Condensed heteroaryl compound, preparation method thereof and application of fused heteroaryl compound in medicine

Abstract

The invention relates to a fused heteroaryl compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular to application of the compound as a TLR7 / 8 / 9 inhibitor and application of the compound in preparation of drugs for treating and / or preventing inflammatory and autoimmune diseases.

Description

Condensed heteroaryl compounds, preparation methods thereof and their applications in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to fused heteroaryl compounds, methods for preparing the same, and their use in medicine. In particular, the present disclosure relates to fused heteroaryl compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and their use as TLR7 / 8 / 9 inhibitors in the treatment of inflammatory and autoimmune diseases or conditions. Background Art

[0002] Toll-like receptors (TLRs) are a class of evolutionarily conserved transmembrane innate immune receptors that participate in the first line of defense in protecting human health and play a crucial role in recognizing pathogen-associated molecular patterns (PAMPs) (Kawai, T. et al., Nature Immunol., 11, 2010, 373-384). TLRs are expressed on various immune cells and can be divided into two categories based on their expression site: TLRs expressed on the cell membrane (TLR1 / 2 / 4 / 5 / 6) and TLRs expressed on the endosomal membrane (TLR3 / 7 / 8 / 9), each of which recognizes different components and molecules in PAMPs. Among them, TLR7 / 8 / 9 are highly expressed primarily in DCs and B cells. TLR7 / 8 primarily recognizes ssRNA, while TLR9 primarily recognizes CpG-DNA. TLR7 / 8 / 9 are activated upon binding to their ligands. They bind to the adaptor protein MyD88 in the cytoplasm, initiating the NF-κB and IRF pathways, activating DCs and producing type I interferons and various 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, the type I interferon secreted by DC cells also promotes the further proliferation and activation of autoimmune B cells, thereby causing a series of inflammatory reactions.

[0003] Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease. Three main clinical first-line treatments for SLE are steroids, immunosuppressants, and antimalarials. Only one new drug, belimumab, has been approved by the FDA this century, but it has only modest and delayed efficacy in a small subset of SLE patients (Navarra, SV et al., Lancet 2011, 377, 721), leaving very limited treatment options. Therefore, there is an urgent need for new therapies that can improve the treatment of a larger proportion of patients and are safe for long-term use. Significant upregulation of TLR7 / 9 and type I interferon expression has been found 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 The pathological manifestations of lupus mice such as BXSB and SLE were also observed (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 WO2018005586A1, WO2018049089A1, WO2022040293A1, WO2019099336A1, WO2019126083A1, WO2019126082A1, WO2019126113A1, WO2019126242A1, WO2019126253A1, WO2018026620A1, WO2019125977A1 ​​and WO2020048605A1, etc.

[0005] Summary of the Invention

[0006] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0007] in,

[0008] G 5 CR 5a or N; G 6 CR 6a or N;

[0009] Ring B is a spirocycloalkyl or spiroheterocyclyl;

[0010] R a and R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, R 5 , -alkylene-R 5 and wherein the alkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently optionally substituted with one or more R 01 replaced by;

[0011] The condition is that R a and R b Not all hydrogen atoms at the same time;

[0012] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0013] Each R 1 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 、=CR 25 R 26 and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently optionally substituted with one or more R 02 replace;

[0014] Or, two R 1 and the ring atoms to which it is attached together form a ring optionally substituted by one or more R 4 substituted cycloalkyl or heterocyclic groups;

[0015] L is selected from a bond, alkylene, heteroalkylene, C(O), C(O)NR 24 NR 24 C(O), C(O)alkylene and alkyleneC(O), wherein said alkylene and heteroalkylene are each independently optionally substituted with one or more R 02 replaced by;

[0016] Ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0017] Each R 3 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5, nitro, hydroxy, hydroxyalkyl, =NR 24 、=CR 25 R 26 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0018] Each R 4 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 、=CR 25 R 26 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0019] R 5 Selected from-NR 22 R 23 、-C(O)R 20 、-OR 21 、-C(O)OR 21 、-OC(O)R 20 、-OC(O)OR 21 、-C(O)NR 22 R 23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O) v NR 22 R 23 、-NR 24 S(O) v R 20 、-NR 24 S(O) v NR 22 R 23 、-S(O) v OR 21 、-OS(O) v R 20 、-OS(O) v OR21 、-C(=NR 24 )R 20 and -C(=NR 24 )NR 22 R 23 ;

[0020] Each R 20 、R 21 、R 22 、R 23 、R 24 and R c are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, amino, hydroxyl, hydroxyalkyl, -NR 32 R 33 、-OR 31 、-C(O)R 30 、-C(O)OR 31 、-OC(O)R 31 、-OC(O)OR 31 、-C(O)NR 32 R 33 、-NR 34 C(O)R 30 、-NR 34 C(O)NR 32 R 33 、-S(O) v R 30 、-S(O) v NR 32 R 33 、-NR 34 S(O) v R 31 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from one or more R 02 replaced by;

[0021] or, R 22 、R 23 and the nitrogen atom to which it is attached together form a 02 substituted heterocyclic group;

[0022] R 5a 、R 6a 、R 25 and R 26 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, R 5 , -alkylene-R5 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by;

[0023] Each R 01 、R 02 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, amino, hydroxy, hydroxyalkyl, -C(O)R 30 , OR 31 、-C(O)OR 31 、-OC(O)R 30 、-OC(O)OR 31 、-C(O)NR 32 R 33 、-S(O) v R 30 、-S(O) v NR 32 R 33 、-NR 32 R 33 、-NR 34 S(O) v R 30 、-NR 34 C(O)R 30 、-NR 34 C(O)NR 32 R 33 、=CR 35 R 36 、=NR 34 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] Each R 30 、R 31 、R 32 、R 33 and R 34 are the same or different and are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, -NR e R f 、-C(O)NR e R f 、-C(O)Re 、-C(O)OR e , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0025] R 35 and R 36 are the same or different and are each independently selected from hydrogen, halogen, alkyl and haloalkyl;

[0026] R e and R f are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group;

[0027] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0028] s is 0, 1, 2, 3, 4, 5, or 6;

[0029] t is 0, 1, 2, 3, 4, 5, or 6; and

[0030] v is 0, 1, or 2.

[0031] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0032] in,

[0033] G 5 CR 5a or N; G 6 CR 6a or N;

[0034] Ring B is a bispirocycloalkyl group or a bispiroheterocyclyl group;

[0035] R a and R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, R 5 , -alkylene-R 5 and wherein the alkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently optionally substituted with one or more R 01 replaced by;

[0036] The condition is that R a and R b Not all hydrogen atoms at the same time;

[0037] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0038] Each R 1are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 、=CR 25 R 26 and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently optionally substituted with one or more R 02 replace;

[0039] Or, two R 1 and the ring atoms to which it is attached together form a ring optionally substituted by one or more R 4 substituted cycloalkyl or heterocyclic groups;

[0040] L is selected from a bond, alkylene, heteroalkylene, C(O), C(O)NR 24 NR 24 C(O), C(O)alkylene and alkyleneC(O), wherein said alkylene and heteroalkylene are each independently optionally substituted with one or more R 02 replaced by;

[0041] Ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0042] Each R 3 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 、=CR 25 R 26 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0043] Each R 4 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 、=CR 25 R 26, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0044] R 5 Selected from-NR 22 R 23 、-C(O)R 20 、-OR 21 、-C(O)OR 21 、-OC(O)R 20 、-OC(O)OR 21 、-C(O)NR 22 R 23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O) v NR 22 R 23 、-NR 24 S(O) v R 20 、-NR 24 S(O) v NR 22 R 23 、-S(O) v OR 21 、-OS(O) v R 20 、-OS(O) v OR 21 、-C(=NR 24 )R 20 and -C(=NR 24 )NR 22 R 23 ;

[0045] Each R 20 、R 21 、R 22 、R 23 、R 24 and R c are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, amino, hydroxyl, hydroxyalkyl, -NR 32 R 33 、-OR 31 、-C(O)R 30、-C(O)OR 31 、-OC(O)R 31 、-OC(O)OR 31 、-C(O)NR 32 R 33 、-NR 34 C(O)R 30 、-NR 34 C(O)NR 32 R 33 、-S(O) v R 30 、-S(O) v NR 32 R 33 、-NR 34 S(O) v R 31 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from one or more R 02 replaced by;

[0046] or, R 22 、R 23 and the nitrogen atom to which it is attached together form a 02 substituted heterocyclic group;

[0047] R 5a 、R 6a 、R 25 and R 26 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, R 5 , -alkylene-R 5 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by;

[0048] Each R 01 、R 02 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, amino, hydroxy, hydroxyalkyl, -C(O)R 30 , OR 31 、-C(O)OR 31 、-OC(O)R 30 、-OC(O)OR 31 、-C(O)NR 32 R33 、-S(O) v R 30 、-S(O) v NR 32 R 33 、-NR 32 R 33 、-NR 34 S(O) v R 30 、-NR 34 C(O)R 30 、-NR 34 C(O)NR 32 R 33 、=CR 35 R 36 、=NR 34 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0049] Each R 30 、R 31 、R 32 、R 33 and R 34 are the same or different and are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, -NR e R f 、-C(O)NR e R f 、-C(O)R e 、-C(O)OR e , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0050] R 35 and R 36 are the same or different and are each independently selected from hydrogen, halogen, alkyl and haloalkyl;

[0051] R e and R f are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group;

[0052] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0053] s is 0, 1, 2, 3, 4, 5, or 6;

[0054] t is 0, 1, 2, 3, 4, 5, or 6; and

[0055] v is 0, 1, or 2.

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 7- to 14-membered spiroheterocyclyl; in some embodiments, ring B is a 7- to 14-membered monospiroheterocyclyl; in some embodiments, ring B is an 8-, 9-, or 10-membered monospiroheterocyclyl; in some embodiments, ring B is a 10-membered monospiroheterocyclyl; in some embodiments, ring B is a 6- or 5-membered spiroheterocyclyl.

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 7- to 14-membered bispiro heterocyclic group; in some embodiments, ring B is an 8-, 9-, or 10-membered bispiro heterocyclic group; in some embodiments, ring B is selected from *End and G 5 side connection; in some embodiments, ring B contains at least 1 nitrogen atom; in some embodiments, ring B contains at least 1 oxygen atom; in some embodiments, ring B is In some embodiments, Ring B is In some embodiments, Ring B is *End and G 5 Side connections, *end and The end is the fusion site, and the * end is connected to the G 5 Side connection.

[0058] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0059] in,

[0060] G 1 Selected from CR 1a R 1b NR 1c , O and S(O) v ;

[0061] G 2 CR 1d or N;

[0062] R 1a 、R 1b and R 1d The same or different, and each independently is R 0 ; or R 1a 、R 1b Together they form =O;

[0063] R 1c is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group;

[0064] R 0 Selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -OR 21 、-C(O)R 20 、-C(O)OR 21 、-OC(O)R 20 、-C(O)NR 22 R 23 、-alkylene-C(O)NR 22 R 23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O) v NR 22 R 23 、-C(=NR 24 )R 20 、-NR 22 R 23 、-NR 24 S(O) v R 20 , -alkylene-R 5 , hydroxyl, hydroxyalkyl and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently selected from one or more R 02 replaced by;

[0065] n is 0, 1, 2 or 3; r1 is 0, 1 or 2; r2 is 0, 1 or 2;

[0066] m1 is 0, 1, 2, 3, 4, 5, or 6;

[0067] R 1 , G 5 , G 6 、R a 、R b 、R c 、R 20 to R 24 ,v,R 5 , L, Ring E, R 4 , t and R 02 As defined in general formula (I).

