CN114075212A

CN114075212A - Fused tricyclic derivative, preparation method and application thereof in medicine

Info

Publication number: CN114075212A
Application number: CN202110928898.9A
Authority: CN
Inventors: 张晓敏; 胡伟民; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-08-14
Filing date: 2021-08-13
Publication date: 2022-02-22
Anticipated expiration: 2041-08-13
Also published as: CN114075212B

Abstract

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

Description

Fused tricyclic derivative, preparation method and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to a fused tricyclic derivative, a preparation method and an application thereof in medicines. In particular, the disclosure relates to fused tricyclic derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and use of the fused tricyclic derivatives as a TLR7/8/9 inhibitor in treating inflammatory and autoimmune diseases.

Background

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

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

Patent applications for published TLR7/8/9 inhibitors include WO2019233941a1, WO2020020800a1, WO2018049089a1, WO2019238616a1, WO2017106607a1, CN109923108A, and WO2020048605a1, among others.

Disclosure of Invention

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

wherein:

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

L₁is selected from CH₂、CR^4aR^4bAnd C (O);

L₂selected from the group consisting of CR^4cR^4dC (O), O atom, S atom and NH;

g is CR^2aOr an N atom;

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

each R is¹Is the same as orDifferent and each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH)₂)_rNR^6aR^6bNitro, hydroxy, hydroxyalkyl, -C (O) NR^6aR^6b、-C(O)R⁷、-NR^6cC(O)R⁷、-C(O)OR⁸Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R^2aand R²The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxyl group and hydroxyalkyl group;

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

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

R⁰selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, - (CH)₂)_rC(O)NR^6aR^6bAnd

L₃selected from the group consisting of a bond, alkylene, and heteroalkylene, wherein said alkylene and heteroalkylene are each independently optionally selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroalkyleneAryl is substituted by one or more substituents in the aryl;

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

each R is⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, - (CH)₂)_rNR^6aR^6bNitro, hydroxy, hydroxyalkyl, -C (O) NR^6aR^6b、-C(O)OR⁸、-S(O)_mR⁹、-S(O)_mNR^6aR^6bCycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R^4aand R^4bThe same or different and each is independently selected from the group consisting of hydrogen atom, alkyl group, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, hydroxyl group and hydroxyalkyl group;

R^4cand R^4dThe same or different and each is independently selected from the group consisting of hydrogen atom, alkyl group, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, hydroxyl group and hydroxyalkyl group; or R^4cAnd R^4dTogether with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;

R^6aand R^6bAre the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R^6aAnd R^6bTogether with the nitrogen atom to which they are attached form a heterocyclic group optionally substituted with one member selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroarylSubstituted by one or more substituents;

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

R⁷selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R⁸selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

u is 0, 1,2 or 3;

v is 0, 1,2 or 3;

n is 0 or 1;

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

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

m is 0, 1 or 2;

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

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

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

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

L₁is selected from CH₂、CR^4aR^4bAnd C (O);

L₂selected from the group consisting of C (O), O atoms, S atoms, and NH;

g is CR^2aOr an N atom;

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

each R is¹Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH)₂)_rNR^6aR^6bNitro, hydroxy, hydroxyalkyl, -C (O) NR^6aR^6b、-C(O)R⁷、-NR^6cC(O)R⁷、-C(O)OR⁸Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

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

L₃selected from the group consisting of a bond, alkylene and heteroalkylene, wherein said alkylene and heteroalkylene are each independently optionally selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, ammoniaSubstituted with one or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

R^6aand R^6bAre the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R^6aAnd R^6bTogether with the nitrogen atom to which they are attached form a heterocyclyl group, which heterocyclyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

u is 0, 1,2 or 3;

v is 0, 1,2 or 3;

n is 0 or 1;

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

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

m is 0, 1 or 2;

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

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

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

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is₁Is CH₂. In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁰Selected from hydrogen atoms, C_1-6Alkyl, - (CH)₂)_rC(O)NR^6aR^6bAnd

ring C, L₃、R⁵、R^6a、R^6bR and t are as defined in formula (I); preferably, R⁰Is composed of

Ring C, L₃、R⁵And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is₂Is CR^4cR^4d，R^4cAnd R^4dAs defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^4cAnd R^4dAre the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl and halogen; or R^4cAnd R^4dTogether with the carbon atom to which they are attached form a 3-to 6-membered cycloalkyl group or a 3-to 6-membered heterocyclyl group; preferably, R^4cAnd R^4dTogether with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group; more preferably, R^4cAnd R^4dTogether with the attached carbon atom form a cyclopropyl group.

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

wherein:

ring A, ring B, ring C, G, L₂、L₃、R¹To R³、R⁵P, s, t, n, u and v are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is CR^2a(ii) a And R is^2aIs a hydrogen atom.

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

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is 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 a is 5 to 10 membered heteroaryl; more preferably, ring A is pyridyl or

Most preferably, ring a is pyridyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring 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 a 3 to 12 membered heterocyclic group containing at least one nitrogen atom; more preferably, ring B is piperidinyl.

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

wherein:

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

W¹、W²、W³、W⁴and W⁵Are the same or different and are each independently CR¹Or an N atom;

ring C, R¹To R³、R⁵、R^2a、L₃S, t and v are as defined in formula (I).

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

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or 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 heterocyclic group containing at least one nitrogen atom or a 5 to 10 membered heteroaryl group containing at least one nitrogen atom; more preferably, ring C is piperidinyl or 5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer or mixture thereofIn the form of a isomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen atoms, halogens, C_1-6Alkyl and C_1-6An alkoxy group; preferably, R²Is a hydrogen atom.

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

wherein:

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

Ring D is a 4-to 6-membered heterocyclic group containing at least one nitrogen atom;

Z¹、Z²、Z³and Z⁴One is a carbon atom and the remaining three are the same or different and are each independently CR⁵Or an N atom;

R¹⁰selected from the group consisting of hydrogen atoms, alkyl groups, heteroalkyl groups, haloalkyl groups, and hydroxyalkyl groups;

t is 1,2, 3,4,5 or 6;

R¹、R³、R⁵、L₃s and v are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is piperidinyl or 5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl.

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹⁰Is a hydrogen atom or C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6A hydroxyalkyl group; preferably, each R¹Are the same or different and are each independently a hydrogen atom or C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is³Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; preferably, R³Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is₃Is a bond.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer thereofIn the form of a solid, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_1-6Alkoxy, oxo, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6A hydroxyalkyl group; preferably, each R⁵Are the same or different and are each independently a hydrogen atom or C_1-6An alkyl group.

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

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

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

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

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

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

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

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^6aAnd R^6bAre the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6A hydroxyalkyl group; or R^6aAnd R^6bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered heterocyclic group, said 3-to 12-membered heterocyclic group being optionally selected from halogen, C_1-6Alkyl, oxo, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, hydroxy and C_1-6Substituted with one or more substituents in hydroxyalkyl; preferably, R^6aAnd R^6bAre the same or different and are each independently a hydrogen atom or C_1-6An alkyl group.

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

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or mixture thereof,Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R¹Is C_1-6Alkyl, and p is 0, 1,2, 3 or 4.

In some preferred embodiments of the present disclosure, the compound of formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹Is C_1-6Alkyl, and p is 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is C_1-6Alkyl, and t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (II) or formula (III), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is C_1-6Alkyl, and t is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is C_1-6Alkyl, and t is 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of a 3-to 8-membered cycloalkyl group, a 3-to 12-membered heterocyclyl group, a 6-to 10-membered aryl group, and a 5-to 10-membered heteroaryl group; 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; x is an O atom; l is₁Is CH₂；L₂Is CR^4cR^4d；R^4cAnd R^4dTogether with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group; g is CR^2a；R^2aIs a hydrogen atom;R⁰selected from hydrogen atoms, C_1-6Alkyl, - (CH)₂)_rC(O)NR^6aR^6bAnd

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; l is₃Is a bond; r¹Is C_1-6An alkyl group; r²Is a hydrogen atom; r⁵Is C_1-6An alkyl group; p is 0, 1,2, 3 or 4; t is 0, 1 or 2; n is 0 or 1; u is 1; v is 1,2 or 3; r^6aAnd R^6bAre the same or different and are each independently a hydrogen atom or C_1-6An alkyl group; r is 0, 1 or 2; s is 0.

In some preferred embodiments of the present disclosure, the compound of formula (II), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-to 10-membered heteroaryl; ring B is a 3-to 12-membered heterocyclic group containing at least one nitrogen atom; ring C is a 3-to 12-membered heterocyclic group containing at least one nitrogen atom or a 5-to 10-membered heteroaryl group containing at least one nitrogen atom; g is CR^2a；R^2aIs a hydrogen atom; l is₃Is a bond; r¹Is C_1-6An alkyl group; r²Is a hydrogen atom; r⁵Is C_1-6An alkyl group; p is 2; t is 0 or 1; n is 0; u is 1; v is 1,2 or 3; s is 0.

In some preferred embodiments of the present disclosure, the compound of formula (III), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is piperidinyl; w¹、W²、W³、W⁴And W⁵Are the same or different and are each independently CR¹Or an N atom; ring C is piperidinyl or 5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl; r¹Is a hydrogen atom or C_1-6An alkyl group; r²Is a hydrogen atom; r^2aIs a hydrogen atom; r⁵Is C_1-6An alkyl group; l is₃Is a bond; t is 0 or 1; v is 1,2 or 3; s is 0.

