CN114057759A

CN114057759A - Condensed tetracyclic derivative, preparation method and application thereof in medicine

Info

Publication number: CN114057759A
Application number: CN202110903129.3A
Authority: CN
Inventors: 张晓敏; 费洪博; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-08-07
Filing date: 2021-08-06
Publication date: 2022-02-18
Anticipated expiration: 2041-08-06
Also published as: CN114057759B

Abstract

The present disclosure relates to fused tetracyclic derivatives, processes for their preparation and their use in medicine. Specifically, the disclosure relates to a fused tetracyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular application of the derivative as a TLR7/9 inhibitor and application of the derivative in preparation of drugs for treating and/or preventing inflammatory and autoimmune diseases.

Description

Condensed tetracyclic derivative, preparation method and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to a fused tetracyclic derivative, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to fused tetracyclic derivatives represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof as TLR7/9 inhibitors in the treatment of inflammatory and autoimmune diseases.

Background

Toll Like Receptors (TLRs) are an evolutionarily conserved class of transmembrane innate immune receptors that are involved in the first line of defense in protecting human health and play an important role in the recognition of pathogen-associated molecular patterns (PAMPs) (Kawai, t.et al, Nature immunol.,11,2010, 373-. TLRs are expressed in various immune cells, and can be divided into two types according to different expression sites: TLRs expressed in cell membranes (TLR1/2/4/5/6) and endosomal membranes (TLR3/7/8/9) recognize different components and molecules in PAMP, respectively. Among them, TLR7/8/9 is mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognizes ssRNA, and TLR9 mainly recognizes CpG-DNA. TLR7/8/9 is activated after binding a ligand thereof, is combined with a linker protein MyD88 in cytoplasm, starts NF-kappa B and IRF pathways, activates DC cells, and generates type I interferon and other various inflammatory cytokines; in B cells, TLR7/8/9 and nucleic acids are combined to play an important role in the process of producing antinuclear antibodies by B cells, and type I interferon secreted by DC cells can promote further proliferation and activation of autoimmune B cells so as to cause a series of inflammatory reactions.

Systemic Lupus Erythematosus (SLE) belongs to an autoimmune connective tissue disease, and there are three major classes of first-line clinical drugs for SLE: hormones, immunosuppressants and antimalarial drugs. Only one new drug, belimumab, was approved by the FDA in this century, but it had only modest and delayed efficacy in a small fraction of SLE patients (Navarra, s.v. et al Lancet 2011,377,721), with very limited therapeutic options. Therefore, there is an urgent need for new therapies that improve a larger proportion of the patient population and that can be used safely for long periods of time. A phenomenon in which TLR7/9 and type I interferon expression were significantly upregulated was found in PBMCs of Systemic Lupus Erythematosus (SLE) patients (Beverly D.LC et al, Mol Immunol, 2014,61: 38-43). Mice overexpressing TLR7 were reported to exacerbate autoimmune disease and autoinflammation (Santiago-Raber ML, et al, J Immunol.,2008,181: 1556-E.1562), while functional inhibition of TLR7/9 ameliorated B6-Fas^lprAnd pathological manifestations in lupus mice such as BXSB (Dlight H.Kono et al, PNAS,2009,106(29): 12061-12066). Given the close relationship of TLR7/8/9 to antinuclear antibodies and type I interferons, small molecule inhibitors targeting TLR7/8/9 are likely to have potential for the treatment of SLE.

Published patent applications for inhibitors of TLR7/8/9 include WO2019233941a1, WO2020020800a1, WO2018049089a1, WO2017106607a1, CN109923108A, and WO2020048605a1, among others.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

z is selected from O atom, S atom and NH;

y is selected from the group consisting of a bond, CR^2aR^2bO atom, S atom and NR^2c；

Ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁰selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and

l is selected from the group consisting of a bond, alkylene, and heteroalkylene, wherein said alkylene and heteroalkylene are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is¹The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is²The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, cyano, amino, nitro, hydroxyl, and hydroxyalkyl;

R^2aand R^2bIs the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, deuteratedAlkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R^2cselected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, deuterated alkyl groups, and hydroxyalkyl groups;

each R is³The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxyl group and hydroxyalkyl group;

each R is⁴The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

each R is⁵The same OR different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR⁶、-C(O)NR⁷R⁸、-NR⁷R⁸、-S(O)₂R⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁶selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁷and R⁸Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclic group, said heterocyclic group being optionally selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkaneSubstituted with one or more substituents selected from the group consisting of alkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁹selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups, amino groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

r is 1 or 2;

k is 0, 1,2 or 3;

n is 0, 1,2 or 3;

m is 0, 1 or 2;

p is 0, 1,2 or 3;

q is 0, 1,2,3 or 4; and is

t is 0, 1,2,3 or 4.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an O atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁰Is a hydrogen atom or

Ring B, L, R⁵And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, Y, L, R¹To R⁵R, k, n, m, p, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 3-to 8-membered heterocyclyl; preferably a 4 to 8 membered heterocyclyl group; more preferably a piperidinyl group.

In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (III), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring a is a 4-to 8-membered heterocyclic group containing at least one nitrogen atom;

ring B, Y, L, R¹To R⁵R, k, n, m, p, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), (II) or (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is an O atom or a chemical bond; preferably a chemical bond.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II) or (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is 1.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, L, R¹To R⁵K, n, m, p, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond or CH₂。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-to 8-membered heterocyclyl or 5-to 10-membered heteroaryl; preferably a 3-to 6-membered heterocyclyl or 5-to 6-membered heteroaryl; more preferably piperidinyl or imidazolyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein k is 0, 1, or 2.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III) or formula (IV), or a tautomer thereofIn the form of racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; preferably hydrogen atom, halogen and C_1-6An alkyl group; more preferably C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1,2, or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; preferably C_1-6An alkyl group or a hydrogen atom; more preferably C_1-6Alkyl groups or hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is³Are the same or different and are each independently a hydrogen atom or a halogen; preferably a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁴Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl and halo C_1-6An alkyl group; preferably a hydrogen atom.

In some preferred embodiments of the present disclosureIn the formula (I), the formula (II), the formula (III) or the formula (IV), or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; preferably C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (III), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring a is a 4-to 8-membered heterocyclic group containing at least one nitrogen atom; y is an O atom or a chemical bond; r is 1; k is 0, 1 or 2; l is a bond or CH₂(ii) a Ring B is a 3-to 8-membered heterocyclyl or 5-to 10-membered heteroaryl; r¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; n is 0, 1,2 or 3; r²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; m is 0, 1 or 2; r³Are the same or different and are each independently a hydrogen atom or a halogen; p is 0, 1,2 or 3; r⁴Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl and halo C_1-6An alkyl group; q is 0, 1,2,3 or 4; r⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; t is 0, 1,2,3 or 4.

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring a is a 4-to 8-membered heterocyclic group containing at least one nitrogen atom; k is 0, 1 or 2; l is a bond or CH₂(ii) a Ring B is a 3-to 6-membered heterocyclyl or 5-to 6-membered heteroaryl; r¹Are the same or different and are each independently selectedFrom hydrogen atoms, halogens and C_1-6An alkyl group; n is 0, 1,2 or 3; r²Are the same or different and are each independently C_1-6An alkyl group or a hydrogen atom; m is 0, 1 or 2; r³Are the same or different and are each independently a hydrogen atom; r⁴Are the same or different and are each independently a hydrogen atom; r⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group; t is 0, 1,2,3 or 4.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound of formula (IIIA), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹to R⁴Y, r, k, n, m, p and q are as defined in formula (III).

Another aspect of the present disclosure relates to a compound of formula (IVA), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹to R⁴K, n, m, p and q are as defined in formula (IV).

Another aspect of the present disclosure relates to a compound represented by formula (IIIA) or formula (IVA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is trifluoroacetate or hydrochloride salt.

