CN114057734A

CN114057734A - Fused tricyclic derivative, preparation method and application thereof in medicine

Info

Publication number: CN114057734A
Application number: CN202110884673.8A
Authority: CN
Inventors: 张晓敏; 胡伟民; 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: 2020-08-03
Filing date: 2021-08-03
Publication date: 2022-02-18
Anticipated expiration: 2041-08-03
Also published as: CN114057734B

Abstract

The disclosure relates to fused tricyclic derivatives, processes for their preparation and their use in medicine. In particular to a fused tricyclic 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 TLR7/8/9 inhibitor and application of the derivative in preparing medicines for treating and/or preventing inflammatory and autoimmune diseases.

Description

Fused tricyclic derivative, preparation method and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to a fused tricyclic derivative, a preparation method and an application thereof in medicines. In particular, the disclosure relates to fused tricyclic derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and use of the fused tricyclic derivatives as a TLR7/8/9 inhibitor in treating 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, WO2020020800A, 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 an N-oxide or a pharmaceutically acceptable salt thereof:

wherein:

y is CR^4aOr a nitrogen atom;

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, - (CH)₂)_rC(O)NR⁷R⁸Nitro, 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 C 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, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, arylthio, and heteroarylSubstituted with one or more substituents selected from aryl and heteroaryl;

R²selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, deuterated alkyls, haloalkoxy, deuterated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxys, cycloalkyls, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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;

R^4aselected from the group consisting of 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, arylAnd heteroaryl, substituted with one or more substituents;

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 R⁸The same or different and each is independently selected from the group consisting of hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, amino group, hydroxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

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;

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;

j is 0, 1 or 2;

k is 0, 1 or 2; provided that when Y is a nitrogen atom and J is 1, k is 1 or 2;

n is 0, 1,2,3 or 4;

m is 0, 1 or 2;

s is 0, 1,2,3 or 4;

r is 0, 1 or 2; 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 an N-oxide or a pharmaceutically acceptable salt thereof, wherein:

y is CR^4aOr a nitrogen atom;

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

R⁰selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuteroAlkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl and

ring C 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 atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is³Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy groupCyano, 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;

j is 0, 1 or 2;

n is 0, 1,2,3 or 4;

m is 0, 1 or 2;

s 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein:

j is 0, 1 or 2;

k is 1 or 2;

ring A, R⁰、R¹To R⁴N, m and s 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁰Selected from hydrogen atoms, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

And- (CH)₂)_rC(O)NR⁷R⁸(ii) a Ring C, R⁵、R⁷、R⁸R 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁰Is a hydrogen atom or

Ring C, R⁵And t is as defined in formula (I). 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 an N-oxide 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, R¹To R⁵N, m, s, t, J and k are as defined in formula (I).

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R¹To R⁴N, m, s, J and k are as defined in formula (I).

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, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein J is 0 or 1, and k is 1 or 2; preferably J is 1 and k is 1.

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 an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably 5 to 10 membered heteroaryl; more preferably pyridyl or

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 an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably a pyridyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of a 3-to 8-membered heterocyclyl group, a 3-to 8-membered cycloalkyl group, and a 5-to 10-membered heteroaryl group; preferably selected from 3-to 6-membered heterocyclyl, 3-to 6-membered cycloalkyl and 5-to 10-membered heteroaryl; more preferably from piperidinyl, cyclopropyl and tetrahydronaphthyridinyl.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III), or a tautomer thereofA racemate, an enantiomer, a diastereomer, or a mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring C is a 3-to 8-membered heterocyclic group; preferably piperidinyl. 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹Identical or different, each independently selected from hydrogen atom, halogen, C_1-6Alkyl radical, C_1-6Alkoxy and halo C_1-6An alkyl group; preferably C_1-6Alkyl or C_1-6An alkoxy 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹Are 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.

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Selected from hydrogen atoms, halogens, 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 (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R is³Are 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 a hydrogen atom.

In this disclosureIn some preferred embodiments, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, 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 disclosure, the compound of formula (I), (II) or (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, 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, 3 to 8 membered cycloalkyl and halo C_1-6An alkyl group; preferably C_1-6Alkyl or 3 to 8 membered cycloalkyl.

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 an N-oxide, 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.

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein N is 1 or 2.

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein N is 2.

In some preferred embodiments of the present disclosure, the followingA compound of formula (I) or formula (II) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein R is⁷And R⁸Are all hydrogen atoms, r is 1.

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is trifluoroacetate.

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

R⁰selected from hydrogen atoms, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

And- (CH)₂)_rC(O)NR⁷R⁸；R⁷And R⁸Are all hydrogen atoms, r is 1; ring C is selected from 3-to 8-membered heterocyclyl, 3-to 8-membered cycloalkyl and 5-to 10-membered heteroaryl; r⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl, 3 to 8 membered cycloalkyl and halo C_1-6An alkyl group; t is 1;

j is 1, and k is 1;

ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl;

R¹are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen, C_1-6Alkyl radical, C_1-6Alkoxy and halo C_1-6An alkyl group; n is 1 or 2;

R²selected from hydrogen atoms, halogens, C_1-6Alkyl and halo C_1-6An alkyl group;

R³are 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;

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; s is 0, 1,2,3,4, 5 or 6.

