CN116789641A

CN116789641A - Dihydro isoquinoline compound and medical application thereof

Info

Publication number: CN116789641A
Application number: CN202210267102.4A
Authority: CN
Inventors: 段文虎; 耿美玉; 詹正生; 谢作权; 姚珊燕; 王玺渊; 周晓倩; 张燕; 周鸿飞; 丁健
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2022-03-17
Filing date: 2022-03-17
Publication date: 2023-09-22
Also published as: WO2023174383A1

Abstract

The invention relates to a dihydroisoquinoline compound and medical application thereof, in particular to a compound with a structure shown as a formula (I), which can be used as a secretion regulator of type I interferon, especially as a cGAS/STING signal path targeting inhibitor, and can be used for preparing medicines in medicines for preventing and/or treating inflammatory diseases and autoimmune diseases.

Description

Dihydro isoquinoline compound and medical application thereof

Technical Field

The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular relates to a dihydroisoquinoline compound and medical application thereof, and also relates to a pharmaceutical composition of the compound and application of the compound serving as a secretion regulator of type I interferon, in particular to a cGAS/STING signal path targeting inhibitor in preparation of medicines for preventing and/or treating inflammatory diseases and autoimmune diseases.

Background

STING, also known as transmembrane protein 173 (TMEM 173), MPYS, MITA or ERIS, is a protein encoded by the human TMEM173 gene. The cGAS/STING signaling pathway plays an important role in the innate immune process. Inducing cGAMP (cyclic GMP-AMP) when the DNA receptor cGAS (cyclic GMP-AMP) monitors pathogen DNA; next cGAMP activates interferon gene stimulators (stimulator of interferon genes, STNG) to recruit STING downstream TANK-binding kinase 1 (TBK 1), induces secretion of type i interferons and cytokines by phosphorylating interferon regulatory factor3 (interferon regulatory factor, IRF 3), and activates the acquired immune system through a series of cascades, activating T cells to exert antitumor immunity. Abnormal activation of the innate immune system can induce various diseases, and research on molecular mechanisms of cGAS/STING signal channels provides a new idea for research and development of targeted drugs.

The cGAS/STING signaling pathway can be precisely regulated by physiological processes and pharmaceutical methods of the body, including post-translational modification of proteins (phosphorylation, ubiquitination, etc.), small molecule antagonists (e.g., H-151, C-176), and agonists, etc. (e.g., DMXAA, MSA-2). When the cGAS/STING signaling pathway is abnormally or overactivated, inflammatory and autoimmune diseases, such as AGS syndrome, systemic Lupus Erythematosus (SLE), can be triggered. Thus, unlike the immune killing effect of cGAS/STING activators on tumor cells, targeted inhibition of cGAS/STING signaling pathways can be used in the treatment of such inflammatory and autoimmune diseases.

Small molecule compound studies targeted to inhibit cGAS/STING signaling pathways are in the initiation phase, but have been a hotspot in research in the field of medical physiology. Haag et al in 2018 reported on Nature that nitrofurans and indolylureas (Nature 2018,559,269-273.) that block palmitoylation induced by STING activation by covalently binding to Cys91 on STING proteins, thereby interfering with their assembly into multimeric complexes in the golgi apparatus to inhibit downstream signaling. In addition, the inhibitor can inhibit the secretion of inflammatory cytokines mediated by STING protein in the cells of the mice to alleviate the pathological characteristics of the autoinflammatory diseases of the mice. In 2019, lama et al published on Nature Communication an indolopiperidine series of compounds (nat. Commun.2019,10,2261.) that were effective in inhibiting cGAS activity in human bone marrow-derived macrophages (BMMD). In 2021, group Wang Chen of the university of Chinese medicine reported that sulfonamide compound SN-011, which binds to the cyclic dinucleotide binding domain of STING protein to exert STING inhibitory activity, was found in Trex1 ^-/- Can strongly inhibit inflammatory and autoimmune diseases in mice (Proc.Natl. Acad. Sci.U.S. A.2021,118, e 2105465118.). Therefore, small molecule inhibitors targeted to inhibit cGAS/STING signaling pathways are expected to be important therapeutic agents for autoimmune diseases.

In recent years, known pharmaceutical companies such as Nohua, bayer and Gift have been increasingly involved in the development of small molecule inhibitors targeting the cGAS/STING signaling pathway. Most of researches of the compounds are in a cell activity verification stage, and no small molecule inhibitor in a clinical research stage exists at present. Thus, there is a need to develop high activity and drug-forming small molecule inhibitors targeting cGAS/STING signaling pathways to develop therapeutic agents for autoimmune diseases.

Disclosure of Invention

The invention aims to provide a high-activity and drug-forming small molecule inhibitor targeting the cGAS/STING signal pathway, which can be used as a therapeutic drug for autoimmune diseases.

In a first aspect of the present invention there is provided a compound of formula (I), or a prodrug, enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein Q is selected from O or S;

Ring a is selected from the group consisting of substituted or unsubstituted: a C6-C12 aryl and a 5-12 membered heteroaryl; wherein the substitution means that the substituted chain is substituted by 1 to 5R ¹ Substitution; wherein each R ¹ Independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-C12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; r is R ¹ Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

Ring B is

Wherein E is NR ¹⁰ Or CR (CR) ¹⁰ R ^10’ ；

R ¹⁰ Selected from: COOC1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-to 12-membered heteroarylC 1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclylC 1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C6 alkyl, substituted or unsubstituted C6-membered heteroaryl, substituted or unsubstituted C6-C12-membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;

R ^10’ 、R ^g 、R ^g’ 、R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、R ^j And R is ^j’ Each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ¹⁰ And R is ^10’ Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

Alternatively, R ^g And R is ^g’ Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ^h And R is ^h’ Oxo (=o) common to the C atoms to which they are attached, into a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ⁱ And R is ^i’ Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ^j And R is ^j’ The C atoms to which they are attached together form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

Alternatively, R ^g And R is ^h Together with the C atom to which they are attached form oxygenA substituent (=o), a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ⁱ And R is ^j Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ⁱ And R is ¹⁰ Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

alternatively, R ^h And R is ¹⁰ Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

Ra is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

n is 1 or 2.

In another preferred embodiment, each R ¹ Independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, Nitro group,/->Substituted or unsubstituted benzyl.

In another preferred embodiment, ring a is selected from the group consisting of substituted or unsubstituted: five membered heteroaryl, six membered aryl, six membered heteroaryl, [6+6 ]]Aryl or condensed rings, [6+6 ]]Heteroaryl or condensed rings, [6+5 ]]Heteroaryl or condensed rings, [5+6 ]]Heteroaryl or condensed rings, [5+5 ]]Heteroaryl or condensed rings, wherein the substitution is by 1-5R ¹ Substitution; wherein each R ¹ Independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-C12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; r is R ¹ Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxy, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

In another preferred embodiment, R ¹ Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, trifluoromethoxy, benzyl, HOCH ₂ -、HOCH ₂ CH ₂ -、CF ₂ CH-、 CF ₃ CH ₂ CH ₂ -, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

In another preferred embodiment, ring a is selected from the following structures:

wherein X is selected from: o, S or NH;

R ¹ is substituent groups at any position on the ring, the number of the substituent groups is 1-5, and each R ¹ Independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino,Nitro group,/->A substituted or unsubstituted benzyl group, a substituted or unsubstituted C6-C12 arylmethyl group, a substituted or unsubstituted 5-C12 arylmethyl group, a substituted or unsubstituted heteroarylmethyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylacyl group, a substituted or unsubstituted aminoacyl group, a substituted or unsubstituted C1-C6 alkylamido group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C6-C12 arylamino group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group; r is R ¹ Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxy, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

wherein X is selected from NH;

R ¹ is substituent groups at any position on the ring, the number of the substituent groups is 1, 2 or 3, R ¹ Is defined as above, preferably R ¹ Selected from: hydrogen, halogen, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl NH, -OP (O) (OH) ₂ Substituted C1-C6 alkyl, amino C1-C6 alkyl COO substituted C1-C6 alkyl; more preferably, R ¹ Selected from: trifluoromethyl, phenyl, phenylamino, cyano, methoxy, cl, F, br,

In another preferred embodiment, ring B is selected from the following structures:

wherein, the liquid crystal display device comprises a liquid crystal display device,

m is N or CH;

R ⁴ selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

R ¹⁰ selected from: COOC1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclic group), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-to 12-membered heteroarylC 1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclylC 1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C6 alkyl, substituted or unsubstituted C6-membered heteroaryl, substituted or unsubstituted C6-C12-membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;

R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And R is ⁹ Each independently selected from: H. halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamineA group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C6-C12 arylC 1-C6 alkyl group, a substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl group, -CO (3-8 membered substituted or unsubstituted heterocyclic group), -CO (C3-C8 substituted or unsubstituted cycloalkyl group); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

or R is ² And R is ³ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

Or R is ³ And R is ⁴ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

or R is ⁴ And R is ⁵ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

or R is ⁶ And R is ⁷ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclyl;

or R is ⁷ And R is ⁸ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

Or R is ⁸ And R is ⁹ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

R ^a 、R ^a’ 、R ^b 、R ^b’ 、R ^c 、R ^c’ 、R ^d 、R ^d’ 、R ^e 、R ^e’ 、R ^f 、R ^f’ 、R ^g 、R ^g’ 、R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、 R ^j and R is ^j’ Each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 alkyl, substituted or unsubstituted C1-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted aryl Unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

ring C is selected from: substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 6-12 membered aryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2;

ra is as defined above.

