CN117229208B

CN117229208B - Condensed ring compound, preparation method and medical application thereof

Info

Publication number: CN117229208B
Application number: CN202311498048.5A
Authority: CN
Inventors: 陈庚辉; 蔡亚仙; 贾剑敏; 韩自省; 蔡开明
Original assignee: Shanghai Zedeman Pharmaceutical Technology Co ltd
Current assignee: Shanghai Zedeman Pharmaceutical Technology Co ltd
Priority date: 2023-11-13
Filing date: 2023-11-13
Publication date: 2024-02-23
Anticipated expiration: 2043-11-13
Also published as: CN117229208A

Abstract

The present disclosure relates to fused ring compounds, methods of preparing the same, and their use in medicine. In particular, the present disclosure relates to fused ring compounds represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the same, and use thereof as AhR modulators, particularly in the preparation of medicaments for treating and/or preventing AhR protein-mediated diseases or conditions.

Description

Condensed ring compound, preparation method and medical application thereof

Technical Field

The present disclosure relates to a condensed ring compound, a preparation method thereof and application thereof in medicine, and belongs to the field of medicine. In particular, the present disclosure relates to fused ring compounds represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the same, and use thereof as AhR modulators, particularly in the preparation of medicaments for treating and/or preventing AhR protein-mediated diseases or conditions.

Background

The Aromatic Hydrocarbon Receptor (AHR), also known as the dioxin receptor, is a member of the family of transcription regulators bHLH (basic Helix-Loop-Helix) -PAS (Per-ARNT-Sim). The unique feature of the bHLH-PAS family member is the PAS domain, the name of which originates from the three proteins that were first found to have this motif: drosophila Per, human ARNT and Drosophila Sim. The PAS domain consists of 260-310 amino acids and comprises two very conserved hydrophobic repeats, designated PAS-A and PAS-B, separated by se:Sup>A less conserved sequence. The bHH domain is responsible for binding to DNA, and tandem PAS domains (PAS-se:Sup>A and PAS-B) are involved in protein-protein interactions and ligand binding. In AHR, ligand binding occurs in the PAS-B domain. The N-terminal bHLH-PAS region of the bHLH-PAS family member is better conserved. Most non-conservative changes in AHR occur in the transcriptional activation domain, resulting in different protein-protein interactions with other co-activators, co-inhibitors, or nuclear receptors, regulating different gene expression.

In the absence of ligand, AHR is present in the cytosol and binds to a variety of chaperones, including a dimeric heat shock protein 90 (heat shock protein, HSP 90), accessory chaperone p23, AHR acting protein (AHR-Interacting Protein, AIP) and protein kinase Src. When bound to a ligand, AHR changes its conformation, translocates to the nucleus, separates from the chaperone complex, and then forms a heterodimer with the AHR nuclear translocator (Aryl hydrocarbon Receptor Nucleus Translocator, ARNT). The regulatory region upstream of the AHR regulatory gene comprises a DNA consensus sequence (5 '-TNGCGTG-3'), termed the foreign response element (Xenobiotic Responsive Element, XRE), also termed the dioxin response element (Dioxin Responsive Element, DRE). It acts as a transcriptional enhancer and is a site of binding to AHR. AHR-ARNT heterodimer complex is recruited by XRE to initiate transcription of the target gene.

Research shows that AHR is involved in physiological processes such as cell physiology, host defense, immune cell proliferation differentiation, detoxification and the like. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T cells, NK cells, and the like.

Because the ligand binding site of AHR is structurally flexible, many small molecules can act as ligands, including exogenous ligands such as polycyclic aromatic hydrocarbons, dioxins, polychlorinated biphenyls, and the like; endogenous ligands such as metabolites of tryptophan degradation, food-derived ligands and products of bacterial, microbial metabolic pathways. For example, the AHR modulator, this vitamin, is a naturally-derived small molecule produced by bacterial symbiota of entomopathogenic nematodes, is an aromatic receptor agonist that is first marketed worldwide, and can be used to treat a variety of autoimmune diseases, such as psoriasis, eczema, etc. However, due to the structural characteristics of the present vitamin mod, for example, the phenomenon of unstable light exists, the present vitamin mod is easy to degrade under illumination, and the application of the present vitamin mod is limited. Thus, the development of more stable AHR modulators is significant for expanding its clinical scope of application and reducing potential side effects.

Published related patent applications include WO2018068131A1, CN113797159A, CN112811985A, CN111759803B, CN113004127A, and the like.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

ring a is cycloalkyl or heterocyclyl;

G ¹ is a nitrogen atom or-CR ^g1 ；

G ² Is a nitrogen atom or-CR ^g2 ；

G ³ Is a nitrogen atom or-CR ^g3 The method comprises the steps of carrying out a first treatment on the surface of the And G is ¹ 、G ² And G ³ At least one of which is a nitrogen atom;

R ¹ 、R ² and R is ³ Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, cyano, -NR ⁿ¹ R ⁿ² 、-C(O)NR ⁿ³ R ⁿ⁴ 、-OR ^5a 、-C(O)OR ^5b 、-NR ⁿ⁵ C(O)R ^6a 、-S(O) _p NR ⁿ⁶ R ⁿ⁷ 、-C(O)R ^6b 、-OC(O)R ^6c 、-S(O) _q R ^6d Cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ⁴ Identical or different and are each independently selected from deuterium atoms, halogen, alkyl, alkenyl, alkynyl, oxo, cyano, -NR ⁿ¹ R ⁿ² 、-C(O)NR ⁿ³ R ⁿ⁴ 、-OR ^5a 、-C(O)OR ^5b 、-NR ⁿ⁵ C(O)R ^6a 、-S(O) _p NR ⁿ⁶ R ⁿ⁷ 、-C(O)R ^6b 、-OC(O)R ^6c 、-S(O) _q R ^6d Cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ Is branched alkyl; wherein said branched alkyl is optionally substituted with a member selected from the group consisting of halogen, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, alkylcyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of alkylamino, hydroxy and hydroxyalkyl;

R ^g1 、R ^g2 and R is ^g3 Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, cyano, -NR ⁿ¹ R ⁿ² 、-OR ^5a 、-C(O)OR ^5b and-C (O) R ^6b The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl is optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^5a and R is ^5b And are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, and-NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^6a 、R ^6b 、R ^6c And R is ^6d And are each independently selected from the group consisting of alkyl,Hydroxyalkyl, 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, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁿ¹ 、R ⁿ² 、R ⁿ³ 、R ⁿ⁴ 、R ⁿ⁵ 、R ⁿ⁶ 、R ⁿ⁷ 、R ⁿ⁸ and R is ⁿ⁹ Is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R is ⁿ¹ And R is ⁿ² 、R ⁿ³ And R is ⁿ⁴ 、R ⁿ⁶ And R is ⁿ⁷ 、R ⁿ⁸ And R is ⁿ⁹ Each together with the nitrogen atom to which they are attached form a heterocyclic group, wherein each of said heterocyclic groups is independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

p is 0, 1 or 2; and is also provided with

q is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1):

Wherein:

ring A, G ¹ 、G ² 、G ³ 、R ² 、R ³ 、R ⁴ 、R ⁵ And m is as defined in formula (I).