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein:

j is 1, and k is 1;

ring a is a 5-to 10-membered heteroaryl; preferably pyridyl or

Ring C is selected from 3-to 6-membered heterocyclyl, 3-to 6-membered cycloalkyl and 5-to 10-membered heteroaryl; preferably selected from piperidinyl, cyclopropyl and tetrahydronaphthyridinyl;

R¹are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen, C_1-6Alkyl and C_1-6An alkoxy group; n is 1 or 2;

R²selected from hydrogen atoms, halogens and C_1-6An alkyl group;

R³are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; m is 0, 1 or 2;

R⁴are the same or different and are each independently selected from the group consisting of a hydrogen atom and C_1-6An alkyl group; s is 0, 1,2,3,4, 5 or 6;

R⁵are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl, 3 to 8 membered cycloalkyl and halo C_1-6An alkyl group; t is 1.

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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein:

j is 1, and k is 1;

ring a is a 5-to 10-membered heteroaryl; preferably pyridyl or

R¹Are the same or different and are each independently C_1-6Alkyl or C_1-6An alkoxy group; n is 1 or 2;

R²is C_1-6An alkyl group;

R³are the same or different and are each independently a hydrogen atom or a halogen; m is 0, 1 or 2;

R⁴is a hydrogen atom.

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 (IIA), formula (IVA), formula (IVB), or formula (IVC), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or salt thereof:

wherein:

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

R^w’is an amino protecting group; preferably tert-butoxycarbonyl or p-toluenesulfonyl;

ring A, R⁰、R¹To R⁴N, s, m, J and k are as defined in formula (I).

Table B typical intermediate 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 (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, comprising:

a compound of formula (IV) or a pharmaceutically acceptable salt thereof with R⁰-X undergoes a nucleophilic substitution reaction to yield a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

x is a leaving group; preferably a halogen;

R⁰selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl, - (CH)₂)_rC(O)NR⁷R⁸And

l is a bond or alkylene, wherein said alkylene is 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 A, ring C, R¹To R⁵、R⁷、R⁸M, n, s, t, r, J and k are as defined in formula (II).

removing the protecting group R from the compound of formula (IIA) or a salt thereof^w’To obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

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

the compound of the general formula (IV) or the salt thereof and the general formula (IIIA) are subjected to reductive amination reaction to obtain the compound of the general formula (III) or the pharmaceutically acceptable salt thereof,

wherein:

ring A, ring C, R¹To R⁵N, s, m, t, J and k 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, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, comprising:

removing the protecting group R from the compound of formula (IVA) or a salt thereof^wTo obtain the compound of the general formula (IV) or the pharmaceutically acceptable salt thereof,

wherein:

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

ring A, R¹To R⁴N, s, m, J and k are as defined in formula (IV).

a compound of the formula (IVB)Or a salt thereof, removing the protecting group R^wAnd R^w’(removal of both protecting groups includes simultaneous deprotection also in succession), or removal of the protecting group R from a compound of formula (IVC) or a salt thereof^w’To obtain the compound of the general formula (IV) or the pharmaceutically acceptable salt thereof,

wherein:

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

ring A, R¹To R⁴N, s, m, J and k 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 an N-oxide, 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 N-oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the manufacture of a medicament for inhibiting TLR7 and/or TLR8 and/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 N-oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8 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 an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8, or TLR 9; preferably for use in the manufacture of a medicament for inhibiting TLR7 and TLR 8; or preferably in the manufacture of a medicament 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 an N-oxide, 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 TLR8 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 a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of inhibiting TLR7, TLR8, 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 N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to a method of inhibiting TLR7, TLR8 or TLR9, preferably TLR7 and TLR 8; or preferably TLR7 and TLR9, comprising administering to a patient in need thereof an effective inhibitory 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 N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

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 N-oxide, 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, in a patient in need thereof. 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 a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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 N-oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in medicaments for inhibiting TLR7 and/or TLR8 and/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 N-oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in medicaments for inhibiting TLR7, TLR8 and TLR 9.

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 N-oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in medicaments for inhibiting TLR7, TLR8 or TLR 9; drugs that are preferably TLR7 and TLR 8; or preferably TLR7 and TLR 9.

The disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for the treatment and/or prevention of an inflammatory or autoimmune disease. 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, TLR8 or TLR9, compounds of formula (I), formula (II), formula (III), formula (IV) and table a are useful for treating TLR7, TLR8 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 condition 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 of an alkyl group-CH₂-is substituted by a heteroatom selected from N, O, S and s (o); wherein said alkyl is as defined above; heteroalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being independently optionally substituted with one or more substituents selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups.

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 substituted by a heteroatom selected from N, O, S and s (o); wherein said alkylene is as defined above; the heteroalkylene can be substituted or unsubstituted, and when substituted, can be substituted at any available point of attachmentThe substituents are preferably independently optionally substituted with one or more substituents selected from the group consisting of H atom, 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 from 3 to 12 carbon atoms, preferably from 3 to 8 (e.g., 3,4, 5,6,7, and 8) carbon atoms, more preferably from 3 to 6 carbon atoms. 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 ring alkyls 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 (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described aboveWherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples include

Etc.; preference is given to

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 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 from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which 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, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3,4, 5,6,7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 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 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 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 selected from one or more substituents of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, 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 and nitro. The amino protecting groups are preferably (trimethylsilyl) ethoxymethyl and tert-butyloxycarbonyl.

