WO2023088435A1 - Préparation pour dérivé de pyridine trisubstituée et application en tant que modulateur de récepteur d'hydrocarbures aromatiques - Google Patents

Préparation pour dérivé de pyridine trisubstituée et application en tant que modulateur de récepteur d'hydrocarbures aromatiques Download PDF

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WO2023088435A1
WO2023088435A1 PCT/CN2022/132910 CN2022132910W WO2023088435A1 WO 2023088435 A1 WO2023088435 A1 WO 2023088435A1 CN 2022132910 W CN2022132910 W CN 2022132910W WO 2023088435 A1 WO2023088435 A1 WO 2023088435A1
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compound
membered
alkyl
atoms
independently selected
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Chinese (zh)
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黄奇
殷利科
聂运凤
李应飞
王长立
吴孝全
谢佳雨
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成都奥睿药业有限公司
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the disclosure relates to the field of medicine, in particular to a trisubstituted pyridine derivative with AhR activation function, its use and preparation method.
  • the aryl hydrocarbon receptor is a ligand-activated transcription factor, which is a basic helix-loop-helix (basic helix-loop-helix/Per-ARNT-Sim, bHLH-PAS) transcription factor
  • AhR exists widely in organisms, and AhR protein is contained in the bodies of mammals, amphibians, reptiles and birds. AhR is expressed in a variety of cells in the human body. It not only plays an important role in the regulation of blood vessel development and nerve function, but also plays an important role in regulating the occurrence of various diseases such as autoimmune disorders and tumors. It has become the focus of drug research and development. target.
  • the functional domain of AhR protein consists of three parts: bHLH domain, PAS domain and a glutamic acid-rich domain.
  • the bHLH domain is located at the N-terminus of the AhR protein, assisting AhR to bind to the promoter region of the target gene and protein dimerization;
  • the PAS domain binds to the AhR nuclear transport protein (AhR nuclear translocator, ARNT) and binds to the ligand.
  • Accessory proteins dimerize to form protein complexes;
  • the C-terminal region is a glutamate-rich domain that functions in recruitment and transcriptional activation.
  • AhR In its inactive form, AhR normally forms a multiprotein complex in the cytoplasm with heat shock protein 90 (Hsp90), p23, X-associated protein 2 (XAP2), and AhR-associated protein 9 (ARA9).
  • Hsp90 heat shock protein 90
  • XAP2 X-associated protein 2
  • ARA9 AhR-associated protein 9
  • the classic signaling pathway shows that when AhR binds to a ligand and is activated, its conformation changes, exposing the nuclear localization signal sequence, the receptor-ligand complex translocates to the nucleus, and forms heterodimerization with ARNT in the nucleus In the body, the AhR/ARNT complex binds to the heterologous biological response element (its core sequence: 5'-TNGCGTG-3') of the target gene promoter to initiate the expression of the target gene.
  • Hsp90 heat shock protein 90
  • XAP2 X-associated protein 2
  • ARA9 AhR-associated protein 9
  • Target genes include cytochrome P450 enzymes (CYP1A1, CYP1A2, CYP1B1), glutathione sulfhydryltransferase, guanosine diphosphate glucuronosyltransferase, NAD(P)H-dependent quinone oxidoreductase-1, Aldehyde dehydrogenase 3A1 and anti-breast cancer protein genes, etc.
  • cytochrome P450 enzymes CYP1A1, CYP1A2, CYP1B1
  • glutathione sulfhydryltransferase glutathione sulfhydryltransferase
  • guanosine diphosphate glucuronosyltransferase glutathione sulfhydryltransferase
  • guanosine diphosphate glucuronosyltransferase glutathione sulfhydryltransferas
  • AhR also exhibits different biological effects by binding to exogenous or endogenous ligands with different structural properties.
  • exogenous ligands are mainly composed of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), natural compounds and small molecules; endogenous ligands include tryptophan metabolites, heme metabolites, arachidonic acid metabolites, etc.
  • AhR can be activated by ligands, leading to an increase in the expression level of downstream CYP1A1 and other genes and an increase in the phase I or phase II exogenous substance metabolizing enzymes of the target gene expression products, which promotes the body's metabolism of exogenous toxicants, thereby protecting the body from exogenous substances.
  • Source substances such as the AhR receptor agonist MCDF (6-methyl 1,3,8-trichlorodiphenylfuran), can induce the expression of the target gene CYP1A1 and enhance its metabolism, thereby inhibiting estrogen receptor-negative mammary glands Proliferation of cancerous tumor cells.
  • AhR-ER and AhR-mitogen activated protein kinases which play a role in tumorigenesis.
