Heterocyclic compounds and their use as ahR agonists

Abstract

This disclosure provides a heterocyclic compound and its application as an AhR agonist, the structural formula of which is shown in I-1 or I-2 below: or X1, X2, X3, X4 are implemented as N, CH or CH groups in which the H atom is replaced by a halogen X; X5 is implemented as CH or N, Ra is implemented as H or OH; X6 is implemented as N or CH, Rb is implemented as an alkyl group with 3 or fewer unsubstituted carbon atoms or an alkyl group with at least 3 or fewer carbon atoms in which at least one H atom is replaced by at least one halogen; X7, X8, X9, X 10 The group is defined as CH, N, or CH in which the H element is replaced by any one of a halogen, CN, CH3O−, or NH2; X 11 It is implemented as CH.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field, specifically relating to a heterocyclic compound and its application as an AhR agonist. Background Technology

[0002] The aryl hydrocarbon receptor (AhR) is a ligand-regulated cytoplasmic transcription factor that influences the transcription and expression of various genes and induces the activity of many important exogenous cytochrome P450 enzymes. It is widely distributed in human tissues and cells. Recent studies have shown that AhR not only mediates the toxic effects of various environmental toxins such as polycyclic aromatic hydrocarbons (PAHs), but also participates in many important biological processes, such as cell proliferation and differentiation, immune regulation, growth and development, and the maintenance of physiological homeostasis. Normally, AhR forms a complex in the cytoplasm with heat shock protein 90 (Hsp90), AIP (AhR Interacting Protein), and the chaperone protein p23. In the presence of an agonist, AhR is activated and transported to the nucleus, where it binds to the aryl hydrocarbon receptor nuclear translocator (ARNT) to form a heterodimer. After heterodimer formation, it binds to a xenobiotic response element (XRE) on DNA, activating XRE-controlled gene expression. In addition, AhR can interact with other proteins (such as the NF-κB subunit RelA and estrogen receptors), further broadening the signaling pathways regulated by AhR.

[0003] Further research has found that exogenous ligands of AhR and polycyclic aromatic hydrocarbons (PAHs), which can be exogenous environmental pollutants, have been shown to induce allergic diseases such as contact dermatitis, atopic dermatitis, rhinitis, and asthma. It is speculated that AhR and its signaling pathway may play a role in the pathogenesis of AD.

[0004] Atopic dermatitis, also known as eczema, is one of the most common chronic inflammatory skin diseases, with approximately 80% of cases occurring in infancy or childhood. Symptoms typically include dry and sensitive skin, localized or widespread eczematous lesions, and severe itching. While not a fatal disease, it significantly impacts the quality of life for patients and their families, creating a substantial socioeconomic burden. The pathogenesis of atopic dermatitis is influenced by multiple factors. A characteristic of atopic dermatitis is its diverse clinical symptoms, and its pathogenesis is the result of the interaction of multiple factors, including environmental factors, the skin microbiome, the epidermal barrier, immune and inflammatory responses, and the pruritus-scratching cycle. The interaction between these factors leads to the development of the disease within a specific genetic and epigenetic background. With the dynamic changes in the immune response, atopic dermatitis can also trigger systemic inflammatory responses, affecting organs beyond the skin. Therefore, there is a need to develop novel drugs for the treatment of diseases associated with AhR. Summary of the Invention

[0005] To address the aforementioned technical problems, this disclosure provides a heterocyclic compound with the structural formula shown in I-1 or I-2 below:

[0006] or

[0007] X1, X2, X3, and X4 are implemented as groups in N, CH, or CH in which the H atom is replaced by a halogen X;

[0008] X5 is implemented as CH or N, and Ra is implemented as H or OH;

[0009] X6 is implemented as N or CH, and Rb is implemented as an alkyl group with 3 or fewer carbon atoms that is not substituted or an alkyl group with at least 3 or fewer carbon atoms whose at least H element is substituted by at least one halogen.

[0010] X7, X8, X9, X 10 The group is implemented as CH, N or CH in which the H element is replaced by any one of halogen, CN, CH3O-, NH2;

[0011] X 11 It is implemented as CH.

[0012] According to one embodiment of this application,

[0013] Selected from the following groups: , , , , ;

[0014] Selected from the following groups: or .

[0015] According to one embodiment of this application, the heterocyclic compound structural formula is implemented as selected from any one of the following:

[0016]

[0017] According to another aspect of this application, this application also provides a method for preparing a heterocyclic compound, comprising the following steps: reacting compound a with compound b to obtain the compound of formula (I-1) or reacting compound a with compound c to obtain the compound shown in (I-2);

[0018]

[0019]

[0020] Wherein, X is selected from halogens, and L is selected from borate groups or borate ester groups.

[0021] According to one embodiment of this application, X is selected from Cl, Br, or I, and L is selected from... .

[0022] According to another aspect of this application, this application also provides a pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

[0023] Beneficial effects

[0024] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has good AhR protein activating activity and can be used as an AhR agonist. Detailed Implementation

[0025] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0026] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0027] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0028] The context of this disclosure is used Represents a chemical bond.

