CN114075219B

CN114075219B - Quinoline condensed ring derivative, preparation method and medical application thereof

Info

Publication number: CN114075219B
Application number: CN202110931876.8A
Authority: CN
Inventors: 张晓敏; 王珏; 张静; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-08-14
Filing date: 2021-08-13
Publication date: 2023-11-14
Anticipated expiration: 2041-08-13
Also published as: CN114075219A

Abstract

The present disclosure relates to quinoline fused ring derivatives, methods of preparing the same, and their use in medicine. In particular, the present disclosure relates to quinoline fused ring derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and uses thereof as therapeutic agents, particularly as TLR7/8/9 inhibitors and in the preparation of drugs for the treatment and/or prevention of inflammatory and autoimmune diseases.

Description

Quinoline condensed ring derivative, preparation method and medical application thereof

Technical Field

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

Background

Toll-like receptors (Toll like receptors, TLR) are an evolutionarily conserved class of transmembrane innate immune receptors that are involved in the first line of defense in protecting human health and play an important role in the recognition of pathogen-associated molecular patterns (PAMPs) (Kawai, t., et al Nature immunol.,11,2010,373-384). TLRs are expressed in various immune cells and can be classified into two types according to the site of expression: TLR expressed in cell membrane (TLR 1/2/4/5/6) and TLR expressed in endosomal membrane (TLR 3/7/8/9) recognize different components and molecules in PAMPs, respectively. Wherein TLR7/8/9 is mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognizes ssRNA, and TLR9 mainly recognizes CpG-DNA. TLR7/8/9 binds its ligand and is activated, binds to the adaptor protein MyD88 in the cytoplasm, initiates NF- κb and IRF pathways, activates DC cells, and produces type I interferon and other various inflammatory cytokines. In B cells, TLR7/8/9, in combination with nucleic acids, plays an important role in the production of antinuclear antibodies by B cells, and type I interferons secreted by DC cells also promote further proliferation and activation of such autoimmune B cells, thereby eliciting a series of inflammatory responses.

Systemic Lupus Erythematosus (SLE) belongs to an autoimmune connective tissue disease, and three major classes of clinical first-line drugs for SLE are: hormones, immunosuppressants and antimalarial drugs. In this century, only a new drug belimumab was approved by the FDA, but it had modest and delayed efficacy in only a small proportion of SLE patients (Navarra, s.v., et al, lancet 2011,377,721), with very limited therapeutic options. Thus, there is an urgent need for new therapies that improve a greater proportion of patient populations and that can be used for long periods of time, safely. The phenomenon of significantly up-regulated expression of TLR7/9 and type I interferons was found in PBMC of patients with Systemic Lupus Erythematosus (SLE) (Beverly D.LC et al, mol immunol.,2014, 61:38-43). Mice overexpressing TLR7 have been reported to exacerbate autoimmune diseases and autoinflammation (Santiago-Raber ML, et al, J immunol.,2008, 181:1556-1562), whereas functional inhibition of TLR7/9 can alleviate B6-Fas ^lpr And pathological manifestations of lupus mice such as BXSB (Dlight H.Kono, et al, PNAS,2009,106 (29): 12061-12066). Given the close relationship of TLR7/8/9 to antinuclear antibodies and type I interferons, small molecule inhibitors targeting TLR7/8/9 are likely to have potential for treating SLE.

Published patent applications for inhibitors of TLR7/8/9 include WO2019233941A1, WO 2020020800A 1, WO 2018049089A 1, WO 2017106607A 1, CN109923108A, WO 2020048605A 1 and the like.

Disclosure of Invention

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

wherein:

z is selected from the group consisting of O atom, S atom and NH;

L ¹ is a bond or is selected from C (R ^a R ^b ) And (C (R) ^a R ^b )) _k C(O)；

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

R ⁰ selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, -NR ^c R ^d 、-NHC(R ^e R ^f ) _s C(O)R ¹⁰ 、-NHC(R ^e R ^f ) _s C(O)NR ^c R ^d Nitro, hydroxy, hydroxyalkyl and

L ² is a bond or is selected from alkylene and heteroalkylene, wherein each of the alkylene and heteroalkylene is independently optionally substituted with one or more substituents selected from halogen, oxo, 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;

R ^1a 、R ^1b and each R ¹ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R is ² The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

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

each R is ⁴ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR ^x R ^y Nitro, hydroxy and hydroxyalkyl;

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

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

R ⁹ and R is ¹⁰ And are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with a moiety selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -NR ⁷ R ⁸ One or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R ^c 、R ^d 、R ^x 、R ^y 、R ⁷ and R is ⁸ The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R is ^c And R is ^d 、R ^x And R is ^y 、R ⁷ And R is ⁸ Together with the attached N atom, form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a 、R ^b 、R ^e And R is ^f The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

r is 0, 1, 2 or 3;

k is 0 or 1;

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

n is 0, 1 or 2;

v is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4; and is also provided with

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

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

Z is selected from the group consisting of O atom, S atom and NH;

L ¹ selected from chemical bonds, C (R) ^a R ^b ) And (C (R) ^a R ^b )) _k C(O)；

R ^a And R is ^b The same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

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

R ⁰ selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuteroalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and

L ² Selected from the group consisting of a bond, an alkylene group, and a heteroalkylene group, wherein each of the alkylene and heteroalkylene groups is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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

each R is ⁴ Identical or different and are each independently selected from hydrogen, halogen, alkyl, alkene Alkyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

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

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

R ⁹ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

r is 0, 1, 2 or 3;

k is 0 or 1;

n is 0, 1 or 2;

v is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4; and is also provided with

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

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, halogenated C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ 、-NH(C(R ^e R ^f )) _s C(O)NR ^c R ^d 、-NH(C(R ^e R ^f )) _s NR ^c R ^d Andpreferably, R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ And->Ring B, L ² 、R ⁵ 、R ¹⁰ 、R ^c 、R ^d 、R ^e 、R ^f S and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, halogenated C _1-6 Alkyl groupRing B, L ² 、R ⁵ And t is as defined in formula (I).

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

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

wherein:

ring a, ring B, L ¹ 、R ^1a 、R ^1b 、R ¹ To R ⁵ R, n, v, m, p, q and t are defined in general formula (I).

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

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

wherein:

R ^3a and R is ^3b Identical or different and are each independently selected from the group consisting of hydrogen atoms,Halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

ring A, L ¹ 、R ⁰ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ R, n, v, m and q are as defined in formula (I).

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

wherein:

R ⁰ selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

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

ring A is a 4-to 12-membered heterocyclic group containing at least 1N atom orW ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom;

ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom;

L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ r, n, v, m and q are as defined in formula (I).

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, is a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

Ring B is a 4 to 12 membered heterocyclyl containing at least one N atom;

R ^5a selected from the group consisting of hydrogen atoms, alkyl groups, heteroalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclyl groups;

t is 1, 2, 3 or 4;

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ 、R ⁵ R, n, v, m and q are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring a is a 3 to 12 membered cycloalkyl;

L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ 、R ^d r, n, v, m and q are as defined in formula (I).

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

Wherein:

ring A, R ⁰ 、L ¹ 、R ^3a 、R ^3b 、R ⁴ R and q are as defined in formula (IIIG).

Ext> inext> someext> preferredext> embodimentsext> ofext> theext> presentext> disclosureext>,ext> theext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> VGext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> isext> aext> compoundext> ofext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>:ext>

Wherein:

R ^3a selected from halogen, alkyl, alkoxy, haloAlkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R ^3b selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

r is 1;

ring A, R ⁰ 、L ¹ 、R ⁴ And q is as defined in formula (VG).

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

Wherein:

R ^3a selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

r is 1;

ring A, R ⁰ 、L ¹ 、R ⁴ And q is as defined in formula (VG).

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

wherein:

ring a, ring B, L ¹ 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ 、R ^5a R, q and t are as defined in formula (IV).

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

Wherein:

r is 1;

ring a, ring B, L ¹ 、R ⁴ 、R ⁵ 、R ^5a Q and t are as defined in formula (V).

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

wherein:

r is 1;

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III) or formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, L ¹ 、R ^3a 、R ^3b 、R ⁴ 、R ^d R and q are as defined in formula (IV-2).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III), formula (IV-2) or formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V-2-A), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

r is 1;

ring A, L ¹ 、R ⁴ 、R ^d And q is as defined in formula (V-2).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III), formula (IV-2) or formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

r is 1;

ring A, L ¹ 、R ⁴ 、R ^d And q is as defined in formula (V-2).

Ext> inext> someext> preferredext> embodimentsext> ofext> theext> presentext> disclosureext>,ext> theext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext> orext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> whereinext> Lext> ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)。

In some preferred embodiments of the present disclosure, the compound of formulSup>A (I), formulSup>A (II), formulSup>A (III), formulSup>A (IV), formulSup>A (V-Sup>A), formulSup>A (V-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein ring Sup>A is selected from the group consisting of 3-to 12-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring A is selected from 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclyl,Phenyl and 5 to 6 membered heteroaryl; w (W) ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom; more preferably, ring A is selected from phenyl, pyridyl, -/-> R ⁴ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected fromFrom 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6-10 membered aryl and 5 to 10 membered heteroaryl; preferably, ring A is selected from 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclyl, Phenyl and 5 to 6 membered heteroaryl; w (W) ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom; more preferably, ring A is selected from phenyl, pyridyl, -/->R ⁴ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of 3-to 12-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring A is a 4 to 12 membered heterocyclyl orW ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1 nitrogen atom; more preferably, ring A is selected from phenyl, pyridyl, -/->R ⁴ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (IIIG) or formula (VG), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4 to 12 membered heterocompound containing at least 1N atom Cyclic or cyclic groupsW ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom; preferably, ring A is selected from->R ⁴ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (IV-2), formula (V-2-a), formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 3-to 12-membered cycloalkyl; preferably, ring a is a 3 to 8 membered cycloalkyl; more preferably, ring A is

In some preferred embodiments of the present disclosure, the compound of formula (IV-2) or formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 3-to 12-membered cycloalkyl; preferably, ring A is

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 B is a 4-to 12-membered heterocyclyl; preferably a 4 to 6 membered heterocyclyl; more preferably piperazinyl.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (IV), formulSup>A (V-Sup>A) or formulSup>A (V-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein ring B is Sup>A 4 to 12 membered heterocyclyl containing at least one N atom; preferably, ring B is a 4 to 6 membered heterocyclyl containing at least one N atom; more preferably, ring B is piperazinyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IIIG), formula (IV) or formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1a Is cyano; and R is ¹ Is a hydrogen atom.

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 each R ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably, R ³ Is a hydrogen atom or C _1-6 An alkyl group.

Ext> inext> someext> preferredext> embodimentsext> ofext> theext> presentext> disclosureext>,ext> theext> compoundext> ofext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext> orext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> whereinext> Rext> ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; or R is ^3a Is a hydrogen atom, and R ^3b Is C _1-6 An alkyl group; preferably, R ^3a Is methyl or ethyl, and R ^3b Is a hydrogen atom.

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

Ext> inext> someext> preferredext> embodimentsext> ofext> theext> presentext> disclosureext>,ext> theext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext> orext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> whereinext> eachext> Rext> ⁴ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably, R ⁴ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (I), formulSup>A (II), formulSup>A (III), formulSup>A (IV), formulSup>A (V-A) or formulSup>A (V-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein R ^5a And each R ⁵ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group.

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

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

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

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

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

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 t is 0, 1 or 2.

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

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IIIG), formula (IV) or formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1b Is a hydrogen atom.

