WO2023088435A1 - Preparation for trisubstituted pyridine derivative and application as aromatic hydrocarbon receptor modulator - Google Patents

Preparation for trisubstituted pyridine derivative and application as aromatic hydrocarbon receptor modulator 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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French (fr)
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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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • 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

The present disclosure relates to a compound as represented by formula (I) and having an AHR activation effect, use thereof and a preparation method therefor. The compound has obvious AHR agonistic activity.

Description

三取代吡啶衍生物的制备及作为芳香烃受体调节物的应用Preparation of Trisubstituted Pyridine Derivatives and Their Application as Modulators of Aryl Hydrocarbon Receptors 技术领域technical field
本公开涉及医药领域，特别涉及一种具有AhR激活作用的三取代吡啶衍生物，其用途及制备方法。The disclosure relates to the field of medicine, in particular to a trisubstituted pyridine derivative with AhR activation function, its use and preparation method.
背景技术Background technique
芳香烃受体(aryl hydrocarbon receptor，AhR)是一种靠配体激活的转录因子，为碱性螺旋-环-螺旋转录因子(basic helix-loop-helix/Per-ARNT-Sim，bHLH-PAS)家族的成员之一。AhR广泛存在于生物体内，哺乳动物、两栖动物、爬行动物和鸟类的体内都含有AhR蛋白。AhR在人体内多种细胞中表达，不仅对机体血管发育、神经功能调节发挥着重要作用，还对自身免疫紊乱、肿瘤等多种疾病发生过程中具有重要的调节作用，已成为药物研发重点关注的靶点。The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which is a basic helix-loop-helix (basic helix-loop-helix/Per-ARNT-Sim, bHLH-PAS) transcription factor One of the members of the family. 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.
AhR蛋白的功能结构域由3部分组成：bHLH结构域、PAS结构域和1个富含谷氨酸的结构域。bHLH结构域位于AhR蛋白的N-末端，辅助AhR结合到靶基因的启动子区域和蛋白质二聚化；PAS结构域通过与AhR核转运蛋白(AhR nuclear translocator，ARNT)连接并与配体结合来辅助蛋白二聚化，形成蛋白复合物；C-末端区域是一个富含谷氨酸的结构域，发挥募集和转录激活的作用。在未激活的形式下，AhR通常在细胞质中与热休克蛋白90(Hsp90)、p23、X相关蛋白2(XAP2)和AhR相关蛋白9(ARA9)形成多蛋白复合体。经典信号通路表现为，当AhR与配体结合并被激活，其发生构象的改变，暴露出核定位信号序列，受体-配体复合物易位至细胞核，在核内和ARNT形成异二聚体，AhR/ARNT复合物结合靶基因启动子的异源生物响应元件(其核心序列：5’-TNGCGTG-3’)，启动靶基因表达。靶基因包括细胞色素P450酶(CYP1A1、CYP1A2、CYP1B1)、谷胱甘肽巯基转移酶、鸟苷二磷酸葡糖醛酸糖基转移酶、NAD(P)H依赖的醌氧化还原酶-1、醛脱氢酶3A1和抗乳腺癌蛋白基因等。从而参与许多重要的生理过程，如细胞周期和增殖的调控、免疫应答、昼夜节律、肿瘤诱发、脂类代谢有关基因的表达等。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. 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). 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. 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. Thus participating in many important physiological processes, such as regulation of cell cycle and proliferation, immune response, circadian rhythm, tumor induction, expression of genes related to lipid metabolism, etc.
AhR通过与不同结构性质的外源性或内源性配体结合，还表现出不同的生物学效应。其外源性配体主要由多环芳香烃(PAHs)、多氯联苯(PCBs)、天然化合物和小分子类等组成；内源性配体包括色氨酸代谢产物、血红素代谢产物、花生四烯酸代谢产物等。一方面，AhR可被配体激活，导致下游CYP1A1等基因表达水平提高及靶基因表达产物Ⅰ相或Ⅱ相外源物质代谢酶增多，促进机体对外源性毒物的代谢，从而保护机体不受外源物质影响，例如AhR受体激动剂MCDF(6-甲基1,3,8-三氯二苯呋喃)，能诱导靶基因CYP1A1的表达，增强其代谢，从而抑制雌激素受体阴性的乳腺癌肿瘤细胞的增殖。另一方面调节AhR与其他肿瘤相关信号通路，如AhR-ER、AhR-丝裂原活化蛋白激酶(mitogen activated protein kinases,MAPKs)，在肿瘤发生中起作用。例如，DIM(3,3'-吲哚甲烷)能通过AhR依赖途径强烈地抑制ER-α的表达及雌激素信号通路，减少人类乳腺癌的发病风险。AhR also exhibits different biological effects by binding to exogenous or endogenous ligands with different structural properties. Its 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. On the one hand, 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. On the other hand, it regulates AhR and other tumor-related signaling pathways, such as AhR-ER and AhR-mitogen activated protein kinases (MAPKs), which play a role in tumorigenesis. For example, DIM (3,3'-indolylmethane) can strongly inhibit the expression of ER-α and the estrogen signaling pathway through an AhR-dependent pathway, reducing the risk of human breast cancer.
近年来，AhR在免疫领域备受关注，特别是在炎症发生的过程中AhR可促进具有抗炎作用的Treg细胞的产生。AhR激动剂可通过激活AhR诱导Th0细胞向Treg细胞分化，减轻实验性自身免疫性脑脊髓炎。AhR激动剂TCDD给药可通过增强Treg细胞的增殖，而抑制了小鼠模型中自身免疫疾病的进展，或提高移植物存活率。AhR激动剂本维莫德已经在动物和临床应用中表现出明确的治疗银屑病和特异性皮炎的作用。在动物实验中，本维莫德和拉喹莫德等AhR激动剂还能够通过增强调节treg细胞的免疫功能，具有治疗关节炎、多发性硬化症、炎症性肠炎的作用。最新研究表明，色氨酸代谢物可以通过激活AhR通路减轻神经炎症对帕金森等神经退行性疾病有治疗作用。AhR激动剂-Z425228478可以通过激活AhR可以细菌性角膜炎的炎症反应。In recent years, 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. In animal experiments, 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. The latest research shows that 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.
总之，AhR激动剂对银屑病、关节炎、特应性皮炎、帕金森、多发性硬化症、炎症性肠炎、哮喘、系统性红斑狼疮、移植物抗宿主病、细菌性角膜炎、肿瘤等多种疾病的治疗和预防具有潜在的应用价值。In conclusion, 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.
发明内容Contents of the invention
本公开的目的在于提供一种新型的化合物的合成及其在AhR(芳香烷烃受体)激动剂药物中的应用，所述化 合物作为AhR激动剂，具有活性高，选择性好且毒副作用低等优点。The purpose of this disclosure is to provide the synthesis of a novel compound and its application in AhR (aromatic alkanes receptor) agonist drugs. As an AhR agonist, the compound has high activity, good selectivity and low toxicity and side effects. advantage.
本发明的一方面，提供一种式(I)所代表的化合物或其药学上可接受的盐，In one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022132910-appb-000001
Figure PCTCN2022132910-appb-000001
其中：in:
m选自0、1、2或3；n选自0、1、2或3；m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3;
A环选自5-7元芳基、5-7元的单环杂芳基、9-12元的双环杂芳基、5-7元的杂环烷基、9-12元的部分不饱和双环杂环基；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;
m个R 2彼此相同或不相同，其中，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、-S(O) 2R 6、5-7元杂环烷基，所述C 1-6酰基、5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代，所述C 1-6烷基任选地被一个或多个卤素、-C(＝O)NR 4R 5取代； 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, -S(O) 2 R 6 , 5-7 membered heterocycloalkyl, said C 1-6 acyl, 5-7 membered heterocycloalkyl is optionally replaced by one or more C 1-3 alkyl, -NR 4 R 5 Substituted, the C 1-6 alkyl is optionally substituted by one or more halogens, -C(=O)NR 4 R 5 ;
R 1选自氢、氘、卤素、C 1-6烷基、C 1-6烯基、C 3-6环烷基，所述C 1-6烷基、C 1-6烯基、C 3-6环烷基任选地被一个或多个卤素所取代； 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为-C(O)-、
Figure PCTCN2022132910-appb-000002
L is -C(O)-,
Figure PCTCN2022132910-appb-000002
B环选自5-7元芳基、5-7元单环杂芳基、9-12元双环杂芳基、9-12元部分不饱和双环杂环基、8-12元饱和螺环杂环基；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个R 3彼此相同或不相同，其中，R 3选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、卤素、氰基、含有1-2个分别独立选自N、O、S原子的5-7元杂环烷基，所述C 1-6烷基、C 3-6环烷基、C 1-3酰基任选地被一个或多个卤素、氰基所取代。 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、R 6各自独立地选自氢、C 1-6烷基、C 3-6环烷基。 R 4 , R 5 , and R 6 are each independently selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl.