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0069] in,

[0070] G 1 , G 2 、R 0 、r1、r2、n、G 5 , G 6 、R a 、R b and R c As defined in general formula (II).

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof:

[0072] in,

[0073] G 1 , G 2 、R 0 、r1、r2、n、G 5 , G 6 、R a 、R b and R c As defined in formula (III), and r1 and r2 are different.

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0075] in,

[0076] G 1 , G 2 、R 0 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 and s are as defined in general formula (II).

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof:

[0078] Among them, G 1 , G 2 , R0, r1, r2, n, G 5 , G 6 、R a 、R c , Ring A, R 3 and s are as defined in formula (IV), and r1 and r2 are different.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof:

[0080] Among them, R 0 、r1、r2、G 5 , G 6 、R a 、R c , Ring A, R 3 and s are as defined in general formula (II).

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 1 is O or CH2; in some embodiments, G 1 It is O.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 1 is 0, and / or n is 1.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 2 is CH or N; in some embodiments, G2 is N.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein r1 is 0 or 1; in some embodiments, r1 is 0; in some embodiments, r1 is 1.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein r2 is 0 or 1; in some embodiments, r2 is 0; in some embodiments, r2 is 1.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 2 is N, and / or r1 is 0 or 1, and / or r2 is 0 or 1; in some embodiments, G 2 is N, and / or r1 is 1, and / or r2 is 1.

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -C 1-6 Alkylene-C(O)NR 22 R 23 、C 1-6 Hydroxyalkyl and R 22 、R 23 , L, Ring E, R 4 and t are as defined in Formula (I); in some embodiments, R 0 A hydrogen atom or -C 1-6 Alkylene-C(O)NR 22 R 23 , R 22 and R 23 As defined in formula (I); in some embodiments, R 0 A hydrogen atom or -C 1-6 Alkylene-C(O)NR 22 R 23 , R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6Alkyl; in some embodiments, R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 0, 1 or 2, R 22 and R 23 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 0 is a hydrogen atom or -CH2C(O)NH2; in some embodiments, R 0 is a hydrogen atom; in some embodiments, R 0 -(CH2) a -3 to 6 membered cycloalkyl, a is 0, 1, 2, 3 or 4; in some embodiments, R 0 -(CH2) a -3 to 6 membered cycloalkyl, a is 0, 1 or 2; in some embodiments, R 0 is -CH2cyclopropyl; in some embodiments, R 0 Selected from hydrogen atoms, -(CH2) a -C(O)NR 22 R 23 and -(CH2) a -3 to 6-membered cycloalkyl, a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 0 -(CH2) a -C(O)NR 22 R 23 , a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C1-6 Alkyl; in some embodiments, R 0 It is -CH2C(O)NH2.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 1 The same or different, and each independently selected from C 1-6 Alkyl, -C 1-6 Alkylene-C(O)NR 22 R 23 、C 1- 6-Hydroxyalkyl and R 22 、R 23 , L, Ring E, R 4 and t are as defined in Formula (I); in some embodiments, R 1 -C 1-6 Alkylene-C(O)NR 22 R 23 , R 22 and R 23 As defined in formula (I); in some embodiments, R 1 -C 1-6 Alkylene-C(O)NR 22 R 23 , R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 1 -(CH2) a -C(O)NR 22 R 23 , a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 1 is -CH2C(O)NH2; in some embodiments, R 1 -(CH2) a -3 to 6 membered cycloalkyl, a is 0, 1, 2, 3 or 4; in some embodiments, R 1 -(CH2) a -3 to 6 membered cycloalkyl, a is 0, 1 or 2; in some embodiments, R 1 is -CH2cyclopropyl; in some embodiments, R 1 Selected from hydrogen atoms, -(CH2) a -C(O)NR 22 R 23 and -(CH2)a -3 to 6-membered cycloalkyl, a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0090] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; in some embodiments, m is 0 or 1; in some embodiments, m is 0; in some embodiments, m is 1.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 -C 1-6 Alkylene-C(O)NR 22 R 23 , and / or m is 0 or 1, R 22 and R 23 As defined in formula (I); in some embodiments, R 1 -(CH2) a -C(O)NR 22 R 23 , a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl, and / or m is 0 or 1.

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 5 is CH or N; in some embodiments, G 5 CR 5a , R 5a As defined in formula (I); in some embodiments, G 5 is N; in some embodiments, G 5 For CH.

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 6 is CH or N; in some embodiments, G 6 CR 6a , R 6a As defined in formula (I); in some embodiments, G 6 is N; in some embodiments, G6 For CH.

[0094] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein G 5 CH or N, and / or G 6 is CH or N; in some embodiments, G 5 CH or N, and / or G 6 is CH; in some embodiments, G 5 CH, and / or G 6 is CH; in some embodiments, G 5 N, and / or G 6 For CH.

[0095] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (III-1), (III-2) or pharmaceutically acceptable salts thereof, wherein R a and R b are the same or different and are each independently selected from hydrogen atom, halogen, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy, C 1-6 Hydroxyalkyl and Ring A, R 3 and s are as defined in formula (I), R a and R b Not all hydrogen atoms.

[0096] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (III-1), (III-2) or pharmaceutically acceptable salts thereof, wherein R a C 1-6 Alkyl, R b for or R a for R b C 1-6 Alkyl, Ring A, R 3 and s are as defined in formula (I);

[0097] In some embodiments, R a C 1-6 Alkyl, R b for Ring A, R 3 and s are as defined in Formula (I); in some embodiments, R a for R b C 1-6 Alkyl, Ring A, R 3 and s are as defined in formula (I);

[0098] In some embodiments, R a is isopropyl, R b for or R a for R b It is isopropyl.

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; in some embodiments, R a for Ring A, R 3 and s are as defined in formula (I);

[0100] In some embodiments, R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl; in some embodiments, R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 alkyl halide;

[0101] In some embodiments, R a is isopropyl; in some embodiments, R a for

[0102] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III), (III-1), (III-2) or pharmaceutically acceptable salts thereof, wherein R b C 1-6 Alkyl; in some embodiments, R b for Ring A, R 3 and s are as defined in Formula (I); in some embodiments, R b is isopropyl; in some embodiments, R b for In some embodiments, R bSelected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl; in some embodiments, R b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a 9-membered heteroaryl group; in some embodiments, ring A is a triazolopyridinyl group; in some embodiments, ring A is In some embodiments, Ring A is The end is connected to the pyrrole ring.

[0104] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, hydroxy and C 1-6 Hydroxyalkyl; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; in some embodiments, each R 3 The same or different, and each independently is C 1-6 Alkyl or C 1-6 Alkoxy; in some embodiments, each R 3 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

[0105] In some embodiments of the present disclosure, each R 3 are the same or different and are each independently selected from halogen, C1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy and 3- to 6-membered cycloalkyl.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 3 The same or different, and each independently is C 1-6 Alkyl or C 1-6 alkoxy, and / or s is 0, 1 or 2; in some embodiments, each R 3 The same or different, and each independently is C 1-6 alkyl, and / or s is 0, 1 or 2; in some embodiments, R 3 is methyl, and / or s is 1 or 2.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 2; in some embodiments, s is 1 or 2; in some embodiments, s is 2.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein for s1 is 0, 1, 2, or 3, R 3 As defined in formula (I); in some embodiments, for

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein s1 is 0, 1 or 2; in some embodiments, s1 is 1; in some embodiments, s1 is 2.

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R c Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R c A hydrogen atom or C 1-6Alkyl; in some embodiments, R c A hydrogen atom.

[0111] In some embodiments of the present disclosure, R c A hydrogen atom or C 1-6 Alkyl, and / or R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R c is a hydrogen atom, and / or R 22 and R 23 A hydrogen atom.

[0112] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein L is selected from a single bond, C 1-6 Alkylene and C(O); in some embodiments, L is a single bond or C 1-6 Alkylene; in some embodiments, L is C 1-6 Alkylene; in some embodiments, L is a bond or (CH2) a , a is 0, 1, 2, 3, 4, 5 or 6; in some embodiments, L is (CH2) a , a is 0, 1, 2, 3 or 4; in some embodiments, L is (CH2) a , a is 0, 1 or 2; in some embodiments, L is CH2.

[0113] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring E is a 3- to 6-membered cycloalkyl or a 4- to 7-membered heterocyclyl; in some embodiments, ring E is a 3- to 6-membered cycloalkyl; in some embodiments, ring E is a cyclopropyl.

[0114] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, hydroxy, amino and C 1-6 Hydroxyalkyl.

[0115] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1; in some embodiments, t is 0.

[0116] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from-NR 22 R 23 、-C(O)R 20 、-C(O)OR 21 、- C(O)NR 22 R 23 、-S(O) v R 20 and -S(O) v NR 22 R 23 ; R 20 、R 21 、R 22 、R 23 and v are as defined in Formula (I); in some embodiments, R 5 -C(O)NR 22 R 23 , R 22 and R 23 As defined in formula (I); in some embodiments, R 5 It is -C(O)NH2.

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 5a and R 6a are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl; in some embodiments, R 5a and R 6a are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; in some embodiments, R 5a and R6a are the same or different and are each independently selected from hydrogen atom, halogen, C 1- 6 alkyl and cyano; in some embodiments, R 5a and R 6a All are hydrogen atoms.

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 20 、R 21 and R 24 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 20 、R 21 、R 22 、R 23 and R 24 are the same or different and are each independently a hydrogen atom or a methyl group.

[0119] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 22 and R 23 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, 3 to 6 membered cycloalkyl C 1-6 Alkyl and 3 to 6 membered heterocyclic C 1-6 Alkyl; in some embodiments, R 22 and R 23 are the same or different and are each independently selected from hydrogen atom, C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 22 and R 23 are the same or different and are each independently selected from hydrogen atom, C 1-6 alkyl, and 3 to 6 membered cycloalkyl; in some embodiments, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 22 and R23 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 22 and R 23 All are hydrogen atoms.

[0120] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 30 、R 31 、R 32 、R 33 、R 34 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0121] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), (III-1), (III-2), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 02 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, hydroxy, amino, C 1-6 hydroxyalkyl, 3 to 6 membered cycloalkyl, and 3 to 6 membered heterocyclyl; in some embodiments, each R 02 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, hydroxy, amino and C 1-6 Hydroxyalkyl; in some embodiments, each R 02 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxy and amino groups.