In some implementations of the disclosureIn embodiments, the compound of formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from C _1-6 Branched alkyl group, said C _1-6 The branched alkyl group is optionally substituted with one or more substituents selected from halogen, cyano, amino and hydroxy; preferably, R ⁵ Is isopropyl, optionally substituted with one or more substituents selected from halogen, cyano, amino and hydroxy; more preferably, R ⁵ Is isopropyl.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

wherein:

ring A, G ¹ 、G ² 、G ³ 、R ¹ 、R ² 、R ³ 、R ⁴ And m is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1) or formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, G ¹ 、G ² 、G ³ 、R ² 、R ³ 、R ⁴ And m is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of monocyclic cycloalkyl, fused ring alkyl, bridged cycloalkyl, monocyclic heterocyclyl and fused heterocyclyl; preferably, ring a is selected from monocyclic cycloalkyl, bridged cycloalkyl and monocyclic heterocyclyl; more preferably, ring a is a monocyclic cycloalkyl or a monocyclic heterocyclyl; further preferred, ring a is a 3 to 8 membered heterocyclyl or a 3 to 8 membered cycloalkyl; further preferred, ring a is a 3 to 6 membered heterocyclyl or a 3 to 6 membered cycloalkyl; further preferred, ring a is a 5 to 6 membered cycloalkyl; most preferably, ring a is cyclohexyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ is-CR ^g1 ；G ² Is a nitrogen atom; and G is ³ is-CR ^g3 ；R ^g1 And R is ^g3 As defined in formula (I);

or G ¹ Is a nitrogen atom or-CR ^g1 ；G ² Is a nitrogen atom; and G is ³ Is a nitrogen atom or-CR ^g3 ；G ¹ And G ³ One of them is a nitrogen atom; r is R ^g1 And R is ^g3 As defined in formula (I);

or G ¹ Is a nitrogen atom or-CR ^g1 ；G ² is-CR ^g2 The method comprises the steps of carrying out a first treatment on the surface of the And G is ³ Is a nitrogen atom or-CR ^g3 ；G ¹ And G ³ At least one of which is a nitrogen atom; r is R ^g1 、R ^g2 And R is ^g3 As defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (III):

wherein:

G ¹ 、G ³ 、R ¹ 、R ² 、R ³ 、R ⁴ and m is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), or formula (III) or a pharmaceutically acceptable salt thereof is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof:

wherein:

G ¹ 、G ³ 、R ² 、R ³ 、R ⁴ and m is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, wherein: g ¹ And G ³ Only one of which is a nitrogen atom; or G ¹ is-CR ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And G is ³ is-CR ^g3 ；R ^g1 And R is ^g3 As defined in formula (III); preferably G ¹ And G ³ Only one of which is a nitrogen atom; or G ¹ is-CR ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And G is ³ is-CR ^g3 ；R ^g1 And R is ^g3 Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 Alkyl, amino, cyano, hydroxy and C _1-6 An alkoxy group; more preferably G ¹ And G ³ Only one of which is a nitrogen atom; or G ¹ is-CR ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And G is ³ is-CR ^g3 ；R ^g1 And R is ^g3 Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; most preferably G ¹ And G ³ Only one of which is a nitrogen atom; or G ¹ is-CH; and G is ³ is-CH.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, wherein: r is R ^g1 And R is ^g3 Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 Alkyl, amino, cyano, hydroxy and C _1-6 An alkoxy group; preferably, R ^g1 And R is ^g3 Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^g1 And R is ^g3 The same or different, and are each independently a hydrogen atom or a halogen; most preferably, R ^g1 And R is ^g3 Are all hydrogen atoms.

In some embodiments of the present disclosure, the passingA compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein: r is R ^g2 Selected from hydrogen atom, deuterium atom, halogen, C _1-6 Alkyl, amino, cyano, hydroxy and C _1-6 An alkoxy group; preferably, R ^g2 Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^g2 The same or different, and are each independently a hydrogen atom or a halogen; most preferably, R ^g2 Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, wherein: r is R ² Selected from hydrogen atom, hydroxy, halogen, cyano, C _1-6 Alkylcyano, amino, C _1-6 Alkylamino, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy and C _1-6 An alkyl group; preferably, R ² Selected from hydrogen atom, hydroxy, halogen, C _1-6 Alkoxy and C _1-6 An alkyl group; more preferably, R ² Selected from hydrogen atoms, C _1-6 Alkoxy, halogen and C _1-6 An alkyl group; most preferably, R ² Is a hydrogen atom or a halogen.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, wherein: r is R ³ Selected from hydrogen atom, hydroxy, halogen, cyano, C _1-6 Alkylcyano, amino, C _1-6 Alkylamino, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy and C _1-6 An alkyl group; preferably, R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkoxy and C _1-6 An alkyl group; more preferably, R ³ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; most preferably, R ³ Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereofA salt for use wherein: r is R ² And R is ³ The same or different and are each independently selected from hydrogen atom, hydroxy, halogen, C _1-6 Alkoxy and C _1-6 An alkyl group; preferably, R ² And R is ³ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, wherein: each R is ⁴ Identical or different and are each independently selected from hydroxy, halogen, cyano, C _1-6 Alkylcyano, amino, C _1-6 Alkylamino, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy and C _1-6 Alkyl, and m is 0, 1, 2, 3 or 4; preferably, each R ⁴ Identical or different and are each independently selected from hydroxy, halogen, C _1-6 Alkoxy and C _1-6 Alkyl, and m is 0, 1 or 2; more preferably, each R ⁴ Identical or different and are each independently selected from C _1-6 Alkoxy, halogen and C _1-6 Alkyl, and m is 0, 1 or 2; most preferably, each R ⁴ Identical or different and are each independently C _1-6 Alkyl, and m is 0 or 2.

In some embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein: r is R ¹ Selected from hydrogen atom, hydroxy, halogen, cyano, C _1-6 Alkylcyano, amino, C _1-6 Alkylamino, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy and C _1-6 An alkyl group; preferably, R ¹ Selected from hydrogen atom, halogen, hydroxy, C _1-6 Alkoxy and C _1-6 An alkyl group; more preferably, R ¹ Is hydrogen atom, hydroxy, halogen and C _1-6 An alkyl group; most preferably, R ¹ Hydrogen atoms, hydroxyl groups and halogens.

Typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IA):

wherein:

R ¹ 、R ² and R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, cyano, amino, C _1-6 Alkylcyano, C _1-6 Alkylamino, C _2-6 Alkenyl and C _2-6 Alkynyl;

r is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, whereThe alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R is MOM or C _1-6 An alkyl group;

ring A, G ¹ 、G ² 、G ³ 、R ⁴ 、R ⁵ 、R ⁿ⁸ 、R ⁿ⁹ And m is as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1A):

wherein:

R ² and R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, cyano, amino, C _1-6 Alkylcyano, C _1-6 Alkylamino, C _2-6 Alkenyl and C _2-6 Alkynyl;

r is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R is MOM or C _1-6 An alkyl group;

ring A, G ¹ 、G ² 、G ³ 、R ⁴ 、R ⁵ 、R ⁿ⁸ 、R ⁿ⁹ And m is as defined in formula (I-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

wherein the method comprises the steps of：

ring A, G ¹ 、G ² 、G ³ 、R ⁴ 、R ⁿ⁸ 、R ⁿ⁹ And m is as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A):

wherein:

ring A, G ¹ 、G ² 、G ³ 、R ⁴ 、R ⁿ⁸ 、R ⁿ⁹ And m is as defined in formula (II-1).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIA):

wherein:

G ¹ 、G ³ 、R ⁴ 、R ⁿ⁸ 、R ⁿ⁹ and m is as defined in formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1A):

wherein:

r is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroarylIs optionally substituted independently from ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R is MOM or C _1-6 An alkyl group;

G ¹ 、G ³ 、R ⁴ 、R ⁿ⁸ 、R ⁿ⁹ and m is as defined in formula (III-1).