在另一方面，本公开涉及下式(I)所代表的化合物或其药学上可接受的盐：In another aspect, the present disclosure relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022132910-appb-000003
Figure PCTCN2022132910-appb-000003
其中：in:
m选自0、1、2或3；n选自0、1、2或3；m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3;
A环选自5-7元芳基、5-7元的单环杂芳基、9-12元的双环杂芳基、5-7元的杂环烷基、9-12元的部分不饱和双环杂环基；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;
在一些具体实施方式中，A环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元的单环杂芳基、含有1-2个分别独立选自N、O、S原子的9-12元的双环杂芳基、含有1-2个分别独立选自N、O、S原子的5-7元的杂环烷基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基；In some specific embodiments, 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;
优选地，A环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元的单环杂芳基、含有1-2个分别独立选自N或O的9-12元的双环杂芳基、含有1-2个N原子的5-7元的杂环烷基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基；Preferably, 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. A 9-12-membered bicyclic heteroaryl group of O, a 5-7-membered heterocycloalkyl group containing 1-2 N atoms, a 9-12-membered moiety containing 1-3 independently selected from N or O atoms, etc. Saturated bicyclic heterocyclyl;
优选地，A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、异吲哚啉基、吡啶酮基、异吲哚啉酮基；Preferably, ring A is selected from phenyl, pyrimidinyl, pyrazolyl, benzopyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazole Base, pyrrolopyridyl, isoindolinyl, pyridonyl, isoindolinone;
优选地，A环选自苯基、嘧啶基、吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、异吲哚啉基、吡啶酮基、异吲哚啉酮基；Preferably, ring A is selected from phenyl, pyrimidyl, pyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazolyl, pyrrolopyridyl , isoindolinyl, pyridinone, isoindolinone;
优选地，A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、吡啶酮基、异吲哚啉酮基；Preferably, ring A is selected from phenyl, pyrimidinyl, pyrazolyl, benzopyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazole Base, pyrrolopyridyl, pyridonyl, isoindolinone;
优选地，A环不为苯并咪唑-2-基
Figure PCTCN2022132910-appb-000004
Preferably, ring A is not benzimidazol-2-yl
Figure PCTCN2022132910-appb-000004
在一些具体实施方式中，A环选自
Figure PCTCN2022132910-appb-000005
Figure PCTCN2022132910-appb-000006
In some embodiments, ring A is selected from
Figure PCTCN2022132910-appb-000005
Figure PCTCN2022132910-appb-000006
优选地，A环选自
Figure PCTCN2022132910-appb-000007
Figure PCTCN2022132910-appb-000008
Preferably, ring A is selected from
Figure PCTCN2022132910-appb-000007
Figure PCTCN2022132910-appb-000008
优选地，A环选自
Figure PCTCN2022132910-appb-000009
Figure PCTCN2022132910-appb-000010
Preferably, ring A is selected from
Figure PCTCN2022132910-appb-000009
Figure PCTCN2022132910-appb-000010
优选地，A环选自
Figure PCTCN2022132910-appb-000011
Preferably, ring A is selected from
Figure PCTCN2022132910-appb-000011
优选地，
Figure PCTCN2022132910-appb-000012
选自
Figure PCTCN2022132910-appb-000013
Figure PCTCN2022132910-appb-000014
Preferably,
Figure PCTCN2022132910-appb-000012
selected from
Figure PCTCN2022132910-appb-000013
Figure PCTCN2022132910-appb-000014
优选地，
Figure PCTCN2022132910-appb-000015
选自
Figure PCTCN2022132910-appb-000016
Figure PCTCN2022132910-appb-000017
Preferably,
Figure PCTCN2022132910-appb-000015
selected from
Figure PCTCN2022132910-appb-000016
Figure PCTCN2022132910-appb-000017
优选地，
Figure PCTCN2022132910-appb-000018
选自
Figure PCTCN2022132910-appb-000019
Preferably,
Figure PCTCN2022132910-appb-000018
selected from
Figure PCTCN2022132910-appb-000019
在一些具体实施方式中，m个R 2彼此相同或不相同，其中，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1- 6酰基、5-7元杂环烷基，所述C 1-6酰基、5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代； In some specific embodiments, 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 ;
优选地，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基，所述C 1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代； Preferably, 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;
优选地，R 2选自C 1-3烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、含有1-2个N原子的5-7元杂环烷基，所述C 1-3酰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代； Preferably, 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 ;
优选地，R 2选自C 1-3烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、含有1-2个N原子的5-7元杂环烷基，所述C 1-3羰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个甲基、-N(CH 3) 2所取代； Preferably, 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 ;
优选地，R 2选自甲基、乙基、丙基、异丙基、环丙烷基、甲氧基、甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基，所述甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基任选地被一个或多个甲基、-N(CH 3) 2所取代； Preferably, 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 ;
在一些具体实施方式中，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、-S(O) 2R 6、含有1-2个分别独立选自N、O原子的5-7元杂环烷基，所述C 1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代，所述C 1-6烷基任选地被一个或多个卤素、-C(＝O)NR 4R 5取代；所述 C 1-6烷基任选地被一个或多个卤素、-C(＝O)NR 4R 5取代； In some specific embodiments, 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 Alkyl is optionally substituted by one or more C 1-3 alkyl, -NR 4 R 5 , said C 1-6 alkyl is optionally substituted by one or more halogen, -C(=O)NR 4 R 5 is substituted; the C 1-6 alkyl is optionally substituted by one or more halogens, -C(=O)NR 4 R 5 ;
优选地，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、-S(O) 2R 6、含有1-2个分别独立选自N、O原子的5-7元杂环烷基，所述C 1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代；所述C 1-6烷基任选地被一个或多个氟、氯、溴、碘、-C(＝O)NH 4R 5取代； Preferably, 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 heterocycloalkyl groups independently selected from N and O atoms are optionally is optionally substituted by one or more C 1-3 alkyl, -NR 4 R 5 ; the C 1-6 alkyl is optionally substituted by one or more fluorine, chlorine, bromine, iodine, -C(=O ) NH 4 R 5 substitution;
优选地，R 2选自C 1-3烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、-S(O) 2R 6、含有1-2个N原子的5-7元杂环烷基，所述C 1-3酰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代，所述C 1-6烷基任选地被一个或多个氟、-C(＝O)NH 4R 5取代； Preferably, R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 acyl, -S(O) 2 R 6 , containing 1-2 A 5-7-membered heterocycloalkyl group with N atoms, the C 1-3 acyl group, a 5-7-membered heterocycloalkyl group containing 1-2 N atoms are optionally replaced by one or more C 1-3 alkyl groups , -NR 4 R 5 substituted, the C 1-6 alkyl is optionally substituted by one or more fluorine, -C(=O)NH 4 R 5 ;
优选地，R 2选自C 1-3烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、-S(O) 2R 6、含有1-2个N原子的5-7元杂环烷基，所述C 1-3羰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个甲基、-N(CH 3) 2所取代，所述C 1-6烷基任选地被一个或多个氟、-C(＝O)NH 2取代；在一些具体实施方式中，R 4、R 5各自独立地选自氢、C 1-6烷基，更优选氢和甲基。 Preferably, R 2 is selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 acyl, -S(O) 2 R 6 , containing 1-2 A 5-7 membered heterocycloalkyl group of N atoms, the C 1-3 carbonyl group, a 5-7 membered heterocycloalkyl group containing 1-2 N atoms are optionally replaced by one or more methyl groups, -N( CH 3 ) 2 is substituted, and the C 1-6 alkyl group is optionally substituted by one or more fluorine, -C(=O)NH 2 ; in some specific embodiments, R 4 and R 5 are each independently selected from hydrogen, C 1-6 alkyl, more preferably hydrogen and methyl.
在一些具体实施方式中，R 6各自独立地选自C 1-6烷基和C 3-6环烷基，更优选甲基、丙基和环丙基。 In some specific embodiments, each R 6 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, more preferably methyl, propyl and cyclopropyl.
在一些具体实施方式中，R 2选自甲基、乙基、二氟甲基、异丙基、环丁烷基、环丙烷基、甲氧基、甲酰基、-CH 2C(＝O)NH 2、-S(O) 2CH 3、-S(O) 2(CH 2) 2CH 3、
Figure PCTCN2022132910-appb-000020
-C(＝O)CH 2N(CH 3) 2、
Figure PCTCN2022132910-appb-000021
In some embodiments, R is selected from methyl, ethyl, difluoromethyl, isopropyl, cyclobutanyl, cyclopropyl, methoxy, formyl, -CH 2 C(=O) NH 2 , -S(O) 2 CH 3 , -S(O) 2 (CH 2 ) 2 CH 3 ,
Figure PCTCN2022132910-appb-000020
-C(=O)CH 2 N(CH 3 ) 2 ,
Figure PCTCN2022132910-appb-000021
在一些具体实施方式中，R 2选自甲基、乙基、二氟甲基、异丙基、环丁烷基、环丙烷基、甲氧基、甲酰基、-CH 2C(＝O)NH 2、-S(O) 2CH 3、-S(O) 2(CH 2) 2CH 3、
Figure PCTCN2022132910-appb-000022
In some embodiments, R is selected from methyl, ethyl, difluoromethyl, isopropyl, cyclobutanyl, cyclopropyl, methoxy, formyl, -CH 2 C(=O) NH 2 , -S(O) 2 CH 3 , -S(O) 2 (CH 2 ) 2 CH 3 ,
Figure PCTCN2022132910-appb-000022
优选地，R 2选自甲基、异丙基、环丙烷基、甲氧基、羰基、-C(＝O)CH 2N(CH 3) 2、
Figure PCTCN2022132910-appb-000023
Preferably, R 2 is selected from methyl, isopropyl, cyclopropanyl, methoxy, carbonyl, -C(=O)CH 2 N(CH 3 ) 2 ,
Figure PCTCN2022132910-appb-000023
优选地，
Figure PCTCN2022132910-appb-000024
选自
Figure PCTCN2022132910-appb-000025
Figure PCTCN2022132910-appb-000026
Figure PCTCN2022132910-appb-000027
Preferably,
Figure PCTCN2022132910-appb-000024
selected from
Figure PCTCN2022132910-appb-000025
Figure PCTCN2022132910-appb-000026
Figure PCTCN2022132910-appb-000027
在一些具体实施方式中，R 1选自氢、氘、卤素、C 1-6烷基、C 1-6烯基、C 3-6环烷基，所述C 1-6烷基、C 1-6烯基、C 3-6环烷基任选地被一个或多个卤素所取代； In some specific embodiments, 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;
优选地，R 1选自氢、氘、卤素、C 1-3烷基、C 1-3烯基、C 3-6环烷基，所述C 1-3烷基、C 1-3烯基、C 3-6环烷基任选地被一个至三个卤素所取代； Preferably, 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;
优选地，R 1选自氢、氘、氟、C 1-3烷基、C 1-3烯基，所述C 1-3烷基、C 1-3烯基、C 3-6环烷基任选地被一个至三个氟所取代； Preferably, 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;
优选地，R 1选自氟、甲基、乙基、氟甲基、二氟甲基、三氟甲基、异丙基、异丙烯基、环丙烷基； Preferably, R is selected from fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, isopropyl, isopropenyl, cyclopropenyl;
优选地，R 1选自氟、甲基、异丙基、异丙烯基、环丙烷基； Preferably, R is selected from fluorine, methyl, isopropyl, isopropenyl, cyclopropenyl;
优选地，R 1为甲基； Preferably, R 1 is methyl;
在一些具体实施方式中，L为-C(O)-、
Figure PCTCN2022132910-appb-000028
Figure PCTCN2022132910-appb-000029
In some embodiments, L is -C(O)-,
Figure PCTCN2022132910-appb-000028
Figure PCTCN2022132910-appb-000029
在一些具体实施方式中，L为
Figure PCTCN2022132910-appb-000030
L优选为
Figure PCTCN2022132910-appb-000031
In some specific embodiments, L is
Figure PCTCN2022132910-appb-000030
L is preferably
Figure PCTCN2022132910-appb-000031
在一些具体实施方式中，B环选自5-7元芳基、5-7元单环杂芳基、9-12元双环杂芳基、9-12元部分不饱和双环杂环基、8-12元饱和螺环杂环基；In some specific embodiments, 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;
优选地，B环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元单环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元双环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N、O、S原子8-12元饱和螺环杂环基；Preferably, 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;
优选地，B环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元单环杂芳基、含有1-3个分别独立选自N或O原子的9-12元双环杂芳基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N或O原子8-12元饱和螺环杂环基；Preferably, 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;
优选地，B环选自苯基、吡啶基、吡唑基、苯并二氧戊环基、氮杂螺辛烷基、四氢异喹啉基；Preferably, ring B is selected from phenyl, pyridyl, pyrazolyl, benzodioxolanyl, azaspirooctyl, tetrahydroisoquinolyl;
优选地，B环选自
Figure PCTCN2022132910-appb-000032
Figure PCTCN2022132910-appb-000033
Preferably, the B ring is selected from
Figure PCTCN2022132910-appb-000032
Figure PCTCN2022132910-appb-000033
在一些具体实施方式中，n个R 3彼此相同或不相同，其中，R 3选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、卤素、氰基、含有1-2个分别独立选自N、O、S原子的5-7元杂环烷基，所述C 1-6烷基、C 3-6环烷基、C 1-3酰基任选地被一个或多个卤素、氰基所取代； In some specific embodiments, 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;
优选地，R 3不同时选自烷氧基和杂环烷基； Preferably, R is not simultaneously selected from alkoxy and heterocycloalkyl;
优选地，R 3选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、卤素、氰基、含有1-2个分别独立选自N或O原子的5-7元杂环烷基、所述C 1-6烷基、C 1-3酰基任选地被一个至三个氟所取代，所述C 3-6环烷基任选地被一个或多个氰基所取代； Preferably, 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;
优选地，R 3选自甲基、三氟甲基、甲氧基、环丙基、环己基、卤素、氰基、
Figure PCTCN2022132910-appb-000034
Figure PCTCN2022132910-appb-000035
Preferably, R is selected from methyl, trifluoromethyl, methoxy, cyclopropyl, cyclohexyl, halogen, cyano,
Figure PCTCN2022132910-appb-000034
Figure PCTCN2022132910-appb-000035
优选地，R 3选自溴、氟、氯、氰基、三氟甲基、甲基。 Preferably, R3 is selected from bromo, fluoro, chloro, cyano, trifluoromethyl, methyl.
本公开涉及上述化合物或其药学上可接受的盐，其中，包括式(II)所代表的化合物或其药学上可接受的盐：The present disclosure relates to the above compounds or pharmaceutically acceptable salts thereof, including compounds represented by formula (II) or pharmaceutically acceptable salts thereof:
Figure PCTCN2022132910-appb-000036
Figure PCTCN2022132910-appb-000036
其中，n、m、A、L、R 1、R 2、R 3的定义如上述所定义。 Wherein, the definitions of n, m, A, L, R 1 , R 2 , and R 3 are as defined above.
本公开涉及上述化合物或其药学上可接受的盐，其中，所述化合物具有以下式(IIa)、(IIb)、(IIc)、(IId)、(IIe)或(IIf)所示的结构：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):
Figure PCTCN2022132910-appb-000037
Figure PCTCN2022132910-appb-000037
Figure PCTCN2022132910-appb-000038
Figure PCTCN2022132910-appb-000038
其中，X 4、X 5、X 6选自N、NH或CH，n、m、R 1、R 2、R 3的定义如上述所定义。 Wherein, 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.
