates two possible forms of absolute configuration. The absolute configuration of compounds suffixed P1 or P2 is based on the objectively corresponding absolute configuration marked by a specific retention time.

[0347] Reagent names corresponding to English abbreviations:

[0348]

[0349]

[0350] Example 1 (Compound 1)

[0351]

[0352] Step 1: Synthesis of compound 1b

[0353] At 0°C, sodium hydride (0.34 g, 8.51 mmol) was slowly added to a mixed solution of tetrahydrofuran and dimethyl sulfoxide (20 mL / 20 mL) containing trimethyl sulfoxide (1.88 g, 8.51 mmol). After stirring the mixture at room temperature for 1 hour, a tetrahydrofuran (10 mL) solution of compound 1a (2 g, 5.49 mmol, synthesis method referred to in patent CN116782894A, pages 50-51, paragraphs 0349-0354, synthesis in Example 4) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1b (1.70 g, crude product). The crude product was used directly in the next step without purification.

[0354] Step 2: Synthesis of compound 1c

[0355] At room temperature, zinc powder (1.47 g, 22.47 mmol) and ammonium chloride (2.41 g, 44.94 mmol) were added to a mixture of methanol, tetrahydrofuran, and water (6 mL / 6 mL / 6 mL) of compound 1b (1.70 g, 4.49 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified using a Biotage-Flash rapid preparation system (column: C18 reversed-phase column, acetonitrile-water (0.1% ammonia); gradient: 60%-70%) to obtain compound 1c (180 mg). MS m / z (ESI): 348.0 [M+1] + .

[0356] Step 3: Synthesis of compound 1f

[0357] At room temperature, trimethyl orthoformate (77.6 mg, 0.73 mmol) was added to a 1,4-dioxane (0.5 mL) solution of compound 1d (105.5 mg, 0.49 mmol, synthesis method referred to in patent CN102317291A, page 104, paragraphs 1394-1395, step 1 of method B in intermediate example 44). The reaction mixture was stirred at 45°C for 1 hour, then cooled to room temperature. A 1,4-dioxane (0.5 mL) solution of compound 1c (170 mg, 0.49 mmol) and acetic acid (29.3 mg, 0.49 mmol) was added to the mixture. The reaction mixture was stirred at 120°C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 1f (200 mg, crude product). The crude product was used directly in the next step without purification. MS m / z (ESI): 555.4 [M+1] + .

[0358] Step 4: Synthesis of Compound 1

[0359] Compound 1f (200 mg, 0.36 mmol) was added to a 1,4-dioxane solution (4.0 M, 0.5 mL) of HCl at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 1 (5.50 mg). MS m / z (ESI): 325.0 [M+1] + .1 H NMR(400MHz, DMSO-d6)δ8.62(d,J=3.2Hz,1H),7.39–7.34(m,1H),6.92–6.86(m, 1H),4.58–4.10(m,6H),3.76–3.69(m,1H),1.70–1.61(m,1H),1.51–1.42(m,1H).

[0360] Example 2 (Compound 1-P1 and 1-P2)

[0361]

[0362] Step 1: Synthesis of compounds 1g-P1 and 1g-P2

[0363] At room temperature, di-tert-butyl dicarbonate (181.2 mg, 0.83 mmol) was added to a tetrahydrofuran (2 mL) solution of potassium carbonate (114.8 mg, 0.83 mmol) and compound 1 (90 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IH SFC, 20*250 mm; flow rate: 38 mL / min; column temperature: room temperature; mobile phase: A: carbon dioxide, B: methanol) to obtain compound 1 g-P1 (30 mg) and compound 1 g-P2 (30 mg).

[0364] Compound 1g-P1: MS m / z (ESI): 525.35 [M+1] + Supercritical fluid chromatography (SFC): retention time 1.988 min, UV = 214 nm.

[0365] Compound 1g-P2: MS m / z (ESI): 525.35 [M+1] + Supercritical fluid chromatography (SFC): retention time 2.257 min, UV = 214 nm.

[0366] Step 2: Synthesis of compounds 1-P1 and 1-P2

[0367] At room temperature, 0.5 mL of 4.0 M HCl in 1,4-dioxane was added to a 0.5 mL solution of 1 g-P1 (30 mg, 0.070 mmol) in 1,4-dioxane. The reaction mixture was stirred in a sealed tube at room temperature for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 1-P1 (11.5 mg). MS m / z (ESI): 325.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.33(s,1H),7.34(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.45–4.29(m,1H), 4.19–4.08(m,2H),4.06–3.92(m,2H),3.76–3.68(m,1H),2.46–2.37(m,1H),1.72–1.60(m,1H),1.54–1.40(m,1H).

[0368] At room temperature, 0.5 mL of 4.0 M dioxane in HCl was added to a 0.5 mL solution of 1 g-P2 (30 mg, 0.070 mmol) in 1,4-dioxane. The reaction mixture was stirred in a sealed tube at room temperature for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 1-P2 (12.0 mg). MS m / z (ESI): 325.00 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.56(s,1H),8.31(s,1H),7.35(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),4.39–4.27(m,1H), 4.16–4.05(m,2H),4.01–3.88(m,2H),3.75–3.70(m,1H),2.45–2.40(m,1H),1.71–1.60(m,1H),1.53–1.41(m,1H).

[0369] Example 3 (Compound 8-P1 and 8-P2)

[0370]

[0371] Step 1: Synthesis of compounds 8b-P1 and 8b-P2

[0372] At room temperature, trimethyl orthoformate (434.4 mg, 4.09 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 8a (500 mg, 2.05 mmol, synthesis method referred to patent WO2018037223 A1, page 148, synthesis of intermediate 123). The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. A 1,4-dioxane (3.5 mL) solution of compound 1c (712.9 mg, 4.09 mmol) and acetic acid (122.9 mg, 2.05 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 8b (150 mg). Compound 8b (150 mg) was separated by supercritical fluid chiral chromatography [equipment: SHIMADZUS FC-40P, column: Daicel Chiralpak IH SFC20mm ID*250mmL, 5 μm; mobile phase: A: CO2 B: MeOH [0.1% NH3 (7M solution in MeOH)]; flow rate: 38 mL / min] to obtain compounds 8b-P1 (45 mg) and 8b-P2 (50 mg).

[0373] Compound 8b-P1: MS m / z (ESI): 583.3 [M+1] + Supercritical fluid chromatography (SFC): retention time 4.288 min, UV = 214 nm.

[0374] Compound 8b-P2: MS m / z (ESI): 583.3 [M+1] + Supercritical fluid chromatography (SFC): retention time 5.386 min, UV = 214 nm.

[0375] Step 2: Synthesis of compounds 8-P1 and 8-P2

[0376] At room temperature, a 1,4-dioxane solution of HCl (4.0 M, 2 mL) was added to compound 8b-P1 (45 mg, 0.086 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 8-P1 (35.7 mg). MS m / z (ESI): 353.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ9.29–8.89(m,1H),7.40(d,J=8.8Hz,1H),6.97–6.86(m,1H),3.95–3.83(m,1H),3.54–3.45(m,1H),3.45 –3.34(m,2H),3.12–2.95(m,2H),2.66–2.59(m,1H),2.21–2.11(m,2H),2.02–1.91(m,2H),1.86–1.76(m,1H),1.61–1.50(m,1H).

[0377] At room temperature, a 1,4-dioxane solution of HCl (4.0 M, 2 mL) was added to compound 8b-P2 (50 mg, 0.086 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 8-P2 (18.6 mg). MS m / z (ESI): 353.1 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ9.09(s,1H),7.39(d,J=8.8Hz,1H),6.92(d,J=8.8Hz,1H),3.96–3.85(m,1H),3.51–3.45(m,1H),3.42– 3.32(m,2H),3.09–2.97(m,2H),2.67–2.60(m,1H),2.23–2.10(m,2H),2.02–1.92(m,2H),1.88–1.76(m,1H),1.62–1.50(m,1H).

[0378] Example 4 (Compound 11-1-P1, 11-1-P2, 11-2-P1, 11-2-P2)

[0379]

[0380] Step 1: Synthesis of compound 11b-1

[0381] At room temperature, trimethyl orthoformate (65.8 mg, 0.62 mmol) was added to compound 11a-1 (40.0 mg, 0.31 mmol). (The synthesis method is referenced in patent US20190308969). The reaction mixture was stirred at 45°C for 1 hour in a 1,4-dioxane (1.0 mL) solution of compound 1c (107.6 mg, 0.31 mmol) and acetic acid (18.6 mg, 0.31 mmol) in a 1,4-dioxane (1.0 mL) solution. The mixture was then cooled to room temperature, and the reaction mixture was added to the mixture. The reaction mixture was stirred at 120°C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 11b-1 (25 mg). MS m / z (ESI): 470.05 [M+1] + .

[0382] Step 2: Synthesis of compounds 11-1, 11-1-P1 and 11-1-P2

[0383] Compound 11b-1 (25 mg, 0.053 mmol) was added to a 2.0 M, 2 mL solution of 1,4-dioxane in HCl at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 11-1 (20.0 mg). MS m / z (ESI): 339.95 [M+1] + Compound 11-1 (25 mg) was purified by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IC-10SFC 30mm ID*250mmL, 10μm; mobile phase: A: CO2 B: MeOH [0.1% NH3 (7M solution in MeOH)]; flow rate: 100 ml / min] to obtain compound 11-1-P1 (4.39 mg) and compound 11-1-P2 (3.02 mg).

[0384] Compound 11-1-P1: MS m / z (ESI): 340.05 [M+1] + Supercritical fluid chromatography (SFC): retention time 4.304 min, UV = 214 nm. 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.54(s,1H),7.36(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4 .08(t,J=7.8Hz,1H),3.89–3.69(m,5H),2.38–2.15(m,3H),1.76–1.66(m,1H),1.58–1.49(m,1H).

[0385] Compound 11-1-P2: MS m / z (ESI): 340.00 [M+1] + Supercritical fluid chromatography (SFC): retention time 5.368 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.53(s,1H),7.36(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4 .09(t,J=7.8Hz,1H),3.91–3.72(m,5H),2.35–2.13(m,3H),1.73–1.64(m,1H),1.56–1.49(m,1H).

[0386] Step 3: Synthesis of compound 11b-2

[0387] At room temperature, trimethyl orthoformate (60.8 mg, 0.57 mmol) was added to compound 11a-2 (37.3 mg, 0.28 mmol). (The synthesis method is referenced in patent US20190308969). The reaction mixture was stirred at 45°C for 1 hour in a 1,4-dioxane (1.0 mL) solution of compound 1c (100.0 mg, 0.28 mmol) and acetic acid (17.2 mg, 0.28 mmol) in 1,4-dioxane (1.0 mL) to the mixture after cooling to room temperature. The reaction mixture was then stirred at 120°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 11b-2 (50 mg). MS m / z (ESI): 470.25 [M+1] + .

[0388] Step 4: Synthesis of compounds 11-2, 11-2-P1 and 11-2-P2

[0389] Compound 11b-2 (50 mg, 0.11 mmol) was dissolved in 2 mL of HCl in 1,4-dioxane (2.0 M). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.05% ammonia); gradient: 20-30%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 11-2 (10 mg). MS m / z (ESI): 339.80 [M+1] + Compound 11-2 (10 mg) was resolved by supercritical fluid chiral chromatography [equipment: SHIMADZUS FC-40P, column: Daicel Chiralpak IC-10SFC 30mm ID*250mmL, 10μm; mobile phase: A: CO2 B: MeOH [0.1% NH3 (7M solution in MeOH)]; flow rate: 100 ml / min] to obtain compounds 11-2-P1 (1.94 mg) and 11-2-P2 (2.24 mg).

[0390] Compound 11-2-P1: MS m / z (ESI): 340.15 [M+1] + Supercritical fluid chromatography (SFC): retention time 3.093 min, UV = 214 nm.

[0391] Compound 11-2-P2: MS m / z (ESI): 340.10 [M+1] + Supercritical fluid chromatography (SFC): retention time 3.477 min, UV = 214 nm.

[0392] Example 5 (Compound 12-1-P1, 12-1-P2, 12-2-P1, 12-2-P2)

[0393]

[0394] Step 1: Synthesis of compounds 12b-1, 12b-1-P1 and 12b-1-P2

[0395] At room temperature, trimethyl orthoformate (137.1 mg, 1.29 mmol) was added to a 1,4-dioxane (0.5 mL) solution of compound 12a-1 (218.1 mg, 0.95 mmol, synthesis method referred to the synthesis of intermediate 2 on page 109 of patent CN117946111A). The reaction mixture was stirred at 45 °C for 1 hour. Then, after cooling to room temperature, a 1,4-dioxane (2.5 mL) solution of compound 1c (300 mg, 0.86 mmol) and acetic acid (51.7 mg, 0.86 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 12b-1 (150 mg). Compound 12b-1 (150 mg) was purified by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IHSFC 20 mm ID*250 mmL, 5 μm; mobile phase: A: CO2 B: MeOH [0.1% NH3 (7 M solution in MeOH)]; flow rate: 38 mL / min] to obtain compounds 12b-1-P1 (50 mg) and 12b-1-P2 (50 mg).

[0396] Compound 12b-1-P1: MS m / z (ESI): 569.3 [M+1] + Supercritical fluid chromatography (SFC): retention time 2.590 min, UV = 214 nm.

[0397] Compound 12b-1-P2: MS m / z (ESI): 569.3 [M+1] + Supercritical fluid chromatography (SFC): retention time 2.957 min, UV = 214 nm.

[0398] Step 2: Synthesis of compounds 12-1-P1 and 12-1-P2

[0399] At room temperature, a 4.0 M, 2 mL solution of 1,4-dioxane HCl was added to compound 12b-1-P1 (50 mg, 0.087 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 12-1-P1 (33.6 mg). MS m / z (ESI): 339.1 [M+1] +Supercritical fluid chromatography (SFC): retention time = 2.102 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ8.84–8.73(m,1H),7.39(dd,J=8.8,1.6Hz,1H),6.89(dd,J=8.8,2.4Hz,1H),3.97–3.89(m,1H),3.85–3.79(m ,1H),3.60–3.47(m,3H),3.39–3.29(m,2H),2.45–2.38(m,1H),2.20–2.09(m,1H),2.04–1.93(m,1H),1.77(d,1H),1.63–1.52(m,1H).

[0400] At room temperature, a 4.0 M, 2 mL solution of 1,4-dioxane HCl was added to compound 12b-1-P2 (50 mg, 0.087 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 12-1-P2 (31.9 mg). MS m / z (ESI): 339.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.363 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ8.99–8.76(m,1H),7.39(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.04–3.94(m,1H),3.65–3.59(m,3H),3.5 6–3.49(m,1H),3.40–3.27(m,2H),2.63–2.59(m,1H),2.47–2.38(m,1H),2.25–2.11(m,1H),1.83–1.72(m,1H),1.59–1.51(m,1H).

[0401] Step 3: Synthesis of compounds 12b-2, 12b-2-P1 and 12b-2-P2

[0402] At room temperature, trimethyl orthoformate (182.8 mg, 1.72 mmol) was added to a 1,4-dioxane (2.0 mL) solution of compound 12a-2 (290.9 mg, 1.26 mmol, synthesis method referred to page 109 of patent CN117946111A, synthesis of intermediate 2). The reaction mixture was stirred at 45 °C for 1 hour. Then, after cooling to room temperature, a 1,4-dioxane (4.0 mL) solution of compound 1c (400 mg, 1.14 mmol) and acetic acid (68.9 mg, 1.14 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to obtain compound 12b-2 (300 mg). Compound 12b-2 (300 mg) was resolved by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IH SFC 20mm ID*250mmL, 5μm; mobile phase: A: CO2 B: MeOH [0.1% NH3 (7M solution in MeOH)]; flow rate: 38 ml / min] to obtain compounds 12b-2-P1 (130 mg) and 12b-2-P2 (130 mg).

[0403] Compound 12b-2-P1: MS m / z (ESI): 569.1 [M+1] + Supercritical fluid chromatography (SFC): retention time 2.579 min, UV = 214 nm.

[0404] Compound 12b-2-P2: MS m / z (ESI): 569.1 [M+1] + Supercritical fluid chromatography (SFC): retention time 3.343 min, UV = 214 nm.

[0405] Step 4: Synthesis of compounds 12-2-P1 and 12-2-P2

[0406] At room temperature, a 1,4-dioxane solution of HCl (4.0 M, 2 mL) was added to compound 12b-2-P1 (130 mg, 0.23 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 12-2-P1 (53.8 mg). MS m / z (ESI): 339.0 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.165 min, UV = 214 nm. 1H NMR (400MHz, CD3OD) δ9.83(s,1H),7.31(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H),4.40–4.29(m,1H),4.22–4.13(m,1H),3.88–3.79(m,1H ),3.78–3.68(m,1H),3.65–3.45(m,2H),2.85–2.73(m,1H),2.69–2.58(m,1H),2.49–2.36(m,1H),2.04–1.92(m,1H),1.85–1.69(m,1H).

[0407] At room temperature, a 1,4-dioxane solution of HCl (4.0 M, 2 mL) was added to compound 12b-2-P2 (130 mg, 0.23 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 12-2-P2 (58.5 mg). MS m / z (ESI): 339.0 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.201 min, UV = 214 nm. 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),7.39(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),3.97(p,1H),3.92–3.84(m,1H),3.66–3.61(m,1H), 3.59–3.51(m,1H),3.42–3.26(m,2H),2.67–2.60(m,1H),2.49–2.38(m,1H),2.25–2.09(m,1H),1.90–1.69(m,1H),1.68–1.51(m,1H).

[0408] Example 6 (Compound 23)

[0409]

[0410] Step 1: Synthesis of compound 23c

[0411] At 0°C, sodium hydride (8.19 g, 204.84 mmol) was added to a tetrahydrofuran (300 mL) solution of compound 23c (40.18 g, 204.84 mmol). After stirring the mixture for 30 minutes, a tetrahydrofuran (200 mL) solution of compound 23a (35 g, 170.70 mmol) (synthetic method referred to Example 36, Step A, page 51 of patent WO2016123164A1) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction solution was diluted with water (500 mL), extracted with ethyl acetate (1000 mL), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 23c (36 g). MS m / z (ESI): 275.00 [M+1] + .

[0412] Step 2: Synthesis of compound 23d

[0413] At -20°C, a solution of diazomethane in diethyl ether (727.0 mL, 436.20 mmol) was slowly added dropwise to a solution of compound 23c (20 g, 72.70 mmol) and palladium acetate (0.98 g, 4.36 mmol) in tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 23d (20 g). The crude product was used directly in the next step without purification. MS m / z (ESI): 288.95 [M+1] + .

