WO2023020512A1

WO2023020512A1 - Substituted pyridine analogue, preparation method therefor, and use thereof as ahr modulator

Info

Publication number: WO2023020512A1
Application number: PCT/CN2022/112891
Authority: WO
Inventors: 黄奇; 殷利科; 王长立; 聂运凤; 李应飞; 胡海; 吴孝全
Original assignee: 成都奥睿药业有限公司
Priority date: 2021-08-16
Filing date: 2022-08-16
Publication date: 2023-02-23

Abstract

The present invention relates to a compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, a use thereof as an AhR modulator, and a preparation method therefor.

Description

AhR agonist

technical field

The disclosure relates to the field of medicine, in particular to a compound with AhR agonistic effect, its use and preparation method.

Background technique

The aryl hydrocarbon receptor (AhR) is a ligand activating factor, which belongs to the basic helix-loop-helix-Per/ARNT/Sim family. After ligand binding in the cytoplasm, AhR dissociates from its complex and Hsp90 and the AhR-interacting protein XAP2, allowing translocation of the attached AhR to the nucleus. In the nucleus, AhR dimerizes with the AhR nuclear transposon (ARNT) and then associates with the xenobiotic response element (XRE), thereby promoting the upregulation or downregulation of a large number of target genes in many different tissues. AhR is known for binding to environmental toxins and inducing various members of the cytochrome P450 family, including CYP1A1, CYP1A2 and CYP1B1, which are required for their elimination. Activation of AhR by xenobiotics has demonstrated that this receptor plays a role in a range of physiological processes including embryogenesis, tumorigenesis and development.

AhR is expressed in many immune cell types including dendritic cells, macrophages, T cells, NK cells and B cells and plays an important role in immune regulation. The toxicity/adverse effects of classical exogenous AhR agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are well known and include profound immunosuppression and cause. The physiological effects of AhR agonists on immune cells include promoting the generation of regulatory T cells (Treg) and regulating Th17 cell differentiation and activation. AhR also regulates the function of antigen-presenting cells, such as dendritic cells and macrophages. AhR activation reduces the expression of class II major histocompatibility complex and co-stimulatory molecules and also reduces the production of Th1 and Th17 polarizing cytokines by dendritic cells. Indeed, AhR activation enhances the ability of DCs to promote Treg differentiation.

In addition to their effects on immune cells, such endogenous agonists have also been implicated in cancer progression through direct effects on tumors. For example, KYN increases human glioblastoma cell survival and migration. Several other studies have also implicated AhR in the absence of environmental ligands in cancer progression. The AhR repressor (AHRR) protein acts as a tumor suppressor gene in several human cancers. AhR expression and "constitutive" (endogenous ligand-driven) activity in breast cancer cells correlates with tumor aggressiveness and controls the expression of genes associated with tumor invasion. Ectopic AhR expression in non-malignant human mammary epithelial cells induces epithelial-to-mesenchymal transition and >50% increase in cell growth rate, and AhR knockdown induces genes intermediate to a less invasive phenotype Mesenchymal-to-epithelial reversal is consistently altered in human breast cancer cell lines. AhR antagonists or AhR knockdown have been shown to reduce the proliferation, survival, invasion and migration of human breast cancer cells in culture, the tumorspheres formed by cancer stem cells (CSCs) that drive tumors Subsets of tumor cells that initiate, progress and metastasize.

Thus, AhR agonists released from immune cells and tumor cells act in autocrine and paracrine manners to promote tumor growth, and agents that reduce or block these effects may be useful in the treatment of cancer and/or immune dysfunctional conditions.

Contents of the invention

The purpose of the present disclosure is to provide a new compound with AhR agonism.

Specifically, the present disclosure provides a compound represented by formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug,

in,

X ₁ and X ₂ are independently selected from CR ⁰ or N;

R ⁰ is selected from hydrogen, halogen, cyano, C _1-6 alkyl.

Preferably, R ⁰ is selected from hydrogen, fluorine, chlorine, methyl, cyano.

Preferably, X ₁ and X ₂ are independently selected from CH or N;

Ring A is phenyl or a 6-10 membered monocyclic or bicyclic heteroaryl group containing 1-3 atoms selected from N and S atoms;

^R is selected from nonexistent, hydrogen, deuterium, C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl , halogen, amino, carboxyl, amido, the C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy are optionally replaced by halogen, hydroxyl replace;

Preferably, R ^is selected from nonexistent, hydrogen, deuterium, C _1-6 saturated or partially unsaturated hydrocarbyl, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy, halogen, amino, The C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl group, and C _1-6 alkoxy group are optionally substituted by halogen or hydroxyl.

^R is selected from nonexistent, hydrogen, deuterium, hydroxyl, cyano, C _1-6 alkoxy, 5-8 membered saturated heterocyclic ring, 5-8 membered partially unsaturated heterocyclic ring, 5-8 membered saturated bicyclic heterocyclic ring , the 5-8 membered saturated heterocyclic ring, the 5-8 membered partially unsaturated heterocyclic ring, and the 5-8 membered saturated bicyclic heterocyclic ring are optionally substituted by one or more R;

^R is selected from hydrogen, deuterium, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen, cyano;

R is selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, C _1-6 carbonyloxy, 5-8 membered saturated heterocycle, hydroxyl, hydroxyl C _{1- 6} alkyl, cyano, oxo;

Preferably, R is selected from C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, C _1-6 carbonyloxy, 5-8 membered saturated heterocycle, hydroxyl, hydroxyl C _{1 -6} alkyl, cyano;

n is selected from 0, 1 or 2.

Preferably, ring A is selected from the following groups:

Preferably, ring A is selected from the following groups:

Preferably,

selected from the following groups:

Preferably,

selected from the following groups:

Preferably, R ^is selected from nonexistent, hydrogen, deuterium, C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy, C _1-6 Alkoxycarbonyl, halogen, amino, carboxyl, amido, the C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy is optionally Hydroxy, one to three halogen substitutions.

Preferably, R ^is selected from nonexistent, hydrogen, deuterium, C _1-6 saturated or partially unsaturated hydrocarbyl, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy, halogen, amino, The C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl group, and C _1-6 alkoxy group are optionally substituted by hydroxyl and one to three halogens.

Preferably, R is selected from absent, methyl, ¹ -isopropenyl, methoxy, cyclopropyl, trifluoromethyl, fluoro, chloro, bromo, amino, cyano, isopropyl, cyclohexyl, 1-Cyclohexenyl, ethoxycarbonyl, carboxyl, amido.

Preferably, ^R is selected from absent, methyl, 1-isopropenyl, methoxy, cyclopropyl, trifluoromethyl, fluoro, amino, cyclohexyl, 1-cyclohexen-yl.

Preferably, R ^is selected from hydroxyl, cyano, C _1-3 alkoxy, 5-8 membered saturated heterocycles containing 1-2 independently selected from N, O, and S atoms, containing 1-2 5-6 membered partially unsaturated heterocycles independently selected from N and O atoms, and 5-8 membered saturated bicyclic heterocycles independently selected from N and O atoms, containing 1-2 A 5-8 membered saturated heterocyclic ring independently selected from N, O, and S atoms, and a 5-6 membered partially unsaturated heterocyclic ring independently selected from N, O atoms containing 1-2 are optionally replaced by R replace.

Preferably, R ^is selected from hydroxyl, cyano, C _1-3 alkoxy, 5-6 membered saturated heterocycles containing 1-2 independently selected from N and O atoms, and 1-2 independently 5-6 membered partially unsaturated heterocycles selected from N and O atoms, containing 1-2 5-8 membered saturated bicyclic heterocycles independently selected from N and O atoms, said containing 1-2 A 5-6 membered saturated heterocyclic ring independently selected from N and O atoms, and a 5-6 membered partially unsaturated heterocyclic ring containing 1 to 2 independently selected from N and O atoms are optionally substituted by R.

Preferably, R ^is selected from hydroxyl, cyano, C _1-3 alkoxy, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl Base, 2-azaspiro[3.3]heptanyl, thiomorpholinyl, 1-oxo-7-azaspiro[3.5]nonane, 8-oxo-2-azaspiro[4.5]decane alkane, 2-oxo-5-azabicyclo[2.2.1]heptane, 6-oxo-3-azabicyclo[3.1.0]hexane, 1,5-oxazolidine, the pyrrolidine Ryl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl are optionally substituted by one or more R.

Preferably, R ^is selected from hydroxyl, cyano, C _1-3 alkoxy, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-di Hydropyranyl, 2-azspiro[3.3]heptyl, the pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyryl Acyl is optionally substituted with one or more R.

Preferably, R ^is selected from hydroxyl, cyano, C _1-3 alkoxy, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl base, thiomorpholinyl, 1-oxo-7-azaspiro[3.5]nonane, 8-oxo-2-azaspiro[4.5]decane, the pyrrolidinyl, tetrahydrofuranyl, Piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl are optionally substituted with one or more R.