Term "Hydroxy-protecting Groups "are suitable Groups known in the art for protecting hydroxy 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 the deuterated form of the compound isEach available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. 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; preferably, the pharmaceutically acceptable salt is trifluoroacetate.

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:

the compound of the general formula (IV) or the salt thereof and the compound of the general formula (IIIA) are subjected to reduction amination reaction under alkaline conditions in the presence of a reducing agent (preferably sodium triacetoxyborohydride) to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof,

wherein:

ring A, ring C, R¹To R⁵N, s, m, t, J and k are as defined in formula (III).

Scheme two

A method of treating a compound of the general formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, comprising:

in the first step, the compounds of the general formula (IVA-1) and the general formula (IVA-2) or the salts thereof are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain the compounds of the general formula (IVA) or the salts thereof,

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

wherein:

x is a halogen, preferably a bromine atom;

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

R^mis composed of

Ring A, R¹To R⁴N, s, m, J and k are as defined in formula (IV).

Scheme three

A method of treating a compound of the present disclosure represented by formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, the method comprising:

a compound of formula (IV) or a pharmaceutically acceptable salt thereof with R⁰-X undergoes a nucleophilic substitution reaction under alkaline conditions to give a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably a halogen;

Scheme four

removing the protecting group R from the compound of the general formula (IIA) or a salt thereof under alkaline conditions^w’To obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme five

deprotection of a compound of formula (IVB) or a salt thereofRadical R^wAnd R^w’(removal of both protecting groups includes simultaneous deprotection also in succession), or removal of the protecting group R from a compound of formula (IVC) or a salt thereof^w’To obtain the compound of the general formula (IV) or the pharmaceutically acceptable salt thereof, and deprotection is carried out under the acidic or alkaline condition;

wherein:

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

ring A, R¹To R⁴N, s, m, J and k are as defined in formula (IV).

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

In the first to fifth synthesis schemes, the reagent for providing basic conditions comprises an organic base including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide, aminomethanol, potassium tert-butoxide or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and an inorganic base including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably selected from the group consisting of potassium carbonate, ammonia methanol, cesium carbonate, sodium hydroxide, sodium acetate and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).

In the second synthesis scheme, the catalyst includes, but is not limited to, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, palladium/carbon, raney nickel, tetrakis (triphenylphosphine) palladium, palladium dichloride, palladium acetate, bis (dibenzylideneacetone) palladium, chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl) ] palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, 1' -bis (dibenzylphosphine) dichloropentairon palladium, tris (dibenzylideneacetone) dipalladium, [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] (3-chloropyridyl) palladium dichloride, Bis (triphenylphosphine) palladium dichloride, 1' -bis (diphenylphosphino) ferrocene palladium dichloride (II) dichloromethane complex and dichloro bis (tricyclohexylphosphine) palladium; preferably 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex.

In the second and fifth synthetic 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 a1, 4-dioxane solution of hydrogen chloride. The above synthesis schemes one to five 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 compounds is determined by Nuclear Magnetic Resonance (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 1200/1290DAD-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 1260DAD 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

2- (2, 6-dimethylpyridin-4-yl) -6- (1-isobutylpiperidin-4-yl) -3-isopropyl-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline 1

First step of

6-amino-7-iodo-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester 1b

6-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester 1a (9.0g, 36.0mmol, Bidao medicine) was dissolved in 240mL of dichloromethane and methanol (V: V ═ 5:1), cooled to 0 deg.C, and added sodium bicarbonate (5.6g, 54.8mmol), followed by iodine chloride (6.4g,39.4mmol, adamas) in dichloromethane (40mL) and stirred at room temperature for 0.5 hours. Quenched with saturated aqueous sodium bisulfite (200mL), extracted with ethyl acetate (80 mL. times.2), the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1b (3.0g, yield: 22.2%).

MS m/z(ESI):375.0[M+1]。

Second step of

7-iodo-6- ((3-methylbut-2-en-1-yl) amino) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester 1d

Compound 1b (1.6g, 4.26mmol) and 3-methylbut-2-enal 1c (540mg, 6.42mmol, adamas) were dissolved in methanol (20mL) and stirred at room temperature for 16 hours. Sodium borohydride (330mg, 8.68mmol) was added and the reaction stirred for 1 hour. Water (30mL) was added, extraction was performed with ethyl acetate (70 mL. times.2), the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1d (1.45g, yield: 76.7%).

MS m/z(ESI):387.0[M-55]。

The third step

3-isopropyl-1, 5,7, 8-tetrahydro-6H-pyrrolo [2,3-g ] isoquinoline-6-carboxylic acid tert-butyl ester 1e

Compound 1d (1.45g, 3.28mmol), palladium acetate (70mg, 0.311mmol, adamas), dichlorobis (tricyclohexylphosphine) palladium (240mg, 0.325mmol, adamas), potassium carbonate (1.36g, 9.84mmol) and triphenyl phosphite (100mg, 0.322mmol, adamas) were dissolved in N, N-dimethylformamide (20mL), cesium carbonate (6.4g, 19.6mmol) was added, reaction at 95 ℃ was carried out for 3 hours, the reaction solution was cooled to room temperature, water (50mL) was added, ethyl acetate (50 mL. times.2) was extracted, the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1e (400mg, yield: 38.8%).

