Condensed tricyclic compound, preparation method thereof and application thereof in medicine

Abstract

The invention relates to a fused tricyclic compound, a preparation method thereof and its application in medicine. Specifically, the invention relates to a fused tricyclic compound represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound and its use as a therapeutic agent, especially as a TLR7 / 8 / 9 inhibitor and in the preparation of a drug for treating and / or preventing inflammatory and autoimmune diseases. The definitions of the groups in general formula (I) are as defined in the specification. #imgabs0#

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a fused tricyclic compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a fused tricyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, its use as a TLR7 / 8 / 9 inhibitor and its use in the preparation of a drug for treating and / or preventing inflammatory and autoimmune diseases. Background Art

[0002] Toll-like receptors (TLRs) are a class of evolutionarily conservative transmembrane innate immune receptors that participate in the first line of defense to protect human health and play an important role in identifying pathogen-associated molecular patterns (PAMPs) (Kawai, T., et al., Nature Immunol., 11, 2010, 373-384). TLRs are expressed in various immune cells and can be divided into two categories according to their expression sites: TLRs expressed on the cell membrane (TLR1 / 2 / 4 / 5 / 6) and TLRs expressed on the endosomal membrane (TLR3 / 7 / 8 / 9), which recognize different components and molecules in PAMPs respectively. Among them, TLR7 / 8 / 9 are mainly highly expressed in DC cells and B cells, TLR7 / 8 mainly recognizes ssRNA, and TLR9 mainly recognizes CpG-DNA. TLR7 / 8 / 9 is activated after binding to its ligand, binds to the adaptor protein MyD88 in the cytoplasm, activates the NF-κB and IRF pathways, activates DC cells, and produces type I interferon and other inflammatory cytokines. In B cells, TLR7 / 8 / 9 plays an important role in the production of antinuclear antibodies by B cells after combining with nucleic acid substances. In addition, type I interferon secreted by DC cells will also promote the further proliferation and activation of autoimmune B cells, thereby causing a series of inflammatory responses.

[0003] Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease. There are three main clinical first-line drugs for SLE: hormones, immunosuppressants and antimalarial drugs. Only one new drug, Belimumab, has been approved by the FDA in this century, but it has only moderate and delayed efficacy for a small number of SLE patients (Navarra, SV, et al., Lancet 2011, 377, 721), and the treatment methods are very limited. Therefore, there is an urgent need to improve new therapies for a larger proportion of patient populations, and they can be used safely and for a long time. The expression of TLR7 / 9 and type I interferon was found to be significantly upregulated in PBMCs of patients with systemic lupus erythematosus (SLE) (Beverly D.LC, et al., Mol Immunol., 2014, 61: 38-43). It has been reported that mice overexpressing TLR7 can aggravate autoimmune diseases and autoinflammation (Santiago-Raber ML, et al., J Immunol., 2008, 181: 1556-1562), while functional inhibition of TLR7 / 9 can alleviate B6-Fas lpr and BXSB lupus mice (Dwight H. Kono, et al., PNAS, 2009, 106(29):12061-12066). Given the close relationship between TLR7 / 8 / 9 and antinuclear antibodies and type I interferon, small molecule inhibitors targeting TLR7 / 8 / 9 are likely to have the potential to treat SLE.

[0004] Disclosed patent applications for TLR7 / 8 / 9 inhibitors include WO2019233941A1, WO2020020800A1, WO2018049089A1, WO2017106607A1, CN109923108A and WO2020048605A1, etc. Summary of the invention

[0005] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] Y is CR 4a or nitrogen atoms;

[0009] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0010] R 0 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR g R L, nitro, hydroxy, hydroxyalkyl and wherein the alkyl group is optionally selected from alkoxy, haloalkoxy, cyano, -NR 7 R 8 、-C(O)NR 7 R 8 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0011] L is selected from chemical bonds, NR L , an oxygen atom, a sulfur atom and an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0012] R g and R L are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0013] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0014] Each R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0015] R 2 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0016] R 3Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0017] Each R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0018] R 4a is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0019] Each R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, -NR c R d , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C(O)OR 6 、-C(O)NR 7 R 8 、-NR 7 R 8 、-S(O)2R 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0021] R c , Rd , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0022] or R c and R d Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0023] or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0024] R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0025] J is 0, 1, or 2;

[0026] k is 0, 1, or 2;

[0027] n is 0, 1, 2, 3 or 4;

[0028] s is 0, 1, 2, 3, or 4; and

[0029] t is 0, 1, 2, 3 or 4.

[0030] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0031] Y is CR 4a or nitrogen atoms;

[0032] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0033] R 0 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR g R L , nitro, hydroxy, hydroxyalkyl and

[0034] L is selected from chemical bonds, NR L , an oxygen atom, a sulfur atom and an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0035] R g and R L are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0036] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0037] Each R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0038] R 2 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0039] R 3 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0040] Each R 4are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0041] R 4a is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0042] Each R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, -NR c R d , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C(O)OR 6 、-C(O)NR 7 R 8 、-NR 7 R 8 、-S(O)2R 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0043] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0044] R c , R d , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0045] or R c and R dTogether with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0046] or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0047] R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0048] J is 0, 1, or 2;

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

[0050] n is 0, 1, 2, 3 or 4;

[0051] s is 0, 1, 2, 3, or 4; and

[0052] t is 0, 1, 2, 3 or 4.

[0053] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0054] Y is CR 4a or nitrogen atoms;

[0055] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0056] R 0 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR g R L , nitro, hydroxy, hydroxyalkyl and

[0057] L is selected from chemical bonds, NR L , an oxygen atom, a sulfur atom and an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0058] Rg and R L are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0059] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0060] Each R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0061] R 2 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0062] R 3 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0063] Each R 4are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0064] R 4a is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0065] Each R 5 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, an alkoxy, an oxo, a haloalkyl, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, a cycloalkyl, a heterocyclic radical, an aryl and a heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclic radical, an aryl and a heteroaryl are each independently selected from a halogen, an alkyl, an oxo, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -C(O)OR 6 、-C(O)NR 7 R 8 、-NR 7 R 8 、-S(O)2R 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0066] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0067] R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0068] or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0069] R9 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

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

[0071] k is 0, 1, or 2;

[0072] n is 0, 1, 2, 3 or 4;

[0073] s is 0, 1, 2, 3, or 4; and

[0074] t is 0, 1, 2, 3 or 4.

[0075] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, an alkoxy, an oxo, a haloalkyl, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, a cycloalkyl, a heterocyclic radical, an aryl and a heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclic radical, an aryl and a heteroaryl are each independently selected from a halogen, an alkyl, an oxo, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -C(O)OR 6 、-C(O)NR 7 R 8 、-NR 7 R 8 、-S(O)2R 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0076] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0077] R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0078] or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0079] R9 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0080] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0081]

[0082] in:

[0083] Ring A, R 0 , R 1 To R 4 , J, k, n and s are as defined in the general formula (I).

[0084] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0085]

[0086] in:

[0087] Ring A, R 0 , R 1 To R 4 , R 4a , J, k, n and s are as defined in the general formula (I).

[0088] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0089]

[0090] in:

[0091] Ring A, Ring C, L, R 1 To R 5 , R 4a , J, k, n, s and t are as defined in the general formula (I).

[0092] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IIG) or a pharmaceutically acceptable salt thereof:

[0093]

[0094] in:

[0095] Ring A, Ring C, L, R 1 To R 5 , J, k, n, s and t are as defined in the general formula (I).

[0096] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group, R c and R d are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl and 3 to 12 membered heterocyclic groups; preferably, each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 alkyl, amino and 3 to 6 membered heterocyclic groups; more preferably, each R 5 are the same or different and are each independently selected from a hydrogen atom, an amino group and a piperazinyl group.

[0097] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof:

[0098]

[0099] in:

[0100] Ring D is a 4- to 12-membered heterocyclic group containing at least one nitrogen atom;

[0101] R x Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0102] t is 1, 2, 3, or 4;

[0103] Ring A, Ring C, L, R 1 To R 5 , J, k, n and s are as defined in the general formula (I).

[0104] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof:

[0105]

[0106] in:

[0107] t is 1, 2, 3, or 4;

[0108] Ring A, Ring C, L, R 1 To R 5 , R d , J, k, n and s are as defined in the general formula (I).

[0109] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or pharmaceutically acceptable salts thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is a pyridyl group or More preferably, Ring A is pyridyl.

[0110] In some preferred embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or their pharmaceutically acceptable salts, wherein J is 0 or 1, and k is 1 or 2; preferably, J is 1 and k is 1.

[0111] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 Substitution, L, Ring C, R 5 , R 7 , R 8 , R g , R L and t are as defined in general formula (I); preferably, R 0 A hydrogen atom or L, Ring C, R 5 and t are as defined in general formula (I); most preferably, R 0 A hydrogen atom.

[0112] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein when Y is a nitrogen atom, R 0Selected from hydrogen atoms, C 1-6 Alkyl and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 Replacement; when Y is CR 4a When R 0 For-NR g R L or L, Ring C, R 4a , R 5 , R 7 , R 8 , R g , R L and t are as defined in the general formula (I).

[0113] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and L, Ring C, R 5 , R g , R L and t are as defined in the general formula (I).

[0114] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein when Y is a nitrogen atom, R 0 Selected from hydrogen atoms, C 1-6 Alkyl and When Y is CR 4a When R 0 For-NR g R L or L, Ring C, R 4a , R 5 , R g , R L and t are as defined in the general formula (I).

[0115] In some preferred embodiments of the present disclosure, when Y is a nitrogen atom, R 0 A hydrogen atom or C 1-6 Alkyl; when Y is CR 4a When R 0 For-NR g R L or L, Ring C, R 4a , R 5 , R g, R L and t are as defined in the general formula (I).

[0116] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 Substitution, L, Ring C, R 5 , R 7 , R 8 and t are as defined in general formula (I); preferably, R 0 A hydrogen atom or L, Ring C, R 5 and t are as defined in general formula (I); most preferably, R 0 A hydrogen atom.

[0117] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl and L, Ring C, R 5 and t are as defined in the general formula (I).

[0118] In some preferred embodiments of the present disclosure, the compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof, wherein R 0 For-NR g R L or L, Ring C, R 5 , R g , R L and t are as defined in the general formula (I).

[0119] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 7 and R 8 All are hydrogen atoms.

[0120] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R g is a hydrogen atom, R L A hydrogen atom or C1-6 Alkyl; preferably, R g and R L All are hydrogen atoms.

[0121] In some preferred embodiments of the present disclosure, the compounds represented by formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), and formula (VI), or pharmaceutically acceptable salts thereof, wherein L is NR L or C 1-6 Alkylene, R L A hydrogen atom or C 1-6 Alkyl; preferably, L is NR L or C 1-6 Alkylene, R L A hydrogen atom.

[0122] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein ring C is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; preferably, ring C is selected from 3-8 membered cycloalkyl, 3-6 membered heterocyclyl and 5 or 6 membered heteroaryl; more preferably, ring C is selected from tetrahydrofuranyl, bicyclo[2.2.2]octanyl and pyridinyl; most preferably, ring C is bicyclo[2.2.2]octanyl or pyridinyl.

[0123] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein L is NR L or C 1-6 Alkylene; R L A hydrogen atom or C 1-6 alkyl; and / or Ring C is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl.

[0124] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG), general formula (V), general formula (VI) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 Alkylene.

[0125] In some preferred embodiments of the present disclosure, in the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, ring C is a 5- to 10-membered heteroaryl group; preferably, ring C is a pyridyl group.

[0126] In some preferred embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 8-membered cycloalkyl group; preferably, ring C is a bicyclo[2.2.2]octanyl group.

[0127] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein L is NR L , R L A hydrogen atom or C 1-6 Alkyl; preferably, L is NR L , R L A hydrogen atom.

[0128] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 8-membered heterocyclic group; preferably, ring C is a 3- to 6-membered heterocyclic group; more preferably, ring C is a tetrahydrofuranyl group.