  • DIM 3,3'-indolylmethane
  • AhR- ⁇ and the estrogen signaling pathway through an AhR-dependent pathway, reducing the risk of human breast cancer.
  • AhR has attracted much attention in the field of immunity, especially in the process of inflammation, AhR can promote the production of Treg cells with anti-inflammatory effects.
  • AhR agonists can induce Th0 cells to differentiate into Treg cells by activating AhR and alleviate experimental autoimmune encephalomyelitis.
  • Administration of the AhR agonist TCDD inhibited the progression of autoimmune disease or improved graft survival in mouse models by enhancing the proliferation of Treg cells.
  • the AhR agonist Benvimod has shown clear effects in the treatment of psoriasis and atopic dermatitis in animals and clinical applications.
  • AhR agonists such as Benvimod and Laquinimod can also enhance and regulate the immune function of Treg cells, and have the effect of treating arthritis, multiple sclerosis, and inflammatory bowel disease.
  • tryptophan metabolites can reduce neuroinflammation by activating the AhR pathway and have a therapeutic effect on neurodegenerative diseases such as Parkinson's.
  • AhR agonist-Z425228478 can inhibit the inflammatory response of bacterial keratitis by activating AhR.
  • AhR agonists are effective in psoriasis, arthritis, atopic dermatitis, Parkinson's, multiple sclerosis, inflammatory bowel disease, asthma, systemic lupus erythematosus, graft-versus-host disease, bacterial keratitis, tumors, etc.
  • the treatment and prevention of various diseases have potential application value.
  • the purpose of this disclosure is to provide the synthesis of a novel compound and its application in AhR (aromatic alkanes receptor) agonist drugs.
  • AhR aromatic alkanes receptor
  • the compound has high activity, good selectivity and low toxicity and side effects. advantage.
  • n is selected from 0, 1, 2 or 3;
  • Ring A is selected from 5-7 membered aryl, 5-7 membered monocyclic heteroaryl, 9-12 membered bicyclic heteroaryl, 5-7 membered heterocycloalkyl, 9-12 membered partially unsaturated bicyclic heterocyclyl;
  • R 1 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, the C 1-6 alkyl, C 1-6 alkenyl, C 3 -6 cycloalkyl is optionally substituted by one or more halogens;
  • L is -C(O)-
  • Ring B is selected from 5-7 membered aryl, 5-7 membered monocyclic heteroaryl, 9-12 membered bicyclic heteroaryl, 9-12 partially unsaturated bicyclic heterocyclyl, 8-12 membered saturated spirocyclic heteroaryl ring group;
  • N R 3 are the same or different from each other, wherein R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 acyl, halogen, cyano, Containing 1-2 5-7 membered heterocycloalkyl groups independently selected from N, O, and S atoms, the C 1-6 alkyl group, C 3-6 cycloalkyl group, and C 1-3 acyl group are optionally Substituted by one or more halogen, cyano.
  • R 4 , R 5 , and R 6 are each independently selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl.
  • the present disclosure relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
  • n is selected from 0, 1, 2 or 3;
  • Ring A is selected from 5-7 membered aryl, 5-7 membered monocyclic heteroaryl, 9-12 membered bicyclic heteroaryl, 5-7 membered heterocycloalkyl, 9-12 membered partially unsaturated bicyclic heterocyclyl;
  • ring A is selected from 5-7 membered aryl groups, 5-7 membered monocyclic heteroaryl groups containing 1-2 independently selected from N, O, and S atoms, containing 1-2 A 9-12-membered bicyclic heteroaryl group independently selected from N, O, and S atoms, a 5-7-membered heterocycloalkyl group containing 1-2 independently selected from N, O, and S atoms, and a 1- 3 9-12 membered partially unsaturated bicyclic heterocyclic groups independently selected from N, O, and S atoms;
  • ring A is selected from 5-7 membered aryl groups, 5-7 membered monocyclic heteroaryl groups containing 1-2 independently selected from N or O atoms, and 1-2 independently selected from N or O atoms.
