CN114057734B

CN114057734B - Fused tricyclic derivatives, preparation method thereof and application thereof in medicines

Info

Publication number: CN114057734B
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: 2023-06-16
Anticipated expiration: 2041-08-03
Also published as: CN114057734A

Abstract

The present disclosure relates to fused tricyclic derivatives, methods of preparation and pharmaceutical uses thereof. In particular, the disclosure relates to a fused tricyclic derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application thereof as a therapeutic agent, particularly application as a TLR7/8/9 inhibitor and application in preparing medicines for treating and/or preventing inflammatory and autoimmune diseases.

Description

Fused tricyclic derivatives, preparation method thereof and application thereof in medicines

Technical Field

The present disclosure belongs to the field of medicine, and relates to a fused tricyclic derivative, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to fused tricyclic derivatives of general formula (I), methods for their preparation, pharmaceutical compositions containing the derivatives, and their use as TLR7/8/9 inhibitors in the treatment of inflammatory and autoimmune diseases.

Background

Toll Like Receptors (TLRs) are an evolutionarily conserved class of transmembrane innate immune receptors that are involved in the first line of defense in protecting human health and play an important role in the recognition of pathogen-associated molecular patterns (PAMP) (Kawai, T.et al., nature immunol.,11,2010,373-384). TLRs are expressed in various immune cells and can be classified into two types according to the expression sites: TLRs expressed in cell membranes (TLR 1/2/4/5/6) and TLRs expressed in endosomal membranes (TLR 3/7/8/9) recognize different components and molecules, respectively, in PAMP. Wherein 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 binds its ligand and is activated, binds to the adaptor protein MyD88 in the cytoplasm, initiates NF- κb and IRF pathways, activates DC cells, produces type I interferon and other various inflammatory cytokines; in B cells, TLR7/8/9, in combination with nucleic acids, plays an important role in the production of antinuclear antibodies by B cells, and type I interferons secreted by DC cells also promote further proliferation and activation of such autoimmune B cells, thereby eliciting a series of inflammatory responses.

Systemic Lupus Erythematosus (SLE) belongs to an autoimmune connective tissue disease, and three major classes of clinical first-line drugs for SLE are: hormones, immunosuppressants and antimalarial drugs. Only in this centuryThere is a new drug belimumab approved by the FDA, but it has moderate and delayed efficacy (Navarra, s.v. et al Lancet 2011,377,721) for only a small proportion of SLE patients, and the treatment options are very limited. Thus, there is an urgent need for new therapies that improve a greater proportion of patient populations and that can be used for long periods of time, safely. The phenomenon of significantly up-regulated expression of TLR7/9 and type I interferon was found in PBMCs of patients with Systemic Lupus Erythematosus (SLE) (Beverly d.lc et al, mol immunol.,2014, 61:38-43). Mice overexpressing TLR7 have been reported to exacerbate autoimmune diseases and autoinflammation (Santiago-Raber ML, et al, J immunol.,2008, 181:1556-1562), whereas functional inhibition of TLR7/9 can alleviate B6-Fas ^lpr And pathological manifestations of 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 treating SLE.

Published TLR7/8/9 inhibitor patent applications include WO2019233941A1, WO2020020800A, WO2018049089A1, WO2017106607A1, CN109923108A, WO2020048605A1 and the like.

Disclosure of Invention

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

wherein:

y is CR ^4a Or a nitrogen atom;

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

R ⁰ selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _r C(O)NR ⁷ R ⁸ Nitro, hydroxy, hydroxyalkyl and

l is selected from the group consisting of a bond, an alkylene, and a heteroalkylene, wherein each of the alkylene and heteroalkylene is 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 is ¹ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ² Selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuteroalkyl, haloalkoxy, deuteroalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is 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;

each R is ³ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

each R is ⁴ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ^4a selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

Each R is ⁵ And are each 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 the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with a moiety selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR ⁶ 、-C(O)NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-S(O) ₂ R ⁹ One or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R ⁶ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁷ and R is ⁸ The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R is ⁷ And R is ⁸ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ⁹ Selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, and,Hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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 also provided with

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

y is CR ^4a Or a nitrogen atom;

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

R ⁰ selected from the group consisting of hydrogen, 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 is ¹ And are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is 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;

each R is ⁵ And are the same or different and are each 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 each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally selected from the group consisting of halogen, alkyl, oxygenHalo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR ⁶ 、-C(O)NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-S(O) ₂ R ⁹ One or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R ⁹ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl, 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 also provided with

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

wherein:

j is 0, 1 or 2;

k is 1 or 2;

ring A, R ⁰ 、R ¹ To R ⁴ N, 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl group,

And- (CH) ₂ ) _r C(O)NR ⁷ R ⁸ The method comprises the steps of carrying out a first treatment on the surface of the Ring C, R ⁵ 、R ⁷ 、R ⁸ R 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is a hydrogen atom or