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

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, halogenated C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ 、-NH(C(R ^e R ^f )) _s C(O)NR ^c R ^d 、-NH(C(R ^e R ^f )) _s NR ^c R ^d AndR ^c and R is ^d Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl, or R ^c And R is ^d Together with the attached N atom, form a 4-to 12-membered heterocyclic group, said 4-to 12-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; r is R ^e And R is ^f All are hydrogen atoms; r is R ¹⁰ Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, wherein said C _1-6 Alkyl and 3-to 12-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy, C _1-6 Hydroxyalkyl, -NR ⁷ R ⁸ One or more substituents of 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl; r is R ⁷ And R is ⁸ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl groupAnd 3 to 12 membered heterocyclyl, or R ⁷ And R is ⁸ Together with the attached N atom, form a 4-to 12-membered heterocyclic group, said 4-to 12-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; s is 0, 1, 2 or 3; ring B, L ² 、R ⁵ And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, halogenated C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ 、-NH(C(R ^e R ^f )) _s C(O)NR ^c R ^d 、-NH(C(R ^e R ^f )) _s NR ^c R ^d AndR ^c and R is ^d Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, or R ^c And R is ^d Together with the attached N atom, form a 4-to 12-membered heterocyclic group, said 4-to 12-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; r is R ^e And R is ^f All are hydrogen atoms; r is R ¹⁰ Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, wherein said C _1-6 Alkyl and 3-to 12-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyanoRadicals, amino radicals, nitro radicals, hydroxy radicals, C _1-6 Hydroxyalkyl, -NR ⁷ R ⁸ One or more substituents of 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl; r is R ⁷ And R is ⁸ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, or R ⁷ And R is ⁸ Together with the attached N atom, form a 4-to 12-membered heterocyclic group, said 4-to 12-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; s is 0, 1, 2 or 3; ring B, L ² 、R ⁵ And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from-NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ 、-NH(C(R ^e R ^f )) _s C(O)NR ^c R ^d 、-NH(C(R ^e R ^f )) _s NR ^c R ^d AndR ^c and R is ^d Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, or R ^c And R is ^d Together with the attached N atom, form a 4-to 12-membered heterocyclic group, said 4-to 12-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; r is R ^e And R is ^f All are hydrogen atoms; r is R ¹⁰ Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, wherein theC of (2) _1-6 Alkyl and 3-to 12-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy, C _1-6 Hydroxyalkyl, -NR ⁷ R ⁸ One or more substituents of 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl; r is R ⁷ And R is ⁸ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl, or R ⁷ And R is ⁸ Together with the attached N atom, form a 4-to 12-membered heterocyclic group, said 4-to 12-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; s is 0, 1, 2 or 3; ring B, L ² 、R ⁵ And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (IV-2), formula (V-2-A) or formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^d Selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl.

In some preferred embodiments of the present disclosure, the compound of formula (IV-2) or formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^d Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (V), formulSup>A (V-A) or formulSup>A (V-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein t is 1, or t is 2 and R ⁵ Is C _1-6 Alkyl or halo C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ AndR ^c and R is ^d Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl, or R ^c And R is ^d Together with the attached N atom, form a 4 to 12 membered heterocyclyl; r is R ^e And R is ^f All are hydrogen atoms; r is R ¹⁰ Is a hydrogen atom or C _1-6 Alkyl, wherein said C _1-6 Alkyl groups are each independently optionally substituted with-NR ⁷ R ⁸ Substituted; r is R ⁷ And R is ⁸ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl; s is 0, 1, 2 or 3; ring B is a 4 to 6 membered heterocyclyl; l (L) ² Is a chemical bond; each R is ⁵ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; t is 0, 1 or 2; ring A is selected from 3-to 12-membered cycloalkyl, 4-to 12-membered heterocyclyl,/i>Phenyl and 5 to 6 membered heteroaryl; w (W) ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom; r is R ^1a Is cyano; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; v is 0; m is 0; n is 0; r is 1; qIs 0.

In some preferred embodiments of the present disclosure, the compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ AndR ^c and R is ^d Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ^e And R is ^f All are hydrogen atoms; r is R ¹⁰ Is a hydrogen atom or C _1-6 Alkyl, wherein said C _1-6 Alkyl groups are each independently optionally substituted with-NR ⁷ R ⁸ Substituted; r is R ⁷ And R is ⁸ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl; s is 0, 1, 2 or 3; ring B is a 4 to 6 membered heterocyclyl; l (L) ² Is a chemical bond; each R is ⁵ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; t is 0, 1 or 2; ring A is selected from 3-to 12-membered cycloalkyl, 4-to 12-membered heterocyclyl,/i>Phenyl and 5 to 6 membered heteroaryl; w (W) ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom; r is R ^1a Is cyano; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; v is 0; m is 0; n is 0; r is 1; q is 0.

Ext> inext> someext> preferredext> embodimentsext> ofext> theext> presentext> disclosureext>,ext> theext> compoundext> ofext> formulaext> (ext> VGext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext> orext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext> thereofext>A diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4 to 12 membered heterocyclyl group containing at least 1N atom or W ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom; r is R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (VG), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from ring AR ⁰ Selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formulSup>A (V), formulSup>A (V-A) or formulSup>A (V-B), or Sup>A tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or Sup>A pharmaceutically acceptable salt thereof, wherein ring A is selected from 3-to 12-membered cycloalkyl, 4-to 12-membered heterocyclyl,Phenyl and 5 to 6 membered heteroaryl; w (W) ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is at least containingA 4 to 6 membered heterocyclyl of 1N atom; ring B is a 4 to 6 membered heterocyclyl containing at least one N atom; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; the method comprises the steps of carrying out a first treatment on the surface of the R is R ^5a Selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; t is 1, or t is 2 and R ⁵ Is C _1-6 Alkyl or halo C _1-6 An alkyl group; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl, andring B is piperazinyl; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; the method comprises the steps of carrying out a first treatment on the surface of the R is R ^5a Selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; t is 1, or t is 2 and R ⁵ Is C _1-6 Alkyl or halo C _1-6 An alkyl group; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 3-to 12-membered cycloalkyl; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is R ^d Selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ringA is a 3-to 12-membered cycloalkyl group; l (L) ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is R ^d Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-2), formula (V-2-A) or formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A isL ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is R ^d Selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-2), formula (V-2-A) or formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is L ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is R ^d Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl; r is 1; q is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A isL ¹ Is a chemical bond or is selected from CH ₂ C (O) and CH ₂ C(O)；R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; r is R ^d Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 12 membered heterocyclyl; r is 1; q 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 (IIIGA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

wherein:

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

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ R, n, v, m and q are as defined in formula (IIIG).

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

Wherein:

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

ring B is a 4 to 12 membered heterocyclyl containing at least one N atom;

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ R, n, v, m, q and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a compound of formula (IV-2A), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

wherein:

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

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ 、R ^d R, n, v, m and q are as defined in formula (IV-2).

In another aspect of the present disclosure, a compound of formula (VGA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

wherein:

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

ring A, L ¹ 、R ^3a 、R ^3b 、R ⁴ R and q are as defined in formula (VG).

In another aspect of the present disclosure, a compound of formula (VA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

wherein:

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

ring a, ring B, L ¹ 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ R, q and t are as defined in formula (V).

In another aspect the present disclosure relates to a compound of formula (V-2A), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

wherein:

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

ring A, L ¹ 、R ^3a 、R ^3b 、R ⁴ 、R ^d R and q are as defined in the general formula (V-2).

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

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

removing protecting group R from a compound of formula (IIIGA) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof ^W Optionally further with alkylating agent R ⁰ X or formaldehyde solution to give a compound of formula (IIIG) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

x is a leaving group; preferably halogen;

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

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

removing protecting group R from a compound of formula (IVA) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof ^W Optionally further with alkylating agent R ^5a X or formaldehyde solution to give a compound of the general formula (IV) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

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

R ^5a selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

ring a, ring B, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ R, n, v, m, q and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

Removing protecting group R from a compound of formula (IV-2A) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof ^W Obtaining a compound of formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

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

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

removing protecting groups R from compounds of the general formula (VGA) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or salts thereof ^W Optionally further with alkylating agent R ⁰ X or formaldehyde solution to give a compound of formula (VG) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

x is a leaving group; preferably halogen;

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

ring A, L ¹ 、R ^3a 、R ^3b 、R ⁴ R and q are as defined in formula (VG).

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

removing protecting groups R from compounds of the general formula (VA) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or salts thereof ^W Optionally further with alkylating agent R ^5a X or formaldehyde solution to give a compound of the general formula (V) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

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

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

Removing protecting group R from a compound of formula (V-2A) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof ^W Obtaining a compound of formula (V-2) or a tautomer thereof

In the form of a body, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

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

Ext> anotherext> aspectext> ofext> theext> presentext> disclosureext> relatesext> toext> aext> methodext> forext> preparingext> aext> compoundext> ofext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> comprisingext>:ext>

Ext> aext> compoundext> ofext> theext> generalext> formulaext> (ext> VGext>)ext> orext> aext> tautomerext>,ext> aext> racemateext>,ext> anext> enantiomerext>,ext> aext> diastereomerext> orext> aext> mixtureext> thereofext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> resolvingext> toext> obtainext> aext> compoundext> ofext> theext> generalext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> aext> compoundext> ofext> theext> generalext> formulaext> (ext> VGext> -ext> Bext>)ext> orext> aext> tautomerext>,ext> aext> racemateext>,ext> anext> enantiomerext>,ext> aext> diastereomerext> orext> aext> mixtureext> thereofext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext>

Wherein:

R ^3b Selected from hydrogen atoms, halogen, alkyl groups, alkoxy groupsHaloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

r is 1;

ring A, R ⁰ 、L ¹ 、R ⁴ And q is as defined in formula (VG).

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

Sup>A compound of the general formulSup>A (V) or Sup>A tautomer, racemate, enantiomer, diastereomer or Sup>A mixture thereof or Sup>A pharmaceutically acceptable salt thereof, resolving to obtain Sup>A compound of the general formulSup>A (V-A), sup>A compound of the general formulSup>A (V-B) or Sup>A tautomer, racemate, enantiomer, diastereomer or Sup>A mixture thereof or Sup>A pharmaceutically acceptable salt thereof,

wherein:

r is 1;

Another aspect of the present disclosure relates to a method for preparing a compound of formula (V-2-a), formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

a compound of the general formula (V-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to give a compound of the general formula (V-2-A), general formula (V-2-B) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

r is 1;

ring A, L ¹ 、R ⁴ 、R ^d And q is as defined in formula (V-2).

Ext> anotherext> aspectext> ofext> theext> presentext> disclosureext> relatesext> toext> aext> pharmaceuticalext> compositionext> comprisingext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> formext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> andext> oneext> orext> moreext> pharmaceuticallyext> acceptableext> carriersext>,ext> diluentsext>,ext> orext> excipientsext>.ext>

Ext> theext> disclosureext> furtherext> relatesext> toext> theext> useext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>,ext> inext> theext> manufactureext> ofext> aext> medicamentext> forext> inhibitingext> tlrext> 7ext> andext> /ext> orext> tlrext> 8ext> andext> /ext> orext> tlrext> 9ext>.ext>

Ext> theext> disclosureext> furtherext> relatesext> toext> theext> useext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>,ext> inext> theext> manufactureext> ofext> aext> medicamentext> forext> inhibitingext> tlrext> 7ext>,ext> tlrext> 8ext>,ext> andext> tlrext> 9ext>.ext>

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> theext> useext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>,ext> inext> theext> manufactureext> ofext> aext> medicamentext> forext> inhibitingext> tlrext> 7ext>,ext> tlrext> 8ext>,ext> orext> tlrext> 9ext>;ext> Preferably in the manufacture of a medicament for inhibiting TLR7 and TLR8, or in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> theext> useext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> formext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>,ext> forext> theext> manufactureext> ofext> aext> medicamentext> forext> theext> treatmentext> andext> /ext> orext> preventionext> ofext> anext> inflammatoryext> orext> autoimmuneext> diseaseext>.ext> Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> aext> methodext> ofext> inhibitingext> TLRext> 7ext> andext> /ext> orext> TLRext> 8ext> andext> /ext> orext> TLRext> 9ext> comprisingext> administeringext> toext> aext> patientext> inext> needext> thereofext> anext> effectiveext> inhibitingext> amountext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> formext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>.ext>

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> aext> methodext> ofext> inhibitingext> TLRext> 7ext>,ext> TLRext> 8ext> andext> TLRext> 9ext> comprisingext> administeringext> toext> aext> patientext> inext> needext> thereofext> anext> effectiveext> inhibitingext> amountext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>.ext>

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> aext> methodext> ofext> inhibitingext> TLRext> 7ext>,ext> TLRext> 8ext> orext> TLRext> 9ext>,ext> preferablyext> aext> methodext> ofext> inhibitingext> TLRext> 7ext> andext> TLRext> 8ext>,ext> orext> aext> methodext> ofext> inhibitingext> TLRext> 7ext> andext> TLRext> 9ext>,ext> comprisingext> administeringext> toext> aext> patientext> inext> needext> thereofext> anext> effectiveext> inhibitingext> amountext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>.ext>

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> aext> methodext> ofext> treatingext> andext> /ext> orext> preventingext> anext> inflammatoryext> orext> autoimmuneext> diseaseext> comprisingext> administeringext> toext> aext> patientext> inext> needext> thereofext> aext> therapeuticallyext> effectiveext> amountext> ofext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> formext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> pharmaceuticalext> compositionext> comprisingext> theext> sameext>.ext> Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

Ext> theext> disclosureext> furtherext> relatesext> toext> aext> pharmaceuticalext> compositionext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext> andext> aext> compoundext> shownext> inext> Tableext> Aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> formext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> compositionext> comprisingext> theext> sameext>,ext> forext> useext> asext> aext> medicamentext>.ext>

Ext> theext> disclosureext> furtherext> relatesext> toext> pharmaceuticalext> compositionsext> comprisingext> aext> compoundext> shownext> inext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> tlrext> 7ext> andext> /ext> orext> tlrext> 8ext> andext> /ext> orext> tlrext> 9ext>.ext>

Ext> theext> disclosureext> furtherext> relatesext> toext> aext> pharmaceuticalext> compositionext> comprisingext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> compositionext> comprisingext> theext> sameext>,ext> forext> inhibitingext> tlrext> 7ext>,ext> tlrext> 8ext>,ext> andext> tlrext> 9ext>.ext>

Ext> theext> disclosureext> furtherext> relatesext> toext> aext> pharmaceuticalext> compositionext> comprisingext> aext> compoundext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> tlrext> 9ext>,ext> forext> inhibitingext> tlrext> 7ext>,ext> tlrext> 8ext>,ext> orext> tlrext> 9ext>;ext> Preferably for inhibiting TLR7 and TLR8, or for inhibiting TLR7 and TLR9.