  • ring A is selected from phenyl, pyrimidinyl, pyrazolyl, benzopyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazole Base, pyrrolopyridyl, isoindolinyl, pyridonyl, isoindolinone;
  • ring A is selected from phenyl, pyrimidyl, pyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazolyl, pyrrolopyridyl , isoindolinyl, pyridinone, isoindolinone;
  • ring A is selected from phenyl, pyrimidinyl, pyrazolyl, benzopyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazole Base, pyrrolopyridyl, pyridonyl, isoindolinone;
  • ring A is not benzimidazol-2-yl
  • ring A is selected from
  • ring A is selected from
  • ring A is selected from
  • ring A is selected from
  • m R 2 are the same or different from each other, wherein R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-6 Acyl, 5-7 membered heterocycloalkyl, said C 1-6 acyl, 5-7 membered heterocycloalkyl is optionally substituted by one or more C 1-3 alkyl, -NR 4 R 5 ;
  • R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-6 acyl, containing 1-2 independently selected from N, O atoms 5-7 membered heterocycloalkyl group, the C 1-6 acyl group, containing 1-2 5-7 membered heterocycloalkyl groups independently selected from N and O atoms, optionally replaced by one or more C 1- 3 alkyl, -NR 4 R 5 substituted;
  • R is selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 acyl, 5-7 membered heterocycles containing 1-2 N atoms Alkyl, the C 1-3 acyl, 5-7 membered heterocycloalkyl containing 1-2 N atoms are optionally substituted by one or more C 1-3 alkyl, -NR 4 R 5 ;
  • R is selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 acyl, 5-7 membered heterocycles containing 1-2 N atoms Alkyl, the C 1-3 carbonyl, 5-7 membered heterocycloalkyl containing 1-2 N atoms are optionally substituted by one or more methyl groups, -N(CH 3 ) 2 ;
  • R is selected from methyl, ethyl, propyl, isopropyl, cyclopropanyl, methoxy, formyl, acetyl, piperazinyl, piperidinyl, morpholinyl, said formyl , acetyl, piperazinyl, piperidinyl, morpholinyl are optionally substituted by one or more methyl groups, -N(CH 3 ) 2 ;
  • R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-6 acyl, -S(O) 2 R 6 , containing 1-2 5-7-membered heterocycloalkyl groups independently selected from N and O atoms, the C1-6 acyl group containing 1-2 5-7-membered heterocycles independently selected from N and O atoms
  • each R 6 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, more preferably methyl, propyl and cyclopropyl.
  • R 1 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, said C 1-6 alkyl, C 1 -6 alkenyl, C 3-6 cycloalkyl are optionally substituted by one or more halogens;
  • R 1 is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkenyl, C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkenyl , C 3-6 cycloalkyl is optionally substituted by one to three halogens;
  • R is selected from hydrogen, deuterium, fluorine, C 1-3 alkyl, C 1-3 alkenyl, said C 1-3 alkyl, C 1-3 alkenyl, C 3-6 cycloalkyl optionally substituted by one to three fluorines;
  • R is selected from fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, isopropyl, isopropenyl, cyclopropenyl;
  • R is selected from fluorine, methyl, isopropyl, isopropenyl, cyclopropenyl;
  • R 1 is methyl
  • L is -C(O)-
  • L is L is preferably
  • Ring B is selected from 5-7 membered aryl, 5-7 membered monocyclic heteroaryl, 9-12 membered bicyclic heteroaryl, 9-12 partially unsaturated bicyclic heterocyclic group, 8 -12 membered saturated spirocyclic heterocyclyl;
  • ring B is selected from 5-7 membered aryl groups, 5-7 membered monocyclic heteroaryl groups containing 1-2 independently selected from N, O, and S atoms, and 1-3 membered monocyclic heteroaryl groups independently selected from N , a 9-12-membered bicyclic heteroaryl group with O and S atoms, a 9-12-membered partially unsaturated bicyclic heteroaryl group containing 1-3 independently selected from N, O and S atoms, containing 1-3 independently 8-12 membered saturated spirocyclic heterocyclic groups selected from N, O, and S atoms;
  • ring B is selected from 5-7 membered aryl groups, 5-7 membered monocyclic heteroaryl groups containing 1-2 independently selected from N or O atoms, 1-3 independently selected from N or O atoms Atomic 9-12 membered bicyclic heteroaryl, 9-12 membered partially unsaturated bicyclic heterocyclic group containing 1-3 independently selected from N or O atoms, containing 1-3 independently selected from N or O atoms 8-12 membered saturated spirocyclic heterocyclic group;
  • ring B is selected from phenyl, pyridyl, pyrazolyl, benzodioxolanyl, azaspirooctyl, tetrahydroisoquinolyl;
  • the B ring is selected from
  • n R 3 are the same or different from each other, wherein R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 Acyl, halogen, cyano, 5-7 membered heterocycloalkyl containing 1-2 independently selected from N, O, and S atoms, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 acyl is optionally substituted by one or more halogen, cyano;
  • R is not simultaneously selected from alkoxy and heterocycloalkyl
  • R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 acyl, halogen, cyano, containing 1-2 independently selected from A 5-7-membered heterocycloalkyl group with N or O atoms, the C 1-6 alkyl group, and C 1-3 acyl group are optionally substituted by one to three fluorines, and the C 3-6 cycloalkyl group is optionally optionally substituted by one or more cyano groups;
  • R is selected from methyl, trifluoromethyl, methoxy, cyclopropyl, cyclohexyl, halogen, cyano,
  • R3 is selected from bromo, fluoro, chloro, cyano, trifluoromethyl, methyl.