[0414] Step 3: Synthesis of compound 23e

[0415] At room temperature, sodium hydroxide (13.84 g, 346.00 mmol) was added to a methanol / water mixture (600 mL / 200 mL) containing 23d (80 g, 276.70 mmol). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was adjusted to pH 4 with dilute hydrochloric acid (1000 mL, 2N), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated brine (200 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1%–10%) to give compound 23e (70 g). MS m / z (ESI): 259.05 [M⁻¹] - .

[0416] Step 4: Synthesis of compound 23f

[0417] Under nitrogen protection, diphenyl azidophosphate (81.16 g, 0.29 mol) was added dropwise to a solution of compound 23d (70 g, 0.27 mol) and triethylamine (35.27 g, 0.35 mol) in tert-butanol (700 mL). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1%–30%) to give compound 23f (70 g). MS m / z (ESI): 276.10 [M-55] + .

[0418] Step 5: Synthesis of compound 23g

[0419] Boron tribromide (18.91 g, 75.50 mmol) was added to a solution of compound 23f (5 g, 15.10 mmol) in 100 mL of dichloromethane at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1%–20%) to give compound 23 g (2 g). MS m / z (ESI): 218.05 [M+1] + .

[0420] Step 6: Synthesis of Compound 23

[0421] At room temperature, trimethyl orthoformate (97.2 mg, 0.91 mmol) was added to a 1,4-dioxane (1.0 mL) solution of compound 23h (89.5 mg, 0.68 mmol) (synthetic method referred to step 7 of intermediate 1 on page 91 of patent WO2023158626A1). The reaction mixture was stirred at 45 °C for 1 hour. Then, after cooling to room temperature, a 1,4-dioxane (1.0 mL) solution of compound 23g (50.0 mg, 0.22 mmol) and acetic acid (13.7 mg, 0.22 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 60bar) to obtain compound 23 (1.81mg). MS m / z (ESI): 340.05 [M+1] + .

[0422] Example 7 (Compound 113)

[0423]

[0424] Step 1: Synthesis of compound 113a

[0425] Compound 23f (14 g, 42.10 mmol) was dissolved in a 70 mL solution of 1,4-dioxane in HCl at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 113a (crude product, 9 g). The product was used directly in the next step without purification. MS m / z (ESI): 232.05 [M+1] + .

[0426] Step 2: Synthesis of compound 113c

[0427] At room temperature, hydrazine hydrate (559.3 mg, 11.17 mmol) was added to an ethanol solution (8 mL) of compound 113b (400 mg, 2.79 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 3 / 1) to give compound 113c (300 mg). MS m / z (ESI): 143.90 [M+1] + .

[0428] Step 3: Synthesis of compound 113d

[0429] At room temperature, trimethyl orthoformate (296.1 mg, 2.79 mmol) was added to a 1,4-dioxane (4 mL) solution of compound 113c (200 mg, 1.39 mmol). The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. A 1,4-dioxane (1 mL) solution of compound 113a (324.21 mg, 1.39 mmol) and acetic acid (83.88 mg, 1.39 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 113d (200 mg). MS m / z(ESI): 367.10 [M+1] + .

[0430] Step 4: Synthesis of compound 113e

[0431] Sodium bicarbonate (411.7 mg, 4.90 mmol) and iodine (932.9 mg, 3.67 mmol) were added sequentially to a mixture of tetrahydrofuran and water (3.6 mL / 1.2 mL) containing compound 113d (180 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium thiosulfate solution (5 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel plates (DCM / MeOH = 10 / 1) to give compound 113e (30 mg). MS m / z (ESI): 380.80 [M+1] + .

[0432] Step 5: Synthesis of Compound 113

[0433] Boron tribromide (328.4 mg, 1.31 mmol) was slowly added dropwise to a 2 mL solution of compound 113e (50 mg, 0.13 mmol) in dichloromethane at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 113 (8 mg). MS m / z (ESI): 367.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.57(s,1H),7.36(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),4.02–3.91(m,1H),3 .83–3.72(m,2H),3.70–3.62(m,1H),2.75(d,J=5.2Hz,3H),2.72–2.56(m,3H),1.80–1.68(m,1H),1.56–1.46(m,1H).

[0434] Example 8 (Compound 135)

[0435]

[0436] Step 1: Synthesis of compound 135b

[0437] Under nitrogen protection, compound 135a (1.00 g, 3.30 mmol) (synthetic method referred to Example 4, step d, page 61 of patent WO2021071821 A1), tris(dibenzylacetone)dipalladium (151.1 mg, 0.17 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (96.5 mg, 0.17 mmol) and cesium carbonate (3.22 g, 9.90 mmol) were added sequentially to a 1,4-dioxane (20 mL) solution of cyclopentanone (555.3 mg, 6.60 mmol). The reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 9 / 1) to give compound 135b (400 mg). MS m / z (ESI): 259.0 [M+1] + .

[0438] Step 2: Synthesis of compound 135c

[0439] At room temperature, hydroxylamine hydrochloride (214.5 mg, 3.09 mmol) and sodium acetate (379.7 mg, 4.63 mmol) were added to a 20 mL ethanol solution of compound 135b (400 mg, 1.54 mmol). The reaction mixture was stirred at 50 °C for 5 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 135c (400 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 273.9 [M+1] + .

[0440] Step 3: Synthesis of compound 135d

[0441] Raney nickel (77.1 mg, 1.31 mmol) was added to a methanol solution of compound 135c (180 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0–9 / 1) to give compound 135d (80 mg). MS m / z (ESI): 260.0 [M+1] + .

[0442] Step 4: Synthesis of compound 135e

[0443] Boron tribromide (385.2 mg, 1.54 mmol) was added to a dichloromethane (5 mL) solution of compound 135d (80 mg, 0.31 mmol), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0–5 / 1) to give compound 135e (40 mg). MS m / z (ESI): 245.9 [M+1] + .

[0444] Step 5: Synthesis of Compound 135

[0445] At room temperature, trimethyl orthoformate (34.5 mg, 0.32 mmol) was added to a 2 mL solution of 1,4-dioxane (2 mL) of compound 135f (42.3 mg, 0.32 mmol) (synthetic method referred to in US Patent 20190308969 A1, page 196, Synthesis of Compound 38.2). The reaction mixture was stirred at 45°C for 1 hour. Then, a 0.5 mL solution of 1,4-dioxane (40 mg, 0.16 mmol) of compound 135e and acetic acid (19.5 mg, 0.32 mmol) was added. The reaction mixture was stirred at 120°C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was purified to obtain compound 135 (5.7 mg) using a 150*21.2 mm column (150 x 21.2 mm); mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar). MS m / z (ESI): 368.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)10.13(s,1H),8.33(d,J=4.0Hz,1H),7.21(dd,J=8.8 ,3.2Hz,1H),6.62(dd,J=8.8,3.2Hz,1H),4.94–4.77(m,1H),4.06–4.00(m,1 H),3.84–3.68(m,2H),3.47–3.36(m,1H),3.14(p,J=8.8Hz,1H),2.73(dd,J =15.6,7.2Hz,1H),2.42–2.24(m,3H),2.19–2.08(m,1H),1.98–1.50(m,4H).

[0446] Example 9 (Compound 169)

[0447]

[0448] Step 1: Synthesis of compound 169a

[0449] At room temperature, bromine (879.4 mg, 5.50 mmol) was added to a solution of 23 g (1000 mg, 4.58 mmol) of compound in 10 mL of acetic acid. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound 169a (600 mg). MS m / z (ESI): 296.0 [M+1] + .

[0450] Step 2: Synthesis of compound 169b

[0451] At room temperature, trimethyl orthoformate (482.4 mg, 4.55 mmol) was added to a 1,4-dioxane (10 mL) solution of compound 135f (394.4 mg, 3.03 mmol), and the reaction mixture was stirred at 45 °C for 1 hour. A 1,4-dioxane (5 mL) solution of compound 169a (300 mg, 1.01 mmol) and acetic acid (121.3 mg, 2.02 mmol) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 169b (150 mg). MS m / z (ESI): 418.1 [M+1] + .

[0452] Step 3: Synthesis of Compound 169

[0453] At room temperature, potassium ferricyanide (78.6 mg, 0.24 mmol), palladium acetate (1.1 mg, 0.0048 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.9 mg, 0.0048 mmol) were added to a mixture of compound 169b (10 mg, 0.024 mmol) in n-butanol and water (1 mL / 1 mL). The reaction mixture was stirred at 100 °C for 12 hours. Ten parallel batches were added. After the reaction was completed, the ten batches of reaction solution (total 100 mg of compound 169b) were combined and filtered. The filter cake was washed with methanol (5 mL × 3) and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.05% ammonia); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar. Compound 169 (0.78 mg) was purified. MS m / z (ESI): 364.9 [M+1] + .

[0454] Example 10 (Compound 168)

[0455]

[0456] Step 1: Synthesis of compound 168b

[0457] At room temperature, trimethyl orthoformate (964.8 mg, 9.09 mmol) was added to a 1,4-dioxane (10 mL) solution of compound 168a (1395.8 mg, 6.06 mmol), and the reaction mixture was stirred at 45 °C for 1 hour. A 1,4-dioxane (5 mL) solution of compound 169a (600 mg, 2.02 mmol) and acetic acid (121.3 mg, 2.02 mmol) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 168b (280 mg). MS m / z (ESI): 516.90 [M+1] + .

[0458] Step 2: Synthesis of compound 168c

[0459] At room temperature, potassium ferricyanide (44.2 mg, 0.13 mmol), palladium acetate (10.8 mg, 0.048 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13.7 mg, 0.029 mmol) were added to a mixed solution of compound 168b (5 mg, 0.0096 mmol) in n-butanol and water (1 mL / 1 mL). The reaction mixture was stirred at 100 °C for 12 hours. Ten parallel batches were added. After the reaction was completed, the ten batches of reaction solution (total 50 mg of compound 168b) were combined and filtered. The filter cake was washed with methanol (5 mL × 3) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5µm C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% ammonia); column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 168c (6 mg obtained in ten batches). MS m / z (ESI): 464.1 [M+1] + .

[0460] Step 3: Synthesis of Compound 168

[0461] At room temperature, a 4.0 M, 2 mL solution of 1,4-dioxane hydrochloride was added to a 1 mL solution of compound 168c (6 mg, 0.013 mmol) containing 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 168 (5 mg). MS m / z (ESI): 363.9 [M+1] + .

[0462] Example 11 (Compound 105)

[0463]

[0464] Step 1: Synthesis of compound 105b

[0465] Trimethyl orthoformate (18.2 mg, 0.17 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 105a (synthetic method referred to page 83 of patent WO2018233633A1, synthesis of compound WX083-2). The reaction mixture was stirred at 45 °C for 1 hour. After the reaction was complete, acetic acid (8.6 mg, 0.14 mmol) and compound 1c (50 mg, 0.14 mmol) were added to the reaction mixture, and the reaction mixture was heated to 120 °C and stirred for 15 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 1) to give compound 105b (35 mg). MS m / z (ESI): 456.3 [M+1]+ .

[0466] Step 2: Synthesis of Compound 105

[0467] Trifluoroacetic acid (0.5 mL) was added to a solution of compound 105b (30 mg, 0.06 mmol) in dichloromethane (1.5 mL) at room temperature. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 8 with ammonia, and the solution was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 105 (11.9 mg). MS m / z (ESI): 326.10 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.57(s,1H),7.36(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.95–4.84(m, 4H),4.68–4.59(m,1H),3.69–3.62(m,1H),2.46–2.42(m,1H),1.64–1.56(m,1H),1.44(dd,J=13.6,6.8Hz,1H).

[0468] Example 12 (Compound 114)

[0469]

[0470] Step 1: Synthesis of compound 114b

[0471] Hydrazine hydrate (342.3 mg, 5.47 mmol) was added to a 3 mL ethanol solution of compound 114a (400 mg, 2.74 mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–10%) to give compound 114b (300 mg). MS m / z (ESI): 146.8 [M+1] + .

[0472] Step 2: Synthesis of compound 114c

[0473] At room temperature, trimethyl orthoformate (76.2 mg, 0.72 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 114b (70 mg, 0.48 mmol). The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. A 1,4-dioxane (1 mL) solution of 113a (111.1 mg, 0.48 mmol) and acetic acid (28.7 mg, 0.48 mmol) was then added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1%–15%) to give compound 114c (80 mg). MS m / z (ESI): 370.21 [M+1] + .

[0474] Step 3: Synthesis of compound 114d

[0475] 3-Chloroperoxybenzoic acid (111.8 mg, 0.065 mmol) was added to a solution of compound 114c (80 mg, 0.22 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1%–10%) to give compound 114d (65 mg). MS m / z (ESI): 402.15 [M+1] + .

[0476] Step 4: Synthesis of Compound 114

[0477] Boron tribromide (1.0 M dichloromethane solution, 1 mL, 1.24 mmol) was added to a dichloromethane (5 mL) solution of compound 114d (50 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min) to obtain compound 114 (12.8 mg). MS m / z (ESI): 388.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.60(d,J=2.4Hz,1H),7.37(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),4.19–4.01(m,1H),3.88–3.77(m ,1H),3.69–3.55(m,1H),3.45–3.36(m,2H),3.25–3.11(m,1H),2.70– 2.54(m,2H),2.41–2.30(m,1H),1.81–1.71(m,1H),1.53–1.44(m,1H).

[0478] Example 13 (Compound 126)

[0479]

[0480] Step 1: Synthesis of compound 126a

[0481] At room temperature, trimethyl orthoformate (411.5 mg, 3.87 mmol) was added to a 1,4-dioxane (2.5 mL) solution of compound 135f (336.4 mg, 2.58 mmol). The reaction mixture was stirred at 45 °C for 1 hour. Then, a 1,4-dioxane (0.5 mL) solution of compound 113a (300 mg, 1.29 mmol) and acetic acid (77.6 mg, 1.29 mmol) was added to the mixture. The reaction mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 126a (170 mg). MS m / z (ESI): 353.6 [M+1] + .

[0482] Step 2: Synthesis of compound 126b

[0483] At room temperature, N-chlorosuccinimide (282.7 mg, 2.12 mmol) was added to a solution of compound 126a (150.0 mg, 0.42 mmol) in acetonitrile (2.0 mL). The reaction mixture was stirred at 85 °C for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 126b (30 mg). MS m / z (ESI): 390.0 [M+1] +.

[0484] Step 3: Synthesis of Compound 126

[0485] Compound 126b was dissolved in dilute sulfuric acid (12N, 1 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was purified by reverse-phase preparative chromatography (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to obtain compound 126 (3.0 mg). MS m / z (ESI): 373.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),7.32(d,J=8.8Hz,1H),6.82(d,J=8.4Hz,1H),4.31–4.22(m,1H),4.12–3.96(m,1 H),3.90–3.83(m,2H),3.80–3.75(m,2H),2.80–2.77(m,1H),2.30–2.18(m,2H),1.97–1.86(m,1H),1.74–1.66(m,1H).

[0486] Example 14 (Compound 133)

[0487]

[0488] Step 1: Synthesis of compound 133a

[0489] Compound 1c (120 mg, 0.34 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of compound 168a (93.55 mg, 0.41 mmol), trimethyl orthoformate (0.043 g, 0.41 mmol), and acetic acid (0.20 g, 0.34 mmol). The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, the reaction mixture was cooled to room temperature, 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 0–10%) to give compound 133a (60 mg). MS m / z (ESI): 569.2 [M+1] + .

[0490] Step 2: Synthesis of compound 133b

[0491] Compound 133a (60 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL), and NBS (23.49 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with EA (10 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 0–10%) to give compound 133b (50 mg). MS m / z (ESI): 647.4 [M+1] + .

[0492] Step 3: Synthesis of Compound 133

[0493] Compound 133b (50 mg, 0.077 mmol) was dissolved in 1,4-dioxane hydrochloride (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min) to obtain compound 133 (6.57 mg). MS m / z (ESI): 418.9 [M+1] + .

[0494] Example 15 (Compound 153)

[0495]

[0496] Step 1: Synthesis of compound 153b

[0497] Hydrazine hydrate (372.3 mg, 6.32 mmol) was added to a 10 mL solution of compound 153a (500 mg, 3.16 mmol) in ethanol at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 1) to give compound 153b (140 mg). MS m / z (ESI): 159.1 [M+1] + .

[0498] Step 2: Synthesis of Compound 153

[0499] Trimethyl orthoformate (102.2 mg, 0.96 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 153b (108.8 mg, 0.69 mmol) at room temperature, and the reaction mixture was stirred at 45 °C for 1 hour. After the reaction was complete, acetic acid (16.5 mg, 0.28 mmol) and 23 g of compound 153b (60 mg, 0.28 mmol) were added to the reaction mixture, and the reaction mixture was heated to 120 °C and stirred for 15 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 153 (9.8 mg). MS m / z(ESI): 368.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.83(s,1H),7.37(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),4.01–3.92(m,1H),3.50–3. 39(m,1H),3.08–2.92(m,1H),2.64–2.56(m,1H),2.06–1.83(m,4H),1.82–1.71(m,1H),1.67–1.49(m,3H),1.29–1.18(m,2H).

[0500] Example 16 (Compound 154)

[0501]

[0502] Step 1: Synthesis of compound 154b

[0503] At room temperature, hydrazine hydrate (3.47 g, 69.36 mmol) was added to a 50 mL ethanol solution of compound 154a (synthetic method referred to Example 157, step one, page 148 of patent WO2022106857A1) (5.00 g, 34.68 mmol). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 3 / 1) to give compound 154b (1.00 g). MS m / z (ESI): 145.15 [M+1] + .

[0504] Step 2: Synthesis of Compound 154

[0505] At room temperature, trimethyl orthoformate (194.4 mg, 1.83 mmol) was added to a 1,4-dioxane (2 mL) solution of compound 154b (198.3 mg, 1.37 mmol). The reaction mixture was stirred at 45 °C for 1 hour, cooled to room temperature, and then a 1,4-dioxane (2 mL) solution of compound 23 g (100.0 mg, 0.45 mmol) and acetic acid (27.5 mg, 0.45 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5µm C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 60bar) to obtain compound 154 (24.6mg). MS m / z (ESI): 353.80 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.47(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),5.11(s,1H) ,3.71–3.63(m,1H),3.29–3.21(m,1H),2.49–2.45(m,1H),2.40–2.28(m,4H),1.62–1.50(m,2H),1.30(s,3H).

[0506] Example 17 (Compound 167)

[0507]

[0508] Step 1: Synthesis of compound 167b

[0509] At room temperature, trimethyl orthoformate (97.2 mg, 0.91 mmol) was added to a 2 mL solution of 1,4-dioxane (166.6 mg, 0.68 mmol) of compound 167a (synthetic method referred to Example 127, Step A, page 147 of patent WO2020112706 A1). The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. A 2 mL solution of 1,4-dioxane (50 mg, 0.23 mmol) of compound 167a and acetic acid (13.7 mg, 0.23 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 3 / 1) to give compound 167b (20 mg). MS m / z (ESI): 451.20 [M+1] + .