Typical intermediate compounds of the present disclosure include, but are not limited to:

/>

another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

deprotection reaction of a compound represented by the general formula (IA) or a salt thereof to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of:

deprotection reaction of a compound represented by the general formula (I-1A) or a salt thereof to obtain a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

deprotection reaction of a compound represented by the general formula (IIA) or a salt thereof to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

r is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferablyR is MOM or C _1-6 An alkyl group;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the steps of:

deprotection reaction of a compound represented by the general formula (II-1A) or a salt thereof to obtain a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof;

Wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

deprotection of a compound of formula (IIIA) or a salt thereof to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

deprotection of a compound represented by the general formula (III-1A) or a salt thereof to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

r is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylA group wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁿ⁸ R ⁿ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R is MOM or C _1-6 An alkyl group;

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a, or a pharmaceutically acceptable salt thereof, of the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for modulating an AhR protein; preferably in the manufacture of a medicament for agonizing or antagonizing an AhR protein.

The present disclosure further relates to the use of a compound of general formula (I), general formula (I-1), general formula (II-1), general formula (III) or general formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of an AhR modulator, preferably in the preparation of an AhR agonist or an AhR antagonist.

The present disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or of an AhR protein mediated disease or disorder.

The present disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of an AhR protein mediated disease or disorder, wherein the disease or disorder is selected from cancer, an ophthalmological related disease, an autoimmune disease, a viral infectious disease, a central nervous system disease, an inflammatory disease.

The present disclosure further relates to the preparation of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prophylaxis of dermatological disorders, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, non-alcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphomas, gliomas, cervical cancer, endometrial cancer, colorectal cancer, and colorectal cancer; preferably, the dermatological disorder is selected from the group consisting of psoriasis, acne, vitiligo and atopic dermatitis; preferably in the manufacture of a medicament for the treatment and/or prophylaxis of dermatological disorders; more preferably in the manufacture of a medicament for the treatment and/or prophylaxis of psoriasis, acne, vitiligo and atopic dermatitis.

The present disclosure further relates to a method of modulating an AhR protein comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of antagonizing (inhibiting) an AhR protein comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of agonizing an AhR protein comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing an AhR protein-mediated disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing an AhR protein-mediated disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from cancer, an ophthalmic related disease, an autoimmune disease, a viral infectious disease, a central nervous system disease, an inflammatory disease.

The present disclosure further relates to a method of treating and/or preventing skin disorders, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, non-alcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colorectal cancer, and colorectal cancer; comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a dermatological disorder; comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing psoriasis, acne, vitiligo, and atopic dermatitis; comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an AhR protein modulator.

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an AhR protein antagonist (inhibitor).

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an AhR protein agonist.

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of an AhR protein mediated disease or disorder.

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of an AhR protein mediated disease or disorder, wherein the disease or disorder is selected from cancer, an ophthalmic related disease, an autoimmune disease, a viral infectious disease, an immune disease, a central nervous system disease, an inflammatory or obstructive respiratory disease, an inflammatory disease, and other immunological-factor-bearing disorders or conditions.

The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II-1), formula (III) or formula (III-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prophylaxis of dermatological disorders, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative disorders, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, nonalcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, large intestine cancer and colorectal cancer; preferably, it is used for the treatment and/or prevention of skin disorders; more preferably, it is used for the treatment and/or prevention of psoriasis, acne, vitiligo and atopic dermatitis.

An "arene receptor (AHR) modulator" as described in this disclosure refers to an agent that causes or facilitates a qualitative or quantitative change, alteration or modification of one or more processes, mechanisms, effects, reactions, functions, activities or pathways mediated by the AHR receptor. Such changes mediated by an AHR modulator (an inhibitor of AHR or a non-constitutive agonist as described herein) may refer to a decrease or increase in AHR activity or function, such as a decrease, inhibition, or metastasis of AHR constitutive activity.

By "AHR antagonist" is meant an AHR inhibitor that does not itself elicit a biological response when specifically binding to an AHR polypeptide or an AHR-encoding polynucleotide, but blocks or inhibits an agonist-mediated or ligand-mediated response, i.e., an AHR antagonist may bind to but does not activate an AHR polypeptide or an AHR-encoding polynucleotide, and the binding disrupts interactions, replaces an AHR agonist, and/or inhibits the function of an AHR agonist. Thus, as used herein, when bound to AHR, AHR antagonists do not act as inducers of AHR activity, i.e., they act as pure AHR inhibitors.

As used herein, reference to an "AhR-mediated" disease and/or disorder means any disease or other deleterious condition in which AhR or mutants thereof are known to function. Thus, another embodiment of the invention relates to treating or lessening the severity of one or more diseases for which AhR or mutants thereof are known to play a role.

The term "cancer" as used in this disclosure includes, but is not limited to, the following cancers:

epidermoid oral cavity: oral cavity, lip, tongue, mouth, pharynx;

and (3) heart: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, mesothelioma;

gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectum;

urogenital tract: kidney (adenocarcinoma, wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract;

bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondrioma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor;

the nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, malformed osteomyelitis), meninges (meningioma, glioma disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma;

gynaecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-neoplastic cervical dysplasia), ovary (ovarian carcinoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), breast;

Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma hair cells, lymphopathies;

skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, keratoacanthoma, nevi, dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloids, psoriasis;

thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid carcinoma, type 2A multiple endocrine adenoma, type 2B multiple endocrine adenoma, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; neuroblastoma.

Neurodegenerative diseases described in the present disclosure can affect many activities of the body, such as balance, movement, speech, respiration, and cardiac function. Neurodegenerative diseases may be genetic diseases, but also medical diseases, such as alcoholism, tumors, strokes, toxins, chemicals and viruses.

Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig disease or progressive freezing), friedel-crafts ataxia, huntington's chorea, lewy body disease, parkinson's disease and spinal muscular atrophy.

Non-limiting examples of Central Nervous System (CNS) diseases or conditions described in the present disclosure include brain injury, spinal cord injury, dementia, stroke, alzheimer's disease, amyotrophic lateral sclerosis, parkinson's disease, huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, fahr disease, gauss's disease, wilson's disease, cerebral ischemia, and prion disease.

As used herein, the phrase "disease" or "disorder" broadly refers to any of the diseases or disorders described above that can be treated and/or prevented by administering a compound or arene receptor modulator (antagonist or agonist) described herein to a patient.

The compounds of the present disclosure or compositions thereof are useful for treating and/or preventing inflammatory or obstructive airways diseases, reducing, for example, tissue damage, airway inflammation, bronchial hyperreactivity, remodeling, or disease progression. Inflammatory or obstructive airways diseases to which the present disclosure is applicable include asthma of any type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also understood to encompass treatment of subjects exhibiting wheezing symptoms, e.g. less than 4 or 5 years of age, diagnosed or diagnosable as "wheezing infants", an established patient category of major medical problems and now often identified as early stage or early stage asthma patients.

Other inflammatory or obstructive respiratory diseases and/or conditions to which the present disclosure is applicable and which include Acute Lung Injury (ALI), adult/Acute Respiratory Distress Syndrome (ARDS), chronic obstructive pulmonary disease, respiratory or pulmonary disease, including chronic bronchitis or dyspnea associated therewith, emphysema and exacerbation of tracheal hyperreactivity by other drug therapies, particularly other inhaled drug therapies.

The present disclosure may also be used to treat inflammatory or allergic conditions of the skin, as well as other diseases or conditions, such as diseases or conditions having an inflammatory component, such as treating ocular diseases and conditions, such as ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or etiologies. Inflammatory diseases treatable according to the methods of the present disclosure are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic Juvenile Idiopathic Arthritis (SJIA), cryptopyrene protein-related periodic syndrome (CAPS), and osteoarthritis.

In some embodiments, the inflammatory disease treatable according to the methods of the present disclosure is selected from TH 17-mediated diseases. In some embodiments, the TH 17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including crohn's disease or ulcerative colitis).