  • the present disclosure relates to the above compounds or pharmaceutically acceptable salts thereof, including compounds represented by formula (II) or pharmaceutically acceptable salts thereof:
  • n, m, A, L, R 1 , R 2 , and R 3 are as defined above.
  • the present disclosure relates to the above compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):
  • X 4 , X 5 , and X 6 are selected from N, NH, or CH, and the definitions of n, m, R 1 , R 2 , and R 3 are as defined above.
  • the present disclosure relates to a method for the preparation of the above compound, the method comprising one of the following:
  • Step 1 Suzuki coupling reaction of compound 1A and compound 1A-1 to obtain compound 1B;
  • Step 2 compound 1B is extracted and purified to obtain compound 1C;
  • Step 3 Condensation reaction of compound 1C and compound 1C-1 to obtain compound A 1 .
  • step 1 add compound 1A-1 to compound 1A, add 1,4-dioxane, water, potassium carbonate, [1,1'-bis(diphenyl Phosphine) ferrocene] palladium dichloride dichloromethane complex reaction, after purification to obtain compound 1B;
  • Step 2 dissolving the compound 1B with an alcohol solvent, adding an alkaline solution dropwise, reacting, adjusting the pH to acidity, and obtaining 1C after extraction and purification;
  • Step 3 Dissolving the compound 1C in N,N-dimethylformamide, adding compound 1C-1, HATU and amine, adding DIPEA dropwise, after the reaction, purifying to obtain compound A 1 .
  • Step 1 Condensation reaction of compound 2A and compound 2A-1 to obtain compound 2B;
  • Step 2 Suzuki coupling reaction of compound 2B and compound 2B-1 to obtain compound A 2 .
  • step 1 dissolve compound 2A with N,N-dimethylformamide, add HATU, amine, compound 2A-1, drop DIPEA, after the reaction is completed, purify to obtain Compound 2B;
  • Step 2 Add 2B-1 to the compound 2B, add 1,4-dioxane, water, potassium carbonate, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride The dichloromethane complex was reacted to obtain compound A 2 after purification.
  • Step 1 Condensation reaction of compound 3A and compound to obtain compound 3B;
  • Step 2 compound 3B is reacted with R 1 -B(OH) 2 Suzuki to obtain compound 3C;
  • Step 3 Suzuki coupling reaction of compound 3C and compound 3C-1 to obtain compound A 3 .
  • step 1 dissolve compound 3A with N,N-dimethylformamide, add HATU, amine, compound 3A-1, drop DIPEA, after the reaction is completed, purify to obtain Compound 3B;
  • Step 2 Add R 1 -B(OH) 2 , 1,4-dioxane, water, potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene] to the compound 3B Palladium dichloride dichloromethane complex reaction, obtain compound 3C after purification;
  • Step 3 Add compound 3C-1 to the compound 3C, add 1,4-dioxane, water, add potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene under stirring at room temperature ] Palladium dichloride dichloromethane complex reaction, purification to obtain compound A 3 .
  • Step 1 Condensation reaction of compound 2A and compound 2A-1 to obtain compound 4B;
  • Step 2 Compound 4B is reacted with p-toluenesulfonyl chloride to obtain compound 4C;
  • Step 3 react compound 4C with N,N-diisopropylethylamine (DIPEA) to obtain compound 4D;
  • DIPEA N,N-diisopropylethylamine
  • Step 4 Dehydrogenation reaction of compound 4D to obtain compound 4E;
  • Step 5 Suzuki coupling reaction of compound 4E with compound 4E-1 to obtain compound A 4 .
  • step 1 dissolve compound 2A with N,N-dimethylformamide, add HATU and compound 2A-2, add DIPEA dropwise at room temperature, after the reaction, purify Compound 4B is obtained;
  • Step 2 Dissolve the compound 4B and triethylamine in tetrahydrofuran, react for 5 minutes, add p-toluenesulfonyl chloride to the reaction system, extract and dry after the reaction, remove the solvent to obtain compound 4C, and directly for the next step;
  • Step 3 Dissolving the compound 4C in tetrahydrofuran solution, adding DIPEA, reacting for 10 hours, extracting, drying, and purifying to obtain compound 4D;
  • Step 4 Dissolve the compound 4D in anhydrous dichloromethane, add 2,3-dichloro-5,6-dicyanobenzoquinone and 4A molecular sieves, after the reaction, filter and wash, remove the solvent, and obtain Compound 4D;
  • Step 5 react the compound 4D according to the method and steps of the synthetic route 1 to obtain the compound A 4 .