[0510] Step 2: Synthesis of Compound 167

[0511] At room temperature, 0.5 mL of 1,4-dioxane (4.0 M) hydrochloric acid was added to a 1 mL solution of 1,4-dioxane (20 mg, 0.04 mmol) containing compound 167b. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 167 (0.61 mg). MS m / z (ESI): 351.00 [M+1] + .

[0512] Example 18 (Compound 35)

[0513]

[0514] Step 1: Synthesis of compound 35b

[0515] Trimethyl orthoformate (18.2 mg, 0.17 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 35a (62.1 mg, 0.23 mmol) (synthetic method reference: Journal of Medicinal Chemistry (2021), 64(15), 10641-10665 Synthesis of compound 9e). The reaction mixture was stirred at 45 °C for 1 hour. Then, acetic acid (8.62 mg, 0.14 mmol) and compound 1c (50 mg, 0.14 mmol) were added to the mixture. The reaction mixture was then stirred at 120 °C for 15 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 1) to obtain compound 35b (40 mg). MS m / z (ESI): 609.2 [M+1] + .

[0516] Step 2: Synthesis of Compound 35

[0517] Trifluoroacetic acid (0.5 mL) was added to a solution of compound 35b (40 mg, 0.06 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 8 with ammonia, and the solution was concentrated under reduced pressure. The residue was prepared by high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 35 (10.1 mg). MS m / z (ESI): 379.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.25(s,0.42H),7.36(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),4.02(s,2H),3 .90–3.84(m,1H),2.61–2.53(m,1H),2.19–2.06(m,2H),2.04–1.84(m,7H),1.72–1.65(m,1H),1.64–1.55(m,1H).

[0518] Example 19 (Compound 73)

[0519]

[0520] Step 1: Synthesis of compound 73a

[0521] Acetyl chloride (64.2 mg, 0.81 mmol) was added dropwise to a solution of compound 1c (190 mg, 0.54 mmol) and triethylamine (82.8 mg, 0.81 mmol) in dichloromethane (2.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 73a (55 mg). MS m / z (ESI): 260.0 [M+1] + .

[0522] Step 2: Synthesis of compound 73b

[0523] Lawson's reagent (104.9 mg, 0.26 mmol, CAS: 19172-47-5) was added to a tetrahydrofuran (1.0 mL) solution of compound 73a (45 mg, 0.17 mmol), and the reaction mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 73b (50 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 275.9 [M+1] + .

[0524] Step 3: Synthesis of compound 73c

[0525] At room temperature, trimethyloxonium tetrafluoroboric acid (80.3 mg, 0.54 mmol) was added to a solution of compound 73b (50 mg, 0.18 mmol) in dichloromethane (1.0 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated sodium bicarbonate (10 mL) was added to quench the reaction mixture, followed by extraction with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 73c (60 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 289.9 [M+1] + .

[0526] Step 4: Synthesis of compound 73d

[0527] At room temperature, compound 168a (52.3 mg, 0.22 mmol) was added to a solution of compound 73c (60 mg, 0.20 mmol) and triethylamine (25.1 mg, 0.24 mmol) in n-butanol (1.0 mL). The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 73d (80 mg, crude product). The crude product was used directly in the next step without purification. MS m / z (ESI): 453.4 [M+1] + .

[0528] Step 5: Synthesis of Compound 73

[0529] Compound 73d (75 mg, 0.16 mmol) was dissolved in formic acid (1 mL), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was purified by reverse-phase preparative chromatography (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to obtain compound 73 (8.4 mg). MS m / z (ESI): 353.0 [M+1] + .

[0530] Example 20 (Compound 74)

[0531]

[0532] Step 1: Synthesis of compound 74a

[0533] Compound 1d (65.6 mg, 0.30 mmol) was added to a solution of compound 73c (80 mg, 0.27 mmol) and triethylamine (33.5 mg, 0.33 mmol) in n-butanol (0.5 mL) at room temperature. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to obtain compound 74a (14.0 mg). MS m / z (ESI): 439.1 [M+1] + .

[0534] Step 2: Synthesis of Compound 74

[0535] Compound 74a (12 mg, 0.027 mmol) was dissolved in formic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 74 (7.2 mg). MS m / z (ESI): 339.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.36(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.50–4.38(m,1H),4.3 4–4.25(m,1H),4.24–4.09(m,3H),4.02–3.92(m,1H),3.78–3.71(m,1H),2.44(s,3H),1.62–1.47(m,2H).

[0536] Example 21 (Compound 75)

[0537]

[0538] Step 1: Synthesis of compound 75a

[0539] Compound 8a (74.1 mg, 0.30 mmol) was added to a solution of compound 73c (80 mg, 0.27 mmol) and triethylamine (33.5 mg, 0.33 mmol) in n-butanol (0.5 mL) at room temperature. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to obtain compound 75a (16.0 mg). MS m / z (ESI): 469.1 [M+1] + .

[0540] Step 2: Synthesis of Compound 75

[0541] Formic acid (0.5 mL) was added to compound 75a (13 mg, 0.028 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was lyophilized to give compound 75 (6.3 mg). MS m / z (ESI): 367.0 [M+1] + . 1HNMR(400MHz, DMSO-d6)δ8.34(s,1.4H),7.37(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),4.06–3.98(m,1H),3.40–3.30 (m,3H),2.99–2.87(m,2H),2.65–2.60(m,1H),2.43(s,3H),2.14–2.03(m,2H),1.97–1.88(m,2H),1.71–1.59(m,2H).

[0542] Example 22 (Compound 77)

[0543]

[0544] Step 1: Synthesis of compound 77a

[0545] At room temperature, trimethyl orthoformate (183.6 mg, 1.73 mmol) was added to a 1,4-dioxane (10 mL) solution of compound 168a (265.6 mg, 1.15 mmol). The reaction mixture was stirred at 45 °C for 1 hour. Then, a 1,4-dioxane (5 mL) solution of compound 135d (100 mg, 0.38 mmol) and acetic acid (46.2 mg, 0.77 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 77a (60 mg, yield 32.3%). MS m / z (ESI): 481.35 [M+1] + .

[0546] Step 2: Synthesis of Compound 77

[0547] Boron tribromide (311.6 mg, 1.24 mmol) was added to a dichloromethane (5 mL) solution of compound 77a (60 mg, 0.12 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile / water (0.1% formic acid; gradient: 25-90%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 77 (8.1 mg). MS m / z (ESI): 366.9 [M+1] +. 1H NMR (400MHz, CD3OD) δ8.50(d,J=6.4Hz,1H),7.16(d,J=8.8Hz,1H),6.61–6.52(m,1H),5.00–4.90(m,1H),4.38–4.20(m,1H),3.68 –3.35(m,3H),3.27–3.09(m,2H),2.91–2.75(m,1H),2.72–2.33(m,3H),2.29–2.17(m,1H),2.13–1.97(m,1H),1.96–1.75(m,2H).

[0548] Example 23 (Compound 82)

[0549]

[0550] Step 1: Synthesis of compound 82b

[0551] Compound 82a (950 mg, 3.90 mmol) was dissolved in methanol (10 mL), and hydrazine hydrate (780.94 mg, 15.6 mmol) was added. The reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 0–10%) to give compound 82b (750 mg).

[0552] Step 2: Synthesis of compound 82c

[0553] Compound 82b (73.14 mg, 0.32 mol) was dissolved in 1,4-dioxane (1 mL), and trimethyl orthoformate (46.16 mg, 0.43 mmol) was added. The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. Compound 1c (100 mg, 0.29 mmol) and acetic acid (17.41 mg, 0.29 mmol) were added, and the mixture was stirred overnight at 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 82c (100 mg, crude). The product was used directly in the next step without purification. MS m / z (ESI): 569.1 [M+1] + .

[0554] Step 3: Synthesis of Compound 82

[0555] Compound 82c (100 mg, crude) was dissolved in 2 mL of 1,4-dioxane hydrochloride solution, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Durashell C18(A) 21.2 x 250 mm, 10 nm; mobile phase: (10 mM NH4HCO3); gradient: 25-50%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 82 (7.09 mg). MS m / z (ESI): 339.0 [M+1] + . 1HNMR (400MHz, DMSO-d6) δ8.66–8.35(m,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),4.13(d,J=7 .6Hz,1H),4.05(d,J=7.6Hz,1H),3.78–3.65(m,1H),2.70–2.64(m,1H),1.66(s,3H),1.63–1.50(m,2H).

[0556] Example 24 (Compound 95)

[0557]

[0558] Step 1: Synthesis of Compound 95b

[0559] Trimethyl orthoformate (30 mg, 0.29 mmol) was added to a 1 mL solution of 1,4-dioxane (41 mg, 0.29 mmol) of compound 95a (synthetic method referred to in the specification of patent WO2017021920A1, page 240, paragraphs 1061-1062, for the synthesis of compound 112). The reaction mixture was stirred at 45°C for 1 hour. Then, acetic acid (9 mg, 0.14 mmol) and compound 1c (50 mg, 0.14 mmol) were added to the reaction mixture. The reaction mixture was then heated to 120°C and stirred for 15 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 95b (50 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 484.30 [M+1] + .

[0560] Step 2: Synthesis of Compound 95

[0561] Trifluoroacetic acid (0.5 mL) was added to 1,4-dioxane (1 mL) of compound 95b (50 mg, 0.10 mmol), and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 8 with ammonia. The mixture was then purified by high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 95 (8.5 mg). MS m / z (ESI): 354.10 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.51(s,1H),7.37(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),3.99–3.88(m,2H),3.85– 3.76(m,1H),3.54–3.51(m,1H),3.45–3.36(m,2H),3.34–3.21(m,1H),1.93–1.66(m,5H),1.59–1.51(m,1H).

[0562] Example 25 (Compound 96)

[0563]

[0564] Step 1: Synthesis of compound 96b

[0565] At room temperature, trimethyl orthoformate (30.4 mg, 0.28 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 96a (synthetic method reference: Journal of Medicinal Chemistry (2008), 51(15), 4430-4448 Synthesis of compound 8a) (45.1 mg, 0.28 mmol). The reaction mixture was stirred at 45 °C for 1 hour. Then, after cooling to room temperature, a 1,4-dioxane (1 mL) solution of compound 1c (50.0 mg, 0.14 mmol) and acetic acid (8.6 mg, 0.14 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 ~ 3 / 1) to obtain compound 96b (50 mg). MS m / z (ESI): 497.35 [M+1] + .

[0566] Step 2: Synthesis of Compound 96

[0567] At room temperature, 0.5 mL of 4.0 M dioxane hydrochloride was added to a 1 mL solution of 1,4-dioxane (50.0 mg, 0.10 mmol) of compound 96b. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 96 (10.2 mg). MS m / z (ESI): 366.85 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.14(s,0.25H),7.37(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),3.82–3.76(m,1H),3.29 –3.10(m,4H),2.91–2.74(m,2H),2.66(s,3H),2.22–2.06(m,2H),2.01–1.83(m,2H),1.74–1.68(m,1H),1.54–1.49(m,1H).

[0568] Example 26 (Compound 99)

[0569]

[0570] Step 1: Synthesis of compound 99b

[0571] At room temperature, hydrazine hydrate (164.2 mg, 1.28 mmol) was added to a 2 mL ethanol solution of compound 99a (100 mg, 0.64 mmol), and the reaction mixture was stirred at 80 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 5 / 1) to give compound 99b (70 mg). MS m / z (ESI): 157.1 [M+1] + .

[0572] Step 2: Synthesis of compound 99c

[0573] At room temperature, trimethyl orthoformate (33.9 mg, 0.32 mmol) was added to a 1,4-dioxane (0.5 mL) solution of compound 99b (25 mg, 0.16 mmol). The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. A 1,4-dioxane (0.5 mL) solution of compound 1c (55.8 mg, 0.16 mmol) and acetic acid (9.6 mg, 0.16 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 99c (20 mg, crude product). The product was used directly for the next step without purification. MS m / z (ESI): 496.10 [M+1] + .

[0574] Step 3: Synthesis of Compound 99

[0575] At 0 °C, 0.3 mL of trifluoroacetic acid was added to a tetrahydrofuran (1 mL) solution of compound 99c (15 mg, 0.030 mmol), and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 99 (5.2 mg). MS m / z (ESI): 366.0 [M+1] + .

[0576] Example 27 (Compound 97)

[0577]

[0578] Step 1: Synthesis of compound 97b

[0579] At room temperature, N,N'-carbonyldiimidazole (311.4 mg, 1.92 mmol) was added to a solution of compound 97a (250 mg, 1.60 mmol) and hydrazine hydrate (128.2 mg, 2.56 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 3 / 1) to give compound 97b (200 mg). MS m / z (ESI): 171.15 [M+1] + .

[0580] Step 2: Synthesis of compound 97c

[0581] At room temperature, trimethyl orthoformate (30.4 mg, 0.28 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 97b (48.8 mg, 0.28 mmol). The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. A 1,4-dioxane (1 mL) solution of compound 1c (50.0 mg, 0.14 mmol) and acetic acid (8.6 mg, 0.14 mmol) was then added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0–3 / 1) to give compound 97c (50 mg). MS m / z (ESI): 510.30 [M+1] + .

[0582] Step 3: Synthesis of Compound 97

[0583] At room temperature, 1,4-dioxane hydrochloride (4.0 M, 0.5 mL) was added to a 1 mL solution of compound 97c (50.0 mg, 0.098 mmol) in 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 97 (1.0 mg). MS m / z (ESI): 379.85 [M+1] + .

[0584] Example 28 (Compound 180-1)

[0585]

[0586] Step 1: Synthesis of compound 180b

[0587] At room temperature, hydrazine hydrate (3.12 g, 62.43 mmol) was added to a 40 mL ethanol solution of compound 180a (2.0 g, 12.48 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 10) to give 180b (1.6 g). MS m / z (ESI): 161.10 [M+1] + .

[0588] Step 2: Synthesis of compound 180c

[0589] Compound 180b (1.5 g, 9.36 mmol) was added to a 30 mL solution of trimethyl orthoformate (993.8 mg, 9.36 mmol) in 1,4-dioxane. The reaction mixture was stirred at 45 °C for 1 hour. Then, acetic acid (562.4 mg, 9.36 mmol) and intermediate 23 g (2.04 g, 9.36 mmol) were added to the reaction mixture, and the mixture was stirred at 120 °C for 17 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 30) to give compound 180c (1.0 g). MS m / z (ESI): 369.70 [M+1] + .

[0590] Step 3: Synthesis of Compound 180

[0591] Compound 180c (100 mg, 0.27 mmol) was added to a solution of 1,4-dioxane hydrochloride (4.0 M, 4.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was purified to obtain compound 180-1 using a 150*21.2 mm column (150 x 21.2 mm); mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar). MS m / z (ESI): 329.90 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.56(d,J=2.0Hz,1H),7.35(dd,J=8.8,2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H ),5.82–5.47(m,1H),4.91–4.80(m,2H),3.98–3.72(m,3H),2.63–2.56(m,1H),1.76–1.63(m,1H),1.61–1.48(m,1H).

[0592] Example 29 (Compound 179)

[0593]

[0594] Step 1: Synthesis of compound 179b

[0595] At room temperature, hydrazine hydrate (4.81 g, 76.85 mmol) was added to a methanol (20 mL) solution of compound 179a (2 g, 19.21 mmol), and the reaction mixture was stirred at 50 °C for 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (MeOH / DCM = 0–50%) to give compound 179b (1.30 g). MS m / z (ESI): 105.10 [M+1] + .

[0596] Step 2: Synthesis of Compound 179

[0597] At room temperature, N,N-dimethylformamide dimethyl acetal (228.9 mg, 1.92 mmol) was added to 1,4-dioxane (5 mL) of compound 179b (200 mg, 1.92 mmol). The reaction mixture was stirred at 80 °C for 1 hour and then cooled to room temperature. A solution of 1,4-dioxane (5 mL) of compound 23 g (418.9 mg, 1.92 mmol) and acetic acid (115.36 mg, 1.92 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 15 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18). 150*21.2mm; Mobile phase: acetonitrile-water (0.05% formic acid); Gradient: 5-50%; Column temperature: 25℃; Flow rate: 20mL / min; Wavelength: 214nm; Column pressure: 60bar) Compound 179 (23.4mg) was purified. MS m / z (ESI): 313.65 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.50(s,1H),7.36(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.80(s ,1H),3.84–3.71(m,3H),2.97(t,J=7.0Hz,2H),2.48–2.44(m,1H),1.72–1.62(m,1H),1.58–1.49(m,1H).

[0598] Example 30 (Compound 175-1-P2)

[0599]

[0600] Compound 12-1-P2 (50 mg, 0.15 mmol) was dissolved in acetone (2 mL) at 0 °C, and sodium triacetylborohydride (81.2 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 175-1-P2 (47.3 mg). MS m / z (ESI): 381.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.39(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.11–3.84(m,2H),3.83–3.75(m,2H),3.57–3. 42(m,2H),3.37–3.19(m,1H),2.63–2.55(m,2H),2.34–2.20(m,1H),1.75–1.69(m,1H),1.58–1.52(m,1H),1.29(d,J=6.4Hz,6H).

[0601] Example 31 (Compound 186)

[0602]

[0603] Step 1: Synthesis of compound 186a

[0604] At -78°C under a nitrogen atmosphere, 15.3 mL (15.36 mmol) of diisobutylaluminum hydride was added to a 40 mL solution of compound 23d (3.70 g, 12.79 mmol) in dichloromethane. The reaction mixture was stirred at -78°C for 1 hour. After the reaction was complete, the reaction solution was quenched with 20 mL of saturated ammonium chloride solution, extracted with 3 x 20 mL of dichloromethane, and the combined organic phases were washed with 3 x 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give compound 186a (620 mg). MS m / z (ESI): 244.95 [M+1] + .

[0605] Step 2: Synthesis of compound 186c

[0606] At 0 °C, potassium carbonate (1.39 g, 10.12 mmol) and compound 186b (850.4 mg, 4.43 mmol) were added to a methanol (15 mL) solution of compound 186a (620 mg, 2.53 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, washed with ethyl acetate (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 186c (440 mg). MS m / z (ESI): 240.95 [M+1] + .

[0607] Step 3: Synthesis of compound 186e

[0608] Sodium azide (415.8 mg, 6.39 mmol) was added to a solution of compound 186c (800 mg, 3.198 mmol) in N,N-dimethylformamide (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 186e (600 mg). MS m / z (ESI): 157.05 [M-55] + .