本公开提供了下列化合物或其药学上可接受的盐：The present disclosure provides the following compounds or pharmaceutically acceptable salts thereof:
Figure PCTCN2022132910-appb-000039
Figure PCTCN2022132910-appb-000039
Figure PCTCN2022132910-appb-000040
Figure PCTCN2022132910-appb-000040
Figure PCTCN2022132910-appb-000041
Figure PCTCN2022132910-appb-000041
Figure PCTCN2022132910-appb-000042
Figure PCTCN2022132910-appb-000042
Figure PCTCN2022132910-appb-000043
Figure PCTCN2022132910-appb-000043
Figure PCTCN2022132910-appb-000044
Figure PCTCN2022132910-appb-000044
Figure PCTCN2022132910-appb-000045
Figure PCTCN2022132910-appb-000045
本公开涉及上述化合物的制备方法，所述方法包括以下一种：The present disclosure relates to a method for the preparation of the above compound, the method comprising one of the following:
合成路线1：Synthetic route 1:
Figure PCTCN2022132910-appb-000046
Figure PCTCN2022132910-appb-000046
步骤一：化合物1A与化合物1A-1Suzuki偶联反应得到化合物1B；Step 1: Suzuki coupling reaction of compound 1A and compound 1A-1 to obtain compound 1B;
步骤二：化合物1B经过萃取纯化后得到化合物1C；Step 2: compound 1B is extracted and purified to obtain compound 1C;
步骤三：化合物1C与化合物1C-1缩合反应得到化合物A 1。 Step 3: Condensation reaction of compound 1C and compound 1C-1 to obtain compound A 1 .
在一些具体实施方式中，合成路线1中，步骤一：向化合物1A中加入化合物1A-1，加入1,4-二氧六环、水、碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应，纯化后得到化合物1B；In some specific embodiments, in the synthetic route 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;
步骤二：用醇溶剂溶解所述化合物1B，滴加碱性溶液，反应，调节PH至酸性，经过萃取纯化后得到1C；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;
步骤三：将所述化合物1C用N，N-二甲基甲酰胺溶解，加入化合物1C-1、HATU、胺，滴加DIPEA，反应结束后，纯化得到化合物A 1。 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 .
合成路线2：Synthetic route 2:
Figure PCTCN2022132910-appb-000047
Figure PCTCN2022132910-appb-000047
步骤一：化合物2A与化合物2A-1缩合反应得到化合物2B；Step 1: Condensation reaction of compound 2A and compound 2A-1 to obtain compound 2B;
步骤二：化合物2B与化合物2B-1Suzuki偶联反应得到化合物A 2。 Step 2: Suzuki coupling reaction of compound 2B and compound 2B-1 to obtain compound A 2 .
在一些具体实施方式中，合成路线2中，步骤一：将化合物2A用N，N-二甲基甲酰胺溶解，加入HATU、胺、化合物2A-1，滴加DIPEA，反应结束后，纯化得到化合物2B；In some specific embodiments, in the synthetic route 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;
步骤二：向所述化合物2B中加入2B-1，加入1，4-二氧六环、水、碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应，纯化后得到化合物A 2。 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.
合成路线3：Synthetic route 3:
Figure PCTCN2022132910-appb-000048
Figure PCTCN2022132910-appb-000048
步骤一：化合物3A与化合物缩合反应得到化合物3B；Step 1: Condensation reaction of compound 3A and compound to obtain compound 3B;
步骤二：化合物3B与R 1-B(OH) 2Suzuki偶联反应得到化合物3C； Step 2: compound 3B is reacted with R 1 -B(OH) 2 Suzuki to obtain compound 3C;
步骤三：化合物3C与化合物3C-1Suzuki偶联反应得到化合物A 3。 Step 3: Suzuki coupling reaction of compound 3C and compound 3C-1 to obtain compound A 3 .
在一些具体实施方式中，反应路线3中，步骤一：将化合物3A用N，N-二甲基甲酰胺溶解，加入HATU、胺、化合物3A-1，滴加DIPEA，反应结束后，纯化得到化合物3B；In some specific embodiments, in reaction scheme 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;
步骤二：向所述化合物3B中加入R 1-B(OH) 2、1,4-二氧六环、水、碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应，纯化后得到化合物3C； 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;
步骤三：向所述化合物3C中加入化合物3C-1，加入1,4-二氧六环、水，室温搅拌下加入碳酸钾、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物反应，纯化得到化合物A 3。 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 .
合成路线4：Synthetic route 4:
Figure PCTCN2022132910-appb-000049
Figure PCTCN2022132910-appb-000049
步骤一：化合物2A与化合物2A-1缩合反应得到化合物4B；Step 1: Condensation reaction of compound 2A and compound 2A-1 to obtain compound 4B;
步骤二：化合物4B与对甲苯磺酰氯反应得到化合物4C；Step 2: Compound 4B is reacted with p-toluenesulfonyl chloride to obtain compound 4C;
步骤三：化合物4C与N，N-二异丙基乙胺(DIPEA)反应得到化合物4D；Step 3: react compound 4C with N,N-diisopropylethylamine (DIPEA) to obtain compound 4D;
步骤四：化合物4D脱氢反应得到化合物4E；Step 4: Dehydrogenation reaction of compound 4D to obtain compound 4E;
步骤五：化合物4E与化合物4E-1Suzuki偶联反应得到化合物A 4。 Step 5: Suzuki coupling reaction of compound 4E with compound 4E-1 to obtain compound A 4 .
在一些具体实施方式中，合成路线4中，步骤一：将化合物2A用N，N-二甲基甲酰胺溶解，加入HATU、化合物2A-2，室温条件下滴加DIPEA，反应结束后，纯化得到化合物4B；In some specific embodiments, in synthetic route 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;
步骤二：将所述化合物4B和三乙胺溶于四氢呋喃中，反应5分钟，将对甲苯磺酰氯加到反应体系中，反应结束后萃取、干燥，去除溶剂，得到化合物4C，并且将其直接用于下一步；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;
步骤三：将所述化合物4C溶于四氢呋喃溶液中，加入DIPEA，反应10小时，萃取，干燥，纯化后得到化合物4D；Step 3: Dissolving the compound 4C in tetrahydrofuran solution, adding DIPEA, reacting for 10 hours, extracting, drying, and purifying to obtain compound 4D;
步骤四：将所述化合物4D溶于无水二氯甲烷中，加入2,3-二氯-5,6-二氰基苯醌和4A分子筛，反应结束后，过滤并洗涤，去除溶剂，得到化合物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;
步骤五：将所述化合物4D按照合成路线1的方法和步骤进行反应后，得到化合物A 4。 Step 5: react the compound 4D according to the method and steps of the synthetic route 1 to obtain the compound A 4 .
本公开提供了一种药物组合物，所述药物组合物包含上述的化合物或其药学上可接受的盐和药学上可接受的辅料。The present disclosure provides a pharmaceutical composition, which comprises the above-mentioned compound or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
本公开提供了上述的化合物或其药学上可接受的盐、上述药物组合物在制备治疗患者的AhR介导的病症的药物中的应用。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.
本公开提供了上述的化合物或其药学上可接受的盐、上述药物组合物在制备AHR激动剂中的应用。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.
本公开涉及一种激活有需要的患者中的AhR的方法，其包含向所述患者施用上述化合物或其药学上可接受的盐、上述药物组合物。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.
本公开涉及一种用于治疗有需要的患者的AhR介导的病症的方法，其包含向所述患者施用上述化合物或其药学上可接受的盐、上述的药物组合物。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.
优选地，所述AhR介导的病症包括但不限于银屑病、关节炎、特应性皮炎、帕金森、多发性硬化症、炎症性肠炎、哮喘、系统性红斑狼疮、移植物抗宿主病、细菌性角膜炎、肿瘤。Preferably, 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.
本公开的化合物具有AhR抑制作用。Compounds of the present disclosure possess AhR inhibitory activity.
具体实施方式Detailed ways
根据本公开的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本公开上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。According to the above content of the present disclosure, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present disclosure, other various forms of modification, replacement or change can also be made.
I.定义I. Definition
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。Unless expressly stated otherwise, throughout the specification and claims, the term "comprise" or variations thereof such as "includes" or "includes" and the like will be understood to include the stated elements or constituents, and not Other elements or other components are not excluded.
本发明化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。外消旋体、非对映异构体、对映异构体都包括在本发明的范围之内。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.
在本公开中，
Figure PCTCN2022132910-appb-000050
是指取代基键合的位置。 In this disclosure,
Figure PCTCN2022132910-appb-000050
refers to the position where the substituent is bonded.
在本公开中，数字范围是指给定范围中的各个整数。例如，“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子；“C 1-3”是指该基团可具有1个碳原子、2个碳原子或3个碳原子。 In this disclosure, numerical ranges refer to individual integers within a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 1-3 " means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes that said event or circumstance occurs and that it does not.
术语“被取代的”或“取代”是指特定原子或基团上的任意一个或多个氢原子被取代基取代，只要特定原子或基团的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" or "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by a substituent, as long as the valence of the specified atom or group is normal and the substituted compound is stable of. When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically achievable basis.
当任何变量(例如R n)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因 此，例如，如果一个基团被一个至三个R所取代，则所述基团可以任选地至多被三个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When any variable (eg Rn ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with one to three R, said group may optionally be substituted with up to three R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
术语“烷基”指饱和的脂族烃基团，包括直链的或支链的饱和烃基，所述烃基具有所示出的碳原子数。如术语“C 1-6烷基”包括C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基，实例包括，但不限于，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、正己基、2-己基、3-己基等。其可以是二价的，例如亚甲基、亚乙基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms. For example, the term "C 1-6 alkyl" includes C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It can be divalent, eg methylene, ethylene.
术语“烷氧基”可以为直链、支化或环状的。烷氧基的碳原子数没有特别限制，但优选为1至20。其具体实例包括甲氧基、乙氧基、正丙氧基、异丙氧基(isopropoxy)、异丙基氧基(i-propyloxy)、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、新戊氧基、异戊氧基、正己氧基、3,3-二甲基丁氧基、2-乙基丁氧基、正辛氧基、正壬氧基、正癸氧基等，但不限于此。The term "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.
术语“羰基”或“羧基”包括化合物和片段的碳通过双键与氧原子连接的结构。含有羰基的部分的实例包括醛、酮、羧酸、酰胺、酯、酸酐等。The term "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.
术语“酰基”是羰基的碳原子连接到氢(即甲酰基)，脂族基团(C1-C6烷基，C1-C6烯基，C1-C6炔基，例如乙酰基)，环烷基(C3-C8环烷基)，杂环基(C3-C8杂环烷基和C5-C6杂芳基)，芳基(C6芳基，例如苯甲酰基)相连的羰基结构。酰基可以是未取代的或取代的酰基(例如水杨酰基)。The term "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).
在本公开中，卤素基团的实例可以包括氟、氯、溴或碘。In the present disclosure, examples of the halogen group may include fluorine, chlorine, bromine or iodine.
在本公开中，术语“环烷基”是指单环饱和烃体系，无杂原子和双键。例如，术语“C 3-6环烷基”的实例包括环丙基、环丁基、环戊基、环己基。 In this disclosure, the term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system free of heteroatoms and double bonds. For example, examples of the term "C 3-6 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
在本公开中，术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团，其通过从母体芳香环体系的单一碳原子上除去一个氢原子而得到。其包括饱和、部分不饱和的环，或芳香碳环稠合的芳环的双环基团。其具体实例包括苯基或萘基，但不限于此。In this disclosure, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-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.
在本公开中，术语“杂环烷基”是指具有环碳原子和1至2个环杂原子的5-12元饱和非芳香体系。杂环基的具体实例包括哌啶基或四氢吡咯基，但不限于此。In the present disclosure, the term "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.
在本公开中，术语“杂芳基”指包含至少一个独立地选自氮、氧和硫杂原子的一价芳基，杂芳基可为单环，也可以为多环体系，例如二环，其中两个或两个以上的环以并环、桥环或螺环形式存在，其中至少一个环含有一个或多个杂原子。杂芳基的具体实例包括吡啶基、噻吩基、咪唑基、嘧啶基、吡啶基、呋喃基、吡嗪基、噻唑基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、咪唑并吡啶基、苯并呋喃基、哒嗪基、异吲哚基、吡啶酮基，但不限于此。In this disclosure, the term "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. Specific examples of heteroaryl include pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, Imidazopyridyl, benzofuryl, pyridazinyl, isoindolyl, pyridonyl, but not limited thereto.
