CN114057754B

CN114057754B - Nitrogen-containing bridged ring derivatives, preparation method thereof and application thereof in medicines

Info

Publication number: CN114057754B
Application number: CN202110900484.5A
Authority: CN
Inventors: 张晓敏; 王珏; 张静; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-08-07
Filing date: 2021-08-06
Publication date: 2023-05-16
Anticipated expiration: 2041-08-06
Also published as: CN114057754A

Abstract

The disclosure relates to nitrogen-containing bridged ring derivatives, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to a nitrogen-containing bridged ring derivative shown in a 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

Nitrogen-containing bridged ring derivatives, preparation method thereof and application thereof in medicines

Technical Field

The present disclosure belongs to the field of medicine, and relates to a nitrogen-containing bridged ring derivative, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to nitrogen-containing bridged ring derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and application of the derivatives as TLR7/8/9 inhibitors in treating inflammatory and autoimmune diseases.

Background

Toll-like receptors (Toll like receptors, TLR) are an evolutionarily conserved class of transmembrane innate immune receptors that are involved in the first line of defense in protecting human health and play an important role in the recognition of pathogen-associated molecular patterns (PAMPs) (Kawai, t. Et al, nature immunol.,11,2010,373-384). TLRs are expressed in various immune cells and can be classified into two types according to the site of expression: TLR expressed in cell membrane (TLR 1/2/4/5/6) and TLR expressed in endosomal membrane (TLR 3/7/8/9) recognize different components and molecules in PAMPs, respectively. 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, and 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) is an autoimmune connective tissue disease, the face of SLEThere are three major categories of first-line drugs in beds: hormones, immunosuppressants and antimalarial drugs. In this century, only a new drug belimumab was approved by FDA, but it had moderate and delayed efficacy only in a small proportion of SLE patients (Navarra, s.v. et al, lancet 2011,377,721), and the treatment options were 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 interferons was found in PBMC 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 patent applications for inhibitors of TLR7/8/9 include WO 2019233941A 1, WO 2020020800A 1, WO2018049089A1, WO2019238616A1, WO2017106607A1, CN109923108A and WO 2020048605A 1 and the like.

Disclosure of Invention

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

wherein:

is->

X is selected from CH ₂ 、CH ₂ CH ₂ And CH (CH) ₂ CH ₂ CH ₂ ；

Each R is ¹ The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein each of said alkyl, 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 ² The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, an oxo group, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, and a carboxyl group;

L ₁ Selected from bond, CH ₂ And CR (CR) ^5a R ^5b ；

Ring B is selected from 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, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ⁰ selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a deuterated alkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, and

L ₂ selected from bond, CH ₂ 、CR ^5c R ^5d 、C(O)、NH、NR ^6a O and S (O) _m ；

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

each R is ⁴ Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, oxo, halogen, cyano, amino, -NR ^6b R ^6c 、-COR ⁷ 、-C(O)OR ⁸ 、-OR ⁹ Nitro, hydroxy, carboxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, 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, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^5a 、R ^5b 、R ^5c And R is ^5d The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^6a 、R ^6b and R is ^6c The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

R ⁷ selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl, 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;

R ⁸ and R is ⁹ The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

p is 0, 1, 2 or 3;

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

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

t is 0, 1, 2, 3, 4, 5 or 6; and is also provided with

m is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² Is a hydrogen atom.

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

wherein:

ring B, X, L ₁ 、R ⁰ 、R ¹ 、R ³ And s is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-A) or formula (II-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is that

Ring C, L ₂ 、R ⁴ And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-A) or formula (II-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L ₁ Is CH ₂ 。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-A) or formula (II-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L ₂ Is a key.