[0609] Step 4: Synthesis of compound 186f

[0610] Under nitrogen protection, compound 186e (105.64 mg, 0.498 mmol) and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (18.1 mg, 0.025 mmol) were added to a 1,4-dioxane (5 mL) solution of compound 186c (60 mg, 0.25 mmol). The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 30 / 1) to give compound 186f (50 mg). MS m / z (ESI): 453.35 [M+1] + .

[0611] Step 5: Synthesis of Compound 186

[0612] Boron tribromide (82.9 mg, 0.33 mmol) was added to a dichloromethane (5 mL) solution of compound 186f (50 mg, 0.11 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 186 (11.2 mg). MS m / z (ESI): 339.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.54(s,1H),7.33(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),5.41( s,1H),3.89–3.32(m,2H),3.31–3.06(m,2H),2.46–2.17(m,3H),2.16–2.05(m,1H),1.63–1.43(m,2H).

[0613] Example 32 (Compound 177)

[0614]

[0615] Step 1: Synthesis of compound 177a

[0616] At 0 °C, tert-butyldimethylchlorosilane (8.09 g, 53.65 mmol) was added to a solution of imidazole (5.62 g, 82.54 mmol) and compound 23 g (9 g, 41.27 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–20%) to give compound 177a (9 g). MS m / z (ESI): 332.15 [M+1] + .

[0617] Step 2: Synthesis of compound 177c

[0618] At 0 °C, compound 177b (0.36 mL, 2.32 mmol) was added to a solution of compound 177a (700 mg, 2.11 mmol) and diisopropylethylamine (299.4 mg, 2.32 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction solution was used directly for the next step.

[0619] Step 3: Synthesis of compound 177e

[0620] Compound 177d (325.8 mg, 3.74 mmol) was added to a dichloromethane reaction solution of compound 177c at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 177e (800 mg). MS m / z (ESI): 461.30 [M+1] + .

[0621] Step 4: Synthesis of compound 177f

[0622] At room temperature, iodomethane (0.28 mL, 3.47 mmol) was added to a 10 mL ethanol solution of compound 177e (800 mg, 1.73 mmol), and the reaction mixture was stirred at 85 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 177f (800 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 474.95 [M+1] + .

[0623] Step 5: Synthesis of compound 177g

[0624] At room temperature, hydrazine hydrate (0.077 mL, 1.26 mmol) was added to a 2 mL ethanol solution of compound 177f (200 mg, 0.42 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 177 g (200 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 345.05 [M+1] + .

[0625] Step 6: Synthesis of Compound 177

[0626] Compound 177 g (200 mg, 0.43 mmol) was added to a solution of p-toluenesulfonic acid (82.8 mg, 0.43 mmol) and trimethyl orthoformate (0.19 mL, 1.74 mmol) in ethanol (3 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 177 (25.8 mg). MS m / z (ESI): 355.20 [M+1] + .1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),8.18(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),5. 54(s,1H),3.92–3.76(m,4H),3.57–3.51(m,1H),2.56–2.53(m,1H),1.63–1.49(m,2H),1.41(s,3H).

[0627] Example 33 (Compound 176)

[0628]

[0629] Step 1: Synthesis of compound 176a

[0630] At 0°C, compound 177b (1.05 g, 4.52 mmol) was added to a solution of compound 113a (1.00 g, 4.30 mmol) and diisopropylethylamine (612.5 mg, 4.74 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was used directly in the next step without any further treatment.

[0631] Step 2: Synthesis of compound 176b

[0632] At 0 °C, morpholine (635.6 mg, 7.29 mmol) was added to a solution of 176a (4.52 mmol) in 20 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 176b (1.10 g). MS m / z (ESI): 361.15 [M+1] + .

[0633] Step 3: Synthesis of compound 176d

[0634] At room temperature, potassium tert-butoxide (310.6 mg, 2.76 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 176b (1.00 g, 2.76 mmol). The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of compound 176c (515.5 mg, 2.76 mmol). The reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure to give compound 176d (1 g, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 375.20 [M+1] + .

[0635] Step 4: Synthesis of compound 176e

[0636] At room temperature, trifluoroacetic acid (151.9 mg, 1.33 mmol) was added to a solution of compound 176d (1.00 g, 2.66 mmol) and compound formyl hydrazide (320 mg, 5.33 mmol) in 20 mL of 1,4-dioxane. The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–5%) to give compound 176e (400 mg). MS m / z (ESI): 369.20 [M+1] + .

[0637] Step 5: Synthesis of Compound 176

[0638] Boron tribromide (508.8 mg, 2.03 mmol) was added to a dichloromethane (5 mL) solution of compound 176e (150 mg, 0.40 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with methanol (1 mL), concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 176 (6.2 mg). MS m / z (ESI): 354.80 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.34(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8 .8Hz,1H),3.75–3.60(m,5H),3.24–3.11(m,4H),2.58–2.53(m,1H),1.67–1.58(m,2H).

[0639] Example 34 (Compound 197)

[0640]

[0641] Step 1: Synthesis of compound 197b

[0642] At room temperature, hydrazine hydrate (347.2 mg, 6.93 mmol) was added to a 10 mL ethanol solution of compound 197a (500 mg, 3.46 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 1) to give compound 197b (300 mg). MS m / z (ESI): 145.20 [M+1] + .

[0643] Step 2: Synthesis of Compound 197

[0644] At room temperature, N,N-dimethylformamide dimethyl acetal (109.3 mg, 0.91 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 197b (132.2 mg, 0.91 mmol). After stirring the reaction mixture at 80 °C for 1 hour, acetic acid (55.1 mg, 0.91 mmol) and compound 197c (200 mg, 0.91 mmol) were added. The reaction mixture was heated to 120 °C and stirred for 15 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18150*21.2 mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 197 (14.5 mg). MS m / z(ESI): 354.10 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.48(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.72(s,1H),4.16(s,1H),3.78 –3.70(m,1H),3.38–3.33(m,1H),2.57–2.52(m,1H),2.33–2.26(m,1H),2.04–1.92(m,2H),1.85–1.72(m,2H),1.67–1.51(m,3H).

[0645] Example 35 (Compound 198)

[0646]

[0647] Step 1: Synthesis of compound 198b

[0648] At 0°C, compound 198a (1200 mg, 14.1 mmol) was added to a dichloromethane (30 mL) solution of 176a (6.46 mmol) (synthetic method as described in the first step of Example 33, synthesis of compound 176a). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-50%) to give compound 198b (2 g). MS m / z (ESI): 358.85 [M+1] + .

[0649] Step 2: Synthesis of compound 198c

[0650] Sodium borohydride (105.3 mg, 2.78 mmol) was added to a methanol (10 mL) solution of compound 198b (500 mg, 1.39 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (30 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–75%) to give compound 198c (440 mg). MS m / z (ESI): 360.85 [M+1] + .

[0651] Step 3: Synthesis of compound 198d

[0652] At room temperature, 172.8 mg (1.21 mmol) of iodomethane was added to a 6 mL ethanol solution of compound 198c (400 mg, 1.11 mmol), and the reaction mixture was stirred at 85 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 198d (340 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 374.85 [M+1] + .

[0653] Step 4: Synthesis of compound 198e

[0654] At room temperature, 4-dimethylaminopyridine (208.3 mg, 1.70 mmol), N,N-diisopropylethylamine (220.4 mg, 1.70 mmol), and tert-butyldimethylchlorosilane (192.8 mg, 1.28 mmol) were added sequentially to a solution of compound 198d (340 mg, 0.85 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–5%) to give compound 198e (300 mg). MS m / z (ESI): 488.90 [M+1]+ .

[0655] Step 5: Synthesis of compound 198f

[0656] At room temperature, formyl hydrazide (176e) (71.2 mg, 1.19 mmol) and trifluoroacetic acid (33.8 mg, 0.30 mmol) were added to a 5 mL solution of compound 198e (290 mg, 0.59 mmol) in 1,4-dioxane. The reaction mixture was stirred at 80 °C for 10 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–5%) to give compound 198f (100 mg, yield 33.8%). MS m / z (ESI): 483.35 [M+1] + .

[0657] Step 6: Synthesis of Compound 198

[0658] At room temperature, lithium chloride (175.3 mg, 4.14 mmol) and p-toluenesulfonic acid (393.4 mg, 2.07 mmol) were added to a solution of compound 198f (50 mg, 0.10 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 150 °C for 36 hours. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% ammonia); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 198 (1.3 mg). MS m / z (ESI): 354.95 [M+1] + .

[0659] Example 36 (Compound 196-1-P1, 196-1-P2)

[0660]

[0661] Step 1: Synthesis of compound 196b-1

[0662] Compound 196a-1 (1.48 g, 6.46 mmol) was added to a 1,4-dioxane (15 mL) solution of DMF-DMA (770 mg, 6.46 mmol). The reaction mixture was stirred at 80 °C for 30 min. Then, acetic acid (0.37 mL, 6.46 mmol) and compound 113a (1.5 g, 6.46 mmol) were added to the reaction mixture, and the mixture was stirred at 110 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 30) to give compound 196b-1 (1.2 g). MS m / z (ESI): 453.15 [M+1] + .

[0663] Step 2: Synthesis of compound 196c-1

[0664] Compound 196b-1 (800 mg, 1.76 mmol) was added to a deuterated methanol solution (8 mL) at room temperature. The reaction mixture was stirred at 60 °C for 16 hours, and then concentrated under reduced pressure to obtain compound 196c-1 (800 mg, crude product). MS m / z (ESI): 454.15 [M+1] + .

[0665] Step 3: Synthesis of compounds 196-1-P1 and 196-1-P2

[0666] Boron tribromide (1.32 g, 5.28 mmol) was added to a dichloromethane (10 mL) solution of compound 196c-1 (800 mg, 1.761 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 Compound 196d-1 (300 mg) was purified by supercritical fluid chiral chromatography (preparative column: SHIMADZU SFC-40P, 30 mm ID*250 mmL, 10 μm; flow rate: 100 mL / min; column temperature: room temperature; mobile phase: A: CO2, B: 0.1% DEA in ethanol) to obtain compounds 196d-1-P1 (57.3 mg) and 196-1-P2 (84.5 mg). The column was prepared using a 150*21.2 mm column; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar).

[0667] Compound 196-1-P1: MS m / z (ESI): 339.80 [M+1] +Supercritical fluid chromatography (SFC): retention time = 6.944 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),3.85–3.46(m,3H),3.25–3.11(m ,1H),2.99–2.79(m,2H),2.58–2.52(m,1H),2.17–1.90(m,2H),1.76–1.62(m,1H),1.59–1.48(m,1H).

[0668] Compound 196-1-P2: MS m / z (ESI): 340.10 [M+1] + Supercritical fluid chromatography (SFC): retention time = 8.761 min, UV = 214 nm. 1 H NMR(400MHz, DMSO-d6)δ7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),3.84–3.71(m,2H),3.52–3.48(m,1H),3.2 2–3.17(m,1H),3.03–2.78(m,2H),2.58–2.53(m,1H),2.31–1.95(m,2H),1.77–1.65(m,1H),1.60–1.48(m,1H).

[0669] Example 37 (Compound 199)

[0670]

[0671] Step 1: Synthesis of compound 199b

[0672] At 0°C, methyl magnesium bromide (1.0 M in THF) (16.5 mL, 16.5 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 199a (1.00 g, 5.87 mmol) and cerium trichloride (6.12 g, 16.45 mmol). The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was quenched with ice water (20 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 199b (1.00 g, crude product). The product was used directly in the next step without purification.

[0673] Step 2: Synthesis of compound 199c

[0674] At room temperature, hydrazine hydrate (537.5 mg, 10.73 mmol) was added to a 20 mL ethanol solution of compound 199b (1.00 g, 5.37 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 1) to give compound 199c (120 mg). MS m / z (ESI): 171.15 [M⁻¹] + .

[0675] Step 3: Synthesis of Compound 199

[0676] At room temperature, N,N-dimethylformamide dimethyl acetal (69.2 mg, 0.58 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 199c (126.6 mg, 0.58 mmol). After stirring the reaction mixture at 80 °C for 1 hour, acetic acid (34.8 mg, 0.58 mmol) and 23 g of compound 100 mg (100 mg, 0.58 mmol) were added to the mixture. The reaction mixture was heated to 120 °C and stirred for 15 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 199 (3.8 mg). MS m / z(ESI): 381.85 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.45(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.06(s,1H),3.81–3. 75(m,1H),2.91–2.80(m,1H),2.56–2.53(m,1H),2.00–1.86(m,2H),1.71–1.55(m,6H),1.38–1.29(m,2H),1.11(s,3H).

[0677] Example 38 (Compound 201)

[0678]

[0679] Step 1: Synthesis of compound 201b

[0680] At 0°C, compound 201a (615.2 mg, 5.34 mmol) was added to a dichloromethane (20 mL) solution of 177c (3.16 mmol) (synthetic method as described in step 2 of Example 32, synthesis of compound 177c). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-50%) to give compound 201b (1.40 g). MS m / z (ESI): 489.20 [M+1] + .

[0681] Step 2: Synthesis of compound 201c

[0682] At room temperature, iodomethane (753.8 mg, 5.31 mmol) was added to a 20 mL ethanol solution of compound 201b (1.30 g, 2.65 mmol), and the reaction mixture was stirred at 85 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 201c (1.30 g, crude product), which was used directly in the next step without purification. MS m / z (ESI): 503.40 [M+1] + .

[0683] Step 3: Synthesis of compounds 201d and 201e

[0684] At room temperature, hydrazine hydrate (238.6 mg, 4.76 mmol) was added to an ethanol (20 mL) solution of compound 201c (1.20 g, 2.38 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a mixture of 201d and 201e (1.00 g, crude product), which was used directly in the next step without purification.

[0685] Step 4: Synthesis of Compound 201

[0686] Compound 201d (1.00 g, 2.68 mmol) was added to a 20 mL solution of p-toluenesulfonic acid (509.5 mg, 2.68 mmol) and trimethyl orthoformate (1.13 g, 10.71 mmol) in ethanol at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 201 (30.0 mg). MS m / z (ESI): 383.20 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.28(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),4.28(s,1H),3.80–3. 73(m,1H),3.30–3.23(m,1H),3.22–3.10(m,3H),2.55–2.51(m,1H),1.70–1.55(m,3H),1.52–1.40(m,3H),1.12(s,3H).

[0687] Example 39 (Compound 207)

[0688]

[0689] Step 1: Synthesis of compound 207b

[0690] At 0°C, compound 207a (0.50 g, 3.08 mmol) and diisopropylethylamine (1.14 g, 8.81 mmol) were added to a 10 mL solution of compound 177c (2.93 mmol) (synthesized as described in step 2 of Example 32). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–70%) to give compound 207b (1 g). MS m / z (ESI): 500.90 [M+1] + .

[0691] Step 2: Synthesis of compound 207c

[0692] At room temperature, iodomethane (56.6 mg, 0.39 mmol) was added to a 1.0 mL ethanol solution of compound 207b (100 mg, 0.19 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 207c (100 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 515.15 [M+1] + .

[0693] Step 3: Synthesis of compound 207d

[0694] At room temperature, hydrazine hydrate (38.8 mg, 0.77 mmol) was added to a 1.0 mL ethanol solution of compound 207c (100 mg, 0.19 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 207d (100 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 384.95 [M+1] + .

[0695] Step 4: Synthesis of Compound 207

[0696] Compound 207d (80 mg, 0.16 mmol) was added to a solution of p-toluenesulfonic acid (30.5 mg, 0.16 mmol) and trimethyl orthoformate (67.9 mg, 0.64 mmol) in ethanol (1.0 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% ammonia); gradient: 25-65%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 207 (20.7 mg). MS m / z (ESI): 395.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.15(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),4.88(s,1H) ,4.07–3.92(m,4H),3.55–3.49(m,1H),2.56–2.53(m,1H),2.20–2.11(m,4H),1.64–1.49(m,2H),1.12(s,3H).

[0697] Example 40 (Compound 206)

[0698]

[0699] Step 1: Synthesis of compounds 206c and 206d

[0700] Compound 206b (3.50 g, 13.99 mmol), potassium carbonate (3.36 g, 24.34 mmol), and potassium iodide (6.06 g, 36.50 mmol) were added to a solution of compound 206a (1.20 g, 12.17 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 60 °C and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give compound 206c (300 mg) and compound 206d (900 mg).

[0701] Compound 206c: MS m / z (ES): 266.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.74(d,J=0.8Hz,1H),8.16(s,1H),7.96(d,J=1.2Hz,1H),5.32(d ,J=4.8Hz,1H),3.74(s,1H),3.53–3.36(m,3H),2.05–1.95(m,2H),1.39(d,J=8.4Hz,9H).

[0702] Compound 206d: MS m / z (ES): 266.10 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.15(s,1H),7.97(s,1H),4.96–4.90(m,1H),3.8 2–3.73(m,1H),3.52–3.37(m,3H),2.43–2.37(m,1H),2.31–2.22(m,1H),1.40(s,9H).

[0703] Step 2: Synthesis of compound 206e

[0704] Compound 206c (300 mg, 1.13 mmol) was dissolved in 1,4-dioxane (15 mL), followed by the addition of p-toluenesulfonyl hydrazine (210.6 mg, 1.13 mmol). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 206e (300 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 434.05 [M+1] + .

[0705] Step 3: Synthesis of compound 206h

[0706] At 0°C, sodium hydride (2.34 g, 97.54 mmol) was added to a tetrahydrofuran (200 mL) solution of compound 206 g (29.56 g, 73.16 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Then, compound 206f (10 g, 48.77 mmol) was added (synthetic method referred to Example 36step A, page 51 of patent WO2016123164 A1, for the synthesis of compound Benzaldehyde, 2,3-dichloro-6-methoxy). After the reaction was complete, the reaction solution was quenched with saturated brine (200 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 10) to obtain compound 206h (5.20 g). 1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=8.8Hz,1H),7.08(d,J=8.8Hz,1H),6.76(dd,J=18.0 ,12.0Hz,1H),5.96(dd,J=17.6,2.0Hz,1H),5.66(dd,J=11.6,2.0Hz,1H),3.84(s,3H).

[0707] Step 4: Synthesis of compound 206i

[0708] Compound 206h (468.4 mg, 2.31 mmol) and compound 206e (500 mg, 1.15 mmol) were added to a solution of cobalt tetraphenylporphyrin (38.7 mg, 0.058 mmol) and cesium carbonate (563.6 mg, 1.73 mmol) in 1,4-dioxane (8 mL) at room temperature. The reaction mixture was stirred at 110 °C for 4 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 10) to give compound 206i (230 mg). MS m / z (ESI): 452.25 [M+1] + .