Table B typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

the compound of the general formula (IIIA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IIIB) or the compound of the general formula (IIIC) are subjected to reductive amination reaction to obtain the compound shown in the general formula (III), or the tautomer, the racemate, the enantiomer, the diastereomer, the mixture form or the pharmaceutically acceptable salt thereof,

wherein:

l is a bond or CH₂；

Ring A, ring B, R¹To R⁵Y, r, k, n, m, p, q and t are as defined in formula (III).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

the compound of the general formula (IVA) or the pharmaceutically acceptable salt thereof and the compound of the general formula (IIIB) or the compound of the general formula (IIIC) are subjected to reductive amination reaction to obtain the compound shown in the general formula (IV), or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof,

wherein:

l is a bond or CH₂；

Ring B, R¹To R⁵K, n, m, p, q and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of compounds of formula (I), formula (II), formula (III), formula (IV) and table a, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the manufacture of a medicament for inhibiting TLR7 and/or TLR 9.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting TLR7 or TLR 9.

The disclosure further relates to the use of compounds of formula (I), formula (II), formula (III), formula (IV) and table a, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases. Wherein said inflammatory or autoimmune disease is preferably selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and Sjogren's syndrome.

The disclosure further relates to a method of inhibiting TLR7 and/or TLR9 comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV), and table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to a method of inhibiting TLR7 or TLR9, comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV), and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to a method of inhibiting TLR7 and TLR9, comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV), and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to a use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the treatment and/or prevention of an inflammatory or autoimmune disease, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount. Wherein said inflammatory or autoimmune disease is preferably selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and Sjogren's syndrome.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in a medicament for inhibiting TLR7 or TLR 9.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in medicaments for inhibiting TLR7 and TLR 9.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases; wherein said inflammatory or autoimmune disease is preferably selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and Sjogren's syndrome.

In view of their activity as selective inhibitors of TLR7 or TLR9, the compounds of formula (I), formula (II), formula (III), formula (IV) and table a are useful for the treatment of TLR7 or TLR9 family receptor-related diseases, respectively, but are not limited to inflammatory diseases such as crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis; autoinflammatory diseases including Cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult Steyr's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic disorders including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as those including solid tumors, ocular neovascularisation and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and shigellosis; neurodegenerative diseases such as alzheimer's disease, parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, tumor diseases and viral diseases such as metastatic melanoma, kaposi's sarcoma, multiple myeloma and HIV infection and CMV retinitis, AIDS.

More specifically, specific conditions or diseases that may be treated with the compounds of the disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, 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, crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, 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 pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia from infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyretic disease (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellasis; alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases including acute hepatitis infections (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular proliferation, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin endoperoxidase synthase-2 related conditions, and pemphigus vulgaris. Preferred methods of treatment are those wherein the disorder is selected from crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred for use in the method of treatment, the condition is ischemia reperfusion injury, said ischemia reperfusion injury is cerebral ischemia reperfusion injury caused by stroke or myocardial ischemia reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the disorder is multiple myeloma.

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing 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.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

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

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health 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, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2,3, 4,5, 6, 7, 8, 9,10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally selected from one or more substituents of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroalkyl" refers to one or more-CH's in an alkyl group₂-is substituted by a heteroatom selected from N, O, S and s (o); wherein said alkyl is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from the group consisting of D atom, halogen, alkyl, alkoxyAnd one or more substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1,2,3, 4,5, 6, 7, 8, 9,10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "heteroalkylene" refers to one or more-CH's in an alkylene group₂-is selected from N, O, S, S (O) and S (O)₂Substituted with the heteroatom of (a); wherein said alkylene is as defined above; the heteroalkylene group can be substituted or unsubstituted, and when substituted, can be substituted at any available point of attachment, with the substituents preferably being independently optionally substituted with one or more substituents selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably 3 to 8 (e.g., 3, 4,5, 6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

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

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; superior foodSelecting

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising 3 to 20 ring atoms (i.e. a 3 to 20 membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulphur, which sulphur may optionally be oxo (i.e. form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3, 4,5, 6, 7, 8, 9,10, 11 and 12) ring atoms (i.e., 3 to 12 membered heterocyclyl groups), of which 1-4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 (e.g., 3, 4,5, 6, 7 and 8) ring atoms (i.e., 3 to 8 membered heterocyclyl), wherein 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 4 to 8 ring atoms (i.e. 4 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms (i.e. 3 to 6 membered heterocyclyl), of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms (i.e. 5-membered heterocyclyl or 6-membered heterocyclyl), of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group which shares a single atom (referred to as the spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

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

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations.

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably t-butyloxycarbonyl.

The term "hydroxyl-protecting group" is a suitable group known in the art for protecting hydroxyl Groups, see the literature ("Protective Groups in Organic Synthesis", 5)^Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C)_1-10Alkyl or aryl)₃Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; may be C_1-10Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C_1-6Alkoxy-substituted C_1-6Alkyl or phenyl substituted C_1-6Alkyl, most preferably C_1-4Alkoxy-substituted C_1-4Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, and the like; may be (C)_1-10Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C)_1-6Alkyl or C_6-10Aryl) sulfonyl; or (C)_1-6Alkoxy or C_6-10Aryloxy) carbonyl.

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

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

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

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

The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.

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

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to "═ O".

The term "carbonyl" refers to C ═ O.

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

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

The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein each available hydrogen atom of the compound in deuterated form attached to a carbon atom is independently replaceable with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated forms of the compounds, or they can be prepared using conventional techniques using deuterated reagentsAnd (3) synthesizing, wherein the deuterated reagent comprises but is not limited to deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane and the like. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate 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 as well as organic acids.

The term "therapeutically and/or prophylactically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "inhibiting effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

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

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

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

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

A method of treating a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

in a first step, the compound of formula (IIID) or a salt thereof is deprotected under acidic conditions to remove the protecting group R^wTo obtain the compound of the general formula (IIIA) or pharmaceutically acceptable salt thereof;

secondly, carrying out reductive amination reaction on the compound of the general formula (IIIA) or pharmaceutically acceptable salt thereof and the compound of the general formula (IIIB) or the compound of the general formula (IIIC) under alkaline conditions in the presence of a reducing agent to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

R^wis an amino protecting group; preferably tert-butoxycarbonyl;

l is a bond or CH₂；

Ring A, ring B, Y, R¹To R⁵R, k, n, m, p, q and t are as defined in formula (III).

Scheme two

A method of treating a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

in a first step, the compound of formula (IVD) or a salt thereof is deprotected under acidic conditions to remove the protecting group R^wTo give a compound of formula (IVA) or a pharmaceutically acceptable salt thereof;

secondly, carrying out reductive amination reaction on the compound of the general formula (IVA) or pharmaceutically acceptable salt thereof and the compound of the general formula (IIIB) or the compound of the general formula (IIIC) under alkaline conditions in the presence of a reducing agent to obtain the compound of the general formula (IV) or pharmaceutically acceptable salt thereof;

wherein:

R^wis an amino protecting group; preferably tert-butoxycarbonyl;

l is a bond or CH₂；

Ring B, R¹To R⁵K, n, m, p, q and t are as defined in formula (IV).

In the first and second synthesis schemes, the reducing agent includes, but is not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and the like, and sodium cyanoborohydride is preferred.

In the first and second synthesis schemes, the reagent for providing basic conditions comprises organic bases and inorganic bases, wherein the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; sodium acetate is preferred.

In the first and second schemes, the reagents providing acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me₃SiCl and TMSOTf, preferably trifluoroacetic acid or hydrogen chloride in 1, 4-dioxane.

The first and second synthetic schemes described above are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, and a mixture thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compound is by nuclear magnetismResonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE NEO 500M NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultratate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260 DAD HPLC.