In another preferred embodiment, R ^a 、R ^a’ 、R ^b 、R ^b’ 、R ^c 、R ^c’ 、R ^d 、R ^d’ 、R ^e 、R ^e’ 、R ^f 、R ^f’ 、R ^g 、R ^g’ 、 R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、R ^j 、R ^j’ Each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino,Nitro group,A substituted or unsubstituted benzyl group, a substituted or unsubstituted C6-C12 arylmethyl group, a substituted or unsubstituted 5-to 12-membered heteroarylmethyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkanoyl group, a substituted or unsubstituted aminoacyl group, a substituted or unsubstituted C1-C6 alkylamido group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C6-C12 arylamino group, a substituted or unsubstituted 3-to 8-membered heterocyclic group, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 5-to 8-membered heteroaryl group, a substituted or unsubstituted 6-to 12-membered aryl group; The substitution is mono-substitution or poly-substitution, each substituent is independently halogen, carboxyl, hydroxyl, cyano, amino, nitro, trifluoromethoxy, benzyl, HOCH ₂ -、HOCH ₂ CH ₂ -、CF ₂ CH-、CF ₃ CH ₂ CH ₂ -, C1-C6 alkyl, C1-C6 alkoxy or 3-8 membered heterocyclyl.

In another preferred embodiment, when R ^a And R is ^a’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^b And R is ^b’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^c And R is ^c’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^d And R is ^d’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^e And R is ^e’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^f And R is ^f’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^g And R is ^g’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^h And R is ^h’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ⁱ And R is ^i’ When the two are oxygen atoms, the two are connected with carbon atoms to form carbonyl; when R is ^j And R is ^j’ In the case of oxygen atoms, a carbonyl group is formed with the carbon atom to which they are attached.

M、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ^a 、R ^a’ 、R ^b 、R ^b’ 、R ^c 、R ^c’ 、R ^g 、R ^g’ 、 R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、R ^j 、R ^j’ and n is as defined aboveSaid.

In another preferred embodiment, R ⁴ Selected from: halogen, carboxyl, hydroxyl, cyano, amino,Nitro group,A substituted or unsubstituted benzyl group, a substituted or unsubstituted arylmethyl group, a substituted or unsubstituted heteroarylmethyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkanoyl group, a substituted or unsubstituted aminoacyl group, a substituted or unsubstituted C1-C6 alkylamido group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted 6-12 membered arylamino group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 6-12 membered aryl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, trifluoromethoxy, benzyl, HOCH ₂ -、HOCH ₂ CH ₂ -、CF ₂ CH-、CF ₃ CH ₂ CH ₂ -, C1-C6 alkyl, C1-C6 alkoxy or 3-8 membered heterocyclyl.

In another preferred embodiment, R ⁴ Selected from: halogen, hydroxy, carboxyl,Nitro group,/-> Cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl; wherein the C1-C6 alkyl group, C1-C6 alkoxy group C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl optionally substituted with 1-3 of the following groups: halogen, hydroxy, carboxy, ester, cyano, C1-C6 alkyl, halo C1-C6 alkyl.

In another preferred embodiment, R ¹⁰ Selected from: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl is optionally substituted with 1-3 of the following groups: halogen, hydroxy, carboxy, ester, cyano, C1-C6 alkyl, halo C1-C6 alkyl.

In another preferred embodiment, the compound has the structure of formulas II-1 to II-3

Wherein G is a 6 membered aryl or heteroaryl group;

g' is a C6-C12 aryl or 5-12 membered heteroaryl;

g' is C6-aryl or 5-6 membered heteroaryl;

R _m each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-C12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein said substitution is by one or A plurality of substituents selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; preferably, R _m Each independently selected from: hydrogen, halogen, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, 5-12 membered heteroaryl, C6-C12 aryl NH, -OP (O) (OH) ₂ Substituted C1-C6 alkyl, amino C1-C6 alkyl COO substituted C1-C6 alkyl; more preferably, R _m Each independently selected from: trifluoromethyl, phenyl, phenylamino, cyano, methoxy, cl, F, br,

R _m’ Each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

R _m” and R is _m”’ Each independently selected from: H. halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkyl Oxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

n is 1 or 2;

f. f ', f ", and f'" are each independently 0, 1, 2, or 3;

R ⁴ is defined as above.

In another preferred embodiment, the B ring is selected from:

/>

in another preferred embodiment, a prodrug of a compound of formula I has a structure of formula III-1 or III-2

Wherein L is a C1-C6 alkylene group;

rn is selected from: p (O) (OH) ₂ Or amino C1-C6 alkyl CO; preferably is

G、G’、R _m’ 、R _m” 、R _m”’ The definitions of f ', f ", and f'" are as described above.

In another preferred embodiment, Q, ring A, ring B, G, G', G ", E, R ^a 、R ^a’ 、R ^b 、R ^b’ 、R ^c 、 R ^c’ 、R ^d 、R ^d’ 、R ^e 、R ^e’ 、R ^f 、R ^f’ 、R ^g 、R ^g’ 、R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、R ^j 、R ^j’ 、R ¹ 、R ² 、R ³ 、R ⁴ 、 R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R _m 、R _m’ 、R _m” And R is _m”’ Corresponding groups of each specific compound in the examples.

In another preferred embodiment, the compound is selected from the following compounds:

in a second aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of the first aspect, or a prodrug thereof, an enantiomer, a diastereomer, a racemate, and mixtures thereof, or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.

In a third aspect the present invention provides the use of a compound according to the first aspect, or a prodrug thereof, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for the preparation of a cGAS/STING pathway targeting inhibitor; or (b)

Is used for preparing medicines for preventing and/or treating inflammatory diseases and autoimmune diseases.

In another preferred embodiment, the inflammatory and autoimmune diseases are selected from the group consisting of: singleton-Merten syndrome (SMS), aicardi-gouteres syndrome (AGS), systemic Lupus Erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal vascular disease and white matter dystrophy (RVCL), STING-related infant onset vasculopathy (SAVI), scleroderma, silver shoulder disease, sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, crohn's disease, ulcerative colitis, autoimmune colitis, small intestine malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative disease.

In a fourth aspect of the present invention, there is provided a method of inhibiting the activity of STING proteins, comprising contacting a cell capable of expressing STING proteins with a compound according to the first aspect, whereby secretion of interferon can be inhibited by inhibiting the activity of STING proteins.

In another preferred embodiment, the cells are of human and/or murine origin.

In another preferred embodiment, the cells are THP1-Blue-ISG cells and/or Raw-lucia cells.

It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Detailed Description

The inventor of the present application has studied extensively and intensively to develop a dihydroisoquinoline compound which can be used as a cGAS/STING signal pathway targeting inhibitor for the treatment of inflammatory diseases and autoimmune diseases. On this basis, the present application has been completed.

Terminology

In the present application, the halogen is F, cl, br or I.

In the present application, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.

In the present application, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on.

"5-12 membered" means having 5-12 ring atoms, and so on.

In the present application, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, for example the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.

In the present invention, the term "alkoxy" means an-O- (alkyl) group. For example, the term "C1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

In the present invention, the term "alkenyl" means a straight or branched hydrocarbon moiety containing at least one double bond, for example, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group containing one double bond having 2 to 6 carbon atoms, including without limitation ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

In the present invention, the term "alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond, for example, the term "C2-C6 alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond having 2 to 6 carbon atoms, including, without limitation, ethyl, propyl, butyl, isobutyl, pentyl, hexynyl, and the like.

In the present invention, the term "cycloalkyl" means a saturated cyclic hydrocarbon moiety, for example, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

The term "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O, which may be monocyclic or bicyclic, for example bridged or spiro. The heterocyclic group is preferably a 3-8 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, and still more preferably a 5-6 membered heterocyclic group. Examples of heterocyclyl groups include, but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl,Etc.

In the present invention, the term "aryl" means a hydrocarbyl moiety comprising one or more aromatic rings. For example, the term "C6-C12 aryl" refers to an aromatic cyclic group having 6 to 12 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring. The term "C6-C12 aryl" has similar meaning. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthryl, and phenanthryl.

The term "heteroaryl" refers to a cyclic aromatic group having 1 to 3 atoms which are heteroatoms selected from the group N, S and O, which may be monocyclic or in the form of condensed rings. In the present invention, the heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably a 5-10 membered, still more preferably a 5-8 membered. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3) -triazolyl, and (1, 2, 4) -triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, carbazole, indolyl, indazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazole, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. The term "[6+5+6] heteroaryl" refers to a fused 6, 5, 6 tricyclic ring system such as dibenzo [ b, d ] thiophene, the term "[6+5] heteroaryl" refers to a heteroaryl group in which a 6-membered aryl or heteroaryl group is fused based on a 5-membered heteroaryl group such as benzothienyl, indole, isoindole, benzofuranyl, benzimidazolyl, benzotriazole, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, "[6+6] heteroaryl" refers to a heteroaryl group in which a 6-membered aryl or heteroaryl group is fused to a 6-membered heteroaryl group such as quinoline, isoquinoline, quinoxaline, and the like. "[5+5] heteroaryl" has a similar meaning. Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamide, formyl, carboxamide, carboxyl, carboxylate and the like. In the present invention, the "heteroaryl ring", "aromatic heterocycle", "heteroaryl" have the same meaning as the substituents.

In the present invention, [6+6 ]]Aryl or condensed rings, [6+6 ]]Heteroaryl or condensed rings, [6+5 ]]Heteroaryl or condensed rings, [5+6 ]]Heteroaryl or condensed rings, [5+5 ]]Heteroaryl or fused ring means a ring in which a 5-6 membered aryl or heteroaryl group is fused to a 5-6 membered cycloalkyl or heterocycloalkyl group, e.g/>

Etc.

In the present invention, "amino" means having the structure-N (R) (R '), R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment. Examples of amino groups are NH ₂ 、NHCH ₃ 、N(CH ₃ ) ₂ 。

In the present invention, "carbamoyl" means having NH ₂ -c=o-structural groups, wherein H in the group may be substituted.

Unless otherwise indicated, alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to: hydroxy, amino, nitro, cyano, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C3-C20 heterocycloalkyl, C3-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C10 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfinyl, arylsulfinyl, C1-C10 alkylimino, C1-C10 alkylsulfonimido, arylsulfonyl imino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureyl, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl may also be fused to each other.