[0709] Step 5: Synthesis of Compound 206

[0710] Boron tribromide (332.3 mg, 1.33 mmol) was added to a 206 μL (200 mg, 0.44 mmol) solution of dichloromethane (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar. The compound 206 (105.7 mg) was purified. MS m / z (ESI): 337.85 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.22–9.81(m,1H),8.10–7.85(m,1H),7.38–7.17(m,1H),6.94–5.90(m,2H),5.31– 5.13(m,1H),3.81–3.64(m,1H),3.58–3.41(m,3H),2.63–2.52(m,1H),2.46–2.04(m,3H),1.77–1.23(m,2H).

[0711] Example 41 (Compound 204-P1, 204-P2)

[0712]

[0713] Step 1: Synthesis of compounds 204b-P1 and 204b-P2

[0714] At room temperature, compound 204a (0.76 g, 7.34 mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (0.87 g, 7.34 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 80 °C for 30 minutes, followed by the addition of acetic acid (0.42 mL, 7.34 mmol) and compound 23 g (1.60 g, 7.34 mmol). The reaction mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 10) to give compound 204b (300 mg).

[0715] Compound 204b (300 mg) was resolved by supercritical fluid chiral chromatography (preparative column: SHIMADZU SFC-40P, Daicel Chiralpak IB N-10SFC, 30 mm ID*250 mmL, 10 μm; flow rate: 100 mL / min; column temperature: room temperature; mobile phase: A: CO2, B: ethanol 0.1% NH3) to obtain compounds 204b-P1 (80 mg) and 204b-P2 (80 mg).

[0716] Compound 204b-P1: Supercritical fluid chromatography (SFC): Retention time 6.615 min, UV = 214 nm. MS m / z (ESI): 313.80 [M+1] + .

[0717] Compound 204b-P2: Supercritical fluid chromatography (SFC): Retention time 7.496 min, UV = 214 nm. MS m / z (ESI): 313.80 [M+1] + .

[0718] Step 2: Synthesis of compound 204-P1

[0719] Compound 204b-P1 (80 mg, 0.25 mmol) was dissolved in deuterated methanol (2 mL) at room temperature, and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm. The compound 204-P1 (73.8 mg) was purified. MS m / z (ESI): 315.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.79(t,J=5.0Hz,1 H),3.87–3.69(m,3H),2.97(t,J=7.0Hz,2H),2.49–2.44(m,1H),1.74–1.62(m,1H),1.59–1.47(m,1H).

[0720] Step 3: Synthesis of compound 204-P2

[0721] Compound 204b-P2 (80 mg, 0.25 mmol) was dissolved in deuterated methanol (2 mL) at room temperature. The reaction solution was stirred at 60 °C for 16 hours, then concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm. The compound 204-P2 (69.8 mg) was purified. MS m / z (ESI): 315.05 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.79(t,J=5.0Hz,1 H),3.87–3.69(m,3H),2.97(t,J=7.0Hz,2H),2.49–2.44(m,1H),1.74–1.62(m,1H),1.59–1.47(m,1H).

[0722] Example 42 (Compound 214)

[0723]

[0724] Step 1: Synthesis of compound 214a

[0725] At room temperature, formyl hydrazide (31.05 g, 0.52 mol) and trimethyl orthoformate (73.15 g, 0.69 mol) were added sequentially to an ethanol (200 mL) solution of compound 113a (20 g, 86.17 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 20) to give compound 214a (18 g). MS m / z (ESI): 283.95 [M+1] + .

[0726] Step 2: Synthesis of compound 214b

[0727] At room temperature, N-bromosuccinimide (12.40 g, 69.68 mmol) and azobisisobutyronitrile (10.40 g, 63.35 mmol) were added sequentially to a dichloromethane (200 mL) solution of compound 214a (18 g, 63.35 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL), the pH was adjusted to 7–8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified using a Biotage-Flash rapid preparation system (column: C18 reversed-phase column, acetonitrile-water (0.1% formic acid); gradient: 5%–50%) to obtain compound 214b (8 g). MS m / z (ESI): 361.65, 363.65 [M+1, M+3] + .

[0728] Step 3: Synthesis of compound 214c

[0729] Boron tribromide (27.60 g, 110.18 mmol) was added to a dichloromethane (100 mL) solution of compound 214b (8 g, 22.04 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with methanol (20 mL) in an ice bath, the pH was adjusted to 8–9 with triethylamine, the organic phase was concentrated under reduced pressure, the residue was diluted with ethyl acetate (100 mL), filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 20) to give compound 214c (4 g). MS m / z (ESI): 347.85, 349.85 [M+1, M+3] + .

[0730] Step 4: Synthesis of Compound 214

[0731] At room temperature, compound 214d (166.8 mg, 0.86 mmol), tetratetraphenylphosphine palladium (33.1 mg, 0.029 mmol), and potassium carbonate (118.8 mg, 0.86 mmol) were added to a mixed solution of compound 214c (100 mg, 0.29 mmol) in 1,4-dioxane and water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 214 (11.5 mg). MS m / z (ESI): 336.05 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),10.38(s,1H),8.31(s,1H),8.01(s,1H),7.37(d,J=8.8Hz,1H) ,6.87(d,J=8.8Hz,1H),3.98–3.83(m,1H),2.76–2.62(m,1H),1.73–1.61(m,1H),1.53–1.40(m,1H).

[0732] Example 43 (Compound 208)

[0733]

[0734] Step 1: Synthesis of compound 208b

[0735] Under nitrogen protection, compound 214c (280 mg, 0.80 mmol, synthesis method referred to in step 3 of Example 42, synthesis of compound 214c) was dissolved in a mixed solution of 1,4-dioxane and water (10 mL / 2 mL). Compound 208a (427.0 mg, 1.60 mmol) (synthesis method referred to in Example 32 of patent CN 106336413 A, page 70, synthesis of compound 1,4-Dioxaspiro[4.5]dec-7-ene,8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-), potassium carbonate (332.6 mg, 2.41 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (58.7 mg, 0.080 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 208b (180 mg). MS m / z (ESI): 408.0 [M+1] + .

[0736] Step 2: Synthesis of compound 208c

[0737] Compound 208b (180 mg, 0.441 mmol) was dissolved in a mixed solution of 1,4-dioxane and formic acid (1 mL / 1 mL) at room temperature. The reaction mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 208c (40 mg). MS m / z (ESI): 364.0 [M+1] + .

[0738] Step 3: Synthesis of Compound 208

[0739] At 0 °C, methyl magnesium bromide (0.55 mL, 0.55 mmol) was added dropwise to a tetrahydrofuran (2 mL) solution of compound 208c (40 mg, 0.110 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 208 (1.7 mg). MS m / z (ESI): 380.0 [M+1] + .

[0740] Example 44 (Compound 104, 209-P1, 209-P2)

[0741]

[0742] Step 1: Synthesis of compounds 104-P1 and 104-P2

[0743] Under nitrogen protection, compound 214c (500 mg, 1.43 mmol, synthesis method as described in step 3 of Example 42) was dissolved in a mixed solution of 1,4-dioxane and water (10 mL / 2 mL). Compound 104a (219.9 mg, 1.72 mmol), potassium carbonate (494.9 mg, 3.58 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (104.8 mg, 0.14 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-90%; flow rate: 20 mL / min) to obtain compound 104 (120 mg). MS m / z(ESI): 352.0 [M+1] + Compound 104 (120 mg) was resolved by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak AD-10SFC 30mm ID*250mmL, 10μm, mobile phase: CO2 / MeOH [0.1% NH3 (7M solution in MeOH)], total flow rate: 2.5 mL / min) to obtain compound 104-P1 (33 mg) and compound 104-P2 (27 mg).

[0744] Compound 104-P1: MS m / z (ESI): 352.0 [M+1]+ Supercritical fluid chromatography (SFC): Retention time = 4.661 min

[0745] Compound 104-P2: MS m / z (ESI): 352.0 [M+1] + Supercritical fluid chromatography (SFC): Retention time = 5.171 min

[0746] Step 2: Synthesis of compound 209-P1

[0747] Compound 104-P1 (33 mg, 0.093 mmol) was dissolved in deuterated methanol (2 mL) under nitrogen protection, and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 209-P1 (27.6 mg). MS m / z (ES): 352.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),7.35(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H),6.55(s,1H),4.26–4.17(m,1H),4.14–4.07 (m,1H),3.91–3.86(m,1H),3.79(t,J=5.4Hz,2H),2.72–2.64(m,1H),2.59–2.52(m,2H),1.71–1.64(m,1H),1.57–1.51(m,1H).

[0748] Step 3: Synthesis of compound 209-P2

[0749] Compound 104-P2 (27 mg, 0.077 mmol) was dissolved in deuterated methanol (2 mL) under nitrogen protection, and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 209-P2 (26.9 mg). MS m / z (ES): 353.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),7.35(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H),6.55(s,1H),4.28–4.16(m,1H),4.15–4.06 (m,1H),3.92–3.85(m,1H),3.79(t,J=5.6Hz,2H),2.71–2.63(m,1H),2.59–2.52(m,2H),1.72–1.64(m,1H),1.57–1.50(m,1H).

[0750] Example 45 (Compound 211)

[0751]

[0752] Step 1: Synthesis of Compound 211

[0753] At room temperature, compound 211a (42.1 mg, 0.26 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (29.8 mg, 0.052 mmol), cesium carbonate (252.1 mg, 0.77 mmol), and tris(dibenzylacetone)dipalladium (23.6 mg, 0.026 mmol) were added to a 1,4-dioxane (5 mL) solution of compound 214c (90 mg, 0.27 mmol, synthesis method referred to the third step of Example 42 for the synthesis of compound 214c). The reaction mixture was stirred at 110 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia); gradient: 40-95%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 211 (27.6mg). MS m / z (ESI): 430.85 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.18(s,1H),7.24–7.13(m,1H),6.71–6.59(m,1H),5.76(t,J=56.2Hz,1H),4.06–3 .92(m,4H),3.67–3.58(m,1H),2.49–2.43(m,3H),2.23–2.14(m,2H),1.73–1.64(m,1H),1.50–1.40(m,1H).

[0754] Example 46 (Compound 212)

[0755]

[0756] Step 1: Synthesis of compound 212a

[0757] At room temperature, compound 177d (89.8 mg, 1.03 mmol), tris(dibenzylacetone)palladium (78.7 mg, 0.086 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (99.5 mg, 0.17 mmol), and cesium carbonate (840.2 mg, 2.58 mmol) were added to a 1,4-dioxane (8 mL) solution of compound 214c (300 mg, 0.86 mmol, synthesis method referred to the third step of Example 42 for the synthesis of compound 214c). The reaction mixture was stirred at 110 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% ammonia); gradient: 60-95%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 212a (45mg). MS m / z (ESI): 355.20 [M+1] + .

[0758] Step 2: Synthesis of Compound 212

[0759] Compound 212a (45 mg, 0.13 mmol) was added to a solution of deuterated methanol (1 mL) at room temperature, and the mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 212 (24.2 mg). MS m / z (ESI): 356.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),5.53(s,1H),3.92–3.86(m,2 H),3.86–3.82(m,1H),3.81–3.76(m,1H),3.57–3.51(m,1H),2.56–2.52(m,1H),1.63–1.48(m,2H),1.41(s,3H).

[0760] Example 47 (Compound 213)

[0761]

[0762] Step 1: Synthesis of compound 213b

[0763] At room temperature, 500 mg (1.43 mmol) of compound 213a, 165.8 mg (0.29 mmol) of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), 1.40 g (4.30 mmol) of cesium carbonate and 131.2 mg (0.14 mmol) of tris(benzylacetone)palladium (131.2 mg, 0.14 mmol) of compound 214c (156.2 mg, 1.57 mmol) of 1,4-dioxane (5 mL) were added to the mixture. The reaction mixture was stirred at 110 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% TFA); gradient: 40-95%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 213b (150mg). MS m / z (ESI): 367.15 [M+1] + .

[0764] Step 2: Synthesis of Compound 213

[0765] Compound 213b (50 mg, 0.14 mmol) was added to a deuterated methanol solution (1 mL) at room temperature. The reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% TFA); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 213 (20 mg). MS m / z (ESI): 368.10 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),7.38(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),4.70(dd,J=17.6,7.2Hz,4 H), 4.49 (dd, J = 18.0, 8.8 Hz, 4H), 3.71–3.66 (m, 1H), 2.68–2.62 (m, 1H), 1.74–1.65 (m, 1H), 1.61–1.54 (m, 1H).

[0766] Example 48 (Compound 215)

[0767]

[0768] Step 1: Synthesis of compound 215b

[0769] At room temperature, hydrazine hydrate (1.43 g, 28.54 mmol) was added to a 10 mL ethanol solution of compound 215a (1.00 g, 7.92 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was cooled, filtered to obtain a filter cake, washed with ethanol, and dried under reduced pressure to obtain compound 215b (0.68 g). MS m / z (ESI): 127.05 [M+1] + .

[0770] Step 2: Synthesis of Compound 215

[0771] At room temperature, N,N-dimethylformamide dimethyl acetal (89.8 mg, 0.75 mmol) was added to a 1,4-dioxane (1 mL) solution of compound 215b (100.1 mg, 0.79 mmol). After stirring the reaction mixture at 80 °C for 1 hour, it was cooled to room temperature, and a 1,4-dioxane (1 mL) solution of compound 23 g (173.0 mg, 0.79 mmol) and acetic acid (95.3 mg, 1.58 mmol) was added. The reaction mixture was then stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 60bar) to obtain compound 215 (24.9mg). MS m / z (ESI): 335.90 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),11.18(s,1H),8.62(s,1H),7.84(s,1H),7.72(s,1H),7. 34(d,J=8.8Hz,1H), 6.84(d,J=8.8Hz,1H), 4.27(s,1H), 2.60–2.54(m,1H), 1.66–1.48(m,2H).

[0772] Example 49 (Compound 216)

[0773]

[0774] Step 1: Synthesis of compound 216b

[0775] Compound 216a (0.60 g, 4.54 mmol) and hydrazine hydrate (454.5 mg, 9.08 mmol) were dissolved in ethanol (10 mL), and the reaction mixture was stirred at 90 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to give compound 216b (500 mg).

[0776] Step 2: Synthesis of Compound 216

[0777] Compound 216b (150.0 mg, 1.14 mmol) and N,N-dimethylformamide dimethyl acetal (135.2 mg, 1.14 mmol) were added to a 1,4-dioxane (6 mL) solution. The mixture was stirred at 80 °C for 1 hour. After cooling to room temperature, acetic acid (68.1 mg, 1.14 mmol) and compound 23 g (247.5 mg, 1.14 mmol) were added. The reaction mixture was stirred at 120 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument: SHIMADZULC-20AP-3; column: Gemini 5um C18 150*21.2 mm; mobile phase: ACN / H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 216 (32.0 mg). MS m / z (ESI): 341.75 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.50(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.59(s,1H),3 .88–3.79(m,1H),2.93(s,2H),2.58–2.52(m,1H),1.72–1.60(m,1H),1.60–1.49(m,1H),1.20(d,J=15.6Hz,6H).

[0778] Example 50 (Compound 217)

[0779]

[0780] Step 1: Synthesis of compound 217b

[0781] At room temperature, hydrazine hydrate (833.6 mg, 16.65 mmol) was added to a 10 mL solution of compound 217a (500 mg, 5.55 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 10) to give compound 217b (360 mg). MS m / z (ESI): 91.15 [M+1] + .

[0782] Step 1: Synthesis of Compound 217

[0783] At room temperature, compound 217b (150 mg, 1.66 mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (198.4 mg, 1.66 mmol) in 1,4-dioxane (30 mL). The reaction mixture was stirred at 80 °C for 1 hour, then cooled to room temperature. Acetic acid (99.9 mg, 1.66 mmol) and compound 23 g (363.1 mg, 1.66 mmol) were added to the reaction mixture. The reaction mixture was stirred at 120 °C for another 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar. Compound 217 (57.6 mg) was purified. MS m / z (ESI): 299.75 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.56(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),5. 49(s,1H),4.67(s,2H),3.89–3.81(m,1H),2.57–2.52(m,1H),1.79–1.70(m,1H),1.57–1.50(m,1H).

[0784] Example 51 (Compound 218)

[0785]

[0786] Step 1: Synthesis of compound 218b

[0787] A mixture of compound 214c (200 mg, 0.57 mmol) and compound 218a (1.17 g, 6.30 mmol) was stirred in a molten state at 90 °C for 60 hours. After the reaction was complete, the reaction solution was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give compound 218b (600 mg, crude product), which was used directly in the next step without purification. MS m / z (ES): 454.00 [M+H] + .

[0788] Step 2: Synthesis of Compound 218

[0789] Compound 218b (600 mg, crude) was dissolved in 10 mL of dioxane hydrochloride solution, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: SHIMADZULCMS-2020-2; column: Gemini 5um C18 150*21.2 mm; mobile phase: 95% ACN / 5% H2O (containing 0.05% NH3); flow rate: 20 mL / min) to obtain compound 218 (39.7 mg). MS m / z (ESI): 353.90 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=9.2Hz,1H),3.78– 3.72(m,1H),3.13–3.02(m,4H),2.79–2.68(m,4H),2.57–2.53(m,1H),1.65–1.60(m,2H).

[0790] Example 52 (Compound 219)

[0791]

[0792] Step 1: Synthesis of compound 219b

[0793] At room temperature, 219a (106.3 mg, 0.34 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (20.9 mg, 0.02 mmol), and potassium carbonate (118.8 mg, 0.86 mmol) were sequentially added to a mixed solution of 1,4-dioxane and water (1.0 mL / 0.1 mL) of compound 214c (100 mg, 0.28 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 219b (70 mg). MS m / z (ESI): 451.05 [M+1] + .

[0794] Step 2: Synthesis of Compound 219

[0795] At room temperature, 1,4-dioxane hydrochloride (4.0 M, 1.0 mL) was added to compound 219b (60 mg, 0.13 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 219 (25.7 mg). MS m / z (ESI): 350.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.26(d,J=4.0Hz,1H),7.35(d,J=9.2Hz,1H),6.86(d,J=8.8Hz,1H),6.48(s,1H ),3.89–3.83(m,1H),3.58–3.27(m,4H),3.05–2.93(m,2H),2.68–2.62(m,1H),1.71–1.63(m,1H),1.56–1.49(m,1H).

[0796] Example 53 (Compound 220)

[0797]

[0798] Step 1: Synthesis of compound 220b

[0799] At room temperature, hydrazine hydrate (0.33 mL, 5.45 mmol) was added to a 5 mL ethanol solution of compound 220a (500 mg, 1.82 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give compound 220b (460 mg). MS m / z (ESI): 206.10 [M-55] + .

[0800] Step 2: Synthesis of compound 220c

[0801] Compound 220b (239.6 mg, 0.92 mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (109.3 mg, 0.92 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 80 °C for 1 hour, then cooled to room temperature. Compound 23 g (200 mg, 0.92 mmol) and acetic acid (0.052 mL, 0.92 mmol) were added to the mixture, and the reaction mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give compound 220c (70 mg). MS m / z (ESI): 470.95 [M+1] + .

