WO2022127753A1 - 稠环类AhR抑制剂 - Google Patents

稠环类AhR抑制剂 Download PDF

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WO2022127753A1
WO2022127753A1 PCT/CN2021/137679 CN2021137679W WO2022127753A1 WO 2022127753 A1 WO2022127753 A1 WO 2022127753A1 CN 2021137679 W CN2021137679 W CN 2021137679W WO 2022127753 A1 WO2022127753 A1 WO 2022127753A1
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alkyl
alkoxy
amino
carboxyl
halogenated
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PCT/CN2021/137679
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French (fr)
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刘斌
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山东轩竹医药科技有限公司
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Priority to CN202180036756.XA priority Critical patent/CN115698005B/zh
Publication of WO2022127753A1 publication Critical patent/WO2022127753A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • 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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a class of fused-ring AhR inhibitor compounds, their pharmaceutically acceptable salts, their esters or their stereoisomers, comprising said compounds, their pharmaceutically acceptable salts, their Pharmaceutical compositions and formulations of esters or stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts thereof, esters or stereoisomers thereof, and said compounds, pharmaceutically acceptable salts thereof , the use of its esters or its stereoisomers.
  • AhR Aryl Hydrocarbon Receptor
  • the bHLH-PAS family of transcriptional regulators is a member of the bHLH-PAS family of transcriptional regulators.
  • the bHLH (basic Helix-Loop-Helix)-PAS (Per-ARNT-Sim) family mainly regulates various developmental and physiological functions, including neurogenesis, tracheal and salivary duct formation, toxin metabolism, circadian rhythms, response to hypoxia, and Hormone receptor functions, etc., can be activated by small molecules of ligands derived from pollutants, microorganisms, food and tryptophan metabolites, and exert different biological effects in different cells.
  • PAS domain A unique feature of members of this family is the presence of the PAS domain, named after the three proteins first identified with this motif: Drosophila Per, Human ARNT and Drosophila Sim.
  • the PAS domain consists of 260-310 amino acids and consists of two very conserved hydrophobic repeats, termed PAS-A and PAS-B, separated by a poorly conserved sequence.
  • PAS domains are not well conserved and can mediate many different biochemical functions.
  • AhR also known as dioxin receptor
  • TCDD 2,3,7,8-tetrachlorobenzodioxin
  • TCDD 2,3,7,8-tetracholrodibenzo-p-dioxin
  • AhR is widely expressed in various tissues, and is highly expressed in liver, lung, spleen, and kidney.
  • cells derived from epithelial cells have the highest expression of AhR.
  • AhR has thus become a key transcription factor controlling many physiological processes, including cell proliferation, apoptosis, differentiation, adhesion, migration, and pluripotency, and is involved in regulating immune responses in autoimmunity, infection, and cancer.
  • AhR forms a dormant complex with HSP90, AIP and HSP90's chaperone p23 in the cytoplasm.
  • HSP90 When it binds the corresponding ligand, the AhR in this complex is activated and a conformational change occurs, thereby exposing a localization signal sequence.
  • HSP90 is released from the complex, and the AhR receptor is transported to the nucleus to form a heterodimer with ARNT. This heterodimer binds to XRE and alters the expression of genes controlled by the enhancer XRE.
  • XREs have the conserved core sequence "GCGTG” and are present in the promoter regions of several genes involved in xenobiotic metabolism, including CYP1A1, CYP1A2, CYP1B1 and NAD(P)H-quinine oxidoreductase.
  • AhR also interacts with other signaling pathways, such as those mediated by estrogen receptors and other hormone receptors, hypoxia, NF- ⁇ B, and Rb.
  • the steroid hormone receptor-related pathway may be the most studied in relation to the AhR pathway.
  • AhR interacts with the ESR, AR and thyroid hormone receptor pathways. Activation of AhR will lead to a decrease in the number of ESR and ESR responsiveness, which will also lead to the metabolism of ESR. Increase.
  • AhR is expressed in many cells of the immune system, including dendritic cells (DC), macrophages, T cells and NK cells, and plays an important role in immune regulation.
  • AhR activation promotes regulatory T cell generation, directly and indirectly inhibits Th1 and Th17 differentiation, and reduces DC activation and maturation.
  • AhR activation modulates the innate immune response, and constitutive AhR expression has been shown to negatively regulate the type I interferon response to viral infection, in addition, mice with constitutively active AhR develop tumors spontaneously.
  • the metabolites of tryptophan activate AhR to inhibit the response of immune cells.
  • Immunohistochemical analysis shows that the expression level of AhR in breast cancer, prostate cancer, stomach, small cell lung cancer, and liver cancer is relatively higher than that in surrounding tissues. It exerts anti-tumor activity from two aspects: inhibiting tumor cell proliferation and enhancing immune response.
  • AhR receptor small molecule inhibitors whether used alone or in combination with other drugs, has broad market prospects. It can be seen that the development of a highly active, selective and drug-like AhR small molecule inhibitor has important clinical significance.
  • the technical problem to be solved by the present invention is to provide a compound with novel structure and good inhibitory effect on AhR activity. Further, such compounds can be used to prepare medicines for the treatment and/or prevention of diseases mediated by AhR activity or related diseases.
  • the technical scheme of the present invention is as follows:
  • the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof,
  • X 1 and X 2 are independently selected from C(R 2 ) or N;
  • X 3 , X 4 , X 6 are each independently selected from C, C(R 2 ) or N;
  • X 5 and X 7 are each independently selected from C(R 2 ), CH(R 2 ), O, N, N(R 3 ) or C(O);
  • L 1 is selected from a chemical bond, -C(R 4 )(R 5 )-, -O-, -S-, -C(O)- or -S(O)-;
  • L 2 is selected from C 1-6 alkylene optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • R 1 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1 -6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, di(C 1-6 alkyl)amino, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy , Carboxyl C 1-6 alkoxy, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl or 6-10-membered aryl;
  • Each R 2 , R 4 , R 5 is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy , halo C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • Each R 3 is independently selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or carboxy C 1-6 alkyl ;
  • Ar 1 is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl or 6-10-membered aryl optionally substituted by 1-3 Q 1 ;
  • Ar 2 is selected from 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl or 6-10-membered aryl optionally substituted by 1-3 Q 2 ;
  • Each Q 1 and each Q 2 are independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy;
  • X 1 and X 2 are independently selected from C(R 2 ) or N;
  • X 3 , X 4 , X 6 are each independently selected from C, C(R 2 ) or N;
  • X 5 and X 7 are each independently selected from C(R 2 ), CH(R 2 ), O, N, N(R 3 ) or C(O);
  • L 1 is selected from a chemical bond, -C(R 4 )(R 5 )-, -O-, -S-, -C(O)- or -S(O)-;
  • L 2 is selected from C 1-6 alkylene optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • R 1 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1 -4 alkoxy, hydroxy C 1-4 alkoxy, amino C 1-4 alkoxy or carboxyl C 1-4 alkoxy;
  • Each R 2 , R 4 , R 5 is independently selected from hydrogen, halogen, nitro , cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • Each R 3 is independently selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl or carboxy C 1-4 alkyl ;
  • Ar 1 is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl or phenyl optionally substituted by 1-3 Q 1 ;
  • Each Q 1 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy ;
  • Ar 2 is selected from 5-6-membered monocyclic cycloalkyl, 5-6-membered monocyclic heterocycloalkyl, 5-6-membered monocyclic heteroaryl or phenyl optionally substituted by 1-3 Q 2 ; each -Q 2 are independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, di(C 1-6 alkyl)amino, hydroxy C 1-6 alkyl, amino C 1-6 alkyl , carboxy C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy;
  • Ar 1 is selected from 5-6 membered monocyclic cycloalkyl optionally substituted with 1-3 Q 1 , 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms , 5-6 membered monocyclic heteroaryl or phenyl containing 1-3 heteroatoms.
  • Ar 1 is selected from 5-6 membered monocyclic cycloalkyl optionally substituted with 1-2 Q 1 , 5-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms , 5-6 membered monocyclic heteroaryl or phenyl containing 1-2 heteroatoms.
  • Ar 1 is selected from 5-6 membered nitrogen-containing monocyclic heteroaryl or phenyl optionally substituted with 1-2 Q 1 .
  • Ar 1 is selected from 5-6 membered monocyclic heteroaryl or phenyl containing 1-2 nitrogens optionally substituted with 1-2 Q 1 .
  • Ar 1 is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, tetrahydrothienyl, optionally substituted with 1-2 Q 1 , Thiazolidinyl, piperidinyl, tetrahydropyridyl, piperidonyl, tetrahydropyridinone, piperazinyl, morpholinyl, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadi oxazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyra
  • Each Q 1 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy .
  • Ar 1 is selected from furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazole optionally substituted with 1-2 Q 1 base, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1, 2,3-triazinyl, 1,3,5-triazinyl or phenyl.
  • Ar 1 is selected from furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazole optionally substituted with 1-2 Q 1 oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl.
  • Ar 1 is selected from pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazole optionally substituted with 1-2 Q 1 base.
  • Ar 2 is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, 5-6 membered monocyclic heterocycloalkyl optionally substituted by 1-3 Q 2 Aryl or phenyl; each Q 2 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, di(C 1-6 alkyl)amino, hydroxy C 1-6 alkyl, Amino C 1-6 alkyl, carboxy C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxy C 1-6 alkoxy.
  • Ar 2 is selected from 5-6 membered monocyclic cycloalkyl optionally substituted with 1-3 Q 1 , 5-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms , 5-6 membered monocyclic heteroaryl or phenyl containing 1-3 heteroatoms.
  • Ar 2 is selected from 5-6 membered monocyclic cycloalkyl optionally substituted with 1-2 Q 1 , 5-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms , 5-6 membered monocyclic heteroaryl or phenyl containing 1-2 heteroatoms.
  • Ar 2 is selected from 5-6 membered monocyclic heteroaryl or phenyl containing 1-2 heteroatoms optionally substituted with 1-2 Q 1 .
  • Ar is selected from morpholinyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl optionally substituted with 1-2 Q2 , isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine 1,2,3-triazinyl, 1,3,5-triazinyl or phenyl;
  • Each Q 2 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy .
  • Ar 2 is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3 - triazinyl, 1,3, 5-triazinyl or phenyl.
  • Ar 2 is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or phenyl optionally substituted with 1-2 Q 2 .
  • L 1 is selected from a chemical bond, -C(R 4 )(R 5 )-, -O-, -S-, -C(O)- or -S(O)-;
  • L 2 is selected from C 1-6 alkylene optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl oxy, isopropoxy, trifluoromethyl, trifluoromethoxy, hydroxymethoxy or aminomethoxy;
  • Each R 2 , R 4 , R 5 is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl group, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl or trifluoromethoxy;
  • Each R 3 is independently selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl or carboxy C 1-4 alkyl ;
  • Ar 1 is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, tetrahydrothienyl, thiazolidinyl, piperidinyl optionally substituted with 1-3 Q 1 , tetrahydropyridyl, piperidone, tetrahydropyridone, piperazinyl, morpholinyl, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, Isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl , 1,2,3-triaziny
  • Each Q 1 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy ;
  • Ar 2 is selected from morpholinyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxazolyl optionally substituted by 1-3 Q2 oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3 - triazinyl, 1,3,5-triazinyl or phenyl;
  • Each Q 2 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy ;
  • L 1 is selected from chemical bond, -CH 2 -, -O-, -S-, -C(O)- or -S(O)-;
  • L 2 is selected from C 1-4 alkylene optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl oxy, isopropoxy, trifluoromethyl, trifluoromethoxy, hydroxymethoxy or aminomethoxy;
  • Each R2 is independently selected from hydrogen , fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl or trifluoromethoxy;
  • Each R 3 is independently selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl or carboxy C 1-4 alkyl ;
  • Ar 1 is selected from furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, optionally substituted by 1-2 Q 1 , Imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl , 1,3,5-triazinyl or phenyl;
  • Each Q 1 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy ;
  • Ar 2 is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl or benzene optionally substituted with 1-2 Q2 base;
  • Each Q 2 is independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogen Substituted C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl carbonyl, di(C 1-6 alkyl) amino, hydroxy C 1-6 alkyl, amino C 1-6 alkane group, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or carboxyl C 1-6 alkoxy ;
  • the compound represented by formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer further has the structure represented by the following general formula (II),
  • X 3 , X 4 , and X 6 are independently selected from C, CH or N;
  • X 5 and X 7 are each independently selected from C(R 2 ), CH(R 2 ), O, N, N(R 3 ) or C(O);
  • L 1 is selected from chemical bond, -CH 2 -, -O-, -S-, -C(O)- or -S(O)-;
  • L 2 is selected from C 1-4 alkylene optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • R 1 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1 -4 alkoxy, hydroxy C 1-4 alkoxy, amino C 1-4 alkoxy or carboxyl C 1-4 alkoxy;
  • Each R 2 is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • Each R 3 is independently selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl or carboxy C 1-4 alkyl ;
  • Ar 2 is selected from morpholinyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiyl optionally substituted by 1-2 Q2 azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3- triazinyl, 1,3,5-triazinyl or phenyl;
  • Each Q 1 and each Q 2 are independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1- 4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl or amino C 1-4 alkyl;
  • X3 , X4 , X6 are each independently selected from C, CH, or N;
  • X 5 , X 7 are each independently selected from CH, CH 2 , O, N, NH or C(O).