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is piperidinyl or 5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl; r¹⁰Is a hydrogen atom or C_1-6An alkyl group; w¹、W²、W³、W⁴And W⁵Are the same or different and are each independently CR¹Or an N atom; r¹Is a hydrogen atom or C_1-6An alkyl group; r⁵Is C_1-6An alkyl group; l is₃Is a bond; t is 1 or 2; v is 1,2 or 3; s is 0.

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

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

wherein:

R¹to R³、R^2aS and v are as defined in formula (III).

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

wherein:

R¹、R³s and v are as defined in formula (IV).

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

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

wherein:

R^wfor protection of amino groupsA group; preferably, R^wIs tert-butyloxycarbonyl;

R¹、R²、R^2a、R³s and v are as defined in formula (IIIa).

wherein:

R^wis an amino protecting group; preferably, R^wIs tert-butyloxycarbonyl;

W¹、W²、W³、W⁴and W⁵Are the same or different and are each independently CR¹Or an N atom; r¹、R³S and v are as defined in formula (IVa).

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

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

method 1

Subjecting a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to reductive amination reaction with a compound of formula (V) to obtain a compound of formula (III) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

or

Method 2

Carrying out coupling reaction on the compound of the general formula (IIIa) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V') to obtain the compound of the general formula (III) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture form thereof or a pharmaceutically acceptable salt thereof;

wherein:

L₃is a bond;

y is halogen; preferably, Y is chloro;

ring C, R¹To R³、R⁵、R^2aS, t and v are as defined in formula (III).

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

method 1

The compound of the general formula (IVa) or the tautomer, racemate, enantiomer, diastereomer or mixture form thereof, or the pharmaceutically acceptable salt thereof, and the compound of the general formula (VI) are subjected to reductive amination reaction to obtain R¹⁰Selected from the group consisting of hydrogen atoms, alkyl groups, heteroalkyl groups, haloalkyl groups, hydroxyalkyl groups and R^wA compound of general formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

or

Method 2

The compound of the general formula (IVa) or the tautomer, racemate, enantiomer, diastereomer or mixture form thereof, or the pharmaceutically acceptable salt thereof and the compound of the general formula (VI') are subjected to coupling reaction to obtain R¹⁰Selected from the group consisting of hydrogen atoms, alkyl groups, heteroalkyl groups, haloalkyl groups, hydroxyalkyl groups and R^wA compound of general formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

and

optionally, when R¹⁰Is R^wWhen it further comprises the step of reacting R¹⁰Is R^wIn the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or removing the protecting group R^wTo obtain R¹⁰A compound of formula (IV) being a hydrogen atom or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

L₃is a bond;

y is halogen; preferably, Y is chloro;

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

R¹、R³、R⁵s, t and v are as defined in formula (IV).

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

removing the protecting group R from the compound of formula (IIIaa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof^wTo obtain a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

R¹、R²、R^2a、R³s and v are as defined in formula (IIIa).

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

removing the protecting group R from the compound of formula (IVaa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof^wTo obtain a compound of general formula (IVa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

R¹、R³s and v are as defined in formula (IVa).

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

The disclosure further relates to the use of compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR 9.

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

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

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

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

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

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

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7, TLR8 and TLR 9.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7, TLR8 or TLR 9; preferably for inhibiting TLR7 and TLR8, or TLR7 and TLR 9.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of inflammatory or autoimmune diseases. Wherein said inflammatory or autoimmune disease is preferably selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and Sjogren's syndrome.

In view of their activity as selective inhibitors of TLR7, TLR8, or TLR9, compounds of formula (I), formula (II), formula (III), formula (IV), and table a are useful for treating TLR7, TLR8, or TLR9 family receptor-related diseases, respectively, 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 Cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis); metabolic disorders (including type 2 diabetes, atherosclerosis, myocardial infarction); destructive bone disorders (such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders); proliferative disorders (such as acute myeloid leukemia, chronic myeloid leukemia); angiogenic disorders (such as angiogenic disorders including solid tumors, ocular neovascularisation and infantile hemangiomas); infectious diseases (such as sepsis, septic shock, and shigellosis); neurodegenerative diseases (such as alzheimer's disease, parkinson's disease, cerebral ischemia 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 disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, graves ' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, Traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia from infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyretic disease (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellasis; alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases including acute hepatitis infections (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular proliferation, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin endoperoxidase synthase-2 related conditions, and pemphigus vulgaris. In a preferred method of treatment, the condition is selected from those of crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred methods of treatment, the disorder 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 disorder is multiple myeloma.

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

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

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

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

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

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

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

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

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

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

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

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

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

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group containing 1 to 12 (e.g., 1,2, 3,4,5, 6,7,8, 9,10, 11, and 12) carbon atoms_1-12Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C)_1-6Alkyl groups). Non-limiting examples of alkyl groups include: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1, 2-trimethylpropyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2, 3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 2-methylpentyl group, 3-methylhexyl group, 4-methylhexyl group, 2-dimethylpropyl group, 2-pentyl group, 2-methylpropyl group, 2-methyl-pentyl group, 3-pentyl group, 2-methyl-pentyl group, 2-pentyl group, and 3-pentyl group, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl,2, 2-dimethylpentyl group, 3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2, 3-dimethylhexyl group, 2, 4-dimethylhexyl group, 2, 5-dimethylhexyl group, 2-dimethylhexyl group, 3-dimethylhexyl group, 4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-diethylhexyl group, and various branched chain isomers thereof, and the like. Most preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

The term "heteroalkyl" refers to one or more-CH's in an alkyl group₂-is selected from N, O, S, S (O) and S (O)₂One or more of; wherein said alkyl is as defined above; heteroalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkylene" refers to saturatedIs a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1,2, 3,4,5, 6,7,8, 9,10, 11, and 12) carbon atoms (i.e., C)_1-12Alkylene) groups, more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C)_1-6Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.

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

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Preferably 2 to 12 (e.g. 2,3, 4,5, 6,7,8, 9,10, 1)Alkenyl of 1 and 12) carbon atoms (i.e. C)_2-12Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl). 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 containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups containing 2 to 12 (e.g., 2,3, 4,5, 6,7,8, 9,10, 11, and 12) carbon atoms are preferred_2-12Alkynyl), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C)_2-6Alkynyl). The alkynyl 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, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3,4,5, 6,7,8, 9,10, 11, and 12) carbon atoms (i.e., 3 to 12 membered cycloalkyl groups), preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

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

the term "fused cyclic alkyl" refers to an all-carbon polycyclic group of 5 to 20 members sharing an adjacent pair of carbon atoms between the rings, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be divided into polycyclic fused-ring alkyls such as bicyclic, tricyclic, tetracyclic, etc., according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-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. Non-limiting examples of fused ring alkyl groups include:

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

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

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being 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 mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4,5, 6,7,8, 9,10, 11 and 12) ring atoms (i.e., 3 to 12 membered heterocyclyl groups), of which 1-4 (e.g., 1,2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (e.g., 3,4,5, 6,7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

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

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

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

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

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being 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 is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

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

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being 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 above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removal of one hydrogen atom from the parent ring atom, or those derived by removal of two hydrogen atoms from the parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

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

The term "hydroxyl-protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5)^Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C)_1-10Alkyl or aryl)₃Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C_1-10Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C_1-6Alkoxy-substituted C_1-6Alkyl or phenyl substituted C_1-6Alkyl, most preferably C_1-4Alkoxy-substituted C_1-4Alkyl groups, for example: methyl, t-butyl, benzyl, methoxymethyl (MOM), ethoxyethyl, and the like; may be (C)_1-10Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C)_1-6Alkyl or C_6-10Aryl) sulfonyl; or (C)_1-6Alkoxy or C_6-10Aryloxy) carbonyl; it may also be allyl, 2-Tetrahydropyranyl (THP).

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

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

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

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

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

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" or "oxo" refers to "═ O".

The term "carbonyl" refers to C ═ O.

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

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

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

The compounds of the present disclosure may also comprise isotopic derivations thereofA compound (I) is provided. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-、¹³C-, or¹⁴C-enriched carbon (C¹¹C-、¹³C-, or¹⁴C-carbon labeling;¹¹C-、¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

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

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

Can be that

Or

Or at the same time contain

And

two configurations.

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

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

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

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

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

The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.

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

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

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

Synthesis of the Compounds of the disclosure

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

scheme one

The preparation method of the compound shown in the general formula (III) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

(a) a compound of the general formula (IIIaa) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the protecting group R is removed in the presence of an acid^WTo obtain a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

(b) carrying out reductive amination reaction on the compound of the general formula (IIIa) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (V) or the pharmaceutically acceptable salt thereof in the presence of a reducing agent under alkaline conditions to obtain the compound of the general formula (III) or the tautomer, the racemate, the enantiomer, the diastereomer or a mixture thereof or the pharmaceutically acceptable salt thereof;

or

wherein:

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

L₃is a bond;

y is halogen; preferably, Y is chloro;

ring C, R¹To R³、R⁵、R^2aS, t and v are as defined in formula (III).