Preferably, R ^is selected from hydroxyl, cyano, methoxy,

said

Optionally substituted with one or two R.

Preferably, R ^is selected from hydroxyl, cyano, methoxy,

said

Optionally substituted with one or two R.

Preferably, R ^is selected from hydroxyl, cyano, methoxy,

said

optionally substituted by one or two R;

Preferably, R ^is selected from hydroxyl, cyano, methoxy,

said

optionally substituted by one or two R;

Preferably, R ^is selected from hydroxyl, cyano, methoxy,

Preferably, R ^is selected from the group consisting of hydroxyl, cyano, methoxy,

Preferably, R ³ is selected from hydrogen, C _1-3 alkyl, halogen, cyano.

Preferably, ^R3 is selected from hydrogen, methyl, fluorine, chlorine, cyano.

Preferably, R ³ is selected from hydrogen, halogen, C _1-3 alkoxy.

Preferably, ^R3 is selected from hydrogen, chlorine, methoxy.

Preferably, R is selected from halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxycarbonyl, 5-6 membered saturated heterocycles containing 1-2 heteroatoms, hydroxyl, oxygen Substituent, hydroxy C _1-3 alkyl.

Preferably, R is selected from C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxycarbonyl, 5-6 membered saturated heterocycle containing 1-2 heteroatoms, hydroxyl, hydroxyl C _{1 -3} alkyl.

Preferably, R is selected from halogen, methyl, methoxy, methoxycarbonyl, morpholinyl, hydroxyl, hydroxymethyl, halogen, oxo.

Preferably, R is selected from methyl, methoxy, methoxycarbonyl, morpholinyl, hydroxy, hydroxymethyl.

Preferably, R is selected from halogen, methyl, methoxycarbonyl, hydroxy, hydroxymethyl, halogen, oxo.

Preferably, the compound described in the present disclosure has the structure shown in formula (II):

in,

X ₁ , X ₂ , R ² , and R ³ are respectively as defined in the present disclosure.

Y ₁ , Y ₂ , Y ₃ , and Y ₄ are each independently selected from CR ⁸ or N.

Preferably, Y ₁ , Y ₂ , Y ₃ , and Y ₄ are each independently selected from CH or N.

R ⁸ is selected from hydrogen, amino, carboxyl, amido, C _1-6 alkoxy, C _1-6 alkoxycarbonyl.

R ⁴ and R ⁵ are independently selected from hydrogen, deuterium, C _1-6 alkyl, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkoxy, C _1-6 alkenyl, halogen , amino, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy are optionally substituted by halogen, hydroxyl.

Preferably, R ⁴ and R ⁵ are independently selected from hydrogen, deuterium, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, halogen, amino, and the C _1-6 Alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy are optionally substituted by halogen, hydroxyl.

Preferably, Y ¹ is selected from CR ⁸¹ or N; wherein, R ⁸¹ is selected from hydrogen, amino, carboxyl, amido, C _1-6 alkoxycarbonyl; more preferably, R ⁸¹ is selected from hydrogen, amino, carboxyl, amide group, ethoxycarbonyl.

Preferably, Y ³ is selected from CR ⁸² or N; wherein, R ⁸² is selected from hydrogen, C _1-6 alkoxy; more preferably, R ⁸² is selected from hydrogen, methoxy.

Preferably, R ^is selected from hydrogen, deuterium, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _1-6 alkenyl, said C _1-6 alkyl, C _Cycloalkyl is optionally substituted by halogen, hydroxyl; more preferably, ^R is selected from methyl, cyclopropyl, trifluoromethyl, cyclohexyl, cyclohexenyl, isopropyl, isopropenyl.

Preferably, R ^is selected from hydrogen, deuterium, C _1-6 alkyl, C _3-6 cycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl are optionally substituted by halogen, hydroxyl .

Preferably, R ⁴ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted by halogen.

Preferably, R ⁴ is selected from methyl, cyclopropyl, trifluoromethyl.

Preferably, R ^is selected from hydrogen, deuterium, C _1-6 alkoxy, halogen, amino.

Preferably, R ⁵ is selected from hydrogen, C _1-3 alkoxy, halogen, trifluoromethyl.

Preferably, R ⁵ is selected from methoxy, fluoro, bromo, trifluoromethyl.

Preferably, R ⁵ is selected from methoxy, fluoro, trifluoromethyl.

^R is selected from nonexistent, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, halogen, amino, cyano, carboxyl, amido, the C _1-6 alkyl , C _3-6 cycloalkyl, C _1-6 alkoxy are optionally substituted by halogen, hydroxyl.

Preferably, R ⁶ is selected from nonexistent, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, halogen, amino, said C _1-6 alkyl, C _3-6 Cycloalkyl, C _1-6 alkoxy are optionally substituted by halogen, hydroxy.

Preferably, R ^is selected from absent, fluoro, trifluoromethyl, chloro, bromo, cyano, amido, methyl, methoxy.

Preferably, ^R6 is selected from absent, fluoro, trifluoromethyl.

Preferably, the compound described in the present disclosure has the structure shown in formula (IIa):

in,

Y ₁ , Y ₂ , Y ₃ , Y ₄ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are respectively as defined in the present disclosure.

Preferably, the compound described in the present disclosure has the structure shown in formula (III):

in,

Y ₁ and Y ₂ are each independently selected from CH or N.

Preferably, both Y ₁ and Y ₂ are N.

R ⁴ and R ⁷ are independently selected from hydrogen, deuterium, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, halogen, amino, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy are optionally substituted by halogen, _hydroxyl .

Preferably, R ⁴ is selected _from hydrogen, deuterium, C _1-6 alkyl optionally substituted by halogen, hydroxy.

Preferably, R ⁴ is selected from C _1-3 alkyl.

Preferably, ^R4 is selected from methyl.

Preferably, ^R7 is selected from hydrogen, deuterium, halogen, amino.

Preferably, ^R7 is selected from hydrogen, amino.

Preferably, the compound described in the present disclosure has the structure shown in formula (IIIa):

in,

X ₁ , Y ₁ , Y ₂ , R ² , R ³ , R ⁴ , and R ⁷ are respectively as defined in the present disclosure.

The present disclosure also provides the following compounds, pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof,

The preparation method of any one of the aforementioned compounds, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, said method comprising the following steps:

Synthetic method I:

Take 4-(5-bromopyridin-2-yl)morpholine, pinacol diborate and 1,4-dioxane, add potassium acetate under stirring, replace with argon, add [1,1'-bis (Diphenylphosphine) ferrocene] palladium dichloride dichloromethane complex, after heating up for a certain period of time, cool naturally, evaporate the solvent under reduced pressure, add ethyl acetate and water to the residue and stir, separate liquid, organic The phase was washed with water until neutral, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent and then purified by silica gel to obtain intermediate I-1.

Take intermediate I-1, 3-chloroisoquinoline and 1,4-dioxane, add water and potassium carbonate under stirring, replace with argon, add [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride dichloromethane complex, after heating up for a certain period of time, cool down, evaporate the solvent under reduced pressure and purify with a silica gel column to obtain 4-(5-(isoquinolin-3-yl)pyridine-2 -base) morpholine.

Synthetic method II:

Take 2,4-dichloroquinazoline, cyclopropylboronic acid and tetrahydrofuran, add potassium phosphate under stirring, replace with argon, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Chloromethane complex, heated up and reacted for a certain period of time, cooled naturally, evaporated under reduced pressure to remove the solvent, and purified with silica gel to obtain intermediate I-2.

Take intermediate I-1, intermediate I-2 and 1,4-dioxane, add potassium phosphate under stirring, replace with argon, add bistriphenylphosphine palladium dichloride, heat up and react for a certain period of time, then cool down After distilling off the solvent under reduced pressure, it was purified by silica gel column to obtain 4-(5-(6-methoxy-4-methylquinazolin-2-yl)pyridin-2-yl)morpholine.

Take 2,4-dichloropyrrolo[2,3-D]pyrimidine, methylboronic acid and tetrahydrofuran, add potassium phosphate under stirring, replace with argon, add [1,1'-bis(diphenylphosphine) Iron] Palladium dichloride dichloromethane complex, heated up for a certain period of time, cooled naturally, evaporated under reduced pressure to remove the solvent, and purified with silica gel to obtain intermediate I-3.

Take 2-chloro-4-methylquinazoline, 2-chloro-5-pyridineboronic acid, 1,4-dioxane and water, add potassium carbonate under stirring, replace with argon, add tetrakis triphenylphosphine palladium , after heating up for a certain period of time, cool naturally, evaporate the solvent under reduced pressure and purify with silica gel to obtain intermediate I-4.

Take intermediate I-4, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, 1,4-dioxane and water, add potassium carbonate under stirring, replace with argon, add four Triphenylphosphine palladium, after heating up for a certain period of time, cool naturally, evaporate the solvent under reduced pressure and purify with silica gel to obtain 2-(6-3,6-dihydro-2H-pyran-4-yl)pyridine-3- base)-4-methylquinazoline.