MS m/z(ESI):259.1[M-55]。

The fourth step

2-bromo-3-isopropyl-1, 5,7, 8-tetrahydro-6H-pyrrolo [2,3-g ] isoquinoline-6-carboxylic acid tert-butyl ester 1f

Compound 1e (400mg, 1.27mmol) was dissolved in 1, 2-dichloroethane (20mL) and a solution of N-bromosuccinimide (227mg, 1.27mmol, Shaoyuan technology) in 1, 2-dichloroethane (20mL) was added dropwise at-20 ℃. After the addition was completed, the mixture was quenched with saturated aqueous sodium hydrogen sulfite (500mL), extracted with dichloromethane (50 mL. times.2), the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1f (390mg, yield: 77.9%).

MS m/z(ESI):337.0[M-55]。

The fifth step

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

Compound 1f (390mg, 0.992mmol) and 1g (2, 6-dimethylpyridin-4-yl) boronic acid (225mg, 1.49mmol, pharmacomad) were dissolved in 6mL dioxane and water (V: V ═ 5:1), and potassium phosphate (630mg, 2.97mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (85mg, 0.1mmol, bi-ethyl-p-hydroxybenzoate) were added. The reaction was carried out at 90 ℃ for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, water (30mL) was added, extraction was performed with ethyl acetate (30 mL. times.2), the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1h (380mg, yield: 91.3%).

MS m/z(ESI):420.2[M+1]。

The sixth step

2- (2, 6-Dimethylpyridin-4-yl) -3-isopropyl-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline 1i

To a solution of compound 1h (380mg, 0.906mmol) in dichloromethane (5.0mL) was added a 4M solution of hydrogen chloride dioxane (5.0 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, basified with 7M methanolic ammonia solution, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1i (280mg, yield: 96.8%).

MS m/z(ESI):320.2[M+1]

Seventh step

Compound 1i (100mg, 0.313mmol) and 1-isobutylpiperidin-4-one 1j (90.0mg, 0.580mmol, Bidao) were dissolved in N, N-dimethylformamide (2.0mL), and sodium acetate (50mg,0.610mmol) was added and the mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (135mg, 0.637mmol, Shaoyuan tech) was added thereto and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (column: Boston Phlex Prep C185. mu.m 30X 150 mm; mobile phase: water (10mmol/L ammonium bicarbonate): acetonitrile 50% -70% acetonitrile (15min), flow rate: 30mL/min) to obtain the title product 1(30mg, yield:

20.9％)。

MS m/z(ESI):459.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.86(s,1H),7.42(s,1H),7.14(s,2H),7.04(s,1H),3.81(s,2H),3.32-3.30(m,2H),2.98-2.87(m,3H),2.78-2.75(m,2H),2.49(s,6H),2.37-2.33(m,1H),2.02-2.00(m,2H),1.89-1.80(m,4H),1.77-1.73(m,1H),1.56-1.50(m,2H),1.41(d,6H),0.86(d,6H)。

example 2

6- (1-Cyclopropylpiperidin-4-yl) -2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline bistrifluoroacetate 2

Compound 1i (50mg, 0.156mmol) and 1-cyclopropylpiperidin-4-one 2a (50mg, 0.359mmol, Dipivalol) were dissolved in N, N-dimethylformamide (1.0mL), and sodium acetate (50mg,0.610mmol) was added and the mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (135mg, 0.637mmol, Shaoyuan tech) was added thereto and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by high performance liquid chromatography (Welch Xtimate C18, 5 μm,30 mm. about.150 mm, elution System: H₂O (0.1% trifluoroacetic acid), acetonitrile from 20% (v/v) to 90% (v/v) in 16 minutes, detection wavelength 214&254nm) to give the title product 2(20mg, 19.0% trifluoroacetic acid salt after acidic preparation).

MS m/z(ESI):443.2[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.88(s,1H),8.29(s,2H),7.41(s,1H),7.14(s,2H),7.04(s,1H),3.81(s,2H),3.35-3.30(m,2H),3.01-2.98(m,2H),2.90-2.86(m,2H),2.78-2.76(m,2H),2.49(s,6H),2.20-2.15(m,2H),1.85-1.81(m,2H),1.56(m,1H),1.48-1.45(m,2H),1.40(d,6H),0.43-0.39(m,2H),0.30-0.27(m,2H)。

Example 3

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

Compound 1i (25mg, 0.0784mmol) and isopropyl iodide (20mg, 0.118mmol, adamas) were dissolved in acetonitrile (1.0mL), potassium carbonate (52mg, 0.380mmol) was added, and the mixture was stirred at 80 ℃ for 4 hours. Concentration and purification of the resulting residue by column chromatography on silica gel with eluent system B gave the title product 3(10mg, 35.7%). MS M/z (ESI) 362.0[ M +1 ].

¹H NMR(500MHz,DMSO-d₆)δ10.95(s,1H),7.49(s,1H),7.15(s,2H),7.10(s,1H),3.82(s,2H),3.43-3.35(m,2H),2.98-2.87(m,3H),2.49(s,6H),1.79(m,1H),1.42(d,6H),1.15(d,6H)。

Example 4

6-cyclopropyl-2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline 4

First step of

2- (2, 6-Dimethylpyridin-4-yl) -3-isopropyl-1-p-toluenesulfonyl-1, 5,7, 8-tetrahydro-6H-pyrrolo [2,3-g ] isoquinoline-6-carboxylic acid tert-butyl ester 4a

Compound 1h (200mg, 0.477mmol) was dissolved in N, N-dimethylformamide (3.0mL), 60% sodium hydride (40mg, 1.00mmol) was added, and the reaction was stirred at room temperature for 1 hour. P-toluenesulfonyl chloride (120mg, 0.632mmol) was added and reacted at room temperature for 16 hours. Quenching with saturated aqueous ammonium chloride (10mL), extraction with ethyl acetate (10 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 4a (200mg, yield: 73.1%).