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

Wherein:

ring B, ring C, X, R ¹ 、R ³ 、R ⁴ S and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-a), formula (II-B), formula (III-a) or formula (III-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring B is phenyl or 5 to 6 membered heteroaryl; more preferably, ring B is pyridinyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-a), formula (II-B), formula (III-a) or formula (III-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring C is a 3 to 12 membered heterocyclyl containing at least one nitrogen atom; more preferably, ring C is a 3 to 6 membered heterocyclyl containing at least one nitrogen atom; most preferably, ring C is piperazinyl.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (I), formulSup>A (II-A), formulSup>A (II-B), formulSup>A (III-A) or formulSup>A (III-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, is Sup>A compound of formulSup>A (IV-A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof:

wherein:

ring C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;

W ¹ to W ⁴ Is CR (CR) ³ Or N;

R ^4a selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, and a hydroxyalkyl group;

t is 1, 2, 3, 4, 5;

X、R ¹ 、R ³ and R is ⁴ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein ring C is Sup>A 3 to 12 membered heterocyclyl containing at least one nitrogen atom; preferably, ring C is a 3 to 6 membered heterocyclyl containing at least one nitrogen atom; more preferably, ring C is piperazinyl.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (I), formulSup>A (II-A), formulSup>A (II-B), formulSup>A (III-A), formulSup>A (III-B), formulSup>A (IV-A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, amino, nitro, hydroxy, 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein, C is as follows _1-6 Alkyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; preferably, each R ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, amino, nitro and hydroxy; more preferably, R ¹ Is cyano.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (I), formulSup>A (II-A), formulSup>A (II-B), formulSup>A (III-A), formulSup>A (III-B), formulSup>A (IV-A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein each R ³ Identical or different and are each independently selected from the group consisting of hydrogen atoms, halogens, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ³ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (I), formulSup>A (II-A), formulSup>A (II-B), formulSup>A (III-A), formulSup>A (III-B), formulSup>A (IV-A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein each R ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, oxo, halogen, cyano, amino, nitro and hydroxy; preferably, R ⁴ Is a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (IV-A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ^4a Is a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-A), formula (II-B), formula (III-A) or formula (III-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1, 2, 3, or 4; preferably, t is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein t is 1, 2, 3, 4, 5; preferably, t is 1 or 2.

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

Is->

Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; ring C is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; x is selected from CH ₂ 、CH ₂ CH ₂ And CH (CH) ₂ CH ₂ CH ₂ ；R ⁰ Is->

Each R is ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, amino, nitro, hydroxy, 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein, C is as follows _1-6 Alkyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; r is R ² Is a hydrogen atom; r is R ³ Is a hydrogen atom; each R is ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, oxo, halogen, cyano, amino, nitro and hydroxy; l (L) ₁ Is CH ₂ ；L ₂ Is a bond; p is 0, 1, 2 or 3; t is 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, the compound of formula (II-A) or formula (II-B), or a tautomer thereofA construct, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or 5-to 6-membered heteroaryl; x is selected from CH ₂ 、CH ₂ CH ₂ And CH (CH) ₂ CH ₂ CH ₂ ；R ⁰ Is that

L ₁ Is CH ₂ ；L ₂ Is a bond; ring C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, amino, nitro and hydroxy; r is R ³ Is a hydrogen atom; r is R ⁴ Is a hydrogen atom or C _1-6 An alkyl group; t is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (III-a) or formula (III-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or 5-to 6-membered heteroaryl; ring C is a 3-to 6-membered heterocyclic group containing at least one nitrogen atom; x is selected from CH ₂ 、CH ₂ CH ₂ And CH (CH) ₂ CH ₂ CH ₂ ；R ¹ Is cyano; r is R ³ Is a hydrogen atom; r is R ⁴ Is a hydrogen atom or C _1-6 An alkyl group; t is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein ring C is Sup>A 3 to 6 membered heterocyclyl containing at least one nitrogen atom; w (W) ¹ To W ⁴ Is CR (CR) ³ Or N; r is R ^4a Is a hydrogen atom or C _1-6 An alkyl group; t is 1 or 2; x is selected from CH ₂ 、CH ₂ CH ₂ And CH (CH) ₂ CH ₂ CH ₂ ；R ¹ Is cyano; r is R ³ Is a hydrogen atom; r is R ⁴ Is a hydrogen atom or C _1-6 An alkyl group.

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

/>

/>

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

wherein:

R ^W is an amino protecting group; preferably, R ^W T-butoxycarbonyl;

W ¹ to W ⁴ Is CR (CR) ³ Or N;

X、R ¹ 、R ³ 、R ⁴ and t is as defined in formulSup>A (IV-A) or formulSup>A (IV-B).