[0029] Term "C" 1-10 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, preferably a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The alkyl group includes C... 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Alkyl, C 1-10 Alkyl groups, etc. "C" 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0030] Term "C" 3-10 "Cycloalkyl" refers to a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spirocyclic) hydrocarbon ring or tricyclic alkane, preferably having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group includes C... 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, C 3-10 Cycloalkyl groups, etc. The C... 3-10Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0031] The term "3-10 membered heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system (preferably 3-8 membered heterocyclic group) containing 1-5 heteroatoms independently selected from N, O, and S, with monovalent or polyvalent rings of 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. For example, a 3-8 membered heterocyclic group can be a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system containing 3, 4, 5, 6, 7, or 8 ring atoms, wherein the 3-8 membered heterocyclic group contains 1-5 heteroatoms independently selected from N, O, and S. The bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic rings, or bridged rings. The 3-10 membered heterocyclic group includes 3-8 membered heterocyclic groups and 5-6 membered heterocyclic groups. The 3-10 membered heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The 3-10 membered heterocyclic groups may include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic groups may include, but are not limited to: 3-membered rings, such as azirropropyl or oxacyclopropyl; 4-membered rings, such as azirrobutyl or oxacyclobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl. Alternatively, it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclic group is linked to other groups to form the compounds of this disclosure, the carbon atom on the 3-10 membered heterocyclic group can be linked to other groups, or a heterocyclic atom (such as a nitrogen atom) on the ring of the 3-10 membered heterocyclic group can be linked to other groups. For example, when the 3-10 membered heterocyclic group is selected from piperazineyl or tetrahydropyrroleyl, the nitrogen atom or carbon atom on the piperazineyl group can be linked to other groups. Alternatively, when the 3-10 membered heterocyclic group is selected from piperidinyl, it can be the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta or para position connected to other groups.

[0032] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0033] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0034] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0035] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0036] "Halogenation" refers to the substitution of a substance by one or more halogens.

[0037] Unless otherwise stated, the definitions of terms in this document also apply to groups that contain the term; for example, the definition of alkyl also applies to the definition of alkyl-containing groups such as alkoxy (i.e., alkyloxy).

[0038] Unless otherwise stated, the term "compound" in the context of this disclosure shall be understood to include the compound itself and its tautomers, stereoisomers, solvates or isotopic labels.

[0039] Crystallization often produces solvates of the compounds disclosed herein. As used herein, a solvate is a combination of one or more molecules of the compounds disclosed and one or more solvent molecules.

[0040] The solvent can be water, in which case the solvate is a hydrate; alternatively, it can be an organic solvate.

[0041] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it does not have a lasting harmful effect on the overall health of the subject of treatment.

[0042] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds disclosed herein and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition.

[0043] Those skilled in the art will understand that the compounds of this disclosure can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0044] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0045] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0046] In this application, "pharmaceutical composition" refers to a formulation of the disclosed compound and a medium generally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0047] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0048] In this application, the term "prodrug" refers to a compound of this disclosure that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of this disclosure are prepared by modifying functional groups in the compound; such modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group in the compound of this disclosure. When a prodrug of the compound of this disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0049] "Isotope" refers to all isotopes of atoms appearing in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds disclosed herein are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 31 P, 32 P, 35 S, 18 F and 36 C1. The isotopically labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically labeled reagents instead of non-isotopically labeled preparations. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0050] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0051] (i) To prevent the occurrence of diseases or conditions in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0052] (ii) To suppress a disease or symptom, that is, to curb its development;

[0053] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0054] (iv) To alleviate the symptoms caused by the disease or condition.

[0055] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0056] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms).

[0057] The term "AHR nuclear positivity" refers to a certain percentage of cells in a sample (such as a tumor sample) having a detectable amount of AHR in the cell nucleus. In some implementations, AHR nuclear positivity means that approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or 100% of the cells in the sample have a detectable amount of AHR in the cell nucleus.

[0058] The term "AHR gene amplification" refers to a certain percentage of cells in a sample (such as a tumor sample) having a detectable amount of AHR gene amplification. In some embodiments, AHR gene amplification refers to approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or 100% of the cells (such as tumor cells) in the sample having at least approximately 3 copies, at least approximately 4 copies, or at least approximately 5 copies of AHR. At least approximately 6 AHR copies, at least approximately 7 AHR copies, at least approximately 8 AHR copies, at least approximately 9 AHR copies, at least approximately 10 AHR copies, at least approximately 11 AHR copies, at least approximately 12 AHR copies, at least approximately 9 AHR copies, at least approximately 10 AHR copies, at least approximately 11 AHR copies, at least approximately 12 AHR copies, at least approximately 13 AHR copies, at least approximately 14 AHR copies, at least approximately 15 AHR copies, at least approximately 20 AHR copies or more.

[0059] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0060] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0061] The liquid chromatography-mass spectrometry (LC-MS) system used was a Waters 2695+ZQ2000, a Shimadzu MS-2020+LC-20AB, and a Shimadzu LC-40D XR+MS-2020. High-performance liquid chromatography (HPLC) analysis used a Shimadzu LC-20AB, Shimadzu LC-20ADXR, and Shimadzu LC-40D XR HPLC system. Preparative HPLC analysis used a Shimadzu LC-20AP and a Gilson GX-281 preparative chromatograph. A CombiFlash rapid preparation system was used (CH-200P, Agela & Phenomenex). Thin-layer chromatography (TLC) used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC had a diameter of 0.15 mm to 0.2 mm, and the plates used for TLC separation and purification had a diameter of 0.4 mm to 0.5 mm. Silica gel column chromatography typically uses 200-300 mesh silica gel from Yantai Huanghai as the support. The average inhibition rate of kinases and IC50 were also discussed. 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0062] The known starting materials disclosed herein can be synthesized using methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. (Shanghai), and Darui Chemicals. Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere refers to a reaction flask connected to an approximately 1L volume argon or nitrogen balloon. A hydrogen atmosphere refers to a reaction flask connected to an approximately 1L volume hydrogen balloon. Pressurized hydrogenation reactions are performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator. The hydrogenation reaction is typically performed under vacuum, followed by hydrogen filling, and repeated three times. Microwave reactions are performed using a CEM Discover-S 908860 microwave reactor.