Ring C, R ⁵ And t is 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, is a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxideA compound, or a pharmaceutically acceptable salt thereof:

wherein:

ring a, ring C, R ¹ To R ⁵ N, m, s, t, J and k 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or pharmaceutically acceptable salt thereof:

wherein:

ring A, R ¹ To R ⁴ N, 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, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably a 5 to 10 membered heteroaryl; more preferably a pyridyl group 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, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl or a 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 3-to 8-membered heterocyclyl, 3-to 8-membered cycloalkyl, and 5-to 10-membered heteroaryl; preferably selected from 3 to 6 membered heterocyclyl, 3 to 6 membered cycloalkyl and 5 to 10 membered heteroaryl; more preferably selected from the group consisting of piperidinyl, cyclopropyl and tetrahydronaphthyridinyl.

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 a 3-to 8-membered heterocyclyl; preferably piperidinyl. 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 N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ¹ The same or different, each independently is selected from hydrogen atom, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and halo C _1-6 An alkyl group; preferably C _1-6 Alkyl or C _1-6 An alkoxy 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, diastereomer, or mixture thereof, or N-oxide, or a salt thereof,Or a pharmaceutically acceptable salt thereof, wherein R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably C _1-6 An 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably a hydrogen atom.

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 N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably a hydrogen atom.

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 N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, 3-to 8-membered cycloalkyl and haloC _1-6 An alkyl group; preferably C _1-6 Alkyl or 3 to 8 membered cycloalkyl.

At the bookIn some preferred embodiments, the compounds of formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, are disclosed, wherein R ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An 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, diastereomer, or mixture thereof, or an N-oxide, 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, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein N is 2.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein R ⁷ And R is ⁸ All are hydrogen atoms, and 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, diastereomer, or mixture thereof, or an N-oxide, 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, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:

R ⁰ selected from hydrogen atoms, C _1-6 Alkyl group,

And- (CH) ₂ ) _r C(O)NR ⁷ R ⁸ ；R ⁷ And R is ⁸ All are hydrogen atoms, and r is 1; ring C is selected from 3 to 8 membered heterocyclyl, 3 to 8 membered cycloalkyl and 5 to 10 membered heteroaryl; r is R ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, 3-to 8-membered cycloalkyl and haloC _1-6 An alkyl group; t is 1;

j is 1, and k is 1;

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

R ¹ identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and halo C _1-6 An alkyl group; n is 1 or 2;

R ² selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

R ³ identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; m is 0, 1 or 2;

R ⁴ identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An 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, diastereomer, or mixture thereof, or N-oxide, 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;

R ¹ identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 An alkoxy group; n is 1 or 2;

R ² selected from hydrogen atoms, halogens and C _1-6 An alkyl group;

R ³ identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; m is 0, 1 or 2;

R ⁴ identical or different and are each independently selected from hydrogen atoms and C _1-6 An alkyl group; s is 0, 1, 2, 3, 4, 5 or 6;

R ⁵ identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, 3-to 8-membered cycloalkyl and haloC _1-6 An alkyl group; t is 1.

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, 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

R ¹ Identical or different and are each independently C _1-6 Alkyl or C _1-6 An alkoxy group; n is 1 or 2;

R ² Is C _1-6 An alkyl group;

R ³ the same or different, and are each independently a hydrogen atom or a halogen; m is 0, 1 or 2;

R ⁴ is 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 compounds of formula (IIA), formula (IVA), formula (IVB) or formula (IVC), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or salt thereof:

wherein:

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

R ^w’ is an amino protecting group; preferably t-butoxycarbonyl or p-toluenesulfonyl;

ring A, R ⁰ 、R ¹ To R ⁴ N, 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:

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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 the formula (IV) or a pharmaceutically acceptable salt thereof and R ⁰ -X undergoes nucleophilic substitution to give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

X is a leaving group; preferably halogen;

R ⁰ selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, hydroxyalkyl, - (CH) ₂ ) _r C(O)NR ⁷ R ⁸ And

l is a bond or an alkylene group, wherein the alkylene group 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, R ¹ To R ⁵ 、R ⁷ 、R ⁸ M, n, s, t, r, J and k are as defined in formula (II).

removing protecting group R from compound of formula (IIA) or salt thereof ^w’ Obtaining 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:

subjecting a compound of the general formula (IV) or a salt thereof to reductive amination with the general formula (IIIA) to give a compound of the general formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

ring a, ring C, R ¹ To R ⁵ N, 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:

deprotection of a compound of formula (IVA) or a salt thereof ^w To obtain a compound of the general formula (IV) or a pharmaceutically acceptable salt thereof,

wherein:

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

ring A, R ¹ To R ⁴ N, s, m, J and k are as defined in formula (IV).