Synthetic method III:

Take intermediate I-4, 4-hydroxypiperidine, anhydrous nitrogen methyl pyrrolidone, add potassium carbonate under stirring, replace with argon three times, raise the temperature to 160°C and react for a certain period of time, cool naturally, and use ethyl acetate and water After layer treatment, purify with silica gel to give 1-(5-(4-methylquinazolin-2-yl)pyridin-2-yl)

piperidin-4-ol.

Take intermediate I-4, 3-methylmorpholine, and 1,4-dioxane, add potassium tert-butoxide under stirring, replace with argon three times, add palladium acetate and 2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl, after heating up for a certain period of time, cool naturally, evaporate the solvent under reduced pressure and purify with silica gel to obtain 3-methyl-4-(5-(4-methyl Quinazolin-2-yl)pyridin-2-yl)morpholine.

Synthetic method IV:

Take R and 2-fluoropyridine-5-carbaldehyde, dissolve in DMF, add potassium carbonate, heat up to a certain temperature and react for 14 hours. The reaction was cooled to 25°C, added to ice water, extracted with ethyl acetate, and the solvent was spun off and purified with silica gel to obtain the compound of formula (IVa).

Take the compound of formula (IVb), dissolve it in anhydrous tetrahydrofuran, protect it with nitrogen, cool down to 0°C, add methyllithium dropwise, after the addition, raise the temperature to 25°C, and keep the reaction for 2 hours. Cool down to 0°C, quench the reaction with ice water, extract with ethyl acetate, distill off the solvent under reduced pressure and purify with silica gel to obtain the compound of formula (IVc).

Dissolve the compound of formula (IVc) and compound of formula (IVa) in DMSO, add ammonium acetate and hydrogen peroxide, and raise the temperature to 65°C. React for 16 hours. After the reaction, it was cooled naturally, added to ice water, extracted with ethyl acetate, washed with saturated sodium bisulfite for 30 minutes, evaporated under reduced pressure and purified with silica gel to obtain the final compound.

Synthetic Method V:

Take the compound of formula (IVd), add phosphorus oxychloride, heat up to 110°C, react for 14 hours, cool the reaction to 25°C, add to ice-saturated sodium carbonate, extract with ethyl acetate, spin off the solvent and purify with silica gel to obtain the formula (IVe) Compounds.

Take the compound of Chinese formula (IVe), methylboronic acid and tetrahydrofuran, add potassium phosphate under stirring, replace with argon, and add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane for complexation After heating up and reacting for a certain period of time, cool naturally, evaporate the solvent under reduced pressure and purify with silica gel to obtain the compound of formula (IVf).

Take the compound of formula (IVf), add phosphorus oxybromide and m-chloroperoxybenzoic acid, dissolve with chloroform, and react at 25° C. for 4 hours. Add it to ice-saturated sodium bisulfite solution, extract with ethyl acetate, spin off the solvent and purify with silica gel to obtain the compound of formula (IVg).

Take intermediate I-1, the compound of formula (IVg) and 1,4-dioxane, add potassium phosphate under stirring, replace with argon, add bistriphenylphosphine palladium dichloride, heat up and react for a certain period of time, then cool down , the solvent was evaporated under reduced pressure and then purified by silica gel column to obtain the compound of formula (IVh).

Take the compound of formula (IVh), dissolve it in ethanol, add sodium hydroxide solution, raise the temperature to 65° C., and react for 4 hours. Cool down, adjust the pH to acidic with hydrochloric acid, extract with ethyl acetate, distill off the solvent under reduced pressure and purify with a silica gel column to obtain the compound of formula (IVi).

Take the compound of formula (IVi), add DPPA, dissolve it with tert-butanol, add triethylamine, heat up to a certain temperature and react for a certain period of time, then extract it with ethyl acetate, evaporate the solvent under reduced pressure and purify it with a silica gel column to obtain the formula (IVj ) compounds.

Take the compound of formula (IVj), dissolve it in methanol, add hydrochloric acid/1,4-dioxane solution, and react at 25°C for 2 hours. After distilling off the solvent under reduced pressure, the final product was purified by silica gel column.

In the above synthetic method, R ^a is defined as R ² ;

R ₁ , R ₂ , and R ₃ are each independently selected from nonexistent, hydrogen, deuterium, C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl group, C _1-6 alkoxy C _1-6 alkoxycarbonyl, halogen, amino, carboxyl, amido, the C _1-6 saturated or partially unsaturated hydrocarbon group, C _3-6 saturated or partially unsaturated cycloalkyl, C _1-6 alkane Oxy is optionally substituted with halogen, hydroxy, or,

If there is an amino group in these groups, it is selected from the derivatives of these groups obtained by replacing the amino group with a protecting group.

Preferably, R ₁ , R ₂ , R ₃ are each independently selected from nonexistent, methyl, 1-isopropenyl, methoxy, cyclopropyl, trifluoromethyl, fluorine, chlorine, bromine, amino, cyano group, isopropyl group, cyclohexyl group, 1-cyclohexen-yl group, ethoxycarbonyl group, carboxyl group, amido group.

The present disclosure also provides a pharmaceutical composition, which is characterized in that the composition comprises any one of the aforementioned compounds of the present disclosure, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug and pharmaceutically acceptable Accepted excipients.

The application of any one of the aforementioned compounds, their pharmaceutically acceptable salts, stereoisomers, solvates or their prodrugs, and the aforementioned pharmaceutical compositions in the preparation of medicines for the treatment of AhR inhibition-mediated diseases in patients is disclosed.

The application of any one of the aforementioned compounds, pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, and the aforementioned pharmaceutical compositions in the preparation of AhR agonists is disclosed.

A method for agonizing AhR in a patient in need thereof, comprising administering to the patient any one of the aforementioned compounds of the present disclosure, a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the aforementioned pharmaceutical composition.

A method for activating AhR in a biological sample, comprising making the biological sample and any one of the aforementioned compounds of the present disclosure, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, or the aforementioned drug composition contact.

A method for treating a disease mediated by AhR inhibition in a patient in need thereof, comprising administering to the patient any one of the aforementioned compounds of the present disclosure, pharmaceutically acceptable salts, stereoisomers, and solvates thereof or its prodrug, or the aforementioned pharmaceutical composition.

The application or method of any one of the foregoing, wherein the disorder mediated by AhR inhibition includes but not limited to inflammatory disease or proliferative disease, preferably, the disorder mediated by AhR inhibition includes but not limited to rheumatoid Arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, atopic dermatitis, asthma, systemic lupus erythematosus, graft-versus-host disease, Hashimoto's thyroiditis, tumors.

Detailed ways

According to the above content of the present disclosure, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present disclosure, other various forms of modification, replacement or change can also be made.

I. Definition

Unless expressly stated otherwise, throughout the specification and claims, the term "comprise" or variations thereof such as "includes" or "includes" and the like will be understood to include the stated elements or constituents, and not Other elements or other components are not excluded.

Compounds of the invention may be asymmetric, eg, possess one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of the present invention can be isolated in optically pure or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents. Racemates, diastereomers, enantiomers are included within the scope of the present invention.

The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond accompanied by the migration of a proton.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes that said event or circumstance occurs and that it does not.

Numerical ranges herein refer to individual integers within a given range. For example, "C _1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C _1-3 " means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

The term "substituted" or "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by a substituent, as long as the valence of the specified atom or group is normal and the substituted compound is stable of. When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically achievable basis.

When any variable (eg ^Rn ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 1-5 R, said group may optionally be substituted with up to 5 R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms. For example, the term "C _1-6 alkyl" includes C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, C ₆ alkyl, examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It can be divalent, eg methylene, ethylene.

The term "halogen substitution" or "halo" refers to substitution by one or more halogen atoms, examples of halogen atoms include fluorine atom, chlorine atom, bromine atom, iodine atom.

The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds. Examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system obtained by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-10 carbon atoms. Included are bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, indene, indane, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene.

The term "heteroaryl" refers to a monovalent aryl group comprising at least one 5-, 6-, 7-membered ring independently selected from nitrogen, oxygen, and sulfur heteroatoms, and includes fused ring systems of 5-10 atoms ( at least one of which is aromatic). Examples of heteroaryl groups include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolyl, indolyl, benzene imidazolyl, imidazopyridyl, benzofuryl, pyridazinyl, isoindolyl.

The term "member" refers to the number of skeletal atoms making up the ring. For example, "5-10 membered" means that the number of skeleton atoms constituting the ring is 5, 6, 7, 8, 9 or 10. Thus, for example, pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene, pyrrole are five-membered rings.

The term "heterocycle" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. The heterocyclic ring can be a monocyclic or polycyclic ring system, such as a bicyclic ring, in which two or more rings exist in the form of fused rings, bridged rings or spiro rings, and at least one of the rings contains one or more heteroatoms.