[0129] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein L is NR L , R L A hydrogen atom or C 1-6 alkyl; and / or Ring C is a 3- to 8-membered heterocyclic group.

[0130] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or pharmaceutically acceptable salts thereof, wherein each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, each R 1 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl.

[0131] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 alkyl and 3 to 12 membered heterocyclic group; preferably, R 2 C 1-6 alkyl or a 3- to 6-membered heterocyclic group; more preferably, R 2 is isopropyl or tetrahydropyranyl (e.g. ).

[0132] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 2 C 1-6 alkyl.

[0133] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 3 A hydrogen atom.

[0134] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or pharmaceutically acceptable salts thereof, wherein each R 4 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 4 A hydrogen atom.

[0135] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4a A hydrogen atom.

[0136] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group, R c and R d are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl and 3 to 12 membered heterocyclic groups; preferably, each R 5are the same or different and are each independently selected from a hydrogen atom, -NR c R d and a 3- to 6-membered heterocyclic group, R c and R d are the same or different and are each independently a hydrogen atom or a C 1-6 More preferably, each R 5 are the same or different and are each independently selected from a hydrogen atom, an amino group and a piperazinyl group.

[0137] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 alkyl and 3 to 12 membered heterocyclic groups; preferably, each R 5 are the same or different and are each independently a hydrogen atom or a 3- to 6-membered heterocyclic group; more preferably, each R 5 are the same or different and are each independently a hydrogen atom or a piperazinyl group.

[0138] In some preferred embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 5 A hydrogen atom.

[0139] In some preferred embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 5 A hydrogen atom.

[0140] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 5 A hydrogen atom.

[0141] In some preferred embodiments of the present disclosure, the compounds represented by formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) or their pharmaceutically acceptable salts, wherein n is 0, 1, 2, 3 or 4; preferably, n is 0, 1 or 2.

[0142] In some preferred embodiments of the present disclosure, the compounds represented by formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) or their pharmaceutically acceptable salts, wherein s is 0, 1, 2, 3 or 4; preferably, s is 0 or 1; more preferably, s is 0.

[0143] In some preferred embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein t is 0, 1, 2, 3 or 4; preferably, t is 0, 1 or 2.

[0144] In some preferred embodiments of the present disclosure, the compound represented by general formula (V) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein t is 1, 2, 3 or 4; preferably, t is 1 or 2; more preferably, t is 1.

[0145] In some preferred embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein ring D is a 4- to 12-membered heterocyclic group containing at least one nitrogen atom; preferably, ring D is a 4- to 6-membered heterocyclic group containing at least one nitrogen atom; more preferably, ring D is a piperazinyl group.

[0146] In some preferred embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R d Selected from hydrogen atoms, C 1-6 alkyl and 3 to 12 membered heterocyclic group; preferably, R d A hydrogen atom.

[0147] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group; R c and R d are the same or different and are each independently selected from a hydrogen atom, a C 1-6alkyl and 3 to 12 membered heterocyclyl; t is 0, 1, 2, 3 or 4.

[0148] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group; R c and R d are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl and 3 to 12 membered heterocyclyl; t is 0, 1 or 2.

[0149] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino and 3- to 6-membered heterocyclic groups; t is 0, 1 or 2.

[0150] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, wherein each R 5 The same or different, and each independently is -NR c R d or a 3- to 6-membered heterocyclic group; R c and R d are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; t is 1.

[0151] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or pharmaceutically acceptable salts thereof, wherein each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; n is 0, 1 or 2.

[0152] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; n is 0, 1 or 2.

[0153] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or pharmaceutically acceptable salts thereof, wherein each R 4 The same or different, and each independently is C 1-6 Alkyl; s is 0, 1, 2, 3 or 4.

[0154] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) or pharmaceutically acceptable salts thereof, wherein each R 4 The same or different, and each independently is C 1-6 Alkyl; s is 0 or 1.

[0155] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0156] Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group;

[0157] Y is CR 4a or nitrogen atoms;

[0158] R 4a is a hydrogen atom;

[0159] R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 replace;

[0160] L is C 1-6 Alkylene or NR L ;

[0161] R g is a hydrogen atom;

[0162] R L A hydrogen atom or C 1-6 alkyl;

[0163] Ring C is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0164] Each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group;

[0165] R c and R d are the same or different and are each independently selected from a hydrogen atom, C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0166] Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0167] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0168] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0169] Each R 4 The same or different, and each independently is C 1-6 alkyl;

[0170] R 7 and R 8 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0171] J is 1, and k is 1;

[0172] n is 0, 1 or 2;

[0173] s is 0, 1, 2, 3, or 4; and

[0174] t is 0, 1, 2, 3 or 4.

[0175] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0176] Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group;

[0177] Y is CR 4a or nitrogen atoms;

[0178] R 4a is a hydrogen atom;

[0179] R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and

[0180] L is C 1-6 Alkylene or NR L ;

[0181] R g is a hydrogen atom;

[0182] R L A hydrogen atom or C 1-6 alkyl;

[0183] Ring C is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0184] Each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group, R c and R d are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0185] Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0186] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0187] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0188] Each R 4 The same or different, and each independently is C 1-6 alkyl;

[0189] J is 1, and k is 1;

[0190] n is 0, 1 or 2;

[0191] s is 0, 1, 2, 3, or 4; and

[0192] t is 0, 1, 2, 3 or 4.

[0193] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0194] Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group;

[0195] Y is CR 4a or nitrogen atoms;

[0196] R 4a is a hydrogen atom;

[0197] R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and

[0198] L is C 1-6 Alkylene or NR L ;

[0199] R g is a hydrogen atom;

[0200] R L A hydrogen atom or C 1-6 alkyl;

[0201] Ring C is a 5- to 10-membered heteroaryl or a 3- to 8-membered heterocyclyl;

[0202] Each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0203] Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0204] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0205] R 3 Selected from hydrogen atoms, halogens, C 1-6Alkyl and halogenated C 1-6 alkyl;

[0206] Each R 4 The same or different, and each independently is C 1-6 alkyl;

[0207] J is 1, and k is 1;

[0208] n is 0, 1 or 2;

[0209] s is 0, 1, 2, 3, or 4; and

[0210] t is 0, 1, 2, 3 or 4.

[0211] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0212] Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group;

[0213] Y is CR 4a or nitrogen atoms;

[0214] R 4a is a hydrogen atom;

[0215] R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and

[0216] L is NR L ;

[0217] R g is a hydrogen atom;

[0218] R L A hydrogen atom or C 1-6 alkyl;

[0219] Ring C is a 3- to 8-membered heterocyclic group;

[0220] Each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0221] Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0222] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C1-6 alkyl;

[0223] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0224] Each R 4 The same or different, and each independently is C 1-6 alkyl;

[0225] J is 1, and k is 1;

[0226] n is 0, 1 or 2;

[0227] s is 0, 1, 2, 3, or 4; and

[0228] t is 0, 1, 2, 3 or 4.

[0229] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0230] Ring A is pyridyl or

[0231] R 0 Selected from hydrogen atoms, C 1-6 Alkyl and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 replace;

[0232] L is C 1-6 Alkylene;

[0233] Ring C is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0234] Each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR c R d and a 3- to 12-membered heterocyclic group;

[0235] R c and R d are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0236] Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C1-6 alkyl;

[0237] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0238] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0239] Each R 4 The same or different, and each independently is C 1-6 alkyl;

[0240] R 7 and R 8 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0241] J is 1, and k is 1;

[0242] n is 0, 1 or 2;

[0243] s is 0 or 1; and

[0244] t is 0, 1, or 2.

[0245] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0246] Ring A is pyridyl or

[0247] R 0 Selected from hydrogen atoms, C 1-6 Alkyl and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 replace;

[0248] L is C 1-6 Alkylene;

[0249] Ring C is selected from tetrahydrofuranyl, bicyclo[2.2.2]octanyl and pyridinyl;

[0250] Each R 5 The same or different, and each independently is -NR c R d or a 3- to 6-membered heterocyclic group;

[0251] R c and R dare the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0252] R 1 C 1-6 alkyl;

[0253] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0254] R 3 is a hydrogen atom;

[0255] R 7 and R 8 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0256] J is 1, and k is 1;

[0257] n is 0, 1 or 2;

[0258] s is 0; and

[0259] t is 1.

[0260] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0261] Ring A is pyridyl;

[0262] R 0 Selected from hydrogen atoms, C 1-6 Alkyl and

[0263] L is C 1-6 Alkylene;

[0264] Ring C is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl;

[0265] Each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino and 3- to 6-membered heterocyclic groups;

[0266] Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0267] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6Alkyl and 3 to 12 membered heterocyclic group;

[0268] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0269] Each R 4 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0270] J is 1, and k is 1;

[0271] n is 0, 1 or 2;

[0272] s is 1; and

[0273] t is 2.

[0274] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0275] Ring A is pyridyl;

[0276] R 0 Selected from hydrogen atoms, C 1-6 Alkyl and

[0277] L is C 1-6 Alkylene;

[0278] Ring C is a 5- to 10-membered heteroaryl group;

[0279] Each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0280] Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0281] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0282] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0283] Each R 4are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0284] J is 1, and k is 1;

[0285] n is 0, 1 or 2;

[0286] s is 1; and

[0287] t is 2.

[0288] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0289] Ring A is pyridyl or

[0290] R 0 A hydrogen atom or

[0291] L is C 1-6 Alkylene;

[0292] Ring C is bicyclo[2.2.2]octanyl or pyridinyl;

[0293] R 1 C 1-6 alkyl;

[0294] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0295] R 3 is a hydrogen atom;

[0296] Each R 5 The same or different, and each independently is -NR c R d or a 3- to 6-membered heterocyclic group;

[0297] R c and R d are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0298] t is 1;

[0299] J is 1, and k is 1;

[0300] n is 0, 1 or 2; and

[0301] s is 0.

[0302] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0303] Ring A is pyridyl or

[0304] R 0 A hydrogen atom or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 replace;

[0305] R 1 C 1-6 alkyl;

[0306] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0307] R 3 is a hydrogen atom;

[0308] R 7 and R 8 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0309] J is 1, and k is 1;

[0310] n is 0, 1 or 2; and

[0311] s is 0.

[0312] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0313] Ring A is pyridyl;

[0314] R 0 is a hydrogen atom;

[0315] R 1 C 1-6 alkyl;

[0316] R 2 C 1-6 alkyl;

[0317] R 3 is a hydrogen atom;

[0318] J is 1, and k is 1;

[0319] n is 0, 1 or 2; and

[0320] s is 0.

[0321] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIG) or a pharmaceutically acceptable salt thereof, wherein:

[0322] Ring A is pyridyl;

[0323] L is C 1-6 Alkylene;

[0324] Ring C is selected from 3- to 8-membered cycloalkyl, 3- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl;

[0325] Each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino and 3- to 6-membered heterocyclic groups;

[0326] Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0327] R 2 Selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0328] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0329] J is 1, and k is 1;

[0330] n is 0, 1 or 2;

[0331] s is 0; and

[0332] t is 0, 1, or 2.

[0333] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIG) or a pharmaceutically acceptable salt thereof, wherein:

[0334] Ring A is pyridyl;

[0335] L is C 1-6 Alkylene;

[0336] Ring C is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl;

[0337] Each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino and 3- to 6-membered heterocyclic groups;

[0338] Each R 1are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0339] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0340] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0341] Each R 4 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0342] J is 1, and k is 1;

[0343] n is 0, 1 or 2;

[0344] s is 1; and

[0345] t is 2.

[0346] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIG) or a pharmaceutically acceptable salt thereof, wherein:

[0347] Ring A is pyridyl;

[0348] L is C 1-6 Alkylene;

[0349] Ring C is a 5- to 10-membered heteroaryl group;

[0350] Each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0351] Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0352] R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group;

[0353] R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C1-6 alkyl;

[0354] Each R 4 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0355] J is 1, and k is 1;

[0356] n is 0, 1 or 2;

[0357] s is 1; and

[0358] t is 2.