Scheme two

The preparation method of the compound shown in the general formula (IV) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof comprises the following steps:

(a) a compound of the general formula (IVaa) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, in the presence of an acid to remove the protecting group R^WTo obtain a compound of general formula (IVa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

(b) the compound of the general formula (IVa) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt thereof and the compound of the general formula (VI) or the pharmaceutically acceptable salt thereof are subjected to reductive amination reaction under the alkaline condition and in the presence of a reducing agent to obtain R¹⁰Selected from the group consisting of hydrogen atoms, alkyl groups, heteroalkyl groups, haloalkyl groups, hydroxyalkyl groups and R^WA compound of general formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

or

A compound of formula (IVa) or a tautomer, thereofRacemic modification, enantiomer, diastereoisomer or mixture thereof, or pharmaceutically acceptable salt thereof, with a compound of formula (VI') to give R¹⁰Selected from the group consisting of hydrogen atoms, alkyl groups, heteroalkyl groups, haloalkyl groups, hydroxyalkyl groups and R^WA compound of general formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

and

optionally, when R¹⁰Is R^WWhen R is the same as R, the method further comprises the step (c) of¹⁰Is R^WIn the form of a compound of the general formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in the presence of an acid to remove the protecting group R^WTo obtain R¹⁰A compound of formula (IV) being a hydrogen atom or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

L₃is a bond;

y is halogen; preferably, Y is chloro;

R¹、R³、R⁵s, t and v are as in formula (IV)As defined.

In the above reaction of steps (a) and (c), the acid includes organic acid and inorganic acid, and the organic acid includes, but is not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me₃SiCl and TMSOTf, preferably trifluoroacetic acid; such 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 step (b), the reducing agent used in the reductive amination reaction includes, but is not limited to, sodium acetate borohydride, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and the like, and preferably sodium acetate borohydride. 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 acetate is preferred.

In the above reaction of step (b), the coupling reaction is well known in the art and includes, but is not limited to, Buchwald-Hartwig coupling reaction, Negishi coupling reaction, etc. The coupling reaction conditions include, but are not limited to, in the presence of a metal catalyst (preferably in the presence of a palladium or nickel containing catalyst) including, but not limited to, 1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene](3-Chloropyridyl) palladium (II) dichloride, chlorine (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II), palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-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), Chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G2), organozinc reagent, bis (triphenylphosphine) chloridePalladium (II) (Pd (PPh)₃)Cl₂) Etc., preferably 1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene](3-Chloropyridyl) palladium (II) dichloride. The metal catalyst may also be used in combination with a ligand including, but 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 (diphenylphosphino) ferrocene (DPPF), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (XANTPHOS), 2' -bis (diphenylphosphino) benzophenone (DPBP), 2' -diallylbisphenol a (dba), and the like, and a base. 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; cesium carbonate is preferred.

The above-described reactions of steps (a) - (c) are preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

Detailed Description

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

Examples

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

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

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Example 1

5- (2, 6-dimethylpyridin-4-yl) -9- (1 '-isobutyl- [1,4' -dipiperidine ] -4-yl) -1,3,4, 6-tetrahydroxepin-o [5,4,3-cd ] indole bistrifluoroacetate 1

First step of

Triethyl (4- ((tetrahydro-2H-pyran-2-yl) oxy) but-1-yn-1-yl) silane 1b

2- (but-3-yn-1-yloxy) tetrahydro-2H-pyran 1a (11.3g, 73.3mmol, Toshibara) was dissolved in anhydrous tetrahydrofuran (130mL), cooled to-70 ℃ and a 2.5M n-hexane solution of n-butyllithium (31mL, 77.7mmol, Toshitanan) was added dropwise. The reaction was stirred at-70 ℃ for 1 hour under nitrogen. Triethylchlorosilane (12.3g, 82.2mmol, obtained from Shanghai) was added. Stirred at room temperature for 4 hours. Jia Jian FuAnd aqueous ammonium chloride (80mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (80 mL. times.2), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1b (19.0g, yield: 96.6%).¹H NMR(500MHz,CDCl₃)δ4.66(t,1H),3.91-3.79(m,2H),3.56-3.48(m,2H),2.53(t,2H),1.86-1.79(m,1H),1.72-1.66(m,1H),1.61-1.47(m,4H),0.96(t,9H),0.56(q,6H)。

Second step of

4- (triethylsilyl) but-3-yn-1-ol 1c

Compound 1b (19.0g, 70.8mmol) was dissolved in methanol (170mL) and 4-toluenesulfonic acid monohydrate (1.4g, 7.1mmol, Shaoshima science) was added. Stirred at room temperature for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (10.9g, yield: 83.9%).

¹H NMR(500MHz,CDCl₃)δ3.70(t,2H),2.51(t,2H),1.98(s,1H),0.97(t,9H),0.58(q,6H)。

The third step

Triethyl (4- ((2-iodo-3-nitrobenzyl) oxy) but-1-yn-1-yl) silane 1e

Sodium hydride (663.1mg, 16.6mmol, 60%, Shanghai Tatan) was suspended in anhydrous tetrahydrofuran (60 mL). At 0 deg.C, compound 1c (3.1g, 16.6mmol) was added and stirred at room temperature for 20 minutes. 1- (bromomethyl) -2-iodo-3-nitrobenzene 1d (4.4g, 12.8mmol, prepared using methods known in the literature "Heterocycles, 2018, vol.97, p.1175-1190") was added. The reaction was stirred at room temperature for 16 hours. Saturated aqueous ammonia chloride (50mL), ethyl acetate (50 mL. times.3) were added, the mixture was extracted, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1e (3.8g, yield: 66.9%).

MS m/z(ESI):445.9[M+1]。

The fourth step

2-iodo-3- (((4- (triethylsilyl) but-3-yn-1-yl) oxy) methyl) aniline 1f

Compound 1e (3.8g, 8.5mmol) was dissolved in ethanol (60mL) and water (12mL), and iron powder (3.4g, 59.8mmol, Shanghai medicine) and ammonium chloride (3.4g, 59.8mmol, Shanghai medicine) were added. The reaction was stirred at 80 ℃ for 1.5 hours. Concentrated under reduced pressure, extracted with ethyl acetate (50 mL. times.3), and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1f (3.1g, yield: 87.5%).

MS m/z(ESI):416.0[M+1]。

The fifth step

4-bromo-2-iodo-3- (((4-triethylsilyl) but-3-yn-1-yl) oxy) methyl) aniline 1g

Compound 1f (4.6g, 11.0mmol) was dissolved in N, N-dimethylformamide (70mL) and N-bromosuccinimide (2.0g, 11.0mmol, Shanghai nationality drug) was added. Stirred at room temperature for 1 hour. Aqueous sodium thiosulfate (140mL) was added and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined and washed with water (30 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain 1g (5.1g, yield: 95.2%) of the title product.

MS m/z(ESI):493.9[M+1]。

The sixth step

9-bromo-5- (triethylsilyl) -1,3,4, 6-tetrahydroxyhepto [5,4,3-cd ] indole for 1h

1g (4.4g, 8.9mmol) of the compound was dissolved in N, N-dimethylformamide (540mL), and palladium acetate (997.1mg, 4.5mmol, Shanghai Tantan), triphenylphosphine (2.4g, 9.0mmol, Shanghai nationality medicine), lithium chloride (1.2g, 26.9mmol, Shanghai nationality medicine) and potassium carbonate (3.7g, 26.7mmol, Shanghai nationality test) were added. The nitrogen was replaced three times. Stirring is carried out for 16 hours at 80 ℃ under the protection of nitrogen. Water (1L) was added, and extraction was performed with ethyl acetate (300 mL. times.3). The organic phases were combined and washed with water (100 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1h (830mg, yield: 25.2%).

MS m/z(ESI):366.0[M+1]。

Seventh step

4- (5- (triethylsilyl) -1,3,4, 6-tetrahydroxyhepto [5,4,3-cd ] indol-9-yl) -3, 6-dihydropyridine-1 (2H) carboxylic acid tert-butyl ester 1j

Compound 1h (830.0mg, 2.3mmol) and compound 1i (1.0g, 3.4mmol, Shaoshima science) were dissolved in 1, 4-dioxane (20mL) and water (4 mL). Bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium dichloride (322.0mg, 0.45mmol, Shanghai Biao) and cesium carbonate (1.5g, 4.6mmol, Shaoshima science) were added. The nitrogen was replaced three times, and the reaction was stirred at 80 ℃ for 3 hours under nitrogen protection. Water (20mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1j (920.0mg, yield: 88.6%).

MS m/z(ESI):469.2[M+1]。

Eighth step

4- (5- (triethylsilyl) -1,3,4, 6-tetrahydroxyhepto [5,4,3-cd ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 1k

Compound 1j (820.0mg, 1.75mmol) was dissolved in methanol (50 mL). 10% palladium on carbon (800.0mg, water content < 1%, Shanghai Wolka) was added. The hydrogen was replaced three times. The reaction was stirred at 40 ℃ for 1 hour under hydrogen. Suction filtration is carried out, 10 percent palladium carbon (800.0mg, the water content is less than 1 percent, and Shanghai Wolka) is added into the filtrate. The hydrogen was replaced three times. The reaction was stirred at 40 ℃ for 3 hours under hydrogen. Suction filtration and concentration of the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 1k (335.0mg, yield: 40.7%).