As used herein, the term "partially unsaturated" refers to ring moieties that include at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

The substituent R ⁿ can be bonded to any atom on the ring, as long as the atomic valence permits. Combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds. It will be appreciated by those skilled in the art that no sterically impossible and/or synthetically impossible substitutions or substitution patterns are introduced for any group comprising one or more ^Rn substituents.

Refers to the chemical bond connection.

drug or pharmaceutical composition

The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without, commensurate with a reasonable benefit/risk ratio, undue toxicity, irritation, allergic response or other problems or complications of those compounds, materials, compositions and/or dosage forms.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy of the free acids and bases of the specified compound without adverse biological effects. For example acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

A drug or pharmaceutical composition of the present disclosure may be formulated orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. apply. Usually it is desired to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

For oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized cornstarch, polyvinylpyrrolidone, or hypromellose based cellulose); fillers (for example, lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (such as , magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (for example, potato starch or hydroxy sodium starch acetate); or wetting agents (for example, sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth, or alginates), Buffer salts, carmellose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical composition can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), anti-settling agent (e.g., sorbitol syrup, cellulose-derived or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia), non-aqueous carriers (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils), preservatives (e.g., p- methyl hydroxybenzoate or p-hydroxybenzoate propyl or sorbic acid) and other combinations. Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

Tablets containing as active compound may be coated by methods well known in the art. The compositions of the present disclosure comprising a compound of formula I as the active compound may also be incorporated into beads, microspheres or microcapsules, for example constructed of polyglycolic/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may suitably be formulated so as to provide controlled or delayed release of the active compound.

A drug or pharmaceutical composition of the present disclosure may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.) Or intradermal (i.d.) administration, by direct injection, via eg bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with added preservatives. The compositions may take such forms as excipients, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as anti-settling, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use.

A medicament or pharmaceutical composition of the present disclosure may also be formulated for rectal administration, eg, as a suppository or retention enema (eg, containing conventional suppository bases such as cocoa butter or other glycerides).

The term "treating" includes ameliorating, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to treat, agitate or alleviate one or more symptoms of the disease state being treated or otherwise provide a desired pharmacological and/or physiological effect. dose. The precise dosage will vary depending on factors such as subject dependent variables (eg, age, immune system health, etc.), the disease or disease, and the treatment being administered. The effect of an effective amount can be relative to a control. These controls are known in the art and discussed herein, and may be, for example, the condition of the subject prior to or without administration of the drug or drug combination, or in the case of drug combinations, the combined effects may be Compared to the effect of administering only one drug.

The term "excipient" is used herein to include any other compound that may be included in or on a microparticle that is not a therapeutic or biologically active compound. Thus, an excipient should be pharmaceutically or biologically acceptable or relevant, eg, the excipient is generally non-toxic to the subject. "Excipient" includes a single such compound, and is also intended to include plural compounds.

The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one selected from the following pharmaceutically acceptable ingredients depending on the mode of administration and the nature of the dosage form, Including but not limited to: carrier, diluent, adjuvant, excipient, preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, flavoring agent, antibacterial agent , antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

Uses and Treatments

The terms "patient", "subject", "individual" and the like are used interchangeably herein and refer to any animal or cells thereof, whether in vitro or in situ, amenable to the methods described herein. In some non-limiting embodiments, the patient, subject or individual is a human.

According to the methods of the invention, the compounds or compositions may be administered in any amount and by any route of administration effective to treat or lessen the severity of an AhR-associated disease.

The present invention relates to a method of agonizing AhR in a biological sample comprising the step of contacting said biological sample with a compound of the invention or a composition comprising said compound.

The term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof things. Activation of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological analysis, gene expression studies, and biological target identification.

A method of agonizing AhR in a patient of the present invention comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.

Provided compounds are AhR agonists and thus are useful in the treatment of one or more disorders associated with AhR activity. Accordingly, in certain embodiments, the invention provides a method for treating an AhR-mediated disorder comprising the step of administering a compound of the invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.

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

AhR-mediated disorders are well established in the art. The relationship between AhR and AhR-mediated disorders, diseases and/or conditions as described herein is well established in the related art. See, for example: Uyttenhove et al., Evidence for a tumoral immune resistance mechanism based on the degradation of tryptophan by indoleamine 2,3-dioxygenase on tryptophan degradation by indoleamine 2,3-dioxygenase), "Nature Medicine (Nature Medicine), 2003, Vol. 9 (10), 1038; Murray et al., "Friend-enemy relationship of AH receptor ligands in cancer (AH RECEPTOR LIGANDS IN CANCER: FRIEND AND FOE) "Natural Review: Cancer (Nat. Rev. Cancer) December 2014, Vol. 14 (12), pp. 801-814; Moen (Moon) et al., "Targeting the indoleamine 2,3-dioxygenase pathway in cancer", "J.ImmunoTherapy of Cancer", Volume 3, 2015 , p. 51; Ishida et al., Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis prognosis and cigarette smoke), Int. J. Cancer, July 2015, Vol. 15, No. 137 (2), pp. 299-310; Ishida et al., Activation of the aryl hydrocarbon receptor pathway Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer by upregulating the expression of MMP "Carcinogenesis "Volume 31 (2), February 2010, pp. 287-295. Su et al., "Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer" (Anticancer Res. )” September 2013, Vol. 33 (9), pp. 3953-3961; Peng et al., “Activation of the aryl hydrocarbon receptor pathway may enhance gastric cancer through c-Jun-dependent induction of matrix metalloproteinase-9 Cell invasion (Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9) "BMC Cell Biology (BMC Cell Biol.)" April 2009 Volume 16; pp. 10-27; Jin et al., Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection, Toxicol Sci .) "August 2010, Vol. 116 (2), pp. 514-522; Hyde (Head) et al., "The aryl hydrocarbon receptor is a modulator of antiviral immunity -viral immunity), "Biochem.Pharmacol.", February 2009, Vol. 15; No. 77 (4), pp. 642-53; New insights into the role of the aryl hydrocarbon receptor in the function of CD11c+ cells during respiratory viral infection (Eur.J.Immunol.) 2014 June, Vol. 44(6), pp. 1685-98; Ruan et al, "Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research" "Front Immunol. " 2014 10 29, No. 5, p. 551; Esser et al., The aryl hydrocarbon receptor in immunity, Trends in Immunology, vol. Volume 30, Issue 9.

The present invention provides a method for treating one or more autoimmune diseases, wherein the disorder, disease or condition is the body's immune response to self-antigens resulting in damage to self-tissue.

In certain embodiments, the invention provides a method for one or more autoimmune diseases comprising administering a compound or composition of the invention to a patient suffering from one or more autoimmune diseases. In certain embodiments, the method of treating one or more autoimmune diseases comprises administering the compounds and compositions of the invention to a mammal. In certain embodiments, the mammal is a human.

combination therapy

The present disclosure provides combination therapy using a compound as described in the present disclosure with other therapeutic agents. The term "combination therapy" as used in this disclosure includes administration of the agents in a sequential manner, ie, wherein each therapeutic agent is administered at different times, as well as administration of the therapeutic agents, or at least two agents, substantially simultaneously. The sequential, or substantially simultaneous, administration of each agent may be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue. The agents can be administered by the same route or different routes. For example, a first agent may be administered orally and a second agent administered intravenously. Additionally, selected combination agents may be administered by intravenous injection, while the other agents of the combination may be administered orally. Alternatively, for example, two or more agents may be administered by intravenous or subcutaneous injection.

II. Example

The present disclosure is further explained below with reference to examples. The descriptions of specific exemplary embodiments of the present disclosure are presented for purposes of illustration and illustration. These descriptions are not intended to limit the disclosure to the precise form disclosed, and obviously many modifications and variations are possible from the teachings of the present specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the disclosure and its practical application, thereby enabling those skilled in the art to make and use various exemplary embodiments of the disclosure, as well as various Choose and change.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Embodiment 1: synthetic method 1

1) 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester

Add 4-(5-bromopyridin-2-yl)morpholine (2g, 8.23mmol), pinacol diborate (5.2g, 47.23mmol) and 1,4-dioxane (40mL ), under stirring, potassium acetate (1.62g, 16.46mmol) was added, argon was replaced 3 times, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex ( 0.1g, 0.14mmol), heated to 95°C for 4 hours, cooled naturally to room temperature, evaporated the solvent under reduced pressure, added ethyl acetate and water to the residue, stirred, separated, washed the organic phase with water until neutral, added anhydrous sulfuric acid Sodium-dried, filtered, and the filtrate was purified by silica gel (ethyl acetate/petroleum ether=1/5) to obtain 2.06 g of light yellow solid intermediate I-1, yield: 86.26%, M+1: 291.2 .