[0122] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or their pharmaceutically acceptable salts, wherein the two R 1 and the same carbon atom to which it is attached together form a 4 Substituted spirocycloalkyl or spiroheterocyclyl; or two R 1 and the two adjacent carbon atoms to which it is attached together form an optionally substituted one or more R 4 Substituted fused cycloalkyl or fused heterocyclic group; or two R 1 and the two intervening carbon atoms to which it is attached together form a carbon atom optionally substituted by one or more R4 Substituted bridged cycloalkyl or bridged heterocyclic group; R 4 As defined in general formula (I).

[0123] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein m1 is 0, 1 or 2; in some embodiments, m1 is 0.

[0124] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 1 are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0125] In some embodiments of the present disclosure, a is 0, 1 or 2; in some embodiments, a is 1.

[0126] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2) or a pharmaceutically acceptable salt thereof, wherein R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 0, 1 or 2, R 22 and R 23 The same or different, and each independently a hydrogen atom or a methyl group; G 2 is N, r1 is 0 or 1, r2 is 0 or 1; G 1 is O, n is 1; G 5 CH or N; G 6 CH or N; R a is isopropyl, R b for or R b is isopropyl, R a for R c A hydrogen atom.

[0127] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (IV-1), (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 0, 1 or 2, R 22 and R 23 The same or different, and each independently a hydrogen atom or a methyl group; G 2is N, r1 is 0 or 1, r2 is 0 or 1; G 1 is O, n is 1; G 5 CH or N; G 6 CH or N; R a C 1-6 Alkyl; R c is a hydrogen atom; Ring A is The end is connected to the pyrrole ring; each R 3 The same or different, and each independently is C 1-6 Alkyl or C 1-6 alkoxy; and s is 0, 1 or 2.

[0128] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein r1 is 0 or 1, r2 is 0 or 1; G 5 CH or N; G 6 CH or N; R c A hydrogen atom or C 1-6 Alkyl; R a C 1-6 alkyl, ring A is a 5- to 10-membered heteroaryl; each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; s is 0, 1 or 2; R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -C 1-6 Alkylene-C(O)NR 22 R 23 、C 1-6 Hydroxyalkyl and R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; L is (CH2) a , a is 0, 1 or 2; ring E is a 3- to 6-membered cycloalkyl group; t is 0.

[0129] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein r1 is 1, r2 is 1; G 5 CH or N; G 6 CH or N; R c is a hydrogen atom; R a C 1-6 Alkyl, Ring A is triazolopyridinyl; each R 3 The same or different, and each independently is C 1-6Alkyl; s is 0, 1 or 2; R 0 Selected from hydrogen atoms, -(CH2) a -C(O)NR 22 R 23 and -(CH2) a -3 to 6-membered cycloalkyl, a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0130] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein r1 is 1, r2 is 1; G 5 CH or N; G 6 CH; R c is a hydrogen atom; R a C 1-6 Alkyl, Ring A is The end is connected to the pyrrole ring; each R 3 The same or different, and each independently is C 1-6 Alkyl; s is 0, 1 or 2; R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 1, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0131] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein r1 is 0 or 1, r2 is 0 or 1; G 5 CH or N; G 6 CH or N; R c A hydrogen atom or C 1-6 Alkyl; R a C 1-6 alkyl, ring A is a 5- to 10-membered heteroaryl; each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; s is 0, 1 or 2; R 0 -(CH2) a -3 to 6-membered cycloalkyl, a is 0, 1 or 2.

[0132] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein r1 is 1, r2 is 1; G 5 CH or N; G 6 CH or N; R c is a hydrogen atom; R a C 1-6 Alkyl, Ring A is triazolopyridinyl; each R 3 The same or different, and each independently is C 1-6 Alkyl; s is 0, 1 or 2; R 0 -(CH2) a -3 to 6-membered cycloalkyl, a is 0, 1 or 2.

[0133] Table A Typical compounds of the present disclosure include, but are not limited to:

[0134] Another aspect of the present disclosure relates to a compound represented by formula (IIA) or a salt thereof:

[0135] in,

[0136] R W is an amino protecting group; in some embodiments, is tert-butyloxycarbonyl;

[0137] G 2 is N;

[0138] G 1 、r1、r2、n、R 1 、m1、G 5 , G 6 、R a 、R b and R c As defined in general formula (II).

[0139] Another aspect of the present disclosure relates to a compound represented by formula (IIIA) or a salt thereof:

[0140] in,

[0141] R W is an amino protecting group; in some embodiments, is tert-butyloxycarbonyl;

[0142] G 2 is N;

[0143] G 1 、r1、r2、n、G 5 , G 6 、R a 、R band R c As defined in general formula (III).

[0144] Another aspect of the present disclosure relates to a compound represented by the general formula (III-1A) or (III-2A) or a salt thereof:

[0145] Among them, R W is an amino protecting group; in some embodiments, is tert-butyloxycarbonyl;

[0146] G 2 is N;

[0147] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b and R c As defined in general formula (III-1) or (III-2).

[0148] Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof:

[0149] in,

[0150] R W is an amino protecting group; in some embodiments, is tert-butyloxycarbonyl;

[0151] G 2 is N;

[0152] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 and s are as defined in formula (IV).

[0153] Another aspect of the present disclosure relates to a compound represented by formula (IV-1A) or (IV-2A) or a salt thereof:

[0154] in,

[0155] R W is an amino protecting group; in some embodiments, is tert-butyloxycarbonyl;

[0156] G 2 is N;

[0157] G 1 、r1、r2、n、G 5 , G 6 、R a、R c , Ring A, R 3 and s are as defined in general formula (IV-1) or (IV-2).

[0158] Another aspect of the present disclosure relates to a compound represented by the general formula (VA) or (Va) or a salt thereof:

[0159] Among them, R W is an amino protecting group; in some embodiments, is tert-butyloxycarbonyl;

[0160] r1, r2, G 5 , G 6 、R a 、R c , Ring A, R 3 and s are as defined in formula (V).

[0161] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0162] 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:

[0163] The compound represented by general formula (IIA) or its salt is subjected to deprotection reaction to obtain R 0 A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0164] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (II) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0165] Among them, G 2 is N;

[0166] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0167] X is halogen, in some embodiments Br;

[0168] G 1 、r1、r2、n、R 1 、m1、G 5, G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (II).

[0169] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0170] The compound represented by general formula (IIIA) or its salt is subjected to deprotection reaction to obtain R 0 A compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0171] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (III) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

[0172] Among them, G 2 is N;

[0173] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0174] X is halogen, in some embodiments Br;

[0175] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (III).

[0176] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0177] The compound represented by the general formula (III-1A) or its salt is subjected to a deprotection reaction to obtain R 0 A compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0178] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (III-1) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0179] Among them, G 2 is N;

[0180] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0181] X is halogen, in some embodiments Br;

[0182] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (III-1).

[0183] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0184] The compound represented by the general formula (III-2A) or its salt is subjected to a deprotection reaction to obtain R 0 A compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0185] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (III-2) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0186] Among them, G 2 is N;

[0187] R Wis an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0188] X is halogen, in some embodiments Br;

[0189] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (III-2).

[0190] 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:

[0191] The compound represented by the general formula (IVA) or its salt is subjected to a deprotection reaction to obtain R 0 A compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0192] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (IV) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0193] Among them, G 2 is N;

[0194] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0195] X is halogen, in some embodiments Br;

[0196] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 22 and R 23 As defined in general formula (IV).

[0197] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0198] The compound represented by the general formula (IV-1A) or its salt is subjected to a deprotection reaction to obtain R 0 A compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0199] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (IV-1) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0200] Among them, G 2 is N;

[0201] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0202] X is halogen, in some embodiments Br;

[0203] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 22 and R 23 As defined in general formula (IV-1).

[0204] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0205] The compound represented by the general formula (IV-2A) or its salt is subjected to deprotection reaction to obtain R 0 A compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0206] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (IV-2) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23The compound shown or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0207] Among them, G 2 is N;

[0208] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0209] X is halogen, in some embodiments Br;

[0210] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 22 and R 23 As defined in general formula (IV-2).

[0211] 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:

[0212] The compound represented by the general formula (VA) or its salt is subjected to deprotection reaction to obtain R 0 A compound represented by the general formula (V) wherein NH is a hydrogen atom, or a pharmaceutically acceptable salt thereof; or

[0213] The compound represented by general formula (Va) or its salt and XR 0 or its salt undergoes a nucleophilic substitution reaction to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof;

[0214] Among them, R W is an amino protecting group, in some embodiments, tert-butyloxycarbonyl; X is a halogen, in some embodiments, Br;

[0215] R 0 Selected from halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -OR 21 、-C(O)R 20 、-C(O)OR 21 、-OC(O)R 20 、-C(O)NR 22 R 23 、-alkylene-C(O)NR 22 R23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O) v NR 22 R 23 、-C(=NR 24 )R 20 、-NR 22 R 23 、-NR 24 S(O) v R 20 , -alkylene-R 5 , hydroxyl, hydroxyalkyl and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently selected from one or more R 02 replaced by;

[0216] r1, r2, G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 20 、R 21 、R 22 、R 23 、R 5 、R 02 and v are as defined in formula (V).

[0217] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by Formulas (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0218] The present disclosure further relates to the use of compounds shown in Formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for inhibiting one or more of TLR7, TLR8 or TLR9; in some embodiments, in the preparation of medicaments for inhibiting TLR7 and TLR8.

[0219] The present disclosure further relates to the use of compounds shown in Formulae (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by one or more of TLR7, TLR8 or TLR9; in some embodiments, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by TLR7 and TLR8.

[0220] The present disclosure further relates to the use of compounds shown in Formulae (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing inflammatory or autoimmune diseases; in some embodiments, the inflammatory or autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjogren's syndrome.

[0221] The present disclosure further relates to a method for inhibiting one or more of TLR7, TLR8 or TLR9, comprising administering to a patient in need thereof a compound represented by Formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the method comprises inhibiting TLR7 and TLR8.

[0222] The present disclosure further relates to a method for treating and / or preventing diseases or conditions mediated by one or more of TLR7, TLR8, or TLR9, comprising administering to a patient in need thereof a compound represented by Formula (I), (II), (II-1), (II-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the method is a method for treating and / or preventing diseases or conditions mediated by TLR7 and TLR8.

[0223] The present disclosure further relates to a method for treating and / or preventing an inflammatory or autoimmune disease, comprising administering to a patient in need thereof a compound represented by Formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the inflammatory or autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome.

[0224] The present disclosure further relates to a compound represented by formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0225] The present disclosure further relates to a compound shown in Formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used to inhibit one or more of TLR7, TLR8 or TLR9; in some embodiments, it is used to inhibit TLR7 and TLR8.

[0226] The present disclosure further relates to a compound shown in Formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing diseases or conditions mediated by one or more of TLR7, TLR8 or TLR9; in some embodiments, for treating and / or preventing diseases or conditions mediated by TLR7 and TLR8.

[0227] The present disclosure further relates to a compound shown in Formula (I) to (V), (III-1), (III-2), (IV-1), (IV-2) 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; in some embodiments, the inflammatory or autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjogren's syndrome.