术语“杂环”是指具有环碳原子和1至2个环杂原子的5-12元饱和非芳香体系，其中杂原子独立地选自氮、硫或氧原子。在含有一或多个氮原子的杂环基团中，连接点可为碳或氮原子，只要原子价容许。杂环可为单环或多环体系，例如二环，其中两个或两个以上的环以并环、桥环或螺环形式存在，其中至少一个环含有一个或多个杂原子。在螺环杂环基中，两个不同的环共有一个原子，螺环杂环基的一个实例是氮杂螺戊烷基，但不限于此。The term "heterocycle" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. The heterocyclic ring can be a monocyclic or polycyclic ring system, such as a bicyclic ring, in which two or more rings exist in the form of fused rings, bridged rings or spiro rings, and at least one of the rings contains one or more heteroatoms. In a spiroheterocyclyl, an atom is shared by two different rings, an example of a spiroheterocyclyl is, but not limited to, azaspiropentyl.
术语“部分不饱和双环杂环”表示包含C原子和N、O、S等杂原子中的至少一种共同作为环成员的双环基团，该双环基团为部分不饱和的，其包含至少一个C-C双键，最大不饱和杂环包含环大小允许的最多的C-C双键以及C原子和杂原子的双键，部分不饱和双环杂环包含低于环大小允许的双键数量，部分不饱和双环杂环的具体实例包括但不限于苯并呋喃基、苯并噻吩基、喹喔啉基、喹唑啉基、异吲哚啉酮基、蝶啶基等。The term "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 Specific examples of heterocyclic rings include, but are not limited to, benzofuryl, benzothienyl, quinoxalinyl, quinazolinyl, isoindolinonyl, pteridinyl, and the like.
缩写：abbreviation:
Ts：对甲苯璜酰基；Ts: p-toluenesulfonyl;
DIPEA：N，N-二异丙基乙胺；DIPEA: N,N-Diisopropylethylamine;
药物或药物组合物drug or pharmaceutical composition
术语“药学上可接受的”是指在合理的医学判断的范围内适合用于与人类和动物的组织接触而没有，与合理利益/风险比相称的，过度毒性、刺激、过敏反应或其它问题或并发症的那些化合物、材料、组合物和/或剂型。The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without, commensurate with a reasonable benefit/risk ratio, undue toxicity, irritation, allergic response or other problems or complications of those compounds, materials, compositions and/or dosage forms.
术语“药学上可接受的盐”是指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例 如酸(包括有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)。The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy of the free acids and bases of the specified compound without adverse biological effects. For example acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
本公开的药物或药物组合物可以经口地、局部地、肠胃外地或粘膜地(例如，含服地、通过吸入或直肠地)以包含常规的非-毒性药学可接受的载体的剂量单位配制剂施用。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.
对于以片剂或胶囊形式的口服给药，活性药物组分可以与非-毒性的、药学可接受的辅料如粘结剂(例如，预胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素)；填料(例如，乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇和其它还原性和非-还原性糖类、微晶纤维素、硫酸钙或磷酸氢钙)；润滑剂(例如，硬脂酸镁、滑石粉或硅土、硬脂酸、硬脂基富马酸酯钠、甘油二十二烷酸酯、硬脂酸钙等)；崩解剂(例如，马铃薯淀粉或羟乙酸淀粉钠)；或润湿剂(例如，月桂基硫酸钠)、着色剂和调味剂、明胶、甜味剂、天然和合成的胶(如阿拉伯胶、黄蓍胶或藻朊酸盐)、缓冲盐、羧甲纤维素、聚乙二醇、蜡、等。对于以液体形式的口服给药，所述药物组分可以与非-毒性、药学可接受的惰性载体(例如，乙醇、甘油、水)、防沉降剂(例如，山梨糖醇糖浆、纤维素衍生物或氢化的可食用脂肪)、乳化剂(例如，卵磷脂或阿拉伯胶)、非-水性载体(例如，扁桃油、油酯类、乙醇或经分馏的植物油)、保藏剂(例如，p-羟基苯甲酸甲酯或p-羟基苯甲酸丙酯或山梨酸)等组合。还可以加入稳定剂如抗氧化剂(BHA、BHT、桔酸丙酯、抗坏血酸钠、柠檬酸)以稳定所述剂型。For oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized cornstarch, polyvinylpyrrolidone, or hypromellose based cellulose); fillers (for example, lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (such as , magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (for example, potato starch or hydroxy sodium starch acetate); or wetting agents (for example, sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth, or alginates), Buffer salts, carmellose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical composition can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), anti-settling agent (e.g., sorbitol syrup, cellulose-derived or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia), non-aqueous carriers (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils), preservatives (e.g., p- methyl hydroxybenzoate or p-hydroxybenzoate propyl or sorbic acid) and other combinations. Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.
包含作为活性化合物的片剂可以通过本领域熟知的方法包衣。包含作为活性化合物的式I化合物的本公开的所述组合物还可以引入小珠、微球或微胶囊，例如由聚乙醇酸/乳酸(PGLA)构建的。用于口服给药的液体的制剂可以采取例如溶液，糖浆剂，乳液或混悬液的形式或者它们可以呈现为在使用前用水或其它适宜的辅料重构的干产品。用于口服给药的制剂可以适宜地配制以使活性化合物受控或延迟地释放。Tablets containing as active compound may be coated by methods well known in the art. The compositions of the present disclosure comprising a compound of formula I as the active compound may also be incorporated into beads, microspheres or microcapsules, for example constructed of polyglycolic/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may suitably be formulated so as to provide controlled or delayed release of the active compound.
本公开的药物或药物组合物可以经肠胃外递送，即，通过静脉内(i.v.)、脑室内(i.c.v.)、皮下(s.c.)、腹膜内(i.p.)、肌内(i.m.)、皮下(s.d.)或皮内(i.d.)施用，通过直接注射，经例如快速浓注或连续输液。用于注射的配制剂可以单位剂型呈现，例如在具有添加的保藏剂的安瓿瓶或多-剂量容器中。所述组合物可以采用赋形剂(excipient)的形状，在油或水性载体中的混悬液、溶液或乳液的形式，并可以包含配制试剂如防沉降剂、稳定剂和/或分散剂。备选地，所述活性成分可以以粉末形式在使用前用适宜的载体(例如无菌无热原水)重构。A drug or pharmaceutical composition of the present disclosure may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.) Or intradermal (i.d.) administration, by direct injection, via eg bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with added preservatives. The compositions may take such forms as excipients, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as anti-settling, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use.
本公开的药物或药物组合物还可以配制用于直肠给药，例如呈栓剂或保留灌肠(例如，包含常规栓剂基质如可可油或其它甘油酯)。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).
术语“治疗”包括抑制、缓解、预防或消除与所治疗的疾病、病症或失调相关的一种或多种症状或副作用。术语“有效量”或“治疗有效量”是指足以治疗、抑制或减轻被治疗的疾病状态的一种或多种症状或以其它方式提供期望的药理学和/或生理学作用的剂量。精确的剂量将根据多种因素而变化，如受试者依赖的变量(例如，年龄、免疫系统健康等)、疾病或病，以及所施用的治疗。有效量的效果可以相对于对照。这些对照在本领域中是已知的并且在本文中讨论，并且可以是例如在药物或药物组合施用之前或没有施用时的受试者的状况，或在药物组合的情况下，可以将组合效果与仅施用一种药物的效果进行比较。The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated. The term "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.
术语“药物组合物”意指包含本公开所述化合物或其药学上可接受的盐，以及依施用方式和剂型的性质而定的至少一种选自以下药学上可接受的成分的组合物，包括但不限于：载体、稀释剂、佐剂、赋形剂、防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂、香味剂、抗菌剂、抗真菌剂、润滑剂、分散剂、温敏材料、温度调节剂、黏附剂、稳定剂、助悬剂等。The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one selected from the following pharmaceutically acceptable ingredients depending on the mode of administration and the nature of the dosage form, Including but not limited to: carrier, diluent, adjuvant, excipient, preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, flavoring agent, antibacterial agent , antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.
II.实施例II. Example
下面参照实施例进一步阐释本公开。对本公开的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本公开限定为所公开的精确形式，并且很显然，根据本公开说明书的教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本公开的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本公开的各种不同的示例性实施方案以及各种不同的选择和改变。The present disclosure is further explained below with reference to examples. The descriptions of specific exemplary embodiments of the present disclosure are presented for purposes of illustration and illustration. These descriptions are not intended to limit the disclosure to the precise form disclosed, and obviously many modifications and variations are possible from the teachings of the present disclosure. The exemplary embodiments were chosen and described in order to explain the specific principles of the disclosure and its practical application, thereby enabling those skilled in the art to make and use various exemplary embodiments of the disclosure, as well as various Choose and change.
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。The experimental methods used in the following examples are conventional methods unless otherwise specified.
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.
由化学式(I)表示的化合物可以如下述合成路线1、2、3或4制备。取代基可以通过该技术领域中已知的方法来结合，取代基的种类、位置或个数可以根据该技术领域中已知的技术而变更。可以如下述合成路线1、2、3或4那样结合取代基，但并不限定于此。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.
本公开化合物采用以下合成路线制备：Compounds of the present disclosure are prepared using the following synthetic routes:
合成路线1：Synthetic route 1:
Figure PCTCN2022132910-appb-000051
Figure PCTCN2022132910-appb-000051
步骤一：向单口瓶中加入6-氯-3-R1基吡啶甲酸甲酯，加入1A-1，1，4-二氧六环和水，加入碳酸钾，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，用硅胶纯化，得到化合物1B；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;
步骤二：向单口瓶中加入1B,用甲醇溶解，滴加2N NaOH水溶液，室温反应4小时，用2N盐酸调节PH至3-4，用乙酸乙酯和水萃取，合并有机相，旋除溶剂得到化合物1C；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;
步骤三：将1C用N，N-二甲基甲酰胺溶解，加入HATU，胺，滴加DIPEA，室温反应。反应结束后，旋除溶剂，用硅胶纯化，得到化合物A 1。 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 .
合成路线2：Synthetic route 2:
Figure PCTCN2022132910-appb-000052
Figure PCTCN2022132910-appb-000052
步骤一：将6-氯-3-R1基吡啶甲酸用N，N-二甲基甲酰胺溶解，加入HATU，胺，滴加DIPEA，室温反应一小时。反应结束后，旋除溶剂，用硅胶纯化,得到化合物2B；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;
步骤二：向单口瓶中加入2B，加入2B-1，1，4-二氧六环和水，加入碳酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，用硅胶纯化，得到化合物A 2。 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 .
合成路线3：Synthetic route 3:
Figure PCTCN2022132910-appb-000053
Figure PCTCN2022132910-appb-000053
步骤一：将3-溴-6-氯-2-吡啶甲酸用N，N-二甲基甲酰胺溶解，加入HATU，胺，滴加DIPEA，室温反应。反应结束后，旋除溶剂，用硅胶纯化,得到化合物3B；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;
步骤二：向单口瓶中加入3B，加入R1-B(OH)2，1，4-二氧六环和水，碳酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，用硅胶纯化得到化合物3C；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;
步骤三：向单口瓶中加入3C，加入硼酸，1，4-二氧六环和水，室温搅拌下加入碳酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，氩气置换3次，升温至100摄氏度反应6小时，自然冷却至室温，用硅胶纯化，得到化合物A 3。 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 .
合成路线4：Synthetic route 4:
Figure PCTCN2022132910-appb-000054
Figure PCTCN2022132910-appb-000054
步骤一：将6-氯-3-R1基吡啶甲酸用N，N-二甲基甲酰胺溶解，加入HATU，D L-苯甘胺醇，室温条件下滴加DIPEA，滴加结束后，室温反应2小时。反应结束后，旋除溶剂，用硅胶纯化,得到化合物4B；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;
步骤二：将4B和三乙胺溶于四氢呋喃中，0摄氏度下搅拌5分钟，然后将对甲苯磺酰氯缓慢滴加到反应体系中，滴加完毕后升至室温反应6小时。旋除溶剂，通过乙酸乙酯和水萃取三次，合并有机相，用无水硫酸钠干燥，旋除溶剂，得到粗品(4C)直接用于下一步；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;
步骤三：将4C溶于四氢呋喃溶液中，加入DIPEA，升温至75摄氏度，保温反应10小时。将反应液旋除溶溶剂，加入乙酸乙酯和水萃取三次，合并有机相，用无水硫酸钠干燥，旋干溶剂，用硅胶纯化得到4D；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;
步骤四：将4D溶于无水二氯甲烷中，加入2,3-二氯-5,6-二氰基苯醌和4A分子筛，室温反应4小时。反应结束后，抽滤，滤饼用无水二氯甲烷洗涤2次，旋除溶剂得到4E；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;
步骤五：将4E按照合成路线1的方法进行操作后，得到最后的终产物。Step 5: After 4E is operated according to the method of synthetic route 1, the final final product is obtained.
