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WO2024152993A1 - Composé cyclique fusionné, son procédé de préparation et son utilisation en médecine - Google Patents

Composé cyclique fusionné, son procédé de préparation et son utilisation en médecine Download PDF

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Publication number
WO2024152993A1
WO2024152993A1 PCT/CN2024/071902 CN2024071902W WO2024152993A1 WO 2024152993 A1 WO2024152993 A1 WO 2024152993A1 CN 2024071902 W CN2024071902 W CN 2024071902W WO 2024152993 A1 WO2024152993 A1 WO 2024152993A1
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group
cycloalkyl
alkyl
heteroaryl
aryl
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Chinese (zh)
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陈庚辉
蔡亚仙
韩自省
蔡开明
贾剑敏
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Thederma Shanghai Co Ltd
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Thederma Shanghai Co Ltd
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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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused ring compound, a preparation method thereof, and its application in medicine. Specifically, the present disclosure relates to a fused ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as an AhR modulator, especially in the preparation of a drug for treating and/or preventing diseases or conditions mediated by AhR protein.
  • a fused ring compound represented by general formula (I) a preparation method thereof, a pharmaceutical composition containing the compound, and its use as an AhR modulator, especially in the preparation of a drug for treating and/or preventing diseases or conditions mediated by AhR protein.
  • the aryl hydrocarbon receptor also known as the dioxin receptor, is a member of the bHLH (basic Helix-Loop-Helix)-PAS (Per-ARNT-Sim) family of transcriptional regulators.
  • a unique feature of members of the bHLH-PAS family is the presence of a PAS domain, named after the first three proteins to be found to have this motif: Drosophila Per, HumanARNT, and Drosophila Sim.
  • the PAS domain consists of 260-310 amino acids and includes two very conserved hydrophobic repeats, called PAS-A and PAS-B, separated by a less conserved sequence.
  • the bHLH domain is responsible for DNA binding, and the tandem PAS domains (PAS-A and PAS-B) are involved in protein-protein interactions and ligand binding.
  • PAS-A and PAS-B tandem PAS domains
  • ligand binding occurs in the PAS-B domain.
  • the N-terminal bHLH-PAS region is well conserved among members of the bHLH-PAS family. Most of the non-conservative changes in AHR occur in the transcriptional activation domain, resulting in different protein-protein interactions with other coactivators, corepressors or nuclear receptors, regulating different gene expressions.
  • AHR In the absence of ligand, AHR is present in the cytosol and binds to multiple chaperone proteins, including a dimer of heat shock protein 90 (HSP90), auxiliary chaperone protein p23, AHR-Interacting Protein (AIP) and protein kinase Src.
  • HSP90 heat shock protein 90
  • AIP AHR-Interacting Protein
  • AHR nuclear translocator Aryl hydrocarbon receptor nucleus translocator, ARNT.
  • the regulatory region upstream of AHR-regulated genes contains a DNA consensus sequence (5'-TNGCGTG-3'), called the xenobiotic responsive element (XRE), also called the dioxin responsive element (DRE). It acts as a transcriptional enhancer and is a site for AHR binding.
  • the AHR-ARNT heterodimer complex is recruited by XRE to initiate transcription of target genes.
  • AHR is involved in physiological processes such as cell physiology, host defense, immune cell proliferation and differentiation, and detoxification.
  • AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T cells, and NK cells.
  • the ligand binding site of AHR is structurally flexible, many small molecules can serve as ligands, including exogenous ligands such as polycyclic aromatic hydrocarbons, dioxins and polychlorinated biphenyls; endogenous ligands such as metabolites of tryptophan degradation, food-derived ligands and products of bacterial and microbial metabolic pathways.
  • exogenous ligands such as polycyclic aromatic hydrocarbons, dioxins and polychlorinated biphenyls
  • endogenous ligands such as metabolites of tryptophan degradation, food-derived ligands and products of bacterial and microbial metabolic pathways.