[0228] In view of their activity as selective inhibitors of TLR7, TLR8 or TLR9, the compounds of general formula (I) to (IV), (III-1), (III-2), (IV-1), (IV-2) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same can be used to treat TLR7, TLR8 or TLR9 family receptor-related diseases, respectively, 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, alopecia areata; autoinflammatory diseases including Cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), family Metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders including bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative disorders including acute myeloid leukemia and chronic myeloid leukemia; angiogenic disorders including those involving solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases including sepsis, septic shock, and shigellosis; neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, tumor diseases, and viral diseases including metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS.

[0229] 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 erythematosus, 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, and leukemia. Enteritis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's 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 solid tumors, ocular neoplasia Tube 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, local 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, and the disease related to prostaglandin endoperoxidase synthase-2 and pemphigus vulgaris.In some embodiments, the disease is selected from those of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris.In some embodiments, its disease is ischemia reperfusion injury, and the ischemia reperfusion injury is cerebral ischemia reperfusion injury caused by stroke or myocardial ischemia reperfusion injury caused by myocardial infarction. In some embodiments, the disorder is multiple myeloma.

[0230] As a general guide, the active compounds of the present disclosure are presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms can range from 0.1 to 1000 mg.

[0231] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0232] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0233] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0234] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0235] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical formulation. Tablets contain the active ingredient and, in admixture, nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0236] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0237] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0238] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents as described above may be added to provide a palatable formulation. These compositions may be preserved by the addition of antioxidants.

[0239] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0240] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solutions and microemulsions may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0241] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspensions for intramuscular and subcutaneous administration. The suspension can be prepared using known techniques with suitable dispersants or wetting agents and suspending agents. 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 suspending media. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

[0242] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0243] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the 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 optimal 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.

[0244] Terminology

[0245] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0246] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 In some embodiments, the alkyl group has an alkyl group with 1 to 12 carbon atoms (i.e., C 1-12 alkyl), in some embodiments an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituent being selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0247] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- is replaced by a heteroatom selected from N, O, S and S(O); 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 point of attachment, the substituent being selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl 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.

[0248] 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 In some embodiments, the alkylene group has an alkylene group of 1 to 12 carbon atoms (i.e., C 1-12 alkylene), in some embodiments an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituents are selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0249] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- is substituted by a heteroatom selected from N, O, S and S(O); wherein the alkylene is as defined above; the heteroalkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, with the substituent being selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0250] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 In some embodiments, the alkenyl group has an alkenyl group of 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, with the substituents being selected from one or more of a D atom, an alkoxy group, a halogen, 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.

[0251] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 In some embodiments, the alkynyl group has 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. When substituted, it can be substituted at any available point of attachment, and the substituent is selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0252] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0253] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl group includes cycloalkyl groups having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), in some embodiments cycloalkyl groups having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and in some embodiments cycloalkyl groups having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

[0254] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0255] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0256] The term "spiroalkyl" refers to a polycyclic ring system that shares a carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spiroalkyl). In some embodiments, the spiroalkyl has 6 to 14 ring atoms (i.e., 6 to 14-membered spiroalkyl), and in some embodiments, has 7 to 10 ring atoms (i.e., 7 to 10-membered spiroalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), in some embodiments monospirocycloalkyl or bispirocycloalkyl, in some embodiments 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 monospirocycloalkyl. Non-limiting examples include:

[0257] Its connection point can be at any position;

[0258] wait.

[0259] The term "fused cycloalkyl" refers to a polycyclic ring system that shares two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl has 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), and in some embodiments, has 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), in some embodiments bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0260] Its connection point can be at any position; wait.

[0261] The term "bridged cycloalkyl" refers to a full-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0262] Its connection point can be at any position.

[0263] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituent being selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0264] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). In some embodiments, the heterocyclyl has 12 to 15 ring atoms (i.e., a 12- to 15-membered heterocyclyl). In some embodiments, the heterocyclyl group has 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl); in some embodiments, the heterocyclyl group has 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl); in some embodiments, the heterocyclyl group has 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl), the heterocyclyl group has 4 to 6 ring atoms (i.e., 4- to 6-membered heterocyclyl), or the heterocyclyl group has 5 to 7 ring atoms (i.e., 5- to 7-membered heterocyclyl); in some embodiments, the heterocyclyl group has 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl).

[0265] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0266] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0267] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). In some embodiments, the spiro heterocyclic radical has a spiro heterocyclic radical (i.e., 7 to 14 yuan spiro heterocyclic radical) of 7 to 14 ring atoms, and in some embodiments, has a spiro heterocyclic radical (i.e., 7 to 10 yuan spiro heterocyclic radical) of 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), in some embodiments, monospiro heterocyclic radical or dispiro heterocyclic radical, in some embodiments, 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0268] wait.

[0269] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). In some embodiments, the fused heterocyclic group has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), in some embodiments, a fused heterocyclic group of 6 to 10 ring atoms (i.e., a 6 to 10-membered fused heterocyclic group), and in some embodiments, a 6-membered or 7-membered fused heterocyclic group. The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (e.g., tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), in some embodiments, a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, and in some embodiments, a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0270] wait.

[0271] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxoed, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclyl). In some embodiments, the bridged heterocyclic group has a bridged heterocyclic group of 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), in some embodiments, a bridged heterocyclic group of 6 to 10 ring atoms (i.e., a 6- to 10-membered bridged heterocyclic group), and in some embodiments, a 6-, 7-, or 8-membered bridged heterocyclic group. According to the number of constituent rings, it can be divided into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (such as a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), and in some embodiments, a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group. Non-limiting examples include:

[0272] wait.

[0273] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituents being selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0274] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 15 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms (i.e., 6 to 15-membered aromatic group). In some embodiments, the aryl group has an aryl group with 12 to 15 ring atoms (i.e., 12 to 15-membered aromatic group), and in some embodiments, the aryl group has an aryl group with 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the point of attachment is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0275] wait.

[0276] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituent being selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0277] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), and has 5 to 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms (i.e., a 5- to 15-membered heteroaryl). In some embodiments, the heteroaryl has 9 ring atoms (i.e., a 9-membered heteroaryl). In some embodiments, the heteroaryl group has 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), in some embodiments, 9 to 10 ring atoms (i.e., a 9- to 10-membered heteroaryl), and in some embodiments, 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0278] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0279] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0280] wait.

[0281] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituents being selected from one or more of a D atom, a halogen, an alkyl, 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 group.

[0282] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0283] The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0284] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0285] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0286] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0287] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0288] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0289] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0290] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0291] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0292] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0293] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; in some embodiments, -alkyl-alkoxy.

[0294] The term "methylidene" refers to =CH2.

[0295] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0296] The term "hydroxy" refers to -OH.

[0297] The term "mercapto" refers to -SH.

[0298] The term "amino" refers to -NH2.

[0299] The term "cyano" refers to -CN.

[0300] The term "nitro" refers to -NO2.

[0301] The term "oxo" or "oxo" refers to "=0".

[0302] The term "carbonyl" refers to C=O.

[0303] The term "carboxy" refers to -C(O)OH.

[0304] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0305] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0306] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0307] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another. It includes all possible tautomers, that is, in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0308] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0309] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0310] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., in some embodiments, deuterium.

[0311] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0312] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0313] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0314] "Substitution" or "substituted" means that one or more hydrogen atoms, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. One skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0315] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0316] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0317] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active agent. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0318] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0319] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0320] 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 within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0321] Synthesis method of the disclosed compound

[0322] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0323] Option 1

[0324] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0325] The compound represented by general formula (IIA) or its salt is subjected to deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0326] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (II) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0327] Among them, G 2 is N;

[0328] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0329] X is halogen, in some embodiments Br;

[0330] G 1 、r1、r2、n、R 1 、m1、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (II).

[0331] Option 2

[0332] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0333] The compound represented by general formula (IIIA) or its salt is subjected to deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0334] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (III) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

[0335] Among them, G 2 is N;

[0336] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0337] X is halogen, in some embodiments Br;

[0338] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (III).

[0339] Option 3

[0340] The present invention discloses a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0341] The compound represented by the general formula (III-1A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0342] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (III-1) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0343] Among them, G 2 is N;

[0344] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0345] X is halogen, in some embodiments Br;

[0346] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23 As defined in general formula (III-1).

[0347] Option 4

[0348] The present invention discloses a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0349] The compound represented by general formula (III-2A) or its salt is subjected to deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0350] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (III-2) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0351] Among them, G 2 is N;

[0352] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0353] X is halogen, in some embodiments Br;

[0354] G 1 、r1、r2、n、G 5 , G 6 、R a 、R b 、R c 、R 22 and R 23As defined in general formula (III-2).

[0355] Plan 5

[0356] The present invention discloses a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0357] The compound represented by general formula (IVA) or its salt is subjected to deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0358] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (IV) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0359] Among them, G 2 is N;

[0360] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0361] X is halogen, in some embodiments Br;

[0362] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 22 and R 23 As defined in general formula (IV).

[0363] Plan 6

[0364] The present invention discloses a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0365] The compound represented by the general formula (IV-1A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0366] Optionally, the preparation method further comprises R0 A compound represented by the general formula (IV-1) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0367] Among them, G 2 is N;

[0368] R W is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0369] X is halogen, in some embodiments Br;

[0370] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 22 and R 23 As defined in general formula (IV-1).

[0371] Plan 7

[0372] The present invention discloses a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0373] The compound represented by the general formula (IV-2A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom;

[0374] Optionally, the preparation method further comprises R 0 A compound represented by the general formula (IV-2) or a salt thereof wherein the compound is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes nucleophilic substitution reaction under alkaline conditions to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0375] Among them, G 2 is N;

[0376] RW is an amino protecting group, in some embodiments, is tert-butyloxycarbonyl;

[0377] X is halogen, in some embodiments Br;

[0378] G 1 、r1、r2、n、G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 22 and R 23 As defined in general formula (IV-2).

[0379] Plan 8

[0380] The present invention discloses a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0381] The compound represented by the general formula (VA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain R 0 A compound represented by the general formula (V) wherein NH is a hydrogen atom, or a pharmaceutically acceptable salt thereof; or

[0382] The compound represented by general formula (Va) or its salt and XR 0 or its salt undergoes a nucleophilic substitution reaction under alkaline conditions to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof;

[0383] Among them, R W is an amino protecting group, in some embodiments, tert-butyloxycarbonyl; X is a halogen, in some embodiments, Br;

[0384] R 0 Selected from halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -OR 21 、-C(O)R 20 、-C(O)OR 21 、-OC(O)R 20 、-C(O)NR 22 R 23 、-alkylene-C(O)NR 22 R 23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O)v NR 22 R 23 、-C(=NR 24 )R 20 、-NR 22 R 23 、-NR 24 S(O) v R 20 , -alkylene-R 5 , hydroxyl, hydroxyalkyl and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently selected from one or more R 02 replaced by;

[0385] r1, r2, G 5 , G 6 、R a 、R c , Ring A, R 3 ,s,R 20 、R 21 、R 22 、R 23 、R 5 、R 02 and v are as defined in formula (V).

[0386] 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, trifluoroacetic acid, formic acid, acetic acid, glacial acetic acid, glacial acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf; in some embodiments, trifluoroacetic acid.