Ext> theext> presentext> disclosureext> furtherext> relatesext> toext> aext> pharmaceuticalext> compositionext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext> andext> aext> compoundext> shownext> inext> Tableext> Aext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> formext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> orext> aext> compositionext> comprisingext> theext> sameext>,ext> forext> useext> inext> theext> treatmentext> andext> /ext> orext> preventionext> ofext> inflammatoryext> orext> autoimmuneext> diseasesext>.ext> Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

Ext> inext> viewext> ofext> theirext> activityext> asext> selectiveext> inhibitorsext> ofext> TLRext> 7ext> orext> TLRext> 9ext>,ext> compoundsext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> bext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> aext>)ext>,ext> formulaext> (ext> vext> -ext> 2ext> -ext> bext>)ext>,ext> andext> tableext> aext> areext> usefulext> forext> treatingext> TLRext> 7ext> orext> TLRext> 9ext> familyext> receptorext> relatedext> diseasesext>,ext> respectivelyext>,ext> includingext>,ext> butext> notext> limitedext> toext>:ext> Inflammatory diseases (such as crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease); autoimmune diseases (such as graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis); autoinflammatory diseases (including cyclic syndrome associated with Cryopyrin (CAPS), cyclic syndrome associated with TNF Receptors (TRAPS), familial Mediterranean Fever (FMF), adult stele disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis); metabolic diseases (including type 2 diabetes, atherosclerosis, myocardial infarction); destructive bone disorders (such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders); proliferative disorders (such as acute myelogenous leukemia, chronic myelogenous leukemia); angiogenic disorders (such as those including solid tumors, ocular neovascularization, and infantile hemangiomas); infectious diseases (such as sepsis, septic shock, and shigellosis); neurodegenerative diseases (such as Alzheimer's disease, parkinson's disease, cerebral ischemia caused by traumatic injury or neurodegenerative diseases), neoplastic diseases (such as metastatic melanoma, kaposi's sarcoma, multiple myeloma) and viral diseases (such as HIV infection, CMV retinitis, AIDS).

More specifically, specific conditions or diseases that may be treated with the compounds of the present disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythema, scleroderma, chronic thyroiditis, graves 'disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, reiter's syndrome (Reiter's syndrome), gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; cerebral ischemia or neurodegenerative diseases caused by Alzheimer's disease, parkinson's disease, traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases including acute hepatitis infection (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; ischemia in stroke, myocardial ischemia, heart attack, organ hypoxia, vascular proliferation, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. In preferred methods of treatment, the condition is selected from the group consisting of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred methods of treatment are those in which the condition is ischemia reperfusion injury, including cerebral ischemia reperfusion injury caused by stroke and myocardial ischemia reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the condition is multiple myeloma.

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

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

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

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

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

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

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

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

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

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

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

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

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

Description of the terms

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

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

The term "heteroalkyl" refers to one or more-CH's in an alkyl group ₂ Is selected from N, O, S, S (O) and S (O) ₂ Is replaced by a heteroatom of (2); wherein said alkyl is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any useful point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

The term "heteroalkylene" refers to one or more-CH's in an alkylene group ₂ -is selected from nitrogen, oxygen, sulfur, S (O) and S (O) ₂ Is replaced by a heteroatom of (2); wherein the alkylene is as defined above; the heteroalkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl groups), more preferably alkynyl groups containing 2 to 6 carbon atoms (i.e. C _2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

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

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

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

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

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

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1-3 is a heteroatom (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, 1-3 of which are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen and sulfur _: Optionally oxo (i.e. forming a sulfoxide or sulfone) and the remaining ring atoms are carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. More preferably 3/5, 3/6, 4/4, 4/5, 4/6, 5/5, 5/6 or 6/6 unitA spiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

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

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

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

etc.

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

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

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

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

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

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

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

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

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

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

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

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

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

The term "carbonyl" refers to c=o.

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

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

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

Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, with the structures of the present disclosure, replacement of hydrogen with "deuterium" or "tritium", or with ¹⁸ F-fluorine labeling [ ] ¹⁸ F isotope) instead of fluorine, or with ¹¹ C-、 ¹³ C-or ¹⁴ C-enriched carbon ¹¹ C-、 ¹³ C-or ¹⁴ C-carbon labeling; ¹¹ C-、 ¹³ c-or ¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Ext> whereinext> eachext> availableext> hydrogenext> atomext> ofext> deuteratedext> formsext> ofext> compoundsext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext> andext> Tableext> Aext> forext> attachmentext> toext> aext> carbonext> atomext> mayext> independentlyext> beext> replacedext> byext> aext> deuteriumext> atomext>.ext> Ext> thoseext> skilledext> inext> theext> artext> areext> ableext> toext> synthesizeext> deuteratedext> formsext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext> andext> theext> compoundsext> ofext> Tableext> Aext> withext> referenceext> toext> theext> relevantext> literatureext>.ext> Ext> inext> preparingext> deuteratedext> formsext> ofext> formulaext> (ext> Iext>)ext>,ext> formulaext> (ext> IIext>)ext>,ext> formulaext> (ext> IIIext>)ext>,ext> formulaext> (ext> IIIGext>)ext>,ext> formulaext> (ext> IVext> -ext> 2ext>)ext>,ext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> formulaext> (ext> VGext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> Bext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Aext>)ext>,ext> formulaext> (ext> Vext> -ext> 2ext> -ext> Bext>)ext> andext> theext> compoundsext> ofext> Tableext> Aext>,ext> commerciallyext> availableext> deuteratedext> startingext> materialsext> mayext> beext> usedext>,ext> orext> theyext> mayext> beext> synthesizedext> usingext> conventionalext> techniquesext> withext> deuteratedext> reagentsext>,ext> includingext> butext> notext> limitedext> toext> Not limited to deuterated borane, trideutero borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations.

Where the compounds of the present disclosure contain two or more chiral centers, the relative stereochemistry of these compounds is identified by NMR studies and/or X-ray diffraction. In these cases, the prefix "rel" is used, followed by the identification of these compounds using R/S nomenclature, where R/S provides only relative stereochemical information (e.g., cis or trans), and does not represent absolute stereochemistry.

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

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

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

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

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

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

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

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

Methods of synthesizing compounds of the present disclosure

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

scheme one

A process for preparing a compound of formula (IIIG) of the disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the process comprising:

the protecting group R is removed under acidic conditions by a compound of the general formula (IIIGA) or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a salt thereof ^W Optionally further with alkylating agent R ⁰ X or formaldehyde solution to give a compound of formula (IIIG) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

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

Scheme II

A process for the preparation of a compound of formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

The compound of formula (IVA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, deprotected under acidic conditions to remove protecting group R ^W Optionally further with alkylating agent R ^5a X or formaldehyde solution to give a compound of the general formula (IV) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

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

Scheme III

A process for the preparation of a compound of formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

the protecting group R is removed under acidic conditions by a compound of the general formula (IV-2A) or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a salt thereof ^W Obtaining a compound of formula (IV-2) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

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

Scheme IV

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

a compound of the general formula (VGA) or a tautomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a salt thereof, deprotected under acidic conditions to give a protecting group R ^W Optionally further with alkylating agent R ⁰ X or formaldehyde solution to give a compound of formula (VG) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

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

ring A, L ¹ 、R ^3a 、R ^3b 、R ⁴ R and q are as defined in formula (VG).

Scheme five

A process for the preparation of a compound of formula (V) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

The compound of formula (VA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, deprotected under acidic conditions to remove protecting group R ^W Optionally further with alkylating agent R ^5a X or formaldehyde solution to give a compound of the general formula (V) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a leaving group; preferably halogen;

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

Scheme six

A process for the preparation of a compound of formula (V-2) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises:

the protecting group R is removed under acidic conditions by a compound of the general formula (V-2A) or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a salt thereof ^W Obtaining a compound of the general formula (V-2)

Or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

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

Scheme seven

Ext> aext> processext> forext> theext> preparationext> ofext> aext> compoundext> ofext> formulaext> (ext> VGext> -ext> aext>)ext>,ext> formulaext> (ext> VGext> -ext> bext>)ext>,ext> orext> aext> tautomerext>,ext> racemateext>,ext> enantiomerext>,ext> diastereomerext>,ext> orext> mixtureext> thereofext>,ext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext> accordingext> toext> theext> presentext> disclosureext>,ext> whichext> comprisesext>:ext>

Ext> chiralext> preparationext> andext> resolutionext> areext> carriedext> outext> onext> theext> compoundext> ofext> theext> generalext> formulaext> (ext> VGext>)ext> orext> aext> tautomerext>,ext> aext> racemateext>,ext> anext> enantiomerext>,ext> aext> diastereoisomerext> orext> aext> mixtureext> formext> orext> aext> pharmaceuticallyext> acceptableext> saltext> thereofext> toext> obtainext> theext> compoundext> ofext> theext> generalext> formulaext> (ext> VGext> -ext> Aext>)ext>,ext> theext> generalext> formulaext> (ext> VGext> -ext> Bext>)ext> orext> theext> tautomerext>,ext> theext> racemateext>,ext> theext> enantiomerext>,ext> theext> diastereoisomerext> orext> theext> mixtureext> formext> orext> theext> pharmaceuticallyext> acceptableext> saltext> thereofext>,ext>

Wherein:

r is 1;

ring A, R ⁰ 、L ¹ 、R ⁴ And q is as defined in formula (VG).

Scheme eight

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

Chiral preparation and resolution are carried out on the compound of the general formulSup>A (V) or Sup>A tautomer, sup>A racemate, an enantiomer, sup>A diastereoisomer or Sup>A mixture form or Sup>A pharmaceutically acceptable salt thereof to obtain the compound of the general formulSup>A (V-A), the general formulSup>A (V-B) or the tautomer, the racemate, the enantiomer, the diastereoisomer or the mixture form or the pharmaceutically acceptable salt thereof,

wherein:

r is 1;

Scheme nine

A process for the preparation of a compound of formula (V-2-a), formula (V-2-B), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

chiral preparation and resolution are carried out on the compound of the general formula (V-2) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form or a pharmaceutically acceptable salt thereof to obtain the compound of the general formula (V-2-A), the general formula (V-2-B) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt thereof,

Wherein:

r is 1;

ring A, L ¹ 、R ⁴ 、R ^d And q is as defined in formula (V-2).

In the above synthetic schemes, reagents providing acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, me ₃ SiCl and TMSOTf, preferably 1, 4-dioxane solutions of trifluoroacetic acid or hydrogen chloride.

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

In the above synthetic scheme, with alkylating agent R ^5a The reaction of-X is carried out in the presence of a base including organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide or tertiary Potassium butoxide, preferably N, N-diisopropylethylamine; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide.