[0359] In some preferred embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein:

[0360] Ring A is pyridyl;

[0361] L is C 1-6 Alkylene;

[0362] Ring C is pyridyl;

[0363] Ring D is a 4- to 6-membered heterocyclic group containing at least one nitrogen atom;

[0364] R x Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0365] R 1 C 1-6 alkyl;

[0366] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0367] R 3 is a hydrogen atom;

[0368] J is 1, and k is 1;

[0369] n is 0, 1 or 2;

[0370] s is 0; and

[0371] t is 1.

[0372] In some preferred embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein:

[0373] Ring A is pyridyl;

[0374] L is C 1-6 Alkylene;

[0375] Ring C is pyridyl;

[0376] Ring D is a 4- to 6-membered heterocyclic group containing at least one nitrogen atom;

[0377] R x Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0378] R 5 is a hydrogen atom;

[0379] Each R 1 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0380] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0381] R 3 is a hydrogen atom;

[0382] R 4 is a hydrogen atom;

[0383] J is 1, and k is 1;

[0384] n is 0, 1 or 2;

[0385] s is 1; and

[0386] t is 2.

[0387] In some preferred embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein:

[0388] Ring A is pyridyl;

[0389] L is C 1-6 Alkylene;

[0390] Ring C is a 3- to 8-membered cycloalkyl group;

[0391] R 1 C 1-6 alkyl;

[0392] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0393] R 3 is a hydrogen atom; J is 1, and k is 1;

[0394] n is 0, 1 or 2;

[0395] s is 0; and

[0396] t is 1.

[0397] In some preferred embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein:

[0398] Ring A is pyridyl;

[0399] L is C 1-6 Alkylene;

[0400] Ring C is a 3- to 8-membered cycloalkyl group;

[0401] R 5 is a hydrogen atom;

[0402] Each R 1 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0403] R 2 C 1-6 Alkyl or 3 to 6 membered heterocyclic group;

[0404] R 3 is a hydrogen atom;

[0405] R 4 is a hydrogen atom;

[0406] J is 1, and k is 1;

[0407] n is 0, 1 or 2;

[0408] s is 1; and

[0409] t is 2.

[0410] Table A Typical compounds of the present disclosure include, but are not limited to:

[0411]

[0412]

[0413]

[0414] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof:

[0415]

[0416] in:

[0417] Ring A, R 1 To R 4 , J, k, n and s are as defined for the compound of formula (II).

[0418] Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a pharmaceutically acceptable salt thereof:

[0419]

[0420] in:

[0421] Ring A, R 1 To R 4 , R 4a , R L , J, k, n and s are as defined for the compound of formula (IV).

[0422] Another aspect of the present disclosure relates to a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof:

[0423]

[0424] in:

[0425] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0426] Ring A, R 1 To R 4 , J, k, n and s are as defined for the compound of formula (II).

[0427] Another aspect of the present disclosure relates to a compound represented by the general formula (VA) or a pharmaceutically acceptable salt thereof:

[0428]

[0429] in:

[0430] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0431] Ring D is a 4- to 12-membered heterocyclic group containing at least one nitrogen atom;

[0432] t is 1, 2, 3, or 4;

[0433] Ring A, Ring C, L, R 1 To R 5 , J, k, n and s are as defined in the general formula (V).

[0434] Another aspect of the present disclosure relates to a compound represented by general formula (VIA) or a pharmaceutically acceptable salt thereof:

[0435]

[0436] in:

[0437] R wis an amino protecting group, preferably tert-butyloxycarbonyl;

[0438] t is 1, 2, 3, or 4;

[0439] Ring A, Ring C, L, R 1 To R 5 , R d , J, k, n and s are as defined in the general formula (VI).

[0440] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIA) or a pharmaceutically acceptable salt thereof, wherein:

[0441] Ring A is pyridyl or

[0442] R 1 C 1-6 alkyl;

[0443] R 2 C 1-6 alkyl;

[0444] R 3 is a hydrogen atom;

[0445] J is 1, and k is 1;

[0446] n is 0, 1 or 2; and

[0447] s is 0.

[0448] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0449]

[0450]

[0451]

[0452] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0453]

[0454] The compound of general formula (IIA) or a pharmaceutically acceptable salt thereof and R 0 -X undergoes a nucleophilic substitution reaction to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0455] in:

[0456] X is a leaving group, preferably a halogen, more preferably bromine or iodine;

[0457] R0 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl and wherein the alkyl group is optionally selected from alkoxy, haloalkoxy, cyano, -NR 7 R 8 、-C(O)NR 7 R 8 , cycloalkyl, heterocyclic, aryl and heteroaryl, preferably, R 0 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl and

[0458] L is a chemical bond or an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0459] Ring A, Ring C, R 1 To R 5 , n, s, t, J and k are as defined for the compound of formula (II).

[0460] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG) or a pharmaceutically acceptable salt thereof, the method comprising:

[0461]

[0462] The compound of general formula (IIA) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with the compound of general formula (XI) to obtain a compound of general formula (IIG) or a pharmaceutically acceptable salt thereof,

[0463] in:

[0464] X is a leaving group, preferably a halogen, more preferably bromine or iodine;

[0465] L is a chemical bond or an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0466] Ring A, Ring C, R 1 To R 5 , n, s, t, J and k are as defined for the compound of formula (IIG).

[0467] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0468]

[0469] The compound of general formula (IIB) or its pharmaceutically acceptable salt is deprotected by removing the protecting group R w , to obtain a compound of formula (IIA) or a pharmaceutically acceptable salt thereof,

[0470] in:

[0471] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0472] Ring A, R 1 To R 4 , n, s, J and k are as defined in the general formula (IIA).

[0473] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0474]

[0475] The compound of general formula (IVA) or a pharmaceutically acceptable salt thereof undergoes a reductive amination reaction with the compound of general formula (IVB) to obtain a compound of general formula (IV) or a pharmaceutically acceptable salt thereof,

[0476] in:

[0477] L is NR L ;

[0478] R L is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; preferably, R L A hydrogen atom or C 1-6 alkyl;

[0479] Ring A, Ring C, R 1 To R 5 , R 4a , n, s, t, J and k are as defined in the general formula (IV).

[0480] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0481]

[0482] The compound of general formula (VA) or its pharmaceutically acceptable salt is deprotected by removing the protecting group R w , optionally further with an alkylating agent R x -W reaction to obtain a compound of formula (V) or a pharmaceutically acceptable salt thereof,

[0483] in:

[0484] W is a leaving group, preferably a halogen;

[0485] R x Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0486] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0487] Ring D is a 4- to 12-membered heterocyclic group containing at least one nitrogen atom;

[0488] t is 1, 2, 3, or 4;

[0489] Ring A, Ring C, L, R 1 To R 5 , J, k, n and s are as defined in the general formula (V).

[0490] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:

[0491]

[0492] The compound of general formula (VIA) or its pharmaceutically acceptable salt is deprotected by removing the protecting group R w , to obtain a compound of formula (VI) or a pharmaceutically acceptable salt thereof,

[0493] in:

[0494] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0495] t is 1, 2, 3, or 4;

[0496] Ring A, Ring C, L, R 1 To R 5 , R d , J, k, n and s are as defined in the general formula (VI).

[0497] Another aspect of the present disclosure relates to a pharmaceutical composition, comprising a compound of the present disclosure represented by formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0498] The present disclosure further relates to the use of compounds shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for inhibiting TLR7 and / or TLR8 and / or TLR9.

[0499] The present disclosure further relates to the use of compounds shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for inhibiting TLR7, TLR8 or TLR9; preferably, the use of compounds in the preparation of drugs for inhibiting TLR7, or in the preparation of drugs for inhibiting TLR7 and TLR8, or in the preparation of drugs for inhibiting TLR7 and TLR9.

[0500] The present disclosure further relates to the use of compounds shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for inhibiting TLR7, TLR8 and TLR9.

[0501] The present disclosure further relates to the use of compounds shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing inflammatory or autoimmune diseases; wherein the inflammatory or autoimmune diseases are preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjogren's syndrome.

[0502] The present disclosure further relates to a method for inhibiting TLR7 and / or TLR8 and / or TLR9, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0503] The present disclosure further relates to a method for inhibiting TLR7, TLR8 or TLR9, preferably a method for inhibiting TLR7, preferably a method for inhibiting TLR7 and TLR8, preferably a method for inhibiting TLR7 and TLR9, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0504] The present disclosure further relates to a method for inhibiting TLR7, TLR8 and TLR9, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0505] The present disclosure further relates to a method for treating and / or preventing inflammatory or autoimmune diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjogren's syndrome.

[0506] The present disclosure further relates to a compound of formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0507] The present disclosure further relates to compounds shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7 and / or TLR8 and / or TLR9.

[0508] The present disclosure further relates to a compound shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for inhibiting TLR7, TLR8 or TLR9; preferably for inhibiting TLR7, or for inhibiting TLR7 and TLR8, or for inhibiting TLR7 and TLR9.

[0509] The present disclosure further relates to a compound shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for inhibiting TLR7, TLR8 and TLR9.

[0510] The present disclosure further relates to a compound shown in formula (I), formula (II), formula (IIG), formula (III), formula (IV), formula (V), formula (VI) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing inflammatory or autoimmune diseases; wherein the inflammatory or autoimmune diseases are preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjogren's syndrome.

[0511] In view of their activity as selective inhibitors of TLR7, TLR8 or TLR9, the compounds of Formula (I), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (V), Formula (VI) and Table A can be used to treat TLR7, TLR8 or TLR9 family receptor-related diseases, including but not limited to: inflammatory diseases (such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic transplant rejection, chronic obstructive pulmonary disease); autoimmune diseases (such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis); autoinflammatory diseases (including Cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF); MF), adult-onset Still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis); metabolic diseases (including type 2 diabetes, atherosclerosis, myocardial infarction); destructive bone disorders (such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder); proliferative disorders (such as acute myeloid leukemia, chronic myeloid leukemia); angiogenic disorders (such as angiogenic disorders of ocular neovascularization and infantile hemangioma); infectious diseases (such as sepsis, septic shock and shigellosis); neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury); neoplastic diseases (such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma) and viral diseases (such as HIV infection and CMV retinitis, AIDS).

[0512] More specifically, specific conditions or diseases that may be treated with the compounds of the present disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythema, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, syndrome), gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury; angiogenesis disorders, including ocular neovascularization and infantile hemangioma; viral diseases, including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignant tumors and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular proliferation, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, disorders associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. In a preferred method of treatment, the disorder is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. In an alternative preferred method of treatment, the disease is ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the disease is multiple myeloma.

[0513] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0514] As a general guide, the active compound is preferably in a unit dose form or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0515] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0516] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0517] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0518] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0519] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0520] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may also contain a sweetener, a flavoring agent, a preservative, and an antioxidant. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0521] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0522] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0523] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0524] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0525] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0526] Terminology

[0527] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0528] The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. Most preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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 the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0529] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0530] The term "heteroalkyl" refers to an alkyl group in which one or more (preferably 1, 2, 3, 4 or 5) -CH2- are replaced by heteroatoms selected from N, O and S; wherein the alkyl group is as defined above. The heteroalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of a deuterium atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.

[0531] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 The term "alkenyl" refers to an alkylene group (alkylene group). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0532] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0533] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a deuterium atom, a halogen, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl.