[0063] Unless otherwise specified in the examples, "solution" refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature, between 20°C and 30°C. The reaction progress in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used for the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: petroleum ether / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0064] In some embodiments, the compound is purified using preparative HPLC.

[0065] Example 1

[0066] 3-(1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0067]

[0068] first step

[0069] N-methylquinoline iodide 1b

[0070] Compound 1a (2.58 g, 20 mmol) and iodomethane (8.52 g, 60 mmol) were added to acetonitrile (40 mL), and the mixture was heated to 80 °C and stirred for 16 h. The reaction solution was cooled to room temperature and concentrated to give compound 1b.

[0071] Step 2

[0072] 3-Iodo-1-methyl-1,2-dihydroquinoline-2-one 1c

[0073] Compound 1b (4.8 g, 18 mmol) was dissolved in a mixture of dichloroethane (40 mL) and water (10 mL). Potassium acetate (4.41 g, 45 mmol), acetic acid (4.32 g, 72 mmol), and sodium periodate (11.56 g, 54 mmol) were then added. The mixture was heated to 80 °C and stirred for 16 h. The reaction solution was cooled to room temperature and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 1c.

[0074] Step 3

[0075] 3-(1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0076] Compound 1c (143 mg, 0.5 mmol) and indole-2-borate pinacol ester (121 mg, 0.5 mmol) were dissolved in dioxane (4 mL) and water (2 mL), and the mixture was purged with nitrogen three times. Potassium carbonate (207 mg, 1.5 mmol) and (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride (36 mg, 50 μmol) were then added, and the mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 1.

[0077] LCMS (ESI, m / z): 275.13 [M+H] + .

[0078] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.57 (s, 1H), 8.55 (s, 1H), 7.81-7.78 (m, 1H), 7.68-7.50 (m, 4H), 7.37-7.32 (m, 2H), 7.14-7.10 (m, 1H), 7.03-6.98 (m, 1H), 3.78 (s, 3H).

[0079] Example 2

[0080] 3-(6-methoxy-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0081]

[0082]

[0083] first step

[0084] 3-(1-tert-Butoxycarbonyl-6-methoxy-indol-2-yl)-1-methyl-1,2-dihydroquinoline-2-one 2a

[0085] Compound 2a was prepared from compound 1c and 1-tert-butoxycarbonyl-6-methoxyindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0086] Step 2

[0087] 3-(6-methoxy-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0088] Compound 2a (167 mg, 0.41 mmol) was dissolved in HCl / ethyl acetate (4 mL, 4 M) and stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 2.

[0089] LCMS (ESI, m / z): 305.35 [M+H] + .

[0090] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.41 (s, 1H), 8.45 (s, 1H), 7.78-7.75 (m, 1H), 7.65-7.57 (m, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.36-7.28 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H).

[0091] Example 3

[0092] 3-(5-methoxy-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0093]

[0094]

[0095] first step

[0096] 3-(1-tert-Butoxycarbonyl-5-methoxy-indol-2-yl)-1-methyl-1,2-dihydroquinoline-2-one 3a

[0097] Compound 3a was prepared from compound 1c and 1-tert-butoxycarbonyl-5-methoxyindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0098] Step 2

[0099] 3-(5-methoxy-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0100] Compound 3 was prepared from compound 3a by referring to the synthesis method in step 2 of Example 2.

[0101] LCMS (ESI, m / z): 305.28 [M+H] + .

[0102] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.44 (s, 1H), 8.51 (s, 1H), 7.81-7.78 (m, 1H), 7.67-7.58 (m, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.8 Hz, 2.4Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H).

[0103] Example 4

[0104] 3-(5-cyano-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 4

[0105]

[0106]

[0107] first step

[0108] 3-(1-tert-Butoxycarbonyl-5-cyano-indol-2-yl)-1-methyl-1,2-dihydroquinoline-2-one 4a

[0109] Compound 4a was prepared from compound 1c and 1-tert-butoxycarbonyl-5-cyanoindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0110] Step 2

[0111] 3-(5-cyano-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 4

[0112] Compound 4 was prepared from compound 4a by referring to the synthesis method in step 2 of Example 2.

[0113] LCMS (ESI, m / z): 300.33 [M+H] + .

[0114] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.14 (s, 1H), 8.64 (s, 1H), 8.13(s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.71-7.61 (m, 3H), 7.47-7.44 (m, 2H), 7.37(t, J = 7.2 Hz, 1H), 3.79 (s, 3H).

[0115] Example 5

[0116] 6-Fluoro-3-(1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 7

[0117]

[0118]

[0119] first step

[0120] 6-Fluoro-N-methylquinoline iodide 7b

[0121] Compound 7b was prepared from compound 7a by referring to the synthesis method in the first step of Example 1.

[0122] Step 2

[0123] 6-Fluoro-3-iodo-1-methyl-1,2-dihydroquinoline-2-one 7c

[0124] Compound 7c was prepared from compound 7b by referring to the synthesis method in step 2 of Example 1.

[0125] Step 3

[0126] 6-Fluoro-3-(1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 7

[0127] Compound 7 was prepared from compound 7c and indole-2-boronic acid pinacol ester, following the synthesis method in step 3 of Example 1.

[0128] LCMS (ESI, m / z): 293.35 [M+H] + .

[0129] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.59 (s, 1H), 8.51 (s, 1H), 7.67-7.50 (m, 5H), 7.34-7.31 (m, 1H), 7.15-7.10 (m, 1H), 7.04-6.98 (m, 1H), 3.78(s, 3H).

[0130] 19 F NMR (400 MHz, DMSO-d6, ppm): δ -121.17 (s, 1F).