MS m/z(ESI):471.2[M+1]。

The ninth step

4- (5-bromo-1, 3,4, 6-tetrahydroxepin [5,4,3-cd ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 1l

Compound 1k (275.0mg, 0.6mmol) was dissolved in 1, 2-dichloroethane (28 mL). A solution of N-bromosuccinimide (2.0g, 11.0mmol, Shanghai nationality drug) in 1, 2-dichloroethane (10mL) was slowly added dropwise at-30 ℃. The reaction was stirred for 10 minutes at-30 ℃. Aqueous sodium thiosulfate (30mL) was added and extracted with dichloromethane (30 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1l (145.0mg, yield: 57.0%).

MS m/z(ESI):457.0[M+23]。

The tenth step

4- (5- (2, 6-dimethylpyridin-4-yl) -1,3,4, 6-tetrahydroxepin [5,4,3-cd ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 1n

Compound 1l (195.0mg, 0.45mmol) and 2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine 1m (88.0mg, 0.58mmol, Shanghai Yam kang) were dissolved in 1, 4-dioxane (8mL) and water (2 mL). [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (73.3mg, 0.09mmol, Beijing carbofuran) and potassium phosphate (284.9mg, 1.3mmol, Beijing carbofuran) were added. The nitrogen was replaced three times, and the reaction was stirred at 90 ℃ for 3 hours. Water (10mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1n (150.0mg, yield: 72.6%).

MS m/z(ESI):462.2[M+1]。

The eleventh step

5- (2, 6-dimethylpyridin-4-yl) -9- (piperidin-4-yl) -1,3,4, 6-tetrahydroxepin [5,4,3-cd ] indole 1o

Compound 1n (75.0mg, 0.16mmol) was dissolved in methanol (2mL) and 4M hydrogen chloride/1, 4-dioxane solution (3mL) was added. Stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 7M ammonia/methanol solution (5mL) was added to the residue. Concentration under reduced pressure gave the title product 1o (58.0mg, yield: 100%).

MS m/z(ESI):362.1[M+1]。

The twelfth step

Compound 1o (58.0mg, 0.16mmol) and 1-isobutylpiperidin-4-one 1p (155.2mg, 0.17mmol) were dissolved in anhydrous N, N-dimethylformamide (5mL), and sodium acetate (223.0mg, 2.7mmol, Shanghaitant) was added. Stirred at room temperature for 1 hour. Sodium borohydride acetate (223.0mg, 2.7mmol, Shaoshima technologies Shanghai, Inc.) was added. Stirred at room temperature for 16 hours. The residue was isolated and purified by high performance liquid chromatography (column: Sharpsil-T C18150 x 30mm,5 μm; mobile phase 1: water (containing 0.1% trifluoroacetic acid), mobile phase 2: acetonitrile; 15 min gradient: 10% -95%, flow rate: 30mL/min) to give the title product 1(30.0mg, yield: 30.5%). MS M/z (ESI) 501.3[ M-227 ].

¹H NMR(500MHz,CD₃OD)δ7.86(s,2H),7.41(d,1H),7.25(d,1H),5.30(s,2H),4.17(t,2H),3.83-3.62(m,6H),3.42(t,2H),3.11-3.01(m,5H),2.81-2.72(m,6H),2.46(d,2H),2.25-2.06(m,8H),1.07(d,6H)。

Example 2

2- (2, 6-Dimethylpyridin-4-yl) -6- (1 '-isobutyl- [1,4' -dipiperidine ] -4-yl) -1, 5-dihydro-3H-pyrano [3,4,5-cd ] indole bistrifluoroacetate 2

First step of

Triethyl (3- ((2-iodo-3-nitrobenzyl) oxy) prop-1-yn-1-yl) silane 2b

1d (2.2g, 6.4mmol, prepared by methods known in the literature "Heterocycles, 2018, vol.97, p.1175-1190") and 3- (triethylsilyl) prop-2-yn-1-ol 2a (1.7g, 9.7mmol, prepared by methods known in the literature "Tetrahedron, 1996, vol.52, p.7487-7510") were dissolved in acetonitrile (25mL) and potassium carbonate (4.5g, 32.2mmol, Shanghai medicine) was added. The reaction was stirred at 80 ℃ for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2b (1.6g, yield: 57.7%).

MS m/z(ESI):432.1[M+1]。

Second step of

2-iodo-3- (((3- (triethylsilyl) prop-2-yn-1-yl) oxy) methyl) aniline 2c

Compound 2b (1.6g, 3.7mmol) was dissolved in ethanol (25mL) and water (5mL), and iron powder (1.5g, 26.8mmol, Shanghai medicine) and ammonium chloride (1.5g, 26.8mmol, Shanghai medicine) were added. The reaction was stirred at 80 ℃ for 1.5 hours. Concentrated under reduced pressure, extracted with ethyl acetate (30 mL. times.3), and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2c (1.1g, yield: 73.9%).

MS m/z(ESI):402.0[M+1]。

The third step

4-bromo-2-iodo-3- (((3- (triethylsilyl) prop-2-yn-1-yl) oxy) methyl) aniline 2d

Compound 2c (1.1g, 2.7mmol) was dissolved in N, N-dimethylformamide (18mL) and N-bromosuccinimide (487.8g, 2.7mmol, Shanghai nationality) was added. Stirred at room temperature for 1 hour. Aqueous sodium thiosulfate (40mL) was added and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined and washed with water (20 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2d (1.1g, yield: 85.0%).

MS m/z(ESI):479.9[M+1]。

The fourth step

6-bromo-2- (triethylsilyl) -1, 5-dihydro-3H-pyrano [3,4,5-cd ] indole 2e

Compound 2d (650.0mg, 1.4mmol) was dissolved in N, N-dimethylformamide (90mL), and palladium acetate (151.6mg, 0.7mmol, Shanghai Tantan), triphenylphosphine (354.7mg, 1.4mmol, Shanghai nationality), lithium chloride (57.4mg, 1.4mmol, Shanghai nationality) and potassium carbonate (186.8mg, 1.4mmol, Shanghai nationality). The nitrogen was replaced three times. Stirring is carried out for 16 hours at 80 ℃ under the protection of nitrogen. Water (180mL) was added, and extraction was performed with ethyl acetate (100 mL. times.3). The organic phases were combined and washed with water (50 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2e (400.0mg, yield: 83.9%). MS M/z (ESI) 352.0[ M +1 ].

The fifth step

4- (2- (triethylsilyl) -1, 5-dihydro-3H-pyrano [3,4,5-cd ] indol-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 2f

Compound 2e (400.0mg, 1.1mmol) and compound 1i (526.6g, 1.7mmol, Shaoshima science) were dissolved in 1, 4-dioxane (10mL) and water (2 mL). Bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium dichloride (160.8mg, 0.23mmol, Shanghai Biao) and cesium carbonate (738.0mg, 2.3mmol, Shaoshima science) were added. The nitrogen was replaced three times. The reaction was stirred at 80 ℃ for 3 hours under nitrogen. Water (20mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2f (500.0mg, yield: 96.9%).

MS m/z(ESI):455.2[M+1]。

The sixth step

4- (2- (triethylsilyl) -1, 5-dihydro-3H-pyrano [3,4,5-cd ] indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester 2g

Compound 2f (1.0g, 2.2mmol) was dissolved in methanol (60mL), 10% palladium on carbon (1.0g, water content < 1%, Shanghai Wolka) was added, and hydrogen was replaced three times. The reaction was stirred at 40 ℃ for 1 hour under hydrogen. Suction filtration is carried out, 10% palladium carbon (1.0g, water content is less than 1%, Shanghai Wolka) is added into the filtrate. The hydrogen was replaced three times. The reaction was stirred at 40 ℃ for 3 hours under hydrogen. Suction filtration and concentration of the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave 2g (760.0mg, yield: 75.7%) of the title product.

MS m/z(ESI):457.2[M+1]。

Seventh step

4- (2-bromo-1, 5-dihydro-3H-pyrano [3,4,5-cd ] indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester 2H

Compound 2g (200.0mg, 0.44mmol) was dissolved in 1, 2-dichloroethane (20 mL). A solution of N-bromosuccinimide (78.0g, 0.44mmol, Shanghai nationality drug) in 1, 2-dichloroethane (7mL) was slowly added dropwise at-30 ℃. The reaction was stirred for 10 minutes at-30 ℃. Aqueous sodium thiosulfate (20mL) was added and extracted with dichloromethane (20 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2h (115.0mg, yield: 62.3%).

MS m/z(ESI):365.0[M-55]。

Eighth step

4- (2- (2, 6-dimethylpyridin-4-yl) -1, 5-dihydro-3H-pyrano [3,4,5-cd ] indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester 2i

Compound 2h (420.0mg, 1.0mmol) and compound 1m (200.7mg, 1.2mmol, Shanghai Yao Ming kang) were dissolved in 1, 4-dioxane (16mL) and water (4 mL). [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (163.1mg, 0.2mmol, Beijing carbofuran) and potassium phosphate (634.0mg, 3.0mmol, Beijing carbofuran) were added. The nitrogen was replaced three times, and the reaction was stirred at 90 ℃ for 3 hours. Water (10mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2i (380.0mg, yield: 85.2%).