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

/>

/>

another aspect of the present disclosure relates to Sup>A method for preparing Sup>A compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, comprising:

/>

Removing protecting group R from a compound of formula (IVa-A) or formula (IVa-B) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof ^W Obtaining Sup>A compound of formulSup>A (IV-A) or formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Is a hydrogen atom; r is R ^W Is an amino protecting group, preferably R ^W T-butoxycarbonyl;

and

Optionally further comprising the step of subjecting R as defined above to ^4a Sup>A compound of the general formulSup>A (IV-A) or (IV-B) which is Sup>A hydrogen atom or Sup>A tautomer, racemate, enantiomer, diastereomer or Sup>A mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, with an alkylating agent R ^4a -Z (VI) is reacted to give Sup>A compound of formulSup>A (IV-A) or formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Selected from alkyl, deuterated alkyl, haloalkyl, and hydroxyalkyl; z is halogen, preferablyZ is iodine;

wherein:

W ¹ To W ⁴ Is CR (CR) ³ Or N;

Another aspect of the present disclosure relates to Sup>A pharmaceutical composition comprising Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B) and table Sup>A or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, of the present disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, in the manufacture of Sup>A medicament for inhibiting TLR7, TLR8, and TLR 9.

The present disclosure further relates to the use of Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, in the manufacture of Sup>A medicament for inhibiting TLR7, TLR8, or TLR 9; preferably in the manufacture of a medicament for inhibiting TLR7 and TLR8, or in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

The present disclosure further relates to the use of Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, in the manufacture of Sup>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 Sup>A method of inhibiting TLR7, TLR8 and TLR9 comprising administering to Sup>A patient in need thereof an effective inhibiting amount of Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B) and formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same.

The present disclosure further relates to Sup>A method of inhibiting TLR7, TLR8 or TLR9, preferably Sup>A method of inhibiting TLR7 and TLR8, or Sup>A method of inhibiting TLR7 and TLR9, comprising administering to Sup>A patient in need thereof an effective inhibiting amount of Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture form thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same.

The present disclosure further relates to Sup>A use in Sup>A medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases comprising administering to Sup>A patient in need thereof Sup>A therapeutically effective amount of Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B) and formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>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 Sup>A compound of formulSup>A (I), formulSup>A (II-A), formulSup>A (II-B), formulSup>A (III-A), formulSup>A (III-B), formulSup>A (IV-A), formulSup>A (IV-B) and formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, for use as Sup>A medicament.

The disclosure further relates to Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B), and table Sup>A or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, for inhibiting TLR7, TLR8, and TLR9.

The present disclosure further relates to Sup>A compound of formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B), and formulSup>A Sup>A or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, for inhibiting TLR7, TLR8, or TLR9; preferably for inhibiting TLR7 and TLR8, or inhibiting TLR7 and TLR9.

The present disclosure further relates to Sup>A compound of formulSup>A (I), formulSup>A (II-A), formulSup>A (II-B), formulSup>A (III-A), formulSup>A (III-B), formulSup>A (IV-A), formulSup>A (IV-B) and formulSup>A A or Sup>A tautomer, racemate, enantiomer, diastereomer or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, or Sup>A pharmaceutical composition comprising the same, for use in 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 formulSup>A (I), formulSup>A (II-Sup>A), formulSup>A (II-B), formulSup>A (III-Sup>A), formulSup>A (III-B), formulSup>A (IV-Sup>A), formulSup>A (IV-B) and table Sup>A are useful for treating TLR7, TLR8 or TLR9 family receptor related diseases, respectively, including but not limited to: inflammatory diseases (such as crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease); autoimmune diseases (such as graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis); autoinflammatory diseases (including 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 caused by traumatic injury or neurodegenerative diseases), neoplastic diseases (such as metastatic melanoma, kaposi's sarcoma, multiple myeloma) and viral diseases (such as HIV infection, CMV retinitis and 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. In preferred methods of treatment, the condition is selected from the group consisting of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred methods of treatment are those in which the condition is ischemia reperfusion injury, including cerebral ischemia reperfusion injury caused by stroke and myocardial ischemia reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the 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 specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; 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 (i.e., C) containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl and 2, 2-diethylhexyl, and various branched isomers thereof, and the like. Most 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 selected from one or more of H, D, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and 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 containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C _1-12 Alkylene groups), more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-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 (-) and 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, the substituents preferably being selected from alkyl groups,Alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, oxo, 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 Is selected from N, O, S, S (O) and S (O) ₂ Substituted; wherein said alkyl is as defined above; the heteroalkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of H, D, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, oxo, 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 (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