[0131] Example 6

[0132] 3-(6-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0133]

[0134]

[0135] first step

[0136] 3-(1-tert-Butoxycarbonyl-6-fluoro-indole-2-yl)-1-methyl-1,2-dihydroquinoline-2-one 8a

[0137] Compound 8a was prepared from compound 1c and 1-tert-butoxycarbonyl-6-fluoroindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0138] Step 2

[0139] 3-(6-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one

[0140] Compound 8 was prepared from compound 8a by referring to the synthesis method in step 2 of Example 2.

[0141] LCMS (ESI, m / z): 293.28 [M+H] + .

[0142] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.71 (s, 1H), 8.55 (s, 1H), 7.82-7.79 (m, 1H), 7.69-7.56 (m, 3H), 7.38-7.29 (m, 3H), 6.91-6.85 (m, 1H), 3.79(s, 3H).

[0143] 19 F NMR (400 MHz, DMSO-d6, ppm): δ -120.41 (s, 1F).

[0144] Example 7

[0145] 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 9

[0146]

[0147]

[0148] first step

[0149] 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 9

[0150] Compound 9 was prepared from compound 1c and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrrolo[2,3-b]pyridine, following the synthetic method in step 3 of Example 1.

[0151] LCMS (ESI, m / z): 276.16 [M+H] + .

[0152] 1H NMR (400 MHz, DMSO-d6, ppm): δ 11.96 (s, 1H), 8.67 (s, 1H), 8.26 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.02-7.99 (m, 1H), 7.78-7.75 (m, 1H), 7.70-7.60(m, 2H), 7.50 (d, J = 2.0 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.11-7.07 (m,1H), 3.78 (s, 3H).

[0153] Example 8

[0154] 3-(6-cyano-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 10

[0155]

[0156]

[0157] first step

[0158] 3-(1-tert-Butoxycarbonyl-6-cyano-indole-2-yl)-1-methyl-1,2-dihydroquinoline-2-one 10a

[0159] Compound 10a was prepared from compound 1c and 1-tert-butoxycarbonyl-6-cyanoindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0160] Step 2

[0161] 3-(6-cyano-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 10

[0162] Compound 10 was prepared from compound 10a by referring to the synthesis method in step 2 of Example 2.

[0163] LCMS (ESI, m / z): 300.37 [M+H] + .

[0164] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.15 (s, 1H), 8.68 (s, 1H), 8.02(s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.76-7.60 (m, 3H), 7.42-7.33 (m, 3H), 3.79(s, 3H).

[0165] Example 9

[0166] 3-(5-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 11

[0167]

[0168]

[0169] first step

[0170] 3-(1-tert-Butoxycarbonyl-5-fluoro-indole-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 11a

[0171] Compound 11a was prepared from compound 1c and 1-tert-butoxycarbonyl-5-fluoroindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0172] Step 2

[0173] 3-(5-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 11

[0174] Compound 11 was prepared from compound 11a by referring to the synthesis method in the second step of Example 2.

[0175] LCMS (ESI, m / z): 293.22 [M+H] + .

[0176] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.71 (s, 1H), 8.58 (s, 1H), 7.83-7.79 (m, 1H), 7.70-7.51 (m, 3H), 7.38-7.31 (m, 3H), 6.99-6.94 (m, 1H), 3.79(s, 3H).

[0177] 19 F NMR (400 MHz, DMSO-d6, ppm): δ -124.64 (s, 1F).

[0178] Example 10

[0179] 3-(1H-benzo[d]imidazol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 12

[0180]

[0181]

[0182] first step

[0183] 2-O-O-1H-quinoline-3-formaldehyde 12b

[0184] Compound 12a (3.82 g, 20 mmol) was added to an aqueous hydrochloric acid solution (50 mL, 4 M), and the mixture was heated to 100 °C and stirred for 4 h. The reaction solution was cooled to room temperature, filtered, and dried to obtain compound 12b.

[0185] Step 2

[0186] 1-Methyl-2-oxomylidenequinoline-3-carboxaldehyde 12c

[0187] Compound 12b (3.3 g, 19 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of potassium carbonate (5.2 g, 38 mmol) and methyl iodoforme (5.4 g, 38 mmol). The mixture was heated to 60 °C and stirred for 16 h. The reaction solution was cooled to room temperature, added to water (200 mL), filtered, and dried to obtain compound 12c.

[0188] Step 3

[0189] 3-(1H-benzo[d]imidazol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 12

[0190] Compound 12c (374 mg, 2 mmol) was added to water (15 mL), followed by the addition of o-phenylenediamine (216 mg, 2 mmol) and sodium bisulfite (2.3 g, 22 mmol). The mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and filtered. The residue was purified by silica gel column chromatography to obtain compound 12.

[0191] LCMS (ESI, m / z): 276.05 [M+H] + .

[0192] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.72 (s, 1H), 9.14 (s, 1H), 8.06-8.04 (m, 1H), 7.78-7.65 (m, 4H), 7.40 (t, J = 7.2 Hz, 1H), 7.25-7.19 (m, 2H),3.85 (s, 3H).

[0193] Example 11

[0194] 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 13

[0195]

[0196]

[0197] first step

[0198] 3-[4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[2,3-d]pyrimidin-6-yl]-1-methyl-1,2-dihydroquinolin-2-one 13a

[0199] Compound 13a was prepared from compound 1c and 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, following the synthetic method in step 3 of Example 1.

[0200] Step 2

[0201] 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 13

[0202] Compound 13a (110 mg, 0.25 mmol) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) and stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 13.

[0203] LCMS (ESI, m / z): 311.21 [M+H] + .

[0204] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.85 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 7.79-7.68 (m, 2H), 7.64-7.60 (m, 1H), 7.55 (s, 1H), 7.37 (t, J = 7.2Hz, 1H), 3.77 (s, 3H).