[0534] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0535] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between the rings, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl or a multi-spirocycloalkyl (such as a double spiral cycloalkyl), preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan or 6 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0536]

[0537] The term "condensed cycloalkyl" refers to 5 to 20 yuan, a full carbon polycyclic group sharing a pair of adjacent carbon atoms between the rings, wherein one or more rings may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into polycyclic condensed cycloalkyls such as bicyclic, tricyclic, tetracyclic, preferably bicyclic or tricyclic condensed cycloalkyls, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan of bicyclic alkyl. Non-limiting examples of condensed cycloalkyl include:

[0538]

[0539] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, polycyclic bridged cycloalkyls such as bicyclic, tricyclic, and tetracyclic can be divided, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls include:

[0540]

[0541] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0542] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0543] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, it has 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms (i.e., 3- to 12-membered heterocyclyl) (e.g., 4- to 12-membered heterocyclyl containing at least one nitrogen atom); more preferably, it has 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g., 1, 2 and 3) (i.e., 3- to 8-membered heterocyclyl); more preferably, it has 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e., 3- to 6-membered heterocyclyl) (e.g., 4- to 6-membered heterocyclyl containing at least one nitrogen atom); and most preferably, it has 5 or 6 ring atoms, of which 1-3 are heteroatoms (i.e., 5- or 6-membered heterocyclyl). Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0544] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a monospiro heterocyclic group or a polyspiro heterocyclic group (e.g., a bispiro heterocyclic group), preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0545]

[0546] The term "fused heterocyclic radical" refers to 5 to 20 yuan, a polycyclic heterocyclic group sharing a pair of adjacent atoms between the rings, 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, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into polycyclic fused heterocyclic radicals such as bicyclic, tricyclic, tetracyclic, preferably bicyclic or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples of fused heterocyclic groups include:

[0547]

[0548] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

[0549]

[0550] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0551] wait.

[0552] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0553] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0554]

[0555] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0556] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably a 5-10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) heteroaryl, more preferably a 5-membered or 6-membered heteroaryl, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0557]

[0558] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0559] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing a hydrogen atom, or residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, namely "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0560] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and p-methoxybenzyl, etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

[0561] The term "hydroxy protecting group" refers to a group introduced on a hydroxy group that is easily removed and is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0562] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0563] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0564] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0565] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0566] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0567] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0568] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0569] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0570] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0571] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0572] The term "hydroxy" refers to -OH.

[0573] The term "thiol" refers to -SH.

[0574] The term "amino" refers to -NH2.

[0575] The term "cyano" refers to -CN.

[0576] The term "nitro" refers to -NO2.

[0577] The term "oxo" or "oxo" refers to "=0".

[0578] The term "carbonyl" refers to C=O.

[0579] The term "aldehyde" refers to -C(O)H;

[0580] The term "carboxy" refers to -C(O)OH.

[0581] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0582] In the chemical structures of the compounds disclosed herein, the bonds Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.

[0583] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, keto-enol, imine-enamine, lactam-lactim isomerization. An example of a lactam-lactim equilibrium is between A and B as shown below:

[0584]

[0585] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomer.

[0586] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 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. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacodynamic, pharmacokinetics or receptor studies.

[0587] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally (optionally) substituted with halogen or cyano" 1-6 "Alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0588] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0589] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0590] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0591] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0592] The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0593] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0594] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0595] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0596] Synthesis method of the disclosed compound

[0597] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0598] Solution 1

[0599] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0600]

[0601] The compound of general formula (IIB) or its pharmaceutically acceptable salt is deprotected under acidic conditions. w , to obtain a compound of formula (IIA) or a pharmaceutically acceptable salt thereof;

[0602] The compound of general formula (IIA) or a pharmaceutically acceptable salt thereof and R0 -X, under alkaline conditions, undergoes a nucleophilic substitution reaction to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0603] in:

[0604] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0605] X is a leaving group, preferably a halogen, more preferably bromine or iodine;

[0606] R 0 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl and wherein the alkyl group is optionally selected from alkoxy, haloalkoxy, cyano, -NR 7 R 8 、-C(O)NR 7 R 8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R 0 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl and

[0607] L is a chemical bond or an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0608] Ring A, Ring C, R 1 To R 5 , n, s, t, J and k are as defined for the compound of formula (II).

[0609] Solution 2

[0610] The present invention discloses a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0611]

[0612] The compound of general formula (IVA) or its pharmaceutically acceptable salt and the compound of general formula (IVB) undergo a reductive amination reaction in the presence of a reducing agent to obtain a compound of general formula (IV) or its pharmaceutically acceptable salt.

[0613] in:

[0614] L is NR L ;

[0615] R Lis selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl. L A hydrogen atom or C 1-6 alkyl;

[0616] Ring A, Ring C, R 1 To R 5 , R 4a , n, s, t, J and k are as defined in the general formula (IV).

[0617] Option 3

[0618] The present invention discloses a method for preparing a compound represented by general formula (IIG) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0619]

[0620] The compound of general formula (IIA) or its pharmaceutically acceptable salt and the compound of general formula (XI) undergo nucleophilic substitution reaction under alkaline conditions to obtain the compound of general formula (IIG) or its pharmaceutically acceptable salt.

[0621] in:

[0622] X is a leaving group, preferably a halogen, more preferably bromine or iodine;

[0623] L is a chemical bond or an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0624] Ring A, Ring C, R 1 To R 5 , n, s, t, J and k are as defined for the compound of formula (IIG).

[0625] Option 4

[0626] The present invention discloses a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0627]

[0628] The compound of general formula (VA) or its pharmaceutically acceptable salt is deprotected under acidic conditions. w , optionally further with an alkylating agent R x -W reacts under alkaline conditions to obtain a compound of formula (V) or a pharmaceutically acceptable salt thereof,

[0629] in:

[0630] W is a leaving group, preferably a halogen;

[0631] R x Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0632] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0633] Ring D is a 4- to 12-membered heterocyclic group containing at least one nitrogen atom;

[0634] t is 1, 2, 3, or 4;

[0635] Ring A, Ring C, L, R 1 To R 5 , J, k, n and s are as defined in the general formula (V).

[0636] Option 5

[0637] The present invention discloses a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0638]

[0639] The compound of general formula (VIA) or a pharmaceutically acceptable salt thereof is deprotected under acidic conditions by removing the protecting group R w , to obtain a compound of formula (VI) or a pharmaceutically acceptable salt thereof,

[0640] in:

[0641] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0642] t is 1, 2, 3, or 4;

[0643] Ring A, Ring C, L, R 1 To R 5 , R d , J, k, n and s are as defined in the general formula (VI).

[0644] Option 6

[0645] The present invention discloses a method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0646]

[0647] The compound of general formula (IIB) or its pharmaceutically acceptable salt is deprotected under acidic conditions. w , to obtain a compound of formula (IIA) or a pharmaceutically acceptable salt thereof,

[0648] in:

[0649] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0650] Ring A, R 1 To R 4 , n, s, J and k are as defined in the general formula (IIA).

[0651] Option 7

[0652] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0653]

[0654] The compound of general formula (IIA) or a pharmaceutically acceptable salt thereof and R 0 -X, under alkaline conditions, undergoes a nucleophilic substitution reaction to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0655] in:

[0656] X is a leaving group, preferably a halogen, more preferably bromine or iodine;

[0657] R 0 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl and wherein the alkyl group is optionally selected from alkoxy, haloalkoxy, cyano, -NR 7 R 8 、-C(O)NR 7 R 8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R 0 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl and

[0658] L is a chemical bond or an alkylene group, wherein the alkylene group is optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0659] Ring A, Ring C, R 1 To R 5 , n, s, t, J and k are as defined for the compound of formula (II).

[0660] Option 8

[0661] The present invention discloses a method for preparing a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0662]

[0663] The compound of general formula (IIa) or a pharmaceutically acceptable salt thereof undergoes an addition reaction with a compound of general formula (IIb) (preferably in the presence of cuprous iodide, bis(triphenylphosphine)palladium dichloride and triethylamine) to obtain a compound of formula (IIab) or a pharmaceutically acceptable salt thereof,

[0664] The compound of general formula (IIab) or a pharmaceutically acceptable salt thereof undergoes an intramolecular cyclization reaction under alkaline conditions to obtain a compound of formula (IIaab) or a pharmaceutically acceptable salt thereof,

[0665] The compound of the general formula (IIaab) or a pharmaceutically acceptable salt thereof reacts with a halogenating agent (such as N-bromosuccinimide) to obtain a compound of the formula (IIaabb) or a pharmaceutically acceptable salt thereof,

[0666] A compound of the general formula (IIaabb) or a pharmaceutically acceptable salt thereof is subjected to a coupling reaction with isopropenylboronic acid pinacol ester or 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (preferably in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and anhydrous tripotassium phosphate) to obtain a compound of the formula (IIaaabb) or a pharmaceutically acceptable salt thereof,

[0667] The compound of general formula (IIaaabb) or a pharmaceutically acceptable salt thereof (preferably in palladium carbon and hydrogen atmosphere) is subjected to reduction reaction to obtain a compound of formula (IIB) or a pharmaceutically acceptable salt thereof,

[0668] in:

[0669] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0670] R t or R tt is halogen, preferably bromine;

[0671] R 2 'for

[0672] R 2 isopropyl or

[0673] Ring A, R 1 , R 3 , R 4 , n, s, J and k are as defined in the general formula (IIB).

[0674] Option 9

[0675] The present invention discloses a method for preparing a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0676]

[0677] The compound of the general formula (IIa) or a pharmaceutically acceptable salt thereof undergoes a Larock indole synthesis reaction with a compound of the general formula (IIbb) (preferably in the presence of anhydrous lithium chloride, potassium carbonate and tetrakis(triphenylphosphine)palladium) to obtain a compound of the general formula (IIB) or a pharmaceutically acceptable salt thereof,

[0678] in:

[0679] R w is an amino protecting group, preferably tert-butyloxycarbonyl;

[0680] R t is halogen, preferably bromine;

[0681] Ring A, R 1 To R 4 , n, s, J and k are as defined in the general formula (IIB).

[0682] In the above synthesis scheme, the reagents providing acidic conditions include but are not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf, preferably trifluoroacetic acid or a 1,4-dioxane solution of hydrogen chloride.

[0683] In the above synthesis scheme, the reagents providing alkaline conditions include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium acetate, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide. The inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate and sodium acetate.

[0684] In the above synthesis scheme, the reductive amination reaction is preferably carried out in the presence of a reducing agent and a weak acid; the reducing agent includes but is not limited to sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium acetylborohydride, etc., preferably sodium triacetoxyborohydride; the weak acid is preferably acetic acid.

[0685] The above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof. DETAILED DESCRIPTION

[0686] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0687] Example

[0688] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0689] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0690] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0691] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0692] High performance liquid chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

[0693] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0694] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0695] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0696] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0697] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0698] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0699] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0700] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0701] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0702] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0703] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0704] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0705] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0706] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0707] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0708] Example 1

[0709] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 1

[0710]

[0711] first step

[0712] 2,6-Dimethyl-4-((trimethylsilyl)ethynyl)pyridine 1c

[0713] 4-Bromo-2,6-dimethylpyridine 1a (5.0 g, 26.9 mmol, Shanghai Bidex Pharmaceuticals), trimethylsilyl acetylene 1b (8.0 g, 81.5 mmol, Shaoyuan Technology (Shanghai)), cuprous iodide (550 mg, 2.89 mmol, Alfa Aesar (China)), bis(triphenylphosphine)palladium dichloride (1.0 g, 1.42 mmol, J&K) and triethylamine (8.15 g, 80.7 mmol) were dissolved in anhydrous N,N-dimethylformamide (100 mL) and stirred at 45°C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, ethyl acetate (100 mL) was added, filtered, washed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1c (5.3 g, yield: 97%).

[0714] MS m / z(ESI):204.0[M+1].

[0715] Step 2

[0716] 4-Ethynyl-2,6-dimethylpyridine 1d

[0717] Dissolve compound 1c (5.3 g, 26.1 mmol) in methanol (100 mL) and add potassium carbonate (5.25 g, 38.0 mmol). Stir at room temperature for 2.0 hours. Filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system A to obtain the title product 1d (1.7 g, yield: 49.7%).

[0718] 1H NMR (500MHz, CDCl3) δ7.06 (s, 2H), 3.22 (s, 1H), 2.53 (s, 6H).

[0719] Step 3

[0720] tert-Butyl 3-(((Benzyloxy)carbonyl)amino)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate 1f

[0721] Dissolve 7-(tert-butyloxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylic acid 1e (4.17 g, 15.0 mmol, Jiangsu Aikang Biological), diphenylphosphoryl azide (4.35 g, 17.9 mmol, Shanghai Bid Pharmaceuticals) and N,N-diisopropylethylamine (2.72 g, 21.0 mmol) in anhydrous toluene (85 mL). Stir at room temperature for 1.0 hour under nitrogen atmosphere. Add benzyl alcohol (8.0 g, 74.0 mmol, Sinopharm) and stir at 105°C for 3.0 hours under nitrogen atmosphere. Add water (100 mL) to the reaction solution, extract with ethyl acetate (100 mL×3), combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to obtain the title product 1f (5.5 g, yield: 95.7%).

