CN117624168A

CN117624168A - Condensed ring heterocyclic compound and preparation method and application thereof

Info

Publication number: CN117624168A
Application number: CN202211000595.1A
Authority: CN
Inventors: 张所明
Original assignee: Deming Yaotai Biotechnology Shenzhen Co ltd
Current assignee: Deming Yaotai Biotechnology Shenzhen Co ltd
Priority date: 2022-08-19
Filing date: 2022-08-19
Publication date: 2024-03-01
Also published as: WO2024037667A3; WO2024037667A2

Abstract

The invention discloses a condensed ring heterocyclic compound represented by the following formula I, optical isomers, deuterated matters, prodrugs or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the substituted condensed ring heterocyclic compound and application thereof as an AHR channel inhibitor. According to the present invention, the fused ring heterocyclic compounds bind to AHR and inhibit those functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and tumor cellsInvasiveness, therefore, the substituted condensed ring heterocyclic compound can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of tumor cells.

Description

Condensed ring heterocyclic compound and preparation method and application thereof

Technical Field

The invention belongs to the technical field of biopharmaceuticals, and particularly relates to a condensed ring heterocyclic compound, a pharmaceutically acceptable salt thereof, a preparation method thereof and application of the condensed ring heterocyclic compound serving as an aromatic hydrocarbon receptor inhibitor.

Background

The aromatic hydrocarbon receptor (AHR, aryl hydrocarbon receptor) is one of the subfamily bHLH-PAS (bHLH-PER-ARNT-SIM) members of the basic helix-loop-helix [ basic helix-loop-helix (bHLH-PAS) ] superfamily, which is the only receptor in the bHLH-PAS family that can be activated by a ligand [ nat. Rev. Cancer,2014,14 (12), 801; nat.Rev.cancer,2013,13 (12), 827]. AHR present in the cytoplasm is able to sense the stimulation of dioxins (TCDD) by aromatic heterogenies (xenobiotics) in the external environment, such as 2,3,7, 8-tetrachlorodibenzo, and then migrate into the nucleus to form a heterodimer with the aromatic acceptor nuclear transporter (ARNT), which in turn interacts with XRE (xenobiotic response element) of the AHR corresponding gene, thereby regulating their transcription; AHR can also activate XRE-independent protein-protein interaction pathways.

AHR is the most well known enzyme that binds environmental toxins and induces metabolic machinery, such as cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B 1), which eliminate environmental toxins (Reyes et al, science,1992,256 (5060), 1193-5; murray et al, nat Rev Cancer,2015,14 (12), 801-14). Activation of AHR by environmental toxins has demonstrated a role for AHR in numerous cellular processes, such as embryogenesis, tumorigenesis, and inflammation. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immunomodulation (Nguyen et al, front immunol.2014,5,511). Classical exogenous AHR ligand TCDD, etc. induces deep immunosuppression, promotes carcinogenesis and induces tumor growth (Oncogene, 2009,28 (28), 2593-2605, oncogene,2009,28 (41), 3642-51,Trends Immunol,2009,30,447-454).

AHR regulates many key innate and adaptive immune responses through XRE-dependent or independent activities. In these reactions, AHR agonists promote the production of IL-17 by Th17 cells (T-helper cells) and Treg cells (regulatory T-cells). Activation of AHR further induces lateral differentiation of Th17 cells into Treg cells, enhancing the suppressive activity of Treg. Studies have demonstrated that AHR agonism can produce inhibition of macrophage-mediated innate inflammatory responses (e.g., reduction of LPS-induced IL-1b, IL-6, IL-12 and TNFa expression), and inhibition of dendritic cells (activation of dendritic cells and promotion of IL-10 expression) (Clin Exp Immunol,2014,177 (2), 521-30;J Immunol,2010,185 (), 3190-8;Lab Invest,2014,94 (5), 528-35; PNAS,2010,107 (46), 19961-19966).

In order to establish an effective anti-tumor immune response, antigen presenting cells (antigen presenting cells, APCs) need to be processed, presented, followed by activation of helper cd4+ T-cells (Th) and cytotoxic cd8+ T-cells (Tc) which act synergistically to lyse tumor cells. Tumor cells develop immunity that several mechanisms escape Th and Tc cytolytic regulation. One of these is the release of highly refractory kynurenine (kynurenine) and other potential AHR ligands in the tumor microenvironment (tumor microenvironment, TME).

High concentrations of AHR ligands in the Tumor Microenvironment (TME) can lead to direct inhibition of APCs, th and Tc, and recruitment, production and activation of tregs and Th17, further inhibiting Tc and Th activity. Tumors are able to evade anti-tumor immune responses through these mechanisms. Therefore, AHR inhibitors can block the AHR-dependent immune escape pathway employed by malignant cells, thereby restoring anti-tumor immunity.

Recent studies on tumor immunobiology have shown that malignant tumor cells employ a complex immune escape mechanism. Preclinical and clinical studies have demonstrated that optimal recovery of anti-tumor immune responses can be provided by blocking or boosting these mechanisms through a combination of therapeutic applications (e.g., immune checkpoint inhibition and vaccine). While it is desirable that AHR modulators alone restore anti-tumor immunity, it is contemplated that AHR inhibitors in combination with checkpoint inhibitors and vaccines, even in synergy with other therapeutic approaches, will boost the immunotherapeutic response.

AHR-regulated immune mechanisms are associated with autoimmune and inflammatory diseases, such as multiple sclerosis and inflammatory bowel disease. Thus activation of the AHR pathway by an AHR agonist may be beneficial in the treatment of autoimmune and inflammatory diseases. Although AHR agonists have been described in the art, there is a need for improvements in the compositions and methods of immunomodulation for the treatment of autoimmune and inflammatory diseases by modulating AHR.

Partial aromatic hydrocarbon receptors are disclosed in, for example, chinese patent applications CN101466363A, CN108239083A, CN113480530A, TWI752155B, CN114181208, WO2022078356, etc. There remains an urgent clinical need to develop or improve inhibitors of AHR for the treatment of diseases associated with disorders of the AHR pathway.

Disclosure of Invention

According to one aspect of the present invention, it is an object of the present invention to provide a fused ring heterocyclic compound represented by formula I, each of which is an optical isomer, a deuterate, a prodrug or a pharmaceutically acceptable salt thereof:

wherein,

A ¹ 、A ² 、A ³ and A ⁴ Each is independently a bond, C, O or N, and A ¹ 、A ² 、A ³ And A ⁴ At least one of which is N;

A ⁵ and A ⁶ One of which is N and the other of which is C;

A ⁷ 、A ⁸ 、A ⁹ and A ¹⁰ Each is independently C or N, at least one of which is N.

Preferably, A ¹ 、A ² 、A ³ And A ⁴ One of which is a chemical bond.

Ring B is selected from C _6-10 Aryl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

L is a bond, carbonyl, -C (=O) NH-, or-NH-;

r is selected from-NR ^a R ^b ，C _1-10 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-8 Cycloalkyl, or substituted by 1-3G ¹ Substituted saturated or unsaturated C _1-10 Alkyl, quilt 1-3G ¹ Substituted saturated or unsaturated C _3-10 Cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

R ¹ Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-8 Cycloalkyl, or R ¹ And A is a ¹ -A ⁴ The ring formation is covered by 1-3G ¹ Substituted 8-14 membered ring, saturated or unsaturated, having 1 to 3 heteroatoms selected from N, O and S.

R ² Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-8 Alkyl, saturated or notSaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated C _1-8 Alkylcarboxy, saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 A membered aryl, a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

R ^a And R is ^b Each independently selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated C _1-8 Alkylacyl, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylaminocarbonyl, saturated or unsaturated C _1-8 Alkylsulfonyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated sulfonyl C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkylacyl, saturated or unsaturated amino C _1-8 Alkoxycarbonyl, saturated or unsaturated amino C _1-8 Alkylaminocarbonyl, saturated or unsaturated amino C _1-8 Alkylsulfonyl, saturated or unsaturated amino C _1-8 Alkylamino, saturated or unsaturated amino C _1-8 Alkoxy, saturated or unsaturated sulfonylamino C _1-8 Alkyl, saturated or unsaturated halogenated C _1-8 Alkylacyl, saturated or unsaturated halogenated C _1-8 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-8 Alkylaminocarbonyl, saturated or unsaturated halogenated C _1-8 Alkylsulfonyl, saturated or unsaturated halogenated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkoxy, saturated or unsaturated sulfonyl halides C _1-8 Alkyl, saturated or unsaturated hydroxy C _1-8 Alkanoyl, saturated or unsaturated hydroxy C _1-8 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylaminocarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylsulfonyl, saturated or unsaturated hydroxy C _1-8 Alkylamino, saturated or unsaturated hydroxy C _1-8 Alkoxy, saturated or unsaturated sulfonylhydroxy C _1-8 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-8 Cycloalkyl, or R ^a And R is ^b Together with the N atom to which they are attached form a group of 1 to 3G' s ¹ Substituted saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

R ^c And R is ^d Each independently optionally from hydrogen, -OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ² Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkyl, saturated or unsaturated hydroxy C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _1-8 Alkylmercapto, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, C _6-10 Aryl, a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-8 Cycloalkyl, saturated or unsaturated halogenated 3-8 heterocycloalkyl, saturated or unsaturated halogenated C _1-8 Alkoxy, saturated or unsaturated halogenated C _1-8 Alkylthio, saturated orUnsaturated halogenated C _3-8 Cyclic alkoxy, saturated or unsaturated halogenated C _1-8 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-8 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-8 Alkyl, saturated or unsaturated halogenated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated C _6-10 Aryl, saturated or unsaturated halogenated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy groups C _3-8 Cycloalkyl, saturated or unsaturated hydroxy 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-8 Alkoxy, saturated or unsaturated hydroxy C _1-8 Alkylmercapto, saturated or unsaturated hydroxy C _3-8 Cycloalkoxy, saturated or unsaturated hydroxy C _1-8 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-8 Alkyl, saturated or unsaturated hydroxy 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy 6-10 membered aryl, saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-8 Cycloalkyl, saturated or unsaturated amino 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-8 Alkoxy, saturated or unsaturated amino C _1-8 Alkylmercapto, saturated or unsaturated amino C _3-8 Cycloalkoxy, saturated or unsaturated amino C _1-8 Alkoxycarbonyl, saturated or unsaturated amino C _1-8 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-8 Alkyl, saturated or unsaturated amino 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; - (CH) ₂ ) _n5 Saturated or unsaturated C _3-10 Cycloalkyl, - (CH) ₂ ) _n5 -saturated or unsaturated 3-10 membered heterocycloalkyl, - (CH) containing 1 to 3 heteroatoms selected from N, O and S ₂ ) _n5 -6-10 membered aryl, - (CH) ₂ ) _n5 -a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; or R is ^c And R is ^d Together with the N atom to which they are attached form a group of 1 to 3G' s ³ Substituted 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

R ^e Optionally selected from 1-3G ² Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkyl, saturated or unsaturated hydroxy C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-8 Cycloalkyl, saturated or unsaturated halogenated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated halogenated C _1-8 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-8 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-8 Alkyl, saturated or unsaturated halogenated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated 6-10 membered aryl, saturated or unsaturated halogenated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy 3-8 cycloalkyl, saturated or unsaturated hydroxy 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-8 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-8 Alkyl, saturated or unsaturated hydroxy containing 1 to 3 heteroatoms selected from N, O and S3-10 membered heterocycloalkyl, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-8 Cycloalkyl, saturated or unsaturated amino 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-8 Alkoxycarbonyl, saturated or unsaturated amino C _1-8 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-8 Alkyl, saturated or unsaturated amino 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

R ^f Optionally selected from hydrogen, hydroxy, amino, saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated amino C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkylamino, saturated or unsaturated amino C _1-8 Alkoxy, saturated or unsaturated halogenated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkoxy, saturated or unsaturated hydroxy C _1-8 Alkylamino, saturated or unsaturated hydroxy C _1-8 An alkoxy group.

G ¹ Are each independently selected from H, deuterium, halogen, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f By 1-3 deuterium, halogen, amino, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or R is ^g Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturatedAnd or unsaturated carboxyl groups C _1-8 Alkyl, saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

G ² Optionally selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated amino C _1-8 Alkylacyl, saturated or unsaturated C _1-8 Alkylacyl, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 An alkylaminocarbonyl group.

G ³ Any C selected from hydrogen, deuterium, hydroxy, halogen, cyano, sulfonyl, amino, saturated or unsaturated _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cycloalkoxy, saturated or unsaturated-OC (=O) C _1-8 Alkyl, saturated or unsaturated-OC (=o) C _3-8 Cycloalkyl, saturated or unsaturated-C (=o) OC _1-8 Alkyl, saturated or unsaturated-C (=o) OC _3-8 Cycloalkyl, substituted by halogen, hydroxy, amino or R ^g Substituted by saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 A cycloalkoxy group.