  • X 4 is selected from C or CH; X 3 and X 6 are independently selected from C, CH or N;
  • X 5 , X 7 are each independently selected from CH, CH 2 , O, N, NH or C(O).
  • L 2 is selected from -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - optionally substituted with substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy .
  • L 2 is selected from -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - optionally substituted with substituents selected from hydrogen, Halogen, amino, hydroxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoro Methyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • substituents selected from hydrogen, Halogen, amino, hydroxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoro Methyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • each Q is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl , methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, Trifluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, aminomethyl or aminoethyl.
  • each Q is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl , methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, Trifluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, aminomethyl or aminoethyl.
  • R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy group, ethoxy, propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, hydroxymethoxy or aminomethoxy.
  • each R2, R4, R5 is independently selected from hydrogen , fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl radical, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl or trifluoromethoxy.
  • each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, aminomethyl, or carboxyl methyl.
  • X3 , X4 , X6 are each independently selected from C, CH, or N;
  • X 5 and X 7 are independently selected from CH, CH 2 , O, N, NH or C(O);
  • L 2 is selected from -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy group, difluoromethoxy or trifluoromethoxy;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl oxy, isopropoxy, trifluoromethyl, trifluoromethoxy, hydroxymethoxy or aminomethoxy;
  • Ar 2 is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl or benzene optionally substituted with 1-2 Q2 base;
  • Each Q 1 and each Q 2 are independently selected from fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoro Methoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, aminomethyl or aminoethyl.
  • the compound represented by formula (I) or formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer further has the following general formula (IIIa), general formula ( IIIb), the structure represented by the general formula (IIIc) or the general formula (IIId),
  • Ar 2 , Q 1 , Q 2 , L 1 , L 2 , R 1 , R 4 , and R 5 are as defined in any one of the preceding schemes.
  • L 1 is selected from chemical bond, -CH 2 -, -O- or -S-;
  • L 2 is selected from -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl or trifluoromethoxy;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl oxy, isopropoxy, trifluoromethyl or trifluoromethoxy;
  • Ar 2 is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or phenyl optionally substituted by 1-2 Q 2 ;
  • Each Q 1 and each Q 2 are independently selected from fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoro Methoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, aminomethyl or aminoethyl.
  • the compound represented by formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer further has the following general formula (IVa), general formula (IVb), general formula (IVc) or the structure represented by the general formula (IVd),
  • Ar 1 , Ar 2 , Q 1 , Q 2 , L 1 , L 2 , R 1 , R 4 and R 5 are as defined in any one of the preceding schemes.
  • L 1 is selected from chemical bond, -CH 2 -, -O-, -S-, -C(O)- or -S(O)-;
  • L 2 is selected from C 1-4 alkylene optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • R 1 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1 -4 alkoxy, hydroxy C 1-4 alkoxy, amino C 1-4 alkoxy or carboxyl C 1-4 alkoxy;
  • Ar 1 is selected from furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole optionally substituted by 1-2 Q1 base, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-Triazinyl or phenyl
  • Ar 2 is selected from morpholinyl, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiyl optionally substituted by 1-2 Q2 azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3- triazinyl, 1,3,5-triazinyl or phenyl;
  • Each Q 1 and each Q 2 are independently selected from halogen, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1- 4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl or amino C 1-4 alkyl.
  • L 1 is selected from chemical bond, -CH 2 -, -O- or -S-;
  • L 2 is selected from -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - optionally substituted by substituents selected from hydrogen, halogen, amino, hydroxyl, mercapto , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl or trifluoromethoxy;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl oxy, isopropoxy, trifluoromethyl or trifluoromethoxy;
  • Ar 1 is selected from pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl optionally substituted with 1-2 Q 1 ;
  • Ar 2 is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or phenyl optionally substituted by 1-2 Q 2 ;
  • Each Q 1 and each Q 2 are independently selected from fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, mercapto, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoro Methoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, aminomethyl or aminoethyl.
  • any substituent and any optional group in the aforementioned technical solutions or technical solutions can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.
  • the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, is selected from the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned general formula (I), general formula (II), general formula (IIIa), general formula (IIIb), general formula (IIIc), general formula (IIId), Compounds of general formula (IVa), general formula (IVb), general formula (IVc) or general formula (IVd), pharmaceutically acceptable salts thereof, esters or stereoisomers thereof, and one or more A pharmaceutical carrier and/or diluent;
  • the pharmaceutical composition can be made into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups preparations, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays, etc.
  • the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or via pulmonary administration to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • suitable fillers, binders, disintegrants, lubricants and the like can be added.
  • parenteral administration the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug.
  • the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be formulated into an inhaler or a spray or the like.
  • the pharmaceutically acceptable carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the field of pharmaceutical formulations, and the choice of a particular carrier and/or diluent will depend on the The mode of administration or disease type and state to treat a particular patient.
  • the preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.
  • the present invention also relates to the aforementioned general formula (I), general formula (II), general formula (IIIa), general formula (IIIb), general formula (IIIc), general formula (IIId), general formula (IVa) ), the compound of general formula (IVb), general formula (IVc) or general formula (IVd), its pharmaceutically acceptable salt, its ester or its stereoisomer in the preparation of prevention and/or treatment of abnormal activity caused by AhR Use in a medicament for mediated diseases and related diseases, which can be used in combination with one or more other drugs to prevent or treat diseases mediated by abnormal AhR activity and related conditions.
  • the disease and related conditions are selected from cancers or benign tumors, including but not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervix Cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma, etc.
  • cancers or benign tumors including but not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and
  • the present invention also relates to compounds containing the aforementioned general formula (I), general formula (II), general formula (IIIa), general formula (IIIb), general formula (IIIc), general formula (IIId), general formula (IVa) , the use of a pharmaceutical preparation of the compound of general formula (IVb), general formula (IVc) or general formula (IVd), its pharmaceutically acceptable salt, its ester or its stereoisomer in the preparation of medicine, said The drug can be used in combination with one or more drugs to treat and/or prevent diseases and related disorders mediated by abnormal AhR activity.
  • the general formula (I), the general formula (II), the general formula (IIIa), the general formula (IIIb), the general formula (IIIc), the general formula (IIId), the general formula ( The compounds of formula IVa), general formula (IVb), general formula (IVc) or general formula (IVd), their pharmaceutically acceptable salts, their esters or their stereoisomers can be administered alone or in combination with a
  • One or more second therapeutically active agents are used in combination with the abnormal AhR activity inhibitor compounds of the present application for the treatment and/or prevention of diseases and related disorders mediated by abnormal AhR activity.
  • the pharmaceutical composition further contains one or more second therapeutically active agents.
  • the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and isoprenyl protein transferase inhibitors.
  • anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and
  • the ingredients to be combined may be administered simultaneously or sequentially separate medication.
  • the second therapeutically active agent can be administered before, concurrently with, or after the administration of the compound of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
  • the components to be combined may also be administered in combination in the same formulation or in separate different formulations.
  • the present invention also provides a method for treating diseases and related disorders mediated by abnormal AhR activity, the method comprising administering to a patient in need an effective amount of the aforementioned general formula (I), general formula (II) ), general formula (IIIa), general formula (IIIb), general formula (IIIc), general formula (IIId), general formula (IVa), general formula (IVb), general formula (IVc) or general formula (IVd)
  • the compounds, pharmaceutically acceptable salts thereof, esters or stereoisomers thereof, the aforementioned preparations or pharmaceutical compositions; the diseases and related disorders mediated by abnormal AhR activity are as defined above.
  • the "effective amount” refers to a dose of a drug capable of alleviating, delaying, inhibiting or curing a disorder in a subject.
  • the size of the administered dose is determined by the mode of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual signs (sex, weight, height, age) and the like.
  • halogen in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group in the present invention refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, “C 1-4 alkyl group” and “C 1-3 alkyl group” , “C 1-2 alkyl”, “C 2-6 alkyl”, “C 2-5 alkyl”, “C 2-4 alkyl”, “C 2-3 alkyl”, “C 3- 6 alkyl”, “C 3-5 alkyl", “C 3-4 alkyl”, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl (propyl), isopropyl, n-propyl Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methyl pentyl,
  • C 1-6 alkylene in the present invention refers to a group derived from a straight-chain alkane containing 1-6 carbon atoms by removing two hydrogens not on the same carbon atom, including "C 1-5 alkylene”"Alkyl”,"C 1-4 alkylene", “C 1-3 alkylene", “C 1-2 alkylene", specific examples include but are not limited to: -CH 2 -, -CH 2 CH 2 - , -CH2CH2CH2- , -CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2- . _ _ _ _ _ _
  • C 1-6 alkoxy in the present invention refers to “C 1-6 alkyl-O-", and the “C 1-6 alkyl” is as defined above.
  • C 1-4 alkoxy in the present invention refers to “C 1-4 alkyl-O-”, and the “C 1-4 alkyl” is as defined above.
  • hydroxyl C 1-6 alkyl group, amino C 1-6 alkyl group, halogenated C 1-6 alkyl group, carboxyl C 1-6 alkyl group refers to one of the C 1-6 alkyl group or more hydrogens are respectively replaced by one or more hydroxyl, amino, halogen or carboxyl groups.
  • Said “C 1-6 alkyl” is as defined above.
  • halogenated C 1-6 alkoxy group in the present invention means that one or more hydrogens in the "C 1-6 alkoxy group" are replaced by one or more halogens.
  • hydroxyl C 1-6 alkoxy, amino C 1-6 alkoxy, halogenated C 1-6 alkoxy, carboxyl C 1-6 alkoxy refers to C 1-6 alkoxy
  • One or more hydrogens in the oxy group are replaced by one or more hydroxyl, amino, halogen or carboxyl groups, respectively.
  • Said “C 1-6 alkoxy” is as defined above.
  • C 1-6 alkylamino group, C 1-6 alkyl carbonyl group, and di(C 1-6 alkyl) amino group refer to C 1-6 alkyl-NH-, C 1-6 alkyl group-NH-, and C 1-6 alkyl group respectively.
  • the "3-10-membered cycloalkyl” in the present invention includes “3-8-membered monocyclic cycloalkyl” and "8-10-membered fused-ring cycloalkyl".
  • the "3-8-membered cycloalkyl” in the present invention refers to a specific example of "3-10-membered cycloalkyl" containing 3-8 carbon atoms.
  • the "3-8-membered monocyclic cycloalkyl” in the present invention refers to a saturated or partially saturated monocyclic cyclic group containing 3-8 ring atoms without aromaticity, including "3-7 membered monocyclic cyclic groups”.
  • the "8-10-membered fused-ring cycloalkyl group" in the present invention refers to a saturated or Partially saturated, non-aromatic cyclic groups, examples of which include, but are not limited to:
  • the "3-10-membered heterocyclic group” in the present invention includes “3-8-membered monocyclic heterocyclic group” and "8-10-membered fused heterocyclic group”.
  • the "3-8 membered heterocyclic group” in the present invention refers to at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3-8
  • a saturated or partially saturated and non-aromatic monocyclic cyclic group the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (such as a carbon atom) in the ring structure , nitrogen atom or sulfur atom) can be oxo.
  • the "3-8 membered monoheterocyclic group” in the present invention includes "3-8 membered saturated monoheterocyclic group” and "3-8 membered partially saturated monoheterocyclic group”.
  • the "3-8 membered monocyclic heterocyclic group” is preferably "3-7 membered monocyclic heterocyclic group", "3-6 membered monocyclic heterocyclic group”, “4-7 membered monocyclic heterocyclic group”, “4-6 membered monocyclic heterocyclyl”, “6-8 membered monocyclic heterocyclyl”, “5-7 membered monocyclic heterocyclyl”, "5-6 membered monocyclic heterocyclyl”, “3-membered monocyclic heterocyclyl” -6-membered saturated monocyclic heterocyclic group”, "5-6 membered saturated monocyclic heterocyclic group", "3-6 membered nitrogen-containing monocyclic heterocyclic group”, “3-6 membered saturated nitrogen-containing monocyclic heterocyclic group” "5-6 membered nitrogen-containing monocyclic heterocyclic group”, “5-6 membered saturated nitrogen-containing monocyclic heterocyclic group” and the like.