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 (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl groups), more preferably alkynyl groups containing 2 to 6 carbon atoms (i.e. C _2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxyOne or more of hydroxyl, hydroxyalkyl, oxo, 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 comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably comprising 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably comprising 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered 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 groups are classified into single spirocycloalkyl groups or multiple spirocycloalkyl groups (e.g., double spirocycloalkyl groups) according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. 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, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 20 members with an adjacent pair of carbon atoms shared between the rings, 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 polycyclic condensed ring alkyl group may be classified into a bicyclic ring, a tricyclic ring, a tetracyclic ring and the like according to the number of constituent rings, and is preferably a bicyclic or tricyclic ring, and 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl group. 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). Polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. 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 selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, 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, butoxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, 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 containing 3 to 12 ring atoms, of which 1 to 4 (e.g., 1,2, 3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1-3 is a heteroatom (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, 1-3 of which are heteroatoms (i.e., 5 or 6 membered heterocyclyl). 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 polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) 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. 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 single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. 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, 5-membered/6-membered or 6-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 having a ring sharing an adjacent pair of atoms, one or more of 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 sulfur 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). The polycyclic fused heterocyclic group may be classified into a bicyclic, tricyclic, tetracyclic and the like, 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group, depending on the number of constituent rings. 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). Polycyclic bridged heterocyclic groups such as a bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. 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 selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, 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, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and 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 groups are 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 selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, 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" and "heteroarylene".

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 or nitro. The amino protecting groups are preferably (trimethylsilyl) ethoxymethyl and t-butoxycarbonyl.

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" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

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

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

The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, 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. 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.

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.

"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 and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the 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

Sup>A process for the preparation of Sup>A compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

(a) Coupling a compound of formula (IVaa-A) or formula (IVaa-B) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof with a compound of formula (V) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (IVa-A) or formula (IVa-B) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein: y is halogen, preferably Y is chlorine; r is R ^W Is an amino protecting group, preferably R ^W T-butoxycarbonyl;

(b) Removing the protecting group R in the presence of an acid from a compound of formula (IVa-A) or formula (IVa-B) or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof ^w Obtaining Sup>A compound of formulSup>A (IV-A) or formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Is a hydrogen atom;

and

Optionally further comprising the step of (c) subjecting R as defined above ^4a Sup>A compound of the general formulSup>A (IV-A) or (IV-B) which is Sup>A hydrogen atom or Sup>A tautomer, racemate, enantiomer, diastereomer or Sup>A mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, with R ^4a -alkylation of Z (VI) under basic conditions to give Sup>A compound of formulSup>A (IV-A) or formulSup>A (IV-B) or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Selected from alkyl, deuterated alkyl, haloalkyl, and hydroxyalkyl; z is halogen, preferably Z is iodine;

wherein:

W ¹ To W ⁴ Is CR (CR) ³ Or N;

t is 1, 2, 3, 4, 5;

X、R ¹ 、R ³ and R is ⁴ As defined in formulSup>A (IV-A) or formulSup>A (IV-B).

In the reaction of step (a) above, the coupling reaction is a coupling reaction well known in the art including, but not limited to, buchwald-Hartwig coupling reaction, negishi coupling reaction, etc. The conditions of the coupling reaction include, but are not limited to, the reaction is carried out in the presence of a metal catalyst (preferably a palladium or nickel-containing catalyst), preferably chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G2), palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G3), methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (XPhos Pd G3), an organozinc reagent, bis (triphenylphosphine) palladium (II) (Pd (PPh) ₃ )Cl ₂ ) And the like, more preferred is chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II). The metal catalyst may also be used in combination with a ligand and a base, wherein the ligand includes, but is not limited to: s- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine (S- (-) -BINAP), R- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine (R- (-) -BINAP), 1' -binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP), 1' -bis (diphenylphosphine) ferrocene (DPPF), 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (XANTAHOS), 2' -bis (diphenylphosphine) benzophenone (DPBP), 2' -Diallyl Bisphenol A (DBA), and the like. The base includes organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate Lithium hydroxide and potassium hydroxide; sodium tert-butoxide is preferred.