In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on.

In the present invention, the term "plurality" independently means 2, 3, 4, 5.

The term prodrug, also called prodrug, etc., refers to a compound which is obtained by chemical structure modification of a drug, is inactive or less active in vitro, and releases an active drug in vivo through enzymatic or non-enzymatic conversion to exert drug efficacy.

The term "pharmaceutically acceptable salt" refers to salts (including zwitterionic and like internal salts) that have efficacy similar to the parent compound and are biologically or otherwise acceptable (e.g., are neither toxic nor harmful to the subject). Accordingly, embodiments of the present invention provide pharmaceutically acceptable salts of the compounds of the present invention. The term "salt" as used herein means any of the following acid salts formed from inorganic and/or organic acids, as well as basic salts formed from inorganic and/or organic bases. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of an acid or base (e.g., an equivalent amount of an acid or base) in a medium (e.g., such medium may allow precipitation of the salt therein; or with water as the medium followed by lyophilization).

Active ingredient

As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound) or prodrug thereof. The term also includes racemates and optical isomers.

The compounds are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form. Furthermore, when the compound of the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, carboxylic acids, the possible formation of zwitterions ("inner salts") are included within the term "salts". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during the preparation process. The compounds of the invention may form salts, for example, by reacting compound I with an amount of, for example, an equivalent of, an acid or base, salting out in a medium, or lyophilizing in aqueous solution.

The compounds of the present invention contain basic fragments, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that may be salified include acetates (e.g., with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalene sulfonate (e.g., 2-naphthalene sulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluene sulfonate such as p-toluenesulfonate, dodecanoate, and the like.

Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, that may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (salts with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the invention are also within the scope of coverage. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound, salt, or solvate of the invention when used in the treatment of a related disorder. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention, may exist in tautomeric forms (e.g., amides and imine ethers). All of these tautomers are part of the present invention.

Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The individual stereoisomers of the compounds of the invention may not be present simultaneously with the other isomers (e.g., having particular activity as one pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.

All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and the trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are described in conjunction with Periodic Table of the Elements, CAS version, handbook of Chemistry and Physics,75 ^th Ed.. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.

Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.

According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.

The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, respectively, such as ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, e.g ³ H and ¹⁴ radioisotopes of C are also useful in, among other things, tissue distribution experiments of drugs and substrates. Tritium, i.e. tritium ³ H and carbon-14, i.e ¹⁴ C, their preparation and detection are relatively easy. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, i.e ² H may be preferred in some cases because of its good metabolic stability, which may be advantageous in certain therapies, such as increasing half-life or decreasing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagentsMay be prepared using the protocols disclosed in the examples.

If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.

As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", in the formulas of the present invention includes substituents, means that the specified structural substituent is substituted for the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.

Metabolites of the compounds and pharmaceutically acceptable salts thereof of the present application, as well as prodrugs that can be converted in vivo to structures of the compounds and pharmaceutically acceptable salts thereof of the present application are also encompassed by the claims of the present application.

Process for the preparation of compounds

The following schemes and examples describe methods for preparing compounds of formula I. The starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of the steps of the reaction scheme may be altered to promote the reaction or to avoid unwanted side reaction products.

Typically, in the preparation scheme, each reaction is carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., 0 ℃ to 150 ℃, preferably 10 ℃ to 100 ℃). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5 to 48 hours.

Preferably, the compounds of formula (I) of the present application can be prepared by the following steps

The compounds of formula (I) can be prepared by two methods as shown above:

1) The aromatic amine is treated by triphosgene to obtain isocyanate which is then mixed withReacting to obtain a compound shown in a formula (I);

2) The aromatic acid is treated by DPPA (diphenyl azide phosphate) to obtain acyl azide, and then is converted into isocyanate by heating, and then is reacted with The compound shown in the formula (I) is obtained through reaction.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent STING kinase agonistic activity, the compound of the present invention or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, and a pharmaceutical composition comprising the compound of the present invention as a main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) STING kinase-related inflammatory diseases and autoimmune diseases. The inflammatory and autoimmune diseases are selected from the group consisting of Singleton-Merten syndrome (SMS), aicarpi-Goutigres syndrome (AGS), systemic Lupus Erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal vascular diseases and leukodystrophy (RVCL), STING-related infant onset vascular lesions (SAVI), scleroderma, silver shoulder disease, sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, crohn's disease, ulcerative colitis, autoimmune colitis, small intestine malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease, and neurodegenerative disease.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention within a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (e.g. sodium lauryl sulphate), colouring agents, flavouring agents, stabilisers, anti-oxidantsOxidizing agents, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., STING agonists).

When administered in combination, the pharmaceutical composition also includes a pharmaceutical composition in combination with one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., STING agonists). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately or sequentially with the compounds of the present invention for preventing and/or treating diseases associated with the activity or expression level of STING kinase.

When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain from l to 2000mg of active ingredient per dose, more preferably from 10 to 200mg of active ingredient per dose. Preferably, the "one dose" is a tablet.

The invention has the main advantages that:

1. the compound has inhibitory activity on STING proteins in human cells and/or murine cells, and can be used as a cGAS/STING signal channel targeting inhibitor;

2. the compound of the invention has better drug effect and pharmacokinetics.

The invention will be further specifically illustrated by the following detailed experimental procedures in examples. These exemplary compounds are depicted in neutral form in the examples below. In some cases, the compounds are isolated as salts according to the method and/or intrinsic molecular properties used for final purification. These examples are merely illustrative of the invention and are not intended to limit the scope of the patent in any way. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Examples

Example 1N- (1H-indol-3-yl) -3, 4-dihydro-isoquinoline-2 (1H) -carboxamide (I-1)

Step (1): 1H-indol-3-acyl azide (1-1)

A mixture of 1 g of 1H-indole-3-carboxylic acid, 1.12 ml of triethylamine and 30 ml of dichloromethane was stirred at room temperature for 15 minutes, and after addition of 1.35 ml of diphenyl azide phosphate in portions, stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate: petroleum ether=30:70 column chromatography gives 949 mg of 1H-indol-3-acyl azide (1-1) as a white solid in 82% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.69(br s,1H),8.26–8.28(m,1H),7.96(d, J＝3.2Hz,1H),7.42–7.45(m,1H),7.29–7.35(m,2H).

Step (2): 3-isocyanato-1H-indole (1-2)

A mixture of 400 mg of Compound 1-1 and 40 ml of toluene was heated and stirred overnight at 130℃under argon. The reaction mixture was concentrated to dryness to give 339 mg of 3-isocyanato-1H-indole (1-2) as a pale brown solid in 100% yield. ¹ H NMR (400MHz,CDCl ₃ )δ8.02(s,1H),7.49(d,J＝8.7Hz,2H),7.33(d,J＝8.1Hz,1H),7.21(t, J＝7.5Hz,1H),7.13(t,J＝7.3Hz,1H),6.60(s,1H),3.82(s,3H).

Step (3): n- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-1)

A mixture of 80 mg of Compound 1-2, 80 mg of 1,2,3, 4-tetrahydroisoquinoline and 0.5 ml of N, N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was added with water, extracted with ethyl acetate, and the organic phase was concentrated to dryness, extracted with ethyl acetate: petroleum ether=1:1 to prepare thin layer, obtaining off-white solid N- (1H-indol-3-yl) -3, 4-dihydro isoquinoline-2 (1H) -carboxamide (I)1) 52 mg, yield 35%. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.25(s,1H), 7.61(d,J＝8.0Hz,1H),7.36(d,J＝2.4Hz,1H),7.32(d,J＝8.0Hz,1H),7.17–7.20(m, 4H),7.04–7.08(m,1H),6.93–6.97(m,1H),4.67(s,2H),3.75(t,J＝5.6Hz,2H),2.88(t, J＝5.6Hz,2H).

Example 2N- (1H-indol-3-yl) -3, 4-dihydro-isoquinoline-1 (2H) -carboxamide (I-2)

N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-1 (2H) -carboxamide (I-2) is prepared in the same manner as Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.77(s,1H),8.58(s,1H),7.60(d,J＝7.6Hz,1H), 7.50(d,J＝8.0Hz,1H),7.44(d,J＝2.4Hz,1H),7.33(d,J＝8.0Hz,1H),7.06–7.13(m, 3H),6.92–6.99(m,2H),7.91(t,J＝6.0Hz,2H),7.27(t,J＝6.4Hz,2H),1.88–1.94(m, 2H).

Example 3 6-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-3)

The preparation method of 6-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-3) is the same as that of compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.27(s,1H),7.61(d,J＝8.0Hz,1H), 7.30–7.43(m,4H),7.17(d,J＝7.6Hz,1H),7.08(t,J＝7.6Hz,1H),6.97(t,J＝7.2Hz, 1H),4.63(s,2H),3.73(t,J＝6.0Hz,2H),2.89(t,J＝6.0Hz,2H).

Example 4N- (7-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-4)

Step (1): 7-fluoro-1H-indol-3-acyl azide (4-1)

The preparation method of 7-fluoro-1H-indole-3-acyl azide (4-1) is the same as that of compound 1-1. ¹ H NMR(400MHz, DMSO-d ₆ )δ12.85(s,1H),8.25(d,J＝2.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.19–7.27 (m,1H),7.15(t,J＝8.0Hz,1H).

Step (2): 7-fluoro-3-isocyanato-1H-indole (4-2)

The preparation method of 7-fluoro-3-isocyanato-1H-indole (4-2) is the same as that of the compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ : 177.1.

Step (3): n- (7-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-4)

N- (7-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-4) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.21(s,1H),8.33(s,1H),7.43–7.46(m,2H), 7.19–7.20(m,4H),6.87–6.95(m,2H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.88(t,J＝ 6.0Hz,2H).

Example 5N- (6-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-5)

Step (1): 6-fluoro-1H-indol-3-yl azide (5-1)

6-fluoro-1H-indolesThe preparation method of the-3-acyl azide (5-1) is the same as that of the compound 1-1.LRMS (ESI) M/z [ M+H] ⁺ : 205.3.