In the above synthesis scheme, the reaction with formaldehyde solution is carried out in the presence of a reducing agent, preferably sodium triacetoxyborohydride.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Example 1

(±) -rel- (5 ar,6 r) -6-methyl-7- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 1

First step

(±) -rel- (2R, 3R) -3- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester 1b

(+ -.) -rel- ((2R, 3R) -3-methylpiperazin-2-yl) methanol 1a (2.1 g,16.13mmol, prepared using well-known method "WO2019148132A1, example 88") was dissolved in methanol (100 mL), di-tert-butyl dicarbonate (8.8 g,40.32 mmol) and N, N-diisopropylethylamine (10.5 g,81.24 mmol) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (50 mL), and an aqueous solution (50 mL) containing sodium hydroxide (2.6 g,65.00 mmol) was added thereto and reacted under reflux for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the organic solvent was removed, then diluted with water (50 mL), pH was adjusted to about 8 with 6M hydrochloric acid, extracted with methylene chloride (100 mL. Times.2), washed with saturated sodium chloride solution (30 mL. Times.2), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1b (3.7 g, yield: 99.6%).

MS m/z(ESI):231.0[M+1]。

Second step

5- (((2-bromo-5-fluorophenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione 1d

Compound 1c (20 g,105.26 mmol) and isopropyl malonate (15.2 g,105.46 mmol) were dissolved in trimethyl orthoformate (20 g,188.47 mmol), and the reaction was heated to 110℃and stirred for 0.5 h. The reaction solution was cooled to room temperature, slurried with ethanol (80 mL), filtered, and the resulting solid was washed with ethanol (15 mL. Times.2), and the resulting solid was dried to give the title product 1d (34.6 g, yield: 95.5%).

MS m/z(ESI):344.0[M+1]。

Third step

8-bromo-5-fluoroquinolin-4-ol 1e

Compound 1d (34.6 g,100.54 mmol) was dissolved in diphenyl ether (250 mL), nitrogen was displaced 3 times, and the reaction was heated to 200℃and stirred under nitrogen for 20 minutes. The reaction solution was cooled to room temperature, a large amount of a needle-like yellow solid was precipitated, and was filtered, and the obtained cake was washed with n-hexane (40 mL. Times.2), and the obtained solid was dried to obtain the title product 1e (20.4 g, yield: 83.8%).

MS m/z(ESI):241.8[M+1]。

Fourth step

5-fluoro-4-hydroxyquinoline-8-carbonitrile 1f

Compound 1e (5.0 g,20.66 mmol) and zinc cyanide (4.9 g,41.73 mmol) were dissolved in N, N-dimethylformamide (80 mL), nitrogen was substituted 3 times, and chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (1.6 g,2.06mmol, leyano chemical) was added thereto, nitrogen was substituted 3 times, and the reaction mixture was heated to 100℃and stirred under nitrogen for 4 hours. The reaction solution was cooled, filtered, the filtrate was concentrated under reduced pressure, the resulting residue was slurried with methylene chloride (60 mL), filtered, and the resulting cake was washed with methylene chloride (20 mL. Times.2), and the resulting solid was dried to give the title product 1f (3 g, yield: 77.2%).

MS m/z(ESI):188.9[M+1]。

Fifth step

(+ -.) -rel- (2R, 3R) -4- (8-cyano-4-hydroxyquinolin-5-yl) -3- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester 1g

Compound 1f (400 mg,2.13 mmol) and compound 1b (1 g,4.34 mmol) were dissolved in dimethyl sulfoxide (15 mL), N-diisopropylethylamine (823mg, 6.38 mmol) was added, and the reaction solution was heated to 115℃and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with a saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 1g (500 mg, yield: 59.0%).

MS m/z(ESI):399.0[M+1]。

Sixth step

(±) -rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-7 (5H) -carboxylic acid tert-butyl ester for 1H

1g (500 mg,1.25 mmol) was dissolved in 50mL of toluene and tetrahydrofuran (V: V=1:1), tributylphosphine (1.3 g,6.28 mmol) was added, nitrogen was substituted, a solution of dibenzyl azodicarboxylate (1.6 g,6.34 mmol) in toluene (50 mL) was added dropwise at room temperature to the reaction solution, and the reaction solution was stirred at 60℃for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product (400 mg, yield: 83.8%).

MS m/z(ESI):381.0[M+1]。

Seventh step

(±) -rel- (5 ar,6 r) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 1i

Compound 1h (80 mg,0.21 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1i (59 mg, yield: 100%).

MS m/z(ESI):281.0[M+1]。

Eighth step

(±) -rel- (5 ar,6 r) -7- ((6-chloropyridin-3-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 1k

Compound 1i (59 mg,0.21 mmol), 2-chloro-5- (chloromethyl) pyridine 1j (52 mg,0.32 mmol), potassium carbonate (60 mg,0.43 mmol) and sodium iodide (32 mg,0.21 mmol) were dissolved in acetonitrile (5 mL) and the reaction was stirred at 85℃for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 1k (38 mg, yield: 44.5%).

MS m/z(ESI):406.0[M+1]。

Ninth step

(±) -4- (5- ((rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 1l

Compound 1k (38 mg,0.09 mmol) and 1-t-butoxycarbonyl piperazine (35 mg,0.19 mmol) were dissolved in 1, 4-dioxane (5 mL), sodium t-butoxide (27 mg,0.28 mmol) was added, nitrogen was substituted 3 times, chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (8 mg,0.01mmol, lechen chemical) was added, nitrogen was substituted 3 times, and the reaction solution was heated to 80℃with stirring under nitrogen for 4 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 1l (50 mg, yield: 96.1%).

MS m/z(ESI):556.1[M+1]。

Tenth step

Compound 1l (50 mg,0.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1 (10 mg, yield: 24.4%).

MS m/z(ESI):456.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.74-8.73(m,1H),8.14-8.13(m,1H),7.91-7.89(m,1H),7.53-7.51(m,1H),6.93-6.92(m,1H),6.78-6.76(m,1H),6.67-6.65(m,1H),4.37-4.27(m,2H),3.74(s,1H),3.60-3.48(m,7H),3.41-3.37(m,2H),3.05-3.01(m,5H),2.83-2.78(m,1H),2.64-2.61(m,1H),1.17-1.15(m,3H)。

Example 2

(±) -rel- (5 ar,6 r) -6-methyl-7- (2-oxo-2- (5- (piperazin-1-yl) isoindolin-2-yl) ethyl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 2

First step

5-chloroisoindoline-2-carboxylic acid benzyl ester 2b

5-chloroisoindoline hydrochloride 2a (2 g,10.52mmol, after completion of the reaction) was dissolved in methylene chloride (40 mL), and triethylamine (9.3 g,91.61 mmol) and benzyl chloroformate (1.8 g,10.55 mmol) were added in this order, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane (60 mL), washed with water (40 mL), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2b (2.4 g, yield: 79.3%).

MS m/z(ESI):288.1[M+1]。

Second step

5- (4- (tert-Butoxycarbonyl) piperazin-1-yl) isoindoline-2-carboxylic acid benzyl ester 2c

Compound 2b (800 mg,2.78 mmol) and 1-t-butoxycarbonyl piperazine (1.1 g,5.58 mmol) were dissolved in toluene (30 mL), sodium t-butoxide (803 mg,8.34 mmol) was added, nitrogen substitution was performed 3 times, palladium acetate (63 mg,0.28 mmol) and 2- (di-t-butylphosphine) biphenyl (166 mg,0.57mmol, lev. Chem.) were added, nitrogen substitution was performed 3 times, and the reaction solution was heated to 100℃under nitrogen protection with stirring for 3 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 2c (620 mg, yield: 51.0%).

MS m/z(ESI):438.1[M+1]。

Third step

4- (isoindolin-5-yl) piperazine-1-carboxylic acid tert-butyl ester 2d

Compound 2c (620 mg,1.42 mmol) was dissolved in methanol (20 mL), wet palladium on carbon (151 mg) was added, hydrogen was replaced, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to give the title product 2d (350 mg, yield: 81.4%).

MS m/z(ESI):304.2[M+1]。

Fourth step

(±) -2- (rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) acetic acid tert-butyl ester 2e

Compound 1i (103 mg,0.37 mmol), tert-butyl bromoacetate (108 mg,0.55 mmol), potassium carbonate (153 mg,1.11 mmol) and sodium iodide (72 mg,0.48 mmol) were dissolved in acetonitrile (10 mL), and the reaction solution was heated to 65℃and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 2e (125 mg, yield: 86.2%).

MS m/z(ESI):395.0[M+1]。

Fifth step

(±) -2- (rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) acetic acid 2f

Compound 2e (125 mg,0.32 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 2f (107 mg, yield: 100%), which was used in the next reaction without purification.

MS m/z(ESI):339.0[M+1]。

Sixth step

(+ -) -4- (2- (2- (rel- (5 aR, 6R) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinolin-7 (5H) -yl) acetyl) isoindolin-5-yl) piperazine-1-carboxylic acid tert-butyl ester 2g

Crude compound 2f (107 mg,0.32 mmol) and compound 2d (115 mg,0.38 mmol) were dissolved in N, N-dimethylformamide (5 mL), N, N-diisopropylethylamine (164 mg,1.27 mmol) was added, followed by 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (181 mg,0.48mmol, shaoshao chemical) and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 2g (135 mg, yield: 68.4%).

MS m/z(ESI):624.1[M+1]。

Seventh step

2g (135 mg,0.22 mmol) of the compound was dissolved in methylene chloride (4 mL), and trifluoroacetic acid (4 mL) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2 (40 mg, yield: 35.3%).

MS m/z(ESI):524.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.75-8.74(m,1H),7.92-7.91(m,1H),7.22-7.20(m,1H),6.95-6.94(m,1H),6.93-6.89(m,1H),6.87-6.81(m,1H),6.80-6.79(m,1H),4.95-4.83(m,2H),4.79-4.76(m,2H),4.41-4.33(m,2H),3.86(s,1H),3.55-3.34(m,5H),2.26-2.22(m,1H),3.17-3.13(m,4H),3.06-3.04(m,4H),2.95-2.84(m,2H),1.24-1.22(m,3H)。

Example 3

(±) -rel- (5 ar,6 r) -6-methyl-7- (5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 3

First step

(±) -7- (rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester 3b

Compound 1i (20 mg,0.07 mmol), 7-chloro-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester 3a (20 mg,0.07 mmol) was dissolved in 1, 4-dioxane (5 mL), sodium tert-butoxide (15 mg,0.16 mmol) was added, nitrogen was replaced 3 times, and [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] (3-chloropyridinyl) palladium (II) dichloride (Pd-PEPPI (TM) -IPent,6mg,0.01mmol, sigma-aldrich) was added, nitrogen was replaced 3 times, and the reaction was heated to 100℃under nitrogen atmosphere and stirred for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 3b (20 mg, yield: 54.7%).

MS m/z(ESI):513.1[M+1]。

Second step

Compound 3b (20 mg,0.04 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3 (10 mg, yield: 62.1%).

MS m/z(ESI):413.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.77-8.75(m,1H),8.01(s,1H),7.95-7.92(m,1H),6.98-6.97(m,1H),6.85-6.84(m,1H),6.32(s,1H),4.67-4.63(m,1H),4.49-4.42(m,2H),3.99(s,2H),3.96-3.91(m,1H),3.86-3.84(m,1H),3.66-3.63(m,1H),3.49-3.44(m,1H),3.35-3.29(m,1H),3.18-3.15(m,2H),2.75-2.73(m,2H),1.35-1.25(m,3H)。

Example 3-A, example 3-B

(5 aS, 6S) -6-methyl-7- (5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 3-A

(5 aR, 6R) -6-methyl-7- (5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 3-B

First step

Compound 3 (300 mg,0.73 mmol) was subjected to chiral preparation (isolation conditions: cellulose-3OJ chiral preparation column, 250X 21.2mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=20/80/0.1 (V/V), flow rate: 20 mL/min), the corresponding components thereof were collected, and concentrated under reduced pressure to give the title product (90 mg,60 mg).

Single configuration compounds (90 mg, compounds corresponding to shorter retention times in 3-a and 3-B):

MS m/z(ESI):413.0[M+1]。

Chiral HPLC analysis: retention time 10.251 min, chiral purity: 100% (column: OJ Phenomenex Lux Cellulose-3X 4.6mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=20/80/0.1 (v/v/v)).