2) 4-(5-(isoquinolin-3-yl)pyridin-2-yl)morpholine (compound 1)

Add 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester (140mg, 0.5mmol), 3-chloroisoquinoline (82mg, 0.5mmol) and 1,4-dioxo Hexacyclic (10mL), add water (2mL) and potassium carbonate (140mg, 1mmol) under stirring, replace with argon three times, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Chloromethane complex (82mg, 0.1mmol) was heated to 95°C for 5 hours, cooled to room temperature and evaporated under reduced pressure to remove the solvent, and then purified by silica gel column (EA/PTET=1/5) to obtain light yellow solid compound 1, 28mg , Yield: 19.3%.

Embodiment 2: synthetic method II

1) 2-Chloro-4-cyclopropylquinazoline

Add 2,4-dichloroquinazoline (200mg, 0.1mmol), cyclopropylboronic acid (100mg, 1.16mmol) and tetrahydrofuran (4mL) to a one-necked flask, add potassium phosphate (400mg, 1.89mmol) under stirring, and argon Replaced 3 times, added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (81mg, 0.099mmol), heated to 75°C for 4 hours, cooled naturally to At room temperature, the solvent was distilled off under reduced pressure, and then purified by silica gel (ethyl acetate/petroleum ether=1/5) to obtain light white solid intermediate I-2, 178 mg, yield: 86.6%.

2) 4-(5-(6-methoxy-4-methylquinazolin-2-yl)pyridin-2-yl)morpholine (Compound 5)

Add 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester (110mg, 0.38mmol), 2-chloro-4-cyclopropylquinazoline (78mg, 0.38mmol) and 1,4-Dioxane (6mL), add potassium phosphate (160mg, 0.75mmol) under stirring, replace with argon three times, add bistriphenylphosphine palladium dichloride (30mg, 0.043mmol), heat up to 105°C After reacting for 4 hours, the solvent was distilled off under reduced pressure at room temperature and then purified by silica gel column (EA/PTET=1/5) to obtain light yellow solid compound 5, 100 mg, yield: 79.2%.

Embodiment 3: synthetic method II

1) 2-Chloro-4-methylquinazoline

Add 2,4-dichloroquinazoline (10g, 50mmol), methylboronic acid (3.6g, 60mmol) and 1,4-dioxane (200mL), water (40mL), and add carbonic acid under stirring Potassium (13.87g, 100mmol) was replaced with argon three times, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (816mg, 1mmol) was added. After a period of time, it was cooled naturally, and the solvent was evaporated under reduced pressure and then purified by silica gel to obtain intermediate I-3 2-chloro-4-methylquinazoline, 6.5g, yield: 72.3%.

2) 4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazoline (compound 7)

Add intermediate I-3 (36 mg, 0.02 mmol), 4-(4-methyl-1-piperazinyl) phenylboronic acid (6.6 mg, 0.03 mmol), 1,4-dioxane ( 2.4mL), water (0.4mL), potassium carbonate (5.5mg, 0.04mmol) was added under stirring, argon was replaced 3 times, bistriphenylphosphine palladium dichloride (1.2mg, 0.001mmol) was added, and the temperature was raised to 100°C Reacted for 6 hours, cooled naturally, and purified with silica gel to obtain compound 7 4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazoline 32mg after evaporating the solvent under reduced pressure. Rate: 50%.

Embodiment 4: synthetic method II

1) 2-(6-chloropyridin-3-yl)-4-methylquinazoline

Add 2-chloro-4-methylquinazoline (510mg, 2.86mmol), 2-chloro-5-pyridineboronic acid (450mg, 2.86mmol) and 1,4-dioxane (10mL) into the one-necked bottle, Water (1.5mL), potassium carbonate (870mg, 6.29mmol) was added under stirring, argon was replaced 3 times, tetrakistriphenylphosphine palladium (331mg, 0.29mmol) was added, the temperature was raised to 100°C for 14 hours, and naturally cooled to room temperature , the solvent was distilled off under reduced pressure, and purified by silica gel (ethyl acetate/petroleum ether=1/5) to obtain white solid intermediate I-4, 280 mg, yield: 38.3%.

2) 2-(6-3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-4-methylquinazoline

Add 2-(6-chloropyridin-3-yl)-4-methylquinazoline (40mg, 0.16mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol Ester (37mg, 0.18mmol) and 1,4-dioxane (2.4mL), water (0.4mL), potassium carbonate (48.6mg, 0.35mmol) was added under stirring, argon was replaced 3 times, and tetrakistriphenyl Palladium phosphine (18.5mg, 0.016mmol), heated to 100°C for 14 hours, cooled to room temperature naturally, evaporated the solvent under reduced pressure and purified with silica gel (ethyl acetate/petroleum ether=1/5) to obtain 44mg of white solid, Yield: 90.7%.

3) 4-methyl-2-(6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)quinazoline (compound 16)

Add 2-(6-3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-4-methylquinazoline (44mg, 0.15mmol), ammonium formate ( 37.8 mg, 0.6 mmol) and 10% palladium carbon (5 mg), add methanol (5 mL), replace with argon three times, heat up to 75 ° C for 12 hours, naturally cool to room temperature, spread diatomaceous earth and suction filter, filter cake with methanol Wash twice, combine the organic phases, spin off the solvent and purify with silica gel (ethyl acetate/petroleum ether=1/5) to obtain white solid compound 16, 35 mg, yield: 76.5%.

Embodiment 5: synthetic method III

1) 1-(5-(4-methylquinazolin-2-yl)pyridin-2-yl)piperidin-4-ol (compound 27)

Take intermediate I-4 (51mg, 0.2mmol), 4-hydroxypiperidine (40mg, 0.4mmol), anhydrous nitrogen methyl pyrrolidone (5mL), add potassium carbonate (69mg, 0.5mmol) under stirring, and replace with argon Three times, the temperature was raised to 160 °C for 4 hours, cooled naturally, treated with ethyl acetate and water, and purified with silica gel to obtain compound 27 1-(5-(4-methylquinazolin-2-yl)pyridine-2 -yl)piperidin-4-ol 15 mg, yield: 23.4%.

Embodiment 6: synthetic method III

1) 3-methyl-4-(5-(4-methylquinazolin-2-yl)pyridin-2-yl)morpholine (compound 30)

Add intermediate I-4 (51mg, 0.2mmol), 3-methylmorpholine (30.3mg, 0.3mmol), (2.4mL) to the one-necked bottle, and add potassium tert-butoxide (44.8mg, 0.4mmol) under stirring , replaced with argon three times, added palladium acetate (6.7mg, 0.03mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (28mg, 0.06mmol), Raise the temperature to 100°C for 12 hours, cool naturally, evaporate the solvent under reduced pressure and purify with silica gel to obtain compound 30 3-methyl-4-(5-(4-methylquinazolin-2-yl)pyridine-2- Base) morpholine 30mg, yield: 46.9%.

Embodiment 7: synthetic method III

1) 2-(2-chloropyrimidin-5-yl)-4-methylquinazoline

Add intermediate I-3 (179mg, 1mmol), 2-chloropyrimidine-5-boronic acid (237mg, 1.5mmol), 1,4-dioxane (8mL) to a one-necked bottle, and add potassium carbonate (276mg , 2mmol), replaced with argon for 3 times, added bistriphenylphosphine palladium dichloride (40.8mg, 0.05mmol), raised the temperature to 90°C for 6 hours, cooled naturally, evaporated the solvent under reduced pressure and purified it with silica gel to obtain the intermediate I-5 2-(2-chloropyrimidin-5-yl)-4-methylquinazoline 160mg, yield: 50%.

2) 4-(5-(4-methylquinazolin-2-yl)pyrimidin-2-yl)morpholine (compound 49)

Take intermediate I-5 (32mg, 0.1mmol), morpholine (17.4mg, 0.2mmol), anhydrous nitrogen methyl pyrrolidone (5mL), add potassium carbonate (53.4mg, 0.3mmol) under stirring, and replace with argon three times , heated to 160 °C for 4 hours, cooled naturally, treated with ethyl acetate and water layers and purified with silica gel to obtain compound 49 4-(5-(4-methylquinazolin-2-yl)pyrimidine-2- base) morpholine 22mg, yield: 71.7%

Embodiment 8: synthetic method IV

1) 2-Amino-4-fluoro-3-methoxyphenylethan-1-one

Take 2-amino-3-methoxy-4-fluorobenzoic acid (1.85g, 10mmol), dissolve it in anhydrous tetrahydrofuran (20mL), protect it under nitrogen, cool down to 0°C, add dropwise 1.6M methyllithium (22.5mL , 36mmol), after the dropwise addition, the temperature was raised to 25°C, and the reaction was kept for 2 hours. Cool down to 0°C, quench the reaction with ice water, extract with ethyl acetate, evaporate the solvent under reduced pressure and purify with silica gel to obtain intermediate I-8 2-amino-4-fluoro-3-methoxyphenylethane- 0.9 g of 1-keto yellow oil, yield: 49.2%.