Step (2): 6-fluoro-3-isocyanato-1H-indole (5-2)

The preparation method of 6-fluoro-3-isocyanato-1H-indole (5-2) is the same as that of the compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ : 177.2.

Step (3): n- (6-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-5)

N- (6-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-5) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.78(s,1H),8.30(s,1H),7.60–7.63(m,1H),7.37 (d,J＝1.6Hz,1H),7.19–7.20(m,4H),7.10(dd,J＝2.4,10.4Hz,1H),6.85(td,J＝2.0, 9.6Hz,1H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.87(t,J＝6.0Hz,2H).

Example 6N- (5-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-6)

Step (1): 5-fluoro-1H-indol-3-yl azide (6-1)

The preparation method of 5-fluoro-1H-indole-3-acyl azide (6-1) is the same as that of compound 1-1.LRMS (ESI) M/z [ M+H] ⁺ : 205.1.

Step (2): 5-fluoro-3-isocyanato-1H-indole (6-2)

The preparation method of the 5-fluoro-3-isocyanato-1H-indole (6-2) is the same as that of the compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ : 177.3.

Step (3): n- (5-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-6)

N- (5-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-6) is prepared in the same manner as Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.83(s,1H),8.24(s,1H),7.45(d,J＝2.8Hz,1H), 7.39(dd,J＝2.4,10.4Hz,1H),7.29–7.32(m,1H),7.14–7.21(m,4H),6.93(td,J＝1.8, 9.2Hz,1H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H).

Example 7N- (1H-indol-6-yl) -3, 4-dihydro-isoquinoline-2 (1H) -carboxamide (I-7)

Step (1): 1H-indol-6-acyl azide (7-1)

1H-indol-6-acyl azide (7-1) is prepared in the same manner as compound 1-1. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.67(s,1H),8.11(s,1H),7.30–7.70(m,3H),6.58(s,1H).

Step (2): 6-isocyanato-1H-indole (7-2)

Preparation method of 6-isocyanato-1H-indole (7-2)And compounds 1-2.LRMS (ESI) M/z [ M+H] ⁺ : 159.1.

Step (3): n- (1H-indol-6-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-7)

N- (1H-indol-6-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-7) is prepared in the same manner as Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.91(s,1H),8.45(s,1H),7.67(s,2H),7.38(d,J＝8.4 Hz,1H),7.19–7.21(m,5H),7.05(dd,J＝2.0,8.4Hz,1H),6.32(t,J＝2.8Hz,1H),4.65 (s,2H),3.73(t,J＝6.0Hz,2H),2.87(t,J＝6.0Hz,2H).

Example 8N- (benzo [ b ] thiophen-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-8)

Step (1): benzo [ b ] thiophen-3-acyl azide (8-1)

Benzo [ b ]]Thiophene-3-acyl azide (8-1) was prepared in the same manner as compound 1-1. ¹ H NMR(400MHz, CDCl ₃ )δ8.66(d,J＝8.1Hz,1H),8.46(s,1H),7.88(d,J＝8.1Hz,1H),7.58–7.40(m, 2H).

Step (2): 3-Isocyanulatobenzo [ b ] thiophene (8-2)

3-Isocyanulatobenzo [ b ]]Thiophene (8-2) was prepared in the same manner as in compound 1-2. ¹ H NMR(400MHz, DMSO-d ₆ )δ10.41(s,1H),8.40(d,J＝7.9Hz,1H),7.96(d,J＝7.7Hz,1H),7.77(s,1H), 7.44(dt,J＝7.1,14.8Hz,2H).

Step (3): n- (benzo [ b ] thiophen-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-8)

N- (benzo [ b)]Thiophene-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-8) was prepared in the same manner as compound I-1. ¹ H NMR(400MHz,CDCl ₃ )δ7.87–7.81(m,1H),7.73(s,1H),7.58(d,J＝7.3Hz, 1H),7.40(dt,J＝8.6,6.2Hz,2H),7.22(dd,J＝10.3,5.2Hz,4H),4.75(s,2H),3.81(t,J ＝5.9Hz,2H),2.99(t,J＝5.8Hz,2H).

Example 9N- (1H-indol-3-yl) -6-trifluoromethyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-9)

N- (1H-indol-3-yl) -6-trifluoromethyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-9) may be prepared in the same manner as Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(s,1H),8.32(s,1H),7.60(d,J＝8.2 Hz,2H),7.55(d,J＝8.2Hz,1H),7.42(d,J＝8.0Hz,1H),7.36(d,J＝2.2Hz,1H),7.31 (d,J＝8.1Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.75(s,2H),3.77(t, J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).

Example 10N- (1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-10)

Step (1): 2-Boc-6-phenyl-1, 2,3, 4-tetrahydroisoquinoline (10-1)

500 mg of 2-Boc-6-bromo-1, 2,3, 4-tetrahydroisoquinoline, 391 mg of phenylboronic acid, 1.04 g of carbonA mixture of cesium acid, 185 mg of tetrakis (triphenylphosphine) palladium and 11 ml of ethylene glycol dimethyl ether was stirred under argon at 85 ℃ for 3 hours. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate: petroleum ether=2:98 column chromatography gives 413 mg of 2-Boc-6-phenyl-1, 2,3, 4-tetrahydroisoquinoline as a white solid in 83% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ 7.74(d,J＝7.5Hz,2H),7.56(q,J＝8.5Hz,4H),7.45(t,J＝7.3Hz,1H),7.35(d,J＝7.7 Hz,1H),4.64(s,2H),3.68(t,J＝5.7Hz,2H),3.46(s,3H),2.95(t,J＝5.6Hz,2H),2.61 (s,1H).

Step (2): 6-phenyl-1, 2,3, 4-tetrahydroisoquinoline (10-2)

A mixture of 340 mg of Compound 10-1, 2 ml of trifluoroacetic acid and 8 ml of water was stirred at room temperature for 3 hours. The reaction solution was diluted with saturated sodium bicarbonate, extracted with dichloromethane, washed with organic water and concentrated to dryness to give 213 mg of 6-phenyl-1, 2,3, 4-tetrahydroisoquinoline (10-2) as a white solid in 93% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.62 (d,J＝7.7Hz,2H),7.49–7.30(m,5H),7.09(d,J＝7.8Hz,1H),3.86(s,2H),2.96(t,J＝ 5.8Hz,2H),2.76(d,J＝5.6Hz,2H).

Step (3): n- (1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-10)

N- (1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-10) may be prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.28(s,1H),7.66(d,J＝7.6Hz, 2H),7.62(d,J＝7.8Hz,1H),7.47(dd,J＝16.4,8.6Hz,4H),7.41–7.21(m,4H),7.06(t,J ＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.71(s,2H),3.77(t,J＝5.5Hz,2H),2.95(s,2H).

Example 11N- (5, 6-difluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-11)

Step (1): 5, 6-difluoro-1H-indol-3-acyl azide (11-1)

The preparation method of 5, 6-difluoro-1H-indole-3-acyl azide (11-1) is the same as that of compound 1-1. ¹ H NMR(400MHz, DMSO-d ₆ )δ12.38(s,1H),8.32–8.17(m,1H),7.87(dd,J＝8.1,2.7Hz,1H),7.64–7.48 (m,1H),7.44(d,J＝7.2Hz,1H),7.25(s,1H).

Step (2): 5, 6-difluoro-3-isocyanato-1H-indole (11-2)

The preparation method of 5, 6-difluoro-3-isocyanato-1H-indole (11-2) is the same as that of compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ :195.1.

Step (3): n- (5, 6-difluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-11)

N- (5, 6-difluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-11) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.89(s,1H),8.28(s,1H),7.60(dd,J＝11.6,8.2Hz,1H),7.45(d,J＝2.3Hz,1H),7.32(dd,J＝11.3,7.0Hz,1H),7.20(s,4H), 4.67(s,2H),3.73(t,J＝5.9Hz,2H),2.87(t,J＝5.8Hz,2H).

Example 12N- (1H-indol-3-yl) -4-phenylpiperazine-1-carboxamide (I-12)

N- (1H-indol-3-yl) -4-phenylpiperazine-1-carboxamide (I-12) is prepared in the same manner as for compound I-1. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.70(s,1H),8.31(s,1H),7.61(d,J＝7.9Hz,1H),7.37(d,J＝ 2.0Hz,1H),7.30(d,J＝8.1Hz,1H),7.24(t,J＝7.8Hz,2H),7.09–6.92(m,4H),6.81(t, J＝7.2Hz,1H),3.69–3.55(m,4H),3.22–3.11(m,4H).

Example 13N- (benzofuran-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-13)

Step (1): benzofuran-3-acyl azide (13-1)

Benzofuran-3-acyl azide (13-1) is prepared in the same manner as compound 1-1. ¹ H NMR(400MHz, DMSO-d ₆ )δ8.90(s,1H),8.09–7.99(m,1H),7.82–7.71(m,1H),7.51–7.41(m,2H).

Step (2): 3-isocyanatobenzofuran (13-2)

3-isocyanatobenzofuran (13-2) is prepared in the same manner as in compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ : 160.1.

Step (3): n- (benzofuran-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-13)

N- (benzofuran-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-13) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67(s,1H),8.12(s,1H),7.93(d,J＝7.5Hz,1H),7.51 (d,J＝8.1Hz,1H),7.29(dt,J＝24.9,7.3Hz,2H),7.20(s,4H),4.70(s,2H),3.76(t,J＝ 5.9Hz,2H),2.88(t,J＝5.8Hz,2H).

Example 14N- (benzofuran-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-14)

N- (benzofuran-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-14) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(s,1H),8.14(s,1H),7.95(d,J＝7.6Hz, 1H),7.66(d,J＝7.6Hz,2H),7.40–7.57(m,5H),7.31–7.37(m,4H),4.75(s,2H),3.80(t, J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).