MS m/z(ESI):448.3[M+1]。

The ninth step

2- (2, 6-dimethylpyridin-4-yl) -6- (piperidin-4-yl) -1, 5-dihydro-3H-pyrano [3,4,5-cd ] indole 2j

Compound 2i (340.0mg, 0.76mmol) was dissolved in methanol (5mL) and 4M hydrogen chloride/1, 4-dioxane solution (10mL) was added. Stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 7M ammonia/methanol solution (10mL) was added to the residue. Concentration under reduced pressure gave the title product 2j (268.0mg, yield: 100%).

MS m/z(ESI):348.0[M+1]。

The tenth step

Compound 2j (130.0mg, 0.37mmol) and compound 1p (406.6mg, 2.6mmol) were dissolved in anhydrous N, N-dimethylformamide (7mL), and sodium acetate (521.7mg, 6.4mmol, shanghaitant) was added. Stirred at room temperature for 1 hour. Sodium borohydride acetate (555.4mg, 2.6mmol, Shaoshima science) was added. Stirred at room temperature for 16 hours. The residue was isolated and purified by high performance liquid chromatography (column: Sharpsil-T C18150 x 30mm,5 μm; mobile phase 1: water (containing 0.1% trifluoroacetic acid), mobile phase 2: acetonitrile; 30 min gradient: 5% -95%, flow rate: 30mL/min) to give the title product 2(100.0mg, yield: 44.5%).

MS m/z(ESI):487.3[M-227]。

¹H NMR(500MHz,CD₃OD)δ7.64(s,2H),7.34(d,1H),7.26(d,1H),5.32(s,2H),5.07(s,2H),3.80(s,2H),3.71(d,2H),3.60(s,2H),3.11-3.08(m,3H),3.00(s,2H),2.74(s,6H),2.46(s,2H),2.23-2.07(m,8H),1.07(d,6H)。

Example 3

2- (2, 6-dimethylpyridin-4-yl) -7- (1- (5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) piperidin-4-yl) -1,3,4, 6-tetrahydroxepin-no [5,4,3-cd ] indole tetratrifluoroacetate 3

First step of

5- (2, 6-dimethylpyridin-4-yl) -9- (piperidin-4-yl) -1,3,4, 6-tetrahydroxepin [5,4,3-cd ] indole hydrochloride 3a

Compound 1n (65.0mg, 0.14mmol) was dissolved in dichloromethane (2mL) and 4M hydrogen chloride/1, 4-dioxane solution (2mL) was added. Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 3a (56.0mg, yield: 99.9%).

MS m/z(ESI):362.1[M-35]。

Second step of

7- (4- (2- (2, 6-dimethylpyridin-4-yl) -1,3,4, 6-tetrahydroxepin [5,4,3-cd ] indol-7-yl) piperidin-1-yl) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester 3c

Compound 3a (56.0mg, 0.14mmol) and tert-butyl 7-chloro-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylate 3b (50.0mg, 0.19mmol, Shaoshima Tech.) were dissolved in 1, 4-dioxane (4.0 mL). 1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] (3-chloropyridyl) palladium (II) dichloride (12.0mg, 0.015mmol, Sigma-Aldrich) and cesium carbonate (200.0mg, 0.62mmol, Shao Yuan technology) were added. The nitrogen gas was replaced three times, and the reaction was stirred at 105 ℃ for 16 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3c (20.0mg, yield: 23.9%).

MS m/z(ESI):594.1[M+1]。

The third step

2- (2, 6-dimethylpyridin-4-yl) -7- (1- (5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) piperidin-4-yl) -1,3,4, 6-tetrahydroxepin-no [5,4,3-cd ] indole trifluoroacetate 3

Compound 3c (20.0mg, 0.034mmol) was dissolved in dichloromethane (3.0mL) and trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 1.0 hour. Concentrated under reduced pressure and the residue was isolated and purified by high performance liquid chromatography (column: Sharpsil-TC 18150 x 30mm,5 μm; mobile phase 1: water (containing 0.1% trifluoroacetic acid), mobile phase 2: acetonitrile; 15 min gradient: 10% -95%, flow rate: 30mL/min) to give the title product 3(5.0mg, yield: 6.1%). MS M/z (ESI) 494.3[ M-455 ].

¹H NMR(500MHz,DMSO-d₆)δ11.90(s,1H),9.26(brs,2H),8.03(s,1H),7.89(s,2H),7.33(d,1H),7.28(s,1H),7.18(s,1H),7.15(d,1H),7.08(s,1H),6.96(s,1H),5.25(s,2H),4.36(d,2H),4.28(s,2H),4.08(t,2H),3.40-3.33(m,4H),3.04(t,2H),2.96(m,1H),2.91-2.88(m,2H),2.71(s,6H),1.78-1.67(m,4H)。

Example 4

5- (2, 6-dimethylpyridin-4-yl) -9- (1-isopropylpiperidin-4-yl) -1,3,4, 6-tetrahydroxepin [5,4,3-cd ] indole 4

Compound 1o (105mg, 0.29mmol) was dissolved in acetonitrile (5mL), and potassium carbonate (200mg, 1.45mmol, Shanghai drug) and 2-iodopropane (200mg, 1.18mmol, adamas) were added. Stirred at 80 ℃ for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Boston Phlex Prep C185. mu.m 30 x 150 mM; mobile phase 1: water (containing 10mM ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: 30% -60%, flow rate: 30mL/min) to give the title product 4(57mg, yield: 48.6%).

MS m/z(ESI):404.0[M+1]。

¹H NMR(500MHz,CD₃OD)δ7.38(s,2H),7.32(d,1H),7.17(d,1H),5.24(s,2H),4.11-4.08(m,2H),3.30-3.28(m,2H),3.09-3.07(m,2H),2.85(m,1H),2.68(m,1H),2.57(s,6H),2.45-2.40(m,2H),1.92-1.85(m,2H),1.80-1.78(m,2H),1.17(d,6H)。

Example 5

5'- (2, 6-dimethylpyridin-4-yl) -9' - (piperidin-4-yl) -1',6' -dihydro-3 'H-spiro [ cyclopropane-1, 4' -oxepino [5,4,3-cd ] indole ]5

First step of

(1- ((2, 6-Dimethylpyridin-4-yl) ethynyl) cyclopropyl) methanol 5c

(1-ethynylcyclopropyl) methanol 5a (1.0g, 10.4mmol, Nanjing Yam), 4-bromo-2, 6-dimethylpyridine 5b (1.9g, 10.2mmol, Bidayama), bis (triphenylphosphine) palladium dichloride (720mg, 1.03mmol, carbofuran), cuprous iodide (200mg, 1.05mmol, Alfa Aesar) and N, N-diisopropylethylamine (5.0g, 38.7mmol, adamas) were dissolved in N, N-dimethylformamide (25 mL). Stirring at 90 ℃ for 1.5 hours under the protection of nitrogen. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5c (2.0g, yield: 97.3%).

MS m/z(ESI):202.2[M+1]。

Second step of

4- ((1- (((2-iodo-3-nitrobenzyl) oxy) methyl) cyclopropyl) ethynyl) -2, 6-lutidine 5d

Sodium hydride (820mg, 20.5mmol, 60%, Shanghai Tatan) was suspended in anhydrous tetrahydrofuran (30 mL). At 0 deg.C, compound 5c (2.1g, 10.4mmol) was added and stirred at room temperature for 30 minutes. 1- (bromomethyl) -2-iodo-3-nitrobenzene 1d (3.5g, 10.2mmol) was added. The reaction was stirred at room temperature for 16 hours. Saturated aqueous ammonia chloride (100mL), dichloromethane (80 mL. times.4) were added and the mixture was extracted, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title product 5d (4.2g, yield: 88.8%).

MS m/z(ESI):463.0[M+1]。

The third step

3- (((1- ((2, 6-dimethylpyridin-4-yl) ethynyl) cyclopropyl) methoxy) methyl) -2-iodoaniline 5e

Compound 5d (4.2g, 9.1mmol) was dissolved in ethanol (75mL) and water (15mL), and iron powder (4.0g, 71.6mmol, Shanghai medicine) and ammonium chloride (4.0g, 74.1mmol, Shanghai medicine) were added. The reaction was stirred at 80 ℃ for 2.0 hours. Concentrated under reduced pressure, extracted with ethyl acetate (80 mL. times.4), and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5e (2.5g, yield: 63.7%).

MS m/z(ESI):432.8[M+1]。

The fourth step

4-bromo-3- (((1- ((2, 6-dimethylpyridin-4-yl) ethynyl) cyclopropyl) methoxy) methyl) -2-iodoaniline 5f

Compound 5e (2.45g, 5.7mmol) was dissolved in N, N-dimethylformamide (70mL) and N-bromosuccinimide (1.05g, 5.9mmol, Shanghai nationality drug) was added. Stirred at room temperature for 1 hour. Water (50mL) was added, and extraction was performed with ethyl acetate (50 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5f (2.8g, yield: 96.6%).