High Performance liquid preparation A preparative chromatograph was used from Waters 2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson-281.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: n-hexane/ethyl acetate system, B: the volume ratio of the solvent in the dichloromethane/methanol system is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

9- (1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) -2-methyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole 1

First step of

2- (5-bromo-1H-indol-3-yl) ethanol 1b

2- (5-bromo-1H-indol-3-yl) acetic acid 1a (2.00g, 7.87mmol, Lezhu chemical) was dissolved in tetrahydrofuran (20mL), cooled to 0 deg.C, and 1.0M lithium aluminum hydride in tetrahydrofuran (15.74mL, 15.74mmol) was added dropwise, heated under reflux and stirred for 1 hour. The reaction was quenched by the sequential dropwise addition of water (0.59mL), 15% sodium hydroxide (0.59mL), and water (1.8mL) under ice-bath, filtered through celite, and concentrated under reduced pressure to give the title product 1b (1.80g, yield: 95.2%).

MS m/z(ESI):240.1[M+1]。

Second step of

5-bromo-3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indole 1c

Compound 1b (1.80g, 7.50mmol) was dissolved in N, N-dimethylformamide (20mL), imidazole (1.02g, 14.98mmol) was added, t-butyldimethylsilyl chloride (1.69g, 11.21mmol) was added under ice-bath, and the mixture was stirred at room temperature for 16 hours. Water (30mL) was added, extraction was performed with ethyl acetate (30 mL. times.2), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (2.60g, yield: 97.9%). MS M/z (ESI) 354.2[ M +1 ].

The third step

4- (3- (2- (((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1d

Compound 1c (2.60g, 7.34mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (2.27g, 7.34mmol, Shaoshao Chemicals), dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (520mg, 0.734mmol, Shaoshao Chemicals), cesium carbonate (4.78g, 14.67mmol) was dissolved in 1, 4-dioxane (40mL) and water (4mL) and reacted for 2 hours at 100 ℃ with replacement of nitrogen three times. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 1d (3.00g, yield: 89.5%).

MS m/z(ESI):457.2[M+1]。

The fourth step

4- (3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1e

Compound 1d (3.00g, 6.57mmol) was dissolved in ethyl acetate (30mL) and methanol (30mL), and a wet palladium on carbon hydrogenation catalyst (140mg) was added to replace hydrogen three times, followed by reaction at room temperature for 16 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 1e (950mg, yield: 31.5%).

MS m/z(ESI):459.3[M+1]。

The fifth step

4- (2-bromo-3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1f

Compound 1e (950mg, 2.07mmol) was dissolved in 1, 2-dichloroethane (20mL), and a solution of N-bromosuccinimide (369mg, 2.07mmol) in 1, 2-dichloroethane (20mL) was added dropwise under ice-bath, followed by reaction for 10 minutes under ice-bath. Quenching with saturated aqueous sodium thiosulfate (50mL), extraction with dichloromethane (50 mL. times.2), concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 1f (670mg, yield: 60.2%).

MS m/z(ESI):537.1[M+1]。

The sixth step

5- (methoxymethoxy) -2-methylpyridine 1h

1g (5.00g, 45.82mmol, Lezhu chemical) of 6-methylpyridin-3-ol was dissolved in methylene chloride (50mL), and N, N-diisopropylethylamine (8.88g, 68.71mmol) and bromomethyl ether (7.44g, 59.54mmol) were added dropwise in this order under ice-cooling, and the reaction was carried out at room temperature for 16 hours. Quenched by addition of saturated aqueous sodium bicarbonate (100mL), extracted with dichloromethane (50 mL. times.2), and concentrated under reduced pressure to give the title product 1h (3.30g, yield: 47.0%).

MS m/z(ESI):154.1[M+1]。

Seventh step

4-bromo-5- (methoxymethoxy) -2-methylpyridine 1i

Compound 1h (3.30g, 21.54mmol) was dissolved in tetrahydrofuran (50mL) and nitrogen was replaced three times, 1.3M t-butyllithium (17.4mL, 22.64mmol) was added dropwise at-78 deg.C, the reaction stirred at this temperature for 1h, 1, 2-dibromotetrachloroethane (7.02g, 21.56mmol) was added dropwise at-78 deg.C, and the reaction stirred at this temperature for 1 h. After quenching by addition of saturated aqueous ammonium chloride (100mL), extraction with ethyl acetate (50 mL. times.2), concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A, the title product 1i (3.80g, yield: 76.0%) was obtained.

MS m/z(ESI):232.0[M+1]。

Eighth step

5- (methoxymethoxy) -2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine 1j

Compound 1i (3.80g, 16.37mmol) and bisphenopinacolyl diborate (4.57g, 18.00mmol, Shaoshi Chemicals) were dissolved in 1, 4-dioxane (100mL) and potassium acetate (4.81g, 49.08mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (1.20g, 1.64mmol) were added. The reaction was carried out at 85 ℃ for 16 hours under nitrogen protection. Celite filtration through a pad and concentration under reduced pressure gave the crude title product 1j (7.00g) which was used in the next reaction without purification.

MS m/z(ESI):280.1[M+1]。

The ninth step

4- (3- (2- (tert-butyldimethylsilyl) oxy) ethyl) -2- (5- (methoxymethoxy) -2-methylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1k

Compound 4- (2-bromo-3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1f (1.04g, 1.93mmol) and compound 1j (3.24g, 11.61mmol) were dissolved in 55mL of a mixed solution of 1, 4-dioxane and water (V: V ═ 10:1), and potassium phosphate (3.29g, 15.50mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (141mg, 0.19mmol) were added. And reacting at 80 ℃ for 5 hours under the protection of nitrogen. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1k (900mg, yield: 76.3%).

MS m/z(ESI):610.1[M+1]。

The tenth step

4- (3- (2-hydroxyethyl) -2- (5- (methoxymethoxy) -2-methylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1l

Compound 1k (300mg, 0.49mmol) was dissolved in tetrahydrofuran (10mL) and 1.0M tetrabutylammonium fluoride (1.47mL, 1.47mmol) was added. The reaction was stirred at room temperature for 16 hours. Water (30mL), ethyl acetate (30 mL. times.2) was added, extraction was performed, concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1l (240mg, yield: 98%).

MS m/z(ESI):496.2[M+1]。

The eleventh step

4- (3- (2-hydroxyethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -6-methylpyridine-3-carbo-noxide salt 1m

Compound 1l (240mg, 0.48mmol) was dissolved in dichloromethane (6mL) and 4M hydrogen chloride/1, 4-dioxane solution (7.1mL, 28.4mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to give the crude title product 1m (205mg, yield: 99%) which was directly subjected to the next reaction without purification. MS M/z (ESI) 352.1[ M +1 ].

The twelfth step

5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (5-hydroxy-2-methylpyridin-4-yl) -3- (2-hydroxyethyl) -1H-indole-1-carboxylic acid tert-butyl ester 1n

The crude compound 1m (205mg, 0.48mmol) was dissolved in dichloromethane (10mL), and N, N-diisopropylethylamine (512mg, 3.96mmol) and di-tert-butyl dicarbonate (432mg, 1.98mmol) were added dropwise in this order under ice-bath, and reacted at room temperature for 16 hours. Quenched by addition of saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane (30 mL. times.2), and concentrated to dryness to give the title product 1n (100mg, yield: 37.8%).

MS m/z(ESI):552.2[M+1]。

Thirteenth step

9- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2-methyl-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole-12 (7H) -carboxylic acid tert-butyl ester 1o

Compound 1n (90mg, 0.16mmol) was dissolved in 20mL of a mixed solution of tetrahydrofuran and toluene (V: V ═ 1:1), nitrogen was replaced three times, tri-n-butylphosphine (165mg, 0.82mmol) and a toluene solution (10mL) of azobisformyldipiperidine (206mg, 0.82mmol) were added dropwise at room temperature, and the mixture was heated at 60 ℃ and stirred for 1 hour. Concentration and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 1o (70mg, yield: 80.4%).