Example 15N- (1H-indol-3-yl) -8- (piperidine-1-carbonyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-15)

Step (1): 2-Boc-8- (piperidine-1-carbonyl) -1,2,3, 4-tetrahydroisoquinoline (15-1)

A mixture of 29 mg of 2-Boc-1,2,3, 4-tetrahydroisoquinoline-8-carboxylic acid, 9 mg of piperidine, 22 mg of triethylamine, 32 mg of N-methylmorpholine, 60 mg of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 0.2 ml of N, N-dimethylformamide was stirred overnight at room temperature. Diluting the reaction solution with water, extracting with ethyl acetate, and concentrating the organic phase to dryness; the residue was taken up in methanol: dichloromethane = 1:99 column chromatography, 2-Boc-8- (piperidine-1-carbonyl) -1,2,3, 4-four hydrogen isoquinoline (15-1) colorless oil 46 mg, yield 95%. ¹ H NMR(400MHz,CDCl ₃ )δ8.00 (s,1H),7.17(t,J＝7.4Hz,1H),7.12(d,J＝7.4Hz,1H),7.03(d,J＝7.2Hz,1H),4.52(d, J＝29.0Hz,2H),3.90(s,2H),3.34–3.55(m,2H),3.18(d,J＝17.0Hz,2H),3.03–2.66(m, 4H),1.64(d,J＝17.5Hz,4H),1.55–1.38(m,12H).

Step (2): 8- (piperidine-1-carbonyl) -1,2,3, 4-tetrahydroisoquinoline (15-2)

A mixture of 46 mg of compound 15-1, 200. Mu.l of trifluoroacetic acid and 3 ml of dichloromethane was stirred at room temperature for 3 hours. The reaction solution was treated with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was concentrated to dryness to give 33 mg of 8- (piperidine-1-carbonyl) -1,2,3, 4-tetrahydroisoquinoline (15-2) as an oil in 100% yield. ¹ H NMR(400MHz, CDCl ₃ )δ7.13(t,J＝7.4Hz,1H),7.07(d,J＝7.5Hz,1H),6.96(d,J＝7.2Hz,1H),4.13 (d,J＝16.5Hz,1H),3.77(d,J＝16.5Hz,2H),3.65(s,1H),3.22–3.05(m,4H),2.80–2.93 (m,4H),1.63(s,4H),1.24(d,J＝7.6Hz,1H).

Step (3): n- (1H-indol-3-yl) -8- (piperidine-1-carbonyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-15)

N- (1H-indol-3-yl) -8- (piperidine-1-carbonyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-15) may be prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ ) δ10.70 (s, 1H), 8.35 (s, 1H), 7.58 (d, j=8.0 hz, 1H), 7.35 (d, j=2.4 hz, 1H), 7.30 (d, j=7.9 hz, 1H), 7.24 (d, j=5.6 hz, 2H), 7.06 (t, j=7.3 hz, 2H), 6.94 (t, j=7.3 hz, 1H), 4.52 (d, j=8.2 hz, 2H), 4.11 (q, j=5.2 hz, 1H), 3.84 (s, 1H), 3.64 (s, 3H), 3.17 (d, j=5.2 hz, 3H), 3.12 (s, 2H), 2.91 (s, 2H), 1.58 (s, 5H), 1.39 (s, 2H). Example 16

N- (5-trifluoromethyl-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-16)

Step (1): 5-trifluoromethyl-1H-indol-3-yl azide (16-1)

The preparation method of 5-trifluoromethyl-1H-indole-3-acyl azide (16-1) is the same as that of the compound 1-1. ¹ H NMR(400 MHz,DMSO-d ₆ )δ12.64(s,1H),8.71(d,J＝13.1Hz,1H),8.37(s,1H),7.87(d,J＝8.7 Hz,1H),7.65(d,J＝8.4Hz,1H).

Step (2): 3-isocyanato-5-trifluoromethyl-1H-indole (16-2)

3-isocyanato-5-trifluoromethyl-1H-indole (16-2) was prepared in the same manner as for compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ :227.1.

Step (3): n- (5-trifluoromethyl-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-16)

N- (5-trifluoromethyl-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-16) may be prepared in the same manner as Compound I-1.LRMS (ESI) M/z [ M+H] ⁺ :360.3.

Example 17- ((1H-indol-3-yl) carbamoyl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylic acid (I-17)

2- ((1H-indol-3-yl) carbamoyl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylic acid (I-17) is prepared in the same manner as compound I-1.LRMS (ESI) M/z [ M-H ]] ^– :334.2.

Example 18 methyl 2- ((1H-indol-3-yl) carbamoyl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylate (I-18)

2- ((1H-indol-3-yl) carbamoyl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (I-18) is prepared in the same manner as compound I-1.LRMS (ESI) M/z [ M+H] ⁺ :350.3.

Example 19 6- (furan-3-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-19)

Step (1): 2-Boc-6- (furan-3-yl) -3, 4-dihydroisoquinoline (19-1)

Preparation of 2-Boc-6- (furan-3-yl) -3, 4-dihydroisoquinoline (19-1) was prepared as compound 10-1. ¹ H NMR(400 MHz,DMSO-d ₆ )δ8.15(s,1H),7.72(t,J＝1.7Hz,1H),7.42(d,J＝7.8Hz,2H),7.17(d, J＝7.9Hz,1H),6.94(d,J＝1.0Hz,1H),4.48(s,2H),3.56(t,J＝5.9Hz,2H),2.79(t,J＝ 5.8Hz,2H),1.43(s,10H).

Step (2): 6- (furan-3-yl) -1,2,3, 4-tetrahydroisoquinoline (19-2)

Preparation of 6- (furan-3-yl) -1,2,3, 4-tetrahydroisoquinoline (19-2) was carried out as in compound 10-2. ¹ H NMR(400MHz, DMSO-d ₆ )δ8.13(s,1H),7.71(s,1H),7.42–7.30(m,2H),7.04(d,J＝7.8Hz,1H),6.92 (s,1H),3.89(s,2H),3.01(t,J＝5.9Hz,2H),2.75(t,J＝5.8Hz,2H).

Step (3): 6- (furan-3-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-19)

6- (furan-3-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-19) is prepared in the same manner as Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(s,1H),8.36(s,1H),8.29(s,1H), 7.96(d,J＝7.5Hz,1H),7.74–7.52(m,4H),7.35(ddd,J＝13.5,12.4,5.8Hz,5H),7.06(t, J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H),2.97(t,J＝ 5.4Hz,2H).

Example 20N- (1H-indol-3-yl) -6- (naphthalen-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-20)

Step (1): 2-Boc-6- (naphthalen-1-yl) -3, 4-dihydroisoquinoline (20-1)

Preparation of 2-Boc-6- (naphthalen-1-yl) -3, 4-dihydroisoquinoline (20-1) was prepared as compound 10-1. ¹ H NMR(400MHz, DMSO-d ₆ )δ7.99(d,J＝7.7Hz,1H),7.94(d,J＝8.2Hz,1H),7.82(d,J＝8.2Hz,1H), 7.52(ddd,J＝22.7,14.6,7.0Hz,3H),7.40(d,J＝7.0Hz,1H),7.30(dd,J＝17.3,7.5Hz, 3H),4.60(s,2H),3.61(t,J＝5.9Hz,2H),2.86(t,J＝5.7Hz,2H),1.45(s,10H).

Step (2): 6- (naphthalen-1-yl) -1,2,3, 4-tetrahydroisoquinoline (20-2)

Preparation of 6- (naphthalen-1-yl) -1,2,3, 4-tetrahydroisoquinoline (20-2) was carried out as in compound 10-2. ¹ H NMR(400MHz, DMSO-d ₆ )δ7.99(d,J＝7.7Hz,1H),7.93(d,J＝8.2Hz,1H),7.83(d,J＝8.3Hz,1H), 7.53(ddd,J＝13.0,12.0,7.1Hz,3H),7.40(d,J＝6.3Hz,1H),7.18(q,J＝7.5Hz,3H), 3.94(s,2H),3.01(t,J＝5.9Hz,2H),2.77(t,J＝5.7Hz,2H).

Step (3): n- (1H-indol-3-yl) -6- (naphthalen-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-20)

N- (1H-indol-3-yl) -6- (naphthalen-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-20) may be prepared in the same manner as for Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(s,1H),8.30(s,1H),8.00(d,J＝7.3Hz,1H),7.95(d,J＝8.5Hz,1H),7.85(d,J＝8.5Hz,1H),7.63(d,J＝7.8Hz,1H), 7.60–7.46(m,3H),7.43(d,J＝6.1Hz,1H),7.38(d,J＝2.1Hz,1H),7.33(dd,J＝11.0, 6.7Hz,4H),7.07(t,J＝7.1Hz,1H),6.96(t,J＝7.6Hz,1H),4.78(s,2H),3.81(s,2H), 2.96(s,2H).

Example 21 6- (benzofuran-3-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-21)

Step (1): 2-Boc-6- (benzofuran-3-yl) -3, 4-dihydroisoquinoline (21-1)

Preparation of 2-Boc-6- (benzofuran-3-yl) -3, 4-dihydroisoquinoline (21-1) was prepared as compound 10-1. ¹ H NMR(400 MHz,DMSO-d ₆ )δ8.34(s,1H),7.93(d,J＝7.3Hz,1H),7.66(d,J＝7.8Hz,1H),7.55(d, J＝8.0Hz,2H),7.35(ddd,J＝23.8,16.8,7.4Hz,3H),4.55(s,2H),3.59(t,J＝5.7Hz, 2H),2.87(t,J＝5.7Hz,2H),1.44(s,9H).