MS m/z(ESI):510.7[M+1]。

The fifth step

9 '-bromo-5' - (2, 6-dimethylpyridin-4-yl) -1',6' -dihydro-3 'H-spiro [ cyclopropane-1, 4' -oxepino [5,4,3-cd ] indole ]5g

Compound 5f (800mg, 1.6mmol) was dissolved in N, N-dimethylformamide (80mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (130mg, 0.16mmol, shanghai tatan), lithium chloride (70mg, 1.7mmol, shanghai national drug) and potassium carbonate (650mg, 4.7mmol, shanghai test) were added. The nitrogen was replaced three times. Stirring was carried out at 105 ℃ for 16 hours under nitrogen. Concentrated under reduced pressure, and extracted with water (60mL) and ethyl acetate (50 mL. times.4). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain 5g (530mg, yield: 88.4%) of the title product.

MS m/z(ESI):383.8[M+1]。

The sixth step

4- (5'- (2, 6-dimethylpyridin-4-yl) -1',6 '-dihydro-3' H-spiro [ cyclopropane-1, 4 '-oxepino [5,4,3-cd ] indol ] -9' -yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 5H

Compound 5g (530.0mg, 1.4mmol) and compound 1i (600mg, 1.9mmol, Shaoyuan technology) were dissolved in 1, 4-dioxane (8.0mL) and water (2.0 mL). Bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium dichloride (100mg, 0.14mmol, obtained from Shanghai Biao) and cesium carbonate (1.35g, 4.2mmol, Shaoshima science) were added. The nitrogen was replaced three times and the reaction was stirred at 80 ℃ for 16 hours under nitrogen protection. Water (20mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5h (620.0mg, yield: 92.3%).

MS m/z(ESI):486.0[M+1]。

Seventh step

4- (5'- (2, 6-dimethylpyridin-4-yl) -1',6 '-dihydro-3' H-spiro [ cyclopropane-1, 4 '-oxepino [5,4,3-cd ] indol ] -9' -yl) piperidine-1-carboxylic acid tert-butyl ester 5i

Compound 5h (620.0mg, 1.3mmol) was dissolved in methanol (20 mL). 10% palladium on carbon (300.0mg, water content < 1%, Shanghai Wolka) was added. The hydrogen was replaced three times. The reaction was stirred at room temperature under hydrogen for 16 hours. Suction filtration is carried out, 10% palladium carbon (300.0mg, water content is less than 1%, Shanghai Wolka) is added into the filtrate. The hydrogen was replaced three times. The reaction was stirred at room temperature under hydrogen for 16 hours. Suction was then carried out, and the filtrate was concentrated under reduced pressure to give the crude title product 5i (460.0mg, yield: 73.9%).

MS m/z(ESI):488.0[M+1]。

Eighth step

Crude compound 5i (50.0mg, 0.10mmol) was dissolved in dichloromethane (4.0mL) and trifluoroacetic acid (2.0 mL). The reaction was stirred at room temperature for 1.0 hour. Concentrated under reduced pressure and the residue dissolved in 7M ammonia/methanol (5.0 mL). Stir at room temperature for 10 minutes. Concentrated under reduced pressure and purified by high performance liquid chromatography (column: Boston Phlex Prep C185. mu.m 30 x 150 mM; mobile phase 1: water (containing 10mM ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: 10% -95%, flow rate: 30mL/min) to give the title product 5(20mg, yield: 50.3%). MS M/z (ESI) 388.2[ M +1 ].

¹H NMR(500MHz,CD₃OD)δ7.29(s,2H),7.25(d,1H),7.11(d,1H),5.39(s,2H),4.09(s,2H),3.37-3.34(m,2H),3.10-2.98(m,3H),2.58(s,6H),1.95-1.88(m,4H),0.92-0.89(m,2H),0.69-0.67(m,2H)。

Example 6

2- (4- (5'- (2, 6-dimethylpyridin-4-yl) -1',6 '-dihydro-3' H-spiro [ cyclopropane-1, 4 '-oxepino [5,4,3-cd ] indol ] -9' -yl) piperidin-1-yl) acetamide 6

Compound 5(352.0mg, 0.78mmol) and 2-bromoacetamide 6a (161.5mg, 1.2mmol) were dissolved in N, N-dimethylformamide (5mL) and cesium carbonate (1.3g, 3.9mmol, Shanghai Shao Yuan) was added. Stirred at room temperature for 2 hours. Water (10mL) was added and extraction was performed with ethyl acetate (30 mL). The organic phase was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: Welch Xitinate C18,5 μm,30 mM. about.150 mM; mobile phase 1: water (containing 10mM NH)₄HCO₃) (ii) a Mobile phase 2: acetonitrile; gradient for 18 minutes: 30% -95%, flow rate: 30mL/min) was separated and purified to give the title product 6(165.5mg, yield: 47.7%).

MS m/z(ESI):445.2[M+1]。

¹H NMR(500MHz,DMSO-d6)δ10.98(s,1H),7.22-7.13(m,5H),7.04(d,1H),5.20(s,2H),3.92(s,2H),2.92(d,2H),2.88(s,2H),2.72(t,1H),2.48(m,6H),2.22(t,2H),1.85-1.78(m,2H),1.62(d,2H),0.81(s,2H),0.54(s,2H)。

Example 7

6- (2, 6-dimethylpyridin-4-yl) -10- (piperidin-4-yl) -3,4,5, 7-tetrahydro-1H-oxa-octano [5,4,3-cd ] indole 7

First step of

5- (2, 6-Dimethylpyridin-4-yl) pent-4-yn-1-ol 7b

Pent-4-yn-1-ol 7a (1.0g, 11.9mmol, Pebamedicine), 4-bromo-2, 6-dimethylpyridine 5b (1.5g, 8.1mmol, Pebamedicine), bis (triphenylphosphine) palladium dichloride (565mg, 0.80mmol, carbofuran), cuprous iodide (160mg, 0.84mmol, Alfa Aesar) and N, N-diisopropylethylamine (4.0g, 30.9mmol, adamas) were dissolved in N, N-dimethylformamide (20 mL). Stirring at 90 ℃ for 1.5 hours under the protection of nitrogen. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 7B (1.35g, yield: 88.5%).

MS m/z(ESI):190.2[M+1]。

Second step of

4- (5- ((2-iodo-3-nitrobenzyl) oxy) pent-1-yn-1-yl) -2, 6-dimethylpyridine 7c

Sodium hydride (350mg, 8.75mmol, 60%, shanghaitant) was suspended in anhydrous tetrahydrofuran (20 mL). At 0 deg.C, compound 7b (900mg, 4.76mmol) was added and stirred at room temperature for 30 minutes. 1- (bromomethyl) -2-iodo-3-nitrobenzene 1d (1.5g, 4.39mmol) was added. The reaction was stirred at room temperature for 16 hours. Saturated aqueous ammonia chloride (50mL), ethyl acetate (50 mL. times.4) were added, the mixture was extracted, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7c (1.4g, yield: 70.9%).

MS m/z(ESI):451.0[M+1]。

The third step

3- (((5- (2, 6-dimethylpyridin-4-yl) pent-4-yn-1-yl) oxy) methyl) -2-iodoaniline 7d

Compound 7c (1.6g, 3.55mmol) was dissolved in ethanol (25mL) and water (5mL), and iron powder (1.5g, 26.9mmol, Shanghai medicine) and ammonium chloride (1.5g, 27.8mmol, Shanghai medicine) were added. The reaction was stirred at 80 ℃ for 2.0 hours. Concentrated under reduced pressure, extracted with ethyl acetate (50 mL. times.4), and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7d (1.2g, yield: 80.4%).

MS m/z(ESI):421.1[M+1]。

The fourth step

4-bromo-3- (((5- (2, 6-dimethylpyridin-4-yl) pent-4-yn-1-yl) oxy) methyl) -2-iodoaniline 7e

Compound 7d (1.2g, 2.86mmol) was dissolved in N, N-dimethylformamide (15mL) and N-bromosuccinimide (510mg, 5.87mmol, Shanghai nationality medicine) was added. Stirred at room temperature for 1 hour. Water (50mL) was added, and extraction was performed with ethyl acetate (50 mL. times.3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7e (1.7g, yield: 98.2%).

MS m/z(ESI):499.0[M+1]。

The fifth step

10-bromo-6- (2, 6-dimethylpyridin-4-yl) -3,4,5, 7-tetrahydro-1H-oxa-octa [5,4,3-cd ] indole 7f

Compound 7e (500mg, 1.0mmol) was dissolved in N, N-dimethylformamide (80mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (80mg, 0.098mmol, shanghai taitan), lithium chloride (50mg, 1.18mmol, shanghai national drug) and potassium carbonate (415mg, 3.0mmol, shanghai Hu test) were added. The nitrogen was replaced three times. Stirring was carried out at 105 ℃ for 16 hours under nitrogen. Concentrated under reduced pressure, and extracted with water (20mL) and ethyl acetate (20 mL. times.4). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7f (130mg, yield: 35%).