[0722] MS m / z(ESI):383.9[M+1].

[0723] Step 4

[0724] 3-Amino-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid tert-butyl ester 1g

[0725] Dissolve compound 1f (6.8 g, 17.7 mmol) in methanol (100 mL), add palladium carbon (1.89 g, 1.77 mmol, 10% purity, adamas). Stir and react at room temperature for 2.0 hours under hydrogen atmosphere. Filter and concentrate under reduced pressure to obtain a crude title product 1g (4.42 g, yield: 100%). The product is used directly in the next step without purification.

[0726] MS m / z(ESI):250.0[M+1].

[0727] Step 5

[0728] 3-Amino-2-bromo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid tert-butyl ester 1h

[0729] The crude compound 1g (4.42g, 17.7mmol) was dissolved in N,N-dimethylformamide (120mL), and N-bromosuccinimide (3.35g, 18.8mmol, Shaoyuan Technology (Shanghai)) was added and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1h (4.7g, yield: 80.8%).

[0730] MS m / z(ESI):328.0[M+1].

[0731] Step 6

[0732] 3-Amino-2((2,6-dimethylpyridin-4-yl)ethynyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid tert-butyl ester 1i

[0733] Compound 1h (1.35 g, 4.11 mmol), compound 1d (600 mg, 4.57 mmol), cuprous iodide (160 mg, 0.84 mmol, Alfa Aesar (China)), bis(triphenylphosphine)palladium dichloride (290 mg, 0.41 mmol, J&K) and triethylamine (1.25 g, 12.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL), stirred at 40°C for 16 hours under nitrogen atmosphere. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×4), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1i (1.50 g, yield: 96.4%).

[0734] MS m / z(ESI):379.0[M+1].

[0735] Step 7

[0736] 2-(2,6-Dimethylpyridin-4-yl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6-carboxylic acid tert-butyl ester 1j

[0737] Compound 1i (1.40 g, 3.70 mmol) and potassium tert-butoxide (2.10 g, 18.7 mmol, Shaoyuan Technology (Shanghai)) were dissolved in anhydrous N-methylpyrrolidone (20 mL). The mixture was stirred at 40°C for 16 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×4). The organic phases were combined, washed with saturated sodium chloride solution (50 mL×4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1j (900 mg, yield: 64.3%).

[0738] MS m / z(ESI):378.9[M+1].

[0739] Step 8

[0740] 3-Bromo-2-(2,6-dimethylpyridin-4-yl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6-carboxylic acid tert-butyl ester 1k

[0741] Compound 1j (900 mg, 2.38 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0°C, and N-bromosuccinimide (430 mg, 2.42 mmol, Shaoyuan Technology (Shanghai)) was added. The mixture was stirred at 0°C for 2.0 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL×4) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 1k (1.08 g, yield: 99.3%).

[0742] MS m / z(ESI):457.0[M+1].

[0743] Step 9

[0744] 2-(2,6-Dimethylpyridin-4-yl)-3-(prop-1-en-2-yl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6-carboxylic acid tert-butyl ester

[0745] Compound 1k (1.08 g, 2.36 mmol), isopropenylboronic acid pinacol ester (1.5 g, 8.93 mmol, Shaoyuan Technology (Shanghai)), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (180 mg, 0.25 mmol, Shanghai Bid Pharmaceuticals) and anhydrous tripotassium phosphate (1.50 g, 7.07 mmol) were dissolved in anhydrous dioxane (16.0 mL) and water (4.0 mL), and stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (15 mL) was added, and ethyl acetate (30 mL×4) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1l (900 mg, yield: 91.1%).

[0746] MS m / z(ESI):419.0[M+1].

[0747] Step 10

[0748] 2-(2,6-Dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6-carboxylic acid tert-butyl ester 1m

[0749] Compound 11 (900 mg, 2.15 mmol) was dissolved in methanol (30 mL), and palladium carbon (500 mg, 0.47 mmol, 10% purity, adamas) was added. The reaction was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (30 mL), and palladium carbon (500 mg, 0.47 mmol, 10% purity, adamas) was added. The reaction was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1m (350 mg, yield: 38.7%).

[0750] MS m / z(ESI):421.0[M+1].

[0751] Step 11

[0752] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 1

[0753] Compound 1m (65.0 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). Stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7M ammonia / methanol solution (5 mL) was added to the residue. After concentration under reduced pressure, the residue was purified by high performance liquid chromatography (chromatographic column: Boston Phlex Prep C18, 5 μm30*150 mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile, 28-48% acetonitrile, 15 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 1 (26.0 mg, yield: 52.5%).

[0754] MS m / z(ESI):321.2[M+1].

[0755] 1 H NMR (500MHz, CD3OD) δ7.47(s,1H),7.27(s,2H),4.19(s,2H),3.41(m,1H),3.18(t,2H),3.04(t,2H),2.59(s,6H),1.54(d,6H).

[0756] Example 2

[0757] 2-(2,6-dimethylpyridin-4-yl)-3,6-diisopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 2

[0758]

[0759] first step

[0760] 2-(2,6-dimethylpyridin-4-yl)-3,6-diisopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 2

[0761] Compound 1 (50 mg, 0.16 mmol) and 2-iodopropane (100 mg, 0.59 mmol) were dissolved in acetonitrile (5 mL), and potassium carbonate (100 mg, 0.72 mmol) was added. Stir at 80°C for 2.0 hours. Filter and concentrate under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Boston Phlex Prep C18, 5 μm 30*150 mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile, 40-60% acetonitrile, 15 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 2 (28.0 mg, yield: 49.5%).

[0762] MS m / z(ESI):363.2[M+1].

[0763] 1 H NMR(500MHz,CD3OD)δ7.49(s,1H),7.27(s,2H),3.98(s,2H),3.42(m,1H),3. 08(t,2H),3.01(m,1H),2.93(t,2H),2.59(s,6H),1.54(d,6H),1.26(d,6H).

[0764] Example 3

[0765] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]

[0766] Quinolin-6-amine 3

[0767]

[0768]

[0769] first step

[0770] (3-Nitro-5,6,7,8-tetrahydroquinolin-7-yl)carbamic acid benzyl ester 3c-1

[0771] Benzyl (3-nitro-5,6,7,8-tetrahydroquinolin-5-yl)carbamate 3c-2

[0772] Benzyl (3-oxocyclohexyl)carbamate 3a (3.0 g, 12.1 mmol, Shanghai Bid Pharmaceutical) and 1-methyl-3,6-dinitropyridine-2(1H)-one 3b (3.0 g, 15.1 mmol, Nanjing Yaoshi) were dissolved in 7M ammonia / methanol solution (15 mL) and methanol (15 mL), and stirred at 90°C for 2.0 hours in a sealed container. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 mL), washed with water (100 mL) and saturated sodium chloride solution (100 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain a mixture of the title products 3c-1 and 3c-2 (3.5 g, yield: 88.1%).

[0773] MS m / z(ESI):327.9[M+1].

[0774] Step 2

[0775] (3-Amino-5,6,7,8-tetrahydroquinolin-7-yl)carbamic acid benzyl ester 3d-1

[0776] (3-amino-5,6,7,8-tetrahydroquinolin-5-yl)carbamic acid benzyl ester 3d-2

[0777] The mixture of compounds 3c-1 and 3c-2 (8.0 g, 24.4 mmol) was dissolved in ethanol (100 mL) and water (25 mL). Iron powder (12.0 g, 215 mmol, Chinese medicine) and ammonium chloride (13.0 g, 241 mmol) were added. The reaction was stirred at 80 ° C for 3.0 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and extracted with water (200 mL) and ethyl acetate (200 mL × 4). The organic phases were combined and concentrated under reduced pressure to obtain a crude mixture of the title products 3d-1 and 3d-2 (7.26 g, yield: 99.9%). The crude product was used directly in the next step without purification.

[0778] MS m / z(ESI):298.0[M+1].

[0779] Step 3

[0780] Benzyl 2-(3-amino-2-bromo-5,6,7,8-tetrahydroquinolin-7-yl)carbamate 3e

[0781] The crude mixture of compounds 3d-1 and 3d-2 (7.3 g, 24.6 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-bromosuccinimide (4.50 g, 25.3 mmol, Shaoyuan Technology (Shanghai)) was added. Stir at 0°C for 2.0 hours. The reaction solution was warmed to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3e (3.5 g, yield: 37.9%).

[0782] MS m / z(ESI):376.0[M+1].

[0783] Step 4

[0784] Benzyl (3-amino-2((2,6-dimethylpyridin-4-yl)ethynyl)-5,6,7,8-tetrahydroquinolin-7-yl)carbamate 3f

[0785] Compound 3e (1.0 g, 2.66 mmol), compound 1d (400 mg, 3.05 mmol), cuprous iodide (105 mg, 0.55 mmol, Alfa Aesar (China)), bis(triphenylphosphine)palladium dichloride (190 mg, 0.27 mmol, J&K) and triethylamine (810 mg, 8.02 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and stirred at 40°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, and ethyl acetate (50 mL×4) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 3f (300 mg, yield: 26.5%).

[0786] MS m / z(ESI):426.9[M+1].

[0787] Step 5: Benzyl (2-((2,6-dimethylpyridin-4-yl)ethynyl)-3-(2,2,2-trifluoroacetylamino)-5,6,7,8-tetrahydroquinolin-7-yl)carbamate 3 g

[0788] Compound 3f (580 mg, 1.36 mmol) was dissolved in anhydrous dioxane (20 mL), and potassium carbonate (500 mg, 3.62 mmol) and trifluoroacetic anhydride (450 mg, 2.14 mmol, adamas) were added. The mixture was stirred at room temperature for 3.0 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×4). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3g (270 mg, yield: 38.0%).

[0789] MS m / z(ESI):522.9[M+1].

[0790] Step 6

[0791] Benzyl (2-(2,6-dimethylpyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-yl)carbamate 3h

[0792] Compound 3g (270 mg, 0.52 mmol), cuprous iodide (100 mg, 0.53 mmol, Alfa Aesar (China)) and triethylamine (200 mg, 1.98 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL) and stirred at 105°C for 3.0 hours under a nitrogen atmosphere. Water (20 mL) was added, and ethyl acetate (20 mL×4) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3h (220 mg, yield: 99.8%).

[0793] MS m / z(ESI):426.9[M+1].

[0794] Step 7

[0795] Benzyl (3-bromo-2-(2,6-dimethylpyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-yl)carbamate 3i

[0796] Compound 3h (220 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), cooled to 0°C, and N-bromosuccinimide (95 mg, 0.53 mmol, Shaoyuan Technology (Shanghai)) was added. Stir at room temperature for 2.0 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3i (225 mg, yield: 86.5%).

[0797] MS m / z(ESI):505.8[M+1].

[0798] Step 8

[0799] Benzyl (2-(2,6-dimethylpyridin-4-yl)-3-(prop-1-en-2-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-yl)carbamate 3j

[0800] Compound 3i (225 mg, 0.45 mmol), isopropenylboronic acid pinacol ester (200 mg, 1.19 mmol, Shaoyuan Technology (Shanghai)), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (35 mg, 0.05 mmol, Shanghai Bid Pharmaceuticals) and anhydrous tripotassium phosphate (285 mg, 1.34 mmol) were dissolved in anhydrous dioxane (4.0 mL) and water (1.0 mL), and stirred at 80°C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (15 mL) was added, and ethyl acetate (20 mL×4) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3j (110 mg, yield: 53%).

[0801] MS m / z(ESI):467.0[M+1].

[0802] Step 9

[0803] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-amine 3k

[0804] Compound 3j (110 mg, 0.24 mmol) was dissolved in methanol (10 mL), and palladium carbon (200 mg, 0.19 mmol, 10% purity, adamas) was added. The mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain a crude title product 3k (50 mg, yield: 63.4%). The product was not purified and directly used for the next step.