Deprotection of a compound of formula (IVB) or a salt thereof to remove a protecting group R ^w And R is ^w’ (removal of both protecting groups includes simultaneous and also successive deprotection), or deprotection of a compound of formula (IVC) or a salt thereof ^w’ To obtain a compound of the general formula (IV) or a pharmaceutically acceptable salt thereof,

wherein:

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

ring A, R ¹ To R ⁴ N, 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 formula (I), formula (II), formula (III), formula (IV) and table a of the present disclosure, 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 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 and/or TLR8 and/or TLR 9.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or 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 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 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, in the manufacture of a medicament for the treatment and/or prevention of an inflammatory or autoimmune disease. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

The present 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 an 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 an 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 or TLR9, preferably a method of inhibiting TLR7 and TLR 8; or preferably TLR7 and TLR9, comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a use in a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective 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 an N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

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 a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for inhibiting TLR7 and/or TLR8 and/or TLR 9.

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 in a medicament for inhibiting TLR7, TLR8 and TLR 9.

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 in a medicament for inhibiting TLR7, TLR8 or TLR 9; drugs that are preferably TLR7 and TLR 8; or preferably 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 N-oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases. Wherein the inflammatory or autoimmune disease is preferably selected from 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 the treatment of 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 erythema, lupus nephritis, cutaneous lupus, psoriasis; autoinflammatory diseases including cyclic syndrome associated with Cryopyrin (CAPS), cyclic syndrome associated with TNF Receptors (TRAPS), familial Mediterranean Fever (FMF), adult stele disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders, such as those including solid tumors, ocular neovascularization, 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, neoplastic 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 present 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 erythema, scleroderma, chronic thyroiditis, graves 'disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, reiter's syndrome (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 diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; cerebral ischemia or neurodegenerative diseases caused by Alzheimer's disease, parkinson's disease, traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases including acute hepatitis infection (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; ischemia in stroke, myocardial ischemia, heart attack, organ hypoxia, vascular proliferation, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. Preferred methods of treatment are those in which the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred is a method of treatment wherein the condition is ischemia reperfusion injury, which is cerebral ischemia reperfusion injury caused by stroke or myocardial ischemia reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the condition is multiple myeloma.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, 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) administration, 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, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

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

The 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. The above-described sweeteners 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 an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and 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 sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

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 suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare 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 will therefore melt in the rectum to release the drug.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the 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 from 1 to 20 carbon atoms, preferably an alkyl group containing from 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 from 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, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and 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, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it 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 D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroalkyl" refers to one or more-CH's in an alkyl group ₂ -substituted with a heteroatom selected from N, O, S and S (O); wherein said alkyl is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the 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 "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkylene group containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably containing from 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -)、11-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from 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 group ₂ -substituted with a heteroatom selected from N, O, S and S (O); wherein the alkylene is as defined above; the heteroalkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally substituted with one or more substituents selected from the group consisting of H, D, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

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

The term "alkynyl" refers to an alkyl compound having 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, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. 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-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

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

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

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

Etc.; preferably->

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably 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 "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atom, 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 monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 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 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 heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. 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 single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl 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 which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/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 bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, 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., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

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

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably 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 being 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. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, 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, they 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, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 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, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they 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 cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

In the chemical structure of the compounds of the present disclosure, the bond

Indicating the unspecified configuration, i.e.the bond +.>

Can be +.>

Or->

Or at the same time contain->

And->

Two configurations.

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, 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 t-butoxycarbonyl.

The term "hydroxy protecting group" is a suitable group known in the art for protecting hydroxy groups, see literature ("Protective Groups in Organic Synthesis", 5) ^Th Ed.T.W.Greene&P.g.m.wuts). As an example, preferably, the hydroxyl protecting group may be (C _1-10 Alkyl or aryl radicals ₃ Silyl groups, for example: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy substituted C _1-4 Alkyl groups such as: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, and the like; may be (C) _1-10 Alkyl or aryl) acyl groups, for example: formyl, acetyl, benzoyl and p-nitroA phenylbenzoyl group, and the like; may be (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; may also be (C) _1-6 Alkoxy or C _6-10 Aryloxy) carbonyl.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, where 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 a cycloalkyl-O-group, 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-, 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-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

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.

Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, with the structures of the present disclosure, replacement of hydrogen with "deuterium" or "tritium", or with ¹⁸ F-fluorine labeling [ ] ¹⁸ F isotope) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enriched carbon ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein each available hydrogen atom of the deuterated form of the compound attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus 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 group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

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

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups 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 and organic acids; preferably, the pharmaceutically acceptable salt is trifluoroacetate salt.

The term "therapeutically and/or prophylactically effective amount" with respect to a drug or pharmacologically active agent means a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

For a drug or pharmacologically active agent, the term "an inhibitory effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the intended effect. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

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 are effective for the intended use.