实施例1:化合物1的制备Embodiment 1: the preparation of compound 1
以合成路线1的方式制备化合物1，具体反应如下：Compound 1 is prepared in the manner of synthetic route 1, and the specific reaction is as follows:
Figure PCTCN2022132910-appb-000055
Figure PCTCN2022132910-appb-000055
步骤一：向单口瓶中加入6-氯-3-甲基吡啶甲酸甲酯(185.6mg，1mmol)，加入5-嘧啶硼酸(185.9mg，1.5mmol)，1，4-二氧六环(10mL)和水(2mL)，室温搅拌下加入碳酸钾(414mg，3mmol)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40.8mg,0.05mmol)，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，残留物加入乙酸乙酯和水萃取，分液，有机相水洗至中性，加入无水硫酸钠干燥，过滤，滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚＝1/5)，得到化合物1A(3-甲基-6-(嘧啶-5-基)吡啶甲酸甲酯)184.1mg，收率：80％，Ms+1:230.1；Step 1: Add methyl 6-chloro-3-picolinate (185.6mg, 1mmol) to a single-necked bottle, add 5-pyrimidineboronic acid (185.9mg, 1.5mmol), 1,4-dioxane (10mL ) and water (2mL), potassium carbonate (414mg, 3mmol) was added under stirring at room temperature, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (40.8mg , 0.05mmol), replaced with argon 3 times, raised the temperature to 95°C for 4 hours, cooled naturally to room temperature, evaporated the solvent under reduced pressure, extracted the residue with ethyl acetate and water, separated the liquid, washed the organic phase with water until neutral, Add anhydrous sodium sulfate to dry, filter, and the filtrate is purified by silica gel (ethyl acetate/petroleum ether=1/5) after evaporating the solvent under reduced pressure to obtain compound 1A (3-methyl-6-(pyrimidin-5-yl) Methyl picolinate) 184.1 mg, yield: 80%, Ms+1: 230.1;
步骤二：向单口瓶中加入3-甲基-6-(嘧啶-5-基)吡啶甲酸甲酯(92mg，0.5mmol),加入甲醇(5mL)溶解，于0℃下滴加2N NaOH水溶液(1mL)，滴加结束后，室温反应4小时，TLC点板，原料反应完全，用2N盐酸调节PH至3-4，用乙酸乙酯和水萃取三次，合并有机相，旋除溶剂得到化合物1B(3-甲基-6-(嘧啶-5-基)吡啶甲酸)的粗品80mg，直接用于下一步。Ms+1:216.1；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 The crude product of (3-methyl-6-(pyrimidin-5-yl)picolinic acid), 80 mg, was directly used in the next step. Ms+1:216.1;
步骤三：将上一步得到的粗品用N，N-二甲基甲酰胺溶解至于50mL单口瓶中，加入HATU(212.8mg，0.56mmol)，4-溴苯胺(78mg，0.45mmol)，室温条件下滴加DIPEA(144mg，1.12mmol)，滴加结束后，室温反应一小时。反应结束后，旋除溶剂，用硅胶纯化(乙酸乙酯/石油醚＝1/3)，得到化合物1(N-(4-溴苯基)-3-甲基-6-(嘧啶-5-基)吡啶酰胺)45mg，收率：32.7％，Ms+1:370.2。Step 3: Dissolve the crude product obtained in the previous step with N,N-dimethylformamide into a 50mL single-necked bottle, add HATU (212.8mg, 0.56mmol), 4-bromoaniline (78mg, 0.45mmol), at room temperature Add DIPEA (144mg, 1.12mmol) dropwise, and react at room temperature for one hour after the dropwise addition. After the reaction, the solvent was removed and purified with silica gel (ethyl acetate/petroleum ether=1/3) to obtain compound 1 (N-(4-bromophenyl)-3-methyl-6-(pyrimidine-5- Base) pyridine amide) 45 mg, yield: 32.7%, Ms+1: 370.2.
表1 按照实施例1的方法合成的化合物和数据表征Table 1 Compounds synthesized according to the method of Example 1 and data characterization
Figure PCTCN2022132910-appb-000056
Figure PCTCN2022132910-appb-000056
Figure PCTCN2022132910-appb-000057
Figure PCTCN2022132910-appb-000057
Figure PCTCN2022132910-appb-000058
Figure PCTCN2022132910-appb-000058
Figure PCTCN2022132910-appb-000059
Figure PCTCN2022132910-appb-000059
实施例2:化合物14的制备Embodiment 2: the preparation of compound 14
以合成路线2的方式制备化合物14，具体反应如下：Compound 14 was prepared in the manner of synthetic route 2, and the specific reaction was as follows:
Figure PCTCN2022132910-appb-000060
Figure PCTCN2022132910-appb-000060
步骤一：将6-氯-3-甲基吡啶甲酸用(79.8mg，0.47mmol)N，N-二甲基甲酰胺溶解至于50mL单口瓶中，加入HATU(212.8mg，0.56mmol)，间甲基苯胺(48mg，0.45mmol)，室温条件下滴加DIPEA(144mg，1.12mmol)，滴加结束后，室温反应一小时。反应结束后，旋除溶剂，用硅胶纯化(乙酸乙酯/石油醚＝1/3),得到化合物14A(6-氯-3-甲基-N-(间甲苯基)吡啶酰胺)56.5mg，收率：46.6％，Ms+1:260.1；Step 1: Dissolve 6-chloro-3-picolinic acid with (79.8mg, 0.47mmol) N,N-dimethylformamide into a 50mL single-necked bottle, add HATU (212.8mg, 0.56mmol), m-formazine Aniline (48mg, 0.45mmol), DIPEA (144mg, 1.12mmol) was added dropwise at room temperature, and after the addition was completed, the reaction was carried out at room temperature for one hour. After the reaction, the solvent was removed and purified with silica gel (ethyl acetate/petroleum ether=1/3) to obtain 56.5 mg of compound 14A (6-chloro-3-methyl-N-(m-tolyl)pyridine amide). Yield: 46.6%, Ms+1: 260.1;
步骤二：向单口瓶中加入6-氯-3-甲基-N-(间甲苯基)吡啶酰胺(56.5mg，0.22mmol)，加入吲唑-6-硼酸(53mg，0.33mmol)，1，4-二氧六环(5mL)和水(1mL)，室温搅拌下加入碳酸钾(91mg，0.66mmol)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8mg,0.01mmol)，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，残留物加入乙酸乙酯和水萃取，分液，有机相水洗至中性，加入无水硫酸钠干燥，过滤，滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚＝1/3)，得到化合物14(6-(1H-吲唑-6-基)-3-甲基-N-(间甲苯基)吡啶酰胺)52mg，收率：69.5％，Ms+1:343.2。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/petroleum ether=1/3) after the solvent was evaporated under reduced pressure to obtain compound 14 (6-(1H-ind Azol-6-yl)-3-methyl-N-(m-tolyl)pyridinamide) 52 mg, yield: 69.5%, Ms+1: 343.2.
表2 按照实施例14的方法合成的化合物和数据表征Table 2 Compounds and data characterizations synthesized according to the method of Example 14
Figure PCTCN2022132910-appb-000061
Figure PCTCN2022132910-appb-000061
Figure PCTCN2022132910-appb-000062
Figure PCTCN2022132910-appb-000062
Figure PCTCN2022132910-appb-000063
Figure PCTCN2022132910-appb-000063
Figure PCTCN2022132910-appb-000064
Figure PCTCN2022132910-appb-000064
Figure PCTCN2022132910-appb-000065
Figure PCTCN2022132910-appb-000065
Figure PCTCN2022132910-appb-000066
Figure PCTCN2022132910-appb-000066
Figure PCTCN2022132910-appb-000067
Figure PCTCN2022132910-appb-000067
Figure PCTCN2022132910-appb-000068
Figure PCTCN2022132910-appb-000068
Figure PCTCN2022132910-appb-000069
Figure PCTCN2022132910-appb-000069
实施例3:化合物38的制备Embodiment 3: the preparation of compound 38
以合成路线3的方式制备化合物38，具体反应如下：Compound 38 was prepared in the manner of synthetic route 3, and the specific reaction was as follows:
Figure PCTCN2022132910-appb-000070
Figure PCTCN2022132910-appb-000070
步骤一：将3-溴-6-氯-2-吡啶甲酸用(237mg，1mmol)N，N-二甲基甲酰胺溶解至于50mL单口瓶中，加入HATU(456mg，1.2mmol)，对三氟甲基苯胺(177.2mg，1.1mmol)，室温条件下滴加DIPEA(387mg，3mmol)，滴加结束后，室温反应一小时。反应结束后，旋除溶剂，用硅胶纯化(乙酸乙酯/石油醚＝1/3),得到化合物38A(3-溴-6-氯-N-(4-(三氟甲基)苯基)吡啶酰胺)265mg，收率：69.8％，Ms+1:379.1；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. After the reaction, the solvent was removed and purified with silica gel (ethyl acetate/petroleum ether=1/3) to obtain compound 38A (3-bromo-6-chloro-N-(4-(trifluoromethyl)phenyl) Pyridinamide) 265mg, yield: 69.8%, Ms+1: 379.1;
步骤二：向单口瓶中加入3-溴-6-氯-N-(4-(三氟甲基)苯基)吡啶酰胺(75.8mg，0.2mmol)，加入环丙基硼酸(25.8mg，0.3mmol)，1，4-二氧六环(5mL)和水(1mL)，室温搅拌下加入碳酸钾(82.8mg，0.6mmol)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(16mg,0.02mmol)，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，残留物加入乙酸乙酯和水萃取，分液，有机相水洗至中性，加入无水硫酸钠干燥，过滤，滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚＝1/3)，得到化合物38B(5-氯-3-环丙基-N-(4-(三氟甲基)苯基)吡啶酰胺)37mg，收率：54.2％，Ms+1:341.1；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 (ethyl acetate/petroleum ether=1/3) after removing the solvent under reduced pressure to obtain compound 38B ( 5-Chloro-3-cyclopropyl-N-(4-(trifluoromethyl)phenyl)pyridinamide) 37 mg, yield: 54.2%, Ms+1: 341.1;
步骤三：向单口瓶中加入5-氯-3-环丙基-N-(4-(三氟甲基)苯基)吡啶酰胺(18mg，0.053mmol)，加入1-甲基-1H-吡唑-4-硼酸(10mg，0.08mmol)，1，4-二氧六环(5mL)和水(1mL)，室温搅拌下加入碳酸钾(18mg，0.13mmol)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(3mg,0.004mmol)，氩气置换3次，升温至100摄氏度反应6小时，自然冷却至室温，减压蒸除溶剂，残留物加入乙酸乙酯和水萃取，分液，有机相水洗至中性，加入无水硫酸钠干燥，过滤，滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚＝1/4)，得到化合物38(3-环丙基-6-(1-甲基-1H-吡唑-4-基)-N-(4(三氟甲基)苯基)吡啶酰胺)6mg，收率：29.3％，Ms+1:387.1。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 (ethyl acetate/petroleum ether=1 /4), to obtain compound 38 (3-cyclopropyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(4(trifluoromethyl)phenyl)pyridineamide) 6mg, Yield: 29.3%, Ms+1: 387.1.