In the reaction of step (b) above, the acid includes organic acids including, but not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, me ₃ SiCl and TMSOTf, preferably trifluoroacetic acid; the inorganic acids include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

In the reaction of the step (c), the base includes organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; potassium carbonate is preferred.

The reactions of steps (a) - (c) above are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, 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 HPLC1200 DAD, agilent HPLC1200VWD, and Waters HPLC e2695-2489 high performance 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

5- (6- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) quinoline-8-carbonitrile 1

First step

3- (8-Cyanoquinolin-5-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester 1c

5-fluoroquinoline-8-carbonitrile 1a (100 mg,0.58mmol, prepared as disclosed in example compound 1c at page 16 of the specification of patent application WO2020020800A 1) and 3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester 1b (135 mg,0.68 mmol) were dissolved in dimethyl sulfoxide (5 mL), N-diisopropylethylamine (300 mg,2.3 mmol) was added and the reaction heated to 120℃and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 ml×2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a (n-hexane: ethyl acetate=1:1) to give the title product 1c (150 mg, yield: 73.7%). MS m/z (ESI) 351.0[ M+1].

Second step

5- (3, 6-diazabicyclo [3.1.1] hept-3-yl) quinoline-8-carbonitrile 1d

Compound 1c (150 mg,0.43 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1d (100 mg, yield: 93.3%).

MS m/z(ESI):251.0[M+1]。

Third step

5- (6- ((6-chloropyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) quinoline-8-carbonitrile 1f

Compound 1d (100 mg,0.40 mmol), 2-chloro-5- (chloromethyl) pyridine 1e (100 mg,0.62mmol, lev. Chem., ltd.) cesium carbonate (399mg, 1.20 mmol) and sodium iodide (60 mg,0.40 mmol) were dissolved in N, N-dimethylformamide (6 mL), and the reaction was stirred at 80℃for 1.5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with saturated sodium chloride solution (20 ml×2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B (dichloromethane: methanol=10:1) to give the title product 1f (75 mg, yield: 49.9%).

MS m/z(ESI):376.0[M+1]。

Fourth step

4- (5- ((3- (8-cyanoquinolin-5-yl) -3, 6-diazabicyclo [3.1.1] hept-6-yl) methyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 1g

Compound 1f (75 mg,0.20 mmol) and 1-t-butoxycarbonyl piperazine (75 mg,0.40 mmol) were dissolved in 1, 4-dioxane (5 mL), sodium t-butoxide (60 mg,0.62 mmol) was added, nitrogen was substituted 3 times, chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (16 mg,0.02mmol, shao Yuan chemical) was added, nitrogen was substituted 3 times, and the reaction solution was heated to 80℃with stirring under nitrogen for 4 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a (n-hexane: ethyl acetate=1:1) to give the title product 1g (70 mg, yield: 66.7%).

MS m/z(ESI):526.2[M+1]。

Fifth step

1g (70 mg,0.13 mmol) of the compound was dissolved in methylene chloride (4 mL), and trifluoroacetic acid (4 mL) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, extracted with dichloromethane (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B (dichlorohexane: methanol=10:1) to give the title product 1 (25 mg, yield: 44.1%).

MS m/z(ESI):426.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ9.02-9.01(m,1H),8.60-8.57(m,1H),8.13(s,1H),8.03-8.01(m,1H),7.56-7.54(m,1H),7.42-7.40(m,1H),7.26-7.21(m,1H),6.65-6.63(m,1H),3.87-3.94(m,2H),3.72-3.71(m,2H),3.58(s,2H),3.58-3.56(m,2H),3.50-3.47(m,4H),3.00-2.98(m,4H),2.73-2.70(m,1H),2.07-2.06(m,1H)。

Example 2

5- ((1R, 4R) -5- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) quinoline-8-carbonitrile 2

First step

(1R, 4R) -5- (8-Cyanoquinolin-5-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester 2b

Compound 1a (130 mg,0.76 mmol) and tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate 2a (150 mg,0.76 mmol) were dissolved in dimethyl sulfoxide (5 mL), N-diisopropylethylamine (300 mg,2.3 mmol) was added, and the reaction was heated to 120℃and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 ml×2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a (n-hexane: ethyl acetate=1:1) to give the title product 2b (250 mg, yield: 94.5%).