[0205] Example 12

[0206] 3-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 14

[0207]

[0208]

[0209] first step

[0210] 3-[7-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[2,3-d]pyrimidin-6-yl]-1-methyl-1,2-dihydroquinolin-2-one 14a

[0211] Compound 13a (220 mg, 0.5 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), followed by the addition of ammonium formate (315 mg, 5 mmol) and Pd / C (220 mg). The mixture was heated to reflux and stirred for 4 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with dichloromethane (50 mL) and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 14a.

[0212] Step 2

[0213] 3-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 14

[0214] Compound 14 was prepared from compound 14a according to the synthesis method in step 2 of Example 13.

[0215] LCMS (ESI, m / z): 277.21[M+H] + .

[0216] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.43 (s, 1H), 9.03 (s, 1H), 8.78(s, 1H), 8.67 (s, 1H), 7.78-7.74 (m, 1H), 7.72-7.67 (m, 1H), 7.63-7.58 (m,2H), 7.39-7.34 (m, 1H), 3.77 (s, 3H).

[0217] Example 13

[0218] 3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 15

[0219]

[0220]

[0221] first step

[0222] 3-[4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[2,3-d]pyrimidin-6-yl]-1-methyl-1,2-dihydroquinolin-2-one 15a

[0223] Compound 13a (220 mg, 0.5 mmol) was dissolved in methanol (3 mL) and dimethyl sulfoxide (3 mL), and sodium methoxide (54 mg, 1 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15a.

[0224] Step 2

[0225] 3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 15

[0226] Compound 15 was prepared from compound 15a according to the synthesis method in step 2 of Example 13.

[0227] LCMS (ESI, m / z): 306.97 [M+H] + .

[0228] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.34 (s, 1H), 8.60 (s, 1H), 8.42(s, 1H), 7.74-7.57 (m, 3H), 7.47 (s, 1H), 7.34 (t, J = 7.2 Hz, 1H), 4.07 (s,3H), 3.74 (s,3H).

[0229] Example 14

[0230] 3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 16

[0231]

[0232]

[0233] first step

[0234] 3-(4-{[(2,4-dimethoxyphenyl)methyl]amino}-7-(5,5-dimethyl-2-oxa-5-silazhex-1-yl)pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 16a

[0235] Compound 13a (110 mg, 0.25 mmol) was dissolved in dimethyl sulfoxide (5 mL), and (2,4-dimethoxyphenyl)methylamine (84 mg, 0.5 mmol) was added. The mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 16a.

[0236] Step 2

[0237] 3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one 16

[0238] Compound 16 was prepared from compound 16a according to the synthesis method in step 2 of Example 13.

[0239] LCMS (ESI, m / z): 292.2 [M+H] + .

[0240] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.84 (s, 1H), 8.47 (s, 1H), 8.06 (s, 1H), 7.72-7.56 (m, 4H), 7.35-7.31 (m, 1H), 7.07 (br s, 2H), 3.76 (s, 3H).

[0241] Example 15

[0242] 3-(4-fluoro-1H-benzo[d]imidazol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 17

[0243]

[0244]

[0245] first step

[0246] 3-(4-fluoro-1H-benzo[d]imidazol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 17

[0247] Compound 17 was prepared from compound 12c and 3-fluorobenzene-1,2-diamine using the synthesis method described in step 3 of Example 12.

[0248] LCMS (ESI, m / z): 295.0 [M+H] + .

[0249] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.96 (s, 1H), 9.17 (s, 1H), 8.10-8.07 (m, 1H), 7.78-7.66 (m, 2H), 7.57-7.54 (m, 1H), 7.42-7.37 (m, 1H), 7.21-7.15 (m, 1H), 7.04-6.98 (m, 1H), 3.84 (s, 3H).

[0250] 19 F NMR (400 MHz, DMSO-d6, ppm): δ -129.42 (1F).

[0251] Example 16

[0252] 3-(5-fluoro-1H-benzo[d]imidazol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 18

[0253]

[0254]

[0255] first step

[0256] 3-(5-fluoro-1H-benzo[d]imidazol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 18

[0257] Compound 18 was prepared from compound 12c and 4-fluorobenzene-1,2-diamine using the synthesis method described in step 3 of Example 12.

[0258] LCMS (ESI, m / z): 294.9 [M+H] + .

[0259] 1H NMR (400 MHz, DMSO-d6, ppm): δ 12.83-12.79 (m, 1H), 9.12-9.08 (m,1H), 8.05-8.01 (m, 1H), 7.78-7.63 (m, 3H), 7.49-7.37 (m, 2H), 7.10-7.04 (m,1H), 3.83 (s, 3H).

[0260] 19 F NMR (400 MHz, DMSO-d6, ppm): δ -119.70 (0.5F), -121.09 (0.5F).

[0261] Example 17

[0262] 3-(1H-indol-2-yl)-1-cyclopropyl-1,2-dihydroquinolin-2-one 19

[0263]

[0264]

[0265] first step

[0266] 1-Cyclopropyl-1,2-Dihydroquinoline-2-one 19b

[0267] Compound 19a (1 g, 6.89 mmol), 1,10-phenanthroline (155.18 mg, 0.86 mmol), potassium carbonate (1.90 g, 13.78 mmol), copper acetate (312.82 mg, 1.72 mmol), and potassium cyclopropyltrifluoroborate (3.06 g, 20.67 mmol) were dissolved in toluene (30 mL) and water (9 mL). The mixture was purged three times with oxygen and heated to 80 °C with stirring for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 19b.