Wherein R is ^g Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-6 Alkyl, C substituted by deuterium, halogen, hydroxy or amino, saturated or unsaturated _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cycloalkoxy, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-6 Alkoxy, saturated or unsaturated C3-6 cycloalkoxy substituted with deuterium, halogen, hydroxy or amino.

n1 and n2 are each independently integers of 0, 1, 2, 3, 4 or 5.

n3 is an integer of 0, 1, 2 or 3.

n4 is an integer of 0, 1 or 2.

n5 is an integer of 0, 1, 2, 3, 4, 5, 6, 7 or 8.

Preferably, R is selected from the group consisting of-NR ^a R ^b ，C _1-6 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or substituted by 1-3G ¹ Substituted saturated or unsaturated C _1-6 Alkyl, quilt 1-3G ¹ Substituted saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

Preferably, R ¹ Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ¹ And A is a ¹ -A ⁴ The ring formation is covered by 1-3G ¹ Substituted 8-10 membered ring, saturated or unsaturated, having 1 to 3 heteroatoms selected from N, O and S.

More preferably, R ¹ Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ¹ And A is a ¹ -A ⁴ The ring formation is covered by 1-3G ¹ Substituted 8-9 membered ring, saturated or unsaturated, with 1 to 3 heteroatoms selected from N, O and S.

Preferably, R ² Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated C _1-6 Alkylcarboxy, saturated or unsaturated 3-6 membered cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

More preferably, R ² Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated C _1-4 Alkylcarboxyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

Preferably, R ^a And R is ^b Each independently selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated C _1-6 Alkylacyl, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylaminocarbonyl, saturated or unsaturated C _1-6 Alkylsulfonic acidsAcyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated sulfonyl C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkylacyl, saturated or unsaturated amino C _1-6 Alkoxycarbonyl, saturated or unsaturated amino C _1-6 Alkylaminocarbonyl, saturated or unsaturated amino C _1-6 Alkylsulfonyl, saturated or unsaturated amino C _1-6 Alkylamino, saturated or unsaturated amino C _1-6 Alkoxy, saturated or unsaturated sulfonylamino C _1-6 Alkyl, saturated or unsaturated halogenated C _1-6 Alkylacyl, saturated or unsaturated halogenated C _1-6 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-6 Alkylaminocarbonyl, saturated or unsaturated halogenated C _1-6 Alkylsulfonyl, saturated or unsaturated halogenated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkoxy, saturated or unsaturated sulfonyl halides C _1-6 Alkyl, saturated or unsaturated hydroxy C _1-6 Alkanoyl, saturated or unsaturated hydroxy C _1-6 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylaminocarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylsulfonyl, saturated or unsaturated hydroxy C _1-6 Alkylamino, saturated or unsaturated hydroxy C _1-6 Alkoxy, saturated or unsaturated sulfonylhydroxy C _1-6 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ^a And R is ^b Together with the N atom to which they are attached form a group of 1 to 3G' s ¹ Substituted saturated or unsaturated 5-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

More preferably, R ^a And R is ^b Each independently selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated C _1-4 Alkylacyl, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylaminocarbonyl, saturated or unsaturated C _1-4 Alkylsulfonyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated sulfonyl C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkylacyl, saturated or unsaturated amino C _1-4 Alkoxycarbonyl, saturated or unsaturated amino C _1-4 Alkylaminocarbonyl, saturated or unsaturated amino C _1-4 Alkylsulfonyl, saturated or unsaturated amino C _1-4 Alkylamino, saturated or unsaturated amino C _1-4 Alkoxy, saturated or unsaturated sulfonylamino C _1-4 Alkyl, saturated or unsaturated halogenated C _1-4 Alkylacyl, saturated or unsaturated halogenated C _1-4 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-4 Alkylaminocarbonyl, saturated or unsaturated halogenated C _1-4 Alkylsulfonyl, saturated or unsaturated halogenated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkoxy, saturated or unsaturated sulfonyl halides C _1-4 Alkyl, saturated or unsaturated hydroxy C _1-4 Alkanoyl, saturated or unsaturated hydroxy C _1-4 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylaminocarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylsulfonyl, saturated or unsaturated hydroxy C _1-4 Alkylamino, saturated or unsaturated hydroxy C _1-4 Alkoxy, saturated or unsaturated sulfonylhydroxy C _1-4 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ^a And R is ^b Together with the N atom to which they are attached form a group of 1 to 3G' s ¹ Substituted saturated or unsaturated 5-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

Preferably, R ^c And R is ^d Each independently optionally from hydrogen, -OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ² Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkyl, saturated or unsaturated hydroxy C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _1-6 Alkylmercapto, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-8 Cycloalkyl, saturated or unsaturated halogenated 3-8 heterocycloalkyl, saturated or unsaturated halogenated C _1-6 Alkoxy, saturated or unsaturated halogenated C _1-6 Alkylmercapto, saturated or unsaturated halogenated C _3-6 Cyclic alkoxy, saturated or unsaturated halogenated C _1-6 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-6 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-6 Alkyl, saturated or unsaturated halogenated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated C _6-10 Aryl, saturated or unsaturated halogenated 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy groups C _3-6 Cycloalkyl group,Saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl, saturated or unsaturated hydroxy C containing 1 to 3 heteroatoms selected from N, O and S _1-6 Alkoxy, saturated or unsaturated hydroxy C _1-6 Alkylmercapto, saturated or unsaturated hydroxy C _3-6 Cycloalkoxy, saturated or unsaturated hydroxy C _1-6 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-6 Alkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-6 Cycloalkyl, saturated or unsaturated amino 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-6 Alkoxy, saturated or unsaturated amino C _1-6 Alkylmercapto, saturated or unsaturated amino C _3-6 Cycloalkoxy, saturated or unsaturated amino C _1-6 Alkoxycarbonyl, saturated or unsaturated amino C _1-6 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-6 Alkyl, saturated or unsaturated amino 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; - (CH) ₂ ) _n5 Saturated or unsaturated C _3-6 Cycloalkyl, - (CH) ₂ ) _n5 -saturated or unsaturated 3-6 membered heterocycloalkyl, - (CH) containing 1 to 3 heteroatoms selected from N, O and S ₂ ) _n5 -6-10 membered aryl, - (CH) ₂ ) _n5 -a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; or R is ^c And R is ^d Together with the N atom to which they are attached form a group of 1 to 3G' s ³ Substituted 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

More preferably, R ^c And R is ^d Each independently optionally from hydrogen, -OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ² Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkyl, saturated or unsaturated hydroxy C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _1-4 Alkylmercapto, saturated or unsaturated C _4-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _4-6 Cycloalkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl, saturated or unsaturated halogenated C _1-4 Alkoxy, saturated or unsaturated halogenated C _1-4 Alkylmercapto, saturated or unsaturated halogenated C _4-6 Cyclic alkoxy, saturated or unsaturated halogenated C _1-4 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-4 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-4 Alkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated C _6-10 Aryl, saturated or unsaturated halogenated 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy groups C _4-6 Cycloalkyl, saturated or unsaturated hydroxy 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-4 Alkoxy, saturated or unsaturated hydroxy C _1-4 Alkylmercapto, saturated or unsaturated hydroxy C _4-6 Cycloalkoxy, saturated or unsaturated hydroxy C _1-4 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-4 Alkyl, saturated or unsaturated hydroxy containing 1 to 3 heteroatoms selected from N, O and S4-6 membered heterocycloalkyl, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _4-6 Cycloalkyl, saturated or unsaturated amino 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-4 Alkoxy, saturated or unsaturated amino C _1-4 Alkylmercapto, saturated or unsaturated amino C _4-6 Cycloalkoxy, saturated or unsaturated amino C _1-4 Alkoxycarbonyl, saturated or unsaturated amino C _1-4 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-4 Alkyl, saturated or unsaturated amino 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; - (CH) ₂ ) _n5 Saturated or unsaturated C _4-6 Cycloalkyl, - (CH) ₂ ) _n5 -a saturated or unsaturated 4-6 membered heterocycloalkyl, - (CH) containing 1 to 3 heteroatoms selected from N, O and S ₂ ) _n5 -6-10 membered aryl, - (CH) ₂ ) _n5 -a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; or R is ^c And R is ^d Together with the N atom to which they are attached form a group of 1 to 3G' s ³ Substituted 5-8 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

Preferably, R ^e Optionally selected from 1-3G ² Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkyl, saturated or unsaturated hydroxy C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkyl, saturated or unsaturated C _3-6 A membered cycloalkyl, a saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl groups containing 1 to 3 members selected from NSaturated or unsaturated 3-8 membered heterocycloalkyl of heteroatoms of O and S, C _6-10 A membered aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-6 Cycloalkyl, saturated or unsaturated halogenated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated halogenated C _1-6 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-6 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-6 Alkyl, saturated or unsaturated halogenated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated 6-10 membered aryl, saturated or unsaturated halogenated 5-8 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy 3-6 cycloalkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-6 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-6 Alkyl, saturated or unsaturated hydroxy 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-6 Cycloalkyl, saturated or unsaturated amino 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-6 Alkoxycarbonyl, saturated or unsaturated amino C _1-6 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-6 Alkyl, saturated or unsaturated amino 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _6-10 A membered aryl, a saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

More preferably, R ^e Optionally selected from 1-3G ² Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkyl group,Saturated or unsaturated hydroxy groups C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkyl, saturated or unsaturated C _4-6 A membered cycloalkyl, a saturated or unsaturated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 A membered aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _4-6 Cycloalkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated halogenated C _1-4 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-4 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-4 Alkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated 6-10 membered aryl, saturated or unsaturated halogenated 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy 4-6 cycloalkyl, saturated or unsaturated hydroxy 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-4 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-4 Alkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _4-6 Cycloalkyl, saturated or unsaturated amino 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-4 Alkoxycarbonyl, saturated or unsaturated amino C _1-4 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-4 Alkyl, saturated or unsaturated amino containing 1 to 3 heteroatoms selected from N, O and S3-6 membered heterocycloalkyl, saturated or unsaturated amino C _6-10 A membered aryl, a saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

Preferably, R ^f Optionally selected from hydrogen, hydroxy, amino, saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated amino C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkylamino, saturated or unsaturated amino C _1-6 Alkoxy, saturated or unsaturated halogenated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkoxy, saturated or unsaturated hydroxy C _1-6 Alkylamino, saturated or unsaturated hydroxy C _1-6 An alkoxy group.

More preferably, R ^f Optionally selected from hydrogen, hydroxy, amino, saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated amino C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkylamino, saturated or unsaturated amino C _1-4 Alkoxy, saturated or unsaturated halogenated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkoxy, saturated or unsaturated hydroxy C _1-4 Alkylamino, saturated or unsaturated hydroxy C _1-4 An alkoxy group.

Preferably G ¹ Are each independently selected from H, deuterium, halogen, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f By 1-3 deuterium, halogen, amino, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or R is ^g Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cycloalkoxy, saturated orUnsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, saturated or unsaturated 3-8 membered cycloalkyl, saturated or unsaturated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, 6-10 membered aryl, saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

More preferably G ¹ Are each independently selected from H, deuterium, halogen, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f By 1-3 deuterium, halogen, amino, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or R is ^g Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, saturated or unsaturated 4-6 membered cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, 6-10 membered aryl, saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

Preferably G ² Optionally selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated amino C _1-6 Alkylacyl, saturated or unsaturated C _1-6 Alkylacyl, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 An alkylaminocarbonyl group.

More preferably G ² Optionally selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated amino C _1-4 Alkylacyl, saturated or unsaturated C _1-4 Alkylacyl, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 An alkylaminocarbonyl group.

Preferably G ³ Any C selected from hydrogen, deuterium, hydroxy, halogen, cyano, sulfonyl, amino, saturated or unsaturated _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cycloalkoxy, saturated or unsaturated-OC (=O) C _1-6 Alkyl, saturated or unsaturated-OC (=o) C _3-6 Cycloalkyl, saturated or unsaturated-C (=o) OC _1-6 Alkyl, saturated or unsaturated-C (=o) OC _3-6 Cycloalkyl, substituted by halogen, hydroxy, amino or R ^g Substituted by saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 A cycloalkoxy group.

More preferably G ³ Any C selected from hydrogen, deuterium, hydroxy, halogen, cyano, sulfonyl, amino, saturated or unsaturated _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 Cycloalkoxy, saturated or unsaturated-OC (=O) C _1-4 Alkyl, saturated or unsaturated-OC (=o) C _4-6 Cycloalkyl, saturated or unsaturated-C (=o) OC _1-4 Alkyl, saturated or unsaturated-C (=o) OC _4-6 Cycloalkyl, substituted by halogen, hydroxy, amino or R ^g Substituted by saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 A cycloalkoxy group.

Preferably, R ^g Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-4 Alkyl, C substituted by deuterium, halogen, hydroxy or amino, saturated or unsaturated _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 Cycloalkoxy group, deuterium-substituted,Halogen-, hydroxy-or amino-substituted saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _4-6 A cycloalkoxy group.

Preferably, n1 is an integer of 0, 1 or 2.

Preferably, n2 is an integer of 0, 1 or 2.

Preferably, n5 is an integer of 0, 1, 2, 3 or 4.

Preferably, L is-C (=o) NH-or-NH-.