[0802] Step 3: Synthesis of Compound 220

[0803] Hydrochloric acid / 1,4-dioxane (4.0 M, 2 mL) was added to a solution of compound 220c (60 mg, 0.13 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 220 (21.5 mg). MS m / z (ESI): 370.85 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.23(s,1H),7.34(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H), 4.00–3.94(m,1H),2.99–2.85(m,4H),2.83–2.77(m,1H),2.30–2.15(m,4H),1.73–1.58(m,2H).

[0804] Example 54 (Compound 221)

[0805]

[0806] Step 1: Synthesis of Compound 221

[0807] Compound 153 (50.0 mg, 0.13 mmol, synthesis method as described in step 2 of Example 15) was added to a deuterated methanol (2 mL) solution, and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 221 (14.8 mg). MS m / z (ESI): 368.85 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.35(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),4.59(d,J=4.4Hz,1H),3.88–3.76(m,1H),3.5 1–3.40(m,1H),2.96–2.82(m,1H),2.56–2.52(m,1H),1.99–1.84(m,4H),1.72–1.64(m,1H),1.64–1.51(m,3H),1.32–1.13(m,2H).

[0808] Example 55 (Compound 223)

[0809]

[0810] Step 1: Synthesis of compound 223b

[0811] A mixture of compound 214c (200 mg, 0.57 mmol) and compound 223a (450 mg, 2.12 mmol) was stirred in a molten state at 90 °C for 16 hours. After the reaction was complete, the mixture was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 1 / 10) to give compound 223b (180 mg). MS m / z (ESI): 480.05 [M+1] + .

[0812] Step 2: Synthesis of compound 223c

[0813] Compound 223b (80 mg, 0.17 mmol) was added to a solution of deuterated methanol (1 mL), and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar. The compound 223c (30 mg) was purified. MS m / z (ESI): 481.10 [M+1] + .

[0814] Step 3: Synthesis of Compound 223

[0815] Compound 223c (30 mg, 0.06 mmol) was added to a solution of 1,4-dioxane hydrochloride (4.0 M, 1 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was lyophilized to give compound 223 (20.7 mg). MS m / z (ESI): 381.05 [M+1] + . 1 H NMR (400MHz, CD3OD) δ7.31(d,J=8.8Hz,1H),6.82(d,J=8.8Hz,1H),4.26–4.16(m,2H),4.08–3.91(m,2H),3.80–3.70(m, 1H),3.69–3.51(m,2H),2.81–2.68(m,1H),2.35–2.25(m,1H),2.23–2.09(m,3H),2.00–1.89(m,1H),1.84–1.74(m,1H).

[0816] Example 56 (Compound 210)

[0817]

[0818] Step 1: Synthesis of compound 210a

[0819] Compound 201f (100 mg, 0.20 mmol, synthesis method as described in step 4 of Example 38) was added to a deuterated methanol solution (5 mL), and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 210a (100 mg). MS m / z (ESI): 498.40 [M+1] + .

[0820] Step 2: Synthesis of Compound 210

[0821] Cesium fluoride (152.3 mg, 1.00 mmol) was added to a solution of compound 210a (100 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 210 (28.6 mg). MS m / z (ESI): 383.80 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),4.28(s,1H),3.78–3.73(m,1 H),3.29–3.23(m,1H),3.22–3.08(m,3H),2.56–2.51(m,1H),1.70–1.55(m,3H),1.52–1.41(m,3H),1.12(s,3H).

[0822] Example 57 (Compound 222)

[0823]

[0824] Step 1: Synthesis of compound 222b

[0825] At room temperature, compound 222a (100 mg, 0.31 mmol) (synthetic method referred to the synthesis of compound H-Azepine-1-carboxylic acid, 2,3,4,7-tetrahydro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-,1,1-dimethylethyl ester, page 43 of patent WO2023086575 A12023-05-19), compound 214c (107.9 mg, 0.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (45.2 mg, 0.06 mmol) and potassium carbonate (85.5 mg, 0.63 mmol) were added to a mixed solution of 1,4-dioxane and water (3 mL / 0.3 mL). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 222b (100 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 465.30 [M+1] + .

[0826] Step 2: Synthesis of Compound 222

[0827] Compound 222b (100 mg, 0.21 mmol) was added to a 1 mL solution of 1,4-dioxane hydrochloride, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar. Compound 222 (21.8 mg) was purified. MS m / z (ESI): 364.85 [M+1] + . 1 H NMR (400MHz, CD3OD) δ8.74(s,1H),8.50(s,1H),7.27(d,J=8.8Hz,1H),6.79(d,J=8.8Hz,1H),6.50(t,J=6.0Hz,1H),3.97–3.92(m,1H),3. 88(d,J=6.4Hz,2H),3.43(t,J=5.8Hz,2H),3.03–2.88(m,2H),2.68–2.62(m,1H),2.08–1.98(m,2H),1.84–1.76(m,1H),1.69–1.62(m,1H).

[0828] Example 58 (Compound 174-P1, 224-P1)

[0829]

[0830] Step 1: Synthesis of compound 174-P1

[0831] Compound 214c (0.30 g, 0.86 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (99.5 mg, 0.17 mmol), cesium carbonate (840.2 mg, 2.58 mmol), tris(dibenzylacetone)dipalladium (88.97 mg, 0.086 mmol), and compound 224a (86.9 mg, 0.86 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was stirred at 110 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1-3 / 1) to give compound 174-P1 (180 mg). MS m / z (ESI): 368.85 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.14(d,J=5.4Hz,1H),7.33(dd,J=8.8,3.5Hz,1H),6.82(dd,J=8.8,4.7Hz,1H),4.73(s ,1H),3.74–3.54(m,2H),3.50–3.35(m,3H),2.64–2.53(m,1H),1.90–1.71(m,2H),1.68–1.49(m,2H),1.26(d,J=21.6Hz,3H).

[0832] Step 2: Synthesis of compound 224-P1

[0833] Compound 224b (150 mg, 0.41 mmol) was added to a deuterated methanol solution (0.5 mL), and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: SHIMADZU LC-20AP-1; column: Xbridge Prep C18 5 μm OBD; mobile phase: ACN / H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 224-P1 (27.0 mg). MS m / z (ESI): 369.85 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.34(dd,J=8.8,3.2Hz,1H),6.83(dd,J=8.8,4.0Hz,1H),4.74(d,J=12.8Hz,1H), 3.73–3.54(m,2H),3.49–3.33(m,3H),2.64–2.52(m,1H),1.89–1.71(m,2H),1.69–1.51(m,2H),1.26(d,J=20.8Hz,3H).

[0834] Example 59 (Compound 174-P2, 224-P2)

[0835]

[0836] Step 1: Synthesis of compound 174-P2

[0837] Tris(dibenzylacetone)dipalladium (52.4 mg, 0.057 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (66.3 mg, 0.12 mmol), and cesium carbonate (560.1 mg, 1.72 mmol) were added to a 1,4-dioxane (5 mL) solution of compound 214c (200 mg, 0.57 mmol) and compound 224b (57.9 mg, 0.57 mmol). The reaction mixture was stirred at 110 °C for 18 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give compound 174-P2 (70 mg). MS m / z (ES): 369.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.14(d,J=5.9Hz,1H),7.31(dd,J=8.8,3.8Hz,1H),6.80(dd,J=8.8,5.1Hz,1H),4.73(s ,1H),3.80–3.60(m,2H),3.57–3.40(m,3H),2.65–2.54(m,1H),1.93–1.71(m,2H),1.67–1.54(m,2H),1.26(d,J=22.0Hz,3H).

[0838] Step 2: Synthesis of compound 224-P2

[0839] Compound 174-P2 (65 mg, 0.17 mmol) was dissolved in deuterated methanol (10 mL), and the reaction mixture was heated to 60 °C and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: SHIMADZU LCMS-2020-2; column: Gemini 5 μm C18 150*21.2 mm; mobile phase: 95% ACN / 5% H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 224-P2 (5.5 mg). MS m / z (ESI): 369.90 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.31(d,J=12.8Hz,1H),7.34(dd,J=8.8,2.8Hz,1H),6.83(dd,J=8.8,4.0Hz,1H),4.73(d,J=13.6Hz ,1H),3.74–3.53(m,2H),3.49–3.32(m,3H),2.63–2.53(m,1H),1.88–1.71(m,2H),1.69–1.49(m,2H),1.26(d,J=20.8Hz,3H).

[0840] Example 60 (Compound 225-P1)

[0841]

[0842] Step 1: Synthesis of compound 225b

[0843] At room temperature, hydrazine hydrate (529.7 mg, 8.47 mmol) was added to a 10 mL solution of compound 225a (500 mg, 4.23 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 3 / 1) to give compound 225b (400 mg). MS m / z (ESI): 119.1 [M+1] + .

[0844] Step 2: Synthesis of compound 225-P1

[0845] At room temperature, N,N-dimethylformamide dimethyl acetal (302.6 mg, 2.54 mmol) was added to a 1,4-dioxane (5 mL) solution of compound 225b (300 mg, 2.54 mmol), and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, and a 1,4-dioxane (5 mL) solution of compound 23 g (830.7 mg, 3.81 mmol) and acetic acid (152.5 mg, 2.54 mmol) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 60bar) to obtain compound 225-P1 (20.6mg). MS m / z (ESI): 328.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.47(d,J=3.2Hz,1H),7.35(dd,J=8.8,2.4Hz,1H),6.85(dd,J=8.8,2.0Hz,1H),4.89–4 .74(m,1H),3.87–3.72(m,1H),3.68–3.54(m,2H),3.29–3.21(m,1H),2.63–2.53(m,1H),1.80–1.47(m,2H),1.30–1.24(m,3H).

[0846] Example 61 (Compound 225-P2)

[0847]

[0848] Step 1: Synthesis of compound 225d

[0849] At room temperature, hydrazine hydrate (847.5 mg, 16.93 mmol) was added to a 20 mL ethanol solution of compound 225c (1.0 g, 8.46 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 3 / 1) to give compound 225d (500 mg). MS m / z (ESI): 117.15 [M⁻¹] + .

[0850] Step 2: Synthesis of compound 225e

[0851] At room temperature, N,N-dimethylformamide dimethyl acetal (107.5 mg, 0.90 mmol) was added to a 1,4-dioxane (5 mL) solution of compound 225d (106.6 mg, 0.90 mmol), and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was then cooled to room temperature, and a 1,4-dioxane (5 mL) solution of compound 177a (300.0 mg, 0.90 mmol) and acetic acid (54.2 mg, 0.90 mmol) was added. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain compound 225e (300 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 442.35 [M+1] + .

[0852] Step 3: Synthesis of compound 225-P2

[0853] 1,4-Dioxane hydrochloride (4.0 M, 5 mL) was added to a solution of compound 225e (300 mg, 0.67 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 225-P2 (18.6 mg). MS m / z (ES): 327.80 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.47(d,J=2.8Hz,1H),7.35(dd,J=8.8,3.2Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.80(s,1 H),3.88–3.73(m,1H),3.68–3.52(m,2H),3.29–3.23(m,1H),2.60–2.52(m,1H),1.78–1.48(m,2H),1.25(dd,J=6.8,2.4Hz,3H).

[0854] Example 62 (Compound 226)

[0855]

[0856] Step 1: Synthesis of compound 226b

[0857] Hydrazine hydrate (227.8 mg, 3.64 mmol) was added to a 5 mL ethanol solution of compound 226a (450 mg, 1.82 mmol), and the reaction mixture was stirred at 90 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 226b (400 mg). MS m / z (ESI): 192.15 [M-55] + .

[0858] Step 2: Synthesis of compound 226c

[0859] At room temperature, N,N-dimethylformamide dimethyl acetal (180.3 mg, 1.51 mmol) was added to a 1,4-dioxane (5 mL) solution of compound 226b (374.2 mg, 1.51 mmol). The reaction mixture was stirred at 90 °C for 1 hour, then cooled to room temperature. Acetic acid (90.9 mg, 1.51 mmol) and compound 23 g (330 mg, 1.51 mmol) were added, and the reaction mixture was heated to 120 °C and stirred for 18 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound 226c (200 mg). MS m / z (ESI): 457.25 [M+1] + .

[0860] Step 3: Synthesis of compound 226d

[0861] At room temperature, 1,4-dioxane (2 mL, 4.0 M) was added to a 2 mL solution of 1,4-dioxane (180 mg, 0.39 mmol) of compound 226c. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% NH3); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 226d (65 mg). MS m / z (ESI): 357.15 [M+1] + .

[0862] Step 4: Synthesis of Compound 226

[0863] Compound 226d (55 mg, 0.15 mmol) was added to a deuterated methanol solution (2 mL), and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 226 (55 mg). MS m / z (ESI): 358.10 [M+1]+ . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.35(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),4.05–3.88(m,1H),3.66– 3.36(m,2H),3.08–2.87(m,1H),2.84–2.72(m,1H),2.63–2.51(m,1H),2.49–2.36(m,2H),1.77–1.59(m,2H).

[0864] Example 63 (Compound 227-P1, P2)

[0865]

[0866] Step 1: Synthesis of compounds 227-P1 and P2

[0867] Compound 8-P1 (70 mg, 0.20 mmol, synthesis method as described in step 3 of Example 3) was added to a 2 mL solution of deuterated methanol at room temperature. The reaction mixture was heated to 50 °C and stirred for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 227-P1 or 227-P2 (25.9 mg). MS m / z (ESI): 354.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),7.33(d,J=8.8Hz,1H),6.91(d,J=9.2Hz,1H),3.86–3.77(m,1H),3.37– 3.17(m,3H),2.91–2.78(m,2H),2.06–1.94(m,2H),1.92–1.78(m,2H),1.76–1.67(m,1H),1.56–1.47(m,1H).

[0868] Compound 8-P2 (90 mg, 0.26 mmol, synthesis method as described in step 3 of Example 3) was added to a deuterated methanol (2 mL) solution, and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 227-P2 or 227-P1 (27.8 mg). MS m / z (ESI): 354.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),7.33(d,J=8.8Hz,1H),6.92(d,J=8.8Hz,1H),3.84–3.79(m,1H),3.45–3.17(m,3 H),2.99–2.80(m,2H),2.50–2.45(m,1H),2.12–1.99(m,2H),1.97–1.82(m,2H),1.77–1.65(m,1H),1.60–1.46(m,1H).

[0869] Example 64 (Compound 228-P1, P2)

[0870]

[0871] Step 1: Synthesis of compounds 220c-P1 and 220c-P2

[0872] Compound 220c (280 mg, synthesis method referred to in the second step of Example 53, synthesis of compound 220c) was separated by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak AD-10SFC 30mm I.D.*250mmL, 10μm, mobile phase: CO2 / MeOH [0.1% NH3 (7M solution in MeOH)] 60 / 40, total flow rate: 100 ml / min) to obtain compounds 220c-P1 (110 mg) and 220c-P2 (110 mg).

[0873] Compound 220c-P1: MS m / z (ESI): 470.90 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.725 min, UV = 214 nm.

[0874] Compound 220c-P2: MS m / z (ESI): 470.90 [M+1] + Supercritical fluid chromatography (SFC): retention time = 3.127 min, UV = 214 nm.

[0875] Step 2: Synthesis of compounds 228a-P1 and 228a-P2

[0876] Compound 220c-P1 (200 mg, 0.23 mmol) was dissolved in deuterated methanol (3 mL), and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 228a-P1 (100 mg, crude product), which was used directly in the next reaction without purification. MS m / z (ESI): 471.95 [M+1] + .

[0877] Compound 220c-P2 (200 mg, 0.23 mmol) was dissolved in deuterated methanol (3 mL). The reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 228a-P2 (100 mg, crude product), which was used directly in the next reaction without purification. MS m / z (ESI): 472.00 [M+1] + .

[0878] Step 3: Synthesis of compounds 228-P1 and 228-P2

[0879] Compound 228a-P1 (100 mg, 0.21 mmol) was dissolved in 5 mL of hydrochloric acid-dioxane solution, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 228-P1 (40.5 mg). MS m / z (ESI): 371.90 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ7.37(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),4.03–3.95(m,1H),3.42–3.28(m,2H),3.2 5–3.12(m,2H),2.90–2.81(m,1H),2.66–2.54(m,3H),2.51–2.40(m,1H),1.80–1.69(m,1H),1.69–1.60(m,1H).

[0880] Compound 228a-P2 (100 mg, 0.21 mmol) was dissolved in a hydrochloric acid-dioxane solution (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was lyophilized to give compound 228-P2 (32.8 mg). MS m / z (ESI): 371.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.01–3.92(m,1H),3.41–3.29(m ,2H),3.26–3.13(m,2H),2.88–2.80(m,1H),2.66–2.54(m,3H),2.50–2.37(m,1H),1.78–1.61(m,2H).

[0881] Example 65 (Compound 229)

[0882]

[0883] Step 1: Synthesis of compound 229b

[0884] Compound 229a (500 mg, 1.84 mmol) and hydrazine hydrate (922.4 mg, 14.74 mmol) were dissolved in ethanol (5 mL), and the reaction mixture was stirred at 90 °C for 15 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to give compound 229b (421 mg). MS m / z (ESI): 202.10 [M-55] + .

[0885] Step 2: Synthesis of compound 229c

[0886] Compound 229b (280 mg, 1.09 mmol) and trimethyl orthoformate (230.9 mg, 2.18 mmol) were added to a solution of 1,4-dioxane (28 mL). The reaction mixture was heated to 45 °C and stirred for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, and acetic acid (65.3 mg, 1.09 mmol) and compound 113a (252.5 mg, 1.09 mmol) were added. The reaction mixture was stirred at 120 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to give compound 229c (200.0 mg). MS m / z (ESI): 481.35 [M+1] + .

[0887] Step 3: Synthesis of compound 229d

[0888] Boron tribromide (187.34 mg, 0.75 mmol) was added to a dichloromethane (6 mL) solution of compound 229c (120.0 mg, 0.25 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: SHIMADZU LC-20AP-1; column: Xbridge Prep C18 5um OBD; mobile phase: ACN / H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 229d (60.0 mg). MS m / z (ESI): 366.85 [M+1] + .

[0889] Step 4: Synthesis of Compound 229

[0890] Compound 229d (60 mg, 1.14 mmol) was added to a solution of deuterated methanol (2 mL), and the reaction mixture was heated to 45 °C and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 229 (22.1 mg). MS m / z (ESI): 367.95 [M+1] + . 1 HNMR(400MHz,CD3OD)δ8.56(s,1H),7.30(d,J=8.8Hz,1H),6.81(d,J=8.8Hz,1H),3.97–3.87(m,1H),3.69–3.60(m,1H ),3.51–3.42(m,1H),3.30–3.16(m,3H),2.66–2.57(m,1H),2.36–2.17(m,3H),2.13–1.90(m,3H),1.84–1.68(m,2H).