2) 5-(7-chloro-4-methylquinazolin-2-yl)pyridin-2-yl-3-methylmorpholine (compound 50)

Take 2-amino-4-fluoro-3-methoxyphenylethan-1-one (0.6g, 3.3mmol) and 7 (1.36g, 6.6mmol), dissolve with DMSO (20mL), add ammonium acetate ( 1.02g, 13.2mmol) and 30% hydrogen peroxide (2.25g, 19.8mmol), the temperature was raised to 65°C. React for 16 hours. After the reaction, cool naturally, add ice water, extract with ethyl acetate, wash with saturated sodium bisulfite for 30 minutes, evaporate the solvent under reduced pressure and purify with silica gel to obtain yellow solid compound 50 5-(7-chloro-4- Methylquinazolin-2-yl)pyridin-2-yl-3-methylmorpholine 0.23 g, yield: 18.9%.

Embodiment 9: synthetic method IV

1) tert-butyl 4,4-difluoropiperidine-1-carboxylate

Take tert-butyl 4-oxopiperidine-1-carboxylate (2g, 10mmol), dissolve it in dichloromethane (50mL), cool down to 0°C, add DAST (3.3g, 20mmol) reagent, heat up to 25°C, keep warm React for 2 hours. Cool down to 0°C, quench the reaction with ice water, extract with ethyl acetate, evaporate the solvent under reduced pressure and purify with silica gel to obtain white solid intermediate I-9 4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester 1.95 g, yield: 87.7%.

2) 4,4-difluoropiperidine

Take tert-butyl 4,4-difluoropiperidine-1-carboxylate (1.2g, 5.4mmol), dissolve it in dichloromethane (25mL), add trifluoroacetic acid (10mL), react at 25°C for 1 hour, and spin off the solvent , to obtain orange-red solid intermediate I-10 4,4-difluoropiperidine 0.65g, which was directly used in the next step.

3) 6-(4,4-difluoropiperidin-1-yl)nicotinaldehyde

Take 4,4-difluoropiperidine (0.65g, 5.4mmol) and 2-fluoropyridine-5-carbaldehyde (0.68g, 5.4mmol), dissolve it with DMF (15mL), add potassium carbonate (1.12g, 8.1mmol ), heated up to a certain temperature and reacted for 14 hours. Cool the reaction to 25°C, add ice water, extract with ethyl acetate, spin off the solvent and purify with silica gel to obtain yellow oil intermediate I-11 6-(4,4-difluoropiperidin-1-yl)nicotinaldehyde 1.1 g, yield: 90.6%.

4) 5-(7-chloro-4-methylquinazolin-2-yl)pyridin-2-yl-3-methylmorpholine (compound 59)

Take intermediate I-8 (0.6g, 3.3mmol) and 7 (1.36g, 6.6mmol), dissolve with DMSO (20mL), add ammonium acetate (1.02g, 13.2mmol) and 30% hydrogen peroxide (2.25g, 19.8mmol ), heated up to 65°C. React for 16 hours. After the reaction, cool naturally, add ice water, extract with ethyl acetate, wash with saturated sodium bisulfite for 30 minutes, evaporate the solvent under reduced pressure and purify with silica gel to obtain yellow solid compound 59 5-(7-chloro-4- Methylquinazolin-2-yl)pyridin-2-yl-3-methylmorpholine 0.23 g, yield: 18.9%.

Embodiment 10: synthetic method IV

1) 5-(7-chloro-4-methylquinazolin-2-yl)pyridin-2-yl-3-methylmorpholine (compound 64)

Take intermediate I-6 2-amino-4-chlorophenyl ethyl ketone (169mg, 1mmol) and intermediate I-7R-6-(3-methylmorpholinyl)nicotinaldehyde (412mg, 2mmol), with DMSO (15mL) was dissolved, ammonium acetate (308mg, 4mmol) and 30% hydrogen peroxide (680mg, 6mmol) were added, and the temperature was raised to 65°C. React for 16 hours. After the reaction, cool naturally, add to ice water, extract with ethyl acetate, wash with saturated sodium bisulfite for 30 minutes, evaporate the solvent under reduced pressure and purify with silica gel to obtain compound 64 5-(7-chloro-4-methyl Quinazolin-2-yl)pyridin-2-yl-3-methylmorpholine yellow solid 155 mg, yield: 42.4%.

Embodiment 11: synthetic method IV

1) (R)-4-methyl-2-(6-(3-methylmorpholine)pyridin-3-yl)quinazoline-7-carbonitrile (compound 65)

Take 5-(7-chloro-4-methylquinazolin-2-yl)pyridin-2-yl-3-methylmorpholine (70mg, 0.198mmol), add zinc cyanide (28mg, 0.24mmol), Tetrakistriphenylphosphopalladium (5.8mg, 0.005mmol), added 1,4-dioxane (5mL), protected by argon, heated up for 16 hours, cooled naturally, evaporated the solvent under reduced pressure and purified with silica gel to obtain Compound 65 (R)-4-methyl-2-(6-(3-methylmorpholine)pyridin-3-yl)quinazoline-7-carbonitrile 30 mg light yellow solid, yield: 44%.

Embodiment 12: synthetic method IV

1) (R)-4-methyl-2-(6-(3-methylmorpholinyl)pyridin-3-ylquinazoline-7-carboxamide (compound 66)

Take (R)-4-methyl-2-(6-(3-methylmorpholine)pyridin-3-yl)quinazoline-7-carbonitrile (20mg, 0.058mmol) and dissolve it with DMSO (3mL) Finally, add 30% hydrogen peroxide (3mL), react at 25°C for 2 hours, add ice water, quench with saturated sodium bisulfite, extract with ethyl acetate, evaporate the solvent under reduced pressure and purify with silica gel to obtain compound 66 (R )-4-methyl-2-(6-(3-methylmorpholinyl)pyridin-3-ylquinazoline-7-carboxamide 10 mg yellow solid, yield: 47.5%.

Embodiment 13: synthetic method IV

1) tert-butyl 1-oxa-7-azaspiro[3.5]nonane-7-carboxylate

Take tert-butyl 4-oxopiperidine-1-carboxylate (1.99g, 10mmol), add trimethylsulfoxide iodide (8.8g, 40mmol), dissolve with DMF (100mL), heat up to 110°C, and react for 34 After 1 hour, the reaction was cooled to 25°C, added to ice water, extracted with ethyl acetate, and purified by silica gel to obtain a pale yellow oil intermediate I-12 1-oxa-7-azaspiro[3.5]nonane - 1.95 g of tert-butyl 7-carboxylate, yield: 85.9%.

2) 1-Oxa-7-azaspiro[3.5]nonane

Take tert-butyl 1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (1.95g, 8.6mmol), dissolve it in dichloromethane (20mL), add trifluoroacetic acid (10mL), at 25°C After reacting for 1 hour, the solvent was spun off to obtain 1.09 g of yellow oil intermediate I-131-oxa-7-azaspiro[3.5]nonane crude product, which was directly used in the next step.

3) 6-(1-Oxa-7-azaspiro[3.5]nonan-7-yl)nicotinaldehyde

Take intermediate I-13 (1.09g, 8.6mmol) and 2-fluoropyridine-5-carbaldehyde (1.07g, 8.6mmol), dissolve it with DMF (20mL), add potassium carbonate (1.79g, 12.9mmol), and heat up to 110°C and react for 14 hours. The reaction was cooled to 25°C, added to ice water, extracted with ethyl acetate, and purified by silica gel to obtain intermediate I-14 6-(1-oxa-7-azaspiro[3.5]nonan-7-yl ) nicotinaldehyde 0.82g, yield: 41.1%.

4) 7-(5-(7-fluoro-4-methylquinazolin-2-yl)pyridin-2-yl)-1-oxa-7-azaspiro[3.5]nonane (compound 66)

Take intermediate I-8 (0.6g, 3.3mmol) and intermediate I-11 (1.53g, 6.6mmol), dissolve with DMSO (20mL), add ammonium acetate (1.02g, 13.2mmol) and 30% hydrogen peroxide (2.25 g, 19.8mmol), the temperature was raised to 65°C. React for 16 hours. After the reaction, cool naturally, add ice water, extract with ethyl acetate, wash with saturated sodium bisulfite for 30 minutes, evaporate the solvent under reduced pressure and purify with silica gel to obtain yellow solid compound 667-(5-(7-fluoro- 0.32 g of 4-methylquinazolin-2-yl)pyridin-2-yl)-1-oxa-7-azaspiro[3.5]nonane, yield: 26.6%.

Embodiment 14: synthetic method V

1) Ethyl 4-chloroquinoline-3-carboxylate

Take ethyl 4-hydroxyquinoline-3-carboxylate (2.17g, 10mmol), add phosphorus oxychloride (20mL), heat up to 110°C, react for 14 hours, cool the reaction to 25°C, add ice saturated sodium carbonate , extracted with ethyl acetate, spin off the solvent and purify with silica gel to obtain 2.1 g of off-white solid intermediate I-15 ethyl 4-chloroquinoline-3-carboxylate, yield: 89.4%.