"subject" and "patient" as described in this disclosure refer to an organism, such as a human, that is undergoing treatment for a particular disease or disorder described herein. The term subject or patient as used herein may refer to a mammal, such as a dog, cat, horse, cow, pig, guinea pig, and the like. For example, a patient, such as a human patient, in need of an arene receptor antagonist may receive treatment comprising an arene receptor antagonist to treat a disease or disorder described herein, such as cancer, an autoimmune disease, or an inflammatory disease.

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 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 the Deltec CADD-PLUS model TM. 5400 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 chain aliphatic hydrocarbon group (i.e., straight chain alkyl) or a branched aliphatic hydrocarbon group (i.e., branched alkyl) having from 1 to 20 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C _1-20 Alkyl group including C _1-20 Straight chain alkyl or C _1-20 Branched alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 Alkyl group including C _1-12 Straight chain alkyl or C _1-12 Branched alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl group including C _1-6 Straight chain alkyl or C _1-6 Branched alkyl). 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 Pentyl, 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, 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. 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, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having from 1 to 20 (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C _1-20 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples include: -CH ₂ -、-CH(CH ₃ )-、-C(CH ₃ ) ₂ -、-CH ₂ CH ₂ -、-CH(CH ₂ CH ₃ )-、-CH ₂ CH(CH ₃ )-、-CH ₂ C(CH ₃ ) ₂ -、-CH ₂ CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ CH ₂ -and the like. 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 D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxyOne or more of heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C _2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where alkyl is as defined above having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C _2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy 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, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8 membered cycloalkyl group), or preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group).

Non-limiting examples of such monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

The polycyclic cycloalkyl group includes: spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl group, more preferably 3/4-, 3/5-, 3-membered 6-, 4-, 5-, 4-, 6-, 5-, 3-, 5-, 4-, 5-, 6-, 5-, 7-, 5-, and 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 single spirocycloalkyl. Non-limiting examples include:the connection point can be at any position;etc.

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed ring alkyl group, 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, or 7-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples include:

The connection point can be at any position;

etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and which has from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:

the connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, 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 heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-), and having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered heterocyclyl) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12 membered heterocyclic group); further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6 membered heterocyclic group) or preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heterocyclic group).

Non-limiting examples of such monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The polycyclic heterocyclic group includes spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spiroheterocyclyl group). The spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6/6-, 6/7-, 7/5-or 7-membered mono-spiroheterocyclyl group. Non-limiting examples include:

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, 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 bicyclic fused heterocyclic group. Non-limiting examples include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10 membered bridged heterocyclic group). The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples 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 D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14 membered aryl) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group), more preferably an aryl group having 8 to 10 ring atoms (i.e., an 8 to 10 membered polycyclic aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cycloalkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

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

The term "heteroaryl" refers to a monocyclic heteroaryl ring having a conjugated pi electron system (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl group) containing at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-) within the ring having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5 to 14 membered heteroaryl group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered monocyclic heteroaryl group) or preferably a heteroaryl group having 8 to 10 ring atoms (i.e., an 8 to 10 membered polycyclic heteroaryl group).

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.) Etc.), pyrimidinone group, pyrimidineDiketone group (/ -)>) Aminopyrimidinone (+)>) Pyrazinyl, pyridazinyl, and the like.

Non-limiting examples of such polycyclic heteroaryl groups include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7, 8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2,4 ]]Triazolo [1,5-a ]]Pyridyl, and the like. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more of a cycloalkyl or heterocyclic group, where the point of attachment is on the monocyclic heteroaryl ring, and in such a case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: /> etc. Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2, 4-Dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group for blocking or protecting the hydroxy group to react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

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 "methylene" refers to =ch ₂ 。

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

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

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of atoms in space. Which includes cis and trans (orZAndE) Isomers, (-) -and (+) -isomersR) -sum%S) Enantiomers, diastereomers,(D) -sum%L) Isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g. racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (-) -can be prepared by chiral synthesis, chiral reagents or other conventional techniquesR) -sum%S) Enantiomers and their use(D) -sum%L) -an isomer. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods well known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bond'"means the unspecified configuration, i.e. if chiral isomers are present in the chemical structure, the bond" -/->"can be">"or" -/->", or also includes">"and">"two configurations".

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of lactam-lactam balances are shown below:

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Can be incorporated into the compounds of the present disclosure Examples of isotopes of (C) include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, e.g., respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ Iand the like, deuterium is preferable.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

In the compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to mean that the abundance of deuterium is at least 1000-fold greater than the natural abundance of deuterium (which is 0.015%), i.e., at least 15% deuterium incorporation. In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500-fold greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the event or circumstance includes instances where it occurs or is not. For example, "alkyl optionally substituted with halogen or cyano" includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms 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 bonds (e.g., alkenes).

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as 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.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, 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 an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art based on 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

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound represented by the general formula (IA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme II

The preparation method of the compound shown in the general formula (I-1) or the pharmaceutically acceptable salt thereof comprises the following steps:

Deprotection reaction of a compound shown in the general formula (I-1A) or a salt thereof under acidic conditions to obtain a compound shown in the general formula (I-1) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme III

The preparation method of the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound represented by the general formula (IIA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme IV

The preparation method of the compound shown in the general formula (II-1) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound shown in the general formula (II-1A) or a salt thereof under acidic conditions to obtain a compound shown in the general formula (II-1) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme five

The preparation method of the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound represented by the general formula (IIIA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme six

The preparation method of the compound shown in the general formula (III-1) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound represented by the general formula (III-1A) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

The reaction of the above steps is preferably carried out in solvents including, but not limited to: pyridine, 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,NDimethylformamide (DMA),N,NDimethylacetamide, 1, 2-dibromoethane and mixtures thereof.

The deprotection reaction of the above step is preferably carried out under acidic conditions, and the acidic reagent used is preferably selected from the group consisting of boron tribromide, hydrobromic acid, hydrochloric acid, 1, 4-dioxane solution of hydrochloric acid and pyridine hydrochloride.

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 compound isAs determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR Displacement (d) at 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO)d ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

The LC-40D XR+MS-2020 was used with waters 2695+ZQ2000, shimadzu MS-2020+LC-20AB and Shimadzu LC-40D.

High Performance Liquid Chromatography (HPLC) analysis uses Shimadzu LC-20AB, shimadzu LC-20ADXR, and Shimadzu LC-40D XR high performance liquid chromatographs.

Chiral HPLC analysis was performed using a Shimadzu LC-30AD high performance liquid chromatograph.

The high performance liquid phase preparation uses a Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparation was performed using Waters 150Mgm,Waters SFC 350 preparative chromatograph.

The CombiFlash rapid preparation instrument used CH-200P (Agela & Phenomnex).

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 the technology of yellow sea or Taitan on a tobacco table as a carrier.

The known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from the company of taitan technology, an Naiji chemistry, gossyphon biotechnology, pichia medicine, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

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

Examples the reaction is illustrated under hydrogen atmosphere, which means that the reactor flask is 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.

In the examples, the reaction was carried out under microwave conditions using a microwave reactor of the CEM Discover-S908860 type as illustrated.

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: petroleum ether/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.

In certain embodiments the purification of the compounds employs preparative HPLC.

Example 1

2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) benzene-1, 3-diol 1

First step

2- (2, 6-Dimethoxyphenyl) propyl-2-ol 1b

Compound 1a (15 g,108.5 mmol) and tetramethyl ethylenediamine (14.5 g,124.8 mmol) were dissolved in tetrahydrofuran (100 mL), replaced three times with nitrogen, the reaction system was cooled to-78 ℃ and n-butyllithium (65.1 mL,162.75 mmol) was added continuously, stirred for 0.5 h, then warmed to room temperature and stirred for 2 h. The reaction was cooled to-78 ℃, acetone (12.6 g,217.1 mmol) was added continuously, and then warmed to room temperature and stirred for 2 h. The reaction mixture was poured into saturated aqueous ammonium chloride (200 mL) cooled with an ice-water bath, and extracted with ethyl acetate (200 mL ×2). The organic phases were combined and washed with water (200 mL) and saturated brine (200 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 1b.