  • 3-8 membered monoheterocyclyl include, but are not limited to: aziridyl, 2H-aziridinyl, diaziridinyl, 3H-diaziridenyl, aza Cyclobutanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxanyl Dialkenyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydro thienyl, tetrahydrothienyl, 4,5-
  • the "8-10-membered fused heterocyclic group” in the present invention refers to at least one ring formed by two or more cyclic structures sharing two adjacent atoms with each other and containing 8-10 ring atoms.
  • the atom is a heteroatom, saturated or partially saturated, non-aromatic cyclic group, one of the rings in the fused ring can be an aromatic ring, but the fused ring as a whole is not aromatic, and the heteroatom is nitrogen Atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo, including but not limited to "8-9 membered fused heterocyclic group" ", "9-10-membered fused heterocyclic group", etc.; specific examples of the "8-10-membered fused heterocyclic group” include but are not limited to: pyrrolidinocyclopropyl, cyclopentylazepin
  • the "3-8-membered heterocycloalkyl” in the present invention refers to a specific example of the "3-10-membered heterocycloalkyl" containing 3-8 ring carbon atoms.
  • the "6-10-membered aryl group" in the present invention includes “6-8-membered monocyclic aryl group” and "8-10-membered fused-ring aryl group”.
  • the "6-8-membered monocyclic aryl group" in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably benzene base.
  • the "8-10-membered fused-ring aryl group” mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring carbon atoms, not
  • the saturated and aromatic cyclic group is preferably a "9-10-membered fused-ring aryl group", and specific examples are naphthyl and the like.
  • the "5-10-membered heteroaryl” in the present invention includes “5-8-membered monocyclic heteroaryl” and "8-10-membered fused heteroaryl”.
  • the "5-8 membered monocyclic heteroaryl" in the present invention refers to containing at least one (eg 1, 2, 3, 4, 5 or 6) heteroatoms (eg nitrogen atom, oxygen atom) or sulfur atom) and an aromatic monocyclic cyclic group with 5-8 ring atoms.
  • heteroatoms eg nitrogen atom, oxygen atom
  • sulfur atom e.g, sulfur atom
  • 5-8 membered monocyclic heteroaryl includes, for example, "5-7 membered monocyclic heteroaryl", “5-6 membered monocyclic heteroaryl", “5-6 membered nitrogen-containing monocyclic heteroaryl” , “6-membered nitrogen-containing monocyclic heteroaryl group”, etc.
  • the heteroatom in the "nitrogen-containing heteroaryl group” contains at least one nitrogen atom, for example, only contains 1 or 2 nitrogen atoms, or, contains one Nitrogen atoms and 1 or 2 other heteroatoms (such as oxygen and/or sulfur atoms), or, containing 2 nitrogen atoms and 1 or 2 other heteroatoms (such as oxygen and/or sulfur atoms) .
  • 5-8 membered monocyclic heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadi azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-Triazinyl, 1,3,5-Triazinyl, 1,2,4,5-Tetrazinyl, Azacyclotrienyl, 1,3-Diazepinyl Alkenyl,
  • the "8-10-membered fused heteroaryl group” in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (at least one of which is Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms), unsaturated aromatic ring structures.
  • Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms
  • unsaturated aromatic ring structures such as nitrogen atoms, oxygen atoms or sulfur atoms
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • ring atoms eg, carbon, nitrogen, or sulfur atoms
  • heteroatoms are selected from nitrogen, oxygen Or sulfur” etc., and its condensing mode can be benzo 5-6-membered heteroaryl, 5-6-membered heteroaryl and 5-6-membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrole furan, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benzisofuryl, benzothienyl, indolyl, isoindolyl, benzo oxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquino
  • L 2 is directly connected to X 6 .
  • C(R 3 )(R 4 ) in the present invention refers to a group formed by R 3 and R 4 respectively replacing two hydrogen atoms on the methylene group, and the specific connection method is as follows
  • heteroatom refers to a nitrogen atom, an oxygen atom or a sulfur atom, and a case where a carbon atom, a nitrogen atom or a sulfur atom is oxo-substituted.
  • substituted refers to two situations in which one or more atoms on the substituted group may be "substituted” or “unsubstituted” by one or more substituent groups.
  • the "pharmaceutically acceptable salt” in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) existing in a compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts with appropriate inorganic or organic anions (acids) of basic functional groups (such as -NH 2 , etc.) present in the compounds , including salts formed with inorganic or organic acids (eg, carboxylic acids, etc.).
  • an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • base an appropriate inorganic or organic cation
  • ester in the present invention refers to the ester that can be formed by esterification with alcohol when the compound of the present invention has a carboxyl group, such as methyl ester, ethyl ester, Propyl ester or isopropyl ester; when the compound of formula (I) has a hydroxyl group, it can react with organic acids, organic acid salts, etc. to form esters, for example, with formic acid, acetic acid, propionic acid or isopropionic acid to form methyl esters respectively ester, acetate, propionate or isopropionate.
  • the formed ester can undergo a hydrolysis reaction in the presence of an acid or a base to generate the corresponding acid or alcohol.
  • stereoisomer in the present invention refers to when the compound of the present invention contains one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomers Constituent mixtures and single diastereomers.
  • the compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers.
  • the scope of the present invention includes all possible optical isomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond, unless otherwise specified, cis-isomer and trans-isomer are included.
  • the compounds described in the present invention may exist as tautomers (a type of functional group isomer) that have different hydrogen attachment points by displacement of one or more double bonds, eg, ketones and their alkenes
  • the alcohol forms are keto-enol tautomers, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl are tautomers.
  • Each tautomer and mixtures thereof are included within the scope of the present invention.
  • Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers and the like are included in the scope of the present invention.
  • the "dosage form” referred to in the present invention refers to the form that the drug is made into suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections) , sterile powders for injection and concentrated solutions for injection), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably Powder, tablet, granule, capsule, solution, injection, ointment, gargle or suppository.
  • the compounds of the present invention have excellent AhR activity inhibitory effect, and can be safely used for the treatment of diseases or related disorders mediated by abnormal AhR activity.
  • the compounds of the present invention have good biological stability, high bioavailability, exhibit good pharmacokinetic properties, and have good clinical application prospects.
  • the compounds of the present invention show low toxicity, good drug resistance and high safety.
  • HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • LiHMDS Lithium Hexamethyltrisilylamide
  • N-ethoxycarbonyl-N'-(5-(4-chlorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)thiourea (7.5g , the crude product in the previous step) was dissolved in methanol/ethanol (70/70 mL) mixed solvent, DIEA (7 g, 54 mmol) and hydroxylamine hydrochloride (6.3 g, 90 mmol) were added, and the mixture was stirred at 80° C. for 16 hours. Spin dry, wash the solid with water slurry, and filter to obtain 5.1 g of the target compound, with a two-step yield of 89.5%.
  • 6-(4-Chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2 -Amine (5.1g, 15.7mmol) was dissolved in dichloromethane (100mL), tert-butyl nitrite (9.7g, 94.2mmol) and titanium tetrachloride (3g, 15.7mmol) were added, and the reaction was carried out at 20°C for 3 hours , and methanol was added to quench the reaction.
  • the solvent was spin-dried and purified by silica gel column chromatography (100% ethyl acetate) to obtain 4.5 g of the product with a yield of 83%.
  • 6-Chloro-4-methylpyridin-3-amine (10.0 g, 70.0 mmol) was added to N,N-dimethylformamide (120 mL), and then N-iodobutanedi was added in batches at 40°C
  • the imide (23.7 g, 105.3 mmol) was reacted at 40°C for 6 hours.
  • Test substance the compound of the present invention, its structural formula and preparation method are shown in the preparation example of the present invention.
  • Positive control drug BAY-2416964, purchased or prepared according to the method disclosed in prior art CN110678459A, its structure is as follows:
  • HEK293T cells were cultured according to the conditions recommended by ATCC, and reached the logarithmic growth phase in good condition. The medium was removed, washed with PBS, digested with TrypLE solution, and the cells were collected after termination of the complete medium. Cells were washed twice with PBS to remove phenol red and resuspended to an appropriate concentration. Cell viability greater than 90% will be used for further experiments. Inoculate 2.5*10 6 number of HEK293T into a 6cm petri dish, incubate at 37°C, 5% CO 2 incubator for 16h, add transfection plasmid, and incubate at 37°C, 5% CO 2 incubator for 5-6 hours.
  • the DMSO solution of the prepared compound was transferred to a 384-well plate with Echo550, wherein the positive control well was transferred with a final concentration of 1000 times the positive control drug, and the vehicle control well was transferred with the same amount of 100% DMSO.
  • the transfected cells were seeded on the plate, 17,000 cells/well, the culture medium contained kynuric acid at a final concentration of 50 ⁇ M, and the final concentrations of the compounds tested were 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 370.4 nM, 123.5 nM, 41.2 nM, and 13.7 nM, respectively. , 4.6nM, 1.5nM.
  • Cells were continued to culture for 18-20 hours at 37°C, 5% CO2 incubator. Add 25 ⁇ L of detection reagent, Steady-Glo TM Luciferase Assay Reagent to each well.
  • the Envision microplate reader reads the light signal value.
  • Inhibition rate (%) 100-(Signal test compound -Signal Ave-PC )/(Signal Ave-VC- Signal Ave -PC )*100
  • Signal Ave-pc Average signal intensity of positive control wells
  • Signal Ave-vc Average signal intensity of vehicle control wells.
  • the compounds of the present invention have a good inhibitory effect on AhR.
  • the compounds listed in Table 1 of the detailed description section all have lower IC50 values, especially compounds 1-1, 3-1, 5-1, which are about 2- to 4-fold more active than the positive control drug.
  • DMSO dimethyl sulfoxide
  • MC methyl cellulose
  • HP- ⁇ -CD Hydroxypropyl ⁇ -Cyclodextrin
  • Kolliphor HS 15 Macrogol 15 Hydroxystearate
  • Test sample the compound of the present invention, self-made, its chemical name and preparation method are shown in the preparation examples of each compound.
  • Test animals CD1 mice, female, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., 6 mice/compound/administration route.
  • Preparation method of blank solvent (1) Weigh 28g HP- ⁇ -CD, add an appropriate amount of water for injection to dissolve, then make up to 100mL with water for injection, and vortex to mix to obtain 28% HP- ⁇ -CD.
  • Preparation method of blank solvent (2) Weigh 20g HPC, slowly add 500mL of stirred purified water, then add 1mL of Tween 80, stir until it is clear and transparent, set the volume to 1000mL, and stir evenly to obtain 2%HPC+0.1% Tween 80.
  • 0.5% MC preparation method Weigh 5g of MC, slowly add it to 800ml of stirred purified water, stir until it is clear and transparent, then use purified water to make up the volume to 1000ml, and stir evenly.