Preferably, when L is Carbonyl (CO) or CONH, the fused ring heterocyclic compound of formula i, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof is represented by one of the following structural formulas:

wherein the substituents are B ring, L, R, R ¹ 、R ² 、n ₁ 、n ₂ Is as defined for formula I.

Preferably, when L is NH, the fused ring heterocyclic compound of formula i, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof is represented by one of the following structural formulas:

More preferably, R is-NR ^a R ^b In this case, the following structure is preferable:

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more preferably, the fused ring heterocyclic compound according to the present invention, each of its optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof is selected from the following compounds:

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according to a second aspect of the present invention, it is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a fused ring heterocyclic compound according to the present invention, each of its optical isomers, deuterides, prodrugs or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient or carrier.

According to a third aspect of the present invention, it is a further object of the present invention to provide the use of a fused ring heterocyclic compound according to the present invention, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof in the preparation of an AHR disorder inhibitor.

According to a fourth aspect of the present invention, it is a further object of the present invention to provide the use of a fused ring heterocyclic compound according to the present invention, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a tumor associated with an AHR disorder.

According to a fifth aspect of the present invention, it is a further object of the present invention to provide a method of treating a tumor associated with AHR disorders, the method comprising administering to a subject in need thereof an effective amount of a fused ring heterocyclic compound according to the present invention, each of its optical isomers, deuterides, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to the present invention.

According to a sixth aspect of the present invention, there is another object of the present invention to provide a method for preparing each of optical isomers, deuterated compounds, prodrugs or pharmaceutically acceptable salts thereof according to the condensed ring heterocyclic compounds of the present invention, which is shown in the following reaction formula 1

The synthesis of the fused ring heterocyclic compounds of formula i, their respective optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts according to the invention may be carried out according to the following reaction formula i, for example, with substituent L being C (=o) NH:

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Wherein carboxylic acid compound II reacts with compound II to form a condensed ring heterocyclic compound of the formula II, wherein the carbonyl group in substituent L is derived from carboxylic acid compound II and the amino group in substituent L is derived from compound II.

Wherein the carboxylic acid compound II can be prepared according to one of the following methods, which are exemplified below.

Method A

Step 1: preparation of intermediate IV

Mixing, stirring and heating the ethanone compound containing the B ring structure with diethyl ketomalonate for reaction, cooling, adding petroleum ether, continuously stirring and cooling to room temperature, filtering, washing a filter cake with a small amount of petroleum ether, and drying to obtain a white solid compound IV.

Step 2: preparation of intermediate V

Compound IV was dissolved in ethanol with hydrazine hydrochloride and stirred at reflux overnight. Spin-drying the reaction solution, adding ethyl acetate and water, stirring vigorously, extracting, washing the organic phase, drying, and evaporating the solvent under reduced pressure to obtain an intermediate V.

Step 3: preparation of intermediate VI

Intermediate V and POCl ₃ The mixture of (2) is refluxed under the protection of nitrogen, concentrated to dryness under reduced pressure, stirred with ice water, filtered and dried to obtain intermediate VI.

Step 4: preparation of intermediate VIII

Intermediate VI and R containing substituents ¹ Dissolving the acethydrazide compound in n-butanol, adding acetic acid, heating and stirring overnight under the protection of nitrogen, concentrating under reduced pressure to dryness, and purifying by silica gel column chromatography to obtain an intermediate VIII.

Step 5: preparation of intermediate IIa

Intermediate VIII is added to THF/MeOH/H ₂ Adding lithium hydroxide into the mixed solvent of O (1:1:1), stirring at room temperature, removing part of the solvent under reduced pressure, adjusting the pH to 2-3, filtering, washing the filter cake with water and ethyl acetate, and drying to obtain a compound IIa.

Method B

Step 1: preparation of intermediates VIII and VIIIc

And (3) cooling and stirring a mixed solution of anhydrous ethanol of diethyl oxalate and sodium ethoxide, dropwise adding an anhydrous ethanol solution of an ethanone compound containing a B ring structure, removing the ice bath, stirring at room temperature overnight, filtering, washing with a small amount of ethanol, and drying to obtain VIII or VIIIc.

Step 2: preparation of intermediates IX and X

Intermediate VIIIb and VIIIc and amino compoundDissolving in n-butanol, adding acetic acid, heating and stirring overnight, concentrating under reduced pressure to dry, adding ice water and stirring, filtering, washing with water, and drying to obtain IX and X mixture. Purifying by silica gel column chromatography to obtain compounds IX and X.

Step 3: preparation of intermediates IIb and IIc

The intermediate IIb and IIc-1 are obtained by hydrolysis of compounds IX and X, respectively, in a similar manner to step 5 of preparing intermediate compound IIa in Process A.

Method C

Step 1: preparation of intermediate XI

3, 6-dichloropyrazine-4-carboxylic acid ethyl ester and substituent R ¹ Dissolving the acethydrazide in n-butanol, adding acetic acid, heating and stirring overnight under the protection of nitrogen, concentrating under reduced pressure to dryness, and purifying by silica gel column chromatography to obtain the intermediate XI.

Step 2: preparation of intermediate XII

Compound XI and boric acid containing a B-ring structure were dissolved in 20ml of dioxane, and a saturated sodium carbonate solution and tetrakis (triphenylphosphine) palladium were added thereto, followed by stirring overnight under nitrogen. Concentrating under reduced pressure to dry, adjusting pH to 6-7, filtering, washing with dichloromethane, and purifying with silica gel column chromatography to obtain compound XII.

Step 3: preparation of intermediate IId-1

The hydrolysis of intermediate XII to compound IId-1 is carried out in a similar manner to step 5 of preparing intermediate compound IIa in Process A.

Method D

Step 1: preparation of intermediate VI

3, 6-dichloropyridazine-4-carboxylic acid ethyl ester and substituent R ² Aryl boric acid/boric acid of (a)Under the protection of inert gas, the ester uses palladium compound as catalyst, and the target compound VI is reacted by SUZUKI.

Step 2: preparation of intermediate XIII

Intermediate VI and 4-methoxybenzylamine were dissolved in dioxane and DIPEA was added. The mixture is heated and stirred under the protection of nitrogen, concentrated to dryness under reduced pressure, the intermediate is obtained by purifying by silica gel column chromatography, the obtained mixture of the intermediate and TFA is heated and refluxed and stirred under the protection of nitrogen, the mixture is concentrated to dryness under reduced pressure, ice water and ethyl acetate are added for extraction, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography, and the intermediate XIII is obtained.

Step 3: preparation of intermediate XIV

Intermediate XIII is dissolved in isopropanol and a substituent A is added ¹ And A ² Heating and stirring, concentrating under reduced pressure to dryness, extracting with dichloromethane, washing with water, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by silica gel column chromatography to obtain XIV.

Step 4: preparation of intermediate IIe

The hydrolysis of intermediate XIV gives compound IIe in a similar manner to step 5 for the preparation of intermediate compound IIa-1.

Method E

Step 1: preparation of intermediate XVII

Will contain substituent R ¹ Dissolving amino cyano pyrazole in n-butanol, heating p-toluenesulfonic acid and ethyl phenylpropionate containing a B ring structure, heating and stirring the mixture, cooling to room temperature, filtering, washing with methanol, and drying to obtain the compound XVII.

Step 2: preparation of intermediate XVIII

Dissolving intermediate XVII in phosphorus oxychloride, heating and refluxing, concentrating under reduced pressure until the mixture is dry, adding ice water and stirring, filtering, washing with water, and drying to obtain a compound XVIII.

Step 3: preparation of intermediate IIb-11

Intermediate XVIII, pd (OAc) ₂ Dppf and triethylamine were dissolved in dry DMSO/MeOH, the reaction mixture was replaced with CO gas, heated and stirred overnight under CO gas, concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give the ester intermediate. According to a similar method to the step 5 of preparing the intermediate compound IIa by the method A, the ester intermediate is hydrolyzed to obtain the compound IIb-11.

The synthesis method of the compound III in the preparation method of the condensed ring heterocyclic compound shown in the formula I is exemplified as follows when the compound III is a hydrazine compound:

method F

1) BocNHNH ₂ (Boc) hydrazine is dissolved in an alcoholic solvent such as methanol or ethanol, and then ketone compound (R) ^a (C＝O)R ^a ) Or aldehyde compound (R) ^a (c=o) H, then adding sodium borohydride for hydrogenation reduction, purifying and separating to obtain the compound

2) The compound is preparedDissolving in amine solvent such as N, N-Diisopropylethylamine (DIEA), and adding ketone compound (Rb (C=O) Rb), aldehyde compound (Rb (C=O) H) or corresponding R ₂ The substituted epoxide is reacted to give the compound +.>

3) The compound is preparedDissolving in alcohol solvent such as methanol and ethanol, and adding excessive methanol solution of HCl to obtain hydrochloride of compound represented by formula III.

Method G

1) Substituted amino compounds (HNR) ^a R ^b ) Dissolving in solvent, adding nitrosation reagent selected from tert-butyl nitrite and isobutyl nitrite, heating and refluxing, concentrating under reduced pressure to obtain intermediate nitrosamine compound (R) ^a N(R ^b )-N＝O)；

2) Nitrosamine group Compound (R) ^a N(R ^b ) -n=o) is dissolved in a solvent, and a hydrogenation reagent such as lithium aluminum hydride is added to perform hydrogenation reaction, thereby obtaining a compound represented by formula III.

The above reaction methods are merely exemplary and are merely for illustrating the preparation methods of some compounds according to the present invention, but the person skilled in the art can fully obtain other compounds based on the above exemplary preparation methods in combination with general common general knowledge of the preparation means.

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.

All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.

If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.

In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.

In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is also meant that the claim of X as X1 and/or X2 have been fully described. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3" and Y is described as "selected from the group consisting of Y1, Y2, and Y3," then the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

Definition of the definition

"alkyl" refers to a group ("C") that is a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms _1–8 Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C _1-7 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C _1-6 Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C _1-5 Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C _1-4 Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C _1-3 Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C _1-6 Alkyl "). C (C) _1–6 Examples of alkyl groups include methyl (C) ₁ ) Ethyl (C) ₂ ) Propyl (C) ₃ ) (e.g., n-propyl, isopropyl), butyl (C) ₄ ) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C) ₅ ) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl) and hexyl (C) ₆ ) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C ₇ ) N-octyl (C) ₈ ) Etc. Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl is unsubstituted C _1-8 Alkyl (e.g. unsubstituted C ₁ Alkyl radicals, e.g. -CH ₃ ). In certain embodiments, the alkyl is substituted C _1-8 Alkyl (e.g. substituted C ₁ Alkyl radicals, e.g. -CF ₃ )。

"alkoxy" means a monovalent-O-alkyl group in which the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups in this disclosure typically contain 1-8 carbon atoms ("C1-C8 alkoxy"), 1-6 carbon atoms ("C1-C6 alkoxy"), or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy") or substituted (a "substituted alkoxy") with one or more substituents. In certain embodiments, the alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, the alkoxy is a substituted C1 to C6 alkoxy.

"cycloalkyl" means a non-aromatic ring system having 3 to 8 ring carbon atoms ("C _3-8 Cycloalkyl ") and zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C _3-8 Cycloalkyl "). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 8 ring carbon atoms ("C _5-8 Cycloalkyl "). Exemplary C _3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C) ₃ ) Cyclopropenyl (C) ₃ ) Cyclobutyl (C) ₄ ) Cyclobutenyl (C) ₄ ) Cyclopentyl (C) ₅ ) Cyclopentenyl (C) ₅ ) Cyclohexyl (C) ₆ ) Cyclohexenyl (C) ₆ ) Cyclohexadienyl (C) ₆ ) Etc. Exemplary C _3-8 Cycloalkyl groups include, but are not limited to, C described above _3-6 Cycloalkyl group and cycloheptyl (C) ₇ ) Cycloheptenyl (C) ₇ ) Cycloheptadienyl (C) ₇ ) Cycloheptatrienyl (C) ₇ ) Cyclooctyl (C) ₈ ) Cyclooctenyl (C) ₈ ) Etc. Each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents, unless otherwise specified. In certain embodiments, cycloalkyl is unsubstituted C _3-8 Cycloalkyl; in certain embodiments, cycloalkyl is substituted C _3-8 Cycloalkyl groups.

"heterocycloalkyl" refers to a group of a 4 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("4-14 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as the valence permits. The heterocyclic group may be a single ring ("monocyclic heterocyclic group") or a fused, bridged or spiro ring system, for example a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or may be partially unsaturated. "heterocyclic group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic system. Each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted by one or more substituents ("substituted heterocycloalkyl"), unless otherwise specified. In certain embodiments, the heterocycloalkyl is an unsubstituted 4-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 4-14 membered heterocycloalkyl.

"aryl" or "aromatic ring group" refers to a group ("C") of a single or multiple ring (e.g., bi-or tri-cyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system _6-14 Aryl "). In some embodiments, aryl groups have 6 ring carbon atoms ("C ₆ Aryl "; for example, phenyl). In some embodiments, aryl groups have 10 ring carbon atoms ("C ₁₀ Aryl "; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C ₁₄ Aryl "; for example, anthracyl). "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the point of attachment is on the aromatic ring, and in such cases, a carbon atomContinues to refer to the number of carbon atoms in the aromatic ring system. Each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, unless otherwise indicated. In certain embodiments, aryl is unsubstituted C _6-14 Aryl groups. In certain embodiments, aryl is substituted C _6-14 Aryl groups.