Second step

2-isopropyl-1, 3-dimethoxybenzene 1c

Compound 1b (4.9 g,24.9 mmol) was dissolved in dichloromethane (40 mL), replaced three times with nitrogen, the system was cooled to-78℃and triethylsilane (9.4 g,81.0 mmol) and trifluoroacetic acid (14.1 g,123.9 mmol) were added continuously, followed by stirring at room temperature for reaction 12 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL) cooled with an ice-water bath and extracted with dichloromethane (100 mL ×2). The organic phases were combined and washed with water (100 mL) and saturated brine (100 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 1c.

Third step

2-isopropyl-benzene-1, 3-diol 1d

Compound 1c (2 g,11.1 mmol) was dissolved in dichloromethane (15 mL), replaced with nitrogen three times, boron tribromide (5.5 g,22.1 mmol) was added dropwise at 0deg.C, and then the reaction was stirred at room temperature for 1 h. Diluted with dichloromethane (200 mL), quenched with saturated aqueous sodium bicarbonate (100 mL), the organic phase separated and washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 1d.

Fourth step

2-isopropyl-1, 3-bis (methoxymethoxy) benzene 1e

Compound 1d (1.5 g,9.8 mmol) and diisopropylethylamine (5.1 g,39.4 mmol) were dissolved in dichloromethane (15 mL), replaced with nitrogen three times, bromo (methoxy) methane (3.7 g,29.5 mmol) was added at 0deg.C, and then the reaction was stirred at room temperature for 2 h. Diluted with dichloromethane (100 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 1e.

Fifth step

2- [ 4-isopropyl-3, 5- (methoxymethoxy) phenyl ] -4, 5-tetramethyl-1, 3, 2-dioxapentaborane 1f

Compound 1e (0.6 g,2.5 mmol) and pinacol diboronate (1.2 g,4.9 mmol) were dissolved in tetrahydrofuran (7 mL) and replaced three times with nitrogen, and 4,4 '-di-tert-butyl-2, 2' -bipyridine (26.8 mg, 99.8. Mu. Mol) and methoxy (cyclooctadiene) iridium (I) dimer (33.1 mg, 49.9. Mu. Mol) were added successively followed by stirring at 80℃for reaction 3 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL ×2). The organic phases were combined and washed with water (50 mL) and saturated brine (50 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 1f.

Sixth step

1g of 2- [ 4-isopropyl-3, 5- (methoxymethoxy) phenyl ] -5,6,7, 8-tetrahydroisoquinoline

Compound 1f (400 mg,1.0 mmol) and 3-chloro-5, 6,7, 8-tetrahydroisoquinoline (183.0 mg,1.0 mmol) were dissolved inN,NTo dimethylformamide (4 mL), replaced with nitrogen three times, tetrakis (triphenylphosphine) palladium (126.2 mg, 109.2. Mu. Mol) and cesium carbonate (1.0 g,3.2 mmol) were added continuously, and then the reaction was stirred at 80℃for 6h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), and washed with water (60 mL) and saturated brine (60 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate, and subjecting the residue to silica gel column chromatographyPurification by chromatography (petroleum ether: ethyl acetate) gave the title product 1g.

Seventh step

2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) benzene-1, 3-diol 1

1g (250 mg, 673.0. Mu. Mol) of the compound was dissolved in dioxane (3 mL), and a dioxane solution (4M, 588.8. Mu.L) of hydrochloric acid was added dropwise at 0℃and then the reaction was stirred at room temperature for 1 h. Dilute with ethyl acetate (40 mL), quench with saturated aqueous sodium bicarbonate (50 mL), separate the organic phase, wash with water (50 mL) and saturated brine (50 mL), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated and the residue purified by preparative HPLC to give the title product 1.

LCMS (ESI, m/z): 284.2 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.39 (br s, 2H), 8.43 (s, 1H), 7.58 (s, 1H), 6.80 (s, 2H), 3.54-3.42 (m, 1H), 2.95-2.74 (m, 4H), 1.89-1.68 (m, 4H), 1.26 (d, J = 6.8 Hz, 6H)。

Example 2

2-isopropyl-5- (5, 6,7, 8-tetrahydroquinazolin-2-yl) phenol 2

First step

2- (4-bromo-2-methoxyphenyl) propyl-2-ol 2b

Compound 2a (10.0 g,40.8 mol) was dissolved in tetrahydrofuran (100 mL), cooled to-78℃under nitrogen, and then methyl magnesium bromide solution (89.7 mL,89.7 mmol) was added dropwise. After the completion of the dropwise addition, the reaction system was gradually warmed to 25℃and stirred for reaction 1 h. The reaction mixture was poured into saturated ammonium chloride solution (500 mL) at 0 ℃ and extracted with ethyl acetate (300 mL ×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the title product 2b.

Second step

4-bromo-1-isopropyl-2-methoxybenzene 2c

Referring to the second step of the synthesis in example 1, the title product 2c was prepared from intermediate 2b.

Third step

(4-isopropyl-3-methoxyphenyl) boronic acid 2d

Compound 2c (1.1 g,5.0 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to-78℃and then n-butyllithium solution (2.4 mL, 2.5M) was added dropwise. After the completion of the dropwise addition, the reaction mixture was stirred at-78℃for 0.5. 0.5 h, and triisopropyl borate (1.4 g,7.5 mmol) was further added. After the reaction mixture was slowly warmed to-30℃and diluted hydrochloric acid (10.0 mL, 2.5M) was added dropwise, the mixture was reacted at 25℃with stirring to give 0.5. 0.5 h. The reaction solution was quenched with water (20 mL), and then extracted with ethyl acetate (40 mL ×2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 2d.

Fourth step

5,6,7, 8-tetrahydroquinazoline-2, 4 (1 hydrogen, 3 hydrogen) -dione 2f

Compound 2e (2.8 g,16.45 mmol) and urea (4.94 g,82.25 mmol) were dissolved in ethanol (60 mL), sodium methoxide (4.00 g,74.03 mmol) was added, and then the reaction was stirred at 80 ℃ for 16 h. The system was cooled to room temperature, filtered, the filtrate was concentrated, water (50 mL) was added, and extracted with ethyl acetate (40 mL ×2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 2f.

Fifth step

2g of 2, 4-dichloro-5, 6,7, 8-tetrahydroquinazoline

Compound 2f (2.1 g,12.64 mmol) was added to phosphorus oxychloride (10 mL) and then reacted at 120 ℃ with stirring for 1 h. The system was cooled to room temperature, concentrated, and ethyl acetate (40 mL) and water (20 mL) were added. The organic phase was separated, washed with saturated aqueous sodium bicarbonate (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 2g.

Sixth step

2-chloro-5, 6,7, 8-tetrahydroquinazoline for 2h

2g (1 g,4.92 mmol) of the compound was dissolved in methylene chloride (15 mL), and aqueous ammonia (11.38 g,97.37 mmol) and zinc powder (1 g,15.29 mmol) were further added, followed by stirring at 40℃for reaction 16 h. The system was cooled to room temperature, filtered, and the filtrate was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product for 2h.

Seventh step

3- (4-isopropyl-3-methoxyphenyl) -5,6,7, 8-tetrahydroquinazoline 2i

Referring to the synthesis in the sixth step of example 1, the title product 2i was prepared from intermediates 2h and 2 d.