  • the iv administration volume is 5mL/kg, the iv administration dose is 5mg/kg, and the administration concentration is 1mg/mL;
  • the volume of po administration is 10mL/kg, the dose of po administration is 10mg/kg, and the administration concentration is 1mg/mL;
  • Blood collection time point 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 30, 48h after administration, and the blood collection is as follows:
  • T 1/2 represents the half-life
  • Cmax represents the maximum plasma concentration value
  • AUC last represents the area under the curve 0 ⁇ t
  • CL represents the clearance rate
  • MRT represents the mean residence time
  • Vss represents the apparent volume of distribution
  • F represents bioavailability

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Abstract

本发明属于医药技术领域，具体涉及一类稠环类AhR抑制剂化合物、其药学上可接受的盐、其酯或其立体异构体，含有所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐、其酯或其立体异构体的方法，以及所述化合物、其药学上可接受的盐、其酯或其立体异构体的用途。

Description

稠环类AhR抑制剂 技术领域
本发明属于医药技术领域，具体涉及一类稠环类AhR抑制剂化合物、其药学上可接受的盐、其酯或其立体异构体，含有所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐、其酯或其立体异构体的方法，以及所述化合物、其药学上可接受的盐、其酯或其立体异构体的用途。
背景技术
AhR(Aryl Hydrocarbon Receptor)：是转录调节子bHLH-PAS家族的一员。bHLH(basic Helix-Loop-Helix)-PAS(Per-ARNT-Sim)家族主要调控各种发育和生理功能，包括神经发生、气管和唾液管形成、毒素代谢、昼夜节律、对缺氧的反应和激素受体功能等，可被污染物、微生物、食物和色氨酸代谢产物来源的配体小分子活化，在不同的细胞发挥不同的生物学效应。该家族成员的独特特征是具有PAS域，此域的名称来源于最先发现具有这个基序的三个蛋白：Drosophila Per，Human ARNT和Drosophila Sim。PAS结构域由260-310个氨基酸组成，包括两个非常保守的疏水重复序列，称为PAS-A和PAS-B，由一个保守性比较差的序列所间隔。总之，PAS结构域保守性并不好，并且可以介导许多不同的生化功能。
AhR，也称为二恶英受体，最初被认为主要调控2,3,7,8-四氯代苯并二噁英(2,3,7,8-tetracholrodibenzo-p-dioxin，TCDD)等化合物的毒性作用，因此而得名。但是目前发现膳食、共生细菌和宿主的新陈代谢物等也提供多种AhR的生理配体。AhR在各种组织广泛表达，在肝脏、肺、脾脏、肾脏高表达，组织中，上皮细胞来源的细胞AhR表达量最高。AhR因此也成为控制许多生理过程的关键转录因子，包括细胞的增殖、凋亡、分化、黏附、迁移和多能干性，参与调节自身免疫、感染和癌症的免疫应答。
通常情况下，AhR会在胞浆内与HSP90、AIP和HSP90的伴侣蛋白p23形成一个复合物处于休眠状态。当其结合相应的配体后，这个复合物中的AhR会被激活，并且发生构象的改变，从而暴露出一个定位信号序列。其中HSP90会从复合物中被释放出来，而AhR受体则被转运至核内，与ARNT形成异二聚体。这个异二聚体会与XRE结合，并改变增强子XRE控制的基因的表达。XREs具有保守的核心序列“GCGTG”，存在于异种生物代谢的几个基因的启动子区域，包括CYP1A1，CYP1A2，CYP1B1和NAD(P)H-奎宁氧化还原酶。
AhR还与其他信号通路有相互作用，例如由雌激素受体和其他激素受体、低氧、NF-κB和Rb介导的那些信号通路。与AhR通路互相关联研究最多的可能是类固醇激素受体相关通路，AhR与ESR、AR和甲状腺激素受体途径相互作用，AhR的激活会导致ESR数量和ESR 反应性降低，同样会导致ESR代谢的增加。
AhR在免疫系统的许多细胞中表达，包括树突细胞(DC)、巨噬细胞、T细胞和NK细胞，并且在免疫调节中起重要作用。AhR激活促进调节性T细胞产生，直接和间接抑制Th1和Th17分化，并降低DC的激活和成熟。AhR激活调节先天免疫反应，并且组成型AhR表达已显示负调节对病毒感染的I型干扰素应答，另外，具有组成型活性AhR的小鼠自发地发展肿瘤。
色氨酸的代谢产物犬尿氨酸等激活AhR抑制免疫细胞的响应，免疫组织化学分析乳腺癌、前列腺癌、胃、小细胞肺癌、肝癌中AhR表达水平相对高于周围组织，拮抗AhR，可以从抑制肿瘤细胞增殖和提高免疫响应两方面发挥抗肿瘤活性。
该靶点目前研究处于临床试验阶段，尚无药物上市。因此，开发AhR受体小分子抑制剂，无论是单用还是联合其他药物应用均有广阔的市场前景。由此可见，开发一款高活性、选择性以及类药性的AhR小分子抑制剂具有重要的临床意义。
发明内容
本发明要解决的技术问题是提供一种结构新颖的、对AhR活性具有良好抑制作用的化合物。进一步的，该类化合物可用于制备治疗和/或预防由AhR活性所介导的疾病或相关疾病的药物。本发明的技术方案如下：
在一方面，本发明提供了如下通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，
Figure PCTCN2021137679-appb-000001
其中，
X 1、X 2分别独立地选自C(R 2)或N；
X 3、X 4、X 6分别独立地选自C、C(R 2)或N；
X 5、X 7分别独立地选自C(R 2)、CH(R 2)、O、N、N(R 3)或C(O)；
L 1选自化学键、-C(R 4)(R 5)-、-O-、-S-、-C(O)-或-S(O)-；
L 2选自任选被取代基取代的C 1-6亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基或卤代C 1-6烷氧基；
R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代 C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷氧基、氨基C 1-6烷氧基、羧基C 1-6烷氧基、3-10元环烷基、3-10元杂环烷基、5-10元杂芳基或6-10元芳基；
每一R 2、R 4、R 5分别独立地选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基或卤代C 1-6烷氧基；
每一R 3分别独立的选自氢、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基或羧基C 1-6烷基；
Ar 1选自任选被1-3个Q 1取代的3-10元环烷基、3-10元杂环烷基、5-10元杂芳基或6-10元芳基；
Ar 2选自任选被1-3个Q 2取代的3-10元环烷基、3-10元杂环烷基、5-10元杂芳基或6-10元芳基；
每一Q 1、每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1-6烷氧基；
---选自单键或双键，且相邻两个---不同时为双键。
在某些实施方案中，前述通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
X 1、X 2分别独立地选自C(R 2)或N；
X 3、X 4、X 6分别独立地选自C、C(R 2)或N；
X 5、X 7分别独立地选自C(R 2)、CH(R 2)、O、N、N(R 3)或C(O)；
L 1选自化学键、-C(R 4)(R 5)-、-O-、-S-、-C(O)-或-S(O)-；
L 2选自任选被取代基取代的C 1-6亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基或卤代C 1-6烷氧基；
R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷氧基、氨基C 1-4烷氧基或羧基C 1-4烷氧基；
每一R 2、R 4、R 5分别独立地选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1- 4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
每一R 3分别独立的选自氢、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基或 羧基C 1-4烷基；
Ar 1选自任选被1-3个Q 1取代的5-6元单环环烷基、5-6元单环杂环烷基、5-6元单环杂芳基或苯基；
每一Q 1分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基；
Ar 2选自任选被1-3个Q 2取代的5-6元单环环烷基、5-6元单环杂环烷基、5-6元单环杂芳基或苯基；每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1-6烷氧基；
---选自单键或双键，且相邻两个---不同时为双键。
在某些实施方案中，Ar 1选自任选被1-3个Q 1取代的5-6元单环环烷基、含1-3个杂原子的5-6元单环杂环烷基、含1-3个杂原子的5-6元单环杂芳基或苯基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的5-6元单环环烷基、含1-2个杂原子的5-6元单环杂环烷基、含1-2个杂原子的5-6元单环杂芳基或苯基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的5-6元含氮单环杂芳基或苯基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的含1-2个氮的5-6元单环杂芳基或苯基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的环戊基、环己基、四氢呋喃基、吡咯烷基、咪唑烷基、吡唑烷基、四氢噻吩基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、哌嗪基、吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 1分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基或1,2,4-三唑基。
在某些实施方案中，Ar 1选自任选被1-2个Q 1取代的吡咯基、咪唑基、吡唑基、1,2,3-三唑基或1,2,4-三唑基。
在某些实施方案中，Ar 2选自任选被1-3个Q 2取代的5-6元单环环烷基、5-6元单环杂环烷基、5-6元单环杂芳基或苯基；每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1-6烷氧基。
在某些实施方案中，Ar 2选自任选被1-3个Q 1取代的5-6元单环环烷基、含1-3个杂原子的5-6元单环杂环烷基、含1-3个杂原子的5-6元单环杂芳基或苯基。
在某些实施方案中，Ar 2选自任选被1-2个Q 1取代的5-6元单环环烷基、含1-2个杂原子的5-6元单环杂环烷基、含1-2个杂原子的5-6元单环杂芳基或苯基。
在某些实施方案中，Ar 2选自任选被1-2个Q 1取代的含1-2个杂原子的5-6元单环杂芳基或苯基。
在某些实施方案中，Ar 2选自任选被1-2个Q 2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基。
在某些实施方案中，Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基。
在某些实施方案中，Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基或苯基。
在某些实施方案中，前述通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
L 1选自化学键、-C(R 4)(R 5)-、-O-、-S-、-C(O)-或-S(O)-；
L 2选自任选被取代基取代的C 1-6亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基或卤代C 1-6烷氧基；
R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、三氟甲氧基、羟基甲氧基或氨基甲氧基；
每一R 2、R 4、R 5分别独立地选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基；
每一R 3分别独立的选自氢、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基或羧基C 1-4烷基；
Ar 1选自任选被1-3个Q 1取代的环戊基、环己基、四氢呋喃基、吡咯烷基、咪唑烷基、吡唑烷基、四氢噻吩基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、哌嗪基、吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 1分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基；
Ar 2选自任选被1-3个Q 2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基；
---选自单键或双键，且相邻两个---不同时为双键。
在某些实施方案中，前述通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
L 1选自化学键、-CH 2-、-O-、-S-、-C(O)-或-S(O)-；
L 2选自任选被取代基取代的C 1-4亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、三氟甲氧基、羟基甲氧基或氨基甲氧基；
每一R 2分别独立地选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基；
每一R 3分别独立的选自氢、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基或羧基C 1-4烷基；
Ar 1选自任选被1-2个Q 1取代的呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 1分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基；
Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基；
---选自单键或双键，且相邻两个---不同时为双键。
在某些实施方案中，式(I)所示化合物、其药学上可接受的盐、其酯或其立体异构体，进一步具有如下通式(II)所示的结构，
Figure PCTCN2021137679-appb-000002
其中，X 3、X 4、X 6分别独立地选自C、CH或N；
X 5、X 7分别独立地选自C(R 2)、CH(R 2)、O、N、N(R 3)或C(O)；
L 1选自化学键、-CH 2-、-O-、-S-、-C(O)-或-S(O)-；
L 2选自任选被取代基取代的C 1-4亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷氧基、氨基C 1-4烷氧基或羧基C 1-4烷氧基；
每一R 2分别独立地选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
每一R 3分别独立的选自氢、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基或羧基C 1-4烷基；
Ar 2选自任选被1-2个Q2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 1、每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基或氨基C 1-4烷基；
---选自单键或双键，且相邻两个---不同时为双键。
在某些实施方案中，X 3、X 4、X 6分别独立地选自C、CH或N；
X 5、X 7分别独立地选自CH、CH 2、O、N、NH或C(O)。
在某些实施方案中，X 4选自C或CH；X 3、X 6分别独立地选自C、CH或N；
X 5、X 7分别独立地选自CH、CH 2、O、N、NH或C(O)。
在某些实施方案中，L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1- 4烷氧基。
在某些实施方案中，L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-，所 述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
在某些实施方案中，每一Q 1分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
在某些实施方案中，每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
在某些实施方案中，R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、三氟甲氧基、羟基甲氧基或氨基甲氧基。