MS m/z(ESI):573.9[M+1]。

Second step of

2- (2, 6-Dimethylpyridin-4-yl) -3-isopropyl-1-p-toluenesulfonyl-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline hydrochloride 4b

To a solution of compound 4a (200mg, 0.348mmol) in dichloromethane (3.0mL) was added a 4M solution of hydrogen chloride dioxane (1.0 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product, crude 4b (160mg, yield: 89.9%).

MS m/z(ESI):474.1[M+1]。

The third step

6-cyclopropyl-2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1-p-toluenesulfonyl-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline 4c

Compound 4b (80mg, 0.157mmol) was dissolved in 1, 2-dichloroethane (3.0mL), cyclopropylboronic acid (27mg, 0.314mmol), sodium carbonate (50mg, 0.472mmol), bipyridine (50mg, 0.320mmol), anhydrous copper acetate (60mg, 0.330mmol) was added, and stirring was carried out at 80 ℃ for 4 hours. Concentration and purification of the resulting residue by column chromatography on silica gel with eluent system a gave the title product 4c (50mg, 62.1%).

MS m/z(ESI):513.9[M+1]。

The fourth step

Compound 4c (50mg, 0.0973mmol) was dissolved in methanol (2.0mL), and 1M aqueous sodium hydroxide (1.0mL) was added and the mixture was stirred at 80 ℃ for 16 hours. Concentration and purification of the resulting residue by column chromatography over silica gel with eluent system B gave the title product 4(15mg, 28.6%).

MS m/z(ESI):360.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.88(s,1H),7.41(s,1H),7.14(s,2H),7.05(s,1H),3.81(s,2H),3.35(m,1H),2.91-2.83(m,4H),2.49(s,6H),1.79(m,1H),1.41(d,6H),0.52-0.48(m,2H),0.43-0.41(m,2H)。

Example 5

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

First step of

7- (2- (2, 6-dimethylpyridin-4-yl) -3-isopropyl-1, 5,7, 8-tetrahydro-6H-pyrrolo [2,3-g ] isoquinolin-6-yl) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester 5b

The compound 7-chloro-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester 5a (140mg, 0.522mmol, Shaoyou Tech) and the compound 1i (180mg, 0.564mmol) were dissolved in dioxane (7.0mL), cesium carbonate (350mg,1.07mmol) and [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene were added](3-Chloropyridyl) Palladium (II) dichloride (Pd-PEPSI)^TM-IPent catalyst) (40mg,0.0505mmol, Aldrich) at 100 ℃ for 16 hours. Quenching with saturated aqueous ammonium chloride (10mL), extraction with ethyl acetate (10 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 5b (110mg, yield: 38.2%).

MS m/z(ESI):552.1[M+1]。

Second step of

Compound 5b (110mg, 0.199mmol) was dissolved in dichloromethane (3.0mL), and trifluoroacetic acid (1.0mL) was added and stirred at room temperature for 2 hours. Concentration, basification with 7M methanolic ammonia and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 5(10mg, 11.1%).

MS m/z(ESI):452.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ11.01(s,1H),7.93(s,1H),7.69(s,1H),7.18(s,1H),7.15(s,2H),6.56(s,1H),4.73(s,2H),3.92(s,2H),3.73-3.71(m,2H),3.35(m,1H),3.06-3.04(m,2H),3.02-2.99(m,3H),2.66-2.64(m,2H),2.49(s,6H),1.43(d,6H)。

Example 6

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

First step of

di-tert-butyl 3-isopropyl-7, 8-dihydro-1H-pyrrolo [2,3-g ] isoquinoline-1, 6(5H) -dicarboxylate 6a

Compound 1e (550mg, 1.75mmol), di-tert-butyl dicarbonate (570mg, 2.61mmol, Shaoyou Technology), N, N-diisopropylethylamine (450mg, 3.48mmol, adamas) and 4-dimethylaminopyridine (10mg, 0.08mmol, adamas) were dissolved in acetonitrile (10mL) and stirred at room temperature for 16 h. Quenching with water (20mL), extraction with ethyl acetate (30 mL. times.3), and concentration of the combined organic phases under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 6a (630mg, yield: 86.9%).

MS m/z(ESI):258.9[M-155]。

Second step of

3-isopropyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7, 8-dihydro-1H-pyrrolo [2,3-g ] isoquinoline-1, 6(5H) -dicarboxylic acid di-tert-butyl ester 6b

Compound 6a (580mg, 1.40mmol) was dissolved in anhydrous tetrahydrofuran (12mL), cooled to-78 ℃ under nitrogen, 2.0M lithium diisopropylamide in tetrahydrofuran (1.2mL, 2.4mmol, adamas) was added and stirred at-78 ℃ for 1.0 h. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (520mg, 2.79mmol, Aldrich) was added, and the reaction was stirred at-78 ℃ for 1 hour. Saturated aqueous ammonium chloride (15mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 6b (200mg, yield: 26.4%).