表3 按照实施例38的方法合成的化合物和数据表征Table 3 Compounds and data characterizations synthesized according to the method of Example 38
Figure PCTCN2022132910-appb-000071
Figure PCTCN2022132910-appb-000071
实施例4:化合物42的合成Embodiment 4: the synthesis of compound 42
具体反应如下：The specific reaction is as follows:
Figure PCTCN2022132910-appb-000072
Figure PCTCN2022132910-appb-000072
步骤一：将6-氯-3-甲基吡啶甲酸用(171.6mg，1mmol)N，N-二甲基甲酰胺溶解至于50mL单口瓶中，加入HATU(456mg，1.2mmol)，D L-苯甘胺醇(165.4mg，1.2mmol)，室温条件下滴加DIPEA(322.5mg，2.5mmol)，滴加结束后，室温反应2小时。反应结束后，旋除溶剂，用硅胶纯化(乙酸乙酯/石油醚＝1/4),得到 化合物42A(6-氯-N-(2-羟基-1-苯乙基)-3-甲基吡啶酰胺)220mg，收率:75.8％，Ms+1:291.1；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. After the reaction, the solvent was removed and purified with silica gel (ethyl acetate/petroleum ether=1/4) to obtain compound 42A (6-chloro-N-(2-hydroxyl-1-phenylethyl)-3-methyl Pyridinamide) 220mg, yield: 75.8%, Ms+1: 291.1;
步骤二：将6-氯-N-(2-羟基-1-苯乙基)-3-甲基吡啶酰胺(220mg，0.76mmol)和三乙胺(191.9mg，1.9mmol)溶于四氢呋喃中，至于50mL单口瓶中，0摄氏度下搅拌5分钟，然后将对甲苯磺酰氯(289.8mg，1.52mmol)缓慢滴加到反应体系中，滴加完毕后升至室温反应6小时。通过LC-Ms检测，原料反应完全。旋除溶剂，通过乙酸乙酯和水萃取三次，合并有机相，用无水硫酸钠干燥，旋除溶剂，得淡黄色粗品(化合物42B)直接用于下一步；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. The solvent was spun off, extracted three times with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spun off to obtain a light yellow crude product (compound 42B) which was directly used in the next step;
步骤三：将上一步得到的粗品溶于20mL四氢呋喃溶液置于50mL单口瓶中，加入DIPEA(588.24mg，4.56mmol)，升温至75摄氏度，保温反应10小时。用LC-Ms监测原料反应完全。将反应液旋除溶溶剂，加入乙酸乙酯和水萃取三次，合并有机相，用无水硫酸钠干燥，旋干溶剂，用硅胶纯化(乙酸乙酯/石油醚＝1/3)得到类白色固体(化合物42C，3-(6-氯-3-甲基吡啶-2-基)-4-苯基-4,5-二氢恶唑)180mg，收率:87％，Ms+1:273.1；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. Spin the reaction solution to remove the solvent, add ethyl acetate and water to extract three times, combine the organic phases, dry with anhydrous sodium sulfate, spin to dry the solvent, and purify with silica gel (ethyl acetate/petroleum ether=1/3) to obtain off-white Solid (compound 42C, 3-(6-chloro-3-methylpyridin-2-yl)-4-phenyl-4,5-dihydrooxazole) 180 mg, yield: 87%, Ms+1: 273.1 ;
步骤四：将3-(6-氯-3-甲基吡啶-2-基)-4-苯基-4,5-二氢恶唑(180mg，0.66mmol)溶于无水二氯甲烷中，加入2,3-二氯-5,6-二氰基苯醌(300mg，1.32mmol)和4A分子筛(100mg)，室温反应4小时。用LC-Ms监测原料反应完全。反应结束后，抽滤，滤饼用无水二氯甲烷洗涤2次，旋除溶剂得到淡黄色油状物化合物42D(2-(6-氯-3-甲基吡啶-2-基)-4-苯恶唑)112mg，收率:99％，Ms+1:271.1；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. After the reaction, filter with suction, wash the filter cake twice with anhydrous dichloromethane, and spin off the solvent to obtain light yellow oil compound 42D (2-(6-chloro-3-methylpyridin-2-yl)-4- Benzoxazole) 112mg, yield: 99%, Ms+1: 271.1;
步骤五：将2-(6-氯-3-甲基吡啶-2-基)-4-苯恶唑56mg按照实施例1的方法进行操作后，得到2-(3-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-4-苯恶唑30mg，收率:45.8％，Ms+1:317.1。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.
表4 按照实施例42的方法合成的化合物和数据表征Table 4 Compounds and data characterizations synthesized according to the method of Example 42
Figure PCTCN2022132910-appb-000073
Figure PCTCN2022132910-appb-000073
Figure PCTCN2022132910-appb-000074
Figure PCTCN2022132910-appb-000074
实施例5:化合物92的制备Embodiment 5: the preparation of compound 92
以合成路线2的方式制备化合物92，具体反应如下：Compound 92 was prepared in the manner of synthetic route 2, and the specific reaction was as follows:
Figure PCTCN2022132910-appb-000075
Figure PCTCN2022132910-appb-000075
步骤一：将6-氯-3-甲基吡啶甲酸(798mg，4.7mmol)用N，N-二甲基甲酰胺溶解至于50mL单口瓶中，加入HATU(2128mg，5.6mmol)，间三氟甲基苯胺(720mg，4.5mmol)，室温条件下滴加DIPEA(1440mg，11.2mmol)，滴加结束后，室温反应一小时。反应结束后，旋除溶剂，用硅胶纯化(乙酸乙酯/石油醚＝1/3),得到化合物92A(6-氯-3-甲基-N-(间三氟甲苯基)吡啶酰胺)960mg，收率：65％，Ms+1：315.1；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. After the reaction, the solvent was removed and purified with silica gel (ethyl acetate/petroleum ether=1/3) to obtain 960 mg of compound 92A (6-chloro-3-methyl-N-(m-trifluoromethylphenyl)pyridine amide) , Yield: 65%, Ms+1: 315.1;
步骤二：向单口瓶中加入6-氯-3-三氟甲基-N-(间三氟甲苯基)吡啶酰胺(31.5mg，0.1mmol)，加入4-吡唑硼酸频哪醇酯(19.4mg，0.1mmol)，1，4-二氧六环(5mL)和水(1mL)，室温搅拌下加入碳酸钾(27.6mg，0.2mmol)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8mg,0.01mmol)，氩气置换3次，升温至95摄氏度反应4小时，自然冷却至室温，减压蒸除溶剂，残留物加入乙酸乙酯和水萃取，分液，有机相水洗至中性，加入无水硫酸钠干燥，过滤，滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚＝1/3)，得到化合物92B(3-甲基-6-吡唑-4-基-N-三氟甲基吡啶甲酰胺)32mg，收率：92.2％，Ms+1:347.2。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 silica gel (ethyl acetate/petroleum ether=1/3) to obtain Compound 92B (3-methyl-6-pyrazol-4-yl-N-trifluoromethylpyridinecarboxamide) 32 mg, yield: 92.2%, Ms+1: 347.2.
步骤三：向单口瓶中加入3-甲基-6-吡唑-4-基-N-三氟甲基吡啶甲酰胺(32mg，0.09mmol)，加入二氯甲烷(5mL)，室温搅拌下加入三乙胺(19mg，0.19mmol)，将体系降温至0摄氏度，滴加甲基磺酰氯(11mg，0.1mmol)，升温至25摄氏度反应2小时，减压蒸除溶剂，残留物加入乙酸乙酯和水萃取，分液，有机相水洗至中性，加入无水硫酸钠干燥，过滤，滤液减压蒸除溶剂后用硅胶纯化(乙酸乙酯/石油醚＝1/3)，得到化合物92(3-甲基-6-甲磺酰基-4-吡唑-N-三氟甲基苯吡啶甲酰胺)32mg，收率：83.7％，Ms+1:425.1。Step 3: Add 3-methyl-6-pyrazol-4-yl-N-trifluoromethylpyridinecarboxamide (32mg, 0.09mmol) to the one-necked bottle, add dichloromethane (5mL), and add under stirring at room temperature Triethylamine (19 mg, 0.19 mmol), the system was cooled to 0 degrees Celsius, methanesulfonyl chloride (11 mg, 0.1 mmol) was added dropwise, the temperature was raised to 25 degrees Celsius for 2 hours, the solvent was evaporated under reduced pressure, and ethyl acetate was added 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 (ethyl acetate/petroleum ether=1/3) after removing the solvent under reduced pressure to obtain compound 92 ( 3-methyl-6-methylsulfonyl-4-pyrazole-N-trifluoromethylphenylpyridinecarboxamide) 32 mg, yield: 83.7%, Ms+1: 425.1.
表5 按照实施例92的方法合成的化合物和数据表征Table 5 Compounds and data characterizations synthesized according to the method of Example 92
Figure PCTCN2022132910-appb-000076
Figure PCTCN2022132910-appb-000076
Figure PCTCN2022132910-appb-000077
Figure PCTCN2022132910-appb-000077
实施例6:化合物46的制备Embodiment 6: the preparation of compound 46
Figure PCTCN2022132910-appb-000078
Figure PCTCN2022132910-appb-000078
将6-氯-3-甲基-N-(4-(三氟甲基)苯基)吡啶酰胺(31.4mg，0.1mmol)溶于无水的N-甲基吡咯烷酮(5mL)中，加入碳酸钾(41.4mg，0.3mmol)，升温至165摄氏度反应6小时，自然冷却至室温，用硅胶纯化(乙酸乙酯/石油醚＝1/3)得到3-甲基-6-吗啉-N-(4-(三氟甲基)苯基)吡啶酰胺20mg，收率：54.8％，Ms+1:366.1。 1H NMR(400MHz,CDCl3)δ9.13(s,1H),7.84-7.78(m,2H),7.72-7.66(m,2H),7.42(m,1H),7.13(d,J＝8.6Hz,1H),3.86-3.82(m,4H),3.79-3.75(m,4H),2.62(d,J＝1.0Hz,3H)。 Dissolve 6-chloro-3-methyl-N-(4-(trifluoromethyl)phenyl)pyridineamide (31.4 mg, 0.1 mmol) in anhydrous N-methylpyrrolidone (5 mL), add carbonic acid Potassium (41.4 mg, 0.3 mmol), heated to 165 degrees Celsius for 6 hours, naturally cooled to room temperature, purified with silica gel (ethyl acetate/petroleum ether=1/3) to obtain 3-methyl-6-morpholine-N- (4-(trifluoromethyl)phenyl)pyridine amide 20 mg, yield: 54.8%, Ms+1: 366.1. 1 H NMR (400MHz, CDCl3) δ9.13(s, 1H), 7.84-7.78(m, 2H), 7.72-7.66(m, 2H), 7.42(m, 1H), 7.13(d, J=8.6Hz , 1H), 3.86-3.82 (m, 4H), 3.79-3.75 (m, 4H), 2.62 (d, J=1.0Hz, 3H).
实施例7:本公开化合物体外激动AhR靶点的效果实验Embodiment 7: The effect experiment of the compound of the present disclosure agonizing the AhR target in vitro
以上化合物的体外活性在以下测定中证明：The in vitro activity of the above compounds was demonstrated in the following assays:
使用HepG2-Lucia TM AhR细胞来对小分子化合物激动芳烃受体(aryl hydrocarbon receptor,AhR)进行筛选。HepG2-Lucia TM AhR细胞是由人类HepG2肝癌细胞系改造而来，用于通过监测荧光素酶报告蛋白的活性来研究AhR基因组信号传导诱导。 HepG2-Lucia TM AhR cells were used to screen small molecular compounds that stimulate aryl hydrocarbon receptor (AhR). HepG2-Lucia TM AhR cells are engineered from the human HepG2 hepatoma cell line and used to study AhR genome signaling induction by monitoring the activity of a luciferase reporter protein.
(1)实验材料(1) Experimental materials
DMEM培养基购自Gibco公司，青、链霉素购自Hyclone公司，Tapinarof购自MedChemExpress(MCE)公司，Dual Luciferase Reporter Assay Kit购自诺唯赞生物科技有限公司。DMEM medium was purchased from Gibco Company, penicillin and streptomycin were purchased from Hyclone Company, Tapinarof was purchased from MedChemExpress (MCE) Company, and Dual Luciferase Reporter Assay Kit was purchased from Novozyme Biotechnology Co., Ltd.