  • the present disclosure provides a pharmaceutical composition, which comprises the above-mentioned compound or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
  • the present disclosure provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition in the preparation of a medicament for treating an AhR-mediated disease in a patient.
  • the present disclosure provides the application of the above-mentioned compound or its pharmaceutically acceptable salt and the above-mentioned pharmaceutical composition in the preparation of AHR agonists.
  • the present disclosure relates to a method for activating AhR in a patient in need thereof, comprising administering the above-mentioned compound or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition to the patient.
  • the present disclosure relates to a method for treating an AhR-mediated disorder in a patient in need thereof, comprising administering the above-mentioned compound or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition to the patient.
  • the AhR-mediated diseases include but are not limited to psoriasis, arthritis, atopic dermatitis, Parkinson's, multiple sclerosis, inflammatory bowel disease, asthma, systemic lupus erythematosus, graft-versus-host disease , bacterial keratitis, tumors.
  • Compounds of the present disclosure possess AhR inhibitory activity.
  • 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 of the present invention containing an asymmetric carbon atom 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.
  • 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.
  • 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.
  • the type and number of substituents can be arbitrary on a chemically achievable basis.
  • any variable eg Rn
  • Rn a variable that occurs more than once in the composition or structure of a compound
  • its definition is independent at each occurrence.
  • a group is substituted with one to three R
  • said group may optionally be substituted with up to three R, with independent options for each occurrence of R.
  • combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms.
  • 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.
  • alkoxy may be straight chain, branched or cyclic.
  • the number of carbon atoms of the alkoxy group is not particularly limited, but is preferably 1 to 20. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy , sec-butoxy, n-pentoxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n- Nonyloxy, n-decyloxy, etc., but not limited thereto.
  • carbonyl or “carboxy” includes compounds and moieties in which the carbon is attached to an oxygen atom by a double bond.
  • Examples of carbonyl-containing moieties include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.
  • acyl is a carbonyl group with a carbon atom attached to hydrogen (i.e. formyl), an aliphatic group (C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, such as acetyl), a cycloalkyl ( C3-C8 cycloalkyl), heterocyclyl (C3-C8 heterocycloalkyl and C5-C6 heteroaryl), aryl (C6 aryl, such as benzoyl) linked carbonyl structure.
  • the acyl group can be unsubstituted or substituted (eg salicyloyl).
  • examples of the halogen group may include fluorine, chlorine, bromine or iodine.
  • cycloalkyl refers to a monocyclic saturated hydrocarbon system free of heteroatoms and double bonds.
  • C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system by removing one hydrogen from a single carbon atom of the parent aromatic ring system. atoms are obtained.
  • Bicyclic radicals which include saturated, partially unsaturated rings, or aromatic carbocyclic fused aromatic rings. Specific examples thereof include phenyl or naphthyl, but are not limited thereto.
  • heterocycloalkyl refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms.
  • Specific examples of the heterocyclic group include piperidinyl or tetrahydropyrrolyl, but are not limited thereto.
  • heteroaryl refers to a monovalent aryl group containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group can be a single ring or a polycyclic ring system, such as a bicyclic , wherein two or more rings exist in the form of parallel rings, bridged rings or spiro rings, wherein at least one ring contains one or more heteroatoms.
  • heteroaryl examples include pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, Imidazopyridyl, benzofuryl, pyridazinyl, isoindolyl, pyridonyl, but not limited thereto.
  • 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.
  • 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.
  • a spiroheterocyclyl an atom is shared by two different rings, an example of a spiroheterocyclyl is, but not limited to, azaspiropentyl.
  • partially unsaturated bicyclic heterocyclic ring means a bicyclic group comprising C atoms and at least one of heteroatoms such as N, O, and S as ring members, the bicyclic group is partially unsaturated, and contains at least one C-C double bonds, maximum unsaturated heterocycle contains as many C-C double bonds as ring size allows and double bonds of C atoms and heteroatoms, partially unsaturated bicyclic heterocycle contains less double bonds than ring size allows, partially unsaturated bicycle
  • heterocyclic rings include, but are not limited to, benzofuryl, benzothienyl, quinoxalinyl, quinazolinyl, isoindolinonyl, pteridinyl, and the like.
  • Ts p-toluenesulfonyl
  • DIPEA N,N-Diisopropylethylamine
  • 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.
  • 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.
  • acid including organic and inorganic acids
  • 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.
  • 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.
  • 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 algina
  • binders e.
  • 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.
  • 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).
  • PGLA polyglycolic/lactic acid
  • 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.
  • 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.
  • 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).
  • a suppository or retention enema eg, containing conventional suppository bases such as cocoa butter or other glycerides.