Step (2): 6- (benzofuran-3-yl) -1,2,3, 4-tetrahydroisoquinoline (21-2)

Preparation of 6- (benzofuran-3-yl) -1,2,3, 4-tetrahydroisoquinoline (21-2) was prepared as compound 10-2. ¹ H NMR(400 MHz,DMSO-d ₆ )δ8.31(s,1H),7.91(d,J＝7.3Hz,1H),7.66(d,J＝7.7Hz,1H), 7.50–7.42(m,2H),7.42–7.31(m,2H),7.15(d,J＝7.9Hz,1H),3.91(s,2H),3.00(t,J＝ 5.9Hz,2H),2.79(t,J＝5.7Hz,2H).

Step (3): 6- (benzofuran-3-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-21)

6- (benzofuran-3-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-21) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(s,1H),8.36(s,1H),8.29(s, 1H),7.96(d,J＝7.5Hz,1H),7.74–7.52(m,4H),7.35(ddd,J＝13.5,12.4,5.8Hz,5H), 7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H), 2.97(t,J＝5.4Hz,2H).

Example 22N- (1H-indol-3-yl) -6- (piperidin-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-22)

Step (1): 2-Boc-6- (piperidin-1-yl) -1,2,3, 4-tetrahydroisoquinoline (22-1)

167 mg of 2-Boc-6-bromo-1, 2,3, 4-tetrahydroisoquinoline, 137 mg of piperidine, 257 mg of sodium tert-butoxide, 22 mg of [1, 3-bis (2, 6-diisopropylbenzene) imidazol-2-ylidene](3-chloropyridine) Palladium dichloride and 14The ml of anhydrous dioxane mixture was stirred overnight at 100 ℃ under argon. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate: petroleum ether=5:95 column chromatography gives 117 mg of 2-Boc-6- (piperidin-1-yl) -1,2,3, 4-tetrahydroisoquinoline as a white solid in 69% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ6.98(d,J＝8.6Hz,1H),6.80(d,J＝8.2Hz, 1H),6.70(s,1H),4.48(s,2H),3.62(s,3H),3.14–3.05(m,4H),2.77(s,2H),1.69(d,J＝ 5.3Hz,3H),1.64(s,2H),1.57(d,J＝5.4Hz,2H),1.48(s,9H).

Step (2): 6- (piperidin-1-yl) -1,2,3, 4-tetrahydroisoquinoline (22-2)

Preparation of 6- (piperidin-1-yl) -1,2,3, 4-tetrahydroisoquinoline (22-2) was carried out as compound 10-2.LCMS (ESI) M/z [ M+H] ⁺ :217.2.

Step (3): n- (1H-indol-3-yl) -6- (piperidin-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-22)

N- (1H-indol-3-yl) -6- (piperidin-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-22) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.70(s,1H),8.19(s,1H),7.61(d,J＝ 7.7Hz,1H),7.36(d,J＝2.3Hz,1H),7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.4Hz,1H), 7.02–6.93(m,2H),6.80(d,J＝8.5Hz,1H),6.74(s,1H),4.56(s,2H),3.69(t,J＝5.7Hz, 2H),3.15–3.02(m,4H),2.80(t,J＝5.5Hz,2H),1.62(s,4H),1.53(d,J＝4.9Hz,2H).

Example 23N- (5, 6-difluoro-1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-23)

N- (5, 6-difluoro-1H-indole-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-23) is prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.88(s,1H),8.30(s,1H),7.58–7.67 (m,3H),7.54–7.40(m,5H),7.38–7.25(m,3H),4.71(s,2H),3.76(s,2H),2.94(s,2H).

Example 24N- (5-fluoro-1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-24)

Example 25N- (1H-indol-3-yl) -6-vinyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-25)

EXAMPLE 26 6-ethynyl-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-26)

Example 27 6-Ethyl-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-27)

Example 28 5-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-28)

Preparation of 5-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-28) is identical to Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(s,1H),8.36(s,1H),7.60(d,J＝7.9Hz,1H), 7.51(d,J＝7.7Hz,1H),7.36(d,J＝2.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.23(d,J＝7.6 Hz,1H),7.17(t,J＝7.7Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.69(s, 2H),3.79(t,J＝6.0Hz,2H),2.82(t,J＝6.0Hz,2H).

Example 29 7-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-29)

Preparation of 7-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-29) Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.27(s,1H),7.59(d,J＝8.0Hz,1H), 7.41(s,1H),7.39–7.33(m,2H),7.31(dd,J＝8.1,1.0Hz,1H),7.16(d,J＝8.2Hz,1H), 7.10–7.02(m,1H),6.95(ddd,J＝8.0,7.0,1.0Hz,1H),4.66(s,2H),3.73(t,J＝5.9Hz, 2H),2.83(t,J＝5.8Hz,2H).

Example 30 8-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-30)

Preparation of 8-bromo-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-30) is identical to Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(d,J＝2.3Hz,1H),8.45(s,1H),7.59(d,J＝7.9 Hz,1H),7.49(dd,J＝7.9,1.3Hz,1H),7.36(d,J＝2.5Hz,1H),7.33–7.28(m,1H),7.24 (d,J＝7.5Hz,1H),7.15(t,J＝7.7Hz,1H),7.06(ddd,J＝8.2,6.9,1.2Hz,1H),6.96(ddd, J＝7.9,6.9,1.1Hz,1H),4.59(s,2H),3.75(t,J＝5.8Hz,2H),3.07–2.81(m,2H).

Example 31 6-fluoro-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-31)

Preparation of 6-fluoro-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-31)And the same compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.26(s,1H),7.60(d,J＝7.9Hz,1H), 7.36(d,J＝2.5Hz,1H),7.30(d,J＝8.1Hz,1H),7.22(dd,J＝8.2,5.9Hz,1H),7.09–7.00 (m,3H),6.95(t,J＝7.3Hz,1H),4.64(s,2H),3.72(t,J＝5.9Hz,2H),2.87(t,J＝5.6Hz, 2H).

Example 32 6-chloro-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-32)

Preparation of 6-chloro-N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-32) Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.72(s,1H),8.28(s,1H),7.59(d,J＝8.0Hz,1H), 7.35(d,J＝2.4Hz,1H),7.33–7.28(m,2H),7.27–7.19(m,2H),7.06(t,J＝7.5Hz,1H), 6.95(t,J＝7.5Hz,1H),4.64(s,2H),3.72(t,J＝5.8Hz,2H),2.87(t,J＝6.0Hz,2H).

Example 33N- (1H-indol-3-yl) -6, 9-dihydrofuro [3,2-H ] isoquinoline-8 (7H) -carboxamide (I-33)

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Example 34N- (1H-indol-3-yl) -5-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-34)

Step (1): 5-phenyl-1, 2,3, 4-tetrahydroisoquinoline (34-1)

100 mg of 5-bromo-1, 2,3, 4-tetrahydroisoquinoline, 87 mg of phenylboronic acid, 384 mg of cesium carbonate and 35 mg of PdCl ₂ A mixture of (dppf), 1 ml of tetrahydrofuran and 0.5 ml of water Heated and stirred for 5 hours under argon atmosphere at 70 ℃. The reaction was diluted with water, extracted with ethyl acetate, the organic layer was dried and the residue was taken up in dichloromethane: methanol=95: 5 column chromatography, brown oily liquid 5-phenyl-1, 2,3, 4-four hydrogen isoquinoline (34-1) 75 mg, yield 76%. LCMS (ESI) M/z [ M+H] ⁺ :210.2.

Step (2): n- (1H-indol-3-yl) -5-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-34)

Preparation of N- (1H-indol-3-yl) -5-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-34) Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.21(s,1H),7.61(d,J＝8.0Hz,1H), 7.49–7.34(m,6H),7.30(t,J＝8.1Hz,2H),7.23(d,J＝7.6Hz,1H),7.13(d,J＝7.4Hz, 1H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),4.74(s,2H),3.64(t,J＝5.8Hz,2H), 2.75(t,J＝5.8Hz,2H).

Example 35N- (1H-indol-3-yl) -7-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-35)

Step (1): 7-phenyl-1, 2,3, 4-tetrahydroisoquinoline (35-1)

Preparation of 7-phenyl-1, 2,3, 4-tetrahydroisoquinoline (35-1) was carried out as in compound 34-1.LCMS (ESI) M/z [ M+H] ⁺ :210.2.

Step (2): n- (1H-indol-3-yl) -7-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-35)

Preparation of N- (1H-indol-3-yl) -7-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-35) Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.73(s,1H),8.30(s,1H),7.67(s,2H),7.65(s, 1H),7.61(s,1H),7.49–7.43(m,5H),7.38(s,1H),7.31(d,J＝9.0Hz,1H),7.06(s,1H), 6.96(s,1H),4.75(s,2H),3.78(s,2H),2.91(s,2H).

Example 36N- (1H-indol-3-yl) -8-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-36)

Step (1): 8-phenyl-1, 2,3, 4-tetrahydroisoquinoline (36-1)

Preparation of 8-phenyl-1, 2,3, 4-tetrahydroisoquinoline (36-1) was conducted as in compound 34-1.LCMS (ESI) M/z [ M+H ] ⁺ :210.2.

Step (2): n- (1H-indol-3-yl) -8-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-36)

Preparation of N- (1H-indol-3-yl) -8-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-36) Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),8.19(s,1H),7.53–7.44(m,3H), 7.43–7.39(m,1H),7.38–7.33(m,2H),7.31–7.22(m,4H),7.09(dd,J＝7.1,1.8Hz,1H), 7.04(ddd,J＝8.2,6.9,1.2Hz,1H),6.93(ddd,J＝7.9,6.9,1.0Hz,1H),4.51(s,2H),3.76 (t,J＝6.1Hz,2H),2.99(t,J＝6.1Hz,2H).

Example 37 4-benzyl-N- (1H-indol-3-yl) piperazine-1-carboxamide (I-37)

The preparation method of 4-benzyl-N- (1H-indol-3-yl) piperazine-1-carboxamide (I-37) is the same as that of the compound I-1. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.67(s,1H),8.16(s,1H),7.56(d,J＝7.9Hz,1H),7.40–7.19(m, 7H),6.88–7.08(m,2H),3.45(t,J＝4.9Hz,4H),2.37(t,J＝4.9Hz,4H).