¹ H NMR(500MHz,CDCl ₃ )δ8.77-8.76(m,1H),8.01(s,1H),7.95-7.93(m,1H),6.98-6.97(m,1H),6.86-6.84(m,1H),6.32(s,1H),4.67-4.63(m,1H),4.48-4.42(m,2H),3.98(s,2H),3.95-3.91(m,1H),3.86-3.84(m,1H),3.66-3.62(m,1H),3.49-3.44(m,1H),3.35-3.29(m,1H),3.17-3.14(m,2H),2.74-2.72(m,2H),1.28-1.25(m,4H)。

Single configuration compounds (60 mg, compounds corresponding to longer retention times in 3-a and 3-B):

MS m/z(ESI):413.1[M+1]。

chiral HPLC analysis: retention time 18.399 min, chiral purity: 97.5% (column: OJ Phenomenex Lux Cellulose-3X 4.6mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=20/80/0.1 (v/v/v)).

¹ H NMR(500MHz,CDCl ₃ )δ8.77-8.75(m,1H),8.00(s,1H),7.94-7.92(m,1H),6.98-6.97(m,1H),6.85-6.83(m,1H),6.32(s,1H),4.67-4.62(m,1H),4.48-4.42(m,2H),3.96(s,2H),3.94-3.90(m,1H),3.86-3.84(m,1H),3.66-3.62(m,1H),3.49-3.43(m,1H),3.34-3.29(m,1H),3.15-3.12(m,2H),2.72-2.70(m,2H),1.29-1.24(m,4H)。

Example 4

(±) -rel- (5 ar,6 r) -6-methyl-7- (6-methyl-5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 4

Compound 3 (30 mg,0.07 mmol) and formaldehyde solution (20 mg,0.25mmol, 37%) were dissolved in 10mL of a solution of dichloromethane and methanol (V: V=1:1), sodium triacetoxyborohydride (50 mg,0.24 mmol) was added at room temperature, and the reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with methylene chloride (20 mL), washed with water (20 mL. Times.2), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by high performance liquid chromatography (Sharpsil-T Prep C18 μm 30X 150mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile=40% -90%B (12.2 min), flow rate: 30 mL/min), and concentrated under reduced pressure to give the title product 4 (15 mg, yield: 48.4%).

MS m/z(ESI):427.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.76(s,1H),8.02-7.93(m,2H),6.97-6.84(m,2H),6.32(s,1H),4.65(s,1H),4.45(s,2H),3.93-3.96(m,2H),3.52-3.29(m,5H),2.82-2.69(m,4H),2.45(s,3H),1.27-1.25(m,3H)。

Example 5

(±) -rel- (5 ar,6 r) -7- (6-isopropyl-5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxaazepino [7,6,5-de ] quinoline-13-carbonitrile 5

Compound 3 (30 mg,0.07 mmol), 2-bromopropane (20 mg,0.16 mmol) and N, N-diisopropylethylamine (30 mg,0.23 mmol) were dissolved in acetonitrile (5 mL) and stirred at 90℃for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Sharpsil-T Prep C18. Mu.m 30X 150mm; mobile phase: A-water (10 mmol of ammonium bicarbonate): B-acetonitrile=53% -90%B (12.2 min), flow rate: 30 mL/min) and concentrated under reduced pressure to give the title product 5 (6 mg, yield: 18.1%).

MS m/z(ESI):455.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.77-8.76(m,1H),8.01(s,1H),7.95-7.92(m,1H),6.98-6.97(m,1H),6.86-6.84(m,1H),6.35(s,1H),4.66-4.62(m,1H),4.49-4.42(m,2H),3.92-3.85(m,2H),3.67-3.62(m,3H),3.50-3.45(m,1H),3.34-3.28(m,1H),2.95-2.89(m,1H),2.81-2.74(m,4H),1.26-1.22(m,3H),1.14-1.13(m,6H)。

Example 6

(±) -rel- (5 ar,6 r) -6-methyl-7- (5- (piperazin-1-yl) isoindoline-2-carbonyl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 6

First step

(±) -rel- (5 ar,6 r) -7- (5-chloroisoindoline-2-carbonyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 6a

Triphosgene (32 mg,0.11mmol, shao Yuan) was dissolved in 3mL of dichloromethane, and a solution of compound 1i (30 mg,0.11 mmol) and diisopropylethylamine (84 mg,0.66 mmol) in dichloromethane (3 mL) was added dropwise to the above solution at room temperature. After stirring at room temperature for 10 minutes, 2a (17 mg,0.11 mmol) was added to the above solution, and stirring at room temperature was continued overnight. The residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 6a (37 mg, yield: 75.2%).

MS m/z(ESI):460.1[M+1]。

Second step

(±) -4- (2- (rel- (5 ar,6 r) -13-cyano-6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-7-carbonyl) isoindolin-5-yl) piperazine-1-carboxylic acid tert-butyl ester 6b

Compound 6a (45 mg,0.10 mmol), 1-t-butoxycarbonyl piperazine (35 mg,0.19 mmol) was dissolved in dioxane (5 mL), sodium t-butoxide (27 mg,0.28 mmol) was added, nitrogen was substituted 3 times, chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (8 mg,0.01 mmol) was added, nitrogen was substituted 3 times, and the reaction mixture was heated to 100℃and stirred under nitrogen for 4 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 6B (43 mg, yield: 72%).

MS m/z(ESI):610.2[M+1]。

Third step

Compound 6b (20 mg,0.03 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 6 (10 mg, yield: 51%).

MS m/z(ESI):510.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.72-8.69(m,2H),8.15-8.13(d,1H),7.24-7.20(m,1H),7.12-7.10(m,1H),6.98-6.94(m,2H),5.34-5.32(m,1H),4.73-4.69(m,3H),4.55-4.51(m,2H),4.19-4.17(m,1H),3.82-3.80(m,2H),3.63-3.60(m,4H),3.26-3.20(m,8H),1.33-1.31(d,3H)。

Example 7

(±) -rel- (5 ar,6 r) -6-methyl-7- (5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 7

Using the synthetic route of example 3, substituting starting compound 3a with starting compound 2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (Pichia) gave title compound 7 (12 mg, yield: 68.2%).

MS m/z(ESI):413.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.80-8.79(d,1H),7.97-7.96(d,1H),7.24-7.22(d,1H),7.01-7.00(d,1H),6.88-6.86(d,1H),6.53-6.51(d,1H),4.68-4.67(d,1H),4.49(s,2H),4.15-4.13(m,1H),3.99(s,2H),3.88-3.86(m,1H),3.68-3.66(m,1H),3.51-3.48(m,1H),3.34-3.31(m,3H),2.89-2.86(m,2H),1.29-1.26(d,3H)。

Example 8

(±) -rel- (5 ar,6 r) -6-methyl-7- (1, 2,3, 4-tetrahydroisoquinolin-7-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 8

First step

(±) -7- (rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester 8b

Compound 1i (30 mg,0.11 mmol), compound 8a (37 mg,0.12 mmol) was dissolved in dioxane (5 mL), sodium t-butoxide (21 mg,0.22 mmol) was added, nitrogen substitution was performed 3 times, and [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] (3-chloropyridyl) palladium (II) dichloride (Pd-PEPPI (TM) -IPent catalyst) (9 mg,0.01mmol, sigma Aldrich) was added, nitrogen substitution was performed 3 times, and the reaction solution was heated to 100℃under nitrogen protection and stirred for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 8b (41 mg, yield: 74.9%).

MS m/z(ESI):512.1[M+1]。

Second step

Compound 8b (41 mg,0.08 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 8 (8 mg, yield: 24.3%).

MS m/z(ESI):411.9[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.78-8.76(m,1H),7.97-7.94(m,1H),7.04-7.02(m,1H),6.99-6.97(m,1H),6.88-6.84(m,1H),6.76-6.74(m,1H),6.55-6.54(m,1H),4.48-4.39(m,2H),4.03-3.99(m,3H),3.94-3.92(m,1H),3.65-3.62(m,1H),3.54-3.49(m,1H),3.38-3.35(m,1H),3.32-3.26(m,1H),3.15-3.12(m,2H),2.75-2.72(m,2H),1.19-1.18(m,3H)。

Example 9

(±) -rel- (5 ar,6 r) -7- ((4-aminobicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 9

First step

(±) - (4- ((rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) bicyclo [2.2.2] oct-1-yl) carbamic acid tert-butyl ester 9b

Compound 1i (160 mg,0.57 mmol) and compound 9a (160 mg,0.63mmol, obtained by the well-known method "WO2013003383A1, preparation of intermediate A on pages 66-67") were dissolved in 1, 2-dichloroethane (10 mL), sodium triacetoxyborohydride (190 mg,2.31 mmol) was added at room temperature, and the reaction was stirred at 60℃for 5 hours. The reaction solution was diluted with dichloromethane (40 mL), washed with water (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 9B (50 mg, yield: 16.9%).

MS m/z(ESI):518.2[M+1]。

Second step

Compound 9b (50 mg,0.10 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography (Sharpsil-TPrep C18. Mu.m 30X 150mm; mobile phase: A-water (0.1% trifluoroacetic acid): B-acetonitrile=10% -95% B (10.41 min), flow rate: 30 mL/min), and lyophilized to give the title product 9 (20 mg, yield: 38.9%).

MS m/z(ESI):418.0[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.72-8.69(m,1H),8.13-8.10(m,1H),7.16-7.15(m,1H),7.09-7.07(m,1H),4.59(s,2H),4.26(s,1H),3.94-3.88(m,2H),3.68-3.66(m,2H),3.45-3.42(m,1H),3.17-3.10(m,2H),1.89-1.87(m,12H),1.68-1.64(m,3H)。

Example 9-A, example 9-B

(5 aS, 6S) -7- ((4-aminobicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 9-A

(5 aR, 6R) -7- ((4-aminobicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 9-B

Chiral preparation of compound 9 (400 mg,0.96 mmol) (separation conditions: CHIRALPAK IG chiral preparation column, 20 mm. Times.250 mm; mobile phase: n-hexane/ethanol/diethylamine=50/50/0.1 (V/V), flow rate: 20 mL/min), collection of its corresponding components, concentration under reduced pressure gave the title product (100 mg ).

9-A：

MS m/z(ESI):418.0[M+1]。

Chiral HPLC analysis: retention time 9.470 min, chiral purity: 100% (column CHIRALPAK IG,4.6 mm. Times.150 mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=50/50/0.1 (v/v/v)).

¹ H NMR(500MHz,CDCl ₃ )δ8.73-8.72(m,1H),7.90-7.88(m,1H),6.92-6.91(m,1H),6.77-6.75(m,1H),4.37-4.33(m,1H),4.27-4.23(m,1H),3.79(s,1H),3.44-3.39(m,1H),3.36-3.33(m,1H),2.99-2.94(m,1H),2.82-2.78(m,1H),3.51-2.48(m,1H),2.27-2.25(m,1H),2.06-2.03(m,1H),1.57-1.51(m,12H),1.14-1.13(m,3H)。

9-B：

MS m/z(ESI):418.0[M+1]。

Chiral HPLC analysis: retention time 12.090 min, chiral purity: 100% (column CHIRALPAK IG,4.6 mm. Times.150 mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=50/50/0.1 (v/v/v)).

¹ H NMR(500MHz,CDCl ₃ )δ8.72-8.71(m,1H),7.90-7.88(m,1H),6.92-6.91(m,1H),6.77-6.76(m,1H),4.37-4.33(m,1H),4.28-4.24(m,1H),3.79(s,1H),3.45-3.39(m,1H),3.36-3.33(m,1H),2.99-2.94(m,1H),2.83-2.79(m,1H),3.52-2.49(m,1H),2.25-2.22(m,1H),2.05-2.02(m,1H),1.55-1.48(m,12H),1.14-1.13(m,3H)。

Example 10

(±) -N- (4- ((rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) bicyclo [2.2.2] oct-1-yl) -2- (dimethylamino) acetamide 10

Compound 9 (24 mg,0.06 mmol) and N, N-dimethylglycine (10 mg,0.10 mmol) were dissolved in N, N-dimethylformamide (5 mL), diisopropylethylamine (30 mg,0.23 mmol) was added, followed by addition of 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (33 mg,0.09 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue obtained was purified by high performance liquid chromatography (Boston Prep C18. Mu.m.30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=50% -70% B (15 min), flow rate: 30 mL/min) and eluent lyophilized to give the title product 10 (10 mg, yield: 34.6%).