在某些实施方案中，每一R 2、R 4、R 5分别独立地选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基。
在某些实施方案中，每一R 3分别独立的选自氢、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟基甲基、氨基甲基或羧基甲基。
在某些实施方案中，X 3、X 4、X 6分别独立地选自C、CH或N；
X 5、X 7分别独立地选自CH、CH 2、O、N、NH或C(O)；
L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基；
R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、三氟甲氧基、羟基甲氧基或氨基甲氧基；
Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 1、每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
在某些实施方案中，式(I)或式(II)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，进一步具有如下通式(IIIa)、通式(IIIb)、通式(IIIc)或通式(IIId)所示的结构，
Figure PCTCN2021137679-appb-000003
其中，Ar 2、Q 1、Q 2、L 1、L 2、R 1、R 4、R 5如前文任一方案所定义。
在某些实施方案中，通式(IIIa)、通式(IIIb)、通式(IIIc)或通式(IIId)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
L 1选自化学键、-CH 2-、-O-或-S-；
L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基或三氟甲氧基；
R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基；
Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基或苯基；
每一Q 1、每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
在某些实施方案中，式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，进一步具有如下通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所示的结构，
Figure PCTCN2021137679-appb-000004
其中，Ar 1、Ar 2、Q 1、Q 2、L 1、L 2、R 1、R 4、R 5如前文任一方案所定义。
在某些实施方案中，通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
L 1选自化学键、-CH 2-、-O-、-S-、-C(O)-或-S(O)-；
L 2选自任选被取代基取代的C 1-4亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷氧基、氨基C 1-4烷氧基或羧基C 1-4烷氧基；
Ar 1选自任选被1-2个Q1取代的呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基
Ar 2选自任选被1-2个Q2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
每一Q 1、每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基或氨基C 1-4烷基。
在某些实施方案中，通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
L 1选自化学键、-CH 2-、-O-或-S-；
L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基或三氟甲氧基；
R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙 基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基；
Ar 1选自任选被1-2个Q 1取代的吡咯基、咪唑基、吡唑基、1,2,3-三唑基或1,2,4-三唑基；
Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基或苯基；
每一Q 1、每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
本发明中前述各技术方案或技术方案中的任一取代基及其任一可选基团可以相互组合形成新的技术方案，所形成的新的技术方案同样包括在本发明的范围之内。
在本发明某些实施方案，前述通式(I)所述化合物、其药学上可接受的盐、其酯或其立体异构体，选自如下化合物：
Figure PCTCN2021137679-appb-000005
Figure PCTCN2021137679-appb-000006
Figure PCTCN2021137679-appb-000007
本发明还提供了一种药物组合物，其含有前述通式(I)、通式(II)、通式(IIIa)、通式(IIIb)、通式(IIIc)、通式(IIId)、通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所述的化合物、其药学上可接受的盐、其酯或其立体异构体，及一种或多种药用载体和/或稀释剂；所述药物组合物可以制成临床上或药学上可接受的任一剂型，如片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂等。
在本发明的某些实施方案中，上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成口服制剂，例如可以制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，上述药物制剂也可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。
本发明的药物组合物或药物制剂中可用的药用载体和/或稀释剂可以是药物制剂领域中任何常规的载体和/或稀释剂，特定载体和/或稀释剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。
在另一方面，本发明还涉及前述通式(I)、通式(II)、通式(IIIa)、通式(IIIb)、通式(IIIc)、 通式(IIId)、通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所述化合物、其药学上可接受的盐、其酯或其立体异构体在制备预防和/或治疗由AhR活性异常所介导的疾病及相关疾病的药物中的用途，所述药物可与一种或多种其他药物联用以预防或治疗由AhR活性异常所介导的疾病及相关病症。所述疾病及相关病症选自癌症或良性肿瘤，所述癌症包括但不限于肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、甲状腺癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、白血病、胶质瘤或肉瘤等。
进一步的，本发明还涉及含有前述通式(I)、通式(II)、通式(IIIa)、通式(IIIb)、通式(IIIc)、通式(IIId)、通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物制剂在制备药物中的用途，所述药物可与一种或多种药物联用以治疗及/或预防由AhR活性异常所介导的疾病及相关病症。
在另一方面，本发明涉及的含有前述通式(I)、通式(II)、通式(IIIa)、通式(IIIb)、通式(IIIc)、通式(IIId)、通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物可以单独给药，或者与一种或多种第二治疗活性剂联合使用，所述第二治疗活性剂与本申请的AhR活性异常抑制剂化合物组合用于治疗和/或预防由AhR活性异常所介导的疾病和相关病症。因此，在某些实施方案中，所述的药物组合物还含有一种或多种第二治疗活性剂。在某些实施方案中，所述的第二治疗活性剂选自抗癌剂，包括有丝分裂抑制剂、烷化剂、抗代谢物、反义DNA或RNA、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。
在某些实施方案中，待组合的各成分(例如，本发明的化合物、其药学上可接受的盐、其酯、其立体异构体与第二治疗活性剂)可同时给药或依次顺序地分开用药。例如，可以在施用本发明化合物、其药学上可接受的盐、其酯或其立体异构体之前、同时或之后，施用第二治疗活性剂。此外，待组合的各成分还可以以同一制剂形式或以分开的不同制剂的形式联合给药。
在另一方面，本发明还提供了一种治疗由AhR活性异常介导的疾病及相关病症的方法，该方法包括向有需要的患者施用有效量的前述通式(I)、通式(II)、通式(IIIa)、通式(IIIb)、通式(IIIc)、通式(IIId)、通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所述的化合物、 其药学上可接受的盐、其酯或其立体异构体，前述制剂或药物组合物；所述由AhR活性异常介导的疾病及相关病症如上定义。
所述的“有效量”是指能够减轻、延缓、抑制或治愈受试者病症的药物剂量。给药剂量的大小与药物给药方式、药剂的药代动力学、疾病的严重程度、受试者的个性体征(性别、体重、身高、年龄)等来确定。
【定义和一般术语】
在本申请的说明书和权利要求书中，化合物都是依据化学结构式而命名，如果表示同一化合物时化合物的命名和化学结构式不符，以化学结构为准。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好的理解本发明，下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候，以本发明所提供的术语的定义和解释为准。
本发明所述的“卤素”是指氟原子、氯原子、溴原子或碘原子。
本发明所述的“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C 1-4烷基”、“C 1-3烷基”、“C 1-2烷基”、“C 2-6烷基”、“C 2-5烷基”、“C 2-4烷基”、“C 2-3烷基”、“C 3-6烷基”、“C 3-5烷基”、“C 3-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基(丙基)、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C 1-4烷基”指C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C 1-6亚烷基”是指直链含1-6个碳原子的烷烃去除两个不在同一碳原子上的氢所衍生的基团，包括“C 1-5亚烷基”、“C 1-4亚烷基”、“C 1-3亚烷基”、“C 1-2亚烷基”，具体实例包括但不限于：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2CH 2-。
本发明所述的“C 1-6烷氧基”是指“C 1-6烷基-O-”，所述的“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷氧基”是指“C 1-4烷基-O-”，所述的“C 1-4烷基”如前文所定义。
本发明所述的“羟基C 1-6烷基、氨基C 1-6烷基、卤代C 1-6烷基、羧基C 1-6烷基”是指C 1-6烷基中的一个或多个氢分别被一个或多个羟基、氨基、卤素或羧基所取代。所述的“C 1-6烷基”如前文所定义。
本发明所述“卤代C 1-6烷氧基”是指“C 1-6烷氧基”中的一个或多个氢被一个或多个卤素所取代。
本发明所述的“羟基C 1-6烷氧基、氨基C 1-6烷氧基、卤代C 1-6烷氧基、羧基C 1-6烷氧基”是指C 1-6烷氧基中的一个或多个氢分别被一个或多个羟基、氨基、卤素或羧基所取代。所述的“C 1-6烷氧基”如前文所定义。
本发明所述的“C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基”分别是指C 1-6烷基-NH-、C 1-6烷基-C(O)-、
Figure PCTCN2021137679-appb-000008
本发明所述的“3-10元环烷基”包括“3-8元单环环烷基”和“8-10元稠环环烷基”。本发明所述“3-8元环烷基”指“3-10元环烷基”中的含有3-8个碳原子的具体实例。
本发明所述的“3-8元单环环烷基”是指含有3-8个环原子的饱和或部分饱和的且不具有芳香性的单环环状基团，包括“3-7元单环环烷基”，“3-6元单环环烷基”，“5-6元单环环烷基”，具体实例包括但不限于：环丙基、环丁基、环戊基、环己基或环己烯。
本发明所述的“8-10元稠环环烷基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有8-10个环原子的、饱和或部分饱和的、非芳香性环状基团，其实例包括但不限于：
Figure PCTCN2021137679-appb-000009
本发明所述的“3-10元杂环基”包括“3-8元单环杂环基”和“8-10元稠杂环基”。
本发明所述的“3-8元杂环基”是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。本发明所述的“3-8元单杂环基”包括“3-8元饱和单杂环基”和“3-8元部分饱和单杂环基”。所述“3-8元单环杂环基”优选“3-7元单环杂环基”、“3-6元单环杂环基”、“4-7元单环杂环基”、“4-6元单环杂环基”、“6-8元单环杂环基”、“5-7元单环杂环基”、“5-6元单环杂环基”、“3-6元饱和单环杂环基”、“5-6元饱和单环杂环基”、“3-6元含氮单环杂环基”、“3-6元饱和含氮单环杂环基”、“5-6元含氮单环杂环基”、“5-6元饱和含氮单环杂环基”等。例如，仅包含1个或2个氮原子，或者，包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“3-8元单杂环基”的具体实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、二氢哌啶酮基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、噁唑烷基、 2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等。
本发明所述“8-10元稠杂环基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有8-10个环原子的、且至少一个环原子为杂原子的、饱和或部分饱和的、非芳香性环状基团，所述的稠环中其中一个环可以为芳香性环，但稠环整体不具备芳香性，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代，包括但不限于“8-9元稠杂环基”、“9-10元稠杂环基”等；所述“8-10元稠杂环基”具体实例包括但不仅限于：吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、嘧啶并四氢吡喃基；四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔啉基、苯并[d][1,3]二氧杂环戊烯基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、八氢-苯并[d]咪唑基、十氢喹啉基、六氢噻吩并咪唑基、六氢呋喃并咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基、八氢环戊烯并[c]吡咯基、4H-1,3-苯并噁嗪基等。
本发明所述的“3-8元杂环烷基”指“3-10元杂环烷基”中的含有3-8个环碳原子的具体实例。
本发明所述的“6-10元芳基”包括“6-8元单环芳基”和“8-10元稠环芳基”。
本发明所述的“6-8元单环芳基”是指含有6-8个环碳原子的单环芳基，其实例包括但不限于：苯基、环辛四烯基等；优选苯基。
本发明所述的“8-10元稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团，优选“9-10元稠环芳基”，具体实例如萘基等。
本发明所述的“5-10元杂芳基”包括“5-8元单环杂芳基”和“8-10元稠杂芳基”。
本发明所述的“5-8元单环杂芳基”是指含有至少一个(例如1个、2个、3个、4个、5个或6个)杂原子(例如氮原子、氧原子或硫原子)且环原子数5-8个的具有芳香性的单环环状基团。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。“5-8元单环杂芳基”包括例如“5-7元单环杂芳基”、“5-6元单环杂芳基”、“5-6元含氮单环杂芳基”、“6元含氮单环杂芳基”等，所述的“含氮杂芳基”中的杂原子至少含有一个氮原子，例如，仅包含1个或2个氮原子，或者，包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原 子)，或者，包含2个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“5-8元单环杂芳基”的具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等。所述“5-6元单环杂芳基”是指5-8元杂芳基中含有5-6个环原子的具体实例。
本发明所述的“8-10元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的、不饱和的具有芳香性的环状结构。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。包括“9-10元稠杂芳基”，“8-9元稠杂芳基”，“含1-2个杂原子的9-10元稠杂芳基，所述杂原子选自氮、氧或硫”等，其稠和方式可以为苯并5-6元杂芳基、5-6元杂芳基并5-6元杂芳基等；具体实例包括但不限于：吡咯并吡咯、吡咯并呋喃、吡唑并吡咯、吡唑并噻吩、呋喃并噻吩、吡唑并噁唑、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮基、4-喹啉酮基、1-异喹啉酮基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、嘌呤基、萘啶基等。