Example 38N- (4-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-38)

Step (1): 4-fluoro-1H-indol-3-acyl azide (38-1)

The preparation method of 4-fluoro-1H-indol-3-acyl azide (38-1) is the same as that of compound 1-1.LRMS (ESI) M/z [ M+H] ⁺ :205.1.

Step (2): 4-fluoro-3-isocyanato-1H-indole (38-2)

The preparation method of 4-fluoro-3-isocyanato-1H-indole (38-2) is the same as that of the compound 1-2.LRMS (ESI) M/z [ M+H] ⁺ :177.0.

Step (3): n- (4-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-38)

N- (4-fluoro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-38) may be prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.09(s,1H),8.07(s,1H),7.27(d,J＝2.5Hz, 1H),7.22–7.13(m,5H),7.01(td,J＝8.0,5.1Hz,1H),6.67(dd,J＝11.3,7.7Hz,1H), 4.63(s,2H),3.69(t,J＝5.8Hz,2H),2.85(t,J＝5.9Hz,2H).

Example 39N- (5-chloro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-39)

N- (5-chloro-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-39) may be prepared in the same manner as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.92(s,1H),8.29(s,1H),7.70(s,1H),7.46(d, J＝2.3Hz,1H),7.32(d,J＝8.5Hz,1H),7.19(s,4H),7.07–7.02(m,1H),4.67(s,2H), 3.73(t,J＝5.8Hz,2H),2.86(t,J＝5.8Hz,2H).

Example 40N- (5-anilino-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-40)

Example 41N- (5-phenyl-1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-41)

Example 42 6- (4, 4-Dihalopiperidin-1-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-42)

Example 43 6- (3, 3-Difluorocyclobutyl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-43)

Example 44 6- (6, 6-difluoro-2-azaspiro [3.3] heptane-2-yl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-44)

Example 45N- (1H-indol-3-yl) -6- (6-azaspiro [2.5] octane-6-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-45)

Example 46N- (1H-indol-3-yl) -6- (4- (3, 3-trifluoropropyl) piperazin-1-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-46)

Example 47 6- (2, 2-Dimethylmorpholinyl) -N- (1H-indol-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-47)

Example 48N- (5-cyano-1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-48)

Example 49N- (5-chloro-6-fluoro-1H-indol-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-49)

Example 50N- (5-bromo-1H-pyrrolo [3,2-b ] pyridin-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-50)

Example 51N- (5-methoxy-1H-pyrrolo [3, 2-b)]Pyridin-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-51)

Example 52N- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-52)

Example 53N- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-53)

Example 54N- (5-bromo-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6-phenyl-3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-54)

Example 55 6-phenyl-N- (1H-pyrrolo [3,2-c ] pyridin-3-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-55)

Example 56N- (1H-indol-3-yl) -4-phenyl-1, 4-diazepane-1-carboxamide (I-56)

Example 57 4-benzyl-N- (1H-indol-3-yl) -1, 4-diazacycloheptane-1-carboxamide (I-57)

Example 58N- (1H-indol-3-yl) -4- (pyridin-4-yl) piperazine-1-carboxamide (I-58)

Example 59N- (1H-indol-3-yl) -4- (3-methoxyphenyl) piperazine-1-carboxamide (I-59)

N- (1H-indol-3-yl) -4- (3-methoxyphenyl) piperazine-1-carboxamide (I-59) is prepared in the same way as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.31(s,1H),7.61(d,J＝7.9Hz,1H), 7.37(d,J＝2.4Hz,1H),7.31(d,J＝8.0Hz,1H),7.14(t,J＝8.1Hz,1H),7.06(t,J＝7.2 Hz,1H),6.95(t,J＝7.4Hz,1H),6.59(d,J＝8.4Hz,1H),6.52(s,1H),6.41(d,J＝8.2Hz, 1H),3.73(s,3H),3.67–3.54(m,4H),3.23–3.11(m,4H).

Example 60 4- (2-hydroxyethyl) -N- (1H-indol-3-yl) piperazine-1-carboxamide (I-60)

Example 61N- (1H-indol-3-yl) -4- (2-methoxyphenyl) piperazine-1-carboxamide (I-61)

N- (1H-indol-3-yl) -4The preparation method of- (2-methoxyphenyl) piperazine-1-carboxamide (I-61) is the same as that of the compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.69(s,1H),8.25(s,1H),7.61(d,J＝7.7Hz,1H), 7.37(d,J＝2.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.05(t,J＝7.3Hz,1H),7.01–6.80(m, 5H),3.80(s,3H),3.67–3.53(m,4H),3.05–2.89(m,4H).

Example 62N- (1H-indol-3-yl) -4- (4-methoxyphenyl) piperazine-1-carboxamide (I-62)

N- (1H-indol-3-yl) -4- (4-methoxyphenyl) piperazine-1-carboxamide (I-62) is prepared in the same way as compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.71(s,1H),8.30(s,1H),7.61(d,J＝7.8Hz,1H), 7.38(d,J＝2.4Hz,1H),7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.4Hz,1H),6.95(t,J＝7.2 Hz,3H),6.85(d,J＝9.0Hz,2H),3.70(s,3H),3.67–3.55(m,4H),3.10–2.97(m,4H).

Example 63N- (1H-indol-3-yl) -4- (pyrimidin-2-yl) piperazine-1-carboxamide (I-63)

Example 64N- (1H-indol-3-yl) -4- (4-methylpiperazin-1-yl) piperazine-1-carboxamide (I-64)

Example 65 4-cyclopropyl-N- (1H-indol-3-yl) piperazine-1-carboxamide (I-65)

The preparation method of 4-cyclopropyl-N- (1H-indol-3-yl) piperazine-1-carboxamide (I-65) is the same as that of the compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),8.18(s,1H),7.59(d,J＝7.9Hz,1H),7.35(d, J＝2.4Hz,1H),7.30(d,J＝8.2Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H), 3.45–3.39(m,4H),2.58–2.52(m,4H),1.65(d,J＝3.5Hz,1H),0.47–0.41(m,2H),0.35 (d,J＝3.2Hz,2H).

Example 66N- (1H-indol-3-yl) -4-methylpiperazine-1-carboxamide (I-66)

N- (1H-indol-3-yl) -4-methylpiperazine-1-carboxamide (I-66) is prepared in the same manner as for compound I-1. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.71–10.65(m,1H),8.17(s,1H),7.58(d,J＝8.0Hz,1H),7.34 (d,J＝2.4Hz,1H),7.29(d,J＝8.1Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz, 1H),3.45(t,J＝5.0Hz,4H),2.32(t,J＝5.0Hz,4H),2.20(s,3H).

Example 67N- (1H-indol-7-yl) -3, 4-dihydro-isoquinoline-2 (1H) -carboxamide (I-67)

Step (1): 7-isocyanato-1H-indole (67-1)

100 mg of 1H-indol-7-amine and 225 mg of triphosgene are dissolved in 30 ml of dichloromethane, then 30 ml of saturated sodium bicarbonate solution is added dropwise, the mixture is stirred for 12 hours at room temperature under argon atmosphere, the reaction solution is diluted by adding water, ethyl acetate is extracted, and the organic layer is concentrated to dryness to obtain 100 mg of 7-isocyanato-1H-indole (67-1) as a gray solid, and the yield is 83%. LRMS (ESI) M/z [ M+H ] ⁺ :158.9.

Step (2): n- (1H-indol-7-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-67)

Preparation of N- (1H-indol-7-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-67) Compound I-1 is prepared. LRMS (ESI) M/z [ M+H] ⁺ :292.2.

Example 68N- (1H-indol-5-yl) -3, 4-dihydro-isoquinoline-2 (1H) -carboxamide (I-68)

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Step (1): 5-isocyanato-1H-indole (68-1)

To a mixture of 100 mg of 1H-indol-5-amine, 224.5 mg of triphosgene and 3 ml of tetrahydrofuran was added dropwise 210. Mu.l of triethylamine, and the mixture was stirred at 0℃for 2 hours after the addition, the reaction was concentrated to dryness, and the residue was purified with petroleum ether: ethyl acetate=90:10 column chromatography gave 23.5 mg of 5-isocyanato-1H-indole (68-1) as a pale yellow solid in 20% yield. LRMS (ESI) M/z [ M+H] ⁺ :158.9.

Step (2): n- (1H-indol-5-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-68)

N- (1H-indol-5-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-68) may be prepared in the same manner as Compound I-1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.91(s,1H),8.35(s,1H),7.58(d,J＝2.0Hz,1H), 7.28–7.22(m,2H),7.18(s,4H),7.12(dd,J＝8.6,2.1Hz,1H),6.32(t,J＝2.6Hz,1H), 4.64(s,2H),3.70(t,J＝5.9Hz,2H),2.85(t,J＝5.9Hz,2H).

Example 69N- (1H-indol-4-yl) -3, 4-dihydro-isoquinoline-2 (1H) -carboxamide (I-69)

Step (1): 4-isocyanato-1H-indole (69-1)

100 mg of 1H-indol-5-amine and 225 mg of triphosgene are dissolved in 10 ml of toluene and stirred for 5 hours at 130 ℃, the reaction solution is concentrated to dryness, a small amount of diethyl ether is added for extraction, filtration and concentration of the filtrate to dryness are carried out to obtain 47 mg of yellow oily 4-isocyanato-1H-indole (8-1) with the yield of 39%. LRMS (ESI) M/z [ M+H ] ⁺ :159.1.

Step (2): n- (1H-indol-4-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-69)

Preparation of N- (1H-indol-4-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (I-69) Compound I-1. LRMS (ESI) M/z [ M+H] ⁺ :292.1.