MS m/z(ESI):503.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.71-8.69(m,1H),7.88-7.86(m,1H),6.91-6.89(m,1H),6.84(s,1H),6.76-6.74(m,1H),4.36-4.32(m,1H),4.26-4.23(m,1H),3.77(s,1H),3.42-3.33(m,2H),2.97-2.92(m,1H),2.82-2.78(m,3H),2.51-2.47(m,1H),2.26-2.20(m,7H),2.04-1.99(m,1H),1.90-1.87(m,6H),1.55-1.46(m,6H),1.12-1.11(m,3H)。

Example 11

(±) -rel- (5 ar,6 r) -7- ((3-aminobicyclo [1.1.1] pent-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 11

First step

(±) - (3- ((rel- (5 ar,6 r) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) bicyclo [1.1.1] pent-1-yl) carbamic acid tert-butyl ester 11b

Compound 1i (100 mg,0.36 mmol) and tert-butyl (3-formylbicyclo [1.1.1] pent-1-yl) carbamate 11a (100 mg,0.47mmol, prepared by known methods "European Journal of Organic Chemistry,2017, vol.2017,43, p.6450-6456") were dissolved in 1, 2-dichloroethane (5 mL), sodium triacetoxyborohydride (118 mg,1.44 mmol) was added at room temperature, and the reaction stirred at 60℃for 2 hours. The reaction solution was diluted with dichloromethane (40 mL), washed with water (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 11B (150 mg, yield: 88.4%).

MS m/z(ESI):476.1[M+1]。

Second step

Compound 11b (150 mg,0.31 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2.5 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (10 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 11 (30 mg, yield: 25.3%).

MS m/z(ESI):376.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.74-8.72(m,1H),7.90-7.89(m,1H),6.93-6.92(m,1H),6.78-6.77(m,1H),4.39-4.29(m,2H),3.78(s,1H),3.48-3.40(m,2H),3.07-3.03(m,1H),2.79-2.74(m,1H),2.69-2.56(m,3H),1.77-1.72(m,8H),1.12-1.10(m,3H)。

Example 12

(±) -rel- (5 ar,6 r) -7- ((4-aminobicyclo [2.2.2] oct-1-yl) methyl) -6-ethyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 12

First step

3-Vinylpyrazine-2-carboxylic acid methyl ester 12b

Compound 12a (3.0 g,13.82 mmol), pinacol vinylborate (2.6 g,16.88mmol, bi) was dissolved in a dioxane and water mixed solvent (50 mL, v: v=4:1), potassium carbonate (5.8 g,41.97 mmol) was added, nitrogen was substituted 3 times, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.01 mg,1.38mmol, adamas) was added, nitrogen was substituted 3 times, and the reaction solution was heated to 80℃and stirred under nitrogen for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 12b (960 mg, yield: 42.3%).

MS m/z(ESI):164.9[M+1]。

Second step

(±) -rel- (2R, 3R) -3-ethylpiperazine-2-carboxylic acid methyl ester 12c

Compound 12b (960 mg,5.85 mmol) and platinum dioxide (133 mg,0.59 mmol) were dissolved in methanol (10 mL), replaced with hydrogen 3 times, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 12c (1 g, yield: 99.3%).

MS m/z(ESI):172.9[M+1]。

Third step

(±) - (rel- (2 r,3 r) -3-ethylpiperazin-2-yl) methanol 12d

Compound 12c (1.2 g,6.97 mmol) was dissolved in tetrahydrofuran (20 mL), replaced with nitrogen, and a solution of lithium aluminum hydride in tetrahydrofuran (2.5M, 3.06 mL) was added dropwise at 0deg.C, and the reaction was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding sodium sulfate decahydrate under ice bath conditions, stirred for half an hour, filtered, the filter cake was washed twice with ethyl acetate, the filtrates were combined and concentrated under reduced pressure to give the title product 12d (900 mg, yield: 89.6%).

MS m/z(ESI):144.8[M+1]。

Fourth step

(±) -rel- (2 r,3 r) -2-ethyl-3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester 12e

Compound 12d (340 mg,2.36 mmol) was dissolved in methanol (20 mL), di-tert-butyl dicarbonate (1.7 g,7.79 mmol) and N, N-diisopropylethylamine (1.02 g,7.89 mmol) were added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (10 mL), and a solution of sodium hydroxide (472 mg, 11.80 mmol) in water (10 mL) was added thereto and reacted under reflux for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the organic solvent was removed, then diluted with water (50 mL), pH was adjusted to about 8 with 6M hydrochloric acid, extracted with methylene chloride (100 mL. Times.2), washed with saturated sodium chloride solution (30 mL. Times.2), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 12e (390 mg, yield: 67.7%).

MS m/z(ESI):245.0[M+1]。

Fifth step

(±) -rel- (2 r,3 r) -4- (8-cyano-4-hydroxyquinolin-5-yl) -2-ethyl-3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester 12f

Compound 12e (390 mg,1.60 mmol) and compound 1f (270 mg,4.34 mmol) were dissolved in dimethyl sulfoxide (10 mL), N-diisopropylethylamine (557 mg,4.31 mmol) was added, and the reaction solution was heated to 115℃and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with a saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 12f (370 mg, yield: 62.5%).

MS m/z(ESI):413.0[M+1]。

Sixth step

(+ -) -rel- (5 aR, 6R) -13-cyano-6-ethyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-7 (5H) -carboxylic acid tert-butyl ester 12g

12f (370 mg,0.90 mmol) was dissolved in 20mL of a solution of toluene and tetrahydrofuran (V: V=1:1), tributylphosphine (910 mg,4.50 mmol) was added, nitrogen was substituted, a solution of dibenzyl azodicarboxylate (1.14 g,4.52 mmol) in toluene (10 mL) was added dropwise at room temperature, and the reaction solution was stirred at 60℃for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 12g (350 mg, yield: 98.9%).

MS m/z(ESI):395.0[M+1]。

Seventh step

(±) -rel- (5 ar,6 r) -6-ethyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 12h

12g (350 mg,0.89 mmol) of the compound was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (5 mL) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (165 mg, yield: 63.2%).

MS m/z(ESI):295.0[M+1]。

Eighth step

(±) - (4- ((rel- (5 ar,6 r) -13-cyano-6-ethyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) bicyclo [2.2.2] oct-1-yl) carbamic acid tert-butyl ester 12i

Compound 12h (50 mg,0.17 mmol) and compound 9a (50 mg,0.20 mmol) were dissolved in 1, 2-dichloroethane (5 mL), sodium triacetoxyborohydride (56 mg,0.68 mmol) was added at room temperature, and the reaction was stirred at 60℃for 6 hours. The reaction solution was diluted with dichloromethane (40 mL), washed with water (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 12i (40 mg, yield: 44.3%).

Ninth step

Compound 12i (40 mg,0.07 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 12 (20 mg, yield: 61.6%).

MS m/z(ESI):432.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.74-8.73(m,1H),7.90-7.88(m,1H),6.93-6.92(m,1H),6.76-6.74(m,1H),4.39-4.36(m,1H),4.29-4.26(m,1H),3.85(s,1H),3.50-3.45(m,1H),3.27-3.25(m,1H),3.09-3.03(m,1H),2.52-2.47(m,2H),2.42-2.39(m,1H),2.19-2.16(m,1H),1.78-1.67(m,2H),1.55-1.47(m,12H),1.04-1.01(m,3H)。

Example 12-A, example 12-B

(5 aS, 6S) -7- ((4-aminobicyclo [2.2.2] oct-1-yl) methyl) -6-ethyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 12-A

(5 aR, 6R) -7- ((4-aminobicyclo [2.2.2] oct-1-yl) methyl) -6-ethyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 12-B

Compound 12 (1 g,2.32 mmol) was subjected to chiral preparation (separation conditions: CHIRALPAK IG chiral preparation column, 20 mm. Times.250 mm; mobile phase: n-hexane/ethanol/2M ammonia in ethanol=50/50/0.5 (V/V, flow rate: 20 mL/min), the corresponding components thereof were collected, and concentrated under reduced pressure to give the title product (250 mg,300 mg).

12-A：

MS m/z(ESI):432.1[M+1]。

Chiral HPLC analysis: retention time 9.341 min, chiral purity: 100% (column CHIRALPAK IG,4.6 mm. Times.150 mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=50/50/0.1 (v/v/v)).

¹ H NMR(500MHz,CDCl ₃ )δ8.74-8.73(m,1H),7.89-7.88(m,1H),6.93-6.92(m,1H),6.76-6.74(m,1H),4.39-4.36(m,1H),4.29-4.26(m,1H),3.85(s,1H),3.50-3.44(m,1H),3.28-3.20(m,1H),3.10-3.04(m,1H),2.52-2.46(m,2H),2.43-2.40(m,1H),2.20-2.17(m,1H),1.77-1.68(m,2H),1.59-1.49(m,12H),1.04-1.01(m,3H)。

12-B：

MS m/z(ESI):432.0[M+1]。

Chiral HPLC analysis: retention time 11.081 min, chiral purity: 100% (column CHIRALPAK IG,4.6 mm. Times.150 mm,5 μm; mobile phase: n-hexane/ethanol/diethylamine=50/50/0.1 (v/v/v)).

¹ H NMR(500MHz,CDCl ₃ )δ8.73-8.72(m,1H),7.89-7.88(m,1H),6.93-6.92(m,1H),6.76-6.74(m,1H),4.39-4.36(m,1H),4.29-4.25(m,1H),3.85(s,1H),3.50-3.44(m,1H),3.28-3.20(m,1H),3.10-3.04(m,1H),2.52-2.46(m,2H),2.43-2.40(m,1H),2.19-2.17(m,1H),1.77-1.68(m,2H),1.57-1.49(m,12H),1.04-1.01(m,3H)。

Example 13

(±) -rel- (5 ar,6 r) -6-ethyl-7- (5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 13

First step

(±) -7- (rel- (5 ar,6 r) -13-cyano-6-ethyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) -3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester 13a

Compound 12h (65 mg,0.22 mmol), compound 3a (66 mg,0.25 mmol) was dissolved in dioxane (5 mL), sodium tert-butoxide (44 mg,0.46 mmol) was added, nitrogen was substituted 3 times, palladium (II) chloride [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] (3-chloropyridyl) dichloride (Pd-PEPPI (TM) -IPent catalyst) (19 mg,0.02mmol, sigma Aldrich) was added, nitrogen was substituted 3 times, and the reaction was heated to 100℃and stirred under nitrogen for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 13a (100 mg, yield: 86.0%).

MS m/z(ESI):527.1[M+1]。

Second step

Compound 13a (100 mg,0.19 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 13 (30 mg, yield: 37.0%).

MS m/z(ESI):427.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.77-8.75(m,1H),7.94-7.91(m,1H),6.97-6.96(m,1H),6.81-6.79(m,1H),6.32(s,1H),4.64-4.61(m,1H),4.49-4.42(m,2H),4.11-4.08(m,1H),3.96(s,2H),3.79-3.77(m,1H),3.54-3.51(m,1H),3.44-3.33(m,2H),3.15-3.13(m,2H),2.71-2.69(m,2H),2.05-1.97(m,1H),1.92-1.85(m,2H),0.86-0.83(m,3H)。

Example 14

(5 aR, 6R) -7- ((4- (cyclopropylamino) bicyclo [2.2.2] oct-1-yl) methyl) -6-ethyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 14

Compound 12-B (60 mg,0.14 mmol), cyclopropylboronic acid (24 mg,0.28 mmol), copper acetate (51 mg,0.28 mmol), 2' -bipyridine (44 mg,0.28 mmol) and sodium carbonate (270 mg,4.34 mmol) were dissolved in N, N-dimethylformamide (5 mL), and the reaction was heated to 60℃and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (15 mL. Times.2), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Welch Xtimate Prep C, 5 μm 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=45% -68% B (23 min), flow rate: 30 mL/min) to give the residue, which was lyophilized to give the title product 14 (8 mg, yield: 12.2%).