Eighth step

2-isopropyl-5- (5, 6,7, 8-tetrahydroquinazolin-2-yl) phenol 2

Compound 2i (0.2 g, 708.27. Mu. Mol) was dissolved in water (2 mL) and hydrobromic acid in acetic acid (3 mL) and then reacted at 100℃with stirring to give 17 h. The system was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (40 mL). The organic phase was separated, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by prep HPLC to give the title product 2.

LCMS (ESI, m/z): 269.1 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.47 (s, 1H), 8.52 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.28-3.19 (m, 1H), 2.84 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 1.92-1.73 (m, 4H), 1.19 (d, J = 7.2 Hz, 6H)。

Example 3

5-[(6R,8R) -7, 7-dimethyl-5, 6,7, 8-tetrahydro-6, 8-methyleneisoquinolin-3-yl) -2-isopropylphenol 3

First step

1- (2-ethoxy-2-oxoethyl) pyridine bromide 3b

Compound 3a (454.49 mmol,36.7 mL) was dissolved in ethyl acetate (400 mL), and ethyl 2-bromoacetate (30 g,179.64 mmol) was added dropwise, followed by stirring at 50℃for 1h. The system was cooled to 0 ℃ and filtered. The filter cake was collected and dried to give the title product 3b.

Second step

(6R,8R) -7, 7-dimethyl-5, 6,7, 8-tetrahydro-6, 8-methyleneisoquinolin-3-ol 3c

Compound 3b (1.97 g,7.99 mmol) was dissolved in formamide (15 mL), myrtenal (1.00 g,6.66 mmol) and ammonium acetate (5.00 g,64.87 mmol) were added further and the reaction was stirred at 90℃for 12 h. The system was cooled to room temperature and water (100 mL) and ethyl acetate (50 mL) were added. The organic phase was separated, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 3c.

Third step

(6R,8R) -7, 7-dimethyl-5, 6,7, 8-tetrahydro-6, 8-methyleneisoquinolin-3-yl trifluoromethanesulfonate 3d

Compound 3c (500 mg,2.64 mmol) and triethylamine (3.96 mmol,0.55 mL) were dissolved in dichloromethane (10 mL), cooled to 0℃and trifluoromethanesulfonic anhydride (3.17 mmol,0.52 mL) was slowly added dropwise, followed by stirring to react 1 h. To the reaction mixture was added water (100 mL) and methylene chloride (50 mL). The organic phase was separated, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give the title product 3d.

Fourth step

(6R,8R) -3- (4-isopropyl-3-methoxyphenyl) -7, 7-dimethyl-5, 6,7, 8-tetrahydro-6, 8-methyleneisoquinoline 3e

Referring to the sixth step of the synthesis in example 1, the title product 3e was prepared from intermediates 3d and 2 d.

Fifth step

Compound 3e (200 mg,0.62 mmol) was dissolved in dichloromethane (10 mL), replaced with nitrogen three times, boron tribromide (2.33 mmol,0.22 mL) was added dropwise at 0deg.C, and then the reaction was stirred at room temperature for 1 h. Diluted with dichloromethane (40 mL), quenched with saturated aqueous sodium bicarbonate (50 mL), the organic phase separated and washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue purified by preparative HPLC to give the title product 3.

LCMS (ESI, m/z): 308.1 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.37 (s, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 3.28-3.18 (m, 1H), 3.08-2.95 (m, 2H), 2.89-2.80 (m, 1H), 2.74-2.69 (m, 1H), 2.31-2.28 (m, 1H), 1.40 (s, 3H), 1.19 (d, J = 6.8 Hz, 6H), 1.16-1.14 (m, 1H), 0.61 (s, 3H)。

Example 4

2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) phenol 4

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First step

3- (4-isopropyl-3-methoxyphenyl) -5,6,7, 8-tetrahydroisoquinoline 4a

Referring to the sixth step of the synthesis in example 1, intermediate 2d and 3-chloro-5, 6,7, 8-tetrahydroisoquinoline

The title product 4a was prepared.

Second step

2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) phenol 4

Referring to the synthesis in the fifth step of example 3, the title product 4 was prepared from intermediate 4a.

LCMS (ESI, m/z): 268.1 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.36 (s, 1H), 8.29 (s, 1H), 7.51(d, J = 2.0 Hz, 1H), 7.48 (s, 1H), 7.37 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.25-7.09 (m, 1H), 3.24-3.17 (m, 1H), 2.83-2.68 (m, 4H), 1.82-1.71 (m, 4H), 1.18 (d, J= 6.8 Hz, 6H)。

Example 5

2-isopropyl-5- (5, 6,7, 8-tetrahydrocinnolin-3-yl) phenol 5

First step

3-chloro-5, 6,7, 8-tetrahydrocinnoline 5b

Referring to the synthesis in the fifth step of example 2, the title product 5b was prepared from intermediate 5 a.

Second step

3- (4-isopropyl-3-methoxyphenyl) -5,6,7, 8-tetrahydrocinnoline 5c

Referring to the sixth step of the synthesis in example 1, the title product 5c was prepared from intermediates 5b and 2 d.

Third step

2-isopropyl-5- (5, 6,7, 8-tetrahydrocinnolin-3-yl) phenol 5

Referring to the synthesis in the fifth step of example 3, the title product 5 was prepared from intermediate 5c.

LCMS (ESI, m/z): 269.1 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.68-9.55 (m, 1H), 7.95 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 3.28-3.22 (m, 1H), 3.06 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 1.94-1.85 (m, 2H), 1.83-1.74 (m, 2H), 1.20 (d, J = 7.2 Hz, 6H)。

Example 6

2-isopropyl-5- (5, 6,7, 8-tetrahydroquinoxalin-2-yl) phenol 6

First step

2- (4-isopropyl-3-methoxyphenyl) -5,6,7, 8-tetrahydroquinoxaline 6b

Referring to the sixth step of the synthesis in example 1, the title product 6b was prepared from intermediates 6a and 2 d.

Second step

2-isopropyl-5- (5, 6,7, 8-tetrahydroquinoxalin-2-yl) phenol 6

Referring to the synthesis in the fifth step of example 3, the title product 6 was prepared from intermediate 6b.

LCMS (ESI, m/z): 269.1 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.51 (s, 1H), 8.80 (s, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.28-3.18 (m, 1H), 2.94-2.85 (m, 4H), 1.89-1.84 (m, 4H), 1.19 (d, J = 6.8 Hz, 6H)。

Example 7

5- (6, 6-dimethyl-5, 6,7, 8-tetrahydroquinazolin-2-yl) -2-isopropylphenol 7

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First step

5, 5-dimethyl-2-oxocyclohexane-1-carboxylic acid ethyl ester 7b

Compound 7a (5.00 g,39.6 mmol) was dissolved in tetrahydrofuran (40 mL), sodium hydride (3.96 g,99.0 mmol) was added, and then heated to 70℃and reacted under stirring for 0.5 h. At this temperature, a solution of diethyl carbonate (14.0 g,118 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction system, and the reaction was continued for 2.5. 2.5 h. The system was cooled to room temperature, saturated aqueous ammonium chloride (300 mL) was added, and extracted with ethyl acetate (10 mL ×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the title product 7b.

Second step

6, 6-dimethyl-5, 6,7, 8-tetrahydroquinazoline-2, 4 (1H, 3H) -dione 7c

Referring to the fourth step of the synthesis in example 2, the title product 7c was prepared from intermediate 7b.

Third step

2, 4-dichloro-6, 6-dimethyl-5, 6,7, 8-tetrahydroquinazoline 7d

Referring to the synthesis in the fifth step of example 2, the title product 7d was prepared from intermediate 7 c.