MS m/z(ESI):351.0[M+1]。

Second step

5- ((1R, 4R) -2, 5-diazabicyclo [2.2.1] hept-2-yl) quinoline-8-carbonitrile 2c

Compound 2b (250 mg,0.71 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the extracts were extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2c (181 mg, yield: 100%).

MS m/z(ESI):251.0[M+1]。

Third step

5- ((1R, 4R) -5- ((6-chloropyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) quinoline-8-carbonitrile 2d

Compound 2c (181 mg,0.72 mmol), 1e (176 mg,1.09mmol, leaching chemical), cesium carbonate (707 mg,2.17 mmol) and sodium iodide (110 mg,0.73 mmol) were dissolved in N, N-dimethylformamide (5 mL) and the reaction stirred at 80℃for 1.5 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with saturated sodium chloride solution (20 ml×2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B (dichlorohexane: methanol=10:1) to give the title product 2d (90 mg, yield: 33.1%).

MS m/z(ESI):376.0[M+1]。

Fourth step

4- (5- (((1R, 4R) -5- (8-cyanoquinolin-5-yl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) methyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 2e

Compound 2d (90 mg,0.24 mmol) and 1-t-butoxycarbonylpiperazine (90 mg,0.48 mmol) were dissolved in 1, 4-dioxane (5 mL), sodium t-butoxide (70 mg,0.73 mmol) was added, nitrogen was substituted 3 times, chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (20 mg,0.03mmol, shao Yuan chemical) was added, nitrogen was substituted 3 times, and the reaction solution was heated to 80℃with stirring under nitrogen for 4 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B (dichlorohexane: methanol=10:1) to give the title product 2e (70 mg, yield: 55.6%).

MS m/z(ESI):526.2[M+1]。

Fifth step

Compound 2e (70 mg,0.13 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, extracted with dichloromethane (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B (dichlorohexane: methanol=10:1) to give the title product 2 (25 mg, yield: 44.1%).

MS m/z(ESI):426.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.99-8.98(m,1H),8.44-8.41(m,1H),8.05(s,1H),7.89-7.87(m,1H),7.49-7.47(m,1H),7.35-7.32(m,1H),6.65-6.61(m,2H),4.40(s,1H),3.89-3.87(m,1H),3.67-3.65(m,1H),3.62-3.56(m,3H),3.53-3.49(m,4H),3.06-2.98(m,6H),2.07-2.05(m,1H),1.98-1.95(m,1H)。

Example 3

5- (8- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) quinoline-8-carbonitrile 3

Using the synthetic route of example 1, the first step starting material 1b was replaced with the starting material 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3a (Pichia medicine) to give the title product compound 3 (62 mg).

MS m/z(ESI):440.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ9.07-9.06(m,1H),8.58-8.56(m,1H),8.16(d,1H),8.03-8.01(m,1H),7.65-7.64(m,1H),7.51-7.49(m,1H),7.10-7.08(m,1H),6.70-6.69(m,1H),3.61-3.59(m,3H),3.51(s,2H),3.35(s,2H),3.22-3.17(m,3H),3.09-3.07(m,3H),2.22-2.15(m,4H),1.35-1.27(m,4H)。

Example 4

5- (9- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) -3, 9-diazabicyclo [3.3.1] non-3-yl) quinoline-8-carbonitrile 4

Using the synthetic route of example 1, the first step starting material 1b was replaced with tert-butyl 3, 9-diaza-bicyclo [3.3.1] nonane-9-carboxylate (Nanjing drug stone) to afford the title product 4 (6 mg).