(2)实验方法(2) Experimental method
HepG2-Lucia TM AhR细胞采用DMEM+10％FBS+1％青/链霉素培养基，置于37℃、5％CO 2的培养箱中培养。实验时，消化收集处于对数生长期的HepG2-Lucia TM AhR细胞，以8×10 3cells/well接种于96孔板中，置于37℃、5％CO 2的细胞培养箱中培养过夜。次日，用培养基稀释待测化合物到相应浓度(0.001-10μM)并加入到96孔板相应孔中，每个样品浓度3个复孔，每块板同时设置3个溶剂对照孔和3个阳性药(Tapinarof 10μM)对照孔，每次测试同时也将阳性药Tapinarof稀释后加入测试，加药后将96孔板置于37℃、5％CO 2的细胞培养箱中培养24h。培养结束前10min，将Dual Luciferase Reporter Assay Kit中的5×Cell Lysis Buffer和ddH 2O按照1:4的比例混合制备成1×Cell Lysis Buffer备用，培养结束后，去掉培养基，每孔加入20μL 1×Cell Lysis Buffer，置于水平振荡仪上振荡15min，使细胞充分裂解。期间，以50:1的比例将适量的反应终止缓冲液(Stop&Reaction Buffer)和荧光素酶底物(Renilla Substrate)混匀备用(避光)，同时准备好不透光的96孔白板。细胞裂解完成后将细胞裂解液(取13μL)转移至96孔白板的对应孔中，使用微孔板发光检测仪测定结果。并按照以下公式计算DRE荧光素酶活性倍数(DRE Luciferase activity(fold))： HepG2-Lucia TM AhR cells were cultured in an incubator at 37°C and 5% CO 2 in DMEM+10% FBS+1% penicillin/streptomycin medium. During the experiment, the HepG2-Lucia TM AhR cells in the logarithmic growth phase were digested and collected, seeded in a 96-well plate at 8×10 3 cells/well, and cultured overnight in a cell culture incubator at 37°C and 5% CO 2 . The next day, dilute the test compound to the corresponding concentration (0.001-10μM) with the culture medium and add it to the corresponding well of the 96-well plate. There are 3 duplicate wells for each sample concentration, and 3 solvent control wells and 3 solvent control wells are set on each plate. Positive drug (Tapinarof 10μM) control wells, each test is also diluted positive drug Tapinarof and added to the test. After adding the drug, the 96-well plate was placed in a cell culture incubator at 37°C and 5% CO 2 for 24 hours. 10 minutes before the end of the 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 μL to each well 1×Cell Lysis Buffer, place on a horizontal shaker and shake for 15 minutes to fully lyse the cells. During this period, mix the appropriate amount of reaction stop buffer (Stop&Reaction Buffer) and luciferase substrate (Renilla Substrate) in a ratio of 50:1 for use (protect from light), and prepare a light-tight 96-well white plate at the same time. After the cell lysis was completed, the cell lysate (13 μL) was transferred to the corresponding well of a 96-well white plate, and the results were measured using a microplate luminescence detector. And calculate the DRE luciferase activity fold (DRE Luciferase activity (fold)) according to the following formula:
DRE荧光素酶活性倍数＝样品复孔平均值/溶剂对照复孔平均值DRE luciferase activity multiple = average value of duplicate wells of sample / average value of duplicate wells of solvent control
通过样品和阳性药Tapinarof(10μM)的荧光素酶活性倍数可评估样品对AhR的激动效果。最后，使用Graphpad Prism 5.0软件拟合曲线并计算出待测化合物激动AhR靶点的EC 50值，如下表所示，其中，“AAAAA”表示EC 50＜20nM；“AAAA”表示EC 50大于等于20nM且小于200nM；“AAA”表示EC 50大于等于200nM且小于等于500nM；“AA”表示EC 50大于等于500nM且小于等于1000nM；“A”表示EC 50＞1000nM；对于激动倍数值，其中“BBB”表示高于10倍；“BB”表示倍数大于等于5且小于等于10；“B”表示倍数小于5。 The agonistic effect of the sample on AhR can be evaluated by the multiple of the luciferase activity of the sample and the positive drug Tapinarof (10 μM). Finally, use the Graphpad Prism 5.0 software to fit the curve and calculate the 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.
表6 体外测定各实施例化合物的EC 50值和激动效果 Table 6 EC50 value and agonistic effect of each embodiment compound determined in vitro
化合物compound EC 50/nm EC50 /nm 激动效应Agitation effect 化合物compound EC 50/nm EC50 /nm 激动效应Agitation effect
11 AAAAAAAAAA BBBB 2525 AAAAAA BBBB
22 AAAAAAAA BBBB 2626 AAAAAA BBBB
33 AAAAAAAA BB 2727 AA BBBB
44 AA BB 2828 AAAAAA BB
55 AA BB 2929 AAAAAAAA BBBB
66 AAAAAA BBBBBB 3030 AAAAAA BB
77 AAAAAA BBBB 3131 AAAAA BBBB
88 AA BB 3232 AA BB
99 AAAAAAAA BBBB 3333 AAAAAAAA BB
1010 AAAAAAAA BBBBBB 3434 AAAAAAAA BBBB
1111 AA BB 3535 AAAAAAAA BBBB
1212 AAAAA BBBB 3636 AAAAAAAA BBBB
1313 AA BB 3737 AAAAAAAA BBBB
1414 AAAAAAAA BB 3838 AA BB
1515 AA BBBB 3939 AA BB
1616 AAAAAAAA BBBBBB 4040 AAAAA BB
1717 AAAAAAAA BBBB 4141 AA BB
1818 AAAAAAAA BBBB 4242 AAAAAAAA BBBB
1919 AA BB 4343 AAAAAAAAAA BBBB
2020 AAAAAAAAAA BBBB 4444 AAAAAA BB
21twenty one AA BBBBBB 4545 AAAAAA BB
22twenty two AA BB 4646 AAAAAA BB
化合物compound EC 50/nm EC50 /nm 激动效应Agitation effect 化合物compound EC 50/nm EC50 /nm 激动效应Agitation effect
23twenty three AAAAAAAAAA BBBB 4747 AAAAA BB
24twenty four AAAAAAAA BBBB  the  the  the
4848 AAAAAA BB 5555 AAAAAAAA BBBBBB
4949 AAAAAA BBBB 5656 AAAAAAAAAA BBBBBB
5050 AAAAAA BBBB 5757 AA BB
5151 AAAAAAAA BBBBBB 5858 AAAAAAAAAA BBBBBB
5252 AAAAA BBBBBB 5959 AA BBBB
5353 AAAAAA BBBBBB 6060 AA BB
5454 AAAAAAAA BBBBBB 6161 AA BB
6868 AA BB 6262 AAAAA BB
6969 AAAAA BB 6363 AAAAAAAAAA BBBBBB
7070 AAAAAA BB 6464 AA BB
7171 AA BB 6565 AA BB
7272 AAAAA BB 6666 AAAAAA BB
7373 AAAAAA BB 6767 AA BB
7474 AAAAA BB 7575 AAAAA BB
7676 AAAAA BB 7777 AAAAA BB
7878 AA BB 7979 AA BB
8080 AAAAAA BB 8181 AAAAAA BBBB
8282 AAAAAA BB 8383 AAAAA BB
8484 AAAAA BB 8585 AAAAA BB
8686 AAAAA BB 8787 AAAAAA BB
8888 AAAAAA BB 8989 AAAAA BB
9090 AAAAA BB 9191 AAAAA BB
9292 AAAAAAAAAA BBBBBB 9393 AAAAA BB
9494 AAAAAAAAAA BBBBBB 9595 AAAAAAAAAA BBBBBB
9696 AAAAAAAAAA BBBBBB  the  the  the

Claims (12)

  1. 式(I)所代表的化合物或其药学上可接受的盐，A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022132910-appb-100001
    Figure PCTCN2022132910-appb-100001
    其中：in:
    m选自0、1、2或3；n选自0、1、2或3；m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3;
    A环选自5-7元芳基、5-7元的单环杂芳基、9-12元的双环杂芳基、5-7元的杂环烷基、9-12元的部分不饱和双环杂环基；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;
    m个R 2彼此相同或不相同，其中，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、-S(O) 2R 6、5-7元杂环烷基，所述C 1-6酰基、5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代，所述C 1-6烷基任选地被一个或多个卤素、-C(＝O)NR 4R 5取代； 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, -S(O) 2 R 6 , 5-7 membered heterocycloalkyl, said C 1-6 acyl, 5-7 membered heterocycloalkyl is optionally replaced by one or more C 1-3 alkyl, -NR 4 R 5 Substituted, the C 1-6 alkyl is optionally substituted by one or more halogens, -C(=O)NR 4 R 5 ;
    R 1选自氢、氘、卤素、C 1-6烷基、C 1-6烯基、C 3-6环烷基，所述C 1-6烷基、C 1-6烯基、C 3-6环烷基任选地被一个或多个卤素所取代； 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为-C(O)-、
    Figure PCTCN2022132910-appb-100002
    L is -C(O)-,
    Figure PCTCN2022132910-appb-100002
    B环选自5-7元芳基、5-7元单环杂芳基、9-12元双环杂芳基、9-12元部分不饱和双环杂环基、8-12元饱和螺环杂环基；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;
    R 4、R 5、R 6各自独立地选自氢、C 1-6烷基、C 3-6环烷基。 R 4 , R 5 , and R 6 are each independently selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl.
  2. 根据权利要求1所述的化合物，其中，A环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元的单环杂芳基、含有1-2个分别独立选自N、O、S原子的9-12元的双环杂芳基、含有1-2个分别独立选自N、O、S原子的5-7元的杂环烷基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基；The compound according to claim 1, wherein the A ring is selected from 5-7 membered aryl groups, containing 1-2 5-7 membered monocyclic heteroaryl groups independently selected from N, O, and S atoms, containing 1-2 9-12-membered bicyclic heteroaryls independently selected from N, O, and S atoms, and 5-7-membered heterocycloalkyl containing 1-2 independently selected from N, O, and S atoms , containing 1-3 9-12 membered partially unsaturated bicyclic heterocyclic groups independently selected from N, O, and S atoms;
    优选地，A环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元的单环杂芳基、含有1-2个分别独立选自N或O的9-12元的双环杂芳基、含有1-2个N原子的5-7元的杂环烷基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基；Preferably, 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. A 9-12-membered bicyclic heteroaryl group of O, a 5-7-membered heterocycloalkyl group containing 1-2 N atoms, a 9-12-membered moiety containing 1-3 independently selected from N or O atoms, etc. Saturated bicyclic heterocyclyl;
    优选地，A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、异吲哚啉基、吡啶酮基、异吲哚啉酮基；Preferably, ring A is selected from phenyl, pyrimidinyl, pyrazolyl, benzopyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazole Base, pyrrolopyridyl, isoindolinyl, pyridonyl, isoindolinone;
    优选地，A环选自苯基、嘧啶基、吡唑基、苯并吡唑基、苯并咪唑基、吲唑基、吲哚基、异噁唑基、吗啉基、吡啶基、三唑基、吡咯并吡啶基、吡啶酮基、异吲哚啉酮基；Preferably, ring A is selected from phenyl, pyrimidinyl, pyrazolyl, benzopyrazolyl, benzimidazolyl, indazolyl, indolyl, isoxazolyl, morpholinyl, pyridyl, triazole Base, pyrrolopyridyl, pyridonyl, isoindolinone;
    优选地，A环选自
    Figure PCTCN2022132910-appb-100003
    Preferably, ring A is selected from
    Figure PCTCN2022132910-appb-100003
    Figure PCTCN2022132910-appb-100004
    Figure PCTCN2022132910-appb-100004
    优选地，
    Figure PCTCN2022132910-appb-100005
    选自
    Figure PCTCN2022132910-appb-100006
    Figure PCTCN2022132910-appb-100007
    Preferably,
    Figure PCTCN2022132910-appb-100005
    selected from
    Figure PCTCN2022132910-appb-100006
    Figure PCTCN2022132910-appb-100007
    优选地，
    Figure PCTCN2022132910-appb-100008
    选自
    Figure PCTCN2022132910-appb-100009
    Preferably,
    Figure PCTCN2022132910-appb-100008
    selected from
    Figure PCTCN2022132910-appb-100009
  3. 根据权利要求1或2所述的化合物，其中，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、-S(O) 2R 6、含有1-2个分别独立选自N、O原子的5-7元杂环烷基，所述C 1-6酰基、含有1-2个分别独立选自N、O原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代，所述C 1-6烷基任选地被一个或多个卤素、-C(＝O)NR 4R 5取代； The compound according to claim 1 or 2, wherein 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 , a 5-7-membered heterocycloalkyl group containing 1-2 independently selected from N and O atoms, and the C 1-6 acyl group containing 1-2 independently selected from N and O atoms The 5-7 membered heterocycloalkyl is optionally substituted by one or more C 1-3 alkyl, -NR 4 R 5 , and the C 1-6 alkyl is optionally substituted by one or more halogen, - C(=O)NR 4 R 5 substitution;
    优选地，R 2选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-6酰基、5-7元杂环烷基，所述C 1-6酰基、5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代； Preferably, 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, the C 1- 6 acyl, 5-7 membered heterocycloalkyl is optionally substituted by one or more C 1-3 alkyl, -NR 4 R 5 ;