"heteroaryl" is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted by one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl is an unsubstituted 5-10 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-10 membered heteroaryl.

"halogen" or "halo" means fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

"substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is substituted with an allowable substituent, e.g., a substituent that upon substitution forms a stable compound, e.g., a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein which result in the formation of stable compounds. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

"unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. "partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl). Likewise, "saturated" refers to groups that do not contain double or triple bonds, i.e., all contain single bonds.

In this context, when multiple substitutions are present in defined substituents, there may be instances of repeated definitions in the literal description of such multiple substitutions, but such description should be understood to at least follow the basic rules of general pharmaceutical chemistry, e.g., when repeated definitions of substituents occur, those skilled in the art may determine that such repetition is feasible or infeasible in accordance with common general pharmaceutical chemistry knowledge. Taking definition of substituent R as an example, R can beIs "quilt 1-3G ¹ Substituted saturated or unsaturated C _3-10 Cycloalkyl ", and substituent G ¹ In the definition of (a) may be "saturated or unsaturated 3-10 membered cycloalkyl", etc., and a person skilled in the art may determine whether such repetition is feasible or not based on general knowledge of pharmaceutical chemistry and make a reasonable choice.

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

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) may be obtained by contacting neutral forms of such compounds with sufficient amounts of an acid in pure solution or in a suitable inert solvent, examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; the organic acids include acids such as benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, sulfanilic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, folinic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

As used herein, the modifier term "about" refers to a change in value that may occur, for example, by routine testing and processing; unintentional errors in passing such tests and processing; differences in source or purity by the manufacture of the components used in the present invention; etc. As used herein, "about" a particular value also includes the particular value, e.g., "about 10%" includes 10%. Whether or not modified by the term "about", the claims include equivalents to the listed amounts. In one embodiment, the term "about" means within 20% of the reported numerical value.

As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or disorder and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptom associated therewith. As used herein, the term "treatment" or the like may include "prophylactic treatment" referring to reducing the likelihood of recurrence of a disease or disorder or a previously controlled disease or disorder in a subject that is free of, or at risk of, suffering from, or susceptible to recurrence of the disease or disorder. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

Diseases associated with the AHR pathway according to the invention include, but are not limited to, tumors associated with the AHR pathway.

The following examples are merely illustrative of embodiments of the present invention and are not intended to limit the invention in any way, and those skilled in the art will appreciate that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

Examples

Experimental part:

preparation of intermediate IIa-1 (Process A):

Step 1: preparation of intermediate IVa

4-Trifluoromethylacetophenone (9.7 g,51.7 mmol) and diethyl ketomalonate (22.5 g,129.3 mmol) were mixed, stirred and heated to 130℃for 48 hours, cooled to about 40℃and petroleum ether (50 mL) was added, stirring and cooling were continued to room temperature, filtration was carried out, and the filter cake was washed with a small amount of petroleum ether and dried to give compound IVa (14.6 g, yield 78%) as a white solid. LC/MS (ESI) m/z 363[ M+H ]] ⁺ 。

Step 2: preparation of intermediate Va

Compound IVa (2.4 g,6.63 mmol) and hydrazine hydrochloride (0.84 g,7.96 mmol) are dissolved in 100mL ethanol and stirred at reflux overnight. The reaction mixture was dried by spinning, 100mL of ethyl acetate and 50mL of water were added, stirring vigorously for 30 minutes, extraction was performed, the organic phase was washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressureIntermediate Va. ¹ HNMR:(400MHz,CDCl ₃ )δ＝12.6(s,1H),8.35(s,1H),7.96(d,J＝8.0Hz,2H),7.75(d,J＝8.0Hz,2H),4.49(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)。LC/MS(ESI):m/z 313[M+H] ⁺ 。

Step 3: preparation of intermediate VIa

Intermediate Va (313 mg,1 mmol) and POCl ₃ (5 ml) the mixture was refluxed under nitrogen protection for 6h, concentrated to dryness under reduced pressure, stirred with ice-water for 10min, filtered and dried to give intermediate VIa (255 mg, yield 77%). LC/MS (ESI) m/z 331[ M+H ]] ⁺ 。

Step 4: preparation of intermediate VIIa

Intermediate VIa (255 mg,0.77 mmol) and trifluoroacetyl hydrazine (99 mg,0.77 mmol) were dissolved in n-butanol (100 ml), 5ml of acetic acid was added, heated to 120 ℃ under nitrogen protection, stirred overnight, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to give intermediate VIIa (263 mg, yield 65%). LC/MS (ESI) m/z 405[ M+H ] ] ⁺ 。

Step 5: preparation of intermediate IIa-1

Intermediate VIIa (262 mg,0.65 mmol) was added 18mL THF/MeOH/H ₂ To the mixed solvent of O (1:1:1), 10 equivalents of lithium hydroxide was added, stirred at room temperature for 4 hours, part of the solvent was removed under reduced pressure, pH was adjusted to 2-3 with 6N hydrochloric acid, filtration was carried out, and the cake was washed with water and ethyl acetate and dried to give Compound IIa-1 (201 mg, yield 82%). LC/MS (ESI) m/z 377[ M+H ]] ⁺ 、375[M-H] ^- 。

The following intermediate compounds IIa-2 to IIa-9 can be prepared in the same manner as intermediate compound IIa-1.

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Preparation of intermediates IIb-1 and IIc-1:

step 1: preparation of intermediates VIIIb and VIIIc

A mixed solution of diethyl oxalate (15.2 g,104 mmol) in absolute ethanol (250 ml) and sodium ethoxide (10.9 g,160 mmol) was cooled to below 10℃and stirred for 30min, a solution of trifluoromethyl benzophenone (18.8 g,100 mmol) in absolute ethanol (80 ml) was added dropwise, the ice bath was removed, stirred at room temperature overnight, the reaction solution was almost solidified, filtered, washed with a small amount of ethanol and dried to give VIIIb (28 g, yield 97%). LC/MS (ESI) m/z 289[ M+H ]] ⁺ 。

Step 2: preparation of intermediates IXb and X

Intermediate VIIIb and VIIIc (2.88 g,10 mmol) and 4-cyano-5-aminopyrazole (1.2 g,11 mmol) were dissolved in 200ml n-butanol, 10ml acetic acid was added, heated to 100 ℃, stirred overnight, concentrated to dryness under reduced pressure, ice water was added, stirred for 30min, filtered, washed with water, and dried to give a mixture of IXb and X. The compound IXb (1.03 g, 29%) and X (75 mg, 2.2%) were purified by silica gel column chromatography. LC/MS (ESI) m/z 361[ M+H ] ] ⁺ 。

Step 3: preparation of intermediates IIb-1 and IIc-1

In a similar manner to step 5 of preparing intermediate compound IIa-1, compounds IXb and X were hydrolyzed to give intermediates IIb-1 (yield 81%) and IIc-1 (yield 73%), respectively. LC/MS (ESI) m/z 333[ M+H ]] ⁺ 、313[M-H] ^- 。

The following intermediate compounds IIb-2 to IIb-8 and intermediate compounds IIc-2 to IIc-8 can be prepared according to the same procedure as for intermediate compounds IIb-1 and IIc-1.

Method C

Step 1: preparation of intermediate XI

Ethyl 3, 6-dichloropyrazine-4-carboxylate (4.42 g,20 mmol) and trifluoroacetyl hydrazine (2.69 g,21 mmol) were dissolved in n-butanol (150 ml), 10ml acetic acid was added, heated to 120 ℃ under nitrogen protection, stirred overnight, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to give intermediate XI (4.4 g, yield 74%). LC/MS (ESI) m/z 295[ M+H ]] ⁺ 。

Step 2: preparation of intermediate XII

Compound XI (560 mg,2 mmol) and 6- (trifluoromethyl) pyridine-3-boronic acid (573 mg,3 mmol) were dissolved in 20ml dioxane, and sodium saturated carbonate solution (1 ml) and tetrakis (triphenylphosphine) palladium (231 mg,0.2 mmol) were added and stirred overnight at 110℃under nitrogen. Concentrating under reduced pressure to dryness, adjusting pH to 6-7 with 2N HCl, filtering, washing with dichloromethane, and purifying by silica gel column chromatography to give compound XII (666 mg, yield 82%). LC/MS (ESI) m/z 406[ M+H ] ] ⁺ 。

Step 3: preparation of intermediate IId-1

In a similar manner to step 5 of preparing intermediate compound IIa-1, compound IId-1 (526 mg, yield 85%) was obtained by hydrolysis of intermediate XII. LC/MS (ESI) m/z 378[ M+H ]] ⁺ 、376[M-H] ^- 。

Method D

Step 1: preparation of intermediate XIII

Intermediate VIa (3.31 g,10 mmol) and 4-methoxybenzylamine (1.64 g,12 mmol) were dissolved in dioxane (100 ml) and DIPEA (3.9 g,30 mmol) was added. The mixture was heated to 70℃under nitrogen, stirred for 1h, concentrated to dryness under reduced pressure, and purified by column chromatography on silica gel to give intermediate XIII (2.38 g, yield 55%). LC/MS (ESI) m/z 432[ M+H ]] ⁺ 。

Step 2: preparation of intermediate XIV

A mixture of intermediate XIII (2.31 g,5.3 mmol) and TFA (10 ml) was heated under reflux with stirring under nitrogen for 1h, concentrated to dryness under reduced pressure, and addedIce water was added, extraction was performed with ethyl acetate (3X 50 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give intermediate XIV (1.54 g, 93% yield). LC/MS (ESI) m/z 312[ M+H ]] ⁺ 。

Step 3: preparation of intermediate XV

Intermediate XIV (1.54 g,5 mmol) was dissolved in 30mml of isopropanol, chloroacetaldehyde (50% aqueous solution, 5.05ml,40 mmol) was added, heated to 80℃and stirred for 4 hours, concentrated to dryness under reduced pressure, extracted with dichloromethane, washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to give XV (1.04 g, yield 62%). LC/MS (ESI) m/z 336[ M+H ] ] ⁺ 。

Step 4: preparation of intermediate XVI

Intermediate XV (1.04 g,3.1 mmol) was dissolved in chloroform (60 ml), N-bromosuccinimide (627 mg,3.5 mmol) was added, stirred and refluxed for 4 hours, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to give XVI (1.1 g, yield 86%). LC/MS (ESI) m/z 414[ M+H ]] ⁺ 。

Step 5: preparation of intermediate XVII

Intermediate XVI (1.1 g,2.7 mmol) was dissolved in DMF (20 ml), zinc cyanide (380 mg,3.24 mmol), tris (dibenzylideneacetone) dipalladium (247 mg,0.27 mmol) and 1, 1-bis (diphenylphosphino) ferrocene (150 mg,0.27 mmol) were added under nitrogen, heated to 120℃overnight with stirring, concentrated to dryness under reduced pressure, diluted with water, extracted with ethyl acetate (2X 50 ml), the organic phases combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give XVII (321 mg, 33% yield). LC/MS (ESI) m/z 361[ M+H ]] ⁺ 。

Step 6: preparation of intermediate IIe-1

In a similar manner to step 5 of preparing intermediate compound IIa-1, hydrolysis of intermediate XVII gave compound IIe-1 (272 mg, 92% yield). LC/MS (ESI) m/z 333[ M+H ]] ⁺ 、331[M-H] ^- 。

Preparation of intermediate IIe-2

Step 1: preparation of intermediate XVI-2

Intermediate XV (1.04 g,3.1 mmol) was dissolved in 10ml of N, N-dimethylformamide, N-chlorosuccinimide (418 mg,3.1 mmol) was added, stirred at room temperature for 4h, diluted with water, extracted with ethyl acetate (2X 50 ml), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give XVI-2 (263 mg, yield 23%). LC/MS (ESI) m/z 370[ M+H ] ] ⁺ 。

Step 2: preparation of intermediate IIe-1

In a similar manner to step 5 of preparing intermediate compound IIa-1, intermediate XVI-2 was hydrolyzed to give compound IIe-2 (213 mg, yield 88%). LC/MS (ESI) m/z 342[ M+H ]] ⁺ 、340[M-H] ⁺ 。

Preparation of intermediate IIe-3

Step 1: preparation of intermediate XVI-3

Intermediate XV (1.01 g,3 mmol) was dissolved in N, N-dimethylformamide (15 ml), N-fluoro-N' - (chloromethyl) triethylenediamine bis (tetrafluoroborate) (1274 mg,3.6 mmol) was added, heated to 80 ℃, stirred overnight, diluted with ethyl acetate (100 ml), washed with saturated brine (2X 50 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give XVI-3 (287 mg, yield 27%). LC/MS (ESI) m/z 354[ M+H ]] ⁺ 。