  • treating includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.
  • effective amount or “therapeutically effective amount” refers to a dose sufficient to treat, suppress or alleviate one or more symptoms of the disease state being treated or otherwise provide a desired pharmacological and/or physiological effect.
  • 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.
  • 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.
  • the compound represented by the chemical formula (I) can be prepared as in the following synthetic route 1, 2, 3 or 4.
  • Substituents can be combined by methods known in the technical field, and the type, position or number of substituents can be changed according to techniques known in the technical field.
  • Substituents can be incorporated as in Synthetic Scheme 1, 2, 3 or 4 below, but are not limited thereto.
  • Step 1 Add methyl 6-chloro-3-R1-pyridinecarboxylate to a one-necked bottle, add 1A-1,1,4-dioxane and water, add potassium carbonate, add [1,1'-bis( Diphenylphosphine) ferrocene] dichloropalladium dichloromethane complex, argon replacement 3 times, heated up to 95 degrees Celsius for 4 hours, naturally cooled to room temperature, decompressed to remove solvent, purified with silica gel to obtain Compound 1B;
  • Step 2 Add 1B to the one-mouth bottle, dissolve it with methanol, add dropwise 2N NaOH aqueous solution, react at room temperature for 4 hours, adjust the pH to 3-4 with 2N hydrochloric acid, extract with ethyl acetate and water, combine the organic phases, and spin off the solvent Compound 1C is obtained;
  • Step 3 Dissolve 1C in N,N-dimethylformamide, add HATU, amine, drop DIPEA, and react at room temperature. After the reaction, the solvent was spun off and purified with silica gel to obtain compound A 1 .
  • Step 1 Dissolve 6-chloro-3-R1-pyridinecarboxylic acid in N,N-dimethylformamide, add HATU, amine, drop DIPEA, and react at room temperature for one hour. After the reaction was over, the solvent was removed and purified with silica gel to obtain compound 2B;
  • Step 2 Add 2B to the single-necked bottle, add 2B-1,1,4-dioxane and water, add potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene]dichloride
  • the palladium dichloromethane complex was replaced with argon three times, heated to 95°C for 4 hours, cooled to room temperature naturally, evaporated to remove the solvent under reduced pressure, and purified with silica gel to obtain compound A 2 .
  • Step 1 Dissolve 3-bromo-6-chloro-2-pyridinecarboxylic acid in N,N-dimethylformamide, add HATU, amine, drop DIPEA, and react at room temperature. After the reaction was over, the solvent was removed and purified with silica gel to obtain compound 3B;
  • Step 2 Add 3B to the one-necked bottle, add R1-B(OH)2, 1,4-dioxane and water, potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride dichloromethane complex, replaced by argon 3 times, heated up to 95 degrees Celsius for 4 hours, cooled to room temperature naturally, evaporated the solvent under reduced pressure, and purified with silica gel to obtain compound 3C;
  • Step 3 Add 3C to the one-necked flask, add boric acid, 1,4-dioxane and water, add potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene] dichloride under stirring at room temperature
  • the palladium dichloromethane complex was replaced with argon three times, the temperature was raised to 100°C for 6 hours, the reaction was naturally cooled to room temperature, and purified by silica gel to obtain compound A 3 .
  • Step 1 Dissolve 6-chloro-3-R1-pyridinecarboxylic acid in N,N-dimethylformamide, add HATU, D L-phenyleneglycol, add DIPEA dropwise at room temperature, after the dropwise addition, leave at room temperature React for 2 hours. After the reaction was over, the solvent was removed and purified with silica gel to obtain compound 4B;
  • Step 2 Dissolve 4B and triethylamine in tetrahydrofuran, stir at 0°C for 5 minutes, then slowly add p-toluenesulfonyl chloride dropwise into the reaction system, and rise to room temperature to react for 6 hours after the dropwise addition.
  • the solvent was spun off, extracted three times with ethyl acetate and water, the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was spun off, and the crude product (4C) was directly used in the next step;
  • Step 3 Dissolve 4C in tetrahydrofuran solution, add DIPEA, raise the temperature to 75 degrees Celsius, and keep the reaction for 10 hours.
  • the reaction liquid was spun to remove the solvent, ethyl acetate and water were added to extract three times, the organic phases were combined, dried with anhydrous sodium sulfate, spun to dry the solvent, and purified with silica gel to obtain 4D;
  • Step 4 Dissolve 4D in anhydrous dichloromethane, add 2,3-dichloro-5,6-dicyanobenzoquinone and 4A molecular sieve, and react at room temperature for 4 hours. After the reaction, filter with suction, wash the filter cake twice with anhydrous dichloromethane, spin off the solvent to obtain 4E;
  • Step 5 After 4E is operated according to the method of synthetic route 1, the final final product is obtained.