[0805] MS m / z(ESI):335.0[M+1].

[0806] Step 10

[0807] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-amine 3

[0808] The crude compound 3k (50.0 mg, 0.15 mmol) and dihydrofuran-3(2H)-one (20 mg, 0.23 mmol, Shaoyuan Technology (Shanghai)) were dissolved in dichloromethane (5.0 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (70 mg, 0.33 mmol, Shaoyuan Technology (Shanghai)) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Welch Ultimate XB-C18, 5 μm, 30 mm*150 mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 3 (5.0 mg, yield: 8.3%).

[0809] MS m / z(ESI):405.0[M+1].

[0810] 1H NMR(500MHz,CD3OD)δ7.45(s,1H),7.27(s,2H),4.01-3.94(m,2H),3.82(m,1H),3.73(m,1H),3.62(m,1H),3.46-3.39(m, 2H),3.15(m,1H),3.04-3.00(m,2H),2.84(m,1H),2.58(s,6H),2.28-2.20(m,2H),1.85(m,1H),1.67(m,1H),1.54(d,6H).

[0811] Example 4

[0812] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-(2-(6-(piperazin-4-yl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydro

[0813] -1H-Pyrrolo[3,2-b][1,7]naphthyridine 4

[0814]

[0815] first step

[0816] tert-Butyl 4-(5-(2-(Hydroxyethyl)pyridin-2-yl)piperazine-1-carboxylate 4b

[0817] 4-(5-(2-methoxy-2-oxoethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 4a (120 mg, 0.36 mmol, prepared by the synthesis method of compound 4a on page 37 of the specification of WO2018138356 A1) was dissolved in anhydrous tetrahydrofuran (5.0 mL), cooled to 0 ° C, and lithium borohydride (16 mg, 0.74 mmol, Chinese medicine) was added. The reaction was stirred at room temperature for 16 hours. Sodium sulfate decahydrate was added and stirred for 30 minutes, filtered, washed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography with developing agent system A to obtain the title product 4b (110 mg, yield: 100%).

[0818] MS m / z(ESI):307.8[M+1].

[0819] Step 2

[0820] tert-Butyl 4-(5-(2-((methylsulfonyl)oxy)ethyl)pyridin-2-yl)piperazine-1-carboxylate 4c

[0821] Compound 4b (140 mg, 0.46 mmol), methanesulfonyl chloride (70 mg, 0.61 mmol, Chinese medicine) and triethylamine (90 mg, 0.89 mmol) were dissolved in dichloromethane (5.0 mL). Stirred at 0°C for 2.0 hours. Water (20 mL) was added to the reaction solution, and dichloromethane (20 mL × 3) was used for extraction. The organic phases were combined and concentrated under reduced pressure to obtain the crude product of the title product 4c (175 mg, yield: 99.7%). The product was directly used for the next step without purification.

[0822] MS m / z(ESI):385.9[M+1].

[0823] Step 3

[0824] tert-Butyl 4-(5-(2-iodoethyl)pyridin-2-yl)piperazine-1-carboxylate

[0825] The crude compound 4c (175 mg, 0.45 mmol) and sodium iodide (200 mg, 1.33 mmol, adamas) were dissolved in acetone (10 mL). Stirred at 60°C for 16 hours. Concentrated under reduced pressure, water (20 mL) was added to the residue, extracted with ethyl acetate (20 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4d (140 mg, yield: 73.9%).

[0826] MS m / z(ESI):417.8[M+1].

[0827] Step 4

[0828] 4-(5-(2-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine

[0829] -6-yl)ethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 4e

[0830] Compound 4d (70 mg, 0.17 mmol), compound 1 (30 mg, 0.094 mmol) and cesium carbonate (100 mg, 0.31 mmol, Shaoyuan Technology (Shanghai)) were dissolved in dimethyl sulfoxide (3.0 mL) and stirred at 100°C for 4.0 hours. The reaction solution was washed with ethyl acetate (30 mL), water (10 mL) and saturated sodium chloride solution (10 mL×2), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography with developing solvent system A to obtain the title product 4e (40 mg, yield: 70%).

[0831] MS m / z(ESI):610.3[M+1].

[0832] Step 5

[0833] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-(2-(6-(piperazin-4-yl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydro

[0834] -1H-Pyrrolo[3,2-b][1,7]naphthyridine 4

[0835] Compound 4e (70.0 mg, 0.11 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL). Stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7M ammonia / methanol solution (5 mL) was added to the residue. After concentration under reduced pressure, the residue was purified by high performance liquid chromatography (chromatographic column: Sharpsil-T Prep C18, 5 μm 30*150 mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile, 30-95% acetonitrile, 18 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 4 (25.0 mg, yield: 42.7%).

[0836] MS m / z(ESI):510.3[M+1].

[0837] 1 H NMR(500MHz,CD3OD)δ8.07(d,1H),7.58(dd,1H),7.50(s,1H),7.28(s,2H),6.83(d,1H),3.95(s,2H),3.50-3.48(m,4H),3 .42(m,1H),3.11(t,2H),2.99-2.97(m,4H),2.93(t,2H),2.91-2.87(m,2H),2.85-2.81(m,2H),2.59(s,6H),1.55(d,6H).

[0838] Example 5

[0839] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-((5-(piperazin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro

[0840] -1H-Pyrrolo[3,2-b][1,7]naphthyridine 5

[0841]

[0842]

[0843] first step

[0844] (5-Bromopyridin-2-yl)methyl acetate 5b

[0845] 5-Bromo-2-methylpyridine 5a (4.0 g, 23.3 mmol, Shaoyuan Technology (Shanghai)) was dissolved in dichloromethane (50 mL), cooled to 0 ° C, 3-chloroperoxybenzoic acid (6.1 g, 35.3 mmol, Sinopharm) was added, and the reaction was stirred at room temperature for 16 hours. The reaction solution was washed with saturated sodium bicarbonate solution (50 mL), and the organic phase was concentrated under reduced pressure. The residue was dissolved in acetic anhydride (16 mL) and heated to reflux for 1.0 hour. Ethanol was added to quench the reaction, and the reaction solution was concentrated under reduced pressure. The residue was neutralized with saturated potassium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL × 2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5b (2.1 g, yield: 39.2%).

[0846] MS m / z(ESI):229.6[M+1].

[0847] Step 2

[0848] tert-Butyl 4-(6-(acetoxymethyl)pyridin-3-yl)piperazine-1-carboxylate 5c

[0849] Compound 5b (1.0 g, 4.35 mmol), tert-butyl piperazine-1-carboxylate (1.62 g, 8.7 mmol, Shaoyuan Technology (Shanghai)), cesium carbonate (4.3 g, 13.2 mmol, Shaoyuan Technology (Shanghai)), tris(dibenzylideneacetone)dipalladium (399 mg, 0.44 mmol, Shanghai Bid Pharmaceuticals) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (542 mg, 0.87 mmol, Shanghai Bid Pharmaceuticals) were dissolved in toluene (30 mL). The reaction was stirred at 90°C for 12 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5c (1.2 g, yield: 82.3%).

[0850] MS m / z(ESI):335.9[M+1].

[0851] Step 3

[0852] tert-Butyl 4-(6-(Hydroxymethyl)pyridin-3-yl)piperazine-1-carboxylate 5d

[0853] Compound 5c (390 mg, 1.16 mmol) and lithium hydroxide monohydrate (150 mg, 3.57 mmol, Chinese medicine) were dissolved in tetrahydrofuran (9.0 mL) and water (3.0 mL). The mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5d (240 mg, yield: 70.4%).

[0854] MS m / z(ESI):294.0[M+1].

[0855] Step 4

[0856] 4-(6-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine

[0857] -6-yl)methyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 5e

[0858] Compound 5d (150 mg, 0.51 mmol), methanesulfonyl chloride (60 mg, 0.52 mmol, Chinese medicine) and triethylamine (55 mg, 0.54 mmol) were dissolved in dichloromethane (3.0 mL) and stirred at 0°C for 2.0 hours. The reaction solution was added dropwise to a solution of compound 1 (80 mg, 0.25 mmol) and potassium carbonate (100 mg, 0.72 mmol) in acetonitrile (5.0 mL) and stirred at 70°C for 2.0 hours. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography with developing solvent system A to obtain the title product 5e (100 mg, yield: 67.2%).

[0859] MS m / z(ESI):596.3[M+1].

[0860] Step 5

[0861] 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-((5-(piperazin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro

[0862] -1H-Pyrrolo[3,2-b][1,7]naphthyridine 5

[0863] Compound 5e (100.0 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL). Stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7 M ammonia / methanol solution (5 mL) was added to the residue. After concentration under reduced pressure, the residue was purified by high performance liquid chromatography (chromatographic column: Sharpsil-T Prep C18, 5 μm 30*150 mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile, 26-95% acetonitrile, 18 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 5 (15.0 mg, yield: 18.0%).

[0864] MS m / z(ESI):496.3[M+1].

[0865] 1 H NMR(500MHz,CD3OD)δ8.24(d,1H),7.51-7.47(m,3H),7.26(s,2H),3.86-3.85(m,4H),3.39 (m,1H),3.27-3.25(m,4H),3.09-3.04(m,6H),2.90-2.88(m,2H),2.59(s,6H),1.51(d,6H).

[0866] Example 6

[0867] 2-(2,6-dimethylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]

[0868] Naphthyridine 6

[0869]

[0870]

[0871] first step

[0872] 2-(2,6-Dimethylpyridin-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7]naphthyridine-1,6(5H)-dicarboxylic acid di-tert-butyl ester 6a

[0873] Compound 1j (1.59 g, 4.20 mmol), di-tert-butyl dicarbonate (2.0 g, 9.16 mmol, Shaoyuan Technology (Shanghai)), 4-dimethylaminopyridine (100 mg, 0.81 mmol, adamas) and triethylamine (3.0 g, 29.7 mmol) were dissolved in tetrahydrofuran (30 mL) and stirred at room temperature for 16 hours. Water (60 mL) was added to the reaction solution, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 6a (1.35 g, yield: 67.1%).

[0874] MS m / z(ESI):479.0[M+1].

[0875] Step 2

[0876] 3-Bromo-2-(2,6-dimethylpyridin-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7]naphthyridine-1,6(5H)-dicarboxylic acid di-tert-butyl ester 6b

[0877] Compound 6a (1.35 g, 2.82 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0°C, and N-bromosuccinimide (600 mg, 3.37 mmol, Shaoyuan Technology (Shanghai)) was added. Stir at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 6b (1.05 g, yield: 66.8%).

[0878] MS m / z(ESI):556.9[M+1].

[0879] Step 3

[0880] 3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,6-dimethylpyridin-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7]

[0881] Naphthyridine-1,6(5H)-dicarboxylic acid di-tert-butyl ester 6c

[0882] Compound 6b (100 mg, 0.18 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (50 mg, 0.24 mmol, Shaoyuan Technology (Shanghai)), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (20 mg, 0.03 mmol, Shanghai Bid Pharmaceuticals) and anhydrous tripotassium phosphate (120 mg, 0.57 mmol) were dissolved in dioxane (3.0 mL) and water (1.0 mL), and stirred at 80°C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (15 mL) was added, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 6c (90 mg, yield: 89.5%).

[0883] MS m / z(ESI):561.0[M+1].

[0884] Step 4

[0885] 2-(2,6-dimethylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7]

[0886] Naphthyridine-1,6(5H)-dicarboxylic acid di-tert-butyl ester 6d

[0887] Compound 6c (90 mg, 0.16 mmol) was dissolved in methanol (10 mL), and palladium carbon (100 mg, 0.094 mmol, 10% purity, adamas) was added. The reaction was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 6d (80 mg, yield: 88.6%). The product was used directly in the next step without purification.

[0888] MS m / z(ESI):563.0[M+1].