MS m/z(ESI):373.1[M+1]。

The sixth step

4- (6- (2, 6-dimethylpyridin-4-yl) -3,4,5, 7-tetrahydro-1H-oxaocta-lo [5,4,3-cd ] indol-10-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 7g

Compound 7f (130.0mg, 0.35mmol) and compound 1i (150mg, 0.49mmol, Shaoyou Tech) were dissolved in 1, 4-dioxane (4.0mL) and water (1.0 mL). Bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium dichloride (30mg, 0.042mmol, obtained from Shanghai) and cesium carbonate (345mg, 1.06mmol, Shaoshima science) were added. The nitrogen was replaced three times and the reaction was stirred at 80 ℃ for 16 hours under nitrogen protection. Water (10mL) was added, extraction was performed with ethyl acetate (15 mL. times.3), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain 7g of the title product (150.0mg, yield: 90.5%).

MS m/z(ESI):474.3[M+1]。

Seventh step

4- (6- (2, 6-dimethylpyridin-4-yl) -3,4,5, 7-tetrahydro-1H-oxaocta-cyclo [5,4,3-cd ] indol-10-yl) piperidine-1-carboxylic acid tert-butyl ester 7H

Compound 7g (250.0mg, 0.5mmol) was dissolved in methanol (20 mL). 10% palladium on carbon (200.0mg, water content < 1%, Shanghai Wolka) was added. The hydrogen was replaced three times. The reaction was stirred at room temperature under hydrogen for 16 hours. Suction filtration is carried out, 10% palladium carbon (200.0mg, water content is less than 1%, Shanghai Wolka) is added into the filtrate. The hydrogen was replaced three times. The reaction was stirred at room temperature under hydrogen for 16 hours. Suction filtration and concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title product 7h (150.0mg, yield: 59.7%).

MS m/z(ESI):476.0[M+1]。

Eighth step

Compound 7h (30.0mg, 0.063mmol) was dissolved in dichloromethane (3.0mL) and trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 1.0 hour. Concentrated under reduced pressure and the residue dissolved in 7M ammonia/methanol (5.0 mL). Stir at room temperature for 10 minutes. Concentrated under reduced pressure and purified by high performance liquid chromatography (column: Boston Phlex Prep C185. mu.m 30 x 150 mM; mobile phase 1: water (containing 10mM ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: 10% -95%, flow rate: 30mL/min) to give the title product 7(12mg, yield: 50.7%). MS M/z (ESI) 376.0[ M +1 ].

¹H NMR(500MHz,CD₃OD)δ7.37(d,1H),7.23(s,2H),7.19(d,1H),5.23(s,2H),3.83-3.81(m,2H),3.33-3.19(m,5H),2.85(m,2H),2.58(s,6H),2.00-1.96(m,2H),1.84-1.80(m,4H)。

Example 8

2- (4- (5- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1,3,4, 6-tetrahydroxepin-o [5,4,3-cd ] indol-9-yl) piperidin-1-yl) acetamide 8

First step of

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

The compound 6-bromo-7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridine 8a (500.0mg, 2.2mmol, prepared using the reference "preparation of intermediate F-4 on page 140 of WO2018005586a 1") and pinacol diboride diborate (842.5mg, 3.3mmol, shanghai shao) were dissolved in 1, 4-dioxane (10 mL). [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (161.7mg, 0.22mmol, Shanghai Tantan) and potassium acetate (650.3mg, 6.6mmol, Shanghai Hu test) were added. The nitrogen was replaced three times, and the reaction was stirred at 80 ℃ for 16 hours. Water (20mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phase was concentrated under reduced pressure to give crude compound 8b (1.3 g). The product was used in the next step without purification.

MS m/z(ESI):274.1[M+1]。

Second step of

4- (2- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -1,3,4, 6-tetrahydroxepin-o [5,4,3-cd ] indol-7-yl) piperidine-1-carboxylic acid tert-butyl ester 8c

The crude compound 1l (300.0mg, 0.7mmol) and compound 8b (613.8mg, 1.0mmol, 46% purity) were dissolved in 1, 4-dioxane (10mL) and water (2 mL). Dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (97.6mg, 0.14mmol, Shanghai Biao) and potassium phosphate (438.3mg, 2.1mmol, Beijing carbofuran) were added. The nitrogen gas was replaced three times, and the reaction was stirred at 90 ℃ for 12 hours. Water (10mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), concentration was performed under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product 8c (320.0mg, yield: 92.6%).

MS m/z(ESI):502.1[M+1]。

The third step

2- (7, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -7- (piperidin-4-yl) -1,3,4, 6-tetrahydroxepin-o [5,4,3-cd ] indole hydrochloride salt 8d

Compound 8c (320.0mg, 0.64mmol) was dissolved in methanol (2mL) and 4M hydrogen chloride/1, 4-dioxane solution (3mL) was added. Stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the title product 8d (280.0mg, yield: 100%).

MS m/z(ESI):402.1[M+1]。

The fourth step

Compound 8d (150.0mg, 0.34mmol) and 6a (70.9mg, 0.5mmol) were dissolved in N, N-dimethylformamide (5mL) and cesium carbonate (556.6g, 1.7mmol, Shanghai Shao Yuan) was added. Stirred at room temperature for 2 hours. Water (20mL) was added for dilution, and the mixture was filtered under reduced pressure. The obtained solid was purified by high performance liquid chromatography (column: Welch Xtimate C18,5 μm,30 mM. about.150 mM; mobile phase 1: water (containing 10mM NH)₄HCO₃) (ii) a Mobile phase 2: acetonitrile; gradient for 23 min: 20% -95%, flow rate: 30mL/min) was separated and purified to give the title product 8(37.8mg, yield: 24.1%).

MS m/z(ESI):459.1[M+1]。

¹H NMR(500MHz,DMSO-d6)δ11.17(s,1H),8.82(s,1H),8.46(s,1H),7.24(d,2H),7.14(s,1H),7.10(d,1H),5.16(s,2H),3.96(t,2H),2.92(d,2H),2.88(s,2H),2.83(s,2H),2.63(d,1H),2.58(s,3H),2.22(d,2H),2.19(s,3H),1.86-1.79(m,2H),1.65(d,2H)。

Biological evaluation

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

Test example 1: inhibition of human TLR7 activation pathway by disclosed compounds

First, experimental material and instrument

1.HEK-Blue^TMhTLR7 cell (Invivogen)

2. Racemote (R848/Resiquimod, Invivogen)

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

4. Blasticidin (Invivogen)

5. Bleomycin (Zeocin, Invivogen)

6. Neomycin (Normocin, Invivogen)

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

8. Fetal bovine serum (FBS, Gibco)

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

10. Sterile pure water (homemade Hengrui Shanghai)

11.15ml centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well Flat bottom cell culture plate (Corning)

14. Constant temperature cell culture box (Thermo scientific)

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

PHERAstar FS microplate reader (BMG Labtech)

Second, the experimental procedure

HEK-Blue was purchased from Invivogen^TMhTLR7 cell, which is characterized by that it utilizes human Toll-like receptor 7(TLR7) gene and secretory alkaline phosphatase reporter gene (SEAP) which is placed under the control of IFN-beta minimal promoter containing 5 NF-kB and AP-1 binding sites to cotransfect HEK293 cell, when the TLR7 is activated by agonist, the SEAP secretion can be induced by downstream NF-kB and AP-1, after the antagonist compound is added, the above-mentioned pathway can be inhibited, the SEAP secretion is reduced, and the OD620 can be measured by SEAP substrate so as to evaluate the activity of said compound on TLR7 pathway.

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

HEK-Blue^TMhTLR7 cells were cultured in DMEM high-glucose medium containing 10% inactivated FBS, 100. mu.g/mL neomycin, 10. mu.g/mL blasticidin and 100. mu.g/mL bleomycin. Collecting cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of 37 deg.C preheated PBS to wash the cells once, adding 2-5mL of preheated PBS to placeCulturing at 37 deg.C for 1-2 min, blowing off cells with a pipette, transferring cells to a 15mL centrifuge tube, counting cells, adjusting cell density to 4.8 × 10 with complete medium⁵and/mL. 160 μ L of the cell suspension after density adjustment was added to the above 96 well cell culture plate to give 76500 cells/well per well, R848 was 1 μ M at final concentration, and the test compounds were 10000, 2000, 400, 80, 16, 3.2, 0.64, and 0.128nM, respectively. The cells were incubated at 37 ℃ with 5% CO₂Culturing for 20 hours in an incubator, then taking 20 mu L of supernatant, adding 180 mu L of prepared Quanti-Blue, incubating for 120 minutes in a constant temperature box at 37 ℃ in the dark, and reading OD620 light absorption value by a microplate reader. The inhibition rate was calculated using the following formula: the inhibition rate is {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } × 100%, an inhibition curve is drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the concentration of the compound at which the inhibition rate reaches 50%, i.e., IC, is calculated₅₀The values are shown in Table 1.