MS m/z(ESI):534.3[M+1]。

Fourteenth step

2-methyl-9- (piperidin-4-yl) -7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole trifluoroacetate 1p

Compound 1o (70mg, 0.13mmol) was dissolved in dichloromethane (10mL) and trifluoroacetic acid (2mL) was added. The reaction was stirred at room temperature for 2 hours. Concentration to dryness gave the title product, 1p (70mg, yield: 95.0%), which was directly subjected to the next reaction without purification.

MS m/z(ESI):334.1[M+1]。

The fifteenth step

The crude compound 1p (70mg, 0.21mmol) and 1-isobutylpiperidin-4-one (65mg, 0.42mmol) were dissolved in 11mL of a mixed solution of dichloromethane and methanol (V: V ═ 10:1), and sodium acetate (69mg, 0.84mmol) was added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (25mg, 0.42mmol) was added and the reaction was carried out at room temperature for 48 hours. Quenching with saturated aqueous sodium thiosulfate (50mL), extracting with dichloromethane (50 mL. times.2), concentrating under reduced pressure, and purifying the residue by high performance liquid chromatography (column Boston Phlex Prep C185 um 30: 150 mm; mobile phase: water (10mmol/L NH)₄HCO₃): 45% -65% of acetonitrile; gradient elution 15min, flow rate: 30mL/min) to give the title product 1(10mg, yield: 10.1%).

MS m/z(ESI):473.4[M+1]。

¹H NMR(500MHz,CDCl₃)δ8.65(s,1H),8.29(s,1H),7.40(s,1H),7.32-7.26(m,2H),7.17-7.16(m,1H),4.41-4.39(m,2H),3.33-3.31(m,2H),3.09-3.07(m,2H),2.95-2.93(m,2H),2.61-2.54(m,4H),2.36-2.31(m,3H),2.11-2.00(m,5H),1.90-1.55(m,8H),0.90-0.88(m,6H)。

Example 2

9- (1- ((1H-imidazol-4-yl) methyl) piperidin-4-yl) -2-methyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole 2

Compound 1p (660mg, 1.62mmol) and 4-imidazolecarboxaldehyde (312mg, 3.25mmol) were dissolved in dichloromethane (10mL) and methanol (1mL), and sodium acetate (533mg, 6.50mmol) was added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (194mg, 3.24mmol) was added thereto, and the reaction was completed at room temperature for 48 hours. Quenching with saturated aqueous sodium thiosulfate (50mL), extracting with dichloromethane (50 mL. times.2), concentrating under reduced pressure, and purifying the residue by high performance liquid chromatography (column: Boston Phlex Prep C185 um 30: 150 mm; mobile phase: water (10mmol/L NH)₄HCO₃): 20% -40% of acetonitrile; gradient elution 15min, flow rate: 30mL/min) to give the title product 2(18mg, yield: 2.7%).

MS m/z(ESI):414.2[M+1]。

¹HNMR(500MHz,CDCl₃)δ8.05(s,1H),7.65-7.40(m,2H),7.35-7.20(m,2H),7.15-6.78(m,2H),4.35-4.28(m,2H),3.52(s,2H),3.29-3.22(m,2H),2.98-2.96(m,2H),2.57-2.54(m,1H),2.42(s,3H),2.20-2.08(m,2H),1.94-1.73(m,4H)。

Example 3

9- (1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) -2, 4-dimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole 3

First step of

3- (methoxymethoxy) -2, 6-dimethylpyridine 3b

2, 6-dimethylpyridin-3-ol 3a (2.73g, 22.17mmol, Lezhu chemical) was dissolved in dichloromethane (40mL), and N, N-diisopropylethylamine (4.30g, 33.27mmol) and bromomethyl ether (3.60g, 28.81mmol) were added dropwise in this order under ice-cooling, and the reaction was carried out at room temperature for 16 hours. Quenched by addition of saturated aqueous sodium bicarbonate (100mL), extracted with dichloromethane (50 mL. times.2), concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3b (2.65g, yield: 71.5%).

MS m/z(ESI):168.1[M+1]。

Second step of

4-bromo-3- (methoxymethyloxy) -2, 6-dimethylpyridine 3c

Compound 3b (2.65g, 15.85mmol) was dissolved in tetrahydrofuran (20mL) and nitrogen was replaced three times, 1.3M t-butyllithium (12.8mL, 12.8mmol) was added dropwise at-78 deg.C, the reaction was stirred at this temperature for 1 hour, 1, 2-dibromotetrachloroethane (5.16g, 15.85mmol) was added dropwise at-78 deg.C, and the reaction was stirred at this temperature for 1 hour. After quenching by addition of saturated aqueous ammonium chloride (100mL), extraction with ethyl acetate (50 mL. times.2), concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A, the title product 3c (2.30g, yield: 59.0%) was obtained.

MS m/z(ESI):246.0[M+1]。

The third step

3- (methoxymethyloxy) -2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine 3d

Compound 3c (2.30g, 9.35mmol) and bisphenopinacolyldiborate (2.61g, 10.28mmol) were dissolved in 1, 4-dioxane (100mL), and potassium acetate (2.91g, 29.69mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (683mg, 0.93mmol) were added. The reaction was carried out at 85 ℃ for 16 hours under nitrogen protection. Celite was filtered and concentrated under reduced pressure to give the title product 3d (5.30g), which was used directly in the next reaction.

The fourth step

4- (3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 3e

Crude compound 1f (2.50g, 4.65mmol) and compound 3d (5.45g, 18.59mmol) were dissolved in 55mL of an aqueous solution of 1, 4-dioxane (V: V ═ 10:1), and potassium phosphate (5.92g, 27.89mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (340mg, 0.47mmol) were added. And reacting at 80 ℃ for 5 hours under the protection of nitrogen. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 3e (1.00g, yield: 34.5%).

MS m/z(ESI):624.2[M+1]。

The fifth step

4- (3- (2-hydroxyethyl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 3f

To a solution of compound 3e (1.00g, 1.60mmol) in tetrahydrofuran (10mL) was added 1.0M tetrabutylammonium fluoride (4.80mL, 4.80 mmol). The reaction was stirred at room temperature for 16 hours. Water (30mL), ethyl acetate (30 mL. times.2) was added, the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3f (460mg, yield: 56.3%).

MS m/z(ESI):510.3[M+1]。

The sixth step

4- (3- (2-hydroxyethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 6-dimethylpyridine-3-phenolate 3g

To a solution of compound 3f (460mg, 0.90mmol) in dichloromethane (8mL) was added a 4M solution of hydrogen chloride in 1,4 dioxane (11.28 mL). The reaction was stirred at room temperature for 1 hour. Concentration to dryness gave the title product 3g (460mg, yield: 116.3%).

MS m/z(ESI):366.1[M+1]。

Seventh step

5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (2-hydroxyethyl) -1H-indole-1-carboxylic acid tert-butyl ester 3H

3g (460mg, 1.26mmol) of the compound was dissolved in methylene chloride (20mL), and N, N-diisopropylethylamine (1.30mg, 10.06mmol) and di-tert-butyl dicarbonate (1.10g, 5.04mmol) were added dropwise in this order under ice-cooling, followed by reaction at room temperature for 16 hours. Quenched by addition of saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane (30 mL. times.2), concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3h (620mg, yield: 87.1%).

MS m/z(ESI):566.2[M+1]。

Eighth step

4- (2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (2-hydroxyethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 3i

Compound 3h (620mg, 1.10mmol) was dissolved in tetrahydrofuran (10mL), methanol (10mL) and water (10mL), lithium hydroxide monohydrate (460mg,10.95mmol) was added, and the mixture was heated at 60 ℃ and stirred for 16 hours. After concentration, water (20mL) and methylene chloride (20mL) were added, the reaction solution was adjusted to pH 9 with 1M hydrochloric acid, the mixture was separated, the organic phase was washed with water and then saturated sodium chloride, the organic phase was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3i (290mg, yield: 56.8%).