MS m/z(ESI):485.2[M-55]。

The third step

3-isopropyl-2- (8-methoxy- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -7, 8-dihydro-1H-pyrrolo [2,3-g ] isoquinoline-1, 6(5H) -dicarboxylic acid di-tert-butyl ester 6d

Compound 6b (60mg, 0.11mmol) and 6-bromo-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine 6c (35.0mg, 0.15mmol, prepared by methods well known in the literature "WO 2018/005586A1, p143, intermediate F-5") were dissolved in dioxane (2.0mL) and water (0.5 mL). [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15mg, 0.018mmol, Shanghai Tantan) and potassium phosphate (72mg, 0.34mmol, Shanghai Hu test) were added. The nitrogen was replaced three times, and the reaction was stirred at 80 ℃ for 16 hours. Water (10mL) was added, extraction was performed with ethyl acetate (15 mL. times.3), and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6d (50mg, yield: 89%).

MS m/z(ESI):562.3[M+1]。

The fourth step

Compound 6d (50mg, 0.089mmol) was dissolved in dichloromethane (3.0mL) and trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 1.0 hour. Concentrated under reduced pressure and the residue dissolved in 7M ammonia/methanol (5.0 mL). Stir at room temperature for 10 minutes. Concentrated under reduced pressure and the residue purified by high performance liquid chromatography (column: Sharpsil-T C18150 x 30mm,5 μm; mobile phase 1: water (containing 0.1% trifluoroacetic acid), mobile phase 2: acetonitrile; 15min gradient: 10% -95%, flow rate: 30mL/min) to give the title product 6(5.0mg, yield: 11.8%).

MS m/z(ESI):362.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.48(s,1H),8.43(s,1H),7.70(s,1H),7.31(s,1H),7.22(s,1H),4.50(s,2H),4.15(s,3H),3.58-3.53(m,2H),3.38(m,1H),3.32-3.26(m,2H),3.52(d,6H)。

Example 7

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

First step of

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

6-bromo-7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridine 7a (760mg, 3.36mmol, prepared by the method disclosed in patent application "WO 2018005586A 1, intermediate F-4 on page 140") and 3-methylbut-1-yne (500mg,7.34mmol, Acros), cuprous iodide (130mg,0.682mmol, Alfa), bis-triphenylphosphine palladium dichloride (240mg,0.341mmol, adamas), triethylamine (1.0g,10.0mmol) were dissolved in N, N-dimethylformamide (15mL), and stirred at 60 ℃ for 30 hours under nitrogen. Quenched with water (50mL), extracted with ethyl acetate (50 mL. times.3), the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7b (650mg, yield: 90.6%).

MS m/z(ESI):214.0[M+1]。

Second step of

7-bromo-6-nitro-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester 7d

7-bromo-6-nitro-1, 2,3, 4-tetrahydroisoquinoline 7c (4.24g, 16.5mmol, Lemo reagent) and triethylamine (2.5g, 24.8mmol) were dissolved in dichloromethane (50mL), and di-tert-butyl dicarbonate (4.5g, 20.6mmol) was added and stirred at room temperature for 16 hours. Water (100mL) was added for quenching, ethyl acetate (80 mL. times.2) was extracted, the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7d (5.5g, yield: 93.4%).

MS m/z(ESI):300.9[M-55]。

The third step

6-amino-7-bromo-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester 7e

Compound 7d (5.3g, 14.8mmol) was dissolved in ethanol (60mL) and water (15mL), and iron powder (4.1g,73.4mmol) was added and stirred at 80 ℃ for 2 hours. Cooled to room temperature, filtered, concentrated under reduced pressure from the organic phase, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7e (4.5g, yield: 92.7%). MS M/z (ESI) 271.0[ M-55 ].

The fourth step

2- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1, 5,7, 8-tetrahydro-6H-pyrrolo [2,3-g ] isoquinoline-6-carboxylic acid tert-butyl ester 7f

Compound 7e (4.1g, 12.5mmol), 7b (3.4g,15.9mmol) was dissolved in dimethylacetamide (80mL), anhydrous lithium chloride (535mg,12.6mmol), potassium carbonate (5.2g, 37.7mmol), tetrakis (triphenylphosphine) palladium (1.5g, 1.30mmol, adamas) were added, reacted at 115 ℃ for 40 hours, the reaction was cooled to room temperature, water (100mL) was added, ethyl acetate (50 mL. times.2) was extracted, the combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7f (2.0g, yield: 34.7%).

MS m/z(ESI):460.2[M+1]。

The fifth step

Compound 7f (150mg, 0.237mmol) was dissolved in dichloromethane (5.0mL), and trifluoroacetic acid (1.0mL) was added and stirred at room temperature for 2 hours. Concentrating, basifying with 7M ammonia methanol solution, concentrating the filtrate under reduced pressure, and purifying by high performance liquid chromatography (column: Boston Phlex Prep C185 μ M30X 150mm, elution system: H₂O (10mmol/L ammonium bicarbonate), acetonitrile rising from 15% (v/v) to 95% (v/v) in 18 minutes, detection wavelength 214&254nm) to yield the title product 7(70mg, 59.3%).