Table 1 IC of compounds of the present disclosure by measurement of human TLR7 pathway₅₀Value of

Example numbering	IC₅₀(nM)
		1	37.8
2	124.2
		3	6.0
4	7.3
		5	72.3
6	111.1
		7	2.5
8	1.5

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

Test example 2: inhibition of human TLR8 activation pathway by disclosed compounds

First, experimental material and instrument

1.HEK-Blue^TMhTLR8 cell (Invivogen)

2. Racemote (R848/Resiquimod, Invivogen)

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

4. Blasticidin (Invivogen)

5. Bleomycin (Zeocin, Invivogen)

6. Neomycin (Normocin, Invivogen)

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

8. Fetal bovine serum (FBS, Gibco)

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

10. Sterile pure water (homemade Hengrui Shanghai)

11.15ml centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well Flat bottom cell culture plate (Corning)

14. Constant temperature cell culture box (Thermo scientific)

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

PHERAstar FS microplate reader (BMG Labtech)

Second, the experimental procedure

HEK-Blue was purchased from Invivogen^TMhTLR8 cell, which is characterized by that it utilizes human Toll-like receptor 8(TLR8) gene and secretory alkaline phosphatase reporter gene (SEAP) which is placed under the control of IFN-beta minimal promoter containing 5 NF-kB and AP-1 binding sites to cotransfect HEK293 cell, when the TLR8 is activated by agonist, the SEAP secretion can be induced by downstream NF-kB and AP-1, after the antagonist compound is added, the above-mentioned pathway can be inhibited, the SEAP secretion is reduced, and the OD620 can be measured by SEAP substrate so as to evaluate the activity of said compound on TLR8 pathway.

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

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

Table 2 IC of compounds of the present disclosure by measurement of human TLR8 pathway₅₀Value of

Example numbering	IC₅₀(nM)
		1	26.5
2	238.9
		3	44.3
4	26.3
		5	50.7
6	73.3
		7	3.7
8	1.5

And (4) conclusion: the disclosed compounds have inhibitory effects on the TLR8 pathway.

Test example 3: inhibition of human TLR9 activation pathway by disclosed compounds

First, experimental material and instrument

1.HEK-Blue^TMhTLR9 cell (Invivogen)

2.CpG ODN2006(Invivogen)

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

4. Blasticidin (Invivogen)

5. Bleomycin (Zeocin, Invivogen)

6. Neomycin (Normocin, Invivogen)

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

8. Fetal bovine serum (FBS, Gibco)

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

10. Sterile pure water (homemade Hengrui Shanghai)

11.15ml centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well Flat bottom cell culture plate (Corning)

14. Constant temperature cell culture box (Thermo scientific)

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

PHERAstar FS microplate reader (BMG Labtech)

Second, the experimental procedure

HEK-Blue was purchased from Invivogen^TMhTLR9 cell, which is formed by human Toll-like receptor 9(TLR9) gene and secretory alkaline phosphatase-containing reportGenes (SEAP) were co-transfected into HEK293 cells and alkaline phosphatase reporter genes (SEAP) under the control of an IFN- β minimal promoter containing 5 NF-kB and AP-1 binding sites, SEAP secretion was induced by downstream NF-kB and AP-1 when TLR9 was activated with agonist, the pathway was inhibited by addition of antagonist compounds, SEAP secretion was decreased, and OD620 was measured by SEAP substrate to assess the activity of compounds on the TLR9 pathway.

20mM test compound in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. mu.M in blank wells with 100% DMSO, and further diluted 20-fold in DMEM high-sugar medium (complete medium, the same below) containing 10% inactivated FBS. ODN2006 was diluted to 10 μ M with sterile water. To a 96-well cell culture plate, 20 μ L/well of 10 μ MODN2006 diluted in sterile water was added, and the above-described compound diluted in complete medium and 100% DMSO were added to wells containing ODN2006 at 20 μ L per well. Negative control wells were filled with 20. mu.L of sterile water and 20. mu.L of 100% DMSO diluted in complete medium.

HEK-Blue^TMhTLR9 cells were cultured in DMEM/high glucose medium containing 10% FBS, 100. mu.g/mL neomycin, 10. mu.g/mL blasticidin and 100. mu.g/mL bleomycin. Collecting cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 deg.C for washing cells once, adding 2-5mL of preheated PBS for culturing at 37 deg.C for 1-2 min, blowing off cells with a pipette, transferring cells to a 15mL centrifuge tube, counting cells, adjusting cell density to 4.8 × 10 with the whole medium⁵and/mL. 160. mu.L of the cell suspension after density adjustment was added to the above 96-well cell culture plate, the final cell count per well was 76500/well, the final ODN2006 concentration was 1. mu.M, and the final test compound concentrations were 10000, 2000, 400, 80, 16, 3.2, 0.64, and 0.128nM, respectively. The cells were incubated at 37 ℃ with 5% CO₂Culturing for 20 hours in an incubator, then taking 20 mu L of supernatant, adding 180 mu L of prepared Quanti-Blue, incubating for 15 minutes in a constant temperature box at 37 ℃ in the dark, and reading OD620 light absorption value by a microplate reader. The inhibition rate was calculated using the following formula: inhibition rate {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } × 100%, according to each compound, using Graphpad Prism softwareThe concentration and the corresponding inhibition rate are plotted to obtain an inhibition curve, and the concentration of the compound when the inhibition rate reaches 50 percent, namely IC is calculated₅₀The values are shown in Table 3.

Table 3 IC of compounds of the present disclosure by measurement of human TLR9 pathway₅₀Value of

Example numbering	IC₅₀(nM)
		1	64.3
2	34.6
		3	175.4
4	135.1

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

Claims

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

wherein:

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

L₁is selected from CH₂、CR^4aR^4bAnd C (O);

g is CR^2aOr an N atom;

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

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

L₃selected from the group consisting of a bond, alkylene, and heteroalkylene, wherein said alkylene and heteroalkylene are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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

R^6aand R^6bAre the same or different and are each independently selected from a hydrogen atom,Alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; or R^6aAnd R^6bTogether with the nitrogen atom to which they are attached form a heterocyclyl group, which heterocyclyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

u is 0, 1,2 or 3;

v is 0, 1,2 or 3;

n is 0 or 1;

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

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

m is 0, 1 or 2;

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

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

2. The compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, or non-enantiomer thereofEnantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L₂Selected from the group consisting of C (O), O atoms, S atoms, and NH; and/or R⁰Selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl and

ring C, L₃、R⁵And t is as defined in claim 1.

3. The compound of the general formula (I) according to claim 1 or2, wherein X is an O atom, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. A compound of general formula (I) according to any one of claims 1 to 3, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L₁Is CH₂。

5. A compound of general formula (I) according to any one of claims 1,3 and 4, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁰Selected from hydrogen atoms, C_1-6Alkyl, - (CH)₂)_rC(O)NR^6aR^6bAnd

ring C, L₃、R⁵、R^6a、R^6bR and t are as defined in claim 1; preferably, R⁰Is composed of

Ring C, L₃、R⁵And t is as defined in claim 1.

6. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, which is a compound of general formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, ring C, G, L₂、L₃、R¹To R³、R⁵P, s, t, n, u and v are as defined in claim 1.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

Most preferably, ring a is pyridyl.

9. A compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein 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 a 3 to 12 membered heterocyclic group containing at least one nitrogen atom; more preferably, ring B is piperidinyl.

10. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, which is a compound of general formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring C, R¹To R³、R⁵、R^2a、L₃S, t and v are as defined in claim 1.

11. A compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein 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 heterocyclic group containing at least one nitrogen atom or a 5 to 10 membered heteroaryl group containing at least one nitrogen atom; more preferably, ring C is piperidinyl or 5,6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R²Is a hydrogen atom.

13. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, which is a compound of general formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

t is 1,2, 3,4,5 or 6;

R¹、R³、R⁵、L₃s and v are as defined in claim 1.

14. The compound of general formula (I) according to any one of claims 1 to 13, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R¹Is a hydrogen atom or C_1-6An alkyl group.

15. The compound of general formula (I) according to any one of claims 1 to 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R³Is a hydrogen atom.

16. A compound of general formula (I) according to any one of claims 1 to 15, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L₃Is a bond.

17. The compound of general formula (I) according to any one of claims 1 to 16, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R⁵Is a hydrogen atom or C_1-6An alkyl group.

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

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

wherein:

R¹to R³、R^2aS and v are as defined in claim 10.

20. The compound of formula (IIIa) according to claim 19, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

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

wherein:

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

R¹、R²、R^2a、R³s and v are as defined in claim 10.

22. A compound, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

23. a process for preparing a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

method 1

Subjecting a compound of the general formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to a reductive amination reaction with a compound of the general formula (V) to obtain a compound of the general formula (III) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

or

Method 2

wherein:

L₃is a bond;

y is halogen; preferably, Y is chloro;

ring C, R¹To R³、R⁵、R^2aS, t and v are as defined in claim 10.

24. A process for preparing a compound of formula (IIIa), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

a compound of formula (IIIaa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereofWith salts, removing protecting groups R^WTo obtain a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

R^Wis an amino protecting group; preferably, R^WIs tert-butyloxycarbonyl;

R¹、R²、R^2a、R³s and v are as defined in claim 10.

25. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

26. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for the preparation of a medicament for inhibiting TLR7, TLR8, and TLR 9.

27. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for the manufacture of a medicament for inhibiting TLR7, TLR8, or TLR 9; preferably for the manufacture of a medicament for inhibiting TLR7 and TLR8, or for the manufacture of a medicament for inhibiting TLR7 and TLR 9.

28. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for the preparation of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases.

29. The use according to claim 28, wherein the inflammatory or autoimmune disease is selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and schungren's syndrome.