MS m/z(ESI):466.2[M+1]。

The ninth step

4- (2, 4-dimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 3j

Compound 3i (290mg, 0.62mmol) was dissolved in tetrahydrofuran (10mL) and toluene (10mL) and nitrogen was replaced three times, and tri-n-butylphosphine (630mg,3.11mmol) was added dropwise at room temperature followed by azobisformyldipiperidine (809mg,3.21mmol, Leyan chemical) in toluene (10mL) and stirred at 60 ℃ for 1 hour. The residue was concentrated and purified by silica gel column chromatography with eluent system B to give the title product 3j (1.90g), which was used in the next reaction without purification.

MS m/z(ESI):448.2[M+1]。

The tenth step

2, 4-dimethyl-9- (piperidin-4-yl) -7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole hydrochloride 3k

To a solution of compound 3j (1.90g, 4.38mmol) in dichloromethane (20mL) was added a 4M solution of hydrogen chloride in 1, 4-dioxane (54.8 mL). The reaction was stirred at room temperature for 2 hours. Concentration to dryness gave the title product 3k (1.80g, yield: 97.8%).

MS m/z(ESI):348.1[M+1]。

The eleventh step

Compound 3k (900mg, 2.59mmol) and 1-isobutylpiperidin-4-one (804mg, 5.18mmol) were dissolved in 11mL of a mixture solvent of dichloromethane and methanol (V: V ═ 10:1), and sodium acetate (850mg,10.37mmol) was added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (310mg, 5.18mmol) was added thereto, and the reaction was completed at room temperature for 48 hours. Quenching with saturated aqueous sodium thiosulfate (50mL), extracting with dichloromethane (50 mL. times.2), concentrating the reaction solution under reduced pressure, and purifying by high performance liquid chromatography (column: Xbridge C18 OBD,5um,30 mm. times.150 mm; mobile phase: water (10mmol/L NH)₄HCO₃): 70% -95% acetonitrile; gradient elution 15min, flow rate: 30mL/min) to give the title product 3(10mg, yield: 0.8%).

MS m/z(ESI):487.3[M+1]。

¹H NMR(500MHz,CDCl₃)δ8.38(s,1H),7.41(s,1H),7.32-7.30(m,1H),7.18-7.14(m,2H),4.43-4.40(m,2H),3.34-3.31(m,2H),3.10-3.06(m,2H),2.96-2.93(m,2H),2.62-2.56(m,1H),2.54(s,3H),2.52(s,3H),2.36-2.30(m,3H),2.06-2.05(m,2H),1.93-1.75(m,9H),1.67-1.62(m,2H),0.89-0.86(m,6H)。

Example 4

9- (1- ((1H-imidazol-4-yl) methyl) piperidin-4-yl) -2, 4-dimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole 4

Compound 3k (900mg, 2.59mmol) and 4-imidazolecarboxaldehyde (498mg, 5.18mmol) were dissolved in dichloromethane (20mL) and methanol (1mL), and sodium acetate (850mg,10.37mmol) was added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (310mg, 5.18mmol) was added and the reaction was allowed to proceed for 48h at room temperature. Quenching with saturated aqueous sodium thiosulfate (50mL), extracting with dichloromethane (50 mL. times.2), combining the organic phases, concentrating under reduced pressure, and purifying by high performance liquid chromatography (column: SharpSil T-C18,5um,30 mm. times.150 mm; mobile phase: water (10mmol/L NH)₄HCO₃): acetonitrile 10% -30% acetonitrile; gradient elution 15min, flow rate: 30mL/min)To obtain the title product 4(20mg, yield: 1.8%).

MS m/z(ESI):428.3[M+1]。

¹H NMR(500MHz,CDCl₃)δ7.59(s,1H),7.32-7.26(m,3H),7.11-7.05(m,2H),4.38-4.36(m,2H),3.83(s,2H),3.31-3.24(m,4H),2.75-2.59(m,3H),2.48(s,3H),2.47(s,3H),2.03-1.93(m,4H)。

Example 5

9- (1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) -2,4, 7-trimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole 5

First step of

2- (5-bromo-1H-indol-3-yl) acetic acid methyl ester 5b

Methanol (90mL) was added to the reaction flask in ice bath, thionyl chloride (5.24g, 44.04mmol) was added dropwise, and a methanol solution (30mL) of 5-bromoindole-3-acetic acid 5a (10.00g, 39.36mmol, Doubei medicine) was added dropwise in ice bath, and the mixture was allowed to warm to room temperature naturally, followed by stirring for 16 hours. The reaction was concentrated to 1/3, water (150mL), ethyl acetate (100 mL. times.2) was added and the combined organic phases were concentrated under reduced pressure to give the crude title product 5b (10.50g, yield: 99.5%) which was used in the next reaction without purification.

MS m/z(ESI):268.0[M+1]。

Second step of

5-bromo-3- (2-methoxy-2-oxoethyl) -1H-indole-1-carboxylic acid tert-butyl ester 5c

The crude compound 5b (10.50g, 39.16mmol) was dissolved in dichloromethane (200mL) and reacted at room temperature for 5 minutes successively with 4-dimethylaminopyridine (4.82g, 39.13mmol) and di-tert-butyl dicarbonate (17.09g, 78.31 mmol). 10% aqueous citric acid (1400mL), dichloromethane (200 mL. times.2) was added and the combined organic phases were concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 5c (14.40g, yield: 99.9%).

MS m/z(ESI):311.9[M-55]。

The third step

5-bromo-3- (1-methoxy-1-oxoprop-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester 5d

Compound 5c (14.00g, 38.02mmol) was dissolved in tetrahydrofuran (150mL) and nitrogen was replaced three times, 1.0M lithium bis (trimethylsilyl) amide (43.7mL, 43.7mmol) was added dropwise at-78 deg.C, the reaction was stirred at this temperature for 5 hours, iodomethane (26.98g, 190.08mmol) was added dropwise at-78 deg.C, and the reaction was stirred at-10 deg.C for 0.5 hour. After quenching by addition of saturated aqueous ammonium chloride (150mL), extraction with ethyl acetate (100 mL. times.2), concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A, the title product 5d (13.30g, yield: 91.5%) was obtained.

MS m/z(ESI):325.9[M-55]。

The fourth step

2- (5-bromo-1H-indol-3-yl) propionic acid methyl ester 5e

Compound 5d (13.30g, 34.79mmol) was dissolved in dichloromethane (40mL) and trifluoroacetic acid (20mL) was added. The reaction was stirred at room temperature for 1 hour. Concentrated to dryness, quenched with saturated aqueous sodium bicarbonate (250mL), extracted with ethyl acetate (200 mL. times.2), concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5e (9.80g, yield: 99.8%).

MS m/z(ESI):282.0[M+1]

The fifth step

2- (5-bromo-1H-indol-3-yl) propan-1-ol 5f

Compound 5e (10.10g, 35.80mmol) was dissolved in tetrahydrofuran (60mL), cooled to 0 deg.C, and 1.0M lithium aluminum hydride in tetrahydrofuran (71.63mL, 71.63mmol) was added dropwise, and the reaction was stirred at room temperature for 16 hours. The reaction was quenched by the sequential dropwise addition of water (2.8mL), 15% sodium hydroxide (2.8mL), and water (8.4mL) under ice-bath, filtered through celite, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5f (8.90g, yield: 97.8%).