MS m/z(ESI):360.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.75(s,1H),8.74(s,1H),8.47(s,1H),7.34(s,1H),7.02(s,2H),3.99(s,1H),3.55(m,1H),3.02-2.97(m,2H),2.87-2.81(m,3H),2.59(s,3H),2.14(s,3H),1.30(d,6H)。

Example 8

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

Compound 7(100mg, 0.28mmol) and 2-bromoacetamide (60mg, 0.44mmol, Bi De medicine) were dissolved in dimethylformamide (2.0mL), and cesium carbonate (200mg,0.61mmol) was added, followed by stirring at room temperature for 3 hours. Concentrating, and purifying by high performance liquid chromatography (column: Boston Phlex Prep C185. mu.L)m 30X 150mm, elution System: h₂O (10mmol/L ammonium bicarbonate), acetonitrile rising from 15% (v/v) to 90% (v/v) in 19 minutes, detection wavelength 214&254nm) to yield the title product 8(50mg, 43.2%).

MS m/z(ESI):417.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.75(s,1H),8.75(s,1H),8.47(s,1H),7.38(s,1H),7.23(d,1H),7.17(d,1H),7.07(s,1H),3.77(d,2H),3.06(d,2H),3.00-2.97(m,2H),2.84(m,1H),2.77-2.74(m,2H),2.59(s,3H),2.14(s,3H),1.30(d,6H)。

Example 9

3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -5,6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline 9

First step of

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

Compound 6b (77mg, 0.142mmol) and compound 6-bromo-8-methyl- [1,2,4] triazolo [1,5-a ] pyridine 9a (33mg, 0.156mmol, obtained from Shanghai) were dissolved in dioxane (2.0mL) and water (0.2mL), and potassium phosphate (90mg,0.427mmol) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) dichloromethane complex (12mg,0.0146mmol) were added and reacted at 80 ℃ for 4 hours. Quenching with saturated aqueous ammonium chloride (10mL), extraction with ethyl acetate (10 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 9b (60mg, yield: 76.9%).

MS m/z(ESI):546.2[M+1]。

Second step of

Compound 9b (60mg, 0.110mmol) was dissolved in dichloromethane (3.0mL), and trifluoroacetic acid (1.0mL) was added and stirred at room temperature for 2 hours. ConcentratingBasified with 7M methanolic ammonia, the filtrate is concentrated under reduced pressure and purified by high performance liquid chromatography (column: Boston Phlex Prep C185 μ M30X 150mm, elution: H₂O (10mmol/L ammonium bicarbonate), acetonitrile rising from 15% (v/v) to 95% (v/v) in 18 minutes, detection wavelength 214&254nm) to yield the title product 9(15mg, 39.4%).

MS m/z(ESI):346.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.96(s,1H),8.81(s,1H),8.54(s,1H),7.61(s,1H),7.38(s,1H),7.05(s,1H),3.99(s,2H),3.25(m,1H),3.00-2.98(m,2H),2.84-2.82(m,2H),2.63(s,3H),2.52(m,1H),1.42(d,6H)。

Example 10

2- (3-isopropyl-2- (8-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1,5,7, 8-tetrahydro-6H-pyrrolo [2,3-g ] isoquinolin-6-yl) acetamide 10

Compound 9(10mg, 0.029mmol) and 2-bromoacetamide (6.0mg, 0.044mmol, Bidak drug) were dissolved in dimethylformamide (1.0mL), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (15mg,0.06mmol) was added and stirred at room temperature for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 10(8.0mg, yield: 68.6%).

MS m/z(ESI):403.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.98(s,1H),8.81(s,1H),8.53(s,1H),7.61(s,1H),7.42(s,1H),7.25(s,1H),7.16(s,1H),7.10(s,1H),3.77(s,2H),3.25(m,1H),3.06(s,2H),3.00-2.98(m,2H),2.76-2.74(m,2H),2.64(s,3H),1.42(d,6H)。

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)

11.15 mL 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 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/mLzeocin. Collecting cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of 37 deg.C preheated PBS to wash the cells once, adding 2-5mL of preheated PBS to culture at 37 deg.C for 1-2 min, blowing off the cells with a pipette, transferring the cells to a 15mL centrifuge tube, counting the cells, adjusting the cell density to 4.8 × 10 with the use of the whole 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.

Practice ofExample number	IC₅₀(nM)
		1	8.98
2	22.46
		3	13.08
4	56.29
		5	32.78
6	3.60
		7	2.19
8	8.01
		9	1.31
10	1.17

And (4) conclusion: the disclosed compound has a good inhibition effect on a 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)

11.15 mL 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 secreted alkaline phosphatase reporter gene (SEAP) under the control of IFN-beta minimal promoter containing 5 NF-kB and AP-1 binding sites in HEK293 cell, wherein the SEAP secretion is induced by downstream NF-kB and AP-1 when TLR8 is activated by agonist, the pathway is inhibited and the SEAP secretion is reduced after addition of antagonist compound, and OD620 is determined by SEAP substrate to evaluate the activity of the compound on TLR8 pathway

20mM test compound 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; mu.L/well of 60. mu. M R848 diluted in sterile water was added to a 96 well cell culture plate, and the above compound diluted in complete medium and 100% DMSO were added to wells containing R848 at 20. mu.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^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 cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of 37 deg.C preheated PBS to wash the cells once, adding 2-5mL of preheated PBS to culture at 37 deg.C for 1-2 min, blowing off the cells with a pipette, transferring the cells to a 15mL centrifuge tube, counting the cells, adjusting the cell density to 4.8 × 10 with the use of the whole medium⁵and/mL. 160. mu.L of the cell suspension after density adjustment was added to the above 96-well cell culture plate to give 76500 cells/well per well, a final R848 concentration of 6. mu.M, and final test compound concentrations of 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	2.53
2	3.51
		3	5.49
4	23.18
		5	54.34
6	0.44
		7	0.19
8	1.54
		9	0.55
10	1.35

And (4) conclusion: the disclosed compound has a good inhibition effect on a TLR8 pathway.