Step 2: preparation of intermediate IIe-3

In a similar manner to step 5 of preparing intermediate compound IIa-1, intermediate XVI-3 was hydrolyzed to give compound IIe-3 (214 mg, yield 81%). LC/MS (ESI) m/z 326[ M+H ]] ⁺ 、324[M-H] ⁺ 。

Preparation of intermediates IIb-9 and IIc-9

Step 1: preparation of intermediates IXb-9 and IXc-9

Intermediate VIIIb (2.88 g,10 mmol) and 3-aminopyrazole (913 mg,11 mmol) were dissolved in 100ml of n-butanol, 10ml of acetic acid was added, heated to 100 ℃, stirred overnight, concentrated to dryness under reduced pressure, ice-water added, stirred for 30min, filtered, washed with water, dried IXb-9 and IXc-9 mixture (2.6 g, yield 77%). LC/MS (ESI) M/z336[ M+H ] ] ⁺ 。

Step 2: preparation of intermediates Xb-9 and Xc-9

Xb-9 and Xc-9 mixtures were obtained from intermediate IXb-9 and IXc-9 mixtures (2.6 g,7.7 mmol) and N-fluoro-N' - (chloromethyl) triethylenediamine bis (tetrafluoroborate) according to a similar procedure as in step 1 for the preparation of intermediate compound IIe-3. Purification by silica gel column chromatography gave Xb-9 (1.2 g, 43%) and Xc-9 (164 mg, 6%), LC/MS (ESI) M/z354[ M+H ]] ⁺ 。

Step 3: preparation of intermediates IIb-9 and IIc-9

According to a similar method to step 5 in the preparation of intermediate compound IIa-1, hydrolysis of intermediates Xb-9 and Xc-9, respectively, gave compounds IIb-9 (917 mg, yield 83%) and IIc-9 (110 mg, yield 73%). LC/MS (ESI) M/z326[ M+H ]] ⁺ 、324[M-H] ⁺ 。

Preparation of intermediates IIb-10 and IIc-10

Step 1: preparation of intermediates Xb-10 and Xc-10

A mixture of intermediate IXb-9 and IXc-9 (1.68 g,5 mmol) was dissolved in 10ml of N, N-dimethylformamide, N-chlorosuccinimide (697 mg,5.2 mmol) was added, stirred at room temperature for 4h, diluted with water, extracted with ethyl acetate (2X 50 ml), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give Xb-10 (835 mg, 45%) and Xc-10 (93 mg, 5%) as a LC/MS (ESI) m/z 370[ M+H ]] ⁺ 。

Step 2: preparation of intermediates IIb-10 and IIc-10

According to the preparation processStep 5 of intermediate compound IIa-1 was similarly carried out by hydrolyzing intermediates Xb-9 and Xc-9, respectively, to give compounds IIb-10 (693 mg, yield 90%) and IIc-10 (70 mg, yield 81%). LC/MS (ESI) m/z 342[ M+H ]] ⁺ 、340[M-H] ⁺ 。

Preparation of intermediate IIc-6 (alternative method)

Step 1: preparation of intermediate XVII-6

5-amino-4-cyanopyrazole (1 g,9.26 mmol) was dissolved in 20ml of n-butanol, p-toluenesulfonic acid (120 mg,0.7 mmol) and ethyl 3- (4-chlorophenyl) -3-oxo-propionate (4 g,17.6 mmol) were heated, the mixture was heated to 130℃and stirred for 48h, cooled to room temperature, filtered, washed with methanol and dried to give compound XVII-6 (1.56 g, yield 62%). ¹ HNMR(400MHz,DMSO-d ₆ ):δ13.4(s,1H),8.42(s,1H),7.86(d,J＝8.0Hz,2H),7.65(d,J＝8.0Hz,2H),6.31(s,1H)。LC/MS(ESI):m/z 271[M+H] ⁺ 。

Step 2: preparation of intermediate XVIII-6

Intermediate XVII-6 (1.56 g,5.8 mmol) was dissolved in 15ml phosphorus oxychloride, heated at reflux for 5h, concentrated to dryness under reduced pressure, ice water was added and stirred for 10min, filtered, washed with water and dried to give compound XVIII-6 (1.4 g, yield 83%). LC/MS (ESI) m/z 289[ M+H ]] ⁺ 。

Step 3: preparation of intermediate X-6

Intermediate XVIII-6 (1.4 g,4.8 mmol), pd (OAc) ₂ (80 mg,0.23 mmol), dppf (280 mg,0.5 mmol) and triethylamine (3 ml) were dissolved in dry DMSO/MeOH (3:1, 60 ml), the reaction mixture was replaced with CO gas, heated to 80℃under CO gas (7 par) overnight, stirred, concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give X-6 (1.37 g, yield 91%). LC/MS (ESI) m/z 313[ M+H ] ] ⁺ 。

Step 4: preparation of intermediate IIc-6

According to the preparation of the intermediate compound IIa-Step 5 of 1 was carried out in a similar manner to that of step 5, and intermediate X-6 was hydrolyzed to give Compound IIc-6 (1.13 g, yield 87%). LC/MS (ESI) m/z 299[ M+H ]] ⁺ 、297[M-H] ⁺ 。

Preparation of intermediate IIc-1 (alternative method)

According to a similar method for preparing intermediate compound IIc-6, step 1-4 was performed from ethyl 3- (4-trifluoromethylphenyl) -3-oxo-propionate and 5-amino-4-cyanopyrazole to give intermediate IIc-1 (1.6 g). LC/MS (ESI) M/z333[ M+H ]] ⁺ 、331[M-H] ⁺ 。

Preparation of intermediate IIc-7 (alternative method)

Step 1: preparation of intermediate XVII-7

3-amino-pyrazole (7.68 g,93 mmol) was dissolved in 200ml of n-butanol, p-toluenesulfonic acid (1.2 g,7 mmol) and ethyl 3- (4-chlorophenyl) -3-oxo-propionate (40 g,176 mmol) were heated to 130℃and stirred for 48h, cooled to room temperature, filtered, washed with methanol and dried to give compound XVII-7 (17.4 g, 76% yield). LC/MS (ESI) m/z 246[ M+H ]] ⁺ 。

Step 2: preparation of intermediate XVIII-7

Intermediate XVII (17 g,69 mmol) was dissolved in 15ml phosphorus oxychloride, heated at reflux for 5h, concentrated to dryness under reduced pressure and purified by silica gel column chromatography to give compound XVIII-7 (12.4 g, yield 68%). LC/MS (ESI) M/z264[ M+H ] ] ⁺ 。

Step 3: preparation of intermediate X-7

Intermediate XVIII-7 (1.32 g,5 mmol), pd (OAc) ₂ (80 mg,0.23 mmol), 1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (dppf) (280 g,0.5 mmol) and triethylamine (3 ml) were dissolved in dry DMSO/MeOH (3:1, 60 ml), the reaction mixture was replaced with CO gas, heated to 80℃under CO gas (7 par), stirred overnight, concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel to give X-7 (1.18 g, 81% yield). LC/MS (ESI)):m/z 288[M+H] ⁺ 。

Step 4: preparation of intermediate X-7a

Intermediate X-7 (1.18 g,4.1 mmol) was dissolved in 20ml chloroform, N-bromosuccinimide (697 mg,5.2 mmol) was added, stirred at room temperature for 6h, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to give X-7a (840 mg, yield 56%). LC/MS (ESI) m/z 366[ M+H ]] ⁺ 。

Step 5: preparation of intermediate X-7b

Intermediate X-7a (732 mg,2 mmol), cuI (1.15 g,6 mmol), methyl fluorosulfonyl difluoroacetate (1.15 g,6 mmol) was dissolved in 10ml dry DMF, heated to 75℃and stirred for 7h, quenched with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give X-7b (449 mg, 63% yield). LC/MS (ESI) m/z 356[ M+H ] ] ⁺ 。

Step 6: preparation of intermediate IIc-7

Hydrolysis of intermediate X-7b gives compound IIc-7 (375 mg, 87% yield) following a similar procedure to step 5 for the preparation of intermediate compound IIa-1. LC/MS (ESI) m/z 342[ M+H ]] ⁺ 、340[M-H] ⁺ 。

Preparation of intermediate IIc-5 (alternative method)

Step 1: preparation of intermediate Xc-5a

Intermediate Xc-5a (52 mg, 56% yield) was obtained from the reaction of Xc-5 and methyl fluorosulfonyl difluoroacetate according to a similar manner to step 5 in the preparation of intermediate compound IIc-7. LC/MS (ESI) m/z 390[ M+H ]] ⁺ 。

Step 2: preparation of intermediate IIc-5

According to a similar method to step 5 in the preparation of intermediate compound IIa-1, hydrolysis of intermediate Xc-5a gave compound IIc-5 (37 mg, yield 87%). LC/MS (ESI) m/z 376[ M+H ]] ⁺ 、374[M-H] ⁺ 。

Synthesis of intermediate III-1

Method F

Step 1: preparation of intermediate XIX-1

BocNHNH ₂ (13.2 g,100 mmol) was dissolved in 100ml acetone and 50ml methanol, anhydrous magnesium sulfate (12 g,100 mmol) was added, stirred overnight at room temperature, the magnesium sulfate was removed by filtration, the filtrate was concentrated to dryness under reduced pressure, 100ml methanol was added for dissolution, sodium borohydride (15.2 g,400 mmol) was added in portions at room temperature, stirred for 1h, concentrated to dryness under reduced pressure, 200ml distilled water was added, 100ml x3 times extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20% ethyl acetate/petroleum ether) gave compound XIX-1 (15.1 g, yield 87%). LC/MS (ESI) m/z 175[ M+H ] ] ⁺ 。

Step 2: preparation of intermediate XX-1

Intermediate XIX-1 (1.74 g,10 mmol), propylene oxide (2.9 g,50 mmol), N-Diisopropylethylamine (DIEA) (2.58 g,20 mmol) was dissolved in 20ml ethanol and stirred overnight at 80℃in a sealed reaction flask. Concentrating under reduced pressure to dryness, and purifying by silica gel column chromatography (20% -50% ethyl acetate/petroleum ether) to obtain compound XX-1 (1.82 g, yield 78%). LC/MS (ESI) m/z 233[ M+H ]] ⁺ 。

Step 3: preparation of intermediate III-1

1.82g of Compound XV-1 was dissolved in 10ml of methanol, a methanol solution of HCl (excess) was added, stirred overnight at room temperature, and concentrated to dryness under reduced pressure at 40℃to give intermediate III-1 hydrochloride (2.3 g, yield 95%). LC/MS (ESI) m/z 133[ M+H ]] ⁺ 。

Intermediate III-2

Method G.

Step 1: preparation of intermediate XXI-2

BocNH was added sequentially to a 500ml round bottom flaskNH ₂ (30 g,227 mmol), 300ml of methanol, 20.4g of hydroxyacetone and anhydrous magnesium sulfate (68 g), stirring at room temperature for 3.5 hours, filtering to remove the magnesium sulfate, washing a filter cake with anhydrous methanol, adding sodium borohydride (15.2 g,400 mmol) to the filtrate in portions at 0℃and stirring at room temperature for 1 hour after the addition, concentrating under reduced pressure to dryness, adding 200ml of distilled water, extracting 100ml of x3 times with methylene chloride, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XXI-2 (36 g, yield 84%). LC/MS (ESI) m/z 191[ M+H ] ] ⁺ 。

Step 2: preparation of intermediate XX-2

To a 1L round bottom flask intermediate XXI-2 (19.0 g,100 mmol), acetone (17.4 g,300 mmol), methanol 300ml,1ml acetic acid was added sodium cyanoborohydride (15.7 g,250 mmol) at room temperature and the reaction mixture was stirred overnight at room temperature. Concentrating under reduced pressure to dryness, adding distilled water, extracting with ethyl acetate, drying, filtering, and concentrating. Purification by silica gel column chromatography (10% -50% ethyl acetate/petroleum ether) afforded XX-2 (14.1 g, 61% yield) as a white solid. LC/MS (ESI) m/z 233[ M+H ]] ⁺ 。

Step 3: intermediate III-2, the method is the same as that in step II-1, and the yield is 90%. LC/MS (ESI) m/z 133[ M+H ]] ⁺ 。

Intermediate III-3

Step 1: preparation of intermediate XXII-3

To a solution of 2-hydroxyethylhydrazine (5 g,65 mmol) in methanol (100 ml) at 0deg.C was added 13ml of triethylamine, boc ₂ O (17.2 g,78 mmol), stirring at room temperature under nitrogen protection for 16h, concentrating under reduced pressure to dryness, adding citric acid solution, extracting with ethyl acetate, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XXII-3 (6.8 g, yield 89%). LC/MS (ESI) m/z 177[ M+H ]] ⁺ 。

Step 2: preparation of intermediate III-3

Will be intermediateBody XXII-3 (2 g,11.2 mmol) is dissolved in 50ml THF, lithium Aluminum Hydride (LAH) (1.7 g,44.8 mmol) is added, reflux is continued for 5h under nitrogen, cooling to 0deg.C and Na is added in portions ₂ SO ₄ ·10H ₂ O, filtering, washing a filter cake with THF, drying filtrate with anhydrous magnesium sulfate, and concentrating to obtain a crude product III-3, wherein the crude product III-3 is directly used in the next step without purification. LC/MS (ESI) m/z 91[ M+H ]] ⁺ 。