MS m/z(ESI):253.9[M+1]。

The sixth step

5-bromo-3- (1-methoxy-1-oxoprop-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester 5g

Compound 5f (8.90g, 35.02mmol) was dissolved in N, N-dimethylformamide (60mL), imidazole (4.77g, 70.07mmol) was added, t-butyldimethylsilyl chloride (4.33g, 52.58mmol) was added under ice-bath, and the mixture was stirred at room temperature for 16 hours. Water (100mL) was added, extraction was performed with ethyl acetate (100 mL. times.2), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain 5g of the title product (12.70g, yield: 98.4%).

MS m/z(ESI):366.0[M-1]。

Seventh step

4- (3- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 5H

Compound 5g (12.70g, 34.48mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (10.66g, 34.48mmol, Shaoyuan chemical), dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (2.44g, 3.45mmol, Dokuyao pharmaceutical), cesium carbonate (22.47g, 68.96mmol) was dissolved in 1, 4-dioxane (100mL) and water (5mL) and reacted for 2 hours at 100 ℃ with replacement of nitrogen three times. Filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5h (16.00g, yield: 98.6%).

MS m/z(ESI):471.1[M+1]。

Eighth step

4- (3- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5i

The compound (5 h) (4.70g, 9.98mmol) was dissolved in ethyl acetate (50mL) and methanol (50mL), and a wet palladium on carbon hydrogenation catalyst (106mg) was added to replace hydrogen three times, followed by reaction at room temperature for 16 hours. Filtration and concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5i (4.40g, yield: 93.2%).

MS m/z(ESI):473.2[M+1]。

The ninth step

4- (2-bromo-3- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5j

Compound 5i (4.40g, 9.31mmol) was dissolved in 1, 2-dichloroethane (100mL), and a solution of N-bromosuccinimide (1.66g, 9.33mmol) in 1, 2-dichloroethane (40mL) was added dropwise under ice-bath, followed by reaction for 10 minutes under ice-bath. Quenching with saturated aqueous sodium thiosulfate (100mL), extraction with dichloromethane (100 mL. times.2), concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5j (3.00g, yield: 58.4%).

MS m/z(ESI):551.1[M+1]。

The tenth step

4- (3- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5k

Compound 5j (3.00g, 5.44mmol) and crude compound 3d (10.80g, 36.84mmol) were dissolved in 200mL of a mixed solution of 1, 4-dioxane and water (V: V ═ 10:1), and potassium phosphate (9.24g, 43.53mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (398mg, 0.54mmol) were added. And reacting at 80 ℃ for 5 hours under the protection of nitrogen. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5k (2.60g, yield: 74.9%).

MS m/z(ESI):638.2[M+1]。

The eleventh step

4- (3- (1-hydroxypropan-2-yl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5l

To a solution of compound 5k (2.60g, 4.08mmol) in tetrahydrofuran (30mL) was added 1.0M tetrabutylammonium fluoride (8.17mL, 8.17 mmol). The reaction was stirred at room temperature for 16 hours. Water (60mL), ethyl acetate (60 mL. times.2) was added, the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5l (1.10g, yield: 51.5%).

MS m/z(ESI):524.2[M+1]。

The twelfth step

4- (3- (1-hydroxypropan-2-yl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 6-dimethylpyridine-3-phenolate 5m

To a solution of compound 5l (1.10g, 2.10mmol) in dichloromethane (20mL) was added a 4M solution of hydrogen chloride in 1,4 dioxane (21 mL). The reaction was stirred at room temperature for 1 hour. Concentration to dryness gave the title product 5m (950mg, yield: 99.9%).

MS m/z(ESI):380.1[M+1]。

Thirteenth step

5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (1-hydroxypropan-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester 5n

Compound 5m (950mg, 2.50mmol) was dissolved in dichloromethane (50mL), and N, N-diisopropylethylamine (2.59g, 20.03mmol) and di-tert-butyl dicarbonate (2.19g, 10.01mmol) were added dropwise in this order under ice-cooling, and the reaction was carried out at room temperature for 16 hours. Quenched by addition of saturated aqueous sodium bicarbonate (100mL), extracted with dichloromethane (60 mL. times.2), and concentrated to dryness to give the title product 5n (3.70g), which was used in the next reaction without purification.

MS m/z(ESI):580.2[M+1]。

Fourteenth step

4- (2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (1-hydroxypropan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5o

Crude compound 5n (3.70g, 6.38mmol) was dissolved in tetrahydrofuran (50mL), methanol (50mL) and water (50mL), lithium hydroxide monohydrate (2.68mg,63.82mmol) was added, and the mixture was heated at 60 ℃ and stirred for 16 hours. After concentration, water (50mL) and dichloromethane (50mL) were added, the reaction solution was adjusted to pH 9 with 1M hydrochloric acid, the solution was separated, the organic phase was washed with water and then saturated sodium chloride, the organic phase was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 5o (890mg, yield: 29.1%).

MS m/z(ESI):480.2[M+1]。

The fifteenth step

4- (2,4, 7-trimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 5p

Compound 5o (890mg, 1.86mmol) was dissolved in tetrahydrofuran (30mL) and toluene (30mL) and nitrogen was replaced three times, and tri-n-butylphosphine (1.88g,9.28mmol) and a solution of azobisformyldipiperidine (2.41g,9.28mmol) in toluene (30mL) were added dropwise at room temperature, followed by heating at 60 ℃ and stirring for 1 hour. Concentration and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 5p (420mg, yield: 49.0%). MS M/z (ESI) 462.1[ M +1 ].

Sixteenth step

2,4, 7-trimethyl-9- (piperidin-4-yl) -7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole trifluoroacetate 5q

To a solution of compound 5p (200mg, 0.45mmol) in dichloromethane (5mL) was added trifluoroacetic acid (5 mL). The reaction was stirred at room temperature for 2 hours. Concentration to dryness gave the title product 5q (256mg, yield: 99.5%). MS M/z (ESI) 362.1[ M +1 ].

Seventeenth step

Compound 5q (128mg, 0.35mmol) and 1-isobutylpiperidin-4-one (110mg, 0.71mmol) were dissolved in 11mL of a mixture solvent of dichloromethane and methanol (V: V ═ 10:1), and sodium acetate (116mg,1.41mmol) was added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (42mg, 0.70mmol) was added thereto, and the reaction was completed at room temperature for 16 hours. Quenching with saturated aqueous sodium thiosulfate (50mL), extracting with dichloromethane (50 mL. times.2), concentrating the reaction solution under reduced pressure, and purifying by high performance liquid chromatography (column: Boston Phlex Prep C185 um 30: 150 mm; mobile phase: water (10mmol/L NH)₄HCO₃): acetonitrile 52% -72% acetonitrile; gradient elution 15min, flow rate: 30mL/min) to give the title product 5(8mg, yield: 4.5%).

MS m/z(ESI):501.3[M+1]。

¹H NMR(500MHz,CDCl₃)δ8.55(s,1H),7.48(s,1H),7.32-7.28(m,1H),7.17-7.13(m,2H),4.50-4.47(m,1H),4.06-4.02(m,1H),3.55-3.48(m,1H),3.15-3.07(m,2H),2.99-2.92(m,2H),2.64-2.31(m,11H),2.09-2.04(m,2H),1.96-1.72(m,8H),1.70-1.60(m,2H),1.53-1.51(m,3H),0.90-0.85(m,6H)。

Example 6

9- (1- ((1H-imidazol-4-yl) methyl) piperidin-4-yl) -2,4, 7-trimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxepino [4,5-b ] indole 6

Compound 5q (128mg, 0.35mmol) and 4-imidazolecarboxaldehyde (68mg, 0.71mmol) were dissolved in dichloromethane (20mL) and methanol (1mL), and sodium acetate (850mg,10.37mmol) was added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (310mg, 5.18mmol) was added thereto, and the reaction was completed at room temperature for 16 hours. Quenching with saturated aqueous sodium thiosulfate (50mL), extracting with dichloromethane (50 mL. times.2), combining the organic phases, concentrating under reduced pressure, and purifying by high performance liquid chromatography (column: Boston Phlex Prep C185 um 30: 150 mm; mobile phase: water (10mmol/L NH)₄HCO₃): 25% -45% of acetonitrile; gradient elution 15min, flow rate: 30mL/min) to give the title product 6(20mg, yield: 12.8%).