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)

11.15 mL 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; to a 96-well cell culture plate, 20. mu.L/well of 10. mu.M ODN2006 diluted in sterile water was added, and the above-described compound diluted in complete medium and 100% DMSO were added to wells containing ODN2006 at 20. mu.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 containing 10% FBS, 100. mu.g/mL neomycin, 10. mu.g/mL blasticidin and 100. mu.g/mL bleomycin. Collecting cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 deg.C for washing cells once, adding 2-5mL of preheated PBS for culturing at 37 deg.C for 1-2 min, blowing off cells with a pipette, transferring cells to a 15mL centrifuge tube, counting cells, adjusting cell density to 4.8 × 10 with the whole 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	159
2	279
		3	601

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 an N-oxide, or a pharmaceutically acceptable salt thereof:

wherein:

y is CR^4aOr a nitrogen atom;

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

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

each R is⁵Are the same or different and eachIndependently 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;

j is 0, 1 or 2;

n is 0, 1,2,3 or 4;

m is 0, 1 or 2;

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

r is 0, 1 or 2; and is

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

2. A compound according to claim 1 of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein R is⁰Selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and

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

3. The compound of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, according to claim 1 or2, which is a compound of the general formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof:

wherein:

j is 0, 1 or 2;

k is 1 or 2;

ring A, R⁰、R¹To R⁴N, m and s are as defined in claim 1.

4. A compound of formula (I) according to claim 1 or 3, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein R is⁰Selected from hydrogen atoms, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

And- (CH)₂)_rC(O)NR⁷R⁸(ii) a Ring C, R⁵、R⁷、R⁸R and t are as defined in claim 1.

5. The compound of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, which is a compound of the general formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring C, R¹To R⁵N, m, s, t, J and k are as defined in claim 1.

6. The compound of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, which is a compound of the general formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R¹To R⁴N, m, s, J and k are as defined in claim 1.

7. A compound of general formula (I) according to any one of claims 1 to 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein J is 0 or 1, and k is 1 or 2; preferably J is 1 and k is 1.

8. A compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably 5 to 10 membered heteroaryl; more preferably pyridyl or

9. A compound of general formula (I) according to any one of claims 1 to 5,7 and 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of a 3-to 8-membered heterocyclyl group, a 3-to 8-membered cycloalkyl group, and a 5-to 10-membered heteroaryl group; preferably selected from 3-to 6-membered heterocyclyl, 3-to 6-membered cycloalkyl and 5-to 10-membered heteroaryl; preferably selected from piperidinyl, cyclopropyl and tetrahydronaphthyridinyl.

10. The compound of general formula (I) according to any one of claims 1 to 9, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein R is¹Identical or different, each independently selected from hydrogen atom, halogen, C_1-6Alkyl radical, C_1-6Alkoxy and halo C_1-6An alkyl group.

11. A compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, racemate, enantiomer, or salt thereofIn the form of the isomers, diastereomers or mixtures thereof, or the N-oxides, or pharmaceutically acceptable salts thereof, wherein R²Selected from hydrogen atoms, halogens, C_1-6Alkyl and halo C_1-6An alkyl group.

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 an N-oxide, or a pharmaceutically acceptable salt thereof, wherein R is³Are 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 an N-oxide, 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.

14. A compound of general formula (I) according to any one of claims 1 to 5 and 7 to 13, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, 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, 3 to 8 membered cycloalkyl and halo C_1-6An alkyl group.

15. A compound of general formula (I) according to any one of claims 1 to 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein N is 1 or 2.

16. A compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, selected from any one of the following compounds:

17. a process for the preparation of a compound of formula (III) according to claim 5, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, which comprises:

the compound of the general formula (IV) or the pharmaceutically acceptable salt thereof and the general formula (IIIA) are subjected to reductive amination reaction to obtain the compound of the general formula (III) or the pharmaceutically acceptable salt thereof,

wherein:

ring A, ring C, R¹To R⁵N, s, m, t, J and k are as defined in claim 5.

18. A compound of formula (IIA), formula (IVA), formula (IVB) or formula (IVC), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a salt thereof:

wherein:

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

ring A, R⁰、R¹To R⁴N, s, m, J and k are as defined in claim 1.

19. A compound:

20. a process for the preparation of a compound of formula (IV) according to claim 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

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

ring A, R¹To R⁴N, s, m, J and k are as defined in claim 6.

21. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

22. Use of a compound of general formula (I) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the preparation of a medicament for inhibiting TLR7, TLR8 and TLR 9.

23. Use of a compound of general formula (I) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the manufacture of a medicament for inhibiting TLR7, TLR8, or TLR 9; preferably for use in the manufacture of a medicament for inhibiting TLR7 and TLR 8; or preferably in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

24. Use of a compound of general formula (I) according to any one of claims 1 to 16 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21 for the preparation of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases.

25. The use according to claim 24, 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.