2) Ethyl 4-methylquinoline-3-carboxylate

Take ethyl 4-chloroquinoline-3-carboxylate (470mg, 2mmol), methylboronic acid (300mg, 5mmol) and tetrahydrofuran (10mL), add potassium phosphate (414mg, 3mmol) under stirring, replace with argon, and add [1 , 1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (81mg, 0.1mmol), heated to 100°C, reacted for 12 hours, cooled naturally, evaporated the solvent under reduced pressure After purification with silica gel, 310mg of brown oil intermediate I-16 ethyl 4-methylquinoline-3-carboxylate was obtained, yield: 72.1%.

3) Ethyl 2-bromo-4-methylquinoline-3-carboxylate

Take ethyl 4-methylquinoline-3-carboxylate (215mg, 1mmol), add phosphorus oxybromide (574mg, 2mmol) and m-chloroperoxybenzoic acid (173mg, 1mmol), dissolve with chloroform (15mL), 25 °C for 4 hours. Add ice-saturated sodium bisulfite solution (40mL), extract with ethyl acetate, spin off the solvent and purify with silica gel to obtain yellow solid intermediate I-17 2-bromo-4-methylquinoline-3-ethyl carboxylate 120mg , Yield: 40.9%.

4) ethyl 4-methyl-2-(6-morpholinepyridin-3-yl)quinoline-3-carboxylate (compound 70)

Take intermediate I-1 (174mg, 0.6mmol), ethyl 2-bromo-4-methylquinoline-3-carboxylate (120mg, 0.41mmol) and 1,4-dioxane (10mL) and water ( 2mL), under stirring, potassium phosphate (170mg, 0.8mmol) was added, argon was replaced three times, bistriphenylphosphine palladium dichloride (16mg, 0.02mmol) was added, the temperature was raised to 100°C, and after 12 hours of reaction, evaporated under reduced pressure After removing the solvent, it was purified by a silica gel column to give yellow solid compound 70 ethyl 4-methyl-2-(6-morpholinopyridin-3-yl)quinoline-3-carboxylate, 102 mg, yield: 66.1%.

Embodiment 15: synthetic method V

1) 4-methyl-2-(6-morpholine pyridin-3-yl) quinoline-3-carboxylic acid (compound 77)

Take ethyl 4-methyl-2-(6-morpholinopyridin-3-yl)quinoline-3-carboxylate (37.7mg, 0.1mmol), dissolve it with ethanol (5mL), add 4N sodium hydroxide ( 2mL) solution, heated to 65°C, and reacted for 4 hours. Cool down, adjust the pH to acidic with hydrochloric acid, extract with ethyl acetate, evaporate the solvent under reduced pressure and purify with a silica gel column to obtain a yellow solid compound 77 4-methyl-2-(6-morpholinopyridin-3-yl)quinoline -3-Carboxylic acid 20.4 mg, yield: 58.5%.

Embodiment 16: synthetic method V

1) tert-butyl (4-methyl-2-(6-morpholinopyridin-3-yl) quinolin-3-yl) carbamate

Take 4-methyl-2-(6-morpholinopyridin-3-yl)quinoline-3-carboxylic acid (34.9mg, 0.1mmol), add DPPA (41.3mg, 0.15mmol), wash with tert-butanol (10mL ) was dissolved, added triethylamine (20.2 mg, 0.2 mmol), heated to 80 ° C for 14 hours, extracted with ethyl acetate, evaporated under reduced pressure and purified with silica gel column to obtain yellow solid tert-butyl (4-methyl -2-(6-morpholinopyridin-3-yl)quinolin-3-yl)carbamate 23.3 mg, yield: 55.5%.

2) 4-methyl-2-(6-morpholin-3-yl)quinolin-3-amine (compound 78)

Take tert-butyl (4-methyl-2-(6-morpholinopyridin-3-yl) quinoline-3-yl) carbamate (23 mg, 0.05 mmol), dissolve it in methanol (2 mL), add hydrochloric acid /1,4-dioxane (5 mL) solution, react at 25°C for 2 hours. After distilling off the solvent under reduced pressure, it was purified by silica gel column to obtain 12 mg of yellow solid compound 78 4-methyl-2-(6-morpholin-3-yl)quinolin-3-amine, yield: 75%.

Embodiment 17: according to the similar method of above-mentioned embodiment, prepare the compound shown in table 1

Table 1: Compound 1-78 synthesis method and data characterization

Embodiment 18: Screening experiment of compound agonizing AhR target in vitro

The in vitro activity of the above compounds was demonstrated in the following assays:

HepG2-Lucia ^TM AhR cells were used to screen small molecular compounds that stimulate aryl hydrocarbon receptor (AhR). HepG2-Lucia ^TM AhR cells are engineered from the human HepG2 hepatoma cell line and used to study AhR genome signaling induction by monitoring the activity of a luciferase reporter protein.

1) Experimental materials

DMEM medium was purchased from Gibco Company, penicillin and streptomycin were purchased from Hyclone Company, Tapinarof was purchased from MedChemExpress (MCE) Company, and Dual Luciferase Reporter Assay Kit was purchased from Novozyme Biotechnology Co., Ltd.

2) Experimental method

HepG2-Lucia ^TM AhR cells were cultured in an incubator at 37°C and 5% CO ₂ in DMEM+10% FBS+1% penicillin/streptomycin medium. During the experiment, the HepG2-Lucia ^TM AhR cells in the logarithmic growth phase were digested and collected, seeded in a 96-well plate at 8×10 ³ cells/well, and cultured overnight in a cell culture incubator at 37°C and 5% CO ₂ . The next day, dilute the test compound to the corresponding concentration (0.001-10μM) with the culture medium and add it to the corresponding well of the 96-well plate. There are 3 duplicate wells for each sample concentration, and 3 solvent control wells and 3 solvent control wells are set on each plate. Positive drug Tapinarof (10μM) was added to the control wells for each test. The positive drug Tapinarof was diluted and added to the test. After adding the drug, the 96-well plate was placed in a cell culture incubator at 37° C. and 5% CO ₂ for 24 hours. 10 minutes before the end of the incubation, mix 5× Cell Lysis Buffer (Cell Lysis Buffer) and ddH ₂ O in the Dual Luciferase Reporter Assay Kit (Dual Luciferase Reporter Assay Kit) at a ratio of 1:4 to prepare 1× Cell Lysis The Buffer is ready for use. After the culture is over, remove the medium, add 20 μL of 1×Cell Lysis Buffer to each well, and shake on a horizontal shaker for 15 minutes to fully lyse the cells. During this period, mix the appropriate amount of reaction stop buffer (Stop&Reaction Buffer) and luciferase substrate (Renilla Substrate) in a ratio of 50:1 for use (protect from light), and prepare a light-tight 96-well white plate at the same time. After the cell lysis was completed, the cell lysate (13 μL) was transferred to the corresponding well of a 96-well white plate, and the results were measured using a microplate luminescence detector. And calculate the DRE luciferase activity fold (DRE Luciferase activity (fold)) according to the following formula:

DRE luciferase activity multiple = average value of duplicate wells of sample / average value of duplicate wells of solvent control

The agonistic effect of the sample on AhR can be evaluated by the multiple of the luciferase activity of the sample and the positive drug Tapinarof (10 μM). Finally, the Graphpad Prism 5.0 software was used to fit the curve and calculate the EC50 value of the test compound agonizing the AhR target.

Table 2: EC50 values and agonistic effects of each example compound in in vitro assay 1

Where "-" indicates that no determination was performed.

For EC50 value, "AAAA" means EC50<50nM; "AAA" means 50nM≤EC50<200nM; "AA" means 200nM≤EC50<2μM; "A" means EC50>2μM;

For the activating multiple value, "BBB" means higher than 10 times; "BB" means the multiple is greater than or equal to 5 and less than or equal to 10; "B" means the multiple is less than 5.