MS m/z(ESI):454.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ9.06-9.04(m,1H),8.51-8.49(m,1H),8.15(s,1H),8.04-8.02(m,1H),7.59-7.57(m,1H),7.50-7.47(m,1H),7.04-7.02(m,1H),6.67-6.66(m,1H),3.86(s,2H),3.56-3.54(m,3H),3.40-3.38(m,3H),3.04-2.94(m,4H),2.88-2.80(m,1H),2.30-2.22(m,2H),2.14-2.00(m,4H),1.87-1.82(m,1H),1.73-1.69(m,2H)。

Example 5

5- (8- ((6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) quinoline-8-carbonitrile 5

Compound 3 (20 mg,0.045 mmol), isopropyl iodide (40 mg,0.24mmol, after-treatment) and anhydrous potassium carbonate (19 mg,0.14 mmol) were dissolved in acetonitrile (3 mL) and the reaction was stirred at 80℃for 3 hours. After the reaction solution was cooled to room temperature, methylene chloride (15 mL) was added for dilution, and the resultant organic phase was washed with a saturated sodium chloride solution (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography with eluent system B (dichlorohexane: methanol=10:1) to give the title product 5 (9 mg, yield: 39%).

MS m/z(ESI):482.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ9.07-9.06(m,1H),8.58-8.56(m,1H),8.15(d,1H),8.03-8.01(m,1H),7.64-7.62(m,1H),7.51-7.49(m,1H),7.10-7.08(m,1H),6.70-6.68(m,1H),3.62-3.59(m,3H),3.50(s,2H),3.35(s,2H),3.22-3.17(m,3H),2.83-2.81(m,1H),2.73-2.71(m,3H)2.25-2.18(m,3H),1.35-1.27(m,4H),1.14(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 compounds of the present disclosure

1. 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 (FBS, gibco)

9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

11.15ml 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)

2. Experimental procedure

HEK-Blue purchased from Invivogen ^TM hTLR7 cells obtained by co-transfection of a human Toll-like receptor 7 (TLR 7) 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 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 and SEAP secretion is reduced, and the activity of the compound on the TLR7 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 in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM high-glucose medium (complete medium, supra) containing 10% inactivated FBS. R848 was diluted 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 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 usingThe complete medium adjusts the cell density to 4.8X10 ⁵ /mL. After 160. Mu.L of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell count per well was 76500/well, the final concentration of R848 was 1. Mu.M, and the final concentrations of the test compounds were 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM, respectively. The cells were placed at 37℃in 5% CO ₂ Culturing in incubator for 20 hr, collecting 20 μl of supernatant, adding 180 μl of prepared Quanti-Blue, incubating at 37deg.C in incubator for 120 min under dark condition, and reading OD620 absorbance by enzyme-labeling 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 1.

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

Examples numbering	IC ₅₀ (nM)
		3	162
4	103

Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR7 pathway.

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

1. 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 (FBS, gibco)

9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

11.15ml 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)

2. Experimental procedure

HEK-Blue purchased from Invivogen ^TM hTLR8 cells obtained by co-transfection of 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, wherein upon activation of TLR8 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 TLR8 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 in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM high-glucose medium (complete medium, supra) containing 10% inactivated FBS. R848 was diluted 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-glucose 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. After 160. Mu.L of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell count 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, and 0.128Nm, respectively. The cells were placed at 37℃in 5% CO ₂ Culturing in incubator for 20 hr, collecting 20 μl of supernatant, adding 180 μl of prepared Quanti-Blue, incubating at 37deg.C in incubator for 120 min under dark condition, and reading OD620 absorbance by ELISA. 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 Value of

Examples numbering	IC ₅₀ (nM)
		1	97
3	21
		4	2
5	28

Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR8 pathway.

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

1. 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 (FBS, gibco)

9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

11.15ml 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)

2. Experimental procedure

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 in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM high-glucose medium (complete medium, supra) containing 10% inactivated FBS. ODN2006 was diluted 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, wherein the final cell number per well is 76500/well, ODN2006 final concentration is 1 μM, and test compound final concentrations are 10000, 2000, 400, 80, 16, 3.2, and 0.6 respectively4. 0.128nM. The cells were placed at 37℃in 5% CO ₂ Culturing in incubator for 20 hr, collecting 20 μl of supernatant, adding 180 μl of prepared Quanti-Blue, incubating at 37deg.C in incubator for 15 min under dark condition, and reading OD620 absorbance by enzyme-labeling 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 3.