MS m/z(ESI):442.1[M+1]。

¹H NMR(500MHz,CDCl₃)δ7.58(s,1H),7.41(s,1H),7.32-7.31(m,1H),7.24(s,1H),7.10-7.08(m,1H),6.92(s,1H),4.48-4.45(m,1H),4.01-3.99(m,1H),3.62(s,2H),3.53-3.48(m,1H),3.09-3.07(m,2H),2.75-2.59(m,3H),2.50(s,3H),2.47(s,3H),2.25-2.20(m,2H),1.95-1.79(m,4H),1.50-1.48(m,3H)。

Biological evaluation

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

Test example 1 inhibition of the human TLR7 activation pathway by compounds of the disclosure

Experimental materials and instruments

1.HEK-Blue^TMhTLR7 cell (Invivogen)

2. Racemote (R848/Resiquimod, Invivogen)

3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, Invivogen)

4. Blasticidin (Invivogen)

5. Bleomycin (Zeocin, Invivogen)

6. Neomycin (Normocin, Invivogen)

DMEM HIGH sugar medium (DMEM/HIGH Glucose, GE Healthcare)

8. Fetal bovine serum (Gibco)

9. Phosphate buffer (Shanghai Yuan culture Biotech Co., Ltd.)

10. Sterile pure water (homemade Hengrui Shanghai)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well Flat bottom cell culture plate (Corning)

14. Constant temperature cell culture box (Thermo scientific)

15. Constant temperature box (Shanghai-Heng scientific instruments Co., Ltd.)

PHERAstar FS microplate reader (BMG Labtech)

Second, experimental procedure

HEK-Blue was purchased from Invivogen^TMhTLR7 cell, which is co-transfected by human Toll-like receptor 7(TLR7) gene and secretory alkaline phosphatase reporter gene (SEAP) into HEK293 cell, wherein the alkaline phosphatase reporter gene (SEAP) is under the control of IFN-beta minimal promoter (minor promoter) containing 5 NF-kB and AP-1 binding sites, when TLR7 is activated by agonist, SEAP secretion is caused by downstream NF-kB and AP-1, after addition of antagonist compound, the above pathway is inhibited, SEAP secretion is reduced, OD620 is measured by SEAP substrate, thereby evaluating the activity of the compound on TLR7 pathway.

20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. mu.M in blank wells with 100% DMSO, and further diluted 20-fold in DMEM/high sugar medium (complete medium, the same below) containing 10% inactivated FBS; r848 was diluted to 10 μ M with sterile water; add 20. mu.L/well 10. mu.MR 848 diluted in sterile water to 96-well cell culture plates, and add the above compound diluted in complete medium and 100% DMSO at 20. mu.L per well to the well containing R848; negative control wells were filled with 20. mu.L of sterile water and 20. mu.L of 100% DMSO diluted in complete medium.

HEK-Blue^TMhTLR7 cells were cultured in DMEM/high glucose medium containing 10% inactivated FBS, 100. mu.g/mL neomycin, 10. mu.g/mL blasticidin and 100. mu.g/mL Zeocin. Collecting well-grown cells which grow to 70% -80%, discarding growth medium, washing cells with 5-10mL of 37 deg.C preheated PBS, adding 2-5mL preheated PBS, culturing at 37 deg.C for 1-2 min, blowing off cells with pipette, transferring cells to a 15mL centrifuge tube, counting cells, adjusting cell density to 4.8 x 10 with 10% inactivated FBS-containing DMEM high-glucose medium⁵and/mL. Adding 160 μ L of the cell suspension with adjusted density into the 96-well cell culture plate, wherein the final cell number per well is 76500/well, the final concentration of R848 is 1 μ M, and the final concentrations of the tested compounds are 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM respectively; the cells were cultured in a 37 ℃ 5% CO2 incubator for 20 hours, then 20. mu.L of the supernatant was taken, 180. mu.L of the prepared alkaline phosphatase detection medium was added, and after incubation in a 37 ℃ incubator for 120 minutes in the absence of light, the OD620 absorbance was read by a microplate reader. The inhibition rate was calculated using the following formula: the inhibition rate is {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } × 100%, an inhibition curve is drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the concentration of the compound at which the inhibition rate reaches 50%, i.e., IC, is calculated₅₀The values are shown in Table 1.

Table 1 IC of compounds of the present disclosure by measurement of human TLR7 pathway₅₀The value is obtained.

And (4) conclusion: the disclosed compounds have inhibitory effects on the TLR7 pathway.

Test example 2 inhibition of the human TLR8 pathway by compounds of the disclosure

Experimental materials and instruments

1.HEK-Blue^TMhTLR8 cell (Invivogen)

2. Racemote (R848/Resiquimod, Invivogen)

3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, Invivogen)

4. Blasticidin (Invivogen)

5. Bleomycin (Zeocin, Invivogen)

6. Neomycin (Normocin, Invivogen)

DMEM HIGH sugar medium (DMEM/HIGH Glucose, GE Healthcare)

8. Fetal bovine serum (Gibco)

9. Phosphate buffer (Shanghai Yuan culture Biotech Co., Ltd.)

10. Sterile pure water (homemade Hengrui Shanghai)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well Flat bottom cell culture plate (Corning)

14. Constant temperature cell culture box (Thermo scientific)

15. Constant temperature box (Shanghai-Heng scientific instruments Co., Ltd.)

PHERAstar FS microplate reader (BMG Labtech)

Second, experimental procedure

HEK-Blue was purchased from Invivogen^TMhTLR8 cell co-transfected with human Toll-like receptor 8(TLR8) gene and secretory alkaline phosphatase reporter gene (SEAP) into HEK293 cell, wherein the alkaline phosphatase reporter gene (SEAP) is under the control of IFN-beta minimal promoter containing 5 NF-kB and AP-1 binding sites, when TLR8 is activated by agonist, SEAP secretion is caused by downstream NF-kB and AP-1, and antagonist compound is addedInhibition of the pathway, reduction of SEAP secretion, determination of OD620 by SEAP substrate, evaluation of the Activity of Compounds on the TLR8 pathway

20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. mu.M in blank wells with 100% DMSO, and further diluted 20-fold in DMEM/high sugar medium (complete medium, the same below) containing 10% inactivated FBS; r848 diluted to 60 μ M with sterile water; add 20. mu.L/well sterile water diluted 60. mu. M R848 to a 96 well cell culture plate and add the above compound diluted in complete medium and 100% DMSO at 20. mu.L per well to the well containing R848; negative control wells were filled with 20. mu.L of sterile water and 20. mu.L of 100% DMSO diluted in complete medium.

HEK-Blue^TMhTLR8 cells were cultured in DMEM/high glucose medium containing 10% inactivated FBS, 100. mu.g/mL neomycin, 10. mu.g/mL blasticidin and 100. mu.g/mL bleomycin. Collecting well-grown cells growing to 70% -80%, discarding growth medium, washing the cells with 5-10mL of 37 deg.C preheated PBS, adding 2-5mL preheated PBS, culturing at 37 deg.C for 1-2 min, blowing off the cells with pipette, transferring the cells to a 15mL centrifuge tube, counting the cells, adjusting cell density to 4.8 x 10 with 10% inactivated FBS-containing DMEM high-sugar medium⁵and/mL. Adding 160 μ L of the cell suspension with adjusted density into the 96-well cell culture plate, wherein the final cell number per well is 76500/well, the final concentration of R848 is 6 μ M, and the final concentrations of the tested compounds are 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM respectively; the cells were incubated at 37 ℃ with 5% CO₂Culturing for 20 hours in an incubator, then taking 20 mu L of supernatant, adding 180 mu L of prepared alkaline phosphatase detection culture medium, incubating for 120 minutes in a constant temperature box at 37 ℃ in the dark, and reading OD620 light absorption value by a microplate reader. The inhibition rate was calculated using the following formula: the inhibition rate is {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } × 100%, an inhibition curve is drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the concentration of the compound at which the inhibition rate reaches 50%, i.e., IC, is calculated₅₀The values are shown in Table 2.