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

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

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A method of the present disclosure for the preparation of a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

Subjecting a compound of formula (IV) or a salt thereof to reductive amination with a compound of formula (IIIA) in the presence of a reducing agent, preferably sodium triacetoxyborohydride, under basic conditions to give a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

Scheme II

A method of the present disclosure for 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:

in the first step, the compound of the general formula (IVA-1) and the compound of the general formula (IVA-2) or the salt thereof are subjected to coupling reaction under alkaline conditions in the presence of a catalyst to obtain the compound of the general formula (IVA) or the salt 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 ^w To obtain a compound of the general formula (IV) or a pharmaceutically acceptable salt thereof,

wherein:

x is a halogen, preferably a bromine atom;

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

R ^m is that

Ring A, R ¹ To R ⁴ N, s, m, J and k are as defined in formula (IV).

Scheme III

A method of the present disclosure for 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 the formula (IV) or a pharmaceutically acceptable salt thereof andR ⁰ x undergoes nucleophilic substitution under alkaline conditions to give a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

Scheme IV

removing protecting group R from compound of formula (IIA) or salt thereof under alkaline condition ^w’ Obtaining a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme five

deprotection of a compound of formula (IVB) or a salt thereof to remove a protecting group R ^w And R is ^w’ (removal of both protecting groups includes simultaneous and also successive deprotection), or deprotection of a compound of formula (IVC) or a salt thereof ^w’ Obtaining a compound of the general formula (IV) or a pharmaceutically acceptable salt thereof, and performing deprotection under acidic or basic conditions;

wherein:

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

Ring A, R ¹ To R ⁴ N, 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, etc., preferably sodium triacetoxyborohydride.

In the above synthetic schemes one to five, the reagent providing the basic condition includes organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide, methanolic ammonia, potassium tert-butoxide or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and inorganic bases 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 potassium carbonate, ammonia methanol, cesium carbonate, sodium hydroxide, sodium acetate and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).

In the above synthesis scheme II, the catalyst includes, but is not limited to, 1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, palladium on 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 ] palladium dichloride, 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 dichloride (II) dichloromethane complex and dicyclohexyl palladium; preferred are 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complexes.

In the above synthetic schemes two and five, 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, me ₃ SiCl and TMSOTF, preferably 1, 4-dioxane solutions 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 acetateN-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to 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 ^-6 Units of (ppm) are given. NMR was performed using a Bruker AVANCE NEO 500.500M magnetonucleo-magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high pressure liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

High performance liquid chromatography was performed using Waters 2767, waters 2767-SQ detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

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

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the 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.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline 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

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

Tert-butyl 6-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylate 1a (9.0 g,36.0mmol, pichia-medicinal) was dissolved in 240mL of dichloromethane and methanol (V: V=5:1), cooled to 0deg.C, sodium bicarbonate (5.6 g,54.8 mmol) was added, and a solution of iodine chloride (6.4 g,39.4mmol, adamas) in dichloromethane (40 mL) was added and stirred at room temperature for 0.5 hours. Quench with saturated aqueous sodium bisulfite (200 mL), extract with ethyl acetate (80 mL. Times.2), combine the organic phases and concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 1b (3.0 g, yield: 22.2%).

MS m/z(ESI):375.0[M+1]。

Second step

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

Compound 1b (1.6 g,4.26 mmol) and 3-methylbut-2-enal 1c (540 mg,6.42mmol, adamas) were dissolved in methanol (20 mL) and stirred at room temperature for 16 h. Sodium borohydride (330 mg,8.68 mmol) was added and the reaction stirred for 1 hour. Water (30 mL) was added, extracted 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 (1.45 g, yield: 76.7%).

MS m/z(ESI):387.0[M-55]。

Third step

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

Compound 1d (1.45 g,3.28 mmol), palladium acetate (70 mg,0.311mmol, adamas), bis (tricyclohexylphosphine) dichloride (240 mg,0.325mmol, adamas), potassium carbonate (1.36 g,9.84 mmol) and triphenyl phosphite (100 mg,0.322mmol, adamas) were dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (6.4 g,19.6 mmol) was added, the reaction mixture was allowed to react at 95℃for 3 hours, cooled to room temperature, water (50 mL), ethyl acetate (50 mL. Times.2) was added, and 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 (400 mg, yield: 38.8%).

MS m/z(ESI):259.1[M-55]。

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 (400 mg,1.27 mmol) was dissolved in 1, 2-dichloroethane (20 mL), -1, 2-dichloroethane (20 mL) was added dropwise at 20℃as a solution of N-bromosuccinimide (227 mg,1.27mmol, shaoshima technology). After completion of the addition, quenching with saturated aqueous sodium hydrogensulfite (500 mL), extraction with dichloromethane (50 mL. Times.2), concentration of the combined organic phases under reduced pressure, purification of the resulting residue by silica gel column chromatography with eluent system A afforded the title product 1f (390 mg, yield: 77.9%).