[0891] Example 66 (Compound 232-P1)

[0892]

[0893] Step 1: Synthesis of compound 232b

[0894] A mixture of compound 214c (200 mg, 0.57 mmol) and compound 232a (853.9 mg, 8.0 mmol) was stirred in the molten state at 100 °C for 3 hours. After the reaction was complete, the reaction mixture was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give compound 232b (220 mg, crude product), which was used directly in the next step without purification. MS m / z (ES): 453.90 [M+H] +.

[0895] Step 2: Synthesis of compound 232-P1

[0896] Compound 232b (200 mg, crude) was dissolved in 10 mL of hydrochloric acid-dioxane solution. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: SHIMADZU LCMS-2020-2; column: Gemini 5µm C18 150*21.2mm; mobile phase: 95% ACN / 5% H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 232-P1 (13.8 mg). MS m / z (ESI): 353.90 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.28(s,1H),7.37(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),3.92–3.8 0(m,1H),3.76–3.45(m,5H),2.66–2.59(m,1H),2.37–2.22(m,1H),2.04–1.89(m,1H),1.72–1.60(m,2H).

[0897] Example 67 (compounds 232-P2, 232-P2-1, P2-2)

[0898]

[0899] Step 1: Synthesis of compound 232d

[0900] A mixture of compound 214c (100 mg, 0.28 mmol) and compound 232c (320.2 mg, 1.72 mmol) was stirred in a molten state at 100 °C for 2 hours. After the reaction was complete, the reaction solution was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound 232d (70 mg). MS m / z (ESI): 454.10 [M+1] + .

[0901] Step 2: Synthesis of compound 232-P2

[0902] At room temperature, dioxane hydrochloride (4.0 M, 2 mL) was added to a solution of compound 232d (60 mg, 0.13 mmol) in 1,4-dioxane (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 232-P2 (21.4 mg). MS m / z (ESI): 354.05 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),8.22(s,1H),7.36(d,J=9.2Hz,1H),6.87(d,J=8.8Hz,1H),3.78–3.5 6(m,4H),3.45–3.30(m,2H),2.66–2.57(m,1H),2.25–2.10(m,1H),1.88–1.76(m,1H),1.70–1.49(m,2H).

[0903] Step 3: Synthesis of compounds 232-P2-1 and 232-P2-2

[0904] Compound 232-P2 (20 mg) was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IC-10SFC, column: 30 mm ID*250 mmL, 10 μm, mobile phase: 25% MeOH / CO2 (NH4OH 0.1%), total flow rate: 90 mL / min) to obtain compound 232-P2-1 (4.11 mg) and compound 232-P2-2 (4.48 mg).

[0905] Compound 232-P2-1: MS m / z (ESI): 353.85, 355.65 [M+1, M+3] + Supercritical fluid chromatography (SFC): retention time = 8.95 min, UV = 214 nm.

[0906] Compound 232-P2-2: MS m / z (ESI): 353.80, 355.70 [M+1, M+3] + Supercritical fluid chromatography (SFC): retention time = 10.21 min, UV = 214 nm.

[0907] Example 68 (compounds 177-P1, 177-P2)

[0908]

[0909] Step 1: Synthesis of compounds 177-P1 and 177-P2

[0910] Compound 177 (80.0 mg, 0.23 mmol, synthesis method as described in step 6 of Example 32, synthesis of compound 177) was separated by supercritical fluid chiral chromatography (column Daicel Chiralpak OJ-10SFC; mobile phase: CO2: methanol (0.1% NH3); gradient: 15%; column temperature: 40 °C; flow rate: 80 mL / min; wavelength: 214 nm) to obtain compound 177-P1 (35.9 mg) and compound 177-P2 (33.4 mg).

[0911] Compound 177-P1: MS m / z (ESI): 354.85 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.769 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.17(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),5. 53(s,1H),3.91–3.76(m,4H),3.57–3.52(m,1H),2.66–2.61(m,1H),1.63–1.51(m,2H),1.41(s,3H).

[0912] Compound 177-P2: MS m / z (ESI): 354.75 [M+1] + Supercritical fluid chromatography (SFC): retention time = 3.183 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),8.18(s,1H),7.34(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),5. 53(s,1H),3.92–3.76(m,4H),3.58–3.52(m,1H),2.55–2.53(m,1H),1.62–1.50(m,2H),1.41(s,3H).

[0913] Example 69 (compound 198-P1)

[0914]

[0915] Step 1: Synthesis of compound 198b

[0916] tert-Butyldimethylchlorosilane (1.93 g, 12.81 mmol) and imidazole (1.82 g, 26.70 mmol) were added to a dichloromethane (40 mL) solution of compound 198a (2.0 g, 10.68 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 198b (3.0 g). MS m / z (ESI): 246.15 [M-55] + .

[0917] Step 2: Synthesis of compound 198c

[0918] Compound 198b (1 g, 3.31 mmol) was added to a mixed solution of trifluoroacetic acid and dichloromethane (3 mL / 6 mL), and the reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 8 with a saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phases were concentrated under reduced pressure to give compound 198c (600 mg, crude product). MS m / z (ESI): 202.10 [M+1] + .

[0919] Step 3: Synthesis of compound 198d

[0920] Under nitrogen protection, compound 214c (200 mg, 0.57 mmol), (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (52.6 mg, 0.057 mmol), bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane, and (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (52.6 mg, 0.057 mmol) were sequentially added. [Benzenyl]-2-yl)phosphonane (29.4 mg, 0.057 mmol) and cesium carbonate (560.1 mg, 1.72 mmol) were added to a 1,4-dioxane (10 mL) solution of compound 198c (577.0 mg, 2.86 mmol). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 198d (25 mg). MS m / z (ESI): 469.35 [M+1] + .

[0921] Step 4: Synthesis of compound 198-P1

[0922] Compound 198d (20.0 mg, 0.043 mmol) was added to a solution of 1,4-dioxane (2 mL, 4.0 M) and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 198-P1 (10.6 mg). MS m / z (ESI): 354.85 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.38–10.28(m,1H),8.15(d,J=2.4Hz,1H),7.34(dd,J=8 .8,2.0Hz,1H),6.84(dd,J=8.8,3.2Hz,1H),4.91(dd,J=12.4,3.6Hz,1H),4.35–4. 25(m,1H),3.73–3.66(m,1H),3.65–3.56(m,1H),3.56–3.40(m,2H),3.37–3.33(m ,1H),2.65–2.55(m,1H),2.01–1.88(m,1H),1.83–1.73(m,1H),1.63–1.52(m,2H).

[0923] Example 70 (compound 198-P2)

[0924]

[0925] Step 1: Synthesis of compound 198f

[0926] tert-Butyldimethylchlorosilane (1.93 g, 12.818 mmol) and imidazole (1.82 g, 26.704 mmol) were added to a dichloromethane (20 mL) solution of compound 198e (2 g, 10.682 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 198f (3.0 g). MS m / z (ESI): 246.3 [M-55] + .

[0927] Step 2: Synthesis of 198g of compound

[0928] Compound 198f (1 g, 3.317 mmol) was added to a mixed solution of trifluoroacetic acid and dichloromethane (5 mL / 10 mL). The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was adjusted to pH 8 with a saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 198 g (720 mg). MS m / z (ESI): 202.10 [M+1] + .

[0929] Step 3: Synthesis of compound 198h

[0930] Under nitrogen protection, compound 214c (1.73 g, 8.60 mmol), tris(dibenzylacetone)dipalladium (139.1 mg, 0.17 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (198.9 mg, 0.34 mmol), and cesium carbonate (1.12 g, 3.44 mmol) were added sequentially to a solution of compound 198 g (600 mg, 1.72 mmol) in 6 mL of 1,4-dioxane. The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 198h (110 mg). MS m / z (ESI): 469.30 [M+1] + .

[0931] Step 4: Synthesis of compound 198-P2

[0932] Compound 198h (100 mg, 0.21 mmol) was added to a solution of 1,4-dioxane (3 mL, 4 M) of hydrogen chloride. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 198-P2 (17 mg). MS m / z (ESI): 355.0 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ10.32(d,J=11.6Hz,1H),8.18–8.12(m,1H),7.34(dd ,J=8.8,2.4Hz,1H),6.84(dd,J=8.8,3.2Hz,1H),4.91(dd,J=12.4,3.6Hz,1H) ,4.40–4.21(m,1H),3.75–3.65(m,1H),3.65–3.39(m,3H),3.31–3.24(m,1H) ,2.65–2.54(m,1H),2.02–1.87(m,1H),1.83–1.72(m,1H),1.64–1.52(m,2H).

[0933] Example 71 (compounds 218-P1, 218-P2, 234-P1, 234-P2)

[0934]

[0935] Step 1: Synthesis of compounds 218b-P1 and 218b-P2

[0936] Compound 218b (100 mg, synthesis method as described in Example 51, Step 1: Synthesis of Compound 218b) was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IB N-10SFC, column: CHIRALPAK AD-H 250 mm * 20 mm, 5 μm, mobile phase: 25% MeOH / CO2 (NH4OH 0.1%), total flow rate: 70 mL / min) to obtain compounds 218b-P1 (50 mg) and 218b-P2 (50 mg).

[0937] Compound 218b-P1: MS m / z (ESI): 454.15, 456.05 [M+1, M+3] + Supercritical fluid chromatography (SFC): retention time = 2.29 min, UV = 214 nm.

[0938] Compound 218b-P2: MS m / z (ESI): 454.15, 456.05 [M+1, M+3] + Supercritical fluid chromatography (SFC): retention time = 2.70 min, UV = 214 nm.

[0939] Step 2: Synthesis of compounds 218-P1 and 218-P2

[0940] Compound 218b-P1 (50 mg, 0.11 mmol) was dissolved in 2 mL of 1,4-dioxane solution, and 1,4-dioxane hydrochloride solution (4.0 M, 0.55 mL, 2.20 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 218-P1 (31 mg). MS m / z (ESI): 354.15 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.77–10.56(m,1H),9.71–9.41(m,2H),9.02–8.86(m,1H),7.38(d,J=8.8Hz,1H),7.05–6.89(m ,1H),3.92–3.81(m,1H),3.79–3.60(m,4H),3.33–3.11(m,4H),2.74–2.65(m,1H),1.87–1.76(m,1H),1.67–1.56(m,1H).

[0941] Compound 218b-P2 (50 mg, 0.11 mmol) was dissolved in 2 mL of 1,4-dioxane solution, and 1,4-dioxane hydrochloride solution (4.0 M, 0.55 mL, 2.20 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 218-P2 (36 mg). MS m / z (ESI): 354.15 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.75–10.54(m,1H),9.67–9.36(m,2H),9.03–8.82(m,1H),7.38(d,J=8.8Hz,1H),7.03–6.90(m ,1H),3.90–3.81(m,1H),3.78–3.58(m,4H),3.30–3.12(m,4H),2.74–2.64(m,1H),1.86–1.76(m,1H),1.66–1.56(m,1H).

[0942] Step 3: Synthesis of compounds 234-P1 and 234-P2

[0943] Compound 218-P1 (50 mg, 0.14 mmol) was added to a solution of deuterated methanol (2 mL), and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 234-P1 (22.0 mg). MS m / z (ESI): 355.05 [M+1] + .1 HNMR(400MHz,DMSO-d6)δ10.70(s,1H),9.60(s,2H),7.38(d,J=8.8Hz,1H),6.99(d,J=8.8Hz,1H),3.90 –3.81(m,1H),3.79–3.61(m,4H),3.22(s,4H),2.75–2.63(m,1H),1.87–1.74(m,1H),1.69–1.53(m,1H).

[0944] Compound 218-P2 (50 mg, 0.14 mmol) was added to a solution of deuterated methanol (2 mL), and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 234-P2 (18.2 mg). MS m / z (ESI): 355.0 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ10.65(s,1H),9.50(s,2H),7.38(d,J=8.8Hz,1H),6.97(d,J=8.8Hz,1H),3.88 –3.81(m,1H),3.73–3.61(m,4H),3.22(s,4H),2.73–2.62(m,1H),1.86–1.75(m,1H),1.68–1.58(m,1H).

[0945] Example 72 (compounds 219-P1, 219-P2, 235-P1, 235-P2)

[0946]

[0947] Step 1: Synthesis of compounds 219b-P1 and 219b-P2

[0948] Compound 219 (350 mg, synthesis method referred to the first step of Example 52, synthesis of compound 219b) was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak AD-10 SFC; column: CHIRALPAK AD-10 250 mm * 30 mm, 10 μm, mobile phase: 25% MeOH / CO2 (NH4OH 0.1%), total flow rate: 80 mL / min) to obtain compounds 219b-P1 (150 mg) and 219b-P2 (150 mg).

[0949] Compound 219b-P1: MS m / z (ESI): 450.90 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.57 min, UV = 214 nm.

[0950] Compound 219b-P2: MS m / z (ESI): 450.85 [M+1] + Supercritical fluid chromatography (SFC): retention time = 3.34 min, UV = 214 nm.

[0951] Step 2: Synthesis of compounds 219-P1 and 219-P2

[0952] Compound 219b-P1 (150 mg, 0.33 mmol) was dissolved in 1,4-dioxane hydrochloride (4.0 M, 1.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by supercritical fluid chiral chromatography (equipment: Waters Torus 2-PIC OBD, column: Waters Torus 2-PIC OBD 250 mm * 19 mm, 1 / pkg, mobile phase: 35% MeOH / CO2 (NH4OH 0.1%), total flow rate: 48 mL / min) to obtain compound 219-P1 (70 mg). MS m / z (ESI): 351.00 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.63(s,1H),7.36(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),6.49(s,1H),3.87–3.82(m,1H), 3.50–3.45(m,2H),3.07–3.01(m,2H),2.69–2.64(m,1H),2.61–2.54(m,2H),1.69–1.61(m,1H),1.56–1.49(m,1H).

[0953] Compound 219b-P2 (150 mg, 0.33 mmol) was dissolved in 1,4-dioxane hydrochloride (4.0 M, 1.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 219-P2 (110 mg). MS m / z (ESI): 350.95 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ9.20(s,1H),7.39(d,J=8.8Hz,1H),6.95(d,J=8.8Hz,1H),6.67(s,1H),3.94–3.8 9(m,1H),3.87–3.72(m,2H),3.35–3.28(m,2H),2.90–2.82(m,1H),2.79–2.71(m,2H),1.69–1.61(m,2H).

[0954] Step 3: Synthesis of compounds 235-P1 and 235-P2

[0955] Compound 219-P1 (35 mg, 0.10 mmol) was dissolved in 5.0 mL of deuterated methanol solution, and the reaction mixture was stirred at 60 °C for 48 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 235-P1 (34.5 mg). MS m / z (ESI): 351.80 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ7.35(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),6.49(s,1H),3.87–3.84(m,1H) ,3.51–3.43(m,2H),3.03(d,J=6.0Hz,2H),2.74–2.57(m,3H),1.74–1.62(m,1H),1.58–1.47(m,1H).

[0956] Compound 219-P2 (75 mg, 0.21 mmol) was dissolved in 5.0 mL of deuterated methanol solution, and the reaction mixture was stirred at 60 °C for 48 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 235-P2 (41.8 mg). MS m / z (ESI): 351.80 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=8.8Hz,1H),6.93(d,J=8.8Hz,1H),6.62(s,1H),3.88–3.84(m,1 H),3.84–3.67(m,2H),3.37–3.27(m,2H),2.90–2.81(m,1H),2.78–2.69(m,2H),1.68–1.55(m,2H).

[0957] Example 73 (compounds 220-P1, 220-P2)

[0958]

[0959] Step 1: Synthesis of compounds 220-P1 and 220-P2

[0960] Compound 220c-P1 (50 mg, 0.11 mmol, synthesized as described in Example 64, Step 1: Synthesis of Compound 220c-P1) was dissolved in 5 mL of 1,4-dioxane hydrochloride solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 220-P1 (21.1 mg). MS m / z (ESI): 370.90 [M+1] + . 1 H NMR (400MHz, CD3OD) δ9.43(s,1H),7.18(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,1H),4.19–4.12(m,1H ),3.48–3.37(m,2H),3.37–3.24(m,2H),2.85–2.76(m,1H),2.70–2.40(m,4H),1.84–1.74(m,2H).

[0961] Compound 220c-P2 (50 mg, 0.11 mmol) was dissolved in 5 mL of 1,4-dioxane hydrochloride solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was lyophilized to give compound 220-P2 (14.7 mg). MS m / z (ESI): 370.90 [M+1] + . 1 H NMR(400MHz,CD3OD)δ9.41(s,1H),7.18(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,1H),4.18–4.11(m,1H ),3.48–3.38(m,2H),3.36–3.25(m,2H),2.84–2.76(m,1H),2.70–2.42(m,4H),1.85–1.73(m,2H).

[0962] Example 74 (compounds 236-P1-1, 236-P1-2)

[0963]

[0964] Step 1: Synthesis of compound 236b

[0965] Cesium carbonate (37.3 mg, 0.12 mmol), compound 236a (206.6 mg, 200.3 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (99.5 mg, 0.17 mmol), and tris(dibenzylacetone)dipalladium (78.7 mg, 0.086 mmol) were added sequentially to a 1,4-dioxane (6 mL) solution of compound 214c (300 mg, 0.86 mmol). The reaction mixture was heated to 110 °C and stirred for 18 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated brine (15 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–20%) to obtain compound 236b (100 mg).

[0966] MS m / z(ESI): 468.25 [M+1] +

[0967] Step 2: Synthesis of compounds 236-P1-1 and 236-P1-2

[0968] Compound 236c (100 mg, 0.22 mmol) was dissolved in dichloromethane (1 mL), and 1 mL of hydrochloric acid-1,4-dioxane solution was slowly added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5 μm C18 150*21.2 mm; flow rate: 20 mL / min; column temperature: room temperature; mobile phase: A: water (FA 0.1%) B: acetonitrile 35%) to obtain compound 236c (25 mg). The compounds were resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IB N-10SFC; column: CHIRALPAK AD-H2 50mm*20mm, 5μm; mobile phase: 25% MeOH / CO2 (NH4OH 0.1%); total flow rate: 70mL / min) to obtain compounds 236-P1-1 (11.1mg) and 236-P1-2 (11.0mg).

[0969] Compound 236-P1-1: MS m / z (ESI): 368.10 [M+1] + Supercritical fluid chromatography (SFC): retention time = 5.829 min, UV = 214 nm. 1H NMR (400MHz, CD3OD) δ8.27(s,1H),7.26(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),3.90–3.77(m,2H),3.66–3.58(m, 1H),3.52–3.47(m,1H),3.44-3.40(m,1H),2.64–2.57(m,1H),2.00–1.91(m,2H),1.76–1.70(m,2H),1.38(s,3H).