[0387] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; in some embodiments, triethylamine.

[0388] The reaction in the above steps is carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof. DETAILED DESCRIPTION

[0389] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0390] Example

[0391] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0392] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0393] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0394] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)

[0395] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0396] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0397] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0398] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0399] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0400] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0401] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0402] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0403] 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, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0404] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0405] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0406] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0407] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0408] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0409] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0410] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0411] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0412] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0413] Example 1-p1, 1-p2

[0414] 6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]1-p1

[0415] 5-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]1-p2

[0416] first step

[0417] Methyl 5-((1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-iodonicotinate 1c

[0418] 5-Hydroxy-6-iodonicotinic acid methyl ester 1a (2 g, 9.38 mmol, prepared by the method disclosed in the literature "European Journal of Medicinal Chemistry, 2018, vol. 149, p. 110-121") and 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1b (2.75 g, 9.86 mmol, prepared by the method disclosed in the literature "ACS Medicinal Chemistry" Letters, 2021, vol. 12, #9, p. 1464-1469) was dissolved in tetrahydrofuran (60 mL), and triphenylphosphine (3.7 g, 14.1 mmol) and diisopropyl azodicarboxylate (2.86 g, 14.14 mmol) were added under ice bath. The reaction was restored to room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 1c (4.77 g, yield: 107%).

[0419] MS m / z(ESI):475.2[M+1].

[0420] Step 2

[0421] 1'-(tert-Butyl)6-methyl2H-spiro[furo[3,2-b]pyridine-3,4'-piperidine]-1',6-dicarboxylate 1d

[0422] Compound 1c (4.77 g, 10.05 mmol) and tributyltin hydride (3.5 g, 12.06 mmol, Shanghai Titan) were dissolved in toluene (80 mL), and azobisisobutyronitrile (1.78 g, 10.84 mmol) was added. The mixture was heated to 115° C. under a nitrogen atmosphere and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ether (50 mL). A 10% aqueous potassium fluoride solution (50 mL) was added and stirred for 3.5 hours. The organic phase was separated, washed sequentially with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 1d (2.7 g, yield: 77%).

[0423] MS m / z(ESI):349.2[M+1].

[0424] Step 3

[0425] 1'-(tert-Butoxycarbonyl)-2H-spiro[furo[3,2-b]pyridine-3,4'-piperidine]-6-carboxylic acid 1e

[0426] Compound 1d (2.7 g, 7.75 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), and lithium hydroxide monohydrate (655 mg, 15.6 mmol) was added and stirred for 2 hours. Methyl tert-butyl ether (50 mL) was added to the reaction solution for washing. The organic phase was separated, and the pH of the aqueous phase was adjusted to 4-5 with 1N hydrochloric acid. The mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 1e (2.5 g). The product was used directly in the next reaction without purification.

[0427] MS m / z(ESI):333.2[M-1].

[0428] Step 4

[0429] tert-Butyl 6-amino-2H-spiro[furo[3,2-b]pyridine-3,4'-piperidine]-1'-carboxylate 1f

[0430] The crude compound 1e (100 mg, 299.07 μmol) and triethylamine (80 mg, 790.59 μmol) were mixed in N,N-dimethylformamide (4 mL), and diphenylphosphoryl azide (150 mg, 545.06 μmol, Shanghai Shaoyuan) was added. After stirring for 2 hours, water (2 mL) was added and the mixture was heated to 100°C for 16 hours. After the reaction solution cooled to room temperature, it was diluted with water and extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 1f (60mg, yield: 65.6%).

[0431] MS m / z(ESI):306.2[M+1].

[0432] Step 5

[0433] tert-Butyl 6-amino-5-bromo-2H-spiro[furo[3,2-b]pyridine-3,4'-piperidine]-1'-carboxylate 1g

[0434] Compound 1f (50 mg, 163.73 μmol) was dissolved in acetonitrile (2 mL), and N-bromosuccinimide (29 mg, 162.93 μmol) was added under ice-cooling. The reaction was carried out at 0°C for 30 minutes. Saturated sodium thiosulfate was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give 1 g of the title compound (60 mg, yield: 95.3%).

[0435] MS m / z(ESI):327.9[M-55].

[0436] Step 6

[0437] tert-Butyl 6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]-1'-carboxylate 1i-1

[0438] tert-Butyl 5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]-1'-carboxylate 1i-2

[0439] Compound 1g (60 mg, 156.14 μmol) and 7,8-dimethyl-6-(3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[1,5-a]pyridine 1h (40 mg, 187.54 μmol, prepared by the method disclosed in Example 7 on page 46 of the specification of patent application "CN114057734A") were dissolved in N,N-dimethylacetamide (2 mL), and potassium carbonate (65 mg, 470.31 μmol) and lithium chloride (7 mg, 165.11 μmol) were added. Tetrakis(triphenylphosphine)palladium (27 mg, 23.36 μmol) was added under a nitrogen atmosphere, and the reaction was stirred at 120°C for 18 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), washed with water and saturated sodium chloride solution in that order, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to obtain a crude mixture of the title compounds 1i-1 and 1i-2 (80 mg). The product was used directly in the next step without purification.

[0440] MS m / z(ESI):517.3[M+1].

[0441] Step 7

[0442] 6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]1-p1

[0443] 5-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]1-p2

[0444] A mixture of compounds 1i-1 and 1i-2 (80 mg, 154.8 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (1‰ trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compounds 1-p1 trifluoroacetate (longer retention time) and 1-p2 trifluoroacetate (shorter retention time), which were respectively dissolved in methanol and adjusted to pH>7 by adding N,N-diisopropylethylamine. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30mL / min) to obtain the title compounds 1-p1 (5.5mg, yield: 8.5%) and 1-p2 (8.3mg, yield: 12.9%), respectively.

[0445] MS m / z(ESI):417.2[M+1].

[0446] Single configuration compound (longer retention time): 1-p1 (5.5 mg, yield: 8.5%)

[0447] HPLC analysis: retention time 1.13 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, DMSO-d6): δ10.95(s,1H),8.75(s,1H),8.47(s,1H),7.02(s,1H),4.48(s,2H),3.13(d,2H),2. 85(q,1H),2.69-2.61(m,2H),2.59(s,3H),2.18(s,3H),1.89(d,2H),1.60(d,2H),1.41(d,6H),1.24(s,1H).

[0448] Single configuration compound (shorter retention time): 1-p2 (8.3 mg, yield: 12.9%)

[0449] HPLC analysis: retention time 1.12 minutes, purity: 92% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0450] 1 H NMR (500MHz, CD3OD): δ8.46(s,1H),8.38(s,1H),7.13(s,1H),4.54(s,2H),3.18(ddt,2H),3.05(p,1H),2. 81-2.70(m,2H),2.67(s,3H),2.23(s,3H),2.07-1.95(m,2H),1.76-1.64(m,2H),1.38(d,3H),1.28(d,3H).

[0451] Example 2

[0452] 2-(5-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidin]-1'-yl)acetamide

[0453] Compound 1-p2 (17 mg, 40.8 μmol) and triethylamine (21 mg, 207.5 μmol) were mixed in N,N-dimethylformamide (2 mL), and 2-bromoacetamide 2a (6 mg, 43.5 μmol, Shanghai Shaoyuan) was added. After stirring for 2 hours, the reaction solution was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 2 (5 mg, yield: 25.8%).

[0454] MS m / z(ESI):474.2[M+1].

[0455] 1 H NMR (500MHz, CD3OD): δ8.48(s,1H),8.38(s,1H),7.14(s,1H),4.56-4.50(m,2H),3.09-3.02(m,1H),2.99(d,2H),2.9 0(ddd,2H),2.68(s,3H),2.29-2.23(m,3H),2.22(s,3H),2.18(dd,1H),1.73-1.64(m,2H),1.38(d,3H),1.28(d,3H).

[0456] Example 3

[0457] 2-(6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidin]-1'-yl)acetamide 3

[0458] The synthetic route in Example 2 was adopted, and the raw material compound 1-p2 was replaced by compound 1-p1 to obtain the title compound 3 (3 mg, yield: 26.3%).

[0459] MS m / z(ESI):474.2[M+1].

[0460] 1 H NMR (500MHz, CD3OD): δ8.61(s,1H),8.41(s,1H),7.01(s,1H),4.50(s,2H),3.19-3.12(m, 4H),3.03(p,1H),2.66(s,3H),2.46(t,2H),2.28(s,5H),1.88-1.79(m,2H),1.46(d,6H).

[0461] Example 4

[0462] 6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-f]indole-3,4'-piperidine]

[0463] first step

[0464] tert-Butyl 4-((2-iodo-5-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate 4b

[0465] 2-Iodo-5-nitrophenol 4a (4.6 g, 17.3 mmol, prepared by the method disclosed in Example 12 on page 23 of the specification of patent application "US2009318473") and tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate 1b (3.7 g, 17.3 mmol) were dissolved in tetrahydrofuran (20 mL), and triphenylphosphine (7.3 g, 27.7 mmol) and diisopropyl azodicarboxylate (5.6 g, 27.7 mmol) were added under ice bath. The reaction was restored to room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4b (7.84 g, yield: 98.1%).

[0466] MS m / z(ESI):404.9[M-55].

[0467] Step 2

[0468] tert-Butyl 6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylate 4c

[0469] Compound 4b (7.84 g, 17 mmol) and triethylamine (3.44 g, 34 mmol) were dissolved in N,N-dimethylacetamide (80 mL), and palladium acetate (382.4 mg, 1.7 mmol) and tetrabutylammonium bromide (4.87 g, 17 mmol) were added. The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate (15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 4c (5.4 g, yield: 95%).

[0470] Step 3

[0471] tert-Butyl 6-amino-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate 4d

[0472] Compound 4c (5.4 g, 16.2 mmol) was dissolved in 50 mL of ethyl acetate, and 10% palladium carbon catalyst (wet) (345 mg) and palladium hydroxide (456 mg) were added. The mixture was replaced with hydrogen and stirred for 16 hours. The reaction solution was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give the crude title compound 4d (4.5 g). The product was used directly in the next step without purification.

[0473] MS m / z(ESI):305.1[M+1].

[0474] Step 4

[0475] tert-Butyl 6-amino-5-bromo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate 4e

[0476] Compound 4d (4.5 g, 14.7 mmol) was dissolved in dichloromethane (60 mL). A dichloromethane solution (30 mL) of tetrabutylammonium tribromide (6.4 g, 13.3 mmol) was added under ice-cooling. The mixture was stirred for 2.5 hours. Saturated sodium thiosulfate solution was added to the reaction solution for quenching. The pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 4e (4.2 g, 74.8% yield). MS m / z (ESI): 383.0 [M+1].