MS m/z(ESI):337.0[M-55]。

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 for 1H

Compound 1f (390 mg,0.992 mmol) and 1g (225 mg,1.49mmol, MINGMINGKANG) of (2, 6-dimethylpyridin-4-yl) boric acid were dissolved in 6mL dioxane and water (V: V=5:1), and potassium phosphate (630 mg,2.97 mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (85 mg,0.1mmol, found in medicine) were added. Under the protection of nitrogen, the reaction is carried out for 4 hours at 90 ℃. The reaction solution was cooled to room temperature, water (30 mL), ethyl acetate (30 mL. Times.2) was added, 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 (380 mg, yield: 91.3%).

MS m/z(ESI):420.2[M+1]。

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 (380 mg,0.906 mmol) in dichloromethane (5.0 mL) was added 4M hydrogen chloride dioxane solution (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 (280 mg, yield: 96.8%).

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

Seventh step

Compound 1i (100 mg,0.313 mmol) and 1-isobutylpiperidin-4-one 1j (90.0 mg,0.580mmol, pichia medicine) were dissolved in N, N-dimethylformamide (2.0 mL), sodium acetate (50 mg,0.610 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (135 mg,0.637mmol, shaoshima technology) was added, and the reaction was completed 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 C, 5 μm, 30×150mm; mobile phase: water (10 mmol/L ammonium bicarbonate): acetonitrile=50% -70% acetonitrile (15 min), flow rate: 30 mL/min) to give the title product 1 (30 mg, yield:

20.9％)。

MS m/z(ESI):459.3[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 (50 mg,0.156 mmol) and 1-cyclopropylpiperidin-4-one 2a (50 mg, 0.319 mmol, pichia pastoris) were dissolved in N, N-dimethylformamide (1.0 mL), sodium acetate (50 mg,0.610 mmol) was added, and stirred at room temperature for 3 hours. Adding triacetoxyborohydride Sodium (135 mg,0.637mmol, shao Yuan technology) was added and reacted 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 Xtime C18,5 μm,30 mm. Times.150 mm, elution system: H) ₂ O (0.1% trifluoroacetic acid), acetonitrile was increased from 20% (v/v) to 90% (v/v) in 16 minutes, detection wavelength 214&254 nm) to give the title product 2 (20 mg,19.0%, after acidic preparation to give trifluoroacetate salt).

MS m/z(ESI):443.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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-diisopropyll-5, 6,7, 8-tetrahydro-1H-pyrrolo [2,3-g ] isoquinoline 3

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

¹ H NMR(500MHz,DMSO-d ₆ )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

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 (200 mg,0.477 mmol) was dissolved in N, N-dimethylformamide (3.0 mL), 60% sodium hydride (40 mg,1.00 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Para-toluenesulfonyl chloride (120 mg, 0.630 mmol) was added and reacted at room temperature for 16 hours. Quench with saturated aqueous ammonium chloride (10 mL), extract with ethyl acetate (10 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 4a (200 mg, yield: 73.1%).

MS m/z(ESI):573.9[M+1]。

Second step

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

MS m/z(ESI):474.1[M+1]。

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 (80 mg,0.157 mmol) was dissolved in 1, 2-dichloroethane (3.0 mL), cyclopropylboronic acid (27 mg,0.314 mmol), sodium carbonate (50 mg,0.472 mmol), bipyridine (50 mg,0.320 mmol), anhydrous copper acetate (60 mg,0.330 mmol) and stirred at 80℃for 4 h. The residue was concentrated and purified by silica gel column chromatography with eluent system a to give the title product 4c (50 mg, 62.1%).

MS m/z(ESI):513.9[M+1]。

Fourth step

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

MS m/z(ESI):360.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

7- (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 (140 mg,0.522mmol, remote technology) and compound 1i (180 mg,0.564 mmol) were dissolved in dioxane (7.0 mL) and cesium carbonate (350 mg,1.07 mmol) and [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene were added](3-Chloropyridinyl) Palladium (II) dichloride (Pd-PEPPI) ^TM IPent catalyst) (40 mg,0.0505mmol, aldrich), at 100℃for 16 hours. Quench with saturated aqueous ammonium chloride (10 mL), extract with ethyl acetate (10 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 5b (110 mg, yield: 38.2%).

MS m/z(ESI):552.1[M+1]。

Second step

Compound 5b (110 mg, 0.199mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrated, basified with 7M methanolic ammonia and purified with silica gel column chromatography with eluent system B to give the title product 5 (10 mg, 11.1%).