[0268] Step 2

[0269] 3-Bromo-1-cyclopropyl-1,2-dihydroquinolin-2-one 19c

[0270] Compound 19b (1.0 g, 5.40 mmol) and N-bromosuccinimide (1.15 g, 6.48 mmol) were dissolved in N,N-dimethylformamide (10 mL), purged with nitrogen three times, and stirred at room temperature for 16 h. The solution was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 19c.

[0271] Step 3

[0272] 3-(1H-indol-2-yl)-1-cyclopropyl-1,2-dihydroquinolin-2-one 19

[0273] Compound 19 was prepared from compound 19c and indole-2-boronic acid pinacol ester, following the synthesis method in step 3 of Example 1.

[0274] LCMS (ESI, m / z): 301.1 [M+H] + .

[0275] 1 H NMR (400 MHz, CDCl3, ppm): δ 11.27 (s, 1H), 8.29 (s, 1H), 7.92 (d,J = 8.4 Hz, 1H), 7.69-7.65 (m, 2H), 7.61-7.54 (m, 1H), 7.47-7.44 (m, 1H),7.33-7.27 (m, 1H), 7.24-7.19 (m, 1H), 7.16-7.11 (m, 1H), 7.03-7.01 (m, 1H),3.16-3.10 (m, 1H), 1.52-1.42 (m, 2H), 1.05-0.96 (m, 2H).

[0276] Example 18

[0277] 3-(7-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 20

[0278]

[0279]

[0280] first step

[0281] 7-Fluoro-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indole 20b

[0282] Compound 20a (0.5 g, 3.70 mmol), 4,4-di-tert-butylbipyridine (19.86 mg, 74.00 µmol), methoxy(cyclooctadiene)iridium(I) dimer (24.53 mg, 37.00 µmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)-1,3,2-dioxaborhexacyclopentane (939.55 mg, 3.70 mmol) were dissolved in n-hexane (20 mL), purged with nitrogen three times, and stirred at room temperature for 16 h. The solution was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 20b.

[0283] Step 2

[0284] 3-(7-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 20

[0285] Compound 20 was prepared from compounds 1c and 20b using the synthesis method described in step 3 of Example 1.

[0286] LCMS (ESI, m / z): 293.0 [M+H] + .

[0287] 1 H NMR (400 MHz, CDCl3, ppm): δ 11.43 (s, 1H), 8.31 (s, 1H), 7.69 (d,J = 8.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.45-7.37 (m, 2H), 7.34-7.29 (m, 1H), 7.07-6.98 (m, 2H), 6.92-6.86 (m, 1H), 3.87 (s, 3H).

[0288] 19 F NMR (400 MHz, CDCl3, ppm): δ -134.18 (1F).

[0289] Example 19

[0290] 3-(4-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 21

[0291]

[0292]

[0293] first step

[0294] 3-(1-tert-Butoxycarbonyl-4-fluoro-indole-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 21a

[0295] Compound 21a was prepared from compound 1c and 1-tert-butoxycarbonyl-4-fluoroindole-2-boronic acid, following the synthetic method in step 3 of Example 1.

[0296] Step 2

[0297] 3-(4-fluoro-1H-indol-2-yl)-1-methyl-1,2-dihydroquinolin-2-one 21

[0298] Compound 21 was prepared from compound 21a by referring to the synthesis method in step 2 of Example 2.

[0299] LCMS (ESI, m / z): 293.1 [M+H] + .

[0300] 1 H NMR (400 MHz, CDCl3, ppm): δ 11.42 (s, 1H), 8.30 (s, 1H), 7.66 (d,J = 8.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.33-7.27 (m,1H), 7.20 (d, J = 8.0 Hz, 1H), 7.12-7.05 (m, 2H), 6.79-6.74 (m, 1H), 3.83 (s,3H).

[0301] 19 F NMR (400 MHz, CDCl3, ppm): δ -122.46 (1F).

[0302] Example 20

[0303] 3-(1H-indol-2-yl)-1-ethyl-1,2-dihydroquinolin-2-one 22

[0304]

[0305]

[0306] first step

[0307] 1-Ethyl-1,2-dihydroquinoline-2-one 22a

[0308] Compound 22a was prepared from compound 19a and iodoethane using the synthesis method described in step 2 of Example 12.

[0309] Step 2

[0310] 3-Bromo-1-ethyl-1,2-dihydroquinoline-2-one 22b

[0311] Compound 22b was prepared from compound 22a by referring to the synthesis method in step 2 of Example 19.

[0312] Step 3

[0313] 3-(1H-indol-2-yl)-1-ethyl-1,2-dihydroquinolin-2-one 22

[0314] Compound 22 was prepared from compound 22b and indole-2-boronic acid pinacol ester, following the synthesis method in step 3 of Example 1.

[0315] LCMS (ESI, m / z): 289.1 [M+H] + .

[0316] 1 H NMR (400 MHz, CDCl3, ppm): δ 11.32 (s, 1H), 8.27 (s, 1H), 7.67-7.64(m, 2H), 7.59-7.54 (m, 1H), 7.45-7.39 (m, 2H), 7.31-7.28 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.03 (s, 1H), 4.46 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H).

[0317] Example 21

[0318] 3-(1H-indol-2-yl)-7-fluoro-1-methyl-1,2-dihydroquinolin-2-one 24

[0319]

[0320]

[0321] first step

[0322] N-(3-Fluorophenyl)-3,3-dimethoxypropionamide 24b

[0323] 24a (2 g, 18.00 mmol) was dissolved in tetrahydrofuran (50 mL), purged three times with nitrogen, and cooled to 0 °C. Methyl 3,3-dimethoxypropionate (3.20 g, 21.60 mmol) was then added. Sodium hexamethyldisilamide (27 mL, 27 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 6 h. After cooling to 0 °C, an aqueous solution of citric acid (60 mL, 20 wt%) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 24b.