Fourth step

2-chloro-6, 6-dimethyl-5, 6,7, 8-tetrahydroquinazoline 7e

Referring to the sixth step of the synthesis in example 2, the title product 7e was prepared from intermediate 7d.

Fifth step

2- (4-isopropyl-3-methoxyphenyl) -6, 6-dimethyl-5, 6,7, 8-tetrahydroquinazoline 7f

Referring to the sixth step of the synthesis in example 1, the title product 7f was prepared from intermediates 7e and 2 d.

Sixth step

5- (6, 6-dimethyl-5, 6,7, 8-tetrahydroquinazolin-2-yl) -2-isopropylphenol 7

Referring to the synthesis in the eighth step of example 2, the title product 7 was prepared from intermediate 7f.

LCMS (ESI, m/z): 297.2 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.47 (s, 1H), 8.50 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.27-3.18 (m, 1H), 2.85 (t, J = 6.8 Hz, 2H), 2.53 (s, 2H), 1.66 (t, J = 6.8 Hz, 2H), 1.18 (d, J = 6.8 Hz, 6H), 0.99 (s, 6H)。

Example 8

5- (7, 7-dimethyl-5, 6,7, 8-tetrahydroquinazolin-2-yl) -2-isopropylphenol 8

First step

4, 4-dimethyl-2-oxocyclohexane-1-carboxylic acid ethyl ester 8b

Referring to the first step of the synthesis in example 7, the title product 8b was prepared from intermediate 8 a.

Second step

7, 7-dimethyl-5, 6,7, 8-tetrahydroquinazoline-2, 4 (1H, 3H) -dione 8c

Referring to the fourth step of the synthesis in example 2, the title product 8c was prepared from intermediate 8b.

Third step

2, 4-dichloro-7, 7-dimethyl-5, 6,7, 8-tetrahydroquinazoline 8d

Referring to the fifth step of the synthesis in example 2, the title product 8d was prepared from intermediate 8 c.

Fourth step

2-chloro-7, 7-dimethyl-5, 6,7, 8-tetrahydroquinazoline 8e

Referring to the sixth step of the synthesis in example 2, the title product 8e was prepared from intermediate 8d.

Fifth step

2- (4-isopropyl-3-methoxyphenyl) -7, 7-dimethyl-5, 6,7, 8-tetrahydroquinazoline 8f

Referring to the sixth step of the synthesis in example 1, the title product 8f was prepared from intermediates 8e and 2 d.

Sixth step

5- (7, 7-dimethyl-5, 6,7, 8-tetrahydroquinazolin-2-yl) -2-isopropylphenol 8

Referring to the synthesis in the eighth step of example 2, the title product 8 was prepared from intermediate 8f.

LCMS (ESI, m/z): 297.2 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.45 (s, 1H), 8.55 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.27-3.19 (m, 1H), 2.77 (t, J = 6.8 Hz, 2H), 2.63 (s, 2H), 1.59 (t, J = 6.8 Hz, 2H), 1.19 (d, J = 6.8 Hz, 6H), 1.00 (s, 6H)。

Example 9

4-fluoro-2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) benzene-1, 3-diol 9

First step

4-bromo-2, 6-dimethoxy benzoic acid methyl ester 9b

Compound 9a (29.0 g,115 mmol) was dissolved in methanol (290 mL), sodium methoxide (45.7 g,254 mmol) was added continuously, and the reaction was stirred at 80℃for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL), and washed with water (200 mL) and saturated brine (200 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title product 9b.

Second step

4-bromo-3-fluoro-2, 6-dimethoxybenzoic acid methyl ester 9c

Compound 9b (25.0 g,90.8 mmol) was dissolved in acetonitrile (250 mL) and placed in an ice-water bath under nitrogen protection, 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroboric acid) salt (41.8 g,118 mmol) was added in portions. The reaction mixture was continued to stir at 25 ℃ for reaction 12 h. The reaction solution was poured into ethyl acetate (300 mL), and washed with water (300 mL) and saturated brine (300 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the title product 9c.

Third step

2- (4-bromo-3-fluoro-2, 6-dimethoxyphenyl) propan-2-ol 9d

Referring to the first step of the synthesis in example 2, the title product 9d was prepared from intermediate 9c.

Fourth step

1-bromo-2-fluoro-4-isopropyl-3, 5-dimethoxybenzene 9e

Referring to the second step of the synthesis in example 1, the title product 9e was prepared from intermediate 9d.

Fifth step

(2-fluoro-4-isopropyl-3, 5-dimethoxyphenyl) boronic acid 9f

Referring to the synthesis in the third step of example 2, the title product 9f was prepared from intermediate 9e.

Sixth step

9g of 3- (2-fluoro-4-isopropyl-3, 5-dimethoxyphenyl) -5,6,7, 8-tetrahydroisoquinoline

Referring to the synthesis in the sixth step of example 1, the title product 9g was prepared from intermediate 9f and 3-chloro-5, 6,7, 8-tetrahydroisoquinoline.

Seventh step

Referring to the synthesis in the fifth step of example 3, the title product 9 was prepared from 9g of intermediate.

LCMS (ESI, m/z): 302.1 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.10 (s, 2H), 8.33 (s, 1H), 7.38 (s, 1H), 6.82 (d, J = 6.0 Hz, 1H), 3.52-3.43 (m, 1H), 2.78-2.72 (m, 4H), 1.78-1.75 (m, 4H), 1.28 (d, J = 6.8 Hz, 6H); ¹⁹ F NMR (400 MHz, DMSO-d ₆ , ppm): δ -150.56 (1F)。

Example 10

3, 4-difluoro-2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) phenol 10

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First step

1- (2, 3-difluoro-6-methoxyphenyl) ethyl-2-one 10b

Compound 10a (15.0 g,104 mmol) was dissolved in tetrahydrofuran (100 mL), replaced three times with nitrogen, the system was cooled to-78℃and n-butyllithium (45.8 mL,114.5 mmol) was added continuously and stirred for 0.5h. Continuous addition to the reaction solutionNMethoxy-)NMethylacetamide (12.9 g,124.90 mmol) and then stirred at-78 ℃ for reaction 2 h. The reaction mixture was poured into saturated aqueous ammonium chloride (1000 mL) cooled with an ice-water bath, and extracted with ethyl acetate (100 mL ×3). The organic phases were combined and washed with water (200 mL) and saturated brine (200 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the title product 10b.

Second step

2- (2, 3-difluoro-6-methoxyphenyl) propyl-2-ol 10c

Referring to the first step of the synthesis in example 2, the title product 10c was prepared from intermediate 10 b.

Third step

1, 2-difluoro-3-isopropyl-4-methoxybenzene 10d

Referring to the second step of the synthesis in example 1, the title product 10d was prepared from intermediate 10c.

Fourth step

(2, 3-difluoro-4-isopropyl-5-methoxyphenyl) boronic acid 10e

Referring to the synthesis of the third step in example 2, compound 10e was prepared from intermediate 10d.

Fifth step

3- (2, 3-difluoro-4-isopropyl-5-methoxyphenyl) -5,6,7, 8-tetrahydroisoquinoline 10f

Referring to the synthesis of the sixth step in example 1, compound 10f was prepared from intermediate 10e and 3-chloro-5, 6,7, 8-tetrahydroisoquinoline.

Sixth step

3, 4-difluoro-2-isopropyl-5- (5, 6,7, 8-tetrahydroisoquinolin-3-yl) phenol 10

Referring to the fifth step of the synthesis in example 3, the title product 10 was prepared from intermediate 10f.