  • Embodiment 1 the preparation of compound 1
  • Step 2 Add 3-methyl-6-(pyrimidin-5-yl)picolinate methyl ester (92mg, 0.5mmol) to the one-port bottle, add methanol (5mL) to dissolve, add dropwise 2N NaOH aqueous solution at 0°C ( 1mL), after the dropwise addition, react at room temperature for 4 hours, TLC plate, the raw material reaction is complete, adjust the pH to 3-4 with 2N hydrochloric acid, extract three times with ethyl acetate and water, combine the organic phase, spin off the solvent to obtain compound 1B
  • Embodiment 2 the preparation of compound 14
  • Step 2 Add 6-chloro-3-methyl-N-(m-tolyl)pyridineamide (56.5mg, 0.22mmol) to a one-necked bottle, add indazole-6-boronic acid (53mg, 0.33mmol), 1, 4-dioxane (5mL) and water (1mL), potassium carbonate (91mg, 0.66mmol) was added under stirring at room temperature, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added Dichloromethane complex (8 mg, 0.01 mmol), replaced with argon 3 times, heated to 95 degrees Celsius and reacted for 4 hours, cooled to room temperature naturally, evaporated the solvent under reduced pressure, added ethyl acetate and water to extract the residue, and separated the layers , the organic phase was washed with water until neutral, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel (ethyl acetate/
  • Embodiment 3 the preparation of compound 38
  • Step 1 Dissolve 3-bromo-6-chloro-2-pyridinecarboxylic acid in (237mg, 1mmol) N,N-dimethylformamide into a 50mL single-necked bottle, add HATU (456mg, 1.2mmol), and trifluoro DIPEA (387 mg, 3 mmol) was added dropwise to methylaniline (177.2 mg, 1.1 mmol) at room temperature, and reacted at room temperature for one hour after the addition was completed.
  • Step 2 Add 3-bromo-6-chloro-N-(4-(trifluoromethyl)phenyl)pyridinamide (75.8mg, 0.2mmol) to a one-necked bottle, add cyclopropylboronic acid (25.8mg, 0.3 mmol), 1,4-dioxane (5mL) and water (1mL), potassium carbonate (82.8mg, 0.6mmol) was added under stirring at room temperature, and [1,1'-bis(diphenylphosphine)dicene Iron] Palladium dichloride dichloromethane complex (16mg, 0.02mmol), argon replacement 3 times, heated to 95 degrees Celsius for 4 hours, cooled to room temperature naturally, evaporated the solvent under reduced pressure, and added ethyl acetate to the residue Extracted with water, separated, washed the organic phase with water until neutral, added anhydrous sodium sulfate to dry, filtered, and the filtrate was purified by silica gel (eth
  • Step 3 Add 5-chloro-3-cyclopropyl-N-(4-(trifluoromethyl)phenyl)pyridinamide (18mg, 0.053mmol) to a single-necked bottle, add 1-methyl-1H-pyridine Azole-4-boronic acid (10mg, 0.08mmol), 1,4-dioxane (5mL) and water (1mL), potassium carbonate (18mg, 0.13mmol) was added under stirring at room temperature, and [1,1'-bis (Diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (3mg, 0.004mmol), replaced by argon 3 times, heated to 100 degrees Celsius for 6 hours, naturally cooled to room temperature, evaporated under reduced pressure Solvent, the residue was extracted with ethyl acetate and water, separated, the organic phase was washed with water until neutral, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel
  • Embodiment 4 the synthesis of compound 42
  • Step 1 Dissolve 6-chloro-3-methylpicolinic acid with (171.6mg, 1mmol) N,N-dimethylformamide in a 50mL one-mouth bottle, add HATU (456mg, 1.2mmol), D L-benzene Glyaminoglycerol (165.4mg, 1.2mmol) was added dropwise to DIPEA (322.5mg, 2.5mmol) at room temperature, and after the addition was completed, the mixture was reacted at room temperature for 2 hours.
  • HATU 456mg, 1.2mmol
  • DIPEA 322.5mg, 2.5mmol
  • Step 2 Dissolve 6-chloro-N-(2-hydroxy-1-phenylethyl)-3-methylpicolinamide (220mg, 0.76mmol) and triethylamine (191.9mg, 1.9mmol) in tetrahydrofuran, As for the 50mL single-necked bottle, stir at 0°C for 5 minutes, then slowly add p-toluenesulfonyl chloride (289.8mg, 1.52mmol) into the reaction system dropwise, and rise to room temperature for 6 hours after the dropwise addition. Detected by LC-Ms, the reaction of raw materials was complete.