EXAMPLE 70 preparation of prodrugs

3- (3- (4-phenylpiperazine-1-carboxamide) -1H-indol-1-yl) dimethylglycinyl propyl ester (70-1)

3- (5-fluoro-3- (6-phenyl-1, 2,3, 4-tetrahydroisoquinoline-2-carboxamide) -1H-indol-1-yl) dimethylglycinyl propyl ester (70-2)

(3- (4-phenylpiperazine-1-carboxamide) -1H-indol-1-yl) dihydro-phosphoric acid methyl ester (70-3)

Example 71 Effect of Compounds on the expression of Interferon-stimulated Gene (ISG) in human THP1-Blue-ISG cells

1. The experimental method comprises the following steps:

10. Mu.L of compound diluted with DMSO/physiological saline was added to each well of a 96-well cell culture plate at a concentration of 20. Mu.M, and STING agonist was MSA-2 at a concentration of 200. Mu.M. The control group without drug was added with 20. Mu.L of physiological saline containing 1% DMSO. Each with 3 duplicate wells. THP1-Blue-ISG cell count, and cell concentration was adjusted to 5X 10 ⁵ Per mL, 180 μl of cells were added per well for incubation. Thus, the final volume of each test well was 200. Mu.L, the DMSO content was 0.1% and the test concentration of the compound was 1. Mu.M. The final concentration of STING agonist was 10 μm for MSA-2 and incubated for 24 hours; 200. Mu.L of culture medium was added to the blank.

After 24 hours, 20. Mu.L of the culture solution was taken from each well into a new 96-well plate, 180. Mu.L of the chromogenic solution Quanti-Blue was added, and the plate was placed in an incubator at 37℃for 2 hours, and OD650 was measured.

Analysis of results:

inhibition (%) = (Con) _(OD650) -Treated _(OD650) )/Con _(OD650) ×100％

2. Experimental results

The test results are shown in table 2 below.

Table 2: inhibition ratio of MSA-2 induced ISG Gene expression in human THP1-Blue-ISG cells by the Compounds of the invention

^a H151 is a positive compound:

experimental results show that the dihydroisoquinoline compounds have the function of inhibiting MSA-2 induced ISG gene expression in human THP1-Blue-ISG cells, and the inhibiting activity of partial compounds on STING proteins at the concentration of 1 mu M is equivalent to that of positive compound H151.

Example 72 Effect of Compounds on ISG Gene expression in murine Raw-lucia cells

1. The experimental method comprises the following steps:

raw-lucia cell count, cell concentration was adjusted to 4X 10 ⁵ Per mL, 180 μl of cells were added per well for incubation. Thus, the final volume of each test well was 200. Mu.L, the DMSO content was 0.1%, and the test final concentration of the compound was 1. Mu.M. STING agonist was 50 μm final concentration of MSA-2 and incubated for 24 hours; 200. Mu.L of culture medium was added to the blank. Each with 3 duplicate wells.

After 24 hours, 20. Mu.L of the culture solution was taken from each well into a new bottom-transparent 96-well plate, and luciferase assay reagent QUANTI-Luc was added thereto ^TM 50 μl, fluorescence values were measured immediately (protected from light).

Analysis of results:

inhibition (%) = (Con) _(Lum) -Treated _(Lum) )/Con _(Lum) ×100％

2. Experimental results

The experimental results are shown in table 3 below.

Table 3: inhibition ratio of MSA-2 induced ISG Gene expression in murine Raw-ricia cells by the Compounds of the application

Experimental results show that the dihydroisoquinoline compounds have the function of inhibiting MSA-2 induced ISG gene expression in murine Raw-lucia cells, and the inhibitory activity of partial compounds on STING proteins at the concentration of 1 mu M is equivalent to that of positive compound H151.

EXAMPLE 73 preparation of pharmaceutical composition

Tablet

The above materials are mixed uniformly, and 1000 tablets are prepared by conventional process. Suitable aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability, or delay absorption.

Capsule

Compound I-10 g

140 g of starch

Microcrystalline cellulose 80 g

Mixing the above materials according to conventional method, and making into 1000 capsules.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

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

wherein Q is selected from O or S;

ring B is

Wherein E is NR ¹⁰ Or CR (CR) ¹⁰ R ^10’ ；

R ¹⁰ Selected from: COOC1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C1-C4 alkylaminoOr unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;

R ^10’ 、R ^g 、R ^g’ 、R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、R ^j And R is ^j’ Each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-C8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylaryl, substituted or unsubstituted C12-C12 heteroaryl; wherein the substitution refers to substitution with one or more Ra;

Alternatively, R ^g And R is ^g’ Together with the C atom to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstitutedA C6-C12 aryl group; wherein the substitution refers to substitution with one or more Ra;

Alternatively, R ^g And R is ^h Together with the C atoms to which they are attached form oxo (=o), a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaryl, a substituted or unsubstituted C6-C12 aryl; wherein the substitution refers to substitution with one or more Ra;

n is 1 or 2.

2. The compound of claim 1, or a prodrug, enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of substituted and unsubstituted: five membered heteroaryl, six membered aryl, six membered heteroaryl, [6+6 ] ]Aryl or condensed rings, [6+6 ]]Heteroaryl or condensed rings, [6+5 ]]Heteroaryl or condensed rings, [5+6 ]]Heteroaryl or condensed rings, [5+5 ]]Heteroaryl or condensed rings, wherein the substitution is by 1-5R ¹ Substitution; wherein each R ¹ Independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8 membered substitution)Or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 arylc 1-C6 alkyl, substituted or unsubstituted 5-to 12-membered heteroarylc 1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-to 12-membered heteroaryl, substituted or unsubstituted C6-C12 aryl; r is R ¹ Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

3. The compound of claim 1, or a prodrug thereof, an enantiomer, a diastereomer, a racemate, and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the following structures:

wherein X is selected from: o, S or NH;

R ¹ is substituent groups at any position on the ring, the number of the substituent groups is 1-5, and each R ¹ Independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino,Nitro group,/->Substituted or unsubstituted benzyl, substituted or unsubstitutedA C6-C12 arylmethyl group, a substituted or unsubstituted 5-C12 membered heteroarylmethyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkanoyl group, a substituted or unsubstituted aminoacyl group, a substituted or unsubstituted C1-C6 alkylamido group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C6-C12 arylamino group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group; r is R ¹ Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

4. The compound of claim 1, or a prodrug, enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the following structures:

m is N or CH;

R ⁴ selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstitutedSubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-to 12-membered heteroarylC 1-C6 alkyl, -CO (3-to 8-membered substituted or unsubstituted heterocyclyl), -CO (C3-to 8-substituted or unsubstituted cycloalkyl); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And R is ⁹ Each independently selected from: H. halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino,Substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclic group;

or R is ⁶ And R is ⁷ Form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group with the carbon atom to which they are attached; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylOH, C1-C6 alkoxy or 3-8 membered heterocyclyl;

R ^a 、R ^a’ 、R ^b 、R ^b’ 、R ^c 、R ^c’ 、R ^d 、R ^d’ 、R ^e 、R ^e’ 、R ^f 、R ^f’ 、R ^g 、R ^g’ 、R ^h 、R ^h’ 、R ⁱ 、R ^i’ 、R ^j and R is ^j’ Each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-C8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylaryl, substituted or unsubstituted C12-C12 heteroaryl; wherein the taking Substituted means substituted with one or more Ra;

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2;

ra is as defined in claim 1.

5. The compound of claim 4, or a prodrug, enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Selected from: halogen, carboxyl, hydroxyl, cyano, amino,Nitro group,/->A substituted or unsubstituted benzyl group, a substituted or unsubstituted arylmethyl group, a substituted or unsubstituted heteroarylmethyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkanoyl group, a substituted or unsubstituted aminoacyl group, a substituted or unsubstituted C1-C6 alkylamido group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted 6-12 membered arylamino group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 6-12 membered aryl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, trifluoro Methoxy, benzyl and HOCH ₂ -、HOCH ₂ CH ₂ -、CF ₂ CH-、CF ₃ CH ₂ CH ₂ -, C1-C6 alkyl, C1-C6 alkoxy or 3-8 membered heterocyclyl.

6. The compound of any one of claims 1-5, or a prodrug, enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound has a structure represented by formulas II-1-II-3

Wherein G is a 6 membered aryl or heteroaryl group;

g' is a C6-C12 aryl or 5-12 membered heteroaryl;

g' is C6-aryl or 5-6 membered heteroaryl;

R _m each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-C8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-C12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-C12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, -OP (O) (OH) ₂ Hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; preferably, the method comprises the steps of,R _m each independently selected from: hydrogen, halogen, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, 5-12 membered heteroaryl, C6-C12 aryl NH, -OP (O) (OH) ₂ Substituted C1-C6 alkyl, amino C1-C6 alkyl COO substituted C1-C6 alkyl; more preferably, R _m Each independently selected from: trifluoromethyl, phenyl, phenylamino, cyano, methoxy, cl, F, br,

R _m” and R is _m”’ Each independently selected from: H. halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylC 1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC 1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

n is 1 or 2;

f. f ', f ", and f'" are each independently 0, 1, 2, or 3;

R ⁴ is defined as in claim 4.

7. The compound of claim 1, or a prodrug thereof, an enantiomer, a diastereomer, a racemate, and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

8. a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of any one of claims 1-7, or a prodrug thereof, an enantiomer, a diastereomer, a racemate, and mixtures thereof, or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.

9. Use of a compound according to claims 1-7, or a prodrug thereof, an enantiomer, a diastereomer, a racemate, and mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the preparation of a cGAS/STING pathway targeting inhibitor; or (b)

10. The use according to claim 9, wherein the inflammatory and autoimmune diseases are selected from the group consisting of: singleton-Merten syndrome (SMS), aicardi-gouteres syndrome (AGS), systemic Lupus Erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal vascular disease and white matter dystrophy (RVCL), STING-related infant onset vasculopathy (SAVI), scleroderma, silver shoulder disease, sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, crohn's disease, ulcerative colitis, autoimmune colitis, small intestine malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative disease.