MS m/z(ESI):452.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Compound 1e (550 mg,1.75 mmol), di-tert-butyl dicarbonate (750 mg,2.61mmol, shao-technology), N, N-diisopropylethylamine (450 mg,3.48mmol, adamas) and 4-dimethylaminopyridine (10 mg,0.08mmol, adamas) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 16 hours. Quench with water (20 mL), extract with ethyl acetate (30 mL. Times.3), combine the organic phases, concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 6a (630 mg, yield: 86.9%).

MS m/z(ESI):258.9[M-155]。

Second step

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

MS m/z(ESI):485.2[M-55]。

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 (60 mg,0.11 mmol) and 6-bromo-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine 6c (35.0 mg,0.15mmol, prepared using the methods known from document "WO2018/005586A1, p143, intermediate F-5") were dissolved in dioxane (2.0 mL) and water (0.5 mL). [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (15 mg,0.018mmol, shanghai Taitan) and potassium phosphate (72 mg,0.34mmol, shanghai test) were added. The nitrogen was replaced three times and the reaction was stirred at 80℃for 16 hours. Water (10 mL) 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 (50 mg, yield: 89%).

MS m/z(ESI):562.3[M+1]。

Fourth step

Compound 6d (50 mg,0.089 mmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 1.0 hour. Concentrated under reduced pressure and the residue was dissolved in 7M ammonia/methanol (5.0 mL). Stirring at room temperature for 10 minutes. Concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: sharpsil-T C, 150 x 30mm,5 μm; mobile phase 1: water (0.1% trifluoroacetic acid; mobile phase 2: acetonitrile; 15 min gradient: 10% -95%, flow rate: 30 mL/min) to give the title product 6 (5.0 mg, yield: 11.8%).

MS m/z(ESI):362.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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 (760 mg,3.36mmol, prepared using the method disclosed in patent application "WO 2018005586A 1, page 140 intermediate F-4") and 3-methylbut-1-yne (500 mg,7.34mmol, acros), cuprous iodide (130 mg,0.682mmol, alfa), bis-triphenylphosphine palladium dichloride (240 mg, 0.3411 mmol, adamas), triethylamine (1.0 g,10.0 mmol) were dissolved in N, N-dimethylformamide (15 mL) and stirred under nitrogen at 60℃for 30 hours. Quench with water (50 mL), extract with ethyl acetate (50 mL. Times.3), combine the organic phases, concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 7b (650 mg, yield: 90.6%).

MS m/z(ESI):214.0[M+1]。

Second step

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 (4.24 g,16.5mmol, leaching reagent) and triethylamine (2.5 g,24.8 mmol) were dissolved in dichloromethane (50 mL), di-tert-butyl dicarbonate (4.5 g,20.6 mmol) was added and stirred at room temperature for 16 hours. Quench with water (100 mL), extract with ethyl acetate (80 mL. Times.2), combine the organic phases, concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 7d (5.5 g, yield: 93.4%).

MS m/z(ESI):300.9[M-55]。

Third step

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

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

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 (4.1 g,12.5 mmol), 7b (3.4 g,15.9 mmol) was dissolved in dimethylacetamide (80 mL), anhydrous lithium chloride (535 mg,12.6 mmol), potassium carbonate (5.2 g,37.7 mmol), tetrakis (triphenylphosphine) palladium (1.5 g,1.30mmol, adamas) were added and reacted for 40 h at 115℃and the reaction solution cooled to room temperature, water (100 mL), ethyl acetate (50 mL. Times.2) was added and 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 (2.0 g, yield: 34.7%).

MS m/z(ESI):460.2[M+1]。

Fifth step

Compound 7f (150 mg,0.237 mmol) was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrating, alkalizing with 7M ammonia methanol solution, concentrating the filtrate under reduced pressure, purifying with high performance liquid chromatography (column: boston Phlex Prep C, 5 μm, 30×150mm, eluting)The system comprises: h ₂ O (10 mmol/L ammonium bicarbonate), acetonitrile rise from 15% (v/v) to 95% (v/v) in 18 minutes, detection wavelength 214&254 nm) to give the title product 7 (70 mg, 59.3%).

MS m/z(ESI):360.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 (100 mg,0.28 mmol) and 2-bromoacetamide (60 mg,0.44mmol, bi-medicine) were dissolved in dimethylformamide (2.0 mL), cesium carbonate (200 mg,0.61 mmol) was added, and stirred at room temperature for 3 hours. Concentrating, and purifying by high performance liquid chromatography (chromatographic column: boston Phlex Prep C, 5 μm, 30×150mm, eluting system: H) ₂ O (10 mmol/L ammonium bicarbonate), acetonitrile rise from 15% (v/v) to 90% (v/v) in 19 minutes, detection wavelength 214&254 nm) to give the title product 8 (50 mg, 43.2%).