  • Step 3 Dissolve the crude product obtained in the previous step in 20 mL of tetrahydrofuran solution and place it in a 50 mL single-necked bottle, add DIPEA (588.24 mg, 4.56 mmol), raise the temperature to 75 degrees Celsius, and keep the reaction for 10 hours. The starting material was monitored for complete reaction by LC-Ms.
  • Step 4 Dissolve 3-(6-chloro-3-methylpyridin-2-yl)-4-phenyl-4,5-dihydrooxazole (180mg, 0.66mmol) in anhydrous dichloromethane, Add 2,3-dichloro-5,6-dicyanobenzoquinone (300 mg, 1.32 mmol) and 4A molecular sieves (100 mg), and react at room temperature for 4 hours. The starting material was monitored for complete reaction by LC-Ms.
  • Step 5 After 56 mg of 2-(6-chloro-3-methylpyridin-2-yl)-4-benzoxazole was operated according to the method of Example 1, 2-(3-methyl-6-( 1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-benzoxazole 30 mg, yield: 45.8%, Ms+1: 317.1.
  • Embodiment 5 the preparation of compound 92
  • Step 1 Dissolve 6-chloro-3-methylpicolinic acid (798mg, 4.7mmol) in N,N-dimethylformamide into a 50mL single-necked bottle, add HATU (2128mg, 5.6mmol), m-trifluoroform Aniline (720mg, 4.5mmol), DIPEA (1440mg, 11.2mmol) was added dropwise at room temperature, and after the addition was completed, the reaction was carried out at room temperature for one hour.
  • Step 2 Add 6-chloro-3-trifluoromethyl-N-(m-trifluoromethylphenyl)pyridine amide (31.5mg, 0.1mmol) to the one-mouth bottle, add 4-pyrazoleboronic acid pinacol ester (19.4 mg, 0.1mmol), 1,4-dioxane (5mL) and water (1mL), potassium carbonate (27.6mg, 0.2mmol) was added under stirring at room temperature, and [1,1'-bis(diphenylphosphine ) ferrocene] palladium dichloride dichloromethane complex (8mg, 0.01mmol), argon replacement 3 times, heated up to 95 degrees Celsius for 4 hours, naturally cooled to room temperature, decompressed to remove the solvent, the residue was added Extract with ethyl acetate and water, separate liquid, wash the organic phase with water until neutral, add anhydrous sodium sulfate to dry, filter, evaporate the filtrate to remove the solvent under reduced pressure, and then purify with si
  • Embodiment 6 the preparation of compound 46
  • Embodiment 7 The effect experiment of the compound of the present disclosure agonizing the AhR target in vitro
  • 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.
  • DMEM medium was purchased from Gibco Company
  • penicillin and streptomycin were purchased from Hyclone Company
  • Tapinarof was purchased from MedChemExpress (MCE) Company
  • Dual Luciferase Reporter Assay Kit was purchased from Novozyme Biotechnology Co., Ltd.
  • 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.
  • 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 .
  • each test is also diluted positive drug Tapinarof and added to the test.
  • 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 culture, mix 5 ⁇ Cell Lysis Buffer and ddH 2 O in the Dual Luciferase Reporter Assay Kit at a ratio of 1:4 to prepare 1 ⁇ Cell Lysis Buffer for later use. After the end of the culture, remove the medium and add 20 ⁇ L to each well 1 ⁇ Cell Lysis Buffer, place on a horizontal shaker and shake for 15 minutes to fully lyse the cells.
  • reaction stop buffer Stop&Reaction Buffer
  • luciferase substrate Renilla Substrate
  • 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 ⁇ M).
  • Tapinarof 10 ⁇ M.
  • EC 50 value of the test compound agonizing the AhR target as shown in the table below, where "AAAAA” means EC 50 ⁇ 20nM;”AAAA” means EC 50 is greater than or equal to 20nM and less than 200nM; “AAA” means EC 50 is greater than or equal to 200nM and less than or equal to 500nM; “AA” means EC 50 is greater than or equal to 500nM and less than or equal to 1000nM; “A” means EC 50 >1000nM; Indicates higher than 10 times; "BB” indicates that the multiple is greater than or equal to 5 and less than or equal to 10; “B” indicates that the multiple is less than 5.

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Abstract

La présente invention concerne un composé représenté par la formule (I) et ayant un effet d'activation d'AHR, son utilisation et son procédé de préparation. Le composé présente une activité agoniste évidente vis-à-vis d'AHR.
PCT/CN2022/132910 2021-11-19 2022-11-18 Préparation pour dérivé de pyridine trisubstituée et application en tant que modulateur de récepteur d'hydrocarbures aromatiques WO2023088435A1 (fr)

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