“---”指化学键，包括单键和双键。
当L 1选自化学键时，L 2与X 6直接相连。
本发明所述的“C(R 3)(R 4)”是指R 3、R 4分别取代亚甲基上的两个氢原子形成的基团，具体的连接方式为
Figure PCTCN2021137679-appb-000010
本发明所述的“杂原子”是指氮原子、氧原子或硫原子，以及碳原子、氮原子或硫原子被氧代的情况。
本发明所述的“碳原子、氮原子或硫原子被氧代”是指碳原子、氮原子或硫原子分别形成C＝O、N＝O、S＝O或SO 2的结构。
本发明所述“任选被取代”是指被取代基上的一个或多个原子可以被一个或多个取代基“取代”或“不取代”的两种情形。
本发明所述的“药学上可接受的盐”指化合物中存在的酸性官能团(例如-COOH、-OH、-SO 3H等)与适当的无机或者有机阳离子(碱)形成的盐，包括与碱金属或碱土金属形成的盐、铵 盐，以及与含氮有机碱形成的盐；以及化合物中存在的碱性官能团(例如-NH 2等)与适当的无机或者有机阴离子(酸)形成的盐，包括与无机酸或有机酸(例如羧酸等)形成的盐。
本发明所述的“酯”是指当本发明化合物存在羧基时，可以与醇发生酯化反应而形成的酯，例如与甲醇、乙醇、丙醇或异丙醇分别形成甲酯、乙酯、丙酯或异丙酯；当式(I)化合物存在羟基时，可以与有机酸、有机酸盐等发生酯化反应而形成的酯，例如与甲酸、乙酸、丙酸或异丙酸分别形成甲酸酯、乙酸酯、丙酸酯或异丙酸酯。形成的酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。
本发明所述的“立体异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心，这类不对称中心各自独立地产生两个光学异构体。本发明的范围包括所有可能的光学异构体和它们的混合物。
本发明所述的化合物若含有烯烃双键，除非特别说明，包括顺式异构体和反式异构体。
本发明所述的化合物可以以互变异构体(官能团异构体的一种)形式存在，其通过一个或多个双键位移而具有不同的氢的连接点，例如，酮和它的烯醇形式是酮-烯醇互变异构体、1H-1,2,4-三氮唑基与4H-1,2,4-三氮唑基为互变异构体。各互变异构体及其混合物都包括在本发明的范围中。所有化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明所述的“剂型”指将药物制成的适用于临床使用的形式，包括但不限于散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、贴剂、含漱剂或栓剂，更优选散剂、片剂、颗粒剂、胶囊剂、溶液剂、注射剂、软膏剂、含漱剂或栓剂。
本申请中所引用的参考文件中的技术方案，均包含在本发明的公开范围内，可以用于解释本发明的内容。
发明的有益效果
1、本发明化合物、其药学上可接受的盐或其立体异构体具有优异的AhR活性抑制作用，能被安全地用于治疗由AhR活性异常所介导的疾病或相关病症。
2、本发明化合物、其药学上可接受的盐或其立体异构体具有良好的生物稳定性，生物利用度高，展现出良好的药代动力学性质，具有很好的临床应用前景。
3、本发明化合物、其药学上可接受的盐或其立体异构体显示出较低的毒性，耐药性好，安全性高。
具体实施方案
下面将结合具体实施方式对本发明技术方案进行描述，对本发明的上述内容作进一步的详细说明，但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
制备例中，缩写所代表的含义如下：
DIEA：N,N-二异丙基乙胺            DMF:N,N-二甲基甲酰胺
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
TBDPSCl：叔丁基二苯基氯硅烷
LiHMDS：六甲基三硅基胺基锂
DIAD：偶氮二甲酸二异丙酯           PPh 3：三苯基膦
制备例1：(S)-2-((6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-基)氧基)丙-1-醇(化合物1-1)的制备
1. N-乙氧羰基-N'-(5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)硫脲的制备
Figure PCTCN2021137679-appb-000011
将3-(1-甲基-1H-吡唑-4-基)-5-(4-氯苯基)吡嗪-2-胺(5g,17.5mmol)溶于二氧六环(100mL)中，加入乙基碳硫氰酸盐(2.5g,19.1mmol)，20℃下反应16小时。旋干溶剂，加入甲基叔丁基醚(10mL)，有固体析出。过滤，干燥得粗品7.5g，直接用于下一步反应。
2. 6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-胺的制备
Figure PCTCN2021137679-appb-000012
将N-乙氧羰基-N'-(5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)硫脲(7.5g,上步粗品)溶于甲醇/乙醇(70/70mL)混合溶剂中，加入DIEA(7g,54mmol)和盐酸羟胺(6.3g,90mmol)，80℃搅拌16小时。旋干，水浆洗固体，经过滤得目标化合物5.1g，两步收率89.5％。
3. 2-氯-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪的制备
Figure PCTCN2021137679-appb-000013
将6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-胺(5.1g,15.7mmol)溶于二氯甲烷(100mL)中，加入亚硝酸叔丁酯(9.7g,94.2mmol)、四氯化钛(3g,15.7mmol)，20℃下反应3小时，加入甲醇淬灭反应。旋干溶剂，经硅胶柱层析提纯(100％乙酸乙酯)，得产物4.5g，收率83％。
4.(S)-6-(4-氯苯基)-2-((1-甲氧基丙烷-2-基)氧基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪的制备
Figure PCTCN2021137679-appb-000014
将2-氯-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪(460mg,1.33mmol)溶于二氧六环(5mL)中，加入(S)-1-甲氧基丙烷-2-醇(450mg,5mmol)和氢化钠(120mg,3mmol)，100℃微波反应0.5小时。加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，经过滤、浓缩、柱层析(乙酸乙酯/石油醚＝0-60％)纯化得到产物300mg，收率57％。
5.(S)-2-((6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-基)氧基)丙-1-醇的制备
Figure PCTCN2021137679-appb-000015
将(S)-6-(4-氯苯基)-2-((1-甲氧基丙烷-2-基)氧基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪(300mg,0.75mmol)溶于二氯甲烷(30mL)中，加入三溴化硼(1M in DCM,2.2mL,2.2mmol)，20℃搅拌1小时。加入甲醇淬灭反应，饱和碳酸氢钠洗，二氯甲烷萃取，无水硫酸钠干燥，经过滤、浓缩、柱层析(乙酸乙酯/石油醚＝0-50％)纯化得到粗品，后经甲基叔丁基醚浆洗得到产物41.8mg，收率14％。
分子式:C 18H 17ClN 6O 2分子量:384.8LC-MS(M/e):385.1(M+H +)
1H-NMR(400MHz,DMSO)δ：9.35(s,1H),8.82(s,1H),8.45(s,1H),8.30-8.25(m,2H),7.65-7.59(m,2H),5.15-4.95(m,2H),4.01(s,3H),3.72-3.60(m,2H),3.42-3.35(m,3H).
制备例2：(R)-3-(6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-基)-2-甲基丙烷-1-醇的制备(化合物3-1)
1.(S)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙酸甲酯的制备
Figure PCTCN2021137679-appb-000016
将(S)-3-羟基-2-甲基丙酸甲酯(2.5g,21.2mmol)溶解于二氯甲烷(100ml)中，加入TBDPSCl(6.4g,23.3mmol)，加入咪唑(2.2g,31.8mmol)，15℃搅拌2小时。反应结束后，旋干溶剂，经硅胶柱层析提纯(石油醚/乙酸乙酯＝9/1)，得目标化合物7.4g,收率98.1％。
2.(R)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙烷-1-醇的制备
Figure PCTCN2021137679-appb-000017
将(S)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙酸甲酯(6.0g,16.8mmol)溶于乙醇(100mL)中，加入氯化钙(1.8g,16.8mmol)，15℃搅拌，加入硼氢化钠(635mg,16.8mmol)，继续搅拌2小时。反应结束后，旋干溶剂，经硅胶柱层析提纯(石油醚/乙酸乙酯＝9/1)，得目标化合物4.3g,收率78％。
3.(S)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙醛的制备
Figure PCTCN2021137679-appb-000018
将草酰氯(2.3g,18.3mmol)溶解于二氯甲烷(50ml)中，-78℃搅拌15分钟，加入二甲基亚砜(1.9g,24.4mmol)的二氯甲烷溶液，继续搅拌30分钟。加入(R)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙烷-1-醇(4.0g,12.2mmol)的二氯甲烷溶液，继续搅拌30分钟。加入三乙胺(6.2g,61.0mmol)，升温至20℃，加入水淬灭反应，分液，有机相旋干，经硅胶柱层析提纯(石油醚/乙酸乙酯＝8/1)，得目标化合物3.7g,收率93.1％。
4.(R)-叔丁基((4-甲氧基-2-甲基-3-烯-1-基)氧基)二苯基硅烷的制备
Figure PCTCN2021137679-appb-000019
将(甲氧基甲基)三苯基氯化磷(3.8g,11.0mmol)溶于四氢呋喃(50mL)中，-20℃搅拌15分钟，加入LiHMDS(11mL,11.0mmol)，继续搅拌15分钟。加入(S)-3-((叔丁基二苯基硅基) 氧基)-2-甲基丙醛(3.0g,9.2mmol)，继续搅拌0.5小时，旋干，经硅胶柱层析提纯(石油醚/乙酸乙酯＝9/1)，得目标化合物1.9g,收率58.3％。
5.(R)-4-((叔丁基二苯基硅基)氧基)-3-甲基丁醛的制备
Figure PCTCN2021137679-appb-000020
将(R)-叔丁基((4-甲氧基-2-甲基-3-烯-1-基)氧基)二苯基硅烷(1.8g,5.1mmol)溶解于二氯甲烷(60ml)中，加入四氢呋喃(15mL)，0℃搅拌。加入5N盐酸(8mL)，升温20℃搅拌1小时，加入碳酸氢钠水溶液调节pH＝8，分液，有机相旋干，经硅胶柱层析提纯(石油醚/乙酸乙酯＝20/1)，得目标化合物1.6g,收率92.6％。
6.(R)-4-((叔丁基二苯基硅基)氧基)-3-甲基丁酸的制备
Figure PCTCN2021137679-appb-000021
将(R)-4-((叔丁基二苯基硅基)氧基)-3-甲基丁醛(1.5g,4.4mmol)溶于四氢呋喃(15mL)中，加入磺酸氨(553mg,5.7mmol)和水(5mL)，降温至0℃搅拌。加入亚氯酸钠(515mg,5.7mmol)，升温15℃搅拌1小时，旋干，经硅胶柱层析提纯(石油醚/乙酸乙酯＝10/1)，得目标化合物1.5g,收率95.5％。
7.(R)-2-(3-((叔丁基二苯基硅基)氧基)-2-甲基丙基)-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪的制备
Figure PCTCN2021137679-appb-000022
将(R)-4-((叔丁基二苯基硅基)氧基)-3-甲基丁酸(314mg,0.88mmol)溶于二氯甲烷(4mL)中，加入HATU(422mg,1.1mmol)，20℃搅拌。加入1,2-二氨基-5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪-1-鎓均三甲苯磺酸盐(400mg,0.8mmol)和二异丙基乙胺(227mg,1.8mmol)，继续搅拌18小时。反应结束后，旋干溶剂，经硅胶柱层析提纯(石油醚/乙酸乙酯＝4/1)，得目标化合物220mg,收率40％。
8.(R)-3-(6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-基)-2-甲基丙烷-1-醇的制备
Figure PCTCN2021137679-appb-000023
将(R)-2-(3-((叔丁基二苯基硅基)氧基)-2-甲基丙基)-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪(220mg,0.35mmol)加入四氢呋喃(7mL)溶解，加入四丁基氟化铵的四氢呋喃溶液(1M,2mL)，30℃下反应2小时。反应结束后，旋干溶剂，经硅胶柱层析提纯(二氯甲烷/甲醇＝25/1)，得目标化合物100mg,收率73.8％。
分子式:C 19H 19ClN 6O分子量:382.13LC-MS(M/e):383.2(M+H +)
1H-NMR(400MHz,CDCl 3)δ：8.68(s,1H),8.66(s,1H),8.58(s,1H),8.07-7.99(m,2H),7.55-7.50(m,2H),4.08(s,3H),3.73-3.60(m,2H),3.15-3.02(m,2H),2.66(s,1H),2.43-2.35(m,1H),1.10-1.08(d,3H,J＝6.8Hz).
制备例3：(R)-3-(6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-基)-1-甲基-乙烷-1-醇的制备(化合物5-1)
1.(R)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙烷-1-酸的制备
Figure PCTCN2021137679-appb-000024
将(S)-3-((叔丁基二苯基硅基)氧基)-2-甲基丙酸甲酯(1.1g,3.1mmol)溶于四氢呋喃(12.0mL)中，加入氢氧化锂(254.9mg,6.18mmol)、水(3.0mL)和甲醇(3.0mL)，15℃搅拌2小时。反应结束后，用1mol/L盐酸调节体系pH＝4，乙酸乙酯萃取，旋干溶剂，经硅胶柱层析提纯(石油醚/乙酸乙酯＝2/1)，得目标化合物1.0g,收率94.6％。
2. 1,2-二氨基-5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪-1-基2,4,6-三甲基苯磺酸盐的制备
Figure PCTCN2021137679-appb-000025
将5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪-2-胺(452.6mg,2.1mmol)溶于二氯甲烷(10mL)中，加入O-(间甲磺酰基)羟胺(500.0mg,1.8mmol)，25℃反应1小时。反应结束后，浓缩溶剂至1mL二氯甲烷，加入甲基叔丁基醚(5mL)析出固体，过滤得到目标化合物680.0mg，直接用于下步反应。
3.(R)-2-(3-((叔丁基二苯基硅基)氧基)-1-甲基乙基)-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)- [1,2,4]三唑并[1,5-a]吡嗪的制备
Figure PCTCN2021137679-appb-000026
将(R)-4-((叔丁基二苯基硅基)氧基)-3-甲基丁酸(126.6mg,0.37mmol)溶于四氢呋喃(10.0mL)中，加入HATU(140.7mg,0.37mmol)和三乙胺(112.3mg,1.1mmol)，20℃搅拌。加入1,2-二氨基-5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪-1-鎓均三甲苯磺酸盐(0.28g,0.56mmol)，继续搅拌3小时。反应结束后，旋干溶剂，经硅胶柱层析提纯(石油醚/乙酸乙酯＝3/1)，得目标化合物100.0mg,收率44.6％。
4.(R)-3-(6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-2-基)-1-甲基-乙烷-1-醇的制备
Figure PCTCN2021137679-appb-000027
将(R)-2-(3-((叔丁基二苯基硅基)氧基)-2-甲基乙基)-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[1,5-a]吡嗪(100.0mg,0.16mmol)加入四氢呋喃(5.0mL)溶解，加入四丁基氟化铵(129.4mg,0.49mmol)，30℃下反应2小时.反应结束后，旋干溶剂，经硅胶柱层析提纯(二氯甲烷/甲醇＝25/1)，得目标化合物18.6mg,收率31.6％。
分子式:C 18H 17ClN 6O分子量:368.12LC-MS(M/e):369.1(M+H +)
1H-NMR(400MHz,CDCl 3)δ：8.71(s,2H),8.68(s,1H),8.00(d,J＝8.8Hz,2H),7.52(d,J＝8.4Hz,2H),4.10(s,3H),4.10-3.90(m,2H),3.52-3.40(m,1H),3.26-3.15(m,1H),1.52(d,J＝7.2Hz,3H).