MS m/z(ESI):472.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.73(d,1H),7.89(d,1H),6.92(d,1H),6.76(d,1H),4.40-4.36(m,1H),4.30-4.26(m,1H),3.86(s,1H),3.51-3.46(m,1H),3.33-3.17(m,1H),3.10-3.05(m,1H),2.53-2.48(m,2H),2.43-2.39(m,1H),2.24-2.16(m,1H),2.12-2.09(m,1H),2.09-1.97(m,1H),1.65-1.59(m,8H),1.52-1.49(m,6H),1.05-1.01(m,3H),0.45-0.42(m,2H),0.36-0.22(m,2H)。

Example 15

(5 aR, 6R) -6-ethyl-7- ((4- (pyrrolidin-1-yl) bicyclo [2.2.2] oct-1-yl) methyl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 15

Compound 12-B (60 mg,0.14 mmol), 1, 4-dibromobutane (33 mg,0.15 mmol) and triethylamine (44 mg,0.43 mmol) were dissolved in ethanol (5 mL), and the reaction solution was heated to 80℃and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Xtimate Prep C, 5 μm, 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=40% -70% B (20 min), flow rate: 30mL/min resulting residue, eluent was lyophilized to give the title product 15 (8 mg, yield: 11.8%).

MS m/z(ESI):486.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.73(d,1H),7.89(d,1H),6.93(d,1H),6.75(d,1H),4.39-4.36(m,1H),4.29-4.26(m,1H),3.84(s,1H),3.49-3.44(m,1H),3.32-3.17(m,1H),3.10-3.05(m,1H),2.97-2.71(m,4H),2.52-2.47(m,2H),2.43-2.40(m,1H),2.23-2.17(m,2H),2.02-1.98(m,1H),1.92-1.79(m,4H),1.77-1.68(m,6H),1.60-1.44(m,6H),1.04-1.01(m,3H)。

Example 16

2- ((4- (((5 aR, 6R) -13-cyano-6-ethyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) bicyclo [2.2.2] oct-1-yl) amino) acetamide 16

Compound 12-B (30 mg,0.07 mmol), 2-bromoacetamide (20 mg,0.14 mmol) and cesium carbonate (47 mg,0.14 mmol) were dissolved in N, N-dimethylformamide (5 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (15 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and purified by high performance liquid chromatography (YMC Triart-Exrs Prep C18 μm 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=50% -58% B (8 min), flow rate: 30 mL/min), the residue obtained was purified by high performance liquid chromatography, and the eluate was lyophilized to give the title product 16 (10 mg, yield: 29.4%).

MS m/z(ESI):489.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.73(d,1H),7.89(d,1H),6.93(d,1H),6.75(d,1H),5.46(s,1H),4.39-4.36(m,1H),4.29-4.26(m,1H),3.93-3.76(m,1H),3.49-3.44(m,1H),3.32-3.22(m,2H),3.21(s,1H),3.10-3.05(m,1H),2.52-2.46(m,2H),2.42-2.39(m,1H),2.22-2.17(m,1H),1.78-1.67(m,2H),1.61-1.57(m,2H),1.55-1.45(m,12H),1.04-1.01(m,3H)。

Example 17

(5 aR, 6R) -7- ((4- ((2, 2-difluoroethyl) amino) bicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 17

Compound 9-B (40 mg,0.095 mmol) was dissolved in N, N-dimethylformamide (3 mL), triethylamine (96 mg,0.95mmol, national drug) and 2, 2-difluoroethyl triflate (170 mg,0.79mmol, adamas) were added, and the reaction was stirred at 90℃for 5 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by high performance liquid chromatography (Welch Ultimate XB-C18. Mu.m 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=60% -76% (16 min), flow rate: 30 mL/min) to give the title product 17 (20 mg, yield: 46.3%).

MS m/z(ESI):482.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.76(d,1H),7.92(d,1H),6.95(d,1H),6.80(d,1H),5.80(tt,1H),4.38(dd,1H),4.28(dd,1H),3.82(s,1H),3.48-3.33(m,2H),3.04-2.82(m,4H),2.53(dt,1H),2.27(d,1H),2.07(d,1H),1.54(d,12H),1.16(d,3H)。

Example 18

(5 aR, 6R) -7- ((4- ((1R, 5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 18

First step

((2R, 5S) -tetrahydrofuran-2, 5-diyl) bis (methylene) bis (4-methylbenzenesulfonate) 18b

The compound (2R, 5S) -2, 5-dimethyloltetrahydrofuran 18a (200 mg,1.51mmol, shao Yuan) was dissolved in tetrahydrofuran (8 mL), and triethylamine (760 mg,7.51mmol, guo Yao) and p-toluenesulfonyl chloride (900 mg,4.72mmol, guo Yao) were added and the reaction was stirred for 16 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 18b (500 mg, yield: 75.0%).

MS m/z(ESI):441.1[M+1]。

Second step

(5 aR, 6R) -7- ((4- ((1R, 5S) -oxa-3-azabicyclo [3.2.1] oct-3-yl) bicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxaazepino [7,6,5-de ] quinoline-13-carbonitrile 18

Compound 9-B (100 mg,0.239 mmol) and compound 18B (211 mg,0.479 mmol) were dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (100 mg,0.723mmol, guozhi) was added thereto, and the reaction was stirred at 120℃for 16 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by high performance liquid chromatography (Welch Ultimate XB-C18. Mu.m, 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=80% -95% (15 min), flow rate: 30 mL/min) to give the title product 18B (30 mg, yield: 24.3%).

MS m/z(ESI):514.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.76(d,1H),7.92(d,1H),6.95(d,1H),6.79(d,1H),4.38(dd,1H),4.29(td,3H),3.81(s,1H),3.49-3.32(m,2H),2.99(td,1H),2.84(dd,1H),2.61-2.51(m,3H),2.48(dt,2H),2.24(d,1H),2.05(d,1H),1.86(dd,2H),1.79(dd,2H),1.57-1.41(m,12H),1.16(d,3H)。

Example 19

(5 aR, 6R) -6-methyl-7- ((4- (pyrrolidin-1-yl) bicyclo [2.2.2] oct-1-yl) methyl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 19

Compound 9-B (24 mg,0.05 mmol) and 1, 4-dibromobutane (11 mg,0.05 mmol) were dissolved in ethanol (5 mL), and the reaction was heated to 80℃and stirred for 24 hours. The filtrate was concentrated under reduced pressure and the resulting residue was purified by high performance liquid chromatography (Boston Prep C18 μm 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=50% -70% B (15 min), flow rate: 30 mL/min) and the eluate was lyophilized to give the title product 19 (15 mg, yield: 66.4%).

MS m/z(ESI):471.9[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.63-8.62(m,1H),8.02-8.00(m,1H),7.03-6.97(m,2H),4.47-4.37(m,2H),3.86(s,1H),3.47-3.44(m,2H),3.03-2.93(m,2H),2.74-2.71(m,4H),2.58-2.55(m,1H),2.34-2.31(m,1H),2.11-2.09(m,1H),1.81-1.79(m,4H),1.72-1.69(m,6H),1.60-1.57(m,6H),1.17-1.16(m,3H)。

Example 20

(5 aR, 6R) -6-methyl-7- ((4- (oxetan-3-ylamino) bicyclo [2.2.2] oct-1-yl) methyl) -5,5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-13-carbonitrile 20

Compound 9-B (30 mg,0.07 mmol) and 3-oxetanone (51 mg,0.07 mmol) were dissolved in 1, 2-dichloroethane (5 mL), sodium acetyl borohydride (46 mg,0.22 mmol) was added, and the reaction was stirred at room temperature overnight. The residue obtained was purified by silica gel column chromatography with eluent system B, and the title product 20 (10 mg, yield: 29.4%) was obtained.

MS m/z(ESI):473.9[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.63-8.62(m,1H),8.02-8.00(m,1H),7.03-6.97(m,2H),4.82-4.80(m,2H),4.60-4.58(m,2H),4.46-4.36(m,3H),3.84(s,1H),3.46-3.43(m,2H),3.05-2.92(m,2H),2.56-2.53(m,1H),2.36-2.33(m,1H),2.12-2.09(m,1H),2.05-1.99(m,4H),1.63-1.54(m,8H),1.17-1.15(m,3H)。

Example 21

2- ((4- (((5 aR, 6R) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinolin-7 (5H) -yl) methyl) bicyclo [2.2.2] oct-1-yl) amino) acetamide 21

Compound 9-B (50 mg,0.120 mmol) was dissolved in N, N-dimethylformamide (3 mL), 2-bromoacetamide (33 mg,0.239mmol, bi) and cesium carbonate (78 mg,0.239mmol, shao) were added, and the reaction was stirred for 3 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by high performance liquid chromatography (Welch Ultimate XB-C18. Mu.m 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=35% -55% (20 min), flow rate: 30 mL/min) to give the title product 21 (30 mg, yield: 53.5%).

MS m/z(ESI):475.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.62(d,1H),8.01(d,1H),7.02(d,1H),6.97(d,1H),4.47-4.34(m,2H),3.85(s,1H),3.50-3.39(m,2H),3.24(s,2H),3.02(td,1H),2.93(dd,1H),2.56(dt,1H),2.33(d,1H),2.09(d,1H),1.59(d,12H),1.16(d,3H)。

Example 22

(5 aR, 6R) -7- ((4- (cyclopropylamino) bicyclo [2.2.2] oct-1-yl) methyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 22

Compound 9-B (50 mg,0.12 mmol), cyclopropylboronic acid (23 mg,0.27 mmol), copper acetate (45 mg,0.25 mmol), 2' -bipyridine (38 mg,0.24 mmol), sodium carbonate (28 mg,0.26 mmol) were dissolved in DMF (10 mL) and the reaction was heated to 60℃and stirred for 4 h. The filtrate was concentrated under reduced pressure and the resulting residue was purified by high performance liquid chromatography (Boston Prep C18 μm 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile=50% -70% B (15 min), flow rate: 30 mL/min) and the eluate was lyophilized to give the title product 22 (10 mg, yield: 18.2%).

MS m/z(ESI):457.9[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.63-8.62(m,1H),8.02-8.00(m,1H),7.03-6.97(m,2H),4.47-4.36(m,2H),3.86(s,1H),3.47-3.44(m,2H),3.05-2.92(m,2H),2.58-2.55(m,1H),2.34-2.31(m,1H),2.18-2.15(m,1H),2.11-2.08(m,1H),1.71-1.66(m,5H),1.63-1.54(m,5H),1.35-1.31(m,3H),1.17-1.15(m,3H),0.52-0.48(m,2H),0.34-0.32(m,2H)。

Example 23

(5 aR, 6R) -7- (4-aminobicyclo [2.2.2] octane-1-carbonyl) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 23

First step

(±) -rel- (2 r,3 r) -2- (hydroxymethyl) -3-methylpiperazine-1, 4-dicarboxylic acid di-tert-butyl ester 23a

(3-methylpiperazin-2-yl) methanol 1a (12.0 g,92.17mmol, obtained by the known method "preparation example 88 of WO2019148132A 1") was dissolved in methanol (100 mL), and di-tert-butyl dicarbonate (50.3 g,230.47 mmol) and N, N-diisopropylethylamine (59.6 g,461.15 mmol) were added thereto and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was diluted with water (100 mL), extracted with ethyl acetate (300 mL. Times.3), washed with saturated sodium chloride solution (50 mL. Times.2), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 23a (18.0 g, yield: 59.2%).

MS m/z(ESI):331.1[M+1]。

Second step

(2R, 3R) -2- (hydroxymethyl) -3-methylpiperazine-1, 4-dicarboxylic acid di-tert-butyl ester 23b

Chiral preparation of Compound 23a (43 g,130.14 mmol) (isolation conditions: waters SFC 150 DAICEL)250X 40mm 10 μm; mobile phase: a-supercritical CO ₂ : b-methanol (0.1% 7m methanolic ammonia solution) =85:15, flow rate: 120 mL/min) and its corresponding fractions were collected and concentrated under reduced pressure to give the title product 23b (21.4 g, yield: 49.76%).

Single configuration compounds (shorter retention time):

MS m/z(ESI):331.1[M+1]。

chiral HPLC analysis: retention time 7.805 min, chiral purity: 100% (column: OJ Phenomenex Lux Amylose-1X 4.6mm,5 μm; mobile phase: n-hexane/ethanol/methanol/diethylamine=95/1/4/0.1 (v/v/v)).