[0889] Step 5

[0890] 2-(2,6-dimethylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]

[0891] Naphthyridine 6

[0892] The crude compound 6d (80.0 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7M ammonia / methanol solution (5 mL) was added to the residue. After concentration under reduced pressure, the residue was purified by high performance liquid chromatography (chromatographic column: Sharpsil-T Prep C18, 5 μm30*150 mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile, 28-95% acetonitrile, 18 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 6 (14 mg, yield: 27.2%).

[0893] MS m / z(ESI):363.3[M+1].

[0894] 1 H NMR(500MHz,CD3OD)δ7.49(s,1H),7.28(s,2H),4.20(s,2H),4.08-4.05(m,2H),3.59-3.54(m,2H),3 .26(m,1H),3.21-3.19(m,2H),3.06-3.04(m,2H),2.82-2.73(m,2H),2.59(s,6H),1.66-1.62(m,2H).

[0895] Example 7

[0896] 4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridin-6-yl)methyl)bicyclo[2.2.2]octan-1-amine 7

[0897]

[0898] First step: tert-Butyl (4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridin-6-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate 7b

[0899] Compound 1 (1.05 g, 3.28 mmol) and (4-formylbicyclo[2.2.2]octan-1-yl)carbamic acid tert-butyl ester 7a (1.60 g, 6.32 mmol, prepared by the synthesis method of intermediate A on page 67 of the specification of WO2013003383A1) were dissolved in 1,2-dichloroethane (20 mL) and N,N-dimethylformamide (4.0 mL), 1 drop of acetic acid was added, and the mixture was stirred at room temperature for 2.0 hours. Sodium triacetoxyborohydride (1.50 g, 7.08 mmol) was added, and the mixture was stirred at 60°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was added with water (50 mL) and extracted with ethyl acetate (50 mL×4). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 7b (1.05 g, yield: 57.4%).

[0900] MS m / z(ESI):558.3[M+1].

[0901] Step 2

[0902] 4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridin-6-yl)methyl)bicyclo[2.2.2]octan-1-amine 7

[0903] Compound 7b (1.05 g, 0.11 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and a 7M ammonia / methanol solution (20 mL) was added to the residue. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Waters XBridge C18, 5 μm, 30 mm*150 mm; mobile phase: A-aqueous phase (0.5% ammonium hydroxide): B-acetonitrile (0.5% ammonium hydroxide), 80-95% acetonitrile, 18 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 7 (330 mg, yield: 38.3%).

[0904] MS m / z(ESI):458.3[M+1].

[0905] 1 H NMR(500MHz,CD3OD)δ7.45(s,1H),7.27(s,2H),3.86(s,2H),3.42(m,1H),3.02-3.00(m,2H),2 .83-2.80(m,2H),2.59(s,6H),2.30(s,2H),1.66-1.62(m,6H),1.60-1.57(m,6H),1.53(d,6H).

[0906] Example 8

[0907] 2-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridin-6-yl)

[0908] Acetamide 8

[0909]

[0910] Compound 1 (300 mg, 0.94 mmol), 2-bromoacetamide (200 mg, 1.45 mmol, Shaoyuan Technology (Shanghai)) and 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 1.99 mmol, adamas) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 6.0 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: BostonPhlex Prep C18, 5μm 30*150mm; mobile phase: A-water phase (10 mmol ammonium bicarbonate): B-acetonitrile, 20-80% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 8 (120 mg, yield: 34%).

[0911] MS m / z(ESI):378.0[M+1].

[0912] 1 H NMR(500MHz,DMSO-d6)δ11.14(s,1H),7.43(s,1H),7.30(d,1H),7.20(s,2H),7.17(d,1H),3.78( s,2H),3.34(s,6H),3.31(m,1H),3.11(s,2H),3.01-2.99(m,2H),2.78-2.76(m,2H),1.50(d,6H).

[0913] Example 9

[0914] 2-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 9

[0915]

[0916] first step

[0917] 7,8-Dimethyl-6-(3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[1,5-a]pyridine 9b

[0918] 6-Bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine 9a (760 mg, 3.36 mmol, prepared by the synthesis method of intermediate F-4 on page 140 of the patent application "WO2018005586A1 specification") and 3-methyl-1-alkyne (500 mg, 7.34 mmol, Acros), cuprous iodide (130 mg, 0.682 mmol, Alfa), bistriphenylphosphine palladium dichloride (240 mg, 0.341 mmol, adamas), triethylamine (1.0 g, 10.0 mmol) were dissolved in N,N-dimethylformamide (15 mL) and stirred at 60 ° C for 30 hours under nitrogen atmosphere. The mixture was quenched by adding water (50 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 9b (650 mg, yield: 90.6%).

[0919] MS m / z(ESI):214.0[M+1].

[0920] Step 2

[0921] 2-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6-carboxylic acid tert-butyl ester 9c

[0922] Compound 1h (1.0 g, 3.05 mmol) and compound 9b (650 mg, 3.05 mmol) were dissolved in dimethylacetamide (20 mL), and anhydrous lithium chloride (130 mg, 3.07 mmol), potassium carbonate (1.27 g, 9.20 mmol), and tetrakis(triphenylphosphine)palladium (360 mg, 0.31 mmol, adamas) were added. The reaction was carried out at 115°C for 20 hours. The reaction solution was cooled to room temperature, and water (60 mL) was added. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 9c (700 mg, yield: 49.9%).

[0923] MS m / z(ESI):461.0[M+1].

[0924] Step 3

[0925] 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[1,5-a]pyridin-6-yl)-

[0926] [3,2-b][1,7]naphthyridine 9

[0927] Compound 9c (700 mg, 1.52 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain a crude product. The crude product was purified by chiral column chromatography (chromatographic column: CHIRALPAK IF 20*250 mm, mobile phase: A-n-hexane, B-ethanol (containing 10 mM NH3), flow rate: 20 mL / min, detection wavelength 214 & 254 nm) to obtain the title product 9 (120 mg, 21.9%).

[0928] MS m / z(ESI):361.0[M+1].

[0929] 1 H NMR(500MHz,DMSO-d6)δ11.30(s,1H),8.84(s,1H),8.50(s,1H),7.56(s,1H),4.32(s,2H),3.39- 3.37(m,2H),3.31(s,1H),3.14-3.12(m,2H),2.91(m,1H),2.60(s,3H),2.15(s,3H),1.37(d,6H).

[0930] Example 10

[0931] 2-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[1,5-a]pyridin-6-yl)-

[0932] [3,2-b][1,7]naphthyridin-6-yl)acetamide 10

[0933]

[0934] Compound 9 (85 mg, 0.24 mmol), 2-bromoacetamide (60 mg, 0.43 mmol, Shaoyuan Technology (Shanghai)) and 1,8-diazabicyclo[5.4.0]undec-7-ene (120 mg, 0.48 mmol, adamas) were dissolved in dichloromethane (5.0 mL) and stirred at room temperature for 6.0 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by chiral chromatography (chromatographic column: CHIRALPAK IF 20*250 mm, mobile phase: A-n-hexane, B-ethanol (containing 10 mM NH3), flow rate: 20 mL / min, detection wavelength 214 & 254 nm) to obtain the title product 10 (20 mg, 20.3%).

[0935] MS m / z(ESI):418.0[M+1].

[0936] 1 H NMR(500MHz,CD3OD)δ8.67(s,1H),8.43(s,1H),7.51(s,1H),3.98(s,2H),3.32(s,2H),3 .22(m,1H),3.15-3.12(m,2H),2.96-2.93(m,2H),2.67(s,3H),2.26(s,3H),1.34(d,6H).

[0937] Biological evaluation

[0938] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0939] Test Example 1 Inhibitory effect of the disclosed compounds on human TLR7 activation pathway

[0940] 1. Experimental Materials and Instruments

[0941] 1. HEK-Blue TM hTLR7 cells (Invivogen)

[0942] 2. Resiquimod (R848 / Resiquimod, Invivogen)

[0943] 3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)

[0944] 4. Blasticidin (Invivogen)

[0945] 5. Zeocin (Invivogen)

[0946] 6. Neomycin (Normocin, Invivogen)

[0947] 7. DMEM / HIGH Glucose (GE Healthcare)

[0948] 8. Fetal bovine serum (FBS, Gibco)

[0949] 9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)

[0950] 10. Sterile pure water (made by Shanghai Hengrui)

[0951] 11. 15mL centrifuge tube (Corning)

[0952] 12. 96-well dispensing plate (Corning)

[0953] 13. 96-well flat-bottom cell culture plate (Corning)

[0954] 14. Constant temperature cell culture incubator (Thermo scientific)

[0955] 15. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0956] 16. PHERAstar FS ELISA Reader (BMG Labtech)

[0957] 2. Experimental steps

[0958] Purchase HEK-Blue from Invivogen TM hTLR7 cells are cells in which the human Toll-like receptor 7 (TLR7) gene and a secretory alkaline phosphatase reporter gene (SEAP) are co-transfected into HEK293 cells. The alkaline phosphatase reporter gene (SEAP) is under the regulation of an IFN-β minimal promoter containing five NF-kB and AP-1 binding sites. When TLR7 is activated by an agonist, SEAP secretion is induced through downstream NF-kB and AP-1. After the addition of antagonistic compounds, the above pathway is inhibited and SEAP secretion is reduced. OD620 is measured using SEAP substrate to evaluate the activity of the compound on the TLR7 pathway.

[0959] The 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256μM, the blank well was 100% DMSO, and then diluted 20 times in DMEM / high glucose medium (complete medium, the same below) containing 10% inactivated FBS. Resiquimod was diluted to 10μM with sterile water. 20μL / well of 10μM resiquimod diluted with sterile water was added to the 96-well cell culture plate. Then the above-mentioned compound diluted in complete medium and 100% DMSO were added to the wells containing resiquimod at 20μL per well. 20μL of sterile water and 20μL of 100% DMSO diluted in complete medium were added to the negative control wells.

[0960] HEK-Blue TMhTLR7 cells were cultured in DMEM / high glucose medium containing 10% inactivated FBS, 100 μg / mL neomycin, 10 μg / mL blasticidin, and 100 μg / mL bleomycin. Take cells that have grown well and grown to 70%-80%, discard the growth medium, add 5-10 mL of 37°C preheated PBS to wash the cells once, add 2-5 mL of preheated PBS and culture at 37°C for 1-2 minutes, blow the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and adjust the cell density to 4.8×10 with complete medium. 5 / mL. Add 160 μL of the cell suspension after adjusting the density to the above 96-well cell culture plate, and the final number of cells per well is 76,500 / well, the final concentration of resimod is 1 μM, and the final concentrations of the test compounds are 10,000, 2,000, 400, 80, 16, 3.2, 0.64, and 0.128 nM, respectively. The cells were cultured in a 37°C, 5% CO2 incubator for 20 hours, then 20 μL of the supernatant was taken, 180 μL of the prepared alkaline phosphatase detection medium was added, and the OD620 absorbance was read by a microplate reader after incubation in a 37°C constant temperature incubator away from light for 120 minutes. The inhibition rate was calculated using the following formula:

[0961] Inhibition rate = {1-(OD 受试化合物 -OD 阴性对照孔 ) / (OD 空白孔 -OD 阴性对照孔 )}×100%

[0962] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 See Table 1 for values.

[0963] Table 1 IC values ​​of the compounds disclosed herein measured on human TLR7 pathway 50 value.

[0964] Example No. <![CDATA[IC 50 (nM)]]> 1 7.7 2 29.9 3 14.9 4 6.8 5 5.7 7 7.1 8 18.2 9 4.9 10 21.5

[0965] Conclusion: The compounds disclosed in the present invention have an inhibitory effect on the TLR7 pathway.