LCMS (ESI, m/z):304.0 [M+H] ⁺ 。

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.90 (s, 1H), 8.43 (s, 1H), 7.52 (s, 1H), 7.14 (d, J = 6.0 Hz, 1H), 3.44-3.36 (m, 1H), 2.83-2.75 (m, 4H), 1.82-1.74 (m, 4H), 1.30 (d, J = 7.2 Hz, 6H)； ¹⁹ F NMR (400 MHz, DMSO-d ₆ , ppm): δ -141.07 (1F), -154.50 (1F)。

Biological evaluation

The present test example is a luciferase reporter gene test experiment performed using method one to test the agonistic effects of the disclosed compounds on AHR proteins with control example 1 (benvimmod) and control example 2 (control example 2 please see WO2018068131A1, example 1, compound 1). Wherein the structures of the comparative example 1 and the comparative example 2 are as follows:

1) Test cell

Human hepatoma cells HepG2-Lucia expressing AHR and luciferase were purchased from InvivoGen under the trade designation hpgl-AHR.

2) Main instrument

Biosafety cabinet, model 307, thermo fisher company;

CO ₂ incubator, model CLM-240B-8-CN, ESCO company;

a cytometer model EVE-MC2, nanoEnTeK company;

ECHO (nanoliter sonic pipetting system), model 655, labcyte corporation;

microplate centrifuge, model PlatePro 3200, monad company;

multifunctional enzyme labeling instrument, model PHERAstar FSX, BMG LRBTECH company.

3) Main reagent

Green streptomycin, gibco company, cat# 15140-122;

EMEM medium, ATCC company, cat# 30-2003;

fetal bovine serum, ausgenex, cat# FBS500-S;

NEAA medium, gibco, cat# 11140-050;

phosphate buffer, gibco, cat# 14190250;

DMSO (dimethyl sulfoxide), solarbio company, cat No. D8371;

FICZ (6-formyl indolo [3,2-B ] carbazole), MCE company, cat# HY-12451;

zeocin (bleomycin), invivoGen company, cat# ant-zn-1;

QUANTI-Luc Gold, invivoGen, cat# rep-qlcg5.

4) Experimental procedure

a. HepG2-Lucia AHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1 XNEAA, green streptomycin and 100. Mu.g/ml Zeocin (bleomycin). The culture temperature is 37 ℃, and the carbon dioxide concentration is 5%;

b. Cells were grown to a confluence of about 80%, and the cells were digested and centrifuged to re-suspend the cells. Inoculating the cells into 384 well plates, 40 μl per well;

c. different concentrations of test compound were added using ECHO, 40nL per well;

d. culturing 384-well plates added with the compound in an incubator for 24 hours;

e. taking the supernatant, adding a QUANTI-Luc Gold detection reagent, and reading a luminescence signal value by using a multifunctional enzyme-labeling instrument.

5) Test results

Activity of Compounds of the present disclosure and control examples against AhR protein EC ₅₀ (luciferase-labeled human hepatoma cell (HepG 2-Lucia) AhR agonist EC) ₅₀ (μm)) are summarized in table 1 below.

TABLE 1 EC of compounds of the present disclosure on AHR activation ₅₀

Conclusion: the results show that the compound disclosed by the invention has better activation activity on AHR protein, which is obviously superior to that of a control example.

Test example 2: luciferase reporter assay

In this test example, a luciferase reporter gene test was performed using method two to test the agonistic activity effects of the disclosed compounds and the control compounds (the control 1 and control 2 compounds and test 1) on AHR proteins.

Test cell

The human hepatoma cell HepG2-Lucia expressing AHR and luciferase was from InvivoGen.

Main instrument

Biological safety cabinet, model BSC-1500 IIa 2-X, BIOBASE company;

CO ₂ incubator, model CLM-240B-8-CN, ESCO company;

a cytometer model EVE-MC2, nanoEnTeK company;

a bench type low-speed centrifuge, model MD-550, meier company;

multifunctional enzyme labeling instrument model Lumistation 1800, flash company.

Main reagent

Green streptomycin, gibco company, cat# 15140-122;

EMEM medium, ATCC company, cat# 30-2003;

fetal bovine serum, gibco, cat No. 10100147C;

NEAA medium, gibco, cat# 11140-050;

phosphate buffer, beyotime company, cat No. C0221A;

DMSO (dimethyl sulfoxide), solarbio company, cat No. D8370;

FICZ (6-formyl indolo [3,2-B ] carbazole), MCE company, cat# HY-12451;

zeocin (bleomycin), invitogen company, cat No. ant-zn-05;

normocin, invivoGen Co., ltd., cat# ant-nr-1

QUANTI-Luc Gold, invivoGen, cat# rep-qlcg5.

Experimental procedure

1. HepG2-Lucia AHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1 XNEAA, penicillin and 100. Mu.g/ml Normocin, 100. Mu.g/ml Zeocin (bleomycin). The culture temperature was 37℃and the carbon dioxide concentration was 5%.

2. Cells were grown to a confluency of about 80%, the cells were digested, centrifuged and counted in EMEM medium containing 10% inactivated fetal bovine serum, 1 XNEAA, and green streptomycin. Cells were seeded into 96-well plates at 180 μl per well.

3. Different concentrations of test compound were added, 20 μl per well.

4. The 96-well plates to which the compounds were added were incubated in an incubator for 24 hours.

5. Taking the supernatant, adding a QUANTI-Luc Gold detection reagent, and reading a luminescence signal value by using a multifunctional enzyme-labeling instrument.

Test results

Activity of Compounds of the disclosure and control Compounds against AHR proteins EC ₅₀ Is summarized in table 2 below:

table 2: EC of compounds of the present disclosure on AHR activation ₅₀

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein: ring a is cyclohexyl;

G ¹ is a nitrogen atom or-CR ^g1 ；

G ² Is nitrogenAtomic or-CR ^g2 ；

R ¹ selected from hydrogen atom, halogen, hydroxy, C _1-6 Alkoxy and C _1-6 An alkyl group;

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

each R is ⁴ Identical or different and are each independently selected from halogen, hydroxy, C _1-6 Alkoxy and C _1-6 Alkyl, and m is 0, 1 or 2;

R ^g1 、R ^g2 and R is ^g3 Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 An alkyl group.

2. The compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, wherein G ¹ is-CR ^g1 ；G ² Is a nitrogen atom; and G is ³ is-CR ^g3 ；R ^g1 And R is ^g3 As defined in claim 1;

or G ¹ Is a nitrogen atom or-CR ^g1 ；G ² Is a nitrogen atom; and G is ³ Is a nitrogen atom or-CR ^g3 ；G ¹ And G ³ One of them is a nitrogen atom; r is R ^g1 And R is ^g3 As defined in claim 1;

or G ¹ Is a nitrogen atom or-CR ^g1 ；G ² is-CR ^g2 The method comprises the steps of carrying out a first treatment on the surface of the And G is ³ Is a nitrogen atom or-CR ^g3 ；G ¹ And G ³ At least one of which is a nitrogen atom; r is R ^g1 、R ^g2 And R is ^g3 As defined in claim 1.

3. A compound or pharmaceutically acceptable salt thereof, as shown below:

4. a compound:

5. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for agonizing an AhR protein.

7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the preparation of an AhR agonist.

8. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for the treatment and/or prophylaxis of an AhR protein mediated disease or condition.

9. The use according to claim 8, wherein the disease or condition is selected from cancer, autoimmune disease, viral infectious disease, central nervous system disease, inflammatory disease.

10. The use according to claim 8, wherein the disease or condition is selected from the group consisting of skin disorders, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, nonalcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, and colorectal cancer.

11. The use according to claim 10, wherein the skin disorder is selected from psoriasis, acne, vitiligo and atopic dermatitis; the inflammatory bowel disease is Crohn's disease or ulcerative colitis.