Table 2 IC of compounds of the present disclosure by measurement of human TLR8 pathway₅₀The value is obtained.

Example numbering	IC₅₀(nM)
		1	>10000
2	>10000
		3	>10000
6	>10000

And (4) conclusion: the disclosed compounds have weak inhibition effect on a TLR8 channel and have selectivity on TLR7 and TLR9 channels.

Test example 3 inhibition of the human TLR9 activation pathway by compounds of the disclosure

Experimental materials and instruments

1.HEK-Blue^TMhTLR9 cell (Invivogen)

2.CpG ODN2006(Invivogen)

3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, Invivogen)

4. Blasticidin (Invivogen)

5. Bleomycin (Zeocin, Invivogen)

6. Neomycin (Normocin, Invivogen)

DMEM HIGH sugar medium (DMEM/HIGH Glucose, GE Healthcare)

8. Fetal bovine serum (Gibco)

9. Phosphate buffer (Shanghai Yuan culture Biotech Co., Ltd.)

10. Sterile pure water (homemade Hengrui Shanghai)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well Flat bottom cell culture plate (Corning)

14. Constant temperature cell culture box (Thermo scientific)

15. Constant temperature box (Shanghai-Heng scientific instruments Co., Ltd.)

PHERAstar FS microplate reader (BMG Labtech)

Second, experimental procedure

HEK-Blue was purchased from Invivogen^TMhTLR9 cell, which is characterized by that it utilizes human Toll-like receptor 9(TLR9) gene and secretory alkaline phosphatase reporter gene (SEAP) which is placed under the control of IFN-beta minimal promoter containing 5 NF-kB and AP-1 binding sites to cotransfect HEK293 cell, when the TLR9 is activated by agonist, the SEAP secretion can be induced by downstream NF-kB and AP-1, after the antagonist compound is added, the above-mentioned pathway can be inhibited, the SEAP secretion is reduced, and the OD620 can be measured by SEAP substrate so as to evaluate the activity of said compound on TLR9 pathway.

20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. mu.M in blank wells with 100% DMSO, and further diluted 20-fold in DMEM/high sugar medium (complete medium, the same below) containing 10% inactivated FBS; ODN2006 was diluted to 10 μ M with sterile water; 20 μ L/well of 10 μ M ODN2006 diluted in sterile water was added to a 96-well cell culture plate, and the above-described compound diluted in complete medium and 100% DMSO were added to wells containing ODN2006 at 20 μ L per well; negative control wells were filled with 20. mu.L of sterile water and 20. mu.L of 100% DMSO diluted in complete medium.

HEK-Blue^TMhTLR9 cells were cultured in DMEM/high-glucose medium (complete medium, the same below) containing 10% FBS, 100. mu.g/mL neomycin, 10. mu.g/mL blasticidin and 100. mu.g/mL bleomycin. Taking the well-grown cells which reach 70% -80% of full cells, discardingRemoving growth medium, washing cells with 5-10mL of 37 deg.C preheated PBS, adding 2-5mL preheated PBS, culturing at 37 deg.C for 1-2 min, blowing off cells with pipette, transferring cells to a 15mL centrifuge tube, counting cells, and adjusting cell density to 4.8 × 10 with 10% inactivated FBS-containing DMEM high-glucose medium⁵and/mL. Adding 160 μ L of the cell suspension with the adjusted density into the 96-well cell culture plate, wherein the final cell number per well is 76500/well, the final concentration of ODN2006 is 1 μ M, and the final concentrations of the tested compounds are 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM respectively; the cells were incubated at 37 ℃ with 5% CO₂Culturing for 20 hours in an incubator, then taking 20 mu L of supernatant, adding 180 mu L of prepared alkaline phosphatase detection culture medium, incubating for 15 minutes in a constant temperature box at 37 ℃ in the dark, and reading OD620 light absorption value by a microplate reader. The inhibition rate was calculated using the following formula: the inhibition rate is {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } × 100%, an inhibition curve is drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the concentration of the compound at which the inhibition rate reaches 50%, i.e., IC, is calculated₅₀The values are shown in Table 3.

Table 3 IC of compounds of the present disclosure by measurement of human TLR9 pathway₅₀The value is obtained.

Example numbering	IC₅₀(nM)
		1	34
2	110
		3	18
4	86
		5	26
6	60

And (4) conclusion: the disclosed compounds have inhibitory effects on the TLR9 pathway.

Claims

1. A compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

z is selected from O atom, S atom and NH;

Ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R^2aand R^2bThe same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, cyano, amino, nitro, hydroxyl, and hydroxyalkyl;

each R is⁵The same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, oxo, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroarylSubstituent, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR⁶、-C(O)NR⁷R⁸、-NR⁷R⁸、-S(O)₂R⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclyl group, which heterocyclyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

r is 1 or 2;

k is 0, 1,2 or 3;

n is 0, 1,2 or 3;

m is 0, 1 or 2;

p is 0, 1,2 or 3;

q is 0, 1,2,3 or 4; and is

t is 0, 1,2,3 or 4.

2. The compound of formula (I) according to claim 1, wherein Z is an O atom, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. According to claim 1 or2The compound shown as the general formula (I), or a tautomer, a racemate, an enantiomer, a diastereoisomer, a mixture form or a pharmaceutically acceptable salt form thereof, wherein R⁰Is a hydrogen atom or

Ring B, L, R⁵And t is as defined in claim 1.

4. A compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, which is a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, Y, L, R¹To R⁵R, k, n, m, p, q and t are as defined in claim 1.

5. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein ring a is a 3-to 8-membered heterocyclyl; preferably piperidinyl.

6. The compound of the general formula (III) according to any one of claims 1 to 5, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Wherein:

ring B, Y, L, R¹To R⁵R, k, n, m, p, q and t are as defined in claim 1.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is an O atom or a chemical bond.

8. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, which is a compound of general formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, L, R¹To R⁵K, n, m, p, q and t are as defined in claim 1.

9. The compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond or CH₂。

10. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein ring B is a 3-to 8-membered heterocyclyl or 5-to 10-membered heteroaryl; preferably piperidinyl or imidazolyl.

11. A compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein k is 0, 1, or 2.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group.

13. The compound of general formula (I) according to any one of claims 1 to 12, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group.

14. The compound of general formula (I) according to any one of claims 1 to 13, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R³Are the same or different and are each independently a hydrogen atom or a halogen.

15. The compound of general formula (I) according to any one of claims 1 to 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R⁴Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl and halo C_1-6An alkyl group.

16. The compound of general formula (I) according to any one of claims 1 to 15, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl and halo C_1-6An alkyl group.

17. A compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, selected from any one of the following compounds:

18. a compound of formula (IIIA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹to R⁴Y, r, k, n, m, p and q are as defined in claim 6.

19. The compound of formula (IIIA) according to claim 18, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is trifluoroacetate or hydrochloride.

20. The compound of formula (IIIA) according to claim 18 or 19, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

21. a process for the preparation of a compound of formula (III) according to claim 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

wherein:

l is a bond or CH₂；

Ring A, ring B, Y, R¹To R⁵R, k, n, m, p, q and t are as defined in claim 6.

22. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 17, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

23. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the preparation of a medicament for inhibiting TLR7 or TLR 9.

24. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for inhibiting TLR7 and TLR 9.

25. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the preparation of a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases.

26. The use according to claim 25, wherein the inflammatory or autoimmune disease is selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and schungren's syndrome.