[0477] Step 5

[0478] tert-Butyl 6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-f]indole-3,4'-piperidine]-1'-carboxylate

[0479] Compound 4e (2.87 g, 7.5 mmol) and 7,8-dimethyl-6-(3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[1,5-a]pyridine 1h (1.6 g, 7.5 mmol, prepared by the method disclosed in Example 7 on page 46 of the specification of patent application "CN114057734A") were dissolved in N,N-dimethylacetamide (10 mL), and potassium carbonate (3.1 g, 22.5 mmol), lithium chloride (318 mg, 7.5 mmol), and palladium acetate (1.68 g, 7.5 mmol) were added, and the reaction was stirred at 120°C under a nitrogen atmosphere for 18 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 4f (359 mg, yield: 9.2%).

[0480] MS m / z(ESI):516.3[M+1].

[0481] Step 6

[0482] 6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-f]indole-3,4'-piperidinyl] 2,2,2-trifluoroacetate

[0483] Compound 4f (156 mg, 302.5 μmol) was dissolved in dichloromethane (1.5 mL). Trifluoroacetic acid (0.5 mL) was added under ice-cooling and the reaction was stirred for 0.5 hour. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to obtain the title compound 4 (25 mg, yield: 19.7%). MS m / z (ESI): 416.2 [M+1].

[0484] 1 H NMR (500MHz, DMSO-d6): δ10.73(s,1H),8.68(s,1H),8.45(s,1H),7.41(s,1H),6.64(s,1H),4.38(s,2 H),2.94(d,2H),2.85(q,1H),2.59-2.54(m,6H),2.15(s,3H),1.81(s,2H),1.61(s,2H),1.30(d,6H).

[0485] Example 5

[0486] 2-(6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-f]indole-3,4'-piperidin]-1'-yl)acetamide 5

[0487] Compound 4 (245 mg, 462.65 μmol) was dissolved in N,N-dimethylformamide (6 mL), and triethylamine (468.4 mg, 4.62 mmol) and 2-bromoacetamide (76.6 mg, 555.2 μmol) were added under ice bath. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give the title compound 5 (110 mg, yield: 50.3%).

[0488] MS m / z(ESI):473.3[M+1].

[0489] 1 H NMR (500MHz, DMSO-d6): δ10.74(s,1H),8.68(s,1H),8.45(s,1H),7.46(s,1H),7.38-7.27(m,1H),7.16(s,1H),6.64(s,1H), 4.36(s,2H),2.90(s,2H),2.83(q,3H),2.57(s,3H),2.15(s,3H),2.11-2.03(m,2H),1.67(s,2H),1.31(d,6H),1.24(s,2H).

[0490] Example 6

[0491] 6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[2,3-b]pyrrolo[3,2-e]pyridine-3,4'-piperidine]6

[0492] MS m / z(ESI):417.2[M+1].

[0493] Example 7

[0494] 2-(6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[2,3-b]pyrrolo[3,2-e]pyridine-3,4'-piperidin]-1'-yl)acetamide 7

[0495] MS m / z(ESI):474.2[M+1].

[0496] Example 8

[0497] 6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[2,3-b]pyrrolo[3,2-e]pyrazine-3,4'-piperidine]8

[0498] MS m / z(ESI):418.2[M+1].

[0499] Example 9

[0500] 2-(6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[2,3-b]pyrrolo[3,2-e]pyrazine-3,4'-piperidin]-1'-yl)acetamide 9

[0501] MS m / z(ESI):475.2[M+1].

[0502] Example 10-p1, 10-p2

[0503] (S)-6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,3'-pyrrolidine]10-p1

[0504] (R)-6-(7,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,3'-pyrrolidine]10-p2

[0505] MS m / z(ESI):403.2[M+1].

[0506] Example 11-p1, 11-p2

[0507] (S)-2-(6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridin-3,3'-pyrrolidin-1'-yl)acetamide 11-p1

[0508] (R)-2-(6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridin-3,3'-pyrrolidin]-1'-yl)acetamide 11-p2

[0509] MS m / z(ESI):460.2[M+1].

[0510] Example 12

[0511] 6'-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5'-isopropyl-2'H,7'H-spiro[azetidine-3,3'-furo[3,2-b]pyrrolo[2,3-e]pyridine]12

[0512] MS m / z(ESI):389.2[M+1].

[0513] Example 13

[0514] 2-(6'-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5'-isopropyl-2'H,7'H-spiro[azetidine-3,3'-furo[3,2-b]pyrrolo[2,3-e]pyridin-1-yl)acetamide 13

[0515] MS m / z(ESI):446.2[M+1].

[0516] Example 14

[0517] 1'-(Cyclopropylmethyl)-6-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-isopropyl-2H,7H-spiro[furo[3,2-b]pyrrolo[2,3-e]pyridine-3,4'-piperidine]14

[0518] Compound 1-p1 (80 mg, 192.1 μmol) was dissolved in acetonitrile (2 mL), and triethylamine (200 mg, 1.97 mmol) and sodium bicarbonate (65 mg, 773.7 μmol) were added. After stirring for 0.5 hour, bromomethylcyclopropane (30 mg, 222.2 μmol, Shanghai Shaoyuan) was added. The reaction was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 14 (41 mg, yield: 45.3%).

[0519] MS m / z(ESI):471.6[M+1].

[0520] 1H NMR (500MHz, CD3OD): δ8.60(s,1H),8.41(s,1H),7.00(s,1H),4.50(s,2H),3.36–3.34(m,1H),2.94(p,1H),2.66(s,3H),2 .46(d,3H),2.29(s,5H),1.90(t,2H),1.48(d,6H),1.41–1.28(m,2H),1.06–0.98(m,1H),0.68–0.57(m,2H),0.23(dt,2H).

[0521] Example 15 (control compound)

[0522] The title compound 15 was prepared with reference to the method of Example 15 on page 179 of WO2018005586A1.

[0523] Biological evaluation

[0524] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0525] Test Example 1: Inhibitory effect of the disclosed compounds on human TLR7 activation pathway

[0526] 1. Experimental Materials and Instruments

[0527] 1. HEK-Blue TM hTLR7 cells (Invivogen)

[0528] 2. Resiquimod (R848 / Resiquimod, Invivogen)

[0529] 3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)

[0530] 4. Blasticidin (Invivogen)

[0531] 5. Bleomycin (Zeocin, Invivogen)

[0532] 6. Neomycin (Normocin, Invivogen)

[0533] 7. DMEM / HIGH Glucose (GE Healthcare)

[0534] 8. Fetal bovine serum (FBS, Gibco)

[0535] 9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)

[0536] 10. Sterile water (made by Shanghai Hengrui)

[0537] 11. 15ml centrifuge tube (Corning)

[0538] 12. 96-well dispensing plate (Corning)

[0539] 13. 96-well flat-bottom cell culture plate (Corning)

[0540] 14. Constant temperature cell culture incubator (Thermo scientific)

[0541] 15. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0542] 16. PHERAstar FS Microplate Reader (BMG Labtech)

[0543] 2. Experimental steps

[0544] Purchase HEK-Blue from Invivogen TM hTLR7 cells are HEK293 cells co-transfected with the human Toll-like receptor 7 (TLR7) gene and a secretory alkaline phosphatase reporter gene (SEAP). The alkaline phosphatase reporter gene (SEAP) is under the control 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. When an antagonist is added, the above pathway is inhibited and SEAP secretion is reduced. The OD620 value is measured using a SEAP substrate to evaluate the activity of the compound on the TLR7 pathway.

[0545] Test compounds dissolved in 100% DMSO at 20 mM were serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, and 0.0256 μM. Blank wells were treated with 100% DMSO. The compounds were then diluted 20-fold in DMEM high-glucose medium (complete medium) supplemented with 10% inactivated FBS. R848 was diluted to 10 μM with sterile water. 20 μL / well of 10 μM R848 diluted with sterile water was added to a 96-well cell culture plate. The compounds diluted in complete medium and 100% DMSO were then added to the wells containing R848 at a rate of 20 μL per well. Negative control wells were treated with 20 μL of sterile water and 20 μL of 100% DMSO diluted in complete medium.

[0546] HEK-Blue TMhTLR7 cells were cultured in DMEM high-glucose medium supplemented with 10% inactivated FBS, 100 μg / mL neomycin, 10 μg / mL blasticidin, and 100 μg / mL bleomycin. Cells that had grown well to 70%-80% were removed from the growth medium and washed once with 5-10 mL of 37°C preheated PBS. Then, 2-5 mL of preheated PBS was added and incubated at 37°C for 1-2 minutes. The cells were dispersed with a pipette and transferred to a 15 mL centrifuge tube. The cells were counted and the cell density was adjusted to 4.8 × 10 cells / mL with complete culture medium. 5 / mL. Add 160 μL of the density-adjusted cell suspension to the above-mentioned 96-well cell culture plate, and the final number of cells per well is 76,500 / well, the final concentration of R848 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, and then 20 μL of the supernatant was taken and 180 μL of the prepared Quanti-Blue was added. After incubation in a 37°C constant temperature incubator in the dark for 120 minutes, the OD620 absorbance value was read by a microplate reader. The inhibition rate was calculated using the following formula: Inhibition rate = {1-(OD test compound-OD negative control well) / (OD blank well-OD negative control well)}×100%. Graphpad Prism software was used to draw an inhibition curve based on the concentrations of the compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, i.e., IC 50 See Table 1 for values.

[0547] Table 1 IC values ​​of the compounds disclosed herein measured on human TLR7 pathway 50 value

[0548] Conclusion: The disclosed compounds have a good inhibitory effect on TLR7 pathway.

[0549] Test Example 2: Inhibitory effect of the disclosed compounds on human TLR8 activation pathway

[0550] 1. Experimental Materials and Instruments

[0551] 1. HEK-Blue TM hTLR8 cells (Invivogen)

[0552] 2. Resiquimod (R848 / Resiquimod, Invivogen)

[0553] 3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)

[0554] 4. Blasticidin (Invivogen)

[0555] 5. Bleomycin (Zeocin, Invivogen)

[0556] 6. Neomycin (Normocin, Invivogen)

[0557] 7. DMEM / HIGH Glucose (GE Healthcare)

[0558] 8. Fetal bovine serum (Gibco)

[0559] 9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)

[0560] 10. Sterile pure water (made by Shanghai Hengrui)

[0561] 11. 15ml centrifuge tube (Corning)

[0562] 12. 96-well dispensing plate (Corning)

[0563] 13. 96-well flat-bottom cell culture plate (Corning)

[0564] 14. Constant temperature cell culture incubator (Thermo scientific)

[0565] 15. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0566] 16. PHERAstar FS Microplate Reader (BMG Labtech)

[0567] 2. Experimental steps

[0568] Purchase HEK-Blue from Invivogen TM hTLR8 cells are HEK293 cells co-transfected with the human Toll-like receptor 8 (TLR8) gene and a secretory alkaline phosphatase reporter gene (SEAP). The alkaline phosphatase reporter gene (SEAP) is under the control of an IFN-β minimal promoter containing five 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. When an antagonist is added, the above pathway is inhibited and SEAP secretion is reduced. The OD620 value is measured using a SEAP substrate to evaluate the activity of the compound on the TLR8 pathway.