Claims

The compound represented by formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug,

in,

X 1 and X 2 are independently selected from CR 0 or N;

Ring A is phenyl or a 6-10 membered monocyclic or bicyclic heteroaryl group containing 1-3 atoms selected from N and S atoms;

R O is selected from hydrogen, halogen, cyano, C 1-6 alkyl;

R is selected from nonexistent, hydrogen, deuterium, C 1-6 saturated or partially unsaturated hydrocarbon group, C 3-6 saturated or partially unsaturated cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl , halogen, amino, carboxyl, amido, the C 1-6 saturated or partially unsaturated hydrocarbon group, C 3-6 saturated or partially unsaturated cycloalkyl, C 1-6 alkoxy are optionally replaced by halogen, hydroxyl replace;

R is selected from nonexistent, hydrogen, deuterium, hydroxyl, cyano, C 1-6 alkoxy, 5-8 membered saturated heterocyclic ring, 5-8 membered partially unsaturated heterocyclic ring, 5-8 membered saturated bicyclic heterocyclic ring , the 5-8 membered saturated heterocyclic ring, the 5-8 membered partially unsaturated heterocyclic ring, and the 5-8 membered saturated bicyclic heterocyclic ring are optionally substituted by one or more R;

R is selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano;

R is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 carbonyloxy, 5-8 membered saturated heterocycle, hydroxyl, hydroxyl C 1- 6 alkyl, cyano, oxo;

n is selected from 0, 1 or 2.
The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, wherein, A ring is selected from the following groups:

Preferably, ring A is selected from the following groups:
The compound, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug according to claim 1, wherein,
selected from the following groups:
A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a prodrug thereof, wherein R 1 is selected from nonexistent, hydrogen, deuterium, C 1-6 saturated or partially unsaturated hydrocarbon group, C 3-6 saturated or partially unsaturated cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkoxycarbonyl group, halogen, amino, carboxyl, amido group, said C 1-6 Saturated or partially unsaturated hydrocarbon groups, C 3-6 saturated or partially unsaturated cycloalkyl groups, C 1-6 alkoxy groups are optionally substituted by hydroxyl, one to three halogens;

Preferably, R is selected from absent, methyl, 1 -isopropenyl, methoxy, cyclopropyl, trifluoromethyl, fluoro, chloro, bromo, amino, cyano, isopropyl, cyclohexyl, 1-cyclohexene-yl, ethoxycarbonyl, carboxyl, amido;

Preferably, R is selected from hydroxyl, cyano, C 1-3 alkoxy, 5-8 membered saturated heterocycles containing 1-2 independently selected from N, O, and S atoms, containing 1-2 5-6 membered partially unsaturated heterocycles independently selected from N and O atoms, and 5-8 membered saturated bicyclic heterocycles independently selected from N and O atoms, containing 1-2 A 5-8 membered saturated heterocyclic ring independently selected from N, O, and S atoms, and a 5-6 membered partially unsaturated heterocyclic ring independently selected from N, O atoms containing 1-2 are optionally replaced by R replace;

Preferably, R is selected from hydroxyl, cyano, C 1-3 alkoxy, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl Base, 2-azaspiro[3.3]heptanyl, thiomorpholinyl, 1-oxo-7-azaspiro[3.5]nonane, 8-oxo-2-azaspiro[4.5]decane alkane, 2-oxo-5-azabicyclo[2.2.1]heptane, 6-oxo-3-azabicyclo[3.1.0]hexane, 1,5-oxazolidine, the pyrrolidine Base, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl are optionally substituted by one or more R;

Preferably, R is selected from hydroxyl, cyano, C 1-3 alkoxy, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl base, thiomorpholinyl, 1-oxo-7-azaspiro[3.5]nonane, 8-oxo-2-azaspiro[4.5]decane, the pyrrolidinyl, tetrahydrofuranyl, Piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 2,3-dihydropyranyl are optionally substituted by one or more R;

Preferably, R is selected from hydroxyl, cyano, methoxy,

said

optionally substituted by one or two R;

Preferably, R is selected from hydroxyl, cyano, methoxy,

said

optionally substituted by one or two R;

Preferably, R is selected from hydroxyl, cyano, methoxy,

said

optionally substituted by one or two R;

Preferably, R is selected from hydroxyl, cyano, methoxy,

Preferably, R is selected from hydroxyl, cyano, methoxy,

Preferably, R is selected from hydrogen, C 1-3 alkyl, halogen, cyano;

Preferably, R is selected from hydrogen, methyl, fluorine, chlorine, cyano;

Preferably, R 3 is selected from hydrogen, halogen, C 1-3 alkoxy;

Preferably, R is selected from hydrogen, chlorine, methoxy;

Preferably, R is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxycarbonyl, 5-6 membered saturated heterocycles containing 1-2 heteroatoms, hydroxyl, oxygen Substituent, hydroxy C 1-3 alkyl;

Preferably, R is selected from halogen, methyl, methoxy, methoxycarbonyl, morpholinyl, hydroxyl, hydroxymethyl, halogen, oxo;

Preferably, R is selected from halogen, methyl, methoxycarbonyl, hydroxyl, hydroxymethyl, halogen, oxo;

Preferably, R 0 is selected from hydrogen, fluorine, chlorine, methyl, cyano.
According to the compound according to any one of claims 1-4, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, said compound has the structure shown in formula (II):

in,

X 1 , X 2 , R 2 , and R 3 are respectively as defined in any one of claims 1-4,

Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from CR 8 or N;

R is selected from hydrogen, amino, carboxyl, amido, C 1-6 alkoxy, C 1-6 alkoxycarbonyl;

R 4 and R 5 are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 saturated or partially unsaturated cycloalkyl, C 1-6 alkoxy, C 1-6 alkenyl, halogen , amino, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy are optionally substituted by halogen, hydroxyl;

Preferably, Y 1 is selected from CR 81 or N; wherein, R 81 is selected from hydrogen, amino, carboxyl, amido, C 1-6 alkoxycarbonyl; more preferably, R 81 is selected from hydrogen, amino, carboxyl, amide base, ethoxycarbonyl;

Preferably, Y 3 is selected from CR 82 or N; wherein, R 82 is selected from hydrogen, C 1-6 alkoxy; more preferably, R 82 is selected from hydrogen, methoxy;

Preferably, R is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkenyl, said C 1-6 alkyl, C Cycloalkyl is optionally substituted by halogen, hydroxyl; more preferably, R is selected from methyl, cyclopropyl, trifluoromethyl, cyclohexyl, cyclohexenyl, isopropyl, isopropenyl;

Preferably, R is selected from C 1-6 alkyl, C 3-6 cycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl are optionally substituted by halogen;

Preferably, R is selected from methyl, cyclopropyl, trifluoromethyl;

Preferably, R is selected from hydrogen, deuterium, C 1-6 alkoxy, halogen, amino;

Preferably, R is selected from hydrogen, C 1-3 alkoxy, halogen, trifluoromethyl;

Preferably, R is selected from methoxy, fluorine, bromine, trifluoromethyl;

R is selected from nonexistent, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogen, amino, cyano, carboxyl, amido, the C 1-6 alkyl , C 3-6 cycloalkyl, C 1-6 alkoxy are optionally substituted by halogen, hydroxyl;

Preferably, R is selected from absent, fluoro, trifluoromethyl, chloro, bromo, cyano, amido, methyl, methoxy.
According to the compound according to claim 5, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, said compound has the structure shown in formula (IIa):

in,

Y 1 , Y 2 , Y 3 , Y 4 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 5, respectively.
According to the compound according to any one of claims 1-4, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, said compound has the structure shown in formula (III):

in,

X 1 , X 2 , R 2 , R 3 are respectively as defined in any one of claims 1-4;

Y 1 and Y 2 are independently selected from CH or N;

Preferably, both Y 1 and Y 2 are N;

R 4 and R 7 are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogen, amino, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy are optionally substituted by halogen, hydroxyl ;

Preferably, R is selected from hydrogen, deuterium, C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by halogen, hydroxyl;

Preferably, R 4 is selected from C 1-3 alkyl;

Preferably, R 4 is selected from methyl;

Preferably, R is selected from hydrogen, deuterium, halogen, amino;

Preferably, R7 is selected from hydrogen, amino.
According to the compound according to claim 7, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, said compound has the structure shown in formula (IIIa):

in,

X 1 , Y 1 , Y 2 , R 2 , R 3 , R 4 , and R 7 are as defined in claim 7, respectively.
The following compounds or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof,
A pharmaceutical composition, characterized in that the composition comprises the compound according to any one of claims 1-9, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof and pharmaceutically acceptable Accepted excipients.
The compound of any one of claims 1-9, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, and the pharmaceutical composition of claim 10 are used in the preparation and treatment of the disease mediated by AhR inhibition in patients application in medicine.
Use of the compound according to any one of claims 1-9, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, and the pharmaceutical composition of claim 10 in the preparation of an AhR agonist.
A method of agonizing AhR in a patient in need thereof, comprising administering to said patient a compound according to any one of claims 1-9, a pharmaceutically acceptable salt, stereoisomer, solvate, or Its prodrug, or the pharmaceutical composition of claim 10.
A method for activating AhR in a biological sample, comprising making the biological sample and the compound according to any one of claims 1-9, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, or the pharmaceutical composition of claim 10.
A method for treating a disease mediated by AhR inhibition in a patient in need thereof, comprising administering to the patient a compound according to any one of claims 1-9, a pharmaceutically acceptable salt thereof, a stereo Isomers, solvates or prodrugs thereof, or the pharmaceutical composition of claim 10.
The application of any one of claims 11-12 or the method of any one of claims 13-15, wherein the disorder mediated by AhR inhibition includes but is not limited to inflammatory disease or proliferative disease, preferably, the Conditions mediated by AhR inhibition include, but are not limited to, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, atopic dermatitis, asthma, systemic lupus erythematosus, graft versus host disease, Hashimoto’s Thyroiditis, tumor.