[0324] Step 2

[0325] 7-Fluoro-1,2-Dihydroquinoline-2-one 24c

[0326] Under ice bath conditions, concentrated sulfuric acid (30 mL) was slowly added to water (13 mL), and the mixture was stirred for 0.5 h. Then, 24b (4 g, 14.96 mmol) was added, and the mixture was brought to room temperature and stirred for 4 h. The reaction mixture was poured into ice water (150 mL), stirred for 0.5 h, and then extracted with ethyl acetate (100 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and slurried with methanol (30 mL) to give compound 24c.

[0327] Step 3

[0328] 7-Fluoro-1-methyl-1,2-dihydroquinolin-2-one 24d

[0329] Compound 24d was prepared from compound 24c and iodoethane using the synthesis method described in step 2 of Example 12.

[0330] Step 4

[0331] 3-Bromo-7-fluoro-1-methyl-1,2-dihydroquinolin-2-one 24e

[0332] Compound 24e was prepared from compound 24d using the synthesis method described in step 2 of Example 19.

[0333] Step 5

[0334] 3-(1H-indol-2-yl)-7-fluoro-1-methyl-1,2-dihydroquinolin-2-one 24

[0335] Compound 24 was prepared from compound 24e and indole-2-boronic acid pinacol ester according to the synthesis method in step 3 of Example 1.

[0336] LCMS (ESI, m / z): 293.0 [M+H] + .

[0337] 1 H NMR (400 MHz, CDCl3, ppm): δ 11.16 (s, 1H), 8.24 (s, 1H), 7.66-7.62(m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.22-7.17 (m, 1H), 7.13-6.99 (m, 4H), 3.78(s, 3H).

[0338] 19 F NMR (400 MHz, CDCl3, ppm): δ -106.52 (1F).

[0339] Example 22

[0340] 3-(1H-indol-2-yl)-1-trifluoroethyl-1,2-dihydroquinolin-2-one 25

[0341]

[0342]

[0343] first step

[0344] 1-Trifluoroethyl-1,2-dihydroquinoline-2-one 25a

[0345] Compound 25a was prepared from compound 19a and 2,2,2-trifluoroethyl methanesulfonate using the synthesis method described in step 2 of Example 12.

[0346] Step 2

[0347] 3-Bromo-1-trifluoroethyl-1,2-dihydroquinoline-2-one 25b

[0348] Compound 25b was prepared from compound 25a by referring to the synthesis method in step 2 of Example 19.

[0349] Step 3

[0350] 3-(1H-indol-2-yl)-1-trifluoroethyl-1,2-dihydroquinolin-2-one 25

[0351] Compound 25 was prepared from compound 25b and indole-2-boronic acid pinacol ester, following the synthesis method in step 3 of Example 1.

[0352] LCMS (ESI, m / z): 343.1 [M+H] + .

[0353] 1 H NMR (400 MHz, CDCl3, ppm): δ 11.00 (s, 1H), 8.31 (s, 1H), 7.70-7.57(m, 3H), 7.43-7.32 (m, 3H), 7.21 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.06-7.02 (m, 1H), 5.18-5.04 (m, 2H).

[0354] 19 F NMR (400 MHz, CDCl3, ppm): δ -67.18 (3F).

[0355] Example 23

[0356] 3-(1H-indol-2-yl)-1-methyl-1,2-dihydroquinoxalin-2-one 26

[0357]

[0358]

[0359] first step

[0360] 3-Bromo-1-methyl-1,2-dihydroquinoxalin-2-one 26b

[0361] Compound 26a (880 mg, 5 mmol) was dissolved in dichloroethane (20 mL), and phosphorus tribromooxyphosphate (2.87 g, 10 mmol) was added. The mixture was heated to reflux and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (100 mL), and washed with saturated sodium bicarbonate aqueous solution (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 26b.

[0362] Step 2

[0363] 3-(1H-indol-2-yl)-1-methyl-1,2-dihydroquinoxalin-2-one 26

[0364] Compound 26 was prepared from compound 26b and indole-2-boronic acid pinacol ester, following the synthesis method in step 3 of Example 1.

[0365] LCMS (ESI, m / z): 276.2 [M+H] + .

[0366] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.66 (s, 1H), 7.93-7.88 (m, 2H), 7.70-7.62 (m, 3H), 7.58-7.55 (m, 1H), 7.49-7.44 (m, 1H), 7.25-7.20 (m, 1H),7.07-7.02 (m, 1H), 3.76 (s, 3H).

[0367] Example 24

[0368] 6-(1H-indol-2-yl)-4-azatricyclic [6.3.1.0] 4,12 [11),6,8(12),9-Tetraen-5-one 27]

[0369]

[0370]

[0371] first step

[0372] 1-(7-bromo-2,3-dihydro-1H-indol-1-yl)prop-2-en-1-one 27b

[0373] Compound 27a (1 g, 5.05 mmol) and potassium carbonate (1.40 g, 10.10 mmol) were added to tetrahydrofuran (20 mL), cooled to room temperature, and acryloyl chloride (502.67 mg, 5.55 mmol) was added. The mixture was stirred for 1 h. The solution was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 27b.

[0374] Step 2

[0375] 1-Azatricyclic [6.3.1.0] 4,12 [12-12-tetraen-11-one 27c]

[0376] Compound 27b (1.1 g, 4.36 mmol), triethylamine (883.03 mg, 8.73 mmol), triphenylphosphine (228.88 mg, 872.65 μmol), and palladium acetate (97.96 mg, 436.32 μmol) were added to acetonitrile (10 mL), purged with nitrogen three times, and heated to 80 °C with stirring for 16 h. The system was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 27c.