制备例4：(S)-2-(5-(4-氯苯基)-7-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[3,4-c]吡啶-2-基)丙-1-醇的制备(化合物7-1)
1. 6-氯-2-碘-4-甲基吡啶-3-胺的制备
Figure PCTCN2021137679-appb-000028
将6-氯-4-甲基吡啶-3-胺(10.0g,70.0mmol)加入N,N-二甲基甲酰胺(120mL)中，后40℃下分批次加入N-碘代丁二酰亚胺(23.7g,105.3mmol)，后40℃下反应6小时。反 应结束后，体系降至25℃，加入饱和氯化钠水溶液(100mL)和乙酸乙酯乙酸乙酯(200mL)萃取分液，有机相旋干，经硅胶柱层析提纯(石油醚:乙酸乙酯＝3:1)得目标化合物11.0g,收率58.5％。
2. 5-氯-7-碘-1H-吡唑并[3,4-c]吡啶的制备
Figure PCTCN2021137679-appb-000029
将6-氯-2-碘-4-甲基吡啶-3-胺(3.35g,12.5mmol)溶于乙酸(20mL)中，后在15℃下分批次加入亚硝酸钠(1.3g,18.8mmol)的水溶液(10mL)，后在25℃反应2小时。体系浓缩后用饱和碳酸氢钠溶液调节pH到8，后旋干经硅胶柱层析提纯(石油醚:乙酸乙酯＝3:1)得目标化合物1.0g,收率28.6％。
3.(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-5-氯-7-碘-2H-吡唑并[3,4-c]吡啶的制备
Figure PCTCN2021137679-appb-000030
将5-氯-7-碘-1H-吡唑并[3,4-c]吡啶(580mg,2.1mmol)、(R)-1-((叔丁基二苯基硅基)氧基)丙烷-2-醇(783mg,2.5mmol)和三苯基膦(1.1g,4.2mmol)溶于四氢呋喃(20mL)中，后滴加入偶氮二甲酸二乙酯(732mg,4.2mmol)，20℃反应2小时。反应结束后，体系浓缩，经硅胶柱层析提纯(石油醚:乙酸乙酯＝10:1)得目标化合物360mg,收率29.8％。
4.(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-5-氯-7-(1-甲基-1H-吡唑基-4-基)-2H-吡唑并[3,4-c]吡啶的制备
Figure PCTCN2021137679-appb-000031
将(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-5-氯-7-碘-2H-吡唑并[3,4-c]吡啶(360mg,0.63mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(143mg,0.69mmol)、Pd(dppf)Cl 2(46mg,0.063mmol)和碳酸铯(411mg,1.3mmol)溶于1,4-二氧六环(12mL)和水(1mL)体系中，氮气保护下100℃反应2h。反应完毕，旋干溶剂，经硅胶柱层析提纯(石油醚:乙酸乙酯＝4:1)得目标化合物220mg,收率65.9％。
5.(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-5-(4-氯苯基)-7-(1-甲基-1H-吡唑基-4- 基)-2H-吡唑并[3,4-c]吡啶的制备
Figure PCTCN2021137679-appb-000032
将(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-5-氯-7-(1-甲基-1H-吡唑基-4-基)-2H-吡唑并[3,4-c]吡啶(200mg,0.38mmol)，(4-氯苯基)硼酸(177mg,1.13mmol)，Pd(dppf)Cl 2(28mg,0.038mmol)，碳酸铯(368mg,1.13mmol)溶于1,4-二氧六环(10mL)和水(1mL)体系中，氮气保护下微波140℃反应2h。反应完毕，旋干溶剂，经硅胶柱层析提纯(石油醚:乙酸乙酯＝2:1)得目标化合物120mg,收率52.1％。
6.(S)-2-(5-(4-氯苯基)-7-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[3,4-c]吡啶-2-基)丙-1-醇的制备
Figure PCTCN2021137679-appb-000033
将(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-5-(4-氯苯基)-7-(1-甲基-1H-吡唑基-4-基)-2H-吡唑并[3,4-c]吡啶(90mg,0.15mmol)溶于四氢呋喃(2mL)中，加入四丁基氟化铵的四氢呋喃溶液(1M,0.3mL,0.3mmol)，25℃反应1小时。体系浓缩，经硅胶柱层析(二氯甲烷:甲醇＝30:1)得目标化合物粗品(50mg)，再经C18反相提纯(水/甲醇＝2/8)得目标化合物40mg,收率72.5％。
分子式:C 19H 18ClN 5O分子量:367.8LC-MS(M/e):368.1(M+H +)
1H-NMR(400MHz,CDCl 3)δ：8.59(s,1H),8.48(s,1H),8.09-8.05(m,3H),7.76(s,1H),7.48-7.42(m,2H),4.85-4.75(m,1H),4.15-4.08(m,2H),4.04(s,3H),2.94-2.89(m,1H),1.75(d,J＝7.2Hz,3H).
制备例5：(S)-2-(6-(4-氯苯基)-4-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[4,3-c]吡啶-2-基)丙烷-1–醇的制备(化合物9-1)
1.(S)-2-(1-((叔丁基二苯基甲硅烷基)氧基)丙-2-基)-4,6-二氯-2H-吡唑并[4,3-c]吡啶的制备
Figure PCTCN2021137679-appb-000034
将4,6-二氯-1H-吡唑并[4,3-c]吡啶(650mg,3.48mmol)、(R)-1-((叔丁基二苯基甲硅烷基)氧基)丙-2-醇(1.3g,4.18mmol)和三苯基膦(1.8g,6.96mmol)溶于四氢呋喃(20mL)中，氮气保护，滴加偶氮二甲酸二乙酯(1.2g,6.96mmol)，25℃下反应4h，LCMS检测反应完成，反应液倒入水中，乙酸乙酯萃取，有机相旋干,硅胶柱层析分离(乙酸乙酯:石油醚＝1:1)得目标化合物300mg，收率17.8％。
2.(S)-2-(1-((叔丁基二苯基甲硅烷基)氧基)丙-2-基)-6-氯-4-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[4,3-c]吡啶的制备
Figure PCTCN2021137679-appb-000035
将(S)-2-(1-((叔丁基二苯基甲硅烷基)氧基)丙-2-基)-4,6-二氯-2H-吡唑并[4,3-c]吡啶(100mg,0.21mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(48mg,0.23mmol)、四(三苯基膦)钯(12mg,0.01mmol)和碳酸钠(45mg,0.42mmol)溶于1,4-二氧六环(6mL)和水(1mL)体系中，氮气保护下100℃反应2h。反应结束后，将反应液倒入水中，乙酸乙酯萃取，有机相旋干,硅胶柱层析分离(乙酸乙酯:石油醚＝1:1)得目标化合物100mg，收率90.4％。
3.(S)-2-(1-((叔丁基二苯基甲硅烷基)氧基)丙-2-基)-6-(4-氯苯基)-4-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[4,3-c]吡啶的制备
Figure PCTCN2021137679-appb-000036
将(S)-2-(1-((叔丁基二苯基甲硅烷基)氧基)丙-2-基)-6-氯-4-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[4,3-c]吡啶(100mg,0.19mmol)、(4-氯苯基)硼酸(45mg,0.29mmol)，Pd(dppf)Cl 2(15mg,0.02mmol)和碳酸铯(124mg,0.38mmol)溶于1,4-二氧六环(10mL)和水(2mL)体系中，氮气保护下100℃反应16h。反应结束后，将反应液倒入水中，乙酸乙 酯萃取，有机相旋干,硅胶柱层析分离(乙酸乙酯:石油醚＝1:1)得目标化合物70mg，收率61.2％。
4.(S)-2-(6-(4-氯苯基)-4-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[4,3-c]吡啶-2-基)丙烷-1–醇的制备
Figure PCTCN2021137679-appb-000037
将(S)-2-(1-((叔丁基二苯基甲硅烷基)氧基)丙-2-基)-6-(4-氯苯基)-4-(1-甲基-1H-吡唑-4-基)-2H-吡唑并[4,3-c]吡啶(70mg,0.12mmol)溶于四氢呋喃(5mL)中，加入四丁基氟化铵的四氢呋喃溶液(1M,0.24mL,0.24mmol)，25℃反应1小时。TLC检测反应完成，乙酸乙酯稀释，水洗，有机相旋干，制备板纯化(甲醇:二氯甲烷＝1:15)得目标化合物18.9mg,收率42.8％。
分子式:C 19H 18ClN 5O分子量:367.8LC-MS(M/e):368.1(M+H +)
1H-NMR(400MHz,MeOD)δ：8.29(s,1H),8.05-8.15(m,4H),7.78(s,1H),7.50-7.60(m,2H),4.70-4.80(m,1H),4.00-4.10(m,5H),1.74(d,J＝3.2Hz,3H).
制备例6：(S)-6-(4-氯苯基)-2-(1-羟基丙烷-2-基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-3(2H)-酮的制备(化合物11-1)
1. 5-(4-氯苯基)-2-肼基-3-(1-甲基-1H-吡唑-4-基)吡嗪的制备
Figure PCTCN2021137679-appb-000038
将2-氯-5-(4-氯苯基)-3-(1-甲基-1H-吡唑-4-基)吡嗪(410mg,1.35mmol)溶解于正丁醇(15mL)中，加入80％水合肼(253mg,4mmol)，升温至110℃搅拌8小时。反应结束后，浓缩溶剂，经水浆洗、过滤得到目标化合物360mg，收率89％。
2. 6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-3(2H)-酮的制备
Figure PCTCN2021137679-appb-000039
将5-(4-氯苯基)-2-肼基-3-(1-甲基-1H-吡唑-4-基)吡嗪(360mg,1.2mmol)溶解于二氯甲烷(15ml)中，加入咪唑(123mg,1.8mmol)、N,N-羰基二咪唑(234mg,1.4mmol)，20℃搅拌4小时。反应结束后，浓缩溶剂，经柱层析(甲醇/二氯甲烷＝0-6％)。得到目标化合物310mg，收率79％。
3.(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-3(2H)-酮的制备
Figure PCTCN2021137679-appb-000040
将6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-3(2H)-酮(130mg,0.4mmol)溶于DMF(5mL)中，加入(R)-1-((叔丁基二苯基硅基)氧基)丙烷-2-醇(150mg,0.48mmol)、DIAD(121mg,0.6mmol)和PPh 3(157mg,0.6mmol)，20℃搅拌16小时。反应结束后，旋干溶剂，直接用于下步反应。
4.(S)-6-(4-氯苯基)-2-(1-羟基丙烷-2-基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-3(2H)-酮的制备
Figure PCTCN2021137679-appb-000041
将(S)-2-(1-((叔丁基二苯基硅基)氧基)丙烷-2-基)-6-(4-氯苯基)-8-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-3(2H)-酮(粗品)溶于四氢呋喃(10mL)中，加入1M四丁基氟化铵的四氢呋喃溶液(0.5mL,0.5mmol)，20℃搅拌2小时。反应结束后，浓缩溶剂，制备板分离(甲醇/二氯甲烷＝1/20)得到目标化合物3.3mg,，两步收率2％。
分子式:C 18H 17ClN 6O 2分子量:385.8LC-MS(M/e):385.1(M+H +)
1H-NMR(400MHz,CDCl 3)δ：8.44(s,1H),8.40(s,1H),7.85-7.75(m,3H),7.44-7.37(m,2H),4.80-4.68(m,1H),4.05-3.98(m,5H),3.75-3.65(m,1H)，1.55-1.50(m,3H).