Intermediate III-4

Step 1: preparation of intermediate XXII-4

2-hydroxyethylhydrazine (7.6 g,100 mmol) was added to a mixed solvent of methanol (100 ml) and acetone (50 ml) at 0℃and anhydrous magnesium sulfate (12 g,100 mmol) was added, stirred at room temperature overnight, the magnesium sulfate was removed by filtration, the filtrate was concentrated to dryness under reduced pressure, 100ml of methylene chloride was added for dissolution, triethylamine (20.2 g,200 mmol) was added, acetic anhydride (10.7 g,105 mmol) was added dropwise at 0℃and stirred at room temperature overnight, 200ml of distilled water was added, extraction with methylene chloride was performed, the organic phases were combined and concentrated to dryness under reduced pressure, tetrahydrofuran (50 ml) and 5ml of hydrochloric acid were added, stirred at room temperature for 12 hours, and concentrated to dryness under reduced pressure to obtain XXII-4 which was used directly in the next step without purification. LC/MS (ESI) m/z 119[ M+H ]] ⁺ 。

Step 2: preparation of intermediate III-4

Intermediate XXII-4 (1.2 g,10 mmol) is dissolved in 50ml THF, lithium Aluminum Hydride (LAH) (1.5 g,44.8 mmol) is added, refluxed for 4h under nitrogen protection, cooled to below 0deg.C and added in portions with Na ₂ SO ₄ ·10H ₂ The reaction was quenched with O, filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give III-4.LC/MS (ESI) m/z 105[ M+H ] ] ⁺ 。

Preparation of intermediate III-5

Step 1: preparation of intermediate XXII-5a

Intermediate XIX-1 (12.8 g,73.5 mmol), ethyl bromoacetate (36.6 g,219 mmol), anhydrous potassium carbonate (30.2 g,219 mmol) dissolved in 250ml DMF, heated to 80℃under nitrogen protection, stirred overnight, cooled to room temperature, extracted with water, ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give 18g of crude XXII-5 a. LC/MS (ESI) m/z 261[ M+H ]] ⁺ 。

Step 2: preparation of intermediate XXII-5

380ml of ethanol and NaBH were added sequentially to a 2L round bottom flask ₄ (7.2 g,189 mmol) and LiCl (7.9 g,188 mmol), then a solution of XXII-5a (18 g,69 mmol) in THF (380 ml) was added dropwise at room temperature, stirred for 6h, concentrated under reduced pressure to remove the bulk of the solvent, extracted with water, ethyl acetate and the combined organic phases were taken up in anhydrous Na ₂ SO ₄ Drying, filtration, and concentration under reduced pressure gave XXII-5 (12.9 g, yield 86%). LC/MS (ESI) m/z 219[ M+H ]] ⁺ 。

Step 3: preparation of intermediate III-5

XXII-5 (12.9 g) is dissolved in 50ml dioxane, HCl dioxane solution (6N, 30 ml) is added, stirred overnight at room temperature, concentrated to dryness under reduced pressure to give intermediate III-5 (12.8 g). LC/MS (ESI) m/z 119[ M+H ]] ⁺ 。

Preparation of intermediate III-6

Step 1: preparation of intermediate XXIII-6

To a solution of 3-methylmorpholine (1.0 g,10 mmol) in THF (15 ml) was added tert-butyl nitrite (1.1 g,11 mmol), refluxed for 12h, and concentrated to dryness under reduced pressure to give XXIII-6 which was used directly in the next step without purification. LC/MS (ESI) m/z 131[ M+H ]] ⁺ 。

Step 2: preparation of intermediate III-6

Intermediate XXIII-6 (80 mmol) from the previous step was dissolved in 200ml THF and LAH (6.1 g,160 mmol) was added in portions at 0deg.C, stirred overnight at room temperature, cooled and Na was added in portions ₂ SO ₄ ·10H ₂ O, filtration, washing of the cake with THF, drying of the filtrate over anhydrous magnesium sulfate, filtration and concentration under reduced pressure gave compound III-6 (yield 72%). LC/MS (ESI) m/z 117[ M+H ]] ⁺ 。

The following hydrazines can be prepared in the same manner as the compound III-6

Example 1: preparation of Compound 1

IIa-1 (38 mg,0.1 mmol), hydrazine hydrochloride (20 mg,0.12 mmol), HATU (57 mg,0.15 mmol) were dissolved in 2ml DMF, DIPEA (79 mg,0.6 mmol) was added, stirred overnight under nitrogen, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford compound 1 (41 mg, 83% yield) which was purified by silica gel chromatography (PE/EA, 1:1). LC/MS (ESI) m/z 491[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.19(s,1H),8.66(d,J＝8.4Hz,2H),8.36(s,1H),7.96(d,J＝8.4Hz,2H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23(m,2H),1.14-1.20(m,6H),0.98(d,J＝6.8Hz,3H)。

The compounds of Table 1 below can be prepared in analogy to compound 1

TABLE 1

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Example 48: preparation of Compound 48

Compound 46 (78 mg,0.2 mmol) was dissolved in 5ml DCM, DIPEA (0.2 ml) was added, cooled to 0deg.C, 0.12ml acetic anhydride was added dropwise, the reaction was stirred overnight at room temperature, washed three times with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography on silica gel (PE/EA, 1:1) to give compound 48 (54 mg, yield 63%). LC/MS (ESI): m/z 431[ M+H ]] ⁺ 。

The compounds of Table 2 below can be prepared in a similar manner to compound 48

TABLE 2

Example 53: preparation of Compound 53

Step 1: preparation of intermediate XXIV

4-bromo-1-methyl-pyrazole-5-carbaldehyde (1.89 g,10 mmol) was dissolved in 1, 4-dioxane (20 mL), and pinacol biborate (3.96 g,15.7 mmol), sodium carbonate (3.18 g,30 mmol) and 1,1' -bis (diphenylphosphine) ferrocene were added]Palladium dichloride (0.37 g,0.5 mmol). The mixture was reacted overnight at 90℃under nitrogen, decompressed and concentrated to dryness, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate) to give compound XXIV (1.79 g, yield 76%). LC/MS (ESI) m/z 264[ M+H ]] ⁺ 。

Step 2: preparation of intermediate XXV

3-amino-2, 6-dichloroisonicotinic acid methyl ester (884 mg,4 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (30 mL) and water (4 mL), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole-5-methyl Aldehyde (Compound XXIV) (944 mg,4 mmol), sodium carbonate (1.27 g,12 mmol) and 1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (149 mg,0.2 mmol). The mixture was reacted at 110℃under nitrogen for 6 hours, decompressed and concentrated to dryness, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to give Compound XXV (166 mg, yield 15%). LC/MS (ESI) m/z 277[ M+H ]] ⁺ 。

Step 3: preparation of intermediate XXVI-1

2-chloro-7-methyl-7H-pyrazolo [3,4-c][1,5]Naphthyridine-4-carboxylic acid methyl ester (166 mg,0.6 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (3 mL), and (4-chlorophenyl) boric acid (103 mg,0.66 mmol), cesium carbonate (318 mg,3 mmol) and 1,1' -bis (diphenylphosphine) ferrocene were added]Palladium dichloride (37 mg,0.05 mmol). The mixture was reacted at 110℃under nitrogen for 6 hours, decompressed and concentrated to dryness, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol), compound XXVI-1 (112 mg, yield 53%). LC/MS (ESI) m/z 353[ M+H ]] ⁺ 。

Step 4: preparation of intermediate IIe-1

Hydrolysis of intermediate XXVI-1, in a similar manner to step 5 of the preparation of intermediate compound IIa-1, gives compound IIe-1 (83 mg, yield 77%). LC/MS (ESI) m/z 339[ M+H ]] ⁺ 、337[M-H] ^- 。

Step 5: preparation of Compound 53

According to a similar manner to example 1, intermediate IIe-1 and intermediate III-6 (R) compound 53 were prepared. LC/MS (ESI) m/z 437[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.23(s,1H),9.58(s,1H),8.77(s,1H),8.68(s,1H),8.39(d,J＝8.6,2H),7.65(d,J＝8.6,2H),4.31(s,3H),3.86(d,J＝11.2Hz,1H),3.80(d,J＝8.0Hz,1H),3.64(dt,J＝1.6,11.2Hz,1H),3.17-3.25(m,3H),2.94(d,J＝10.4Hz,1H),0.92(d,J＝8.0Hz,3H)。

Example 54: preparation of Compound 54

Step 1: preparation of intermediate XXVI-2

Methyl 2-chloro-7-methyl-7H-pyrazolo [3,4-c ] [1,5] naphthyridine-4-carboxylate (166 mg,0.6 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (3 mL), and (4-trifluoromethylphenyl) boric acid (114 mg,0.66 mmol), cesium carbonate (318 mg,3 mmol) and 1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (37 mg,0.05 mmol) were added. The mixture was reacted at 110℃under nitrogen for 6 hours, decompressed and concentrated to dryness, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol) to give Compound XXVI-2 (151 mg, yield 65%).

Step 2: preparation of intermediate IIe-2

Hydrolysis of intermediate XXVI-2 affords compound IIe-2 (116 mg, 80% yield) following a similar procedure to step 5 for the preparation of intermediate compound IIa-1. LC/MS (ESI): m/z 373[ M+H ] + ], 371[ M-H ] +.

Step 3: preparation of Compound 54

Compound 54 was prepared from intermediate IIe-2 and intermediate III-6 (R) following a similar procedure as in example 1. LC/MS (ESI): m/z 471[ M+H ]] ⁺ 。

Example 55: preparation of Compound 55

Compound 55 from intermediate IIe-1 and intermediate III-6 (S) according to a similar preparation method as in example 1. LC/MS (ESI): m/z 437[ M+H ] ] ⁺ 。

EXAMPLE 56 Compound 56

Compound 56 from intermediate IIe-2 and intermediate III-6 (S) according to a similar preparation as in example 1. LC/MS (ESI): m/z 471[ M+H ]] ⁺ 。

EXAMPLE 57 Compound 57

Compound 57 was obtained by reacting intermediate IIc-6 with (S) -N- (2-aminopropyl) -1-methylcyclopropane-1-sulfonylamino according to a similar procedure as in example 1. LC/MS (ESI): m/z 473[ M+H ]] ⁺ 。

Effect example 1 test of Compounds studied for AHR antagonism in human cell lines

Human liver cancer HepG2 cell lines (supplied by the chinese academy of sciences stem cell bank) endogenously expressing AHR proteins were used for the test. CYP1A1 gene expression is regulated by AHR activity, which upon activation binds to a sequence called an exogenous response element (xenobiotic response element, XRE) on the CYP1A1 enhancer and initiates CYP1A1 gene expression. To quantitatively measure the effect of compounds on AHR activity, a regulatory sequence 1200bp (-1143 to +57) upstream of the CYP1A1 gene promoter was inserted into a plasmid vector containing firefly luciferase after gene synthesis. The plasmid was then linearized by single cleavage and then transferred into HepG2 cells by Lipofectamine3000, and the transfected HepG2 cells were screened for stable expression by puromycin. In measuring antagonism of compounds and AHR, expression of firefly luciferase is triggered with AHR agonists (e.g., L-Kynurenine, kynurenic acid, indirubibin, TCDD, ITE (2- (1H-Indol-3-ylcarbonyl) -4-thiazolecarboxylic acid methyl ester)) and the like, while cells are treated with different concentrations of compounds, and inhibition of luciferase expression by the compounds is measured.

Stably transfected HepG2 cells were subcultured in Minimum Eagle's Medium (MEM) at 37℃in 5% carbon dioxide. MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax,1 Xnonessential amino acids, 10% Australian fetal bovine serum, 100U/mL of green streptomycin, and 5ug/mL of puromycin. HepG2 cells were passaged 5-8X 10 before testing ⁴ Density of wells/wells were grown in 96-well plates and grown for 24-48 h to achieve-90% confluency (medium without puromycin) prior to drug treatment. Compound solutions containing AHR agonist at 2 x different concentrations were prepared with the same medium prior to drug treatment and then 96 wells were usedHalf of the cell culture medium in the plate was replaced with 2 x compound solution. The negative control group was set to contain only AHR agonist solutions at the corresponding concentrations of DMSO, while the positive control group was set to CH223191, BAY2416964 at the corresponding concentrations.

Each compound (including positive control and negative control) was tested in 2 independent replicates. HepG2 cells were lysed by a Steady-Glo luciferase assay system from Promega after 24h of compound treatment and luciferase signal was measured using an InfiniteM1000 Pro microplate reader from Tecan.

For each group of compounds, the percentage of inhibition of AHR activity at the different compound concentrations was calculated in sequence using the well signal at compound concentration 0 as 100% and the cell signal of the untreated agonist as 0, and the average of the 2 groups of replicates was fitted by non-linearity according to the formulaCalculation of IC for Compound ₅₀ Where y is the percent inhibition and x is the concentration of the corresponding compound. />

Reference is made to: buckley, s.m. k.et al in vivo bioimaging with tissue-specific transcription factor activated luciferase reports. Sci.rep.5:11842 (2015).