[0377] Step 3

[0378] 10-Chloro-1-azatricyclic [6.3.1.0] 4,12 [27d] Dodeca-4(12),5,7,9-tetraen-11-one

[0379] Compound 27c (320 mg, 1.87 mmol) and N-chlorosuccinimide (374.40 mg, 2.80 mmol) were dissolved in acetonitrile (10 mL), purged with nitrogen three times, and heated to 50 °C with stirring for 1 h. The system was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 27d.

[0380] Step 4

[0381] 6-(1H-indol-2-yl)-4-azatricyclic [6.3.1.0] 4,12 [11),6,8(12),9-Tetraen-5-one 27]

[0382] Compound 27 was prepared from compound 27d and indole-2-boronic acid pinacol ester according to the synthesis method in step 3 of Example 1.

[0383] LCMS (ESI, m / z): 287.2 [M+H] + .

[0384] 1H NMR (400 MHz, DMSO-d6, ppm): δ 11.60 (s, 1H), 8.53 (s, 1H), 7.59-7.53 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 6.8 Hz, 1H), 7.39-7.34(m, 1H), 7.26-7.21 (m, 1H), 7.14-7.10 (m, 1H), 7.03-6.99 (m, 1H), 4.47 (t, J= 8.0 Hz, 2H), 3.44 (t, J= 8.0 Hz, 2H).

[0385] Example 25

[0386] 3-(1H-indol-2-yl)-1-methyl-1,2-dihydropyrido[3,2-b]pyridin-2-one 28

[0387]

[0388]

[0389] first step

[0390] 1-Methyl-1,2-dihydropyrido[3,2-b]pyridin-2-one 28b

[0391] Compound 28b was prepared from compound 28a and iodomethane using the synthesis method described in step 2 of Example 12.

[0392] Step 2

[0393] 3-Bromo-1-methyl-1,2-dihydropyrido[3,2-b]pyridin-2-one 28c

[0394] Compound 28c was prepared from compound 28b by referring to the synthesis method in step 2 of Example 19.

[0395] Step 3

[0396] 3-(1H-indol-2-yl)-1-methyl-1,2-dihydropyrido[3,2-b]pyridin-2-one 28

[0397] Compound 28 was prepared from compound 28c and indole-2-boronic acid pinacol ester, following the synthesis method in step 3 of Example 1.

[0398] LCMS (ESI, m / z): 276.1 [M+H] + .

[0399] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.68 (s, 1H), 8.61 (dd, J = 4.4 Hz,1.2 Hz, 1H), 8.58 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.65-7.56 (m, 3H), 7.51(d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 3.78(s, 3H).

[0400] Biological evaluation

[0401] Test Example 1: Luciferase Reporter Gene Assay Experiment

[0402] 1) Test cells

[0403] HepG2-Lucia, a human liver cancer cell line expressing AhR and luciferase, was purchased from InvivoGen (catalog number hpgl-ahr).

[0404] 2) Main instruments

[0405] Biosafety cabinet, model 307, ThermoFisher;

[0406] CO2 incubator, model CLM-240B-8-CN, ESCO;

[0407] Cell counter, model EVE-MC2, NanoEnTeK Corporation;

[0408] ECHO (Nano-Level Acoustic Plugging System), Model 655, LabCyte Corporation;

[0409] Microplate centrifuge, model PlatePro 3200, Monad Corporation;

[0410] Multifunctional microplate reader, model PHERAstar FSX, BMG LRBTECH.

[0411] 3) Main reagents

[0412] Penicillin-streptomycin, Gibco, catalog number 15140-122;

[0413] EMEM culture medium, ATCC, catalog number 30-2003;

[0414] Fetal bovine serum, Ausgenex, catalog number FBS500-S;

[0415] NEAA medium, Gibco, catalog number 11140-050;

[0416] Phosphate buffer, Gibco, catalog number 14190250;

[0417] DMSO (dimethyl sulfoxide), Solarbio, product number D8371;

[0418] FICZ (6-formylindolo[3,2-B]carbazole), MCE Corporation, catalog number HY-12451;

[0419] Zeocin (bleomycin), InvivoGen, catalog number ant-zn-1;

[0420] QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0421] 4) Experimental Procedure

[0422] a. HepG2-Lucia AhR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1×NEAA, penicillin, streptomycin, and 100 µg / ml zeocin. The culture temperature was 37℃ and the carbon dioxide concentration was 5%.

[0423] b. Once cells have grown to approximately 80% confluence, digest the cells, centrifuge, resuspend, and count them. Seed the cells into 384-well plates, 40 μL per well;

[0424] c. Add different concentrations of the analyte compound using ECHO, 40 nL per well;

[0425] d. Continue to incubate the 384-well plate containing the compound in an incubator for 24 hours;

[0426] e. Take the supernatant, add QUANTI-Luc Gold detection reagent, and read the luminescence signal value using a multi-functional microplate reader.

[0427] 5) Test Results

[0428] The disclosed compound exhibits EC activity against AhR protein. 50 The data is summarized in Table 1 below.

[0429] Table 1. EC5 activation of AhR by the compounds disclosed herein. 50

[0430]

[0431] Conclusion: The above results indicate that the compound disclosed herein has good activating activity against AhR protein.

[0432] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. A heterocyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, Its structural formula is shown below: Among them, X1, X2, and X3 are implemented as CH or groups in which the H atom of CH is replaced by halogen X; X5 is implemented as N; X6, X7, X8, X9, X 10 X 11 It is implemented as CH or a group in which the H element in CH is replaced by any one of halogen, CN, CH3O-, or NH2.

2. The heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Its structure is as follows: 。 3. A pharmaceutical composition, characterized in that, The composition comprises the compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

4. The use of the heterocyclic compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 3, in the preparation of a medicament for treating AhR-mediated conditions.

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