MS m/z(ESI):417.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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 (77 mg,0.142 mmol) and compound 6-bromo-8-methyl- [1,2,4] triazolo [1,5-a ] pyridine 9a (33 mg,0.156mmol, shanghai Bifide) were dissolved in dioxane (2.0 mL) and water (0.2 mL), and potassium phosphate (90 mg,0.427 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (12 mg,0.0146 mmol) were added and reacted at 80℃for 4 hours. Quench with saturated aqueous ammonium chloride (10 mL), extract with ethyl acetate (10 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 9b (60 mg, yield: 76.9%).

MS m/z(ESI):546.2[M+1]。

Second step

Compound 9b (60 mg,0.110 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrating, alkalizing with 7M ammonia methanol solution, concentrating the filtrate under reduced pressure, purifying with high performance liquid chromatography (chromatographic column: boston Phlex Prep C, 5 μm, 30×150mm, eluting with H) ₂ O (10 mmol/L ammonium bicarbonate), acetonitrile rise from 15% (v/v) to 95% (v/v) in 18 minutes, detection wavelength 214&254 nm) to give the title product 9 (15 mg, 39.4%).

MS m/z(ESI):346.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 (10 mg,0.029 mmol) and 2-bromoacetamide (6.0 mg,0.044mmol, bi-medicine) were dissolved in dimethylformamide (1.0 mL), 1, 8-diazabicyclo [5.4.0] undec-7-ene (15 mg,0.06 mmol) was added, and stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 10 (8.0 mg, yield: 68.6%).

MS m/z(ESI):403.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

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

Experimental material and instrument

1.HEK-Blue ^TM hTLR7 cells (Invivogen)

2. Raximote (R848/Resiquimod, invivogen)

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

4. Blasticidin (Blastidin, 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 Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

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 incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

Step II, experiment

HEK-Blue purchased from Invivogen ^TM hTLR7 cells co-transfected with a human Toll-like receptor 7 (TLR 7) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN- β minimal promoter (minimum promoter) containing 5 NF-kB and AP-1 binding sites into HEK293 cells, upon activation of TLR7 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited, SEAP secretion is reduced, and OD620 is measured by the SEAP substrate, thereby assessing the activity of the compound on the TLR7 pathway.

20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM/high-sugar medium (complete medium, supra) containing 10% inactivated FBS. Diluting R848 to 10 μm with sterile water; 10. Mu.M 848 diluted with 20. Mu.L/well sterile water was added to 96 well cell culture plates, 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 added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.

HEK-Blue ^TM hTLR7 cells were cultured in DMEM/high-sugar medium containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL Zeocin. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 with the complete medium ⁵ /mL. Adding 160 mu L of cell suspension with density regulated into the 96-well cell culture plate, wherein the final cell number per well is 76500/well, the final concentration of R848 is 1 mu 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 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 absorbance of OD620 was read by an ELISA reader. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 1.

Table 1 IC of compounds of the present disclosure as measured by the TLR7 pathway in humans ₅₀ Values.

Examples numbering	IC ₅₀ (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

Conclusion: the compound disclosed by the invention has good inhibition effect on a TLR7 pathway.

Test example 2 inhibition of the human TLR8 pathway by the presently disclosed compounds

Experimental material and instrument

1.HEK-Blue ^TM hTLR8 cells (Invivogen)

2. Raximote (R848/Resiquimod, invivogen)

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

4. Blasticidin (Blastidin, 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 Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

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 incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

Step II, experiment

HEK-Blue purchased from Invivogen ^TM hTLR8 cells obtained by co-transfecting a human Toll-like receptor 8 (TLR 8) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN- β minimal promoter comprising 5 NF-kB and AP-1 binding sites into HEK293 cells, whereby upon activation of TLR8 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is reduced, and the activity of the compound on the TLR8 pathway is assessed by measuring OD620 via a SEAP substrate

20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM/high-sugar medium (complete medium, supra) containing 10% inactivated FBS. Diluting R848 to 60 μm with sterile water; mu.L/well of 60. Mu. M R848 diluted with sterile water was added to 96-well cell culture plates, and the above compound diluted in complete medium and 100% DMSO were added to wells containing R848 at 20. Mu.L/well. Negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.

HEK-Blue ^TM hTLR8 cells were cultured in DMEM/high-sugar medium containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL bleomycin. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 with the complete medium ⁵ /mL. Adding 160 mu L of cell suspension with density adjustment to the 96-well cell culture plate The final cell number per well was 76500/well, the final concentration of R848 was 6. Mu.M, and the final concentrations of the test compounds were 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128nM, respectively. The cells were placed at 37℃in 5% CO ₂ Culturing in an incubator for 20 hours, then taking 20 mu L of supernatant, adding 180 mu L of prepared alkaline phosphatase detection medium, incubating for 120 minutes at 37 ℃ in a dark place, and reading an OD620 absorbance value by an enzyme-labeled instrument. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 2.