[0569] Test compounds at 20 mM in 100% DMSO were serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, and 0.0256 μM. Blank wells were treated with 100% DMSO. The compounds were then diluted 20-fold in DMEM high-glucose medium (complete medium) supplemented with 10% inactivated FBS. R848 was diluted to 60 μM with sterile water. 20 μL / well of 60 μM R848 diluted with sterile water was added to a 96-well cell culture plate. The compounds diluted in complete medium and 100% DMSO were then added to the wells containing R848 at a rate of 20 μL / well. Negative control wells were treated with 20 μL of sterile water and 20 μL of 100% DMSO diluted in complete medium.

[0570] HEK-Blue TM hTLR8 cells were cultured in DMEM high-glucose medium supplemented with 10% inactivated FBS, 100 μg / mL neomycin, 10 μg / mL blasticidin, and 100 μg / mL bleomycin. Cells that had grown well to 70%-80% were removed from the growth medium and washed once with 5-10 mL of 37°C preheated PBS. The cells were then incubated at 37°C for 1-2 minutes with 2-5 mL of preheated PBS. The cells were then dispersed with a pipette and transferred to a 15 mL centrifuge tube. The cells were counted and the cell density was adjusted to 4.8 × 10 cells / mL with complete culture medium. 5 / mL. Add 160 μL of the density-adjusted cell suspension to the above-mentioned 96-well cell culture plate. The final number of cells per well is 76,500 / well, the final concentration of R848 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 Quanti-Blue was added, and the cells were incubated in a 37°C constant temperature incubator in the dark for 120 minutes. The OD620 absorbance value was read with a microplate reader. The inhibition rate was calculated using the following formula: Inhibition rate = {1-(OD test compound-OD negative control well) / (OD blank well-OD negative control well)}×100%. Graphpad Prism software was used to draw an inhibition curve based on the concentrations of the compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, i.e., IC 50 See Table 2 for values.

[0571] Table 2 IC values ​​of the compounds disclosed herein measured on human TLR8 pathway 50 value

[0572] Conclusion: The disclosed compounds have a good inhibitory effect on TLR8 pathway.

[0573] Test Example 3: Inhibitory effect of the disclosed compounds on human TLR9 activation pathway

[0574] 1. Experimental Materials and Instruments

[0575] 1. HEK-Blue TM hTLR9 cells (Invivogen)

[0576] 2. CpG ODN2006 (Invivogen)

[0577] 3. Alkaline phosphatase detection medium (Quanti-Blue Detection, Invivogen)

[0578] 4. Blasticidin (Invivogen)

[0579] 5. Bleomycin (Zeocin, Invivogen)

[0580] 6. Neomycin (Normocin, Invivogen)

[0581] 7. DMEM / HIGH Glucose (GE Healthcare)

[0582] 8. Fetal bovine serum (Gibco)

[0583] 9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)

[0584] 10. Sterile pure water (made by Shanghai Hengrui)

[0585] 11. 15ml centrifuge tube (Corning)

[0586] 12. 96-well dispensing plate (Corning)

[0587] 13. 96-well flat-bottom cell culture plate (Corning)

[0588] 14. Constant temperature cell culture incubator (Thermo scientific)

[0589] 15. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0590] 16. PHERAstar FS Microplate Reader (BMG Labtech)

[0591] 2. Experimental steps

[0592] Purchase HEK-Blue from Invivogen TMhTLR9 cells are HEK293 cells co-transfected with the human Toll-like receptor 9 (TLR9) gene and a secretory alkaline phosphatase reporter gene (SEAP). The alkaline phosphatase reporter gene (SEAP) is under the control 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. When an antagonist is added, the above pathway is inhibited and SEAP secretion is reduced. The OD620 value is measured using a SEAP substrate to evaluate the activity of the compound on the TLR9 pathway.

[0593] Test compounds dissolved in 100% DMSO at 20 mM were serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, and 0.0256 μM. Blank wells were treated with 100% DMSO. The compounds were then diluted 20-fold in DMEM high-glucose medium (complete medium) containing 10% inactivated FBS. ODN2006 was diluted to 10 μM with sterile water. 20 μL / well of 10 μM ODN2006 diluted with sterile water was added to a 96-well cell culture plate. The compounds diluted in complete medium and 100% DMSO were then added to the wells containing ODN2006 at a rate of 20 μL per well. Negative control wells were treated with 20 μL of sterile water and 20 μL of 100% DMSO diluted in complete medium.

[0594] HEK-Blue TM hTLR9 cells were cultured in DMEM / high glucose medium supplemented with 10% FBS, 100 μg / mL neomycin, 10 μg / mL blasticidin, and 100 μg / mL bleomycin. Cells that had grown well to 70%-80% were removed from the growth medium and washed once with 5-10 mL of 37°C preheated PBS. The cells were then incubated with 2-5 mL of preheated PBS at 37°C for 1-2 minutes. The cells were then dispersed with a pipette and transferred to a 15 mL centrifuge tube. The cells were counted and the cell density was adjusted to 4.8 × 10 cells / mL with complete culture medium. 5 / mL. Add 160 μL of the density-adjusted cell suspension to the above-mentioned 96-well cell culture plate, and the final number of cells per well is 76,500 / well. The final concentration of 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, and then 20 μL of the supernatant was taken and 180 μL of the prepared Quanti-Blue was added. After incubation in a 37°C constant temperature incubator in the dark for 15 minutes, the OD620 absorbance was read by a microplate reader. The inhibition rate was calculated using the following formula: Inhibition rate = {1-(OD test compound-OD negative control well) / (OD blank well-OD negative control well)}×100%. Graphpad Prism software was used to draw an inhibition curve based on the concentrations of the compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, i.e., IC 50 See Table 3 for values.

[0595] Table 3 IC values ​​of the compounds disclosed herein measured on human TLR9 pathway 50 value

[0596] Conclusion: Based on Tables 1, 2 and 3, the compounds disclosed herein have a good selective inhibitory effect on TLR7 and TLR8 pathways relative to TLR9.

[0597] Test Example 4: Inhibitory effect of the disclosed compounds on the human PBMC TLR7 activation pathway

[0598] 1. Experimental Materials and Instruments

[0599] 1. Human PBMC (Miaoshun or Xuanfeng)

[0600] 2. TLR7 agonist GS-9620 (in-house synthesis)

[0601] 3.RPMI1640 (Gibco)

[0602] 4. Fetal bovine serum (Gibco)

[0603] 5. 96-well round-bottom plate (Corning)

[0604] 6. 96-well flat-bottom plate (Corning)

[0605] 7. Human IL-6 ELISA kit (Xinbosheng)

[0606] 8. Phosphate buffer (Meilun Bio)

[0607] 9. Constant temperature cell culture incubator (Thermo scientific)

[0608] 10. Constant temperature box (Shanghai Boxun Medical Biological Instrument Co., Ltd.)

[0609] 11. PHERAstar FSX microplate reader (BMG Labtech)

[0610] 2. Experimental steps

[0611] After human PBMC cells are activated with the TLR7-specific activator GS-9620, they secrete the cytokine IL-6. Detecting the expression of IL-6 can be used to detect the active effect of the compound on the TLR7 pathway.

[0612] Test compounds at 20 mM in 100% DMSO were serially diluted with 100% DMSO to 80, 16, 3.2, 0.64, 0.128, 0.0256, and 0.00512 μM. Blank wells were treated with 100% DMSO. The compounds were then diluted 20-fold in RPMI1640 medium supplemented with 10% inactivated FBS. 10 μl of the diluted compounds and blank control were added to each well. Purchased human PBMCs were centrifuged at 300×g for 8 minutes at room temperature. The supernatant was removed, the cells were resuspended in complete medium, counted, and diluted to 2.5 × 10⁶ / mL. 80 μl of the cell suspension was added to the compound-treated wells, mixed, and incubated with the compound at 37°C for 30 minutes. GS-9620 was diluted 10-fold to a working concentration of 50 μM in complete medium. After incubation of cells with the compound, 10 μl / well of 50 μM GS-9620 diluted in complete medium was added to each 96-well cell culture plate. Positive controls consisted of cells incubated with 10 μl of complete medium with 5% DMSO and 10 μl of 50 μM GS-9620 diluted in complete medium. Negative controls consisted of cells incubated with 10 μl of complete medium and 10 μl of 5% DMSO diluted in complete medium. The cells, compound, and activator were incubated in a 37°C, 5% CO2 incubator for 24 hours. After 24 hours, the cell culture plate was centrifuged at 2000 rpm for 10 minutes at room temperature, and 80 μL of the supernatant was transferred to a 96-well round-bottom plate. The plate was sealed and stored at -20°C for analysis of cytokine levels.

[0613] ELISA for IL-6 levels: Detect IL-6 in the supernatant according to the kit protocol. Remove the standard sample and add 1 mL of sample diluent. Vortex thoroughly, then let stand at room temperature for 15 minutes to obtain a 200 pg / mL standard sample solution. Serially dilute the standard sample by 2-fold: 500 μL of the previous concentration + 500 μL of sample diluent, resulting in seven standard concentrations: 200, 100, 50, 25, 12.5, 6.25, 3.125, plus a zero point, for a total of eight standard concentrations. Thaw the cell supernatant and dilute it to the appropriate dilution. Add 100 μL of the standard or sample to the ELISA pre-coated plate and incubate in a 37°C oven for 90 minutes. Dilute the 20x wash buffer 20-fold with water, diluting 50 mL to 1 L. Mix thoroughly and set aside. Wash the plate five times, 300 μL per well, removing any remaining liquid from the plate after the final wash. Prepare primary antibody diluent: add 300 μl of human IL-6 biotinylated antibody concentrate to 9 mL of biotinylated antibody diluent, mix thoroughly, add 100 μl to each well, and incubate at 37°C for 60 minutes. Wash the plate five times and prepare secondary antibody diluent: add 300 μl of concentrated enzyme conjugate to 9 mL of concentrated enzyme conjugate diluent, mix thoroughly, add 100 μl to each well, and incubate at 37°C for 30 minutes. After washing the plate five times, add 100 μl of TMB substrate to each well and develop color at 37°C for 10 minutes. Add 100 μl of stop solution to each well and read the OD450.

[0614] The IL-6 concentration in each well was calculated according to the standard curve, and the inhibition rate was calculated using the following formula: inhibition rate = {1-(IL-6 test compound-IL-6 negative control well) / (IL-6 blank well-IL-6 negative control well)}*100%. The inhibition curve was drawn using Graphpad Prism software based on the compound concentrations and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, i.e., IC 50 value.

[0615] The IC values ​​of the disclosed compounds were determined by the human PBMC TLR7 pathway. 50 See Table 4 for values.

[0616] Table 4 Inhibitory effects of the disclosed compounds on human PBMC TLR7 activation pathway

[0617] Conclusion: The disclosed compounds have a good inhibitory effect on the human PBMC TLR7 activation pathway.