IC of each Compound ₅₀ As shown in Table 3, wherein A represents IC ₅₀ Less than or equal to 100nM, B represents 100nM < IC ₅₀ Less than or equal to 500nM, C represents 500nM < IC ₅₀ Less than or equal to 1.0 mu M, D represents IC ₅₀ ＞1.0μM

TABLE 3 IC of each compound ₅₀

As can be seen from table 3, each of the above-mentioned compounds according to the present invention can bind to AHR and inhibit those functions and signaling pathways controlled by AHR, and thus can affect the growth and proliferation of cancer cells and the invasiveness of tumor cells, and thus the fused ring heterocyclic compounds represented by formula (i) according to the present invention, each of optical isomers, deuterides, prodrugs or pharmaceutically acceptable salts thereof can be used to inhibit the growth of cancer cells, inhibit the metastasis and invasion of tumor cells.

The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A fused ring heterocyclic compound of formula i, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof:

wherein,

A ⁵ and A ⁶ One of which is N and the other of which is C;

A ⁷ 、A ⁸ 、A ⁹ and A ¹⁰ Each independently is C or N, at least one of which is N;

preferably, A ¹ 、A ² 、A ³ And A ⁴ A chemical bond of (a);

ring B is selected from saturated or unsaturated C _6-10 Aryl groupA 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

l is a bond, carbonyl, -C (=O) NH-, or-NH-;

r is selected from-NR ^a R ^b ，C _1-10 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-8 Cycloalkyl, or substituted by 1-3G ¹ Substituted saturated or unsaturated C _1-10 Alkyl, C _3-10 Cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

R ¹ each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-8 Cycloalkyl, or R ¹ And A is a ¹ -A ⁴ The ring formation is covered by 1-3G ¹ A substituted 8-14 membered ring containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated;

R ² Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated C _1-8 Alkylcarboxy, saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 A membered aryl, a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

n1 and n2 are each independently integers of 0, 1, 2, 3, 4 or 5;

n3 is an integer of 0, 1, 2 or 3;

n4 is an integer of 0, 1 or 2.

2. The fused ring heterocyclic compound of formula I as described in claim 1, each of which is an optical isomer, a deuterate, a prodrug or a pharmaceutically acceptable salt thereof,

preferably, when L is Carbonyl (CO) or CONH, the fused ring heterocyclic compound of formula I, each of which is an optical isomer, prodrug or pharmaceutically acceptable salt thereof, is represented by one of the following structural formulas:

Wherein the substituents are B ring, L, R, R ¹ 、R ² 、n ₁ 、n ₂ Is as defined for formula I in claim 1;

wherein the substituents are B ring, L, R, R ¹ 、R ² 、n ₁ 、n ₂ Is as defined for formula I in claim 1.

3. The fused ring heterocyclic compound of the formula I as described in claim 1 or 2, which is an optical isomer, a deuterate, a prodrug or a pharmaceutically acceptable salt thereof,

preferably, R ^a And R is ^b Each independently selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated C _1-8 Alkylacyl, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylaminocarbonyl, saturated or unsaturated C _1-8 Alkylsulfonyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated sulfonyl C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkylacyl, saturated or unsaturated amino C _1-8 Alkoxycarbonyl, saturated or unsaturated amino C _1-8 Alkylaminocarbonyl, saturated or unsaturated amino C _1-8 Alkylsulfonyl, saturated or unsaturated amino C _1-8 Alkylamino, saturated or unsaturated amino C _1-8 Alkoxy, saturated or unsaturated sulfonylamino C _1-8 Alkyl, saturated or unsaturated halogenated C _1-8 Alkylacyl, saturated or unsaturated halogenated C _1-8 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-8 Alkylaminocarbonyl, saturated or unsaturated halogenated C _1-8 Alkylsulfonyl, saturated or unsaturated halogenated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkoxy, saturated or unsaturated sulfonyl halides C _1-8 Alkyl, saturated or unsaturated hydroxy C _1-8 Alkanoyl, saturated or unsaturated hydroxy C _1-8 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylaminocarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylsulfonyl, saturated or unsaturated hydroxy C _1-8 Alkylamino, saturated or unsaturated hydroxy C _1-8 Alkoxy, saturated or unsaturated sulfonylhydroxy C _1-8 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-8 Cycloalkyl, or R ^a And R is ^b Together with the N atom to which they are attached form a group of 1 to 3G' s ¹ A substituted saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S;

Preferably, R ^c And R is ^d Each independently selected from hydrogen, -OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ² Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkyl, saturated or unsaturated hydroxy C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl containing 1 to 3 groups selected from N,Saturated or unsaturated 3-10 membered heterocycloalkyl of heteroatoms of O and S, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _1-8 Alkylmercapto, saturated or unsaturated C _3-8 Cyclic alkoxy, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, C _6-10 Aryl, a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-8 Cycloalkyl, saturated or unsaturated halogenated 3-8 heterocycloalkyl, saturated or unsaturated halogenated C _1-8 Alkoxy, saturated or unsaturated halogenated C _1-8 Alkylmercapto, saturated or unsaturated halogenated C _3-8 Cyclic alkoxy, saturated or unsaturated halogenated C _1-8 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-8 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-8 Alkyl, saturated or unsaturated halogenated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated C _6-10 Aryl, saturated or unsaturated halogenated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy groups C _3-8 Cycloalkyl, saturated or unsaturated hydroxy 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-8 Alkoxy, saturated or unsaturated hydroxy C _1-8 Alkylmercapto, saturated or unsaturated hydroxy C _3-8 Cycloalkoxy, saturated or unsaturated hydroxy C _1-8 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-8 Alkyl, saturated or unsaturated hydroxy 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy 6-10 membered aryl, saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-8 Cycloalkyl, saturated or unsaturated amino 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-8 Alkoxy, saturated or unsaturated amino C _1-8 Alkylmercapto, saturated or unsaturated amino C _3-8 Cycloalkoxy, saturated or unsaturated amino C _1-8 Alkoxycarbonyl, saturated or unsaturated amino C _1-8 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-8 Alkyl, saturated or unsaturated amino 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; - (CH) ₂ ) _n5 Saturated or unsaturated C _3-10 Cycloalkyl, - (CH) ₂ ) _n5 -saturated or unsaturated 3-10 membered heterocycloalkyl, - (CH) containing 1 to 3 heteroatoms selected from N, O and S ₂ ) _n5 -6-10 membered aryl, - (CH) ₂ ) _n5 -a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; or R is ^c And R is ^d Together with the N atom to which they are attached form a group of 1 to 3G' s ³ Substituted 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably, R ^e Optionally selected from 1-3G ² Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkyl, saturated or unsaturated hydroxy C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-8 Cycloalkyl, saturated or unsaturated halogenated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated halogenated C _1-8 Alkoxycarbonyl, saturated or unsaturatedSaturated halogenated C _1-8 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-8 Alkyl, saturated or unsaturated halogenated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated 6-10 membered aryl, saturated or unsaturated halogenated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy 3-8 cycloalkyl, saturated or unsaturated hydroxy 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-8 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-8 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-8 Alkyl, saturated or unsaturated hydroxy 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-8 Cycloalkyl, saturated or unsaturated amino 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-8 Alkoxycarbonyl, saturated or unsaturated amino C _1-8 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-8 Alkyl, saturated or unsaturated amino 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably G ¹ Are each independently selected from H, deuterium, halogen, nitro, cyano, hydroxy, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f By 1-3 deuterium, halogen, amino, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or R is ^g Substituted saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cycloalkoxy, saturated or unsaturatedC _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-8 Alkyl, saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably G ² Optionally selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated amino C _1-8 Alkylacyl, saturated or unsaturated C _1-8 Alkylacyl, saturated or unsaturated C _1-8 Alkoxycarbonyl, saturated or unsaturated C _1-8 An alkylaminocarbonyl group;

preferably G ³ Any C selected from hydrogen, deuterium, hydroxy, halogen, cyano, sulfonyl, amino, saturated or unsaturated _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 Cycloalkoxy, saturated or unsaturated-OC (=O) C _1-8 Alkyl, saturated or unsaturated-OC (=o) C _3-8 Cycloalkyl, saturated or unsaturated-C (=o) OC _1-8 Alkyl, saturated or unsaturated-C (=o) OC _3-8 Cycloalkyl, substituted by halogen, hydroxy, amino or R ^g Substituted by saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _3-8 Cycloalkyl, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated C _3-8 A cycloalkoxy group;

preferably, R ^f Optionally selected from hydrogen, hydroxy, amino, saturated or unsaturated C _1-8 Alkyl, saturated or unsaturated C _1-8 Alkylamino, saturated or unsaturated C _1-8 Alkoxy, saturated or unsaturated amino C _1-8 Alkyl, saturated or unsaturated amino C _1-8 Alkylamino, saturated or unsaturated amino C _1-8 Alkoxy, saturated or unsaturated halogenated C _1-8 Alkylamino, saturated or unsaturated halogenated C _1-8 Alkoxy, saturated or unsaturated hydroxy C _1-8 Alkyl ammoniaHydroxy C, saturated or unsaturated _1-8 An alkoxy group;

preferably, R ^g Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-6 Alkyl, C substituted by deuterium, halogen, hydroxy or amino, saturated or unsaturated _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cycloalkoxy, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-6 Alkoxy, saturated or unsaturated C3-6 cycloalkoxy substituted with deuterium, halogen, hydroxy or amino;

preferably, n5 is an integer of 0, 1, 2, 3, 4, 5, 6, 7 or 8.

4. The fused ring heterocyclic compound of the formula I as described in claim 1 or 2, which is an optical isomer, a deuterate, a prodrug or a pharmaceutically acceptable salt thereof,

Preferably, R is selected from the group consisting of-NR ^a R ^b ，C _1-6 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or substituted by 1-3G ¹ Substituted saturated or unsaturated C _1-6 Alkyl, quilt 1-3G ¹ Substituted saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably, R ¹ Each independently selected fromH. Deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containing Saturated or unsaturated, halogenated or unhalogenated C of radicals _1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ¹ And A is a ¹ -A ⁴ The ring formation is covered by 1-3G ¹ A substituted 8-10 membered ring, saturated or unsaturated, having 1 to 3 heteroatoms selected from N, O and S;

more preferably, R ¹ Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, saturated orUnsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ¹ And A is a ¹ -A ⁴ The ring formation is covered by 1-3G ¹ A substituted 8-9 membered ring, saturated or unsaturated, having 1 to 3 heteroatoms selected from N, O and S;

Preferably, R ² Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated C _1-6 Alkylcarboxy, saturated or unsaturated 3-6 membered cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

more preferably, R ² Each independently selected from H, deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ¹ Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated C _1-4 Alkylcarboxyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably, R ^a And R is ^b Each independently selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated C _1-6 Alkylacyl, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylaminocarbonyl, saturated or unsaturated C _1-6 Alkylsulfonyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated sulfonyl C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkylacyl, saturated or unsaturated amino C _1-6 Alkoxycarbonyl, saturated or unsaturated amino C _1-6 Alkylaminocarbonyl, saturated or unsaturated amino C _1-6 Alkylsulfonyl, saturated or unsaturated amino C _1-6 Alkylamino, saturated or unsaturated amino C _1-6 Alkoxy, saturated or unsaturated sulfonylamino C _1-6 Alkyl, saturated or unsaturated halogenated C _1-6 Alkylacyl, saturated or unsaturated halogenated C _1-6 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-6 Alkylaminocarbonyl, saturated or unsaturated halogenated C _1-6 Alkylsulfonyl, saturated or unsaturated halogenated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkoxy, saturated or unsaturated sulfonyl halides C _1-6 Alkyl, saturated or unsaturated hydroxy C _1-6 Alkanoyl, saturated or unsaturated hydroxy C _1-6 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylaminocarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylsulfonyl, saturated or unsaturated hydroxy C _1-6 Alkylamino, saturated or unsaturated hydroxy C _1-6 Alkoxy, saturated or unsaturated sulfonylhydroxy C _1-6 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ^a And R is ^b Together with the N atom to which they are attached form a group of 1 to 3G' s ¹ A substituted saturated or unsaturated, 5-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S;