Table 2 IC of compounds of the present disclosure as measured by the TLR8 pathway in humans ₅₀ Values.

Examples numbering	IC ₅₀ (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

Conclusion: the compound disclosed by the invention has good inhibition effect on a TLR8 pathway.

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

Experimental material and instrument

1.HEK-Blue ^TM hTLR9 cells (Invivogen)

2.CpG ODN2006(Invivogen)

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

4. Blasticidin (Blastidin, 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 Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

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 incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

Step II, experiment

HEK-Blue purchased from Invivogen ^TM hTLR9 cells obtained by co-transfection of a human Toll-like receptor 9 (TLR 9) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN-. Beta.minimal promoter comprising 5 NF-kB and AP-1 binding sites into HEK293 cells, wherein upon activation of TLR9 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is reduced, and the activity of the compound on the TLR9 pathway is assessed by measuring OD620 via the SEAP substrate.

20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M with 100% DMSO and blank wells 100% DMSO and 20-fold diluted in DMEM/high-sugar medium (complete medium, supra) containing 10% inactivated FBS; diluting ODN2006 to 10 μm with sterile water; to 96-well cell culture plates, 10. Mu.M ODN2006 diluted with 20. Mu.L/well 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 added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.

HEK-Blue ^TM hTLR9 cells were cultured in DMEM/high-sugar medium containing 10% FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL bleomycin. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 with the complete medium ⁵ /mL. Adding 160 μL of cell suspension with density regulated into the 96-well cell culture plate, and final cell number per well of 76500/well, ODN2006 final concentration of 1 μM, test compound final concentrationConcentrations were 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128nM, respectively; the cells were placed at 37℃in 5% CO ₂ The culture was carried out in an 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 an incubator at 37℃for 15 minutes in the absence of light, the absorbance of OD620 was read by an microplate reader. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 3.

Table 3 IC of compounds of the present disclosure as measured by the TLR9 pathway in humans ₅₀ Values.

Examples numbering	IC ₅₀ (nM)
		1	159
2	279
		3	601

Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR9 pathway.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

y is a nitrogen atom;

ring a is a 5 to 10 membered heteroaryl;

R ⁰ selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _r C(O)NR ⁷ R ⁸ 、C _1-6 Hydroxyalkyl group

L is a bond;

ring C is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl and 5 to 10 membered heteroaryl;

each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 A hydroxyalkyl group;

R ² selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R is ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R is ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 8 membered cycloalkyl;

R ⁷ and R is ⁸ Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group;

j is 1;

k is 1;

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 also provided with

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

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl group

s is 0, 1, 2, 3 or 4; l, ring C, R ⁵ And t is as defined in claim 1.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl group,

And- (CH) ₂ ) _r C(O)NR ⁷ R ⁸ The method comprises the steps of carrying out a first treatment on the surface of the Ring C, R ⁵ 、R ⁷ 、R ⁸ R and t are as defined in claim 1.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound of formula (III):

wherein:

ring a, ring C, R ¹ To R ⁵ N, m, s, t, J and k are as defined in claim 1.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound of formula (IV):

wherein:

ring A, R ¹ To R ⁴ N, m, s, J and k are as defined in claim 1.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring a is pyridinyl or

7. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from piperidinyl, cyclopropyl and tetrahydronaphthyridinyl.

8. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ¹ The same or different, each independently selected from hydrogen atom, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and halo C _1-6 An alkyl group.

9. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

10. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from any one of the following:

11. a process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 4, which comprises:

subjecting a compound of formula (IV) or a pharmaceutically acceptable salt thereof to reductive amination with formula (IIIA) to give a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

ring a, ring C, R ¹ To R ⁵ N, s, m, t, J and k are as defined in claim 4.

12. A compound represented by the general formula (IIA), the general formula (IVA), the general formula (IVB) or the general formula (IVC), or a salt thereof:

wherein:

R ^w is an amino protecting group;

R ^w’ Is an amino protecting group;

ring A, R ⁰ 、R ¹ To R ⁴ N, s, m, J and k are as defined in claim 1.

13. The compound according to claim 12, or a salt thereof, wherein R ^w T-butoxycarbonyl; and/or R ^w’ Is tert-butyloxycarbonyl or p-toluenesulfonyl.

14. A compound:

15. a process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof according to claim 5, which comprises:

wherein:

R ^w is an amino protecting group;

ring A, R ¹ To R ⁴ N, s, m, J and k are as defined in claim 5.

16. The method of claim 15, wherein R ^w Is tert-butyloxycarbonyl.

17. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of a compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR 9.

19. Use of a compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR 9.

20. Use of a compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for inhibiting TLR7 and TLR 8.

21. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

22. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases.

23. The use according to claim 22, wherein the inflammatory or autoimmune disease is selected from systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and schlemm's syndrome.