[0618] Test Example 5: Glutathione adduct test of the disclosed compound

[0619] 1. Experimental Materials and Instruments

[0620] 1. Phosphate buffer (20×PBS, purchased from Bioscientific)

[0621] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0622] 3. Human liver microsomes (Corning Gentest, Lot No. 9050002, Donor, 35)

[0623] 4. ACQUITY BEH C 18 Column, 2.1×100 mm, 1.7 μm (Waters, USA)

[0624] 5. Glutathione (hereinafter referred to as GSH, SIGMA, Lot No.: SLBW3322)

[0625] 6. Quality control compound (diclofenac, SIGMA, Lot No.: BCBB7312)

[0626] 7. Dionex U3000 Q-Exactive Orbitrap Tandem High-Resolution Mass Spectrometer (Thermo Fisher Scientific)

[0627] 2. Experimental steps

[0628] 2.1. Preparation of Test Compound Solution: Accurately weigh an appropriate amount of test compound, dissolve in DMSO, and mix thoroughly to prepare a 30 mM stock solution. Dilute the 30 mM stock solution 10-fold with 50% acetonitrile / water (v / v) to obtain a 3.0 mM working solution 1. Dilute the 3.0 mM working solution 1 10-fold with PBS to obtain a 300 μM working solution 2.

[0629] 2.2. Preparation of liver microsome solution: Take an appropriate amount of liver microsome stock solution (concentration is 20 mg / mL) and dilute it to 1.43 mg / mL microsome solution with 100 mM phosphate buffer (pH 7.4).

[0630] 2.3. Preparation of NADPH cofactor solution: Weigh appropriate amounts of NADPH and magnesium chloride and dissolve them in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to achieve concentrations of 10 mM NADPH and 30 mM magnesium chloride, respectively.

[0631] 2.4. Preparation of GSH solution: Weigh an appropriate amount of GSH and dissolve it in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to prepare a 50 mM solution.

[0632] 2.5. In vitro incubation: Precisely pipette 40 μL of 300 μM test compound working solution 2 into a 1.5 mL centrifuge tube. Add 280 μL of 1.43 mg / mL liver microsomal solution to a 1 mg / mL liver microsomal protein concentration. Add 40 μL of 10 mM NADPH solution and 40 μL of 50 mM GSH solution. Incubate in a 37°C incubator with shaking and start the timer. After 60 minutes of incubation, remove the incubated sample from the incubator and add 800 μL of ice-cold acetonitrile to terminate the reaction. After incubation at room temperature for 10 minutes, centrifuge at 12,000 rpm for 10 minutes. Remove the entire supernatant into a centrifuge tube and concentrate to dryness under vacuum at 37°C. The residue was reconstituted with 200 μL of 25% acetonitrile / water solution and centrifuged at 12,000 rpm for 10 min. The supernatant was transferred to a 1.5 mL centrifuge tube and 10 μL was aspirated for LC / MS analysis. For the blank sample, 40 μL of PBS was added in place of the test compound working solution 2. A positive control, diclofenac (10 μM), was used with the test compound.

[0633] MetWorks or Compound Discoverer software was used to process the collected data and screen potential GSH binders.

[0634] Table 5 Glutathione addition test results of the disclosed compounds

[0635] Note: Negative means no glutathione conjugated product was detected in the experiment, and positive means glutathione conjugated product was detected.

[0636] Conclusion: The disclosed compounds do not covalently bind to GSH in cells in vivo, and are less likely to cause cytotoxicity by covalently binding to proteins containing free sulfhydryl groups. They have better safety than control compounds.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in, G 5 CR 5a or N; G 6 CR 6a or N; Ring B is a spirocycloalkyl or spiroheterocyclyl; R a and R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, R 5 , -alkylene-R 5 and wherein the alkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently optionally substituted with one or more R 01 replaced by; The condition is that R a and R b Not all hydrogen atoms at the same time; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 1 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 , =CR 25 R 26 and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently optionally substituted with one or more R 02 replace; Or, two R 1 and the ring atoms to which it is attached together form a 4 substituted cycloalkyl or heterocyclic group; L is selected from a bond, alkylene, heteroalkylene, C(O), C(O)NR 24 NR 24 C(O), C(O)alkylene and alkyleneC(O), wherein the alkylene and heteroalkylene are each independently optionally substituted with one or more R 02 replaced by; Ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 3 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, hydroxy, hydroxyalkyl, =NR 24 , =CR 25 R 26 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by; Each R 4 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, R 5 , -alkylene-R 5 , nitro, Hydroxyl, hydroxyalkyl, =NR 24 , =CR 25 R 26 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by; R 5 selected from -NR 22 R 23 、-C(O)R 20 、-OR 21 、-C(O)OR 21 、-OC(O)R 20 、-OC(O)OR 21 、-C(O)NR 22 R 23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O) v NR 22 R 23 、-NR 24 S(O) v R 20 、-NR 24 S(O) v NR 22 R 23 、-S(O) v OR 21 、-OS(O) v R 20 、-OS(O) v OR 21 、-C(=NR 24 )R 20 and -C(=NR 24 )NR 22 R 23 ; Each R 20 , R 21 , R 22 , R 23 , R 24 and R c are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, amino, hydroxyl, hydroxyalkyl, -NR 32 R 33 、-OR 31 、-C(O)R 30 、-C(O)OR 31 、-OC(O)R 31 、-OC(O)OR 31 、-C(O)NR 32 R 33 、-NR 34 C(O)R 30 、-NR 34 C(O)NR 32 R 33 、-S(O) v R 30 、-S(O) v NR 32 R 33 、-NR 34 S(O) v R 31 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from one or more R 02 replaced by; or, R 22 , R 23 and the nitrogen atom to which it is attached together form a 02 a substituted heterocyclic group; R 5a , R 6a , R 25 and R 26 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, R 5 , -alkylene-R 5 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by; Each R 01 , R 02 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, amino, hydroxy, hydroxyalkyl, -C(O)R 30 , OR 31 、-C(O)OR 31 、-OC(O)R 30 、-OC(O)OR 31 、-C(O)NR 32 R 33 、-S(O) v R 30 、-S(O) v NR 32 R 33 、-NR 32 R 33 、-NR 34 S(O) v R 30 、-NR 34 C(O)R 30 、-NR 34 C(O)NR 32 R 33 , =CR 35 R 36 , =NR 34 , cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl; Each R 30 , R 31 , R 32 , R 33 and R 34 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, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, -NR e R f 、-C(O)NR e R f 、-C(O)R e 、-C(O)OR e , cycloalkyl, heterocyclyl, aryl and heteroaryl; R 35 and R 36 are the same or different and are each independently selected from hydrogen, halogen, alkyl and haloalkyl; R e and R f are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; s is 0, 1, 2, 3, 4, 5, or 6; t is 0, 1, 2, 3, 4, 5 or 6; and v is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a 7- to 14-membered spiro heterocyclic group; preferably, ring B is an 8-, 9- or 10-membered monospiro heterocyclic group; preferably, ring B is selected from *End and G 5 Side connection.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: in, G 1 Selected from CR 1a R 1b NR 1c , O and S(O) v ; G 2 CR 1d or N; R 1a , R 1b and R 1d The same or different, and each independently is R 0 ; or R 1a , R 1b Together they form = O; R 1c is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; R 0 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -OR 21 、-C(O)R 20 、-C(O)OR 21 、-OC(O)R 20 、-C(O)NR 22 R 23 、-Alkylene-C(O)NR 22 R 23 、-NR 24 C(O)R 20 、-NR 24 C(O)NR 22 R 23 、-S(O) v R 20 、-S(O) v NR 22 R 23 、-C(=NR 24 )R 20 、-NR 22 R 23 、-NR 24 S(O) v R 20 , -alkylene-R 5 , hydroxyl, hydroxyalkyl and wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy and alkylene groups are each independently selected from one or more R 02 replaced by; n is 0, 1, 2 or 3; r1 is 0, 1 or 2; r2 is 0, 1 or 2; m1 is 0, 1, 2, 3, 4, 5 or 6; R 1 , G 5 , G 6 , R a , R b , R c , R 20 To R 24 ,v,R 5 , L, Ring E, R 4 , t and R 02 As defined in claim 1.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof: in, G 1 , G 2 , R 0 、r1、r2、n、G 5 , G 6 , R a , R b and R c As defined in claim 3.

5. The compound represented by the general formula (I) according to claim 3 or 4 or a pharmaceutically acceptable salt thereof, wherein G 1 is O, and / or n is 1.

6. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 5, wherein G 2 is N, and / or r1 is 0 or 1, and / or r2 is 0 or 1; preferably, G 2 is N, and / or r1 is 1, and / or r2 is 1.

7. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 6, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl, -C 1-6 Alkylene-C(O)NR 22 R 23 , C 1-6 Hydroxyalkyl and R 22 , R 23 , L, Ring E, R 4 and t as defined in claim 1; preferably, R 0 A hydrogen atom or -C 1-6 Alkylene-C(O)NR 22 R 23 , R 22 and R 23 As defined in claim 1; More preferably, R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; further preferably, R 0 It is a hydrogen atom or -CH2C(O)NH2.

8. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 6, wherein R 0 A hydrogen atom or -(CH2) a -C(O)NR 22 R 23 , a is 0, 1, 2, 3 or 4, R 22 and R 23 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

9. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein G 5 CH or N, and / or G 6 is CH or N; preferably, G 5 CH or N, and / or G 6 For CH.

10. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R a C 1-6 Alkyl, R b for or R a for R b C 1- 6-alkyl, ring A, R 3 and s as defined in claim 1; preferably, R a is isopropyl, R b for or R a for R b isopropyl; more preferably, R a is isopropyl, R b for 11. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein ring A is a 5- to 10-membered heteroaryl group; preferably a 9-membered heteroaryl group; more preferably The end is connected to the pyrrole ring.

12. A compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 haloalkoxy and 3 to 6 membered cycloalkyl; preferably, each R 3 The same or different, and each independently is C 1-6 alkyl, and / or s is 0, 1 or 2.

13. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R c A hydrogen atom or C 1-6 Alkyl, and / or R 22 and R 23 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R c is a hydrogen atom, and / or R 22 and R 23 A hydrogen atom.

14. A compound represented by general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

15. A compound represented by general formula (IIA) or a salt thereof: in, R W is an amino protecting group; preferably tert-butyloxycarbonyl; G 2 is N; G 1 , r1, r2, n, R 1 ,m1,G 5 , G 6 , R a , R b and R c As defined in claim 3.

16. The compound represented by the general formula (IIA) or a salt thereof according to claim 15, which is selected from the following compounds:

17. A method for preparing the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof according to claim 3, the method comprising: The compound represented by the general formula (IIA) or its salt is subjected to a deprotection reaction to obtain R 0 A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; Optionally, the preparation method further comprises R 0 The compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof is a hydrogen atom and X-alkylene-C(O)NR 22 R 23 The compound or its salt undergoes a nucleophilic substitution reaction to obtain R 0 -alkylene-C(O)NR 22 R 23 A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof; Among them, G 2 is N; R W is an amino protecting group, preferably tert-butyloxycarbonyl; X is a halogen, preferably Br; G 1 , r1, r2, n, R 1 ,m1,G 5 , G 6 , R a , R b , R c , R 22 and R 23 As defined in claim 3.

18. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for inhibiting one or more of TLR7, TLR8 or TLR9; preferably in the preparation of a medicament for inhibiting TLR7 and TLR8.

20. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing an inflammatory or autoimmune disease; preferably, 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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