    优选地，R 2选自C 1-3烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、含有1-2个N原子的5-7元杂环烷基，所述C 1-3酰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个C 1-3烷基、-NR 4R 5所取代； Preferably, 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 ;
    优选地，R 2选自C 1-3烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、含有1-2个N原子的5-7元杂环烷基，所述C 1-3羰基、含有1-2个N原子的5-7元杂环烷基任选地被一个或多个甲基、-N(CH 3) 2所取代； Preferably, 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 ;
    优选地，R 2选自甲基、乙基、丙基、异丙基、环丙烷基、甲氧基、甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基，所述甲酰基、乙酰基、哌嗪基、哌啶基、吗啉基任选地被一个或多个甲基、-N(CH 3) 2所取代； Preferably, 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 ;
    优选地，R 4、R 5各自独立地选自氢、C 1-6烷基，更优选氢和甲基； Preferably, R 4 and R 5 are each independently selected from hydrogen, C 1-6 alkyl, more preferably hydrogen and methyl;
    优选地，R 6各自独立地选自C 1-6烷基和C 3-6环烷基，更优选甲基、丙基和环丙基； Preferably, each R is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, more preferably methyl, propyl and cyclopropyl;
    优选地，R 2选自甲基、乙基、二氟甲基、异丙基、环丁烷基、环丙烷基、甲氧基、甲酰基、-CH 2C(＝O)NH 2、-S(O) 2CH 3、-S(O) 2(CH 2) 2CH 3、
    Figure PCTCN2022132910-appb-100010
    -C(＝O)CH 2N(CH 3) 2、
    Figure PCTCN2022132910-appb-100011
    Preferably, R 2 is selected from methyl, ethyl, difluoromethyl, isopropyl, cyclobutanyl, cyclopropyl, methoxy, formyl, -CH 2 C(=O)NH 2 , - S(O) 2 CH 3 , -S(O) 2 (CH 2 ) 2 CH 3 ,
    Figure PCTCN2022132910-appb-100010
    -C(=O)CH 2 N(CH 3 ) 2 ,
    Figure PCTCN2022132910-appb-100011
    优选地，
    Figure PCTCN2022132910-appb-100012
    选自
    Figure PCTCN2022132910-appb-100013
    Figure PCTCN2022132910-appb-100014
    Figure PCTCN2022132910-appb-100015
    Preferably,
    Figure PCTCN2022132910-appb-100012
    selected from
    Figure PCTCN2022132910-appb-100013
    Figure PCTCN2022132910-appb-100014
    Figure PCTCN2022132910-appb-100015
  4. 根据权利要求1-3任一项所述的化合物，其中，R 1选自氢、氘、卤素、C 1-3烷基、C 1-3烯基、C 3-6环烷基，所述C 1-3烷基、C 1-3烯基、C 3-6环烷基任选地被一个至三个卤素所取代； The compound according to any one of claims 1-3, wherein R 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 are optionally substituted by one to three halogens;
    优选地，R 1选自氢、氘、氟、C 1-3烷基、C 1-3烯基，所述C 1-3烷基、C 1-3烯基、C 3-6环烷基任选地被一个至三个氟所取代； Preferably, 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;
    优选地，R 1选自氟、甲基、乙基、氟甲基、二氟甲基、三氟甲基、异丙基、异丙烯基、环丙烷基； Preferably, R is selected from fluoro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, isopropyl, isopropenyl, cyclopropenyl;
    优选地，R 1选自氟、甲基、异丙基、异丙烯基、环丙烷基； Preferably, R is selected from fluorine, methyl, isopropyl, isopropenyl, cyclopropenyl;
    优选地，R 1为甲基； Preferably, R 1 is methyl;
    优选地，B环选自5-7元芳基、含有1-2个分别独立选自N、O、S原子的5-7元单环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元双环杂芳基、含有1-3个分别独立选自N、O、S原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N、O、S原子8-12元饱和螺环杂环基；Preferably, 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, and a 9-12-membered partially unsaturated bicyclic heterocyclic group containing 1-3 independently 8-12 membered saturated spirocyclic heterocyclic groups selected from N, O, and S atoms;
    优选地，B环选自5-7元芳基、含有1-2个分别独立选自N或O原子的5-7元单环杂芳基、含有1-3个分别独立选自N或O原子的9-12元双环杂芳基、含有1-3个分别独立选自N或O原子的9-12元部分不饱和双环杂环基、含有1-3个分别独立选自N或O原子8-12元饱和螺环杂环基；Preferably, 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;
    优选地，B环选自苯基、吡啶基、吡唑基、苯并二氧戊环基、氮杂螺辛烷基、四氢异喹啉基；Preferably, ring B is selected from phenyl, pyridyl, pyrazolyl, benzodioxolanyl, azaspirooctyl, tetrahydroisoquinolyl;
    优选地，B环选自
    Figure PCTCN2022132910-appb-100016
    Figure PCTCN2022132910-appb-100017
    Preferably, the B ring is selected from
    Figure PCTCN2022132910-appb-100016
    Figure PCTCN2022132910-appb-100017
    n个R 3彼此相同或不相同，其中，R 3选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、卤素、氰基、含有1-2个分别独立选自N、O、S原子的5-7元杂环烷基，所述C 1-6烷基、C 3-6环烷基、C 1-3酰基任选地被一个或多个卤素、氰基所取代； 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;
    优选地，R 3选自C 1-6烷基、C 3-6环烷基、C 1-3烷氧基、C 1-3酰基、卤素、氰基、含有1-2个分别独立选自N或O原子的5-7元杂环烷基、所述C 1-6烷基、C 1-3酰基任选地被一个至三个氟所取代，所述C 3-6环烷基任选地被一个或多个氰基所取代； Preferably, 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;
    优选地，R 3选自甲基、三氟甲基、甲氧基、环丙基、环己基、卤素、氰基、
    Figure PCTCN2022132910-appb-100018
    Figure PCTCN2022132910-appb-100019
    Preferably, R is selected from methyl, trifluoromethyl, methoxy, cyclopropyl, cyclohexyl, halogen, cyano,
    Figure PCTCN2022132910-appb-100018
    Figure PCTCN2022132910-appb-100019
    优选地，R 3选自溴、氟、氯、氰基、三氟甲基、甲基。 Preferably, R3 is selected from bromo, fluoro, chloro, cyano, trifluoromethyl, methyl.
  5. 根据权利要求1-4任一项所述的化合物或其药学上可接受的盐，其中，包括式(II)所代表的化合物或其药学上可接受的盐：The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, including a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022132910-appb-100020
    Figure PCTCN2022132910-appb-100020
    其中，n、m、A、L、R 1、R 2、R 3的定义同式(I)化合物； Among them, the definitions of n, m, A, L, R 1 , R 2 , and R 3 are the same as those of the compound of formula (I);
    优选地，所述式(II)化合物具有式(IIa)、(IIb)、(IIc)、(IId)、(IIe)或(IIf)所示的结构：Preferably, the compound of formula (II) has a structure shown in formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):
    Figure PCTCN2022132910-appb-100021
    Figure PCTCN2022132910-appb-100021
    其中，X 4、X 5、X 6选自N、NH或CH，n、m、R 1、R 2、R 3的定义同式(I)化合物。 Wherein, 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 the same as those of the compound of formula (I).
  6. 下列化合物或其药学上可接受的盐：The following compounds or pharmaceutically acceptable salts thereof:
    Figure PCTCN2022132910-appb-100022
    Figure PCTCN2022132910-appb-100022
    Figure PCTCN2022132910-appb-100023
    Figure PCTCN2022132910-appb-100023
    Figure PCTCN2022132910-appb-100024
    Figure PCTCN2022132910-appb-100024
    Figure PCTCN2022132910-appb-100025
    Figure PCTCN2022132910-appb-100025
    Figure PCTCN2022132910-appb-100026
    Figure PCTCN2022132910-appb-100026
    Figure PCTCN2022132910-appb-100027
    Figure PCTCN2022132910-appb-100027
    Figure PCTCN2022132910-appb-100028
    Figure PCTCN2022132910-appb-100028
  7. 权利要求1-6任一项的化合物的制备方法，所述方法选自以下合成路线：The preparation method of the compound of any one of claims 1-6, said method is selected from the following synthetic routes:
    合成路线1：Synthetic route 1:
    Figure PCTCN2022132910-appb-100029
    Figure PCTCN2022132910-appb-100029
    步骤一：化合物1A与化合物1A-1 Suzuki偶联反应得到化合物1B；Step 1: Suzuki coupling reaction of compound 1A and compound 1A-1 to obtain compound 1B;
    步骤二：化合物1B经过萃取纯化后得到化合物1C；Step 2: compound 1B is extracted and purified to obtain compound 1C;
    步骤三：化合物1C与化合物1C-1缩合反应得到化合物A 1； Step 3: Condensation reaction of compound 1C and compound 1C-1 to obtain compound A 1 ;
    合成路线2：Synthetic route 2:
    Figure PCTCN2022132910-appb-100030
    Figure PCTCN2022132910-appb-100030
    步骤一：化合物2A与化合物2A-1缩合反应得到化合物2B；Step 1: Condensation reaction of compound 2A and compound 2A-1 to obtain compound 2B;
    步骤二：化合物2B与化合物2B-1 Suzuki偶联反应得到化合物A 2； Step 2: Suzuki coupling reaction of compound 2B and compound 2B-1 to obtain compound A 2 ;
    合成路线3：Synthetic route 3:
    Figure PCTCN2022132910-appb-100031
    Figure PCTCN2022132910-appb-100031
    步骤一：化合物3A与化合物缩合反应得到化合物3B；Step 1: Condensation reaction of compound 3A and compound to obtain compound 3B;
    步骤二：化合物3B与R 1-B(OH) 2Suzuki偶联反应得到化合物3C； Step 2: compound 3B is reacted with R 1 -B(OH) 2 Suzuki to obtain compound 3C;
    步骤三：化合物3C与化合物3C-1 Suzuki偶联反应得到化合物A 3； Step 3: Suzuki coupling reaction of compound 3C and compound 3C-1 to obtain compound A 3 ;
    合成路线4：Synthetic route 4:
    Figure PCTCN2022132910-appb-100032
    Figure PCTCN2022132910-appb-100032
    步骤一：化合物2A与化合物2A-1缩合反应得到化合物4B；Step 1: Condensation reaction of compound 2A and compound 2A-1 to obtain compound 4B;
    步骤二：化合物4B与对甲苯磺酰氯反应得到化合物4C；Step 2: Compound 4B is reacted with p-toluenesulfonyl chloride to obtain compound 4C;
    步骤三：化合物4C与N，N-二异丙基乙胺反应得到化合物4D；Step 3: react compound 4C with N,N-diisopropylethylamine to obtain compound 4D;
    步骤四：化合物4D脱氢反应得到化合物4E；Step 4: Dehydrogenation reaction of compound 4D to obtain compound 4E;
    步骤五：化合物4E与化合物4E-1Suzuki偶联反应得到化合物A 4。 Step 5: Suzuki coupling reaction of compound 4E with compound 4E-1 to obtain compound A 4 .
  8. 一种药物组合物，其特征在于，所述组合物包含根据权利要求1-6任一项所述的化合物或其药学上可接受的盐和药学上可接受的辅料。A pharmaceutical composition, characterized in that the composition comprises the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
  9. 权利要求1-6任一项的化合物或其药学上可接受的盐、权利要求8的药物组合物在制备治疗患者的AhR介导的病症的药物中的应用。Application of the compound according to any one of claims 1-6 or the pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 8 in the preparation of medicines for treating AhR-mediated diseases in patients.
  10. 权利要求1-6任一项的化合物或其药学上可接受的盐、权利要求8的药物组合物在制备AHR激动剂中的应用。Use of the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 8 in the preparation of an AHR agonist.
  11. 一种激活有需要的患者中的AhR的方法，其包含向所述患者施用根据权利要求1-6任一项所述的化合物或其药学上可接受的盐、权利要求7所述的方法制备得到的化合物或权利要求8的药物组合物。A method for activating AhR in a patient in need thereof, comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, prepared by a method according to claim 7 The obtained compound or the pharmaceutical composition of claim 8.
  12. 一种用于治疗有需要的患者的AhR介导的病症的方法，其包含向所述患者施用根据权利要求1-6任一项所述的化合物或其药学上可接受的盐、权利要求7所述的方法制备得到的化合物或权利要求8的药物组合物；A method for treating an AhR-mediated disorder in a patient in need thereof, comprising administering to said patient a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, claim 7 The compound prepared by the method or the pharmaceutical composition of claim 8;
    优选地，所述AhR介导的病症包括但不限于银屑病、关节炎、特应性皮炎、帕金森、多发性硬化症、炎症性肠炎、哮喘、系统性红斑狼疮、移植物抗宿主病、细菌性角膜炎、肿瘤。Preferably, 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.
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