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

Examples numbering	IC ₅₀ (nM)
		1	21
2	66
		3	112
4	87
		5	47

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:

is->

X is selected from CH ₂ 、CH ₂ CH ₂ And CH (CH) ₂ CH ₂ CH ₂ ；

Each R is ¹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, amino, nitro and hydroxy;

each R is ² Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy and halogen;

L ₁ is a bond or CH ₂ ；

Ring B is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl;

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

R ⁰ is that

L ₂ Is a bond or CH ₂ ；

Ring C is a 3 to 12 membered heterocyclyl;

each R is ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, oxo, halogen, cyano, amino, nitro and hydroxy;

p is 0, 1, 2 or 3;

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

s is 0, 1, 2, 3, 4, 5 or 6; and is also provided with

t is 0, 1, 2, 3, 4, 5 or 6.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² Is a hydrogen atom.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II-a) or formula (II-B), or a pharmaceutically acceptable salt thereof:

wherein:

ring B, X, L ₁ 、R ⁰ 、R ¹ 、R ³ And s is as defined in claim 1.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ₁ Is CH ₂ 。

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

wherein:

ring B, ring C, X, R ¹ 、R ³ 、R ⁴ S and t are as defined in claim 1.

6. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or 5-to 6-membered heteroaryl.

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

8. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is a 3 to 12 membered heterocyclyl containing at least one nitrogen atom.

9. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is a 3-to 6-membered heterocyclic group containing at least one nitrogen atom.

10. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is piperazinyl.

11. The compound of formulSup>A (I) according to claim 1, which is Sup>A compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A pharmaceutically acceptable salt thereof:

wherein:

W ¹ to W ⁴ Is CR (CR) ³ Or N;

R ^4a selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group;

t is 1, 2, 3, 4, 5;

X、R ¹ 、R ³ and R is ⁴ As defined in claim 1.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is cyano.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ³ Is a hydrogen atom.

14. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Is a hydrogen atom or C _1-6 An alkyl group.

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

16. A compound of formula (IVa-a) or formula (IVa-B), or a pharmaceutically acceptable salt thereof:

wherein:

R ^W is an amino protecting group;

W ¹ to W ⁴ Is CR (CR) ³ Or N;

X、R ¹ 、R ³ 、R ⁴ and t is as defined in claim 11.

17. The compound of formula (IVa-A) or formula (IVa-B) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R ^W Is tert-butyloxycarbonyl.

18. The compound of formula (IVa-a) or formula (IVa-B) according to claim 16, or a pharmaceutically acceptable salt thereof, which is a compound of:

19. Sup>A process for preparing Sup>A compound of formulSup>A (IV-Sup>A) or formulSup>A (IV-B), or Sup>A pharmaceutically acceptable salt thereof, which comprises:

removing the protecting group R from a compound of the formula (IVa-A) or (IVa-B) or a pharmaceutically acceptable salt thereof ^W Obtaining Sup>A compound of the formulSup>A (IV-A) or formulSup>A (IV-B) or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Is a hydrogen atom; r is R ^W Is an amino protecting group;

and

Optionally further comprising the step of subjecting R as defined above to ^4a Sup>A compound of the formulSup>A (IV-A) or (IV-B) which is Sup>A hydrogen atom or Sup>A pharmaceutically acceptable salt thereof, with an alkylating agent R ^4a Reaction of Z (VI) to give Sup>A compound of formulSup>A (IV-A) or formulSup>A (IV-B) or Sup>A pharmaceutically acceptable salt thereof, wherein R ^4a Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; z is halogen;

wherein:

W ¹ to W ⁴ Is CR (CR) ³ Or N;

X、R ¹ 、R ³ 、R ⁴ and t is as defined in claim 11.

20. The method of claim 19, wherein R ^W Is tert-butyloxycarbonyl.

21. The method of claim 19, wherein Z is iodine.

22. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

23. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22 in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR 9.

24. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22 in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR 9.

25. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22 in the manufacture of a medicament for inhibiting TLR7 and TLR8, or in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

26. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22 in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases.

27. The use according to claim 26, wherein the inflammatory or autoimmune disease is selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.