more preferably, R ^a And R is ^b Each independently selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated C _1-4 Alkylacyl, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylaminocarbonyl, saturated or unsaturated C _1-4 Alkylsulfonyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated sulfonyl C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkylacyl, saturated or unsaturated amino C _1-4 Alkoxycarbonyl, saturated or unsaturated amino C _1-4 Alkylaminocarbonyl, saturated or unsaturated amino C _1-4 Alkylsulfonyl, saturated or unsaturated amino C _1-4 Alkylamino, saturated or unsaturated amino C _1-4 Alkoxy, saturated or unsaturated sulfonylamino C _1-4 Alkyl, saturated or unsaturated halogenated C _1-4 Alkylacyl, saturated or unsaturated halogenated C _1-4 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-4 Alkylaminocarbonyl, saturated or unsaturated halogenated C _1-4 Alkylsulfonyl, saturated or unsaturatedHalogenated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkoxy, saturated or unsaturated sulfonyl halides C _1-4 Alkyl, saturated or unsaturated hydroxy C _1-4 Alkanoyl, saturated or unsaturated hydroxy C _1-4 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylaminocarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylsulfonyl, saturated or unsaturated hydroxy C _1-4 Alkylamino, saturated or unsaturated hydroxy C _1-4 Alkoxy, saturated or unsaturated sulfonylhydroxy C _1-4 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals _1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals _3-6 Cycloalkyl, or R ^a And R is ^b Together with the N atom to which they are attached form a group of 1 to 3G' s ¹ A substituted saturated or unsaturated, 5-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S;

preferably, R ^c And R is ^d Each independently optionally from hydrogen, -OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ² Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkyl, saturated or unsaturated hydroxy C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _1-6 Alkylmercapto, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-6 Alkoxycarbonyl group and saturationAnd or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-8 Cycloalkyl, saturated or unsaturated halogenated 3-8 heterocycloalkyl, saturated or unsaturated halogenated C _1-6 Alkoxy, saturated or unsaturated halogenated C _1-6 Alkylmercapto, saturated or unsaturated halogenated C _3-6 Cyclic alkoxy, saturated or unsaturated halogenated C _1-6 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-6 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-6 Alkyl, saturated or unsaturated halogenated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated C _6-10 Aryl, saturated or unsaturated halogenated 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy groups C _3-6 Cycloalkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-6 Alkoxy, saturated or unsaturated hydroxy C _1-6 Alkylmercapto, saturated or unsaturated hydroxy C _3-6 Cycloalkoxy, saturated or unsaturated hydroxy C _1-6 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-6 Alkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-6 Cycloalkyl, saturated or unsaturated amino 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-6 Alkoxy, saturated or unsaturated amino C _1-6 Alkylmercapto, saturated or unsaturated amino C _3-6 Cycloalkoxy, saturated or unsaturated amino C _1-6 Alkoxycarbonyl, saturated or unsaturated amino C _1-6 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-6 Alkyl radicals, containing 1 to 1Saturated or unsaturated amino 3-6 membered heterocycloalkyl having 3 heteroatoms selected from N, O and S, amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; - (CH) ₂ ) _n5 Saturated or unsaturated C _3-6 Cycloalkyl, - (CH) ₂ ) _n5 -saturated or unsaturated 3-6 membered heterocycloalkyl, - (CH) containing 1 to 3 heteroatoms selected from N, O and S ₂ ) _n5 -6-10 membered aryl, - (CH) ₂ ) _n5 -a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; or R is ^c And R is ^d Together with the N atom to which they are attached form a group of 1 to 3G' s ³ Substituted 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

more preferably, R ^c And R is ^d Each independently optionally from hydrogen, -OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or by 1-3G ² Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkyl, saturated or unsaturated hydroxy C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _1-4 Alkylmercapto, saturated or unsaturated C _4-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, C _6-10 Aryl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _4-6 Cycloalkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl, saturated or unsaturated halogenated C _1-4 Alkoxy, saturated or unsaturated halogenated C _1-4 Alkylmercapto, saturated or unsaturated halogenated C _4-6 Cyclic alkoxy, saturated or unsaturated halogenated C _1-4 Alkoxycarbonyl groupSaturated or unsaturated halogenated C _1-4 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-4 Alkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated C _6-10 Aryl, saturated or unsaturated halogenated 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy groups C _4-6 Cycloalkyl, saturated or unsaturated hydroxy 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-4 Alkoxy, saturated or unsaturated hydroxy C _1-4 Alkylmercapto, saturated or unsaturated hydroxy C _4-6 Cycloalkoxy, saturated or unsaturated hydroxy C _1-4 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-4 Alkyl, saturated or unsaturated hydroxy 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _4-6 Cycloalkyl, saturated or unsaturated amino 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-4 Alkoxy, saturated or unsaturated amino C _1-4 Alkylmercapto, saturated or unsaturated amino C _4-6 Cycloalkoxy, saturated or unsaturated amino C _1-4 Alkoxycarbonyl, saturated or unsaturated amino C _1-4 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-4 Alkyl, saturated or unsaturated amino 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, amino C _6-10 Aryl, saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; - (CH) ₂ ) _n5 Saturated or unsaturated C _4-6 Cycloalkyl, - (CH) ₂ ) _n5 -a saturated or unsaturated 4-6 membered heterocycloalkyl, - (CH) containing 1 to 3 heteroatoms selected from N, O and S ₂ ) _n5 -6-10 membered aryl, - (CH) ₂ ) _n5 Containing 1 to 3 members selected from N, O and SA 5-10 membered heteroaryl group of heteroatoms of (2); or R is ^c And R is ^d Together with the N atom to which they are attached form a group of 1 to 3G' s ³ Substituted 5-8 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably, R ^e Optionally selected from 1-3G ² Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkyl, saturated or unsaturated hydroxy C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkyl, saturated or unsaturated C _3-6 A membered cycloalkyl, a saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, saturated or unsaturated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 A membered aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _3-6 Cycloalkyl, saturated or unsaturated halogenated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated halogenated C _1-6 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-6 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-6 Alkyl, saturated or unsaturated halogenated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated 6-10 membered aryl, saturated or unsaturated halogenated 5-8 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy 3-6 cycloalkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _1-6 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-6 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-6 Alkyl, saturated or unsaturated hydroxy 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl radicals, containing 1 to 3Saturated or unsaturated hydroxy 5-10 membered heteroaryl of heteroatoms selected from N, O and S; saturated or unsaturated amino C _3-6 Cycloalkyl, saturated or unsaturated amino 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-6 Alkoxycarbonyl, saturated or unsaturated amino C _1-6 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-6 Alkyl, saturated or unsaturated amino 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _6-10 A membered aryl, a saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

more preferably, R ^e Optionally selected from 1-3G ² Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkyl, saturated or unsaturated hydroxy C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkyl, saturated or unsaturated C _4-6 A membered cycloalkyl, a saturated or unsaturated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C _6-10 A membered aryl, a saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated halogenated C _4-6 Cycloalkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated halogenated C _1-4 Alkoxycarbonyl, saturated or unsaturated halogenated C _1-4 Alkylcarbonyl, saturated or unsaturated halocarboxyl C _1-4 Alkyl, saturated or unsaturated halogenated 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, halogenated 6-10 membered aryl, saturated or unsaturated halogenated 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated hydroxy 4-6 cycloalkyl containing 1 to 1Saturated or unsaturated hydroxy 4-6 membered heterocycloalkyl, saturated or unsaturated hydroxy C, having 3 heteroatoms selected from N, O and S _1-4 Alkoxycarbonyl, saturated or unsaturated hydroxy C _1-4 Alkylcarbonyl, saturated or unsaturated hydroxycarboxyl C _1-4 Alkyl, saturated or unsaturated hydroxy 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated hydroxy C _6-10 Aryl, a saturated or unsaturated hydroxy 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; saturated or unsaturated amino C _4-6 Cycloalkyl, saturated or unsaturated amino 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _1-4 Alkoxycarbonyl, saturated or unsaturated amino C _1-4 Alkylcarbonyl, saturated or unsaturated aminocarboxyl C _1-4 Alkyl, saturated or unsaturated amino 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated amino C _6-10 A membered aryl, a saturated or unsaturated amino 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably G ¹ Are each independently selected from H, deuterium, halogen, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f By 1-3 deuterium, halogen, amino, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or R is ^g Substituted saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-6 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-6 Alkyl, saturated or unsaturated 3-8 membered cycloalkyl, saturated or unsaturated 3-8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, 6-10 membered aryl, saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

More preferably G ¹ Are each independently selected from H, deuterium, halogen, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f By 1-3 deuterium, halogen, amino, nitro, cyano, -NR ^c R ^d 、-OR ^e 、-CO ₂ R ^e 、-S(O)n ₃ R ^f Or R is ^g Substituted saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 Cyclic alkoxy, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 Alkylcarbonyl, saturated or unsaturated carboxyl C _1-4 Alkyl, saturated or unsaturated 4-6 membered cycloalkyl, saturated or unsaturated 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, 6-10 membered aryl, saturated or unsaturated 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;

preferably G ² Optionally selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated amino C _1-6 Alkylacyl, saturated or unsaturated C _1-6 Alkylacyl, saturated or unsaturated C _1-6 Alkoxycarbonyl, saturated or unsaturated C _1-6 An alkylaminocarbonyl group;

more preferably G ² Optionally selected from hydrogen, hydroxy, amino, cyano, carboxy, saturated or unsaturated amino C _1-4 Alkylacyl, saturated or unsaturated C _1-4 Alkylacyl, saturated or unsaturated C _1-4 Alkoxycarbonyl, saturated or unsaturated C _1-4 An alkylaminocarbonyl group;

preferably G ³ Any C selected from hydrogen, deuterium, hydroxy, halogen, cyano, sulfonyl, amino, saturated or unsaturated _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 Cycloalkoxy, saturated or unsaturated-OC (=O) C _1-6 Alkyl, saturated or unsaturatedis-OC (=O) C _3-6 Cycloalkyl, saturated or unsaturated-C (=o) OC _1-6 Alkyl, saturated or unsaturated-C (=o) OC _3-6 Cycloalkyl, substituted by halogen, hydroxy, amino or R ^g Substituted by saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _3-6 Cycloalkyl, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated C _3-6 A cycloalkoxy group;

more preferably G ³ Any C selected from hydrogen, deuterium, hydroxy, halogen, cyano, sulfonyl, amino, saturated or unsaturated _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 Cycloalkoxy, saturated or unsaturated-OC (=O) C _1-4 Alkyl, saturated or unsaturated-OC (=o) C _4-6 Cycloalkyl, saturated or unsaturated-C (=o) OC _1-4 Alkyl, saturated or unsaturated-C (=o) OC _4-6 Cycloalkyl, substituted by halogen, hydroxy, amino or R ^g Substituted by saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 A cycloalkoxy group;

preferably, R ^f Optionally selected from hydrogen, hydroxy, amino, saturated or unsaturated C _1-6 Alkyl, saturated or unsaturated C _1-6 Alkylamino, saturated or unsaturated C _1-6 Alkoxy, saturated or unsaturated amino C _1-6 Alkyl, saturated or unsaturated amino C _1-6 Alkylamino, saturated or unsaturated amino C _1-6 Alkoxy, saturated or unsaturated halogenated C _1-6 Alkylamino, saturated or unsaturated halogenated C _1-6 Alkoxy, saturated or unsaturated hydroxy C _1-6 Alkylamino, saturated or unsaturated hydroxy C _1-6 An alkoxy group;

more preferably, R ^f Optionally selected from hydrogen, hydroxy, amino, saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _1-4 Alkylamino, saturated or unsaturated C _1-4 Alkoxy group,Saturated or unsaturated amino C _1-4 Alkyl, saturated or unsaturated amino C _1-4 Alkylamino, saturated or unsaturated amino C _1-4 Alkoxy, saturated or unsaturated halogenated C _1-4 Alkylamino, saturated or unsaturated halogenated C _1-4 Alkoxy, saturated or unsaturated hydroxy C _1-4 Alkylamino, saturated or unsaturated hydroxy C _1-4 An alkoxy group;

preferably, R ^g Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C _1-4 Alkyl, saturated or unsaturated C _4-6 Cycloalkyl, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-4 Alkyl, C substituted by deuterium, halogen, hydroxy or amino, saturated or unsaturated _4-6 Cycloalkyl, saturated or unsaturated C _1-4 Alkoxy, saturated or unsaturated C _4-6 Cycloalkoxy, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _1-4 Alkoxy, saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino _4-6 A cycloalkoxy group;

preferably, n1 is an integer of 0, 1 or 2;

preferably, n2 is an integer of 0, 1 or 2;

preferably, n5 is an integer of 0, 1, 2, 3 or 4;

preferably, L is-C (=o) NH-or-NH-.

5. The fused ring heterocyclic compound of the formula I as described in claim 1 or 2, which is an optical isomer, a deuterate, a prodrug or a pharmaceutically acceptable salt thereof,

more preferably, when R is-NR ^a R ^b And is selected from the following structures:

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6. the fused ring heterocyclic compound of formula i according to claim 1 or 2, wherein each of the optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof is selected from the group consisting of:

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7. A pharmaceutical composition comprising a therapeutically effective amount of a fused ring heterocyclic compound of formula i according to any one of claims 1 to 6, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.

8. Use of a fused ring heterocyclic compound of formula i as described in any one of claims 1 to 6, each of its optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts for the preparation of an inhibitor of AHR disorders.

9. Use of a fused ring heterocyclic compound of formula i as described in any one of claims 1 to 6, each of its optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of a tumor associated with an AHR disorder.

10. A method of treating a tumor associated with an AHR disorder, the method comprising administering to a subject in need thereof an effective amount of a fused ring heterocyclic compound of formula i according to any one of claims 1 to 6, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 7.