使用与前述制备例相同或相似的方法制备了以下表格1所示的化合物：
表格1：
Figure PCTCN2021137679-appb-000042
Figure PCTCN2021137679-appb-000043
实验方案
以下提供本发明部分化合物的示例性实验方案，以显示本发明化合物有利活性和有益技术效果。但是应当理解，下述实验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。
实验例1化合物在AhR reporter gene assay对AhR活性的抑制实验
测试物：本发明化合物，其结构式和制备方法见本发明的制备例。
阳性对照药：BAY-2416964，购买或按照现有技术CN110678459A公开的方法制备，其结构如下所示：
Figure PCTCN2021137679-appb-000044
实验方法
1.实验材料和试剂
Figure PCTCN2021137679-appb-000045
Figure PCTCN2021137679-appb-000046
2.实验耗材和仪器
Figure PCTCN2021137679-appb-000047
3.实验过程
3.1化合物准备
测试化合物的10mM DMSO溶液，用DMSO 3倍梯度稀释，10个浓度。
参照阳性对照药的10mM DMSO溶液，用DMSO 3倍梯度稀释，10个浓度。
准备终浓度1000倍的阳性对照(浓度为10mM的阳性对照药的DMSO溶液)和1000倍的vehicle control(溶媒对照)(100％DMSO溶剂)。
3.2试验过程
HEK293T细胞按照ATCC的建议条件培养，至状态良好的对数生长期，去除培养基，PBS洗一遍，TrypLE溶液消化，完全培养基终止后收集细胞。细胞PBS洗两遍去除酚红，重悬至合适的浓度。细胞活力大于90％才会用于继续试验。接种2.5*10 6数量的HEK293T到6cm培养皿，在37℃，5％CO 2培养箱培养16h，加入转染质粒，37℃，5％CO 2培养箱培养5-6小时。
用Echo550转移配置好的化合物的DMSO溶液到384孔板，其中，阳性对照孔转移终浓度1000倍的阳性对照药，vehicle对照孔转移等量的100％DMSO。板上接种转染后的细胞，17000个/孔，培养基中含终浓度50μM的犬尿酸，化合物测试终浓度分别为10μM，3.33μM，1.11μM，370.4nM，123.5nM，41.2nM，13.7nM，4.6nM，1.5nM。细胞在 37℃，5％CO 2培养箱继续培养18-20小时。每孔加入25μL的检测试剂，Steady-Glo TM Luciferase Assay Reagent。Envision酶标仪读取光信号值。
4.数据处理
抑制率(％)＝100-(Signal 待测化合物-Signal Ave-PC)/(Signal Ave-VC-Signal Ave-PC)*100
Signal Ave-pc：阳性对照孔平均信号强度，Signal Ave-vc：vehicle对照孔平均信号强度。
分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。
实验结果
表2本发明化合物体外细胞抑制活性
Figure PCTCN2021137679-appb-000048
实验结论
本发明化合物对AhR有良好的抑制作用。具体实施方案部分表格1中所列出的化合物都具有较低的IC 50值，尤其化合物1-1、3-1、5-1，活性约为阳性对照药的2倍至4倍。
实验例2本发明化合物的药代动力学实验
实验例中，缩写所代表的含义如下：
DMSO:二甲基亚砜           MC：甲基纤维素
HP-β-CD：羟丙基β环糊精
DMA：N,N-二甲基乙酰胺     HPC：羟丙基纤维素
Kolliphor HS 15：聚乙二醇15羟基硬脂酸酯
供试品：本发明化合物，自制，其化学名称和制备方法见各化合物的制备实施例。
受试动物：CD1小鼠，雌性，购自北京维通利华实验动物技术有限公司，6只/化合物/给药途径。
供试品溶液制备：
空白溶媒(1)的配制方法：称取28g HP-β-CD，加入适量注射用水溶解，再用注射用水定容到100mL，涡旋混匀，即得28％HP-β-CD。
空白溶媒(2)的配制方法：称取20g HPC，缓慢加入500mL搅拌着的纯化水中，再加入1mL吐温80，搅拌至澄清透明，定容到1000mL，搅拌均匀即得2％HPC+0.1％吐温80。
0.5％MC配制方法：称取5g MC，缓慢加入至800ml搅拌着的纯化水中，搅拌至澄清透明，再用纯化水定容至1000ml，搅拌均匀即得。
iv(静脉推注)给药：
称取本发明化合物1-1 2.29mg，加入DMA 221μl，振摇溶解，然后加入Kolliphor HS15 221μl，涡旋混匀；最后加入空白溶媒(1)1.77ml，涡旋混匀，得澄清溶液，50℃水浴保温20min，制备得浓度为1mg/mL的澄清溶液，作为测试化合物1-1的iv给药溶液。
称取本发明化合物5-1 2.41mg，加入DMA 446μl，振摇溶解，然后加入Kolliphor HS15 223μl，涡旋混匀；最后加入空白溶媒(1)1.562ml，涡旋混匀，得澄清溶液，50℃水浴保温20min，制备得浓度为1mg/mL的澄清溶液，作为测试化合物5-1的iv给药溶液。
po(灌胃)给药：
称取本发明化合物1-1 3.51mg，置于组织研磨器中，加入空白溶媒(2)3.39ml，研磨均匀得浓度为1mg/mL的混悬药液，作为化合物1-1的po给药药液。
称取本发明化合物5-1 3.33mg，置于组织研磨器中，加入空白溶媒(2)3.084ml，研磨均匀得浓度为1mg/mL的混悬药液，作为化合物5-1的po给药药液。
实验方法
iv给药体积为5mL/kg，iv给药剂量为5mg/kg，给药浓度为1mg/mL；
po给药体积为10mL/kg，po给药剂量为10mg/kg，给药浓度为1mg/mL；
采血时间点：给药后0.083、0.25、0.5、1、2、4、6、8、24、30、48h，具体按下表所示方式采血：
Figure PCTCN2021137679-appb-000049
每个时间点通过眼内眦采集全血约100μL，放置到含有EDTA-K 2抗凝剂的抗凝管中，在4℃条件下8000转/分钟离心6min得到血浆样品，血浆于-80℃冰箱冻存，待分析。
血浆样品分析
采用蛋白沉淀法：取血浆样品20μL，加入内标(含甲苯磺丁脲50ng/mL的乙腈溶液)200μL，涡旋10min后，然后4000转/分钟离心20分钟，取上清液100μL，再加入100μL 水，涡旋混匀3min后，LC-MS/MS分析血浆中的药物浓度。
实验结果
表3本发明化合物的小鼠PK评价结果(iv)
Figure PCTCN2021137679-appb-000050
表4本发明化合物的小鼠PK评价结果(po)
Figure PCTCN2021137679-appb-000051
其中，T 1/2代表半衰期；C max代表最大的血药浓度值；AUC last代表药时曲线下面积0→t；CL代表清除率；MRT代表平均滞留时间；Vss代表表观分布容积；F代表生物利用度；
实验结论：表3、表4实验数据表明，本发明化合物具有良好的药代动力学性质，且具有较高的暴露量和生物利用度。

Claims (13)

  1. 通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，
    Figure PCTCN2021137679-appb-100001
    其中，
    X 1、X 2分别独立地选自C(R 2)或N；
    X 3、X 4、X 6分别独立地选自C、C(R 2)或N；
    X 5、X 7分别独立地选自C(R 2)、CH(R 2)、O、N、N(R 3)或C(O)；
    L 1选自化学键、-C(R 4)(R 5)-、-O-、-S-、-C(O)-或-S(O)-；
    L 2选自任选被取代基取代的C 1-6亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基或卤代C 1-6烷氧基；
    R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷氧基、氨基C 1-6烷氧基、羧基C 1-6烷氧基、3-10元环烷基、3-10元杂环烷基、5-10元杂芳基或6-10元芳基；
    每一R 2、R 4、R 5分别独立地选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基或卤代C 1-6烷氧基；
    每一R 3分别独立的选自氢、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基或羧基C 1-6烷基；
    Ar 1选自任选被1-3个Q 1取代的3-10元环烷基、3-10元杂环烷基、5-10元杂芳基或6-10元芳基；
    Ar 2选自任选被1-3个Q 2取代的3-10元环烷基、3-10元杂环烷基、5-10元杂芳基或6-10元芳基；
    每一Q 1、每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1-6烷氧基；
    ---选自单键或双键，且相邻两个---不同时为双键。
  2. 如权利要求1所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    Ar 1选自任选被1-3个Q 1取代的5-6元单环环烷基、5-6元单环杂环烷基、5-6元单环杂芳基或苯基；
    优选的，Ar 1选自任选被1-2个Q 1取代的环戊基、环己基、四氢呋喃基、吡咯烷基、咪唑烷基、吡唑烷基、四氢噻吩基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、哌嗪基、吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
    每一Q 1分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基。
  3. 如权利要求1-2任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    Ar 2选自任选被1-3个Q 2取代的5-6元单环环烷基、5-6元单环杂环烷基、5-6元单环杂芳基或苯基；
    优选的，Ar 2选自任选被1-2个Q 2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
    每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、二(C 1-6烷基)氨基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基、羟基C 1-6烷氧基、氨基C 1-6烷氧基或羧基C 1- 6烷氧基。
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其进一步具有如下通式(II)所示的结构，
    Figure PCTCN2021137679-appb-100002
    其中，X 3、X 4、X 6分别独立地选自C、CH或N；
    X 5、X 7分别独立地选自C(R 2)、CH(R 2)、O、N、N(R 3)或C(O)；
    L 1选自化学键、-CH 2-、-O-、-S-、-C(O)-或-S(O)-；
    L 2选自任选被取代基取代的C 1-4亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
    R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷氧基、氨基C 1-4烷氧基或羧基C 1-4烷氧基；
    每一R 2分别独立地选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
    每一R 3分别独立的选自氢、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基或羧基C 1-4烷基；
    Ar 2选自任选被1-2个Q2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
    每一Q 1、每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基或氨基C 1-4烷基；
    ---选自单键或双键，且相邻两个---不同时为双键。
  5. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    X 3、X 4、X 6分别独立地选自C、CH或N；
    X 5、X 7分别独立地选自CH、CH 2、O、N、NH或C(O)；
    L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基；
    R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、三氟甲氧基、羟基甲氧基或氨基甲氧基；
    Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
    每一Q 1、每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟 甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其进一步具有如下通式(IIIa)、通式(IIIb)、通式(IIIc)或通式(IIId)所示的结构，
    Figure PCTCN2021137679-appb-100003
    其中，Ar 2、Q 1、Q 2、L 1、L 2、R 1、R 4、R 5如权利要求1-5任一项所定义。
  7. 如权利要求6所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    L 1选自化学键、-CH 2-、-O-或-S-；
    L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基或三氟甲氧基；
    R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基；
    Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基或苯基；
    每一Q 1、每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
  8. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其进一步具有如下通式(IVa)、通式(IVb)、通式(IVc)或通式(IVd)所示的结构，
    Figure PCTCN2021137679-appb-100004
    其中，L 1选自化学键、-CH 2-、-O-、-S-、-C(O)-或-S(O)-；
    L 2选自任选被取代基取代的C 1-4亚烷基，所述取代基选自氢、卤素、氨基、羟基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基；
    R 1选自氢、卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷氧基、氨基C 1-4烷氧基或羧基C 1-4烷氧基；
    Ar 1选自任选被1-2个Q1取代的呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
    Ar 2选自任选被1-2个Q2取代的吗啉基、呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或苯基；
    每一Q 1、每一Q 2分别独立的选自卤素、硝基、氰基、氨基、羟基、羧基、巯基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基或氨基C 1-4烷基。
  9. 如权利要求8所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    L 1选自化学键、-CH 2-、-O-或-S-；
    L 2选自任选被取代基取代的-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-，所述取代基选自氢、卤素、氨基、羟基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基或三氟甲氧基；
    R 1选自氢、氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基或三氟甲氧基；
    Ar 1选自任选被1-2个Q 1取代的吡咯基、咪唑基、吡唑基、1,2,3-三唑基或1,2,4-三唑基；
    Ar 2选自任选被1-2个Q 2取代的吡啶基、嘧啶基、哒嗪基、吡嗪基或苯基；
    每一Q 1、每一Q 2分别独立的选自氟、氯、溴、碘、硝基、氰基、氨基、羟基、羧基、巯 基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、氨基甲基或氨基乙基。
  10. 如权利要求1所述的化合物、其药学上可接受的盐、其酯或其立体异构体，选自如下化合物：
    Figure PCTCN2021137679-appb-100005
    Figure PCTCN2021137679-appb-100006
  11. 含有权利要求1-10任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体的药物制剂，其特征在于，包含一种或多种药学上可接受的赋形剂，该药物制剂为药学上可接受的任一剂型。
  12. 含有权利要求1-10任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物，其特征在于，包含一种或多种第二治疗活性剂，所述的第二治疗活性剂选自有丝分裂抑制剂、烷化剂、抗代谢物、反义DNA或RNA、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。
  13. 权利要求1-10任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体、权利要求11所述的药物制剂、或权利要求12所述的药物组合物在制备用于治疗和/或预防与AhR信号异常所介导的疾病及相关病症的药物中的应用，所述AhR信号异常所介导的疾病及相关病症选自癌症或良性肿瘤，所述癌症选自肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、甲状腺癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、白血病、胶质瘤或肉瘤。
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