Third step

(2R, 3R) -3- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester 23c

Compound 23b (7.4 g,22.40 mmol) was dissolved in ethanol (50 mL), and an aqueous solution (50 mL) containing sodium hydroxide (3.6 g,90.00 mmol) was added and reacted under reflux for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the organic solvent was removed, then diluted with water (50 mL), pH was adjusted to about 8 with 6M hydrochloric acid, extracted with methylene chloride (100 mL. Times.2), washed with saturated sodium chloride solution (30 mL. Times.2), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 23c (5.1 g, yield: 99.6%).

MS m/z(ESI):231.0[M+1]。

Fourth step

(2R, 3R) -4- (8-cyano-4-hydroxyquinolin-5-yl) -3- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester 23d

Compound 1f (4.0 g,21.3 mmol) and compound 23c (5.1 g,22.4 mmol) were dissolved in dimethyl sulfoxide (60 mL), N-diisopropylethylamine (8.3 g,64.2 mmol) was added, and the reaction mixture was heated to 120℃and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with a saturated sodium chloride solution (50 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 23d (4.85 g, yield: 57.3%).

MS m/z(ESI):399.0[M+1]。

Fifth step

(5 aR, 6R) -13-cyano-6-methyl-5 a,6,8, 9-tetrahydropyrazino [2',1:3,4] [1,4] oxazepino [7,6,5-de ] quinoline-7 (5H) -carboxylic acid tert-butyl ester 23e

23d (6.4 g,16.06 mmol) was dissolved in 310mL of toluene and tetrahydrofuran (V: V=1:1), tributylphosphine (4.9 g,24.22 mmol) was added, nitrogen was substituted, a solution of dibenzyl azodicarboxylate (6.1 g,24.18 mmol) in toluene (155 mL) was added dropwise at room temperature, and the reaction solution was warmed to 60℃and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 23e (4.8 g, yield: 78.6%).

MS m/z(ESI):381.0[M+1]。

Sixth step

(5 aR, 6R) -6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 23f

Compound 23e (4.8 g,12.62 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (15 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (50 mL) was added, extracted with methylene chloride (200 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 23f (2.5 g, yield: 70.7%).

MS m/z(ESI):281.0[M+1]。

Seventh step

(4- ((5 aR, 6R) -13-cyano-6-methyl-5, 5a,6,7,8, 9-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [7,6,5-de ] quinoline-7-carbonyl) bicyclo [2.2.2] oct-1-yl) carbamic acid tert-butyl ester 23h

23g (93 mg,0.35mmol, pichia) of compound 23f (80 mg,0.29 mmol) and 23g (93 mg,0.35 mmol) of compound 4- ((tert-butoxycarbonyl) amino) bicyclo [2.2.2] octane-1-carboxylic acid were dissolved in N, N-dimethylformamide (5 mL), N, N-diisopropylethylamine (111 mg,0.86 mmol) was added, followed by 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (163 mg,0.43mmol, shao-far chemical) and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 23h (140 mg, yield: 92.7%).

MS m/z(ESI):532.2[M+1]。

Eighth step

Compound 23h (178 mg,0.34 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2.5 mL) was added and the reaction stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 23 (90 mg, yield: 61.9%).

MS m/z(ESI):432.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.70(d,1H),8.12(d,1H),7.10(d,1H),6.96(d,1H),4.71-4.66(m,1H),4.63-4.53(m,1H),4.50-4.46(m,1H),4.28-4.25(m,1H),3.63-3.62(m,1H),3.52-3.49(m,1H),3.26-3.18(m,2H),3.16(s,2H),1.96-1.87(m,6H),1.72-1.69(m,6H),1.30-1.11(m,3H)。

Example 24

(±) -rel- (5 ar,6 r) -6-methyl-7- (4-methyl-5, 6,7, 8-tetrahydro-2, 6-naphthyridin-3-yl) -5,5a,6,7,8, 9-hexahydropyrazine [2',1':3,4] [1,4] oxazaheptano [7,6,5-de ] quinoline-13-carbonitrile 24

Using the synthetic route of example 3, starting compound 3a was replaced with starting compound 7-chloro-8-methyl-3, 4-dihydro-2, 6-naphthyridine-2 (1H) -carboxylic acid tert-butyl ester (Nanjing medical stone), affording the title compound 24 (28 mg).

MS m/z(ESI):427.0[M+1]

¹ H NMR(500MHz,CDCl ₃ )δ8.78(d,1H),8.00(s,1H),7.96(d,1H),6.98(d,1H),6.90(d,1H),4.47-4.35(m,2H),4.04-3.96(m,3H),3.75-3.65(m,1H),3.65-3.53(m,3H),3.53-3.31(m,3H),3.30-3.20(m,1H),2.87-2.84(m,2H),2.16(s,3H),1.30-1.24(m,3H)。

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

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

1. Experimental material and instrument

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

2. Raximote (R848/Resiquimod, invivogen)

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

4. Blasticidin (Blastidin, invivogen)

5. Bleomycin (Zeocin, invivogen)

6. Neomycin (Normocin, invivogen)

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

8. Fetal bovine serum (FBS, gibco)

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

10. Sterile pure water (Shanghai Hengrui homemade)

11.15ml centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well flat bottom cell culture plate (Corning)

14. Constant temperature cell incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

2. Experimental procedure

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

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

HEK-Blue ^TM hTLR7 cells were cultured in DMEM/Gao Tangpei containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL ZeocinIn the medium. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 with the complete medium ⁵ /mL. After 160. Mu.L of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell count per well was 76500/well, the final concentration of R848 was 1. Mu.M, and the final concentrations of the test compounds were 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM, respectively. The cells were placed at 37℃in 5% CO ₂ The culture was carried out in an incubator for 20 hours, then 20. Mu.L of the supernatant was taken, 180. Mu.L of the prepared alkaline phosphatase detection medium was added, and after incubation in an incubator at 37℃for 120 minutes in the absence of light, the absorbance of OD620 was read by an microplate reader. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 1.

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

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

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

1. Experimental material and instrument

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

2. Raximote (R848/Resiquimod, invivogen)

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

4. Blasticidin (Blastidin, invivogen)

5. Bleomycin (Zeocin, invivogen)

6. Neomycin (Normocin, invivogen)

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

8. Fetal bovine serum (FBS, gibco)

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

10. Sterile pure water (Shanghai Hengrui homemade)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well flat bottom cell culture plate (Corning)

14. Constant temperature cell incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

2. Experimental procedure

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

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

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

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

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

TestingEXAMPLE 3 inhibition of the activation pathway of human TLR9 by Compounds of the present disclosure

1. Experimental material and instrument

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

2.CpG ODN2006(Invivogen)

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

4. Blasticidin (Blastidin, invivogen)

5. Bleomycin (Zeocin, invivogen)

6. Neomycin (Normocin, invivogen)

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

8. Fetal bovine serum (FBS, gibco)

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

10. Sterile pure water (Shanghai Hengrui homemade)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well flat bottom cell culture plate (Corning)

14. Constant temperature cell incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

2. Experimental procedure

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

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

HEK-Blue ^TM hTLR9 cells were cultured in DMEM/high-sugar medium containing 10% FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin, and 100. Mu.g/mL bleomycin. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 by using DMEM high-sugar medium containing 10% inactivated FBS ⁵ /mL. After 160. Mu.l of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell number 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 placed at 37℃in 5% CO ₂ The culture was carried out in an incubator for 20 hours, then 20. Mu.L of the supernatant was taken, 180. Mu.L of the prepared alkaline phosphatase detection medium was added, and after incubation in an incubator at 37℃for 15 minutes in the absence of light, the absorbance of OD620 was read by an microplate reader. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 3.

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

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

Claims

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

wherein:

z is an O atom;

L ¹ selected from chemical bonds, CH ₂ C (O) and CH ₂ C(O)；

Ring A is selected from phenyl, pyridyl,

W ¹ 、W ² 、W ³ and W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom; ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom;

R ⁰ selected from hydrogen atoms, C _1-6 Alkyl, halogenated C _1-6 Alkyl, -NR ^c R ^d 、-NH(C(R ^e R ^f )) _s C(O)R ¹⁰ 、-NH(C(R ^e R ^f )) _s C(O)NR ^c R ^d And

L ² is a chemical bond;

ring B is a 4 to 12 membered heterocyclyl containing at least one N atom;

R ^1a is cyano;

R ^1b is a hydrogen atom;

R ¹ is a hydrogen atom;

R ² is a hydrogen atom;

R ³ is a hydrogen atom or C _1-6 An alkyl group;

each R is ⁴ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

each R is ⁵ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

R ¹⁰ is C _1-6 Alkyl, wherein said C _1-6 Alkyl groups optionally being substituted by one or more-NR groups ⁷ R ⁸ Substitution;

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

R ^c and R is ^d Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, halogenated C _1-6 Alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; or R is ^c And R is ^d Together with the attached N atom, form a 5-or 6-membered heterocyclyl;

R ^e and R is ^f Is a hydrogen atom;

r is 1;

s is 0, 1, 2 or 3;

n is 0, 1 or 2;

v is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4; and is also provided with

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

2. A compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein:

ring a, ring B, L ¹ 、R ^1a 、R ^1b 、R ¹ To R ⁵ R, n, v, m, p, q and t are as defined in claim 1.

3. A compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ^3a and R is ^3b Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group;

ring A, L ¹ 、R ⁰ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ R, n, v, m and q are as defined in claim 1.

4. The compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIIG), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A isW ¹ 、W ² 、W ³ And W is ⁴ One of which is a C atom and the remaining three are the same or different and are each independently CR ⁴ Or an N atom;

ring C is a 4 to 6 membered heterocyclyl containing at least 1N atom;

L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ r, n, v, m and q are as defined in claim 1.

5. A compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B is a 4 to 6 membered heterocyclyl containing at least one N atom;

t is 1, 2, 3 or 4;

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ 、R ⁵ R, n, v, m and q are as defined in claim 1.

6. A compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein:

ring A is

L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ⁴ 、R ^d R, n, v, m and q are as defined in claim 1.

7. A compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 4 to 6 membered heterocyclyl containing at least one N atom.

8. A compound of formula (I) according to any one of claims 3 to 6, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^3a Is C _1-6 Alkyl, and R ^3b Is a hydrogen atom; or R is ^3a Is a hydrogen atom, and R ^3b Is C _1-6 An alkyl group.

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

10. a compound of formula (IIIGA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

Wherein:

R ^W is an amino protecting group;

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ R, n, v, m and q are as defined in claim 4.

11. The compound of formula (IIIGA) according to claim 10, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein R ^W Is tert-butyloxycarbonyl.

12. A compound of formula (IVA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

R ^W is an amino protecting group;

ring a, ring B, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ R, n, v, m, q and t are as defined in claim 5.

13. The compound of formula (IVA) according to claim 12, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein R ^W Is tert-butyloxycarbonyl.

14. A compound of formula (IV-2A), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

R ^W is an amino protecting group;

ring A, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ 、R ^d R, n, v, m and q are as defined in claim 6.

15. The compound of formula (IV-2A) according to claim 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein R ^W Is tert-butyloxycarbonyl.

16. A compound, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof, selected from any one of the following compounds:

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

a compound of formula (IIIGA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereofRemoval of protecting groups R in the form of a compound, or a salt thereof ^W Optionally further with alkylating agent R ⁰ X or formaldehyde solution to give a compound of formula (IIIG) or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ^W is an amino protecting group;

x is a leaving group;

18. The method of claim 17, wherein R ^W T-butoxycarbonyl; x is halogen.

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

wherein:

R ^W is an amino protecting group;

x is a leaving group;

t is 1, 2, 3 or 4;

ring a, ring B, L ¹ 、R ^1a 、R ^1b 、R ¹ 、R ² 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ R, n, v, m and q are as defined in claim 5.

20. The method of claim 19, wherein R ^W T-butoxycarbonyl; x is halogen.

21. A process for preparing a compound of formula (IV-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

Wherein:

R ^W is an amino protecting group;

22. The method of claim 21, wherein R ^W Is tert-butyloxycarbonyl.

23. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

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

25. Use of a compound of formula (I) according to any one of claims 1 to 9 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR 9.

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

27. Use of a compound of general formula (I) according to any one of claims 1 to 9 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the preparation of a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases.

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