[0970] Compound 236-P1-2: MS m / z (ESI): 368.10 [M+1] + Supercritical fluid chromatography (SFC): retention time = 6.822 min, UV = 214 nm. 1 H NMR (400MHz, CD3OD) δ8.27(s,1H),7.26(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),3.83–3.78(m,1H),3.74–3.68(m, 2H),3.56–3.53(m,1H),3.39–3.35(m,1H),2.66–2.58(m,1H),1.98–1.92(m,2H),1.79–1.65(m,2H),1.33(s,3H).

[0971] The following compounds can be synthesized using the preparation methods described in the above examples.

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986] Biological Examples

[0987] 1. Inhibitory activity of the compound on potassium ion channel Kv1.3

[0988] Objective: To detect the inhibitory effect of the compound on the current in HEK-293 cell line stably expressing the human Kv1.3 (KCNA3: NM_002232) channel using automated patch-clamp technique.

[0989] Test method:

[0990] 1) Cell Culture: The Kv1.3-HEK293 cell line was cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% carbon dioxide. For cell passage, the old medium was first removed and the cells were washed once with PBS, then 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for 1 minute. When the cells detached from the bottom of the dish, 5 mL of preheated (37°C) complete medium was added. The cell suspension was gently pipetted to separate aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, cells were seeded in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 100 cells (final volume: 5 mL). Cells were subjected to TrypLE assay before automated patch-clamp detection. TM After separating the cells using Express culture medium to stop digestion, centrifuge, resuspend the cells, count them, and adjust the cell density to 2-3 × 10⁶ cells / year. 6 Cells / mL were collected, and then the cells were gently mixed on a balanced shaker for 15-20 minutes at room temperature before being analyzed.

[0991] 2) When performing electrophysiological assays using the fully automated patch-clamp QPatch 48X (Sophion) device, the prepared cells are first placed on the centrifuge of the Qpatch workbench. The cells are washed using multiple centrifugation / resuspension methods, and the cell culture medium is replaced with extracellular fluid. An MTP-96 plate is removed and placed in the MTP source position. A QPlate chip is removed and placed in the QPlate source position. The robotic arm scans the barcodes on the MTP-96 plate and the QPlate chip and then picks them up and transfers them to the measurement station. Intracellular fluid (145mM KF, 10mM HEPES, 10mM EGTA, 2mM MgCl2·6H2O, pH adjusted to 7.2 with KOH) and extracellular fluid (140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH) were aspirated from the liquid pools and added to the intracellular fluid pool and cell and compound pool of the QPlate chip. At the measurement station, all measurement sites on the QPlate underwent initial quality control. The quality control process included aspirating cell suspension from the centrifuge cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal, forming a whole-cell recording mode. Once a stable baseline control current is obtained, the test substance is aspirated from the MTP-96 plate and applied to the cells in a four-dose regimen, with each dose lasting at least 5 minutes. Blank control solution and working solution of the test compound are applied to the cells sequentially. The current detected in each cell in the solution without the compound serves as its control group. All electrophysiological experiments are performed at room temperature.

[0992] 3) The voltage stimulation protocol for whole-cell patch-clamp recording of Kv1.3 potassium current is as follows: After whole-cell sealing is achieved, the cell membrane voltage is clamped at -80mV, stepped to +40mV, and maintained for 500ms. Data is collected repeatedly every 20s to observe the effect of the drug on the peak value of Kv1.3 current.

[0993] Data Analysis:

[0994] The last dose in a multiple-dose series was used for data analysis. For each drug concentration, the average of the last three data points before the next dose was taken to represent the current value after that concentration. This average represents the current value (Id) for each drug concentration. compound ) and the reference current value (I) used as a blank control control Normalize, then calculate the inhibition rate corresponding to each drug concentration, i.e., inhibition rate (%) = (1-I compound / I control*100%. For each concentration, the inhibition rate was calculated as the mean (Mean), standard deviation (SD), and standard error (SE), expressed as Mean ± SE. Test results are shown in Tables 1 and 2. Where A represents: inhibition rate (%) ≥ 40%; B represents: 20% ≤ inhibition rate (%) < 40%; C represents: 10% ≤ inhibition rate (%) < 20%; D represents: inhibition rate (%) < 10%.

[0995] For IC50 calculation, the Hill equation was used to calculate the IC50 value for each compound, and the dose-response curve was nonlinearly fitted, i.e., Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)), where IC50 is the half-maximal inhibitory concentration. IC50 calculation and curve fitting were performed using GraphPad Prism software. The test results are shown in Table 3.

[0996] Table 1

[0997]

[0998]

[0999] Table 2

[1000]

[1001]

[1002] Table 3

[1003]

[1004]

[1005] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: T is C 3-10 cycloalkyl, C 3-10 Cycloalkenyl or 3-10 membered heterocyclic groups, wherein the C 3-10 cycloalkyl, C 3-10 Cycloalkenyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more R 7 replace; Ring A is a 5-10 member heteroaryl group; Z is OH; R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cycloalkyl groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 The alkoxy, cyano, and amino groups are substituted; R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 5-8 membered heteroaryl, 3-12 membered heterocyclic hydroxyl, 3-12 membered heterocyclic mercapto -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 heterocyclic, 5-8 heteroaryl, 3-12 heterocyclic hydroxyl, and 3-12 heterocyclic mercapto are optionally surrounded by one or more R g replace; R j and R k They may be the same or different, and each is independently selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, R j and R k Together with the atoms attached thereto, they form a 3-6 membered carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered carbon ring and the 3-6 membered heterocycle are optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c NR b R c -S(O)2R e C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic and 3-6 membered heterocyclic oxy groups are optionally selected from halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl, 3-6 membered heterocyclic and 5-8 membered heteroaryl; Or, R 5 And one of the R 6 Or two Rs 6 The atoms bonded to it form a 3-12 membered carbon ring or a 3-12 membered heterocycle, wherein the 3-12 membered carbon ring or 3-12 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, two Rs 7 The atoms bonded to it form a 3-6 membered carbon ring or a 3-6 membered heterocycle, wherein the 3-6 membered carbon ring or 3-6 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms a 3-12 membered carbon ring or a 3-12 membered heterocycle, wherein the 3-12 membered carbon ring or 3-12 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R a and R d The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, OH, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; R b and R c They are the same or different, and each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or R b and R c Together with the nitrogen atom attached thereto, they form a 4-8 membered heterocycle, wherein the 4-8 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; R e Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, amino, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; n is 0, 1, or 2; r is 0, 1, 2, 3, 4, 5, and 6.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, T is C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 3-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace; Ring A is a 5-10 member heteroaryl group; Z is OH; R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cycloalkyl groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 The alkoxy, cyano, and amino groups are substituted; R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, 3-12 membered heterocyclic mercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace; R j and R k They may be the same or different, and each is independently selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, R j and R k Together with the atoms it is attached to, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl groups and 3-6-membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c -S(O)2R e C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic and 3-6 membered heterocyclic oxy groups are optionally selected from halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, R 5 And one of the R 6 Two Rs 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, two Rs 7 The atoms bonded to it form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R a and R d The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, OH, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; R b and R c They are the same or different, and each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or R b and R c Together with the nitrogen atom attached thereto, a 4-8 membered heterocyclic group is formed, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; R e Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, amino, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; n is 0, 1, or 2; r is 0, 1, 2, 3, 4, 5, and 6.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, two Rs 7 The atoms bonded to it form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; Preferably, R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; More preferably, R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, OH, cyano, and amino groups; Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; (3)R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-6 cycloalkyl and C 3-6 Halogenated cycloalkyl groups; (4) T is C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace; (5) Ring A is a 5-membered heteroaryl group; (6)R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxygen group, 3-12 membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace; R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups; R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, R 5 And one of the R 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, It meets one or more of the following conditions: (1) Each of the "C" mentioned 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 aminoalkyl and C 1-6 The alkyl group in "cyanoalkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl or sec-butyl; (2) Each of the "C" mentioned 1-6 Alkyl and C 1-6 The halogen in "halogenated alkyl" is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; (3) Each of the "C" mentioned 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-12 Cycloalkyloxy and C 3-12 The cycloalkyl group in "cycloalkyl mercapto" is independently C10. 3-8 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, or cyclopentyl; (4) The heteroatom in each of the "3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group and 3-6-membered heterocyclic oxy group" is independently N, O or S, for example N or O; the number of heteroatoms is independently 1 or 2; (5) The heterocyclic groups in each of the "3-12-membered heterocyclic oxygen, 3-12-membered heterocyclic mercapto, 3-12-membered heterocyclic group and 3-10-membered heterocyclic group" are independently 3-8-membered heterocyclic groups; (6) The heterocyclic groups in each of the "3-12-membered heterocyclic oxygen group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group and 3-6-membered heterocyclic oxygen group" are independently saturated or partially unsaturated monocyclic, bridged, fused or spirocyclic groups; (7) Each of the "5-10-membered heteroaryl and 5-8-membered heteroaryl" is independently a 5-membered heteroaryl; (8) In each of the "5-10-membered heteroaryl, 5-8-membered heteroaryl and 5-membered heteroaryl", the heteroatom is independently N, O or S, preferably N and O, for example N; the number of heteroatoms is independently 1, 2, 3 or 4, for example 2 or 3; (9) Each of the C's descriptions 3-10 The cycloalkenyl group is independently C 5-6 Cycloalkenyl; (10) Each of the C's descriptions 2-6 The alkenyl group is independently C 2-4 alkenyl; and (11) Each of the C's descriptions 2-6 The alkynyl group is independently C 2-4 Alkyne group.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, It meets one or more of the following conditions: (1) Each of the "C" mentioned 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 aminoalkyl and C 1-6 In "cyanoalkyl", the alkyl group is independently methyl; (2) Each of the "C" mentioned 1-6 Alkyl and C 1-6 The halogen in "halogenated alkyl" is independently fluorine; (3) Each of the "C" mentioned 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, C 3-6 cycloalkyl and C 3-6 The cycloalkyl group in "cycloalkyloxy" is independently cyclopentyl or cyclopropyl; (4) The heterocyclic groups in each of the "3-12-membered heterocyclic oxygen, 3-12-membered heterocyclic mercapto, 3-12-membered heterocyclic group and 3-10-membered heterocyclic group" are independently 4-8-membered heterocyclic groups; (5) The heterocyclic group in each of the described "3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group and 3-6-membered heterocyclic oxy group" is independently aza-heterobutyl, oxoheterobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiaranyl, tetrahydropyranyl, piperidinyl, piperazineyl, morpholinyl and (6) Each of the "5-10-membered heteroaryl, 5-8-membered heteroaryl and 5-membered heteroaryl" is independently selected from triazolyl, tetrazolyl, thiazolyl, pyrazolyl, imidazole and oxazolyl; (7) Each of the C's descriptions 2-6 The alkenyl group is independently a vinyl group; and (8) Each of the C's descriptions 2-6 The alkynyl group is independently an ethynyl group.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) T is selected from The a-terminus is attached to a phenyl group; m is 0, 1, 2, 3, 4, 5, and 6; h is 0, 1, 2, 3, and 4; j is 0, 1, 2, 3, and 4; R 8 Selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, and oxo; and (2)R 5 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 5-8 membered heteroaryl, 3-12 membered heterocyclic oxy group, 3-12 membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 heterocyclic, 5-8 heteroaryl, 3-12 heterocyclic hydroxyl, and 3-12 heterocyclic mercapto are optionally surrounded by one or more R g replace; R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a 、N(R b )C(O)R d C(O)NR b R c C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxy groups; R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, R 5 And one of the R 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted; R 7 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, OH, cyano, and amino groups; Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, characterized in that, It meets one or more of the following conditions: (1)R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group -S(O)2R e C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl mercapto, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxygen group and 3-8 membered heterocyclic mercapto group are optionally surrounded by one or more R g replace; Preferably, R 5 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxygen group and 3-8 membered heterocyclic thiol group are optionally surrounded by one or more R g replace; (2)R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Preferably, R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; and (3)R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, cyano and C 2-6 Alkyne group.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, It meets one or more of the following conditions: (1) T is selected from The a-terminus is connected to a phenyl group; j is 0, h is 0, m is 0, 1, or 2, and R... 7 For deuterium, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, -C 1-6 Alkylene-3-6-membered heterocyclic group or 3-6-membered heterocyclic group; (2) Ring A is selected from triazole, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, pyridinyl, Examples include triazolyl, imidazole, pyrazolyl, isoxazolyl, tetrazolyl, and pyridyl; (3)R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, 3-12-membered heterocyclic, 5-8-membered heteroaryl, 3-12-membered heterocyclic oxy, 3-12-membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkenyl, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy groups and 3-12-membered heterocyclic groups are optionally separated by one or more R groups. g replace; R j and R k Together with the atoms it is attached to, they form 3-6 membered heterocycles; R g They may be the same or different, and each is independently selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, amino, oxo, =NH, C(O)R a NR b R c 3-6 membered heterocyclic groups and 3-6 membered heterocyclic oxygen groups, wherein the C 1-6 Alkyl groups and 3-6-membered heterocyclic groups are optionally selected from halogens and C. 1-6 One or more substituents in the alkoxy group are substituted; R a and R d The same or different, and each independently selected from C 1-6 Alkyl groups and 3-6 membered heterocyclic groups; R b and R c Selected from H and C 1-6 Alkyl, or R b and R c Together with the nitrogen atom attached thereto, they form a 4-8 membered heterocycle; the 4-8 membered heterocycle is optionally selected from OH and C. 1-6 One or more substituents in the alkyl group are substituted; r is 0 or 1; (4)R 6 They may be the same or different, and each is independently selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, -S(O)2R e and C 3-6 cycloalkyl; R e Selected from C 1-6 alkyl; n is 0 or 1; (5) When R 5 and its adjacent R 6 Or two adjacent R 6 When atoms bonded to them form rings, they form 5-10 membered heterocycles, wherein the 5-10 membered heterocycle group is optionally selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and -C(O)-C 1-6 One or more substituents in the alkyl group are substituted; and (6) When R 7 and R 5 、or R 7 and R 6 When atoms connected to them form rings, they form 5-10 membered heterocycles.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, characterized in that, It meets one or more of the following conditions: (1) T is (2) Ring A is a triazole group or an imidazole group; (3)R 5 Selected from H, C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic, 5-8 membered heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 3-12 The cycloalkenyl and 3-12 membered heterocyclic groups are optionally separated by one or more R g Replace; R g They may be the same or different, and each is independently selected from -NH2, halogen, OH, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and oxo groups; (4)R 6 They may be the same or different, and each is independently selected from deuterium, halogens, and C. 1-6 Alkyl; n is 0 or 1; and (5)R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen and cyano groups.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) for (2) T is Preferred (3) Ring A is selected from Preferred (4)R 6 Selected from CH3, CN, (CH2)3OH, CHF2, CF3, Cl, S(O)2CH3, Br, D, F and cyclopropyl; n is 0 or 1; (5) When R 5 and one of its adjacent R 6 Or two adjacent R 6 And when the atoms connected to them form rings, their formation Indicates the key shared with ring A; (6) When R 7 and R 5 、or R 7 and R 6 And when the atoms connected to them form rings, their formation * indicates a site shared with T. Indicates the bond shared with ring A; and (7)R 5 Selected from H, (CH2) t NH2, O-(CH2) t NH2, (CH2) t OH, cyclopropyl, 11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (IIG): in, G is selected from non-existent, CR 7b R 7c NR 7e O and S; u is 1 and 2; v and m are independently 0, 1, and 2; R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; R 7e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Or, R 7b and R 7c The atoms bonded to it form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; Or, R 7a and R 5 、or R 7a And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group; R 1 R 2 R 3 R 4 R 5 R 6 R 7 Ring A and n are as defined in any one of claims 1-10.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II): in, R 1 R 2 R 3 R 4 R 5 R 6 Ring A and n are as defined in any one of claims 1-11; R 7a R 7b R 7c and R 7d As defined in claim 11.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (II-1), formula (II-2), or formula (II-3). in, R 1 R 2 R 3 R 4 R 5 R 6 R a R b R c R d and R g As defined in any one of claims 1-12; R 7a R 7b R 7c and R 7d As defined in claim 11 or 12; Preferably, R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, F, CH3, CH2OH, CH2CN, aziridine, piperidinyl, and Preferably, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl mercapto, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxygen group and 3-8 membered heterocyclic mercapto group are optionally surrounded by one or more R g replace; Preferably, R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Alternatively, R in equation (II-1) 7a and R 5 The atoms bonded to it form 4-12 membered heterocyclic groups; Alternatively, R in equation (II-2) 7a and R 5 、or R 5 and its adjacent R 6 Any group of atoms connected to it forms C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups; Alternatively, R in equation (II-3) 7a and R 6 、or R 5 and R 6 The atoms bonded to it form 4-12 membered heterocyclic groups; The above-mentioned C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents among cycloalkyl and 3-6 membered heterocyclic groups.

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (III). R 1 R 2 R 3 R 4 R 5 R 6 And T as defined in any one of claims 1-13.

15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein, The compound has the following structure:

16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

17. A compound of formula (C) or a pharmaceutically acceptable salt thereof, Where R A It is a hydroxyl protecting group, such as methyl, (trimethylsilyl)ethoxymethyl, tert-butyldimethylsilyl, methoxymethyl, 2-methoxyethoxymethyl or 2-tetrahydropyran; R 1 R 2 R 3 R 4 R 5 and R 6 As defined in claim 1.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (C) is selected from the group consisting of:

19. A method for preparing a compound of formula (IIIA), comprising reacting the compound of formula (A) with the compound of formula (B) in a cyclization reaction to obtain the compound of formula (C1), and then performing a deprotection reaction to obtain the compound of formula (IIIA), the reaction formula being as follows: in, R A It is a hydroxyl protecting group, such as methyl, (trimethylsilyl)ethoxymethyl, tert-butyldimethylsilyl, methoxymethyl, 2-methoxyethoxymethyl or 2-tetrahydropyran; R 1 R 2 R 3 R 4 and R 5 As defined in claim 1.

20. A pharmaceutical composition comprising at least a therapeutically effective amount of the compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

21. Use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 20 in the preparation of a medicament for inhibiting the Kv1.3 channel.

22. Use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, in the preparation of a medicament for the prevention and / or treatment of Kv1.3 channel-mediated diseases; preferably, the Kv1.3 channel-mediated diseases are autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer; more preferably, the Kv1.3 channel-mediated diseases are rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

23. Use in the preparation of a medicament for the prevention and / or treatment of an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease, or a cancer, for example, in the preparation of a medicament for the prevention and / or treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

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