[0966] Test Example 2 Inhibitory effect of the disclosed compounds on human TLR8 pathway

[0967] 1. Experimental Materials and Instruments

[0968] 1. HEK-Blue TM hTLR8 cells (Invivogen)

[0969] 2. Resiquimod (R848 / Resiquimod, Invivogen)

[0970] 3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)

[0971] 4. Blasticidin (Invivogen)

[0972] 5. Zeocin (Invivogen)

[0973] 6. Neomycin (Normocin, Invivogen)

[0974] 7. DMEM / HIGH Glucose (GE Healthcare)

[0975] 8. Fetal bovine serum (FBS, Gibco)

[0976] 9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)

[0977] 10. Sterile pure water (made by Shanghai Hengrui)

[0978] 11. 15mL centrifuge tube (Corning)

[0979] 12. 96-well dispensing plate (Corning)

[0980] 13. 96-well flat-bottom cell culture plate (Corning)

[0981] 14. Constant temperature cell culture incubator (Thermo scientific)

[0982] 15. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0983] 16. PHERAstar FS ELISA Reader (BMG Labtech)

[0984] 2. Experimental steps

[0985] Purchase HEK-Blue from Invivogen TMhTLR8 cells are cells in which the human Toll-like receptor 8 (TLR8) gene and a secretory alkaline phosphatase reporter gene (SEAP) are co-transfected into HEK293 cells. The alkaline phosphatase reporter gene (SEAP) is under the regulation of the IFN-β minimal promoter containing 5 NF-kB and AP-1 binding sites. When TLR8 is activated by an agonist, SEAP secretion is induced through downstream NF-kB and AP-1. After the addition of antagonistic compounds, the above pathway is inhibited and SEAP secretion is reduced. OD620 is measured by SEAP substrate to evaluate the activity of the compound on the TLR8 pathway.

[0986] The 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256μM, the blank well was 100% DMSO, and then diluted 20 times in DMEM / high glucose medium (complete medium, the same below) containing 10% inactivated FBS. Resiquimod was diluted to 60μM with sterile water. 20μL / well of 60μM resiquimod diluted with sterile water was added to the 96-well cell culture plate, and then the above compound diluted in complete medium and 100% DMSO were added to the wells containing resiquimod at 20μL per well. 20μL of sterile water and 20μL of 100% DMSO diluted in complete medium were added to the negative control wells.

[0987] HEK-Blue TM hTLR8 cells were cultured in DMEM / high glucose medium containing 10% inactivated FBS, 100 μg / mL neomycin, 10 μg / mL blasticidin, and 100 μg / mL bleomycin. Take cells that have grown well and grown to 70%-80%, discard the growth medium, add 5-10 mL of 37°C preheated PBS to wash the cells once, add 2-5 mL of preheated PBS and culture at 37°C for 1-2 minutes, blow the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and adjust the cell density to 4.8×10 with complete medium. 5 / mL. Add 160 μL of the cell suspension after adjusting the density to the above 96-well cell culture plate, and the final number of cells per well is 76,500 / well, the final concentration of resimod is 6 μM, and the final concentrations of the test compounds are 10,000, 2,000, 400, 80, 16, 3.2, 0.64, and 0.128 nM, respectively. The cells were cultured in a 37°C, 5% CO2 incubator for 20 hours, then 20 μL of the supernatant was taken, 180 μL of the prepared alkaline phosphatase detection medium was added, and incubated in a 37°C incubator away from light for 120 minutes, and the OD620 absorbance value was read by a microplate reader. The inhibition rate was calculated using the following formula:

[0988] Inhibition rate = {1-(OD受试化合物 -OD 阴性对照孔 ) / (OD 空白孔 -OD 阴性对照孔 )}×100%

[0989] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 See Table 2 for values.

[0990] Table 2 IC values ​​of the compounds disclosed herein measured on human TLR8 pathway 50 value.

[0991] Example No. <![CDATA[IC 50 (nM)]]> 1 0.8 2 30.4 4 1.8 5 2.5 6 10.5 7 2.2 8 18.8 9 0.6 10 8.2

[0992] Conclusion: The compounds disclosed in the present invention have an inhibitory effect on the TLR8 pathway.

[0993] Test Example 3 Inhibitory effect of the disclosed compounds on human TLR9 activation pathway

[0994] 1. Experimental Materials and Instruments

[0995] 1. HEK-Blue TM hTLR9 cells (Invivogen)

[0996] 2. CpG ODN2006 (Invivogen)

[0997] 3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)

[0998] 4. Blasticidin (Invivogen)

[0999] 5. Zeocin (Invivogen)

[1000] 6. Neomycin (Normocin, Invivogen)

[1001] 7. DMEM / HIGH Glucose (GE Healthcare)

[1002] 8. Fetal bovine serum (FBS, Gibco)

[1003] 9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)

[1004] 10. Sterile pure water (made by Shanghai Hengrui)

[1005] 11. 15mL centrifuge tube (Corning)

[1006] 12. 96-well dispensing plate (Corning)

[1007] 13. 96-well flat-bottom cell culture plate (Corning)

[1008] 14. Constant temperature cell culture incubator (Thermo scientific)

[1009] 15. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[1010] 16. PHERAstar FS ELISA Reader (BMG Labtech)

[1011] 2. Experimental steps

[1012] Purchase HEK-Blue from Invivogen TM hTLR9 cells are cells in which the human Toll-like receptor 9 (TLR9) gene and a secretory alkaline phosphatase reporter gene (SEAP) are co-transfected into HEK293 cells. The alkaline phosphatase reporter gene (SEAP) is under the regulation of an IFN-β minimal promoter containing five NF-kB and AP-1 binding sites. When TLR9 is activated by an agonist, SEAP secretion is induced through downstream NF-kB and AP-1. After the addition of antagonistic compounds, the above pathway is inhibited and SEAP secretion is reduced. OD620 is measured using SEAP substrate to evaluate the activity of the compound on the TLR9 pathway.

[1013] The 20mM test compound dissolved in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256μM with 100% DMSO, and the blank well was 100% DMSO, and then diluted 20 times in DMEM / high glucose medium (complete medium, the same below) containing 10% inactivated FBS. CpG ODN2006 was diluted to 10μM with sterile water. 20μL / well of 10μM CpG ODN2006 diluted with sterile water was added to the 96-well cell culture plate, and then the above-mentioned compound diluted in complete medium and 100% DMSO were added to the wells containing CpG ODN2006 at 20μL per well. 20μL of sterile water and 20μL of 100% DMSO diluted in complete medium were added to the negative control wells.

[1014] HEK-Blue TMhTLR9 cells were cultured in DMEM / high glucose medium containing 10% FBS, 100 μg / mL neomycin, 10 μg / mL blasticidin, and 100 μg / mL bleomycin. Take cells that have grown well and grown to 70%-80%, discard the growth medium, add 5-10 mL of 37°C preheated PBS to wash the cells once, add 2-5 mL of preheated PBS and culture at 37°C for 1-2 minutes, blow the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and adjust the cell density to 4.8×10 with DMEM / high glucose medium containing 10% inactivated FBS. 5 / mL. Add 160 μL of the cell suspension after adjusting the density to the above 96-well cell culture plate, and the final number of cells per well is 76,500 / well, the final concentration of CpG ODN2006 is 1 μM, and the final concentrations of the test compounds are 10,000, 2,000, 400, 80, 16, 3.2, 0.64, and 0.128 nM, respectively. The cells were cultured in a 37°C, 5% CO2 incubator for 20 hours, then 20 μL of the supernatant was taken, 180 μL of the prepared alkaline phosphatase detection medium was added, and the OD620 absorbance value was read by a microplate reader after incubation in a 37°C constant temperature incubator away from light for 15 minutes. The inhibition rate was calculated using the following formula:

[1015] Inhibition rate = {1-(OD 受试化合物 -OD 阴性对照孔 ) / (OD 空白孔 -OD 阴性对照孔 )}×100%

[1016] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 See Table 3 for values.

[1017] Table 3 IC values ​​of the compounds disclosed herein measured on human TLR9 pathway 50 value.

[1018] Example No. <![CDATA[IC 50 (nM)]]> 4 74 5 87 7 90

[1019] Conclusion: The compounds disclosed in the present invention have an inhibitory effect on the TLR9 pathway.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Y is CR 4a or nitrogen atoms; A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -NR g R L and The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 replace; L is NR L or C 1-6 Alkylene, R L A hydrogen atom or C 1-6 Alkyl; R g is a hydrogen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; Each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl and 3 to 12 membered heterocyclic group; R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl; Each R 4 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; R 4a is a hydrogen atom; Each R 5 are the same or different and are each independently selected from a hydrogen atom, -NR c R d and a 3- to 6-membered heterocyclic group, R c and R d are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; R 7 and R 8 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; J is 0, 1, or 2; k is 0, 1, or 2; n is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3 or 4.

2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof: in: Ring A, R 0 , R 1 To R 4 , R 4a , J, k, n and s are as defined in claim 1.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (IIG) or the general formula (IV) or a pharmaceutically acceptable salt thereof: in: Ring A, Ring C, L, R 1 To R 5 , R 4a , J, k, n, s and t are as defined in claim 1.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 5- to 10-membered heteroaryl group.

5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is pyridyl or 6. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is pyridyl.

7. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein J is 0 or 1, and k is 1 or 2.

8. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein J is 1 and k is 1.

9. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 0 A hydrogen atom.

10. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is C 1-6 Alkylene.

11. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl.

12. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 An alkyl group or a 3- to 6-membered heterocyclic group.

13. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 alkyl.

14. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl or tetrahydropyranyl.

15. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

16. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from a hydrogen atom, an amino group and a piperazinyl group.

18. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, and a 5- or 6-membered heteroaryl group.

19. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ring C is selected from tetrahydrofuranyl, bicyclo[2.2.2]octanyl and pyridinyl.

20. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, which is selected from any one of the following compounds:

21. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (IIA) or (IVA) or a pharmaceutically acceptable salt thereof: in: Ring A, R 1 To R 4 , R 4a , R L , J, k, n and s are as defined in claim 1.

22. A compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof, in: R w is an amino protecting group; Ring A, R 1 To R 4 , J, k, n and s are as defined in claim 1.

23. The compound represented by the general formula (IIB) or a pharmaceutically acceptable salt thereof according to claim 22, wherein R w It is tert-butyloxycarbonyl.

24. A compound or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

25. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIA) or a pharmaceutically acceptable salt thereof and R 0 -X undergoes a nucleophilic substitution reaction to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof, in: X is a leaving group; R 0 C 1-6 Alkyl or The C 1-6 The alkyl group is optionally substituted with one or more -C(O)NR 7 R 8 replace; L is C 1-6 Alkylene; Ring A, Ring C, R 1 To R 5 , R 7 , R 8 , n, s, t, J and k are as defined in claim 2.

26. The method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof according to claim 25, wherein X is a halogen.

27. The method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof according to claim 25, wherein X is bromine or iodine.

28. A method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIB) or its pharmaceutically acceptable salt is deprotected by removing the protecting group R w , to obtain a compound of formula (IIA) or a pharmaceutically acceptable salt thereof, in: R w is an amino protecting group; Ring A, R 1 To R 4 , n, s, J and k are as defined in claim 21.

29. The method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof according to claim 28, wherein R w It is tert-butyloxycarbonyl.

30. A method for preparing a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIa) or its pharmaceutically acceptable salt undergoes Larock indole reaction with the compound of general formula (IIbb). The reaction is performed to obtain a compound of formula (IIB) or a pharmaceutically acceptable salt thereof, in: R w is an amino protecting group; R t is a halogen; Ring A, R 1 To R 4 , n, s, J and k are as defined in claim 22.

31. The method for preparing a compound of formula (IIB) or a pharmaceutically acceptable salt thereof according to claim 30, wherein R w It is tert-butyloxycarbonyl.

32. The method for preparing a compound of formula (IIB) or a pharmaceutically acceptable salt thereof according to claim 30, wherein R t For bromine.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

34. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 33 in the preparation of a medicament for inhibiting TLR7, TLR8 or TLR9.

35. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33, in the preparation of a medicament for inhibiting TLR7, or in the preparation of a medicament for inhibiting TLR7 and TLR8, or in the preparation of a medicament for inhibiting TLR7 and TLR9.

36. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 33 in the preparation of a medicament for inhibiting TLR7, TLR8 and TLR9.

37. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 33 in the preparation of a medicament for treating and / or preventing inflammatory or autoimmune diseases.

38. The use according to claim 37, wherein the inflammatory or autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjogren's syndrome.

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