  • the AHR modulator benvimod is a naturally derived small molecule produced by the bacterial symbionts of insect pathogenic nematodes. It is the world's first marketed aromatic hydrocarbon receptor agonist and can be used to treat a variety of autoimmune diseases such as psoriasis and ecze
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
  • Ring A is phenyl or 6-membered heteroaryl; wherein Ring A is not pyrimidinyl;
  • G1 is a nitrogen atom or CR g1 ;
  • G 2 is a nitrogen atom or CR g2 ;
  • G 3 is a nitrogen atom or CR g3 ;
  • G 4 is a nitrogen atom or CR g4 ; G 1 , G 2 , G 3 and G 4 are not all nitrogen atoms;
  • R1 , R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, -NRn1Rn2 , -C(O) NRn3Rn4 , -OR5a , -C (O) OR5b , -NRn5C (O) R6a , -S(O) pNRn6Rn7 , -C(O) R6b , -OC(O) R6c , -S(O) qR6d , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, and are optionally substituted by one or more substituents selected from a halogen, an oxo group, an alkyl group, a haloalkyl group, an alkoxy
  • each R4 is the same or different and is independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, -NRn1Rn2 , -C(O) NRn3Rn4 , -OR5a , -C(O) OR5b , -NRn5C (O) R6a , -S(O) pNRn6Rn7 , -C(O) R6b , -OC(O) R6c , -S (O) qR6d , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are independently optionally substituted by one or more substituent
  • Rg1 , Rg2 , Rg3 and Rg4 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, -NRn1Rn2, -C(O)NRn3Rn4, -OR5a , -C ( O) OR5b , -NRn5C (O) R6a , -S(O) pNRn6Rn7 , -C(O) R6b , -OC(O) R6c , -S(O) qR6d , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; where
  • R 5a and R 5b are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from substituted with one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR n8 R n9 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 6a , R 6b , R 6c and R 6d are the same or different at each occurrence and are each independently selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR n8 R n9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 , R n8 and R n9 are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;
  • R n1 and R n2 , R n3 and R n4 , R n6 and R n7 , and R n8 and R n9 together with the nitrogen atom to which they are connected, form a heterocyclic group, wherein the heterocyclic group is each independently substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • n 0, 1, 2 or 3;
  • p 0, 1 or 2;
  • q 0, 1, or 2.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:
  • Ring A, G 1 , G 2 , G 3 , G 4 , R 2 , R 3 , R 4 and m are as defined in the general formula (I).
  • the compound represented by the general formula (I) or (I-1) or a pharmaceutically acceptable salt thereof wherein: Ring A is a 6-membered heteroaryl group, and the 6-membered heteroaryl group contains 1 to 3 nitrogen atoms; preferably, Ring A is a 6-membered heteroaryl group, and the 6-membered heteroaryl group contains 1 or 2 nitrogen atoms.
  • the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof wherein: Selected from G1 is a nitrogen atom or CR g1 , G2 is a nitrogen atom or CR g2 , G3 is a nitrogen atom or CR g3 , G4 is a nitrogen atom or CR g4 , G1 , G2 , G3 and G4 are not all nitrogen atoms, R g1 , R g2 , R g3 and R g4 are as defined in the general formula (I); preferably, Selected from R g1 , R g2 , R g3 and R g4 are the same or different and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably, Selected from Rg2 is a hydrogen atom or a halogen; further preferably, Selected from Rg2 is a hydrogen
  • the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof wherein: G1 is CR g1 ; G2 is CR g2 ; G3 is CR g3 ; G4 is CR g4 ; R g1 , R g2 , R g3 and R g4 are as defined in the general formula (I); preferably, G1 is CR g1 ; G2 is CR g2; G3 is CR g3 ; G4 is CR g4 ; R g1 , R g2 , R g3 and R g4 are the same or different, and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group and a halogenated C 1-6 alkoxy group; more preferably, G1 is CR g1 ; G2 is CR
  • each R4 is the same or different and is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl and halogenated C1-6 alkoxy, and m is 0, 1, 2 or 3; preferably, each R4 is the same or different and is independently halogen or C1-6 alkyl, and m is 0, 1 or 2; more preferably, m is 0.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
  • X 1 is a nitrogen atom or CR 4a ;
  • X 2 is a nitrogen atom or CR 4b ;
  • X 3 is a nitrogen atom or CR 4c ; X 2 and X 3 are not nitrogen atoms at the same time;
  • R4a , R4b and R4c are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, -NRn1Rn2 , -C(O) NRn3Rn4 , -OR5a , -C (O) OR5b , -NRn5C (O) R6a , -S(O) pNRn6Rn7 , -C(O) R6b , -OC(O) R6c , -S(O) qR6d , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the
  • each Rg is the same or different and is independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, -NRn1Rn2 , -C(O) NRn3Rn4 , -OR5a , -C(O) OR5b , -NRn5C (O) R6a , -S(O) pNRn6Rn7 , -C(O) R6b , -OC(O) R6c , -S (O) qR6d , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are independently optionally substituted by one or more substituent
  • n 0, 1, 2, 3 or 4;
  • R 1 , R 2 , R 3 , R n1 to R n8 , R 5a , R 5b and R 6a to R 6d are as defined in the general formula (I).
  • the compound represented by the general formula (I), the general formula (I-1) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , X 3 , R 2 , R 3 , R g and n are as defined in the general formula (II).
  • the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof wherein: R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an amino group, a cyano group, a halogen, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group and a C1-6 haloalkoxy group; preferably, R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; more preferably, R 2 and R 3 are the same or different and are each independently a hydrogen atom or a halogen; most preferably, R 2 is a halogen and R 3 is a hydrogen atom; or R 2 and R 3 are both hydrogen atoms.
  • the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein: R1 is selected from a hydrogen atom, a deuterium atom, a hydroxyl, an amino group, a cyano group, a halogen, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group and a C1-6 haloalkoxy group; preferably, R1 is selected from a hydrogen atom, a hydroxyl, a halogen and a C1-6 alkyl group; more preferably, R1 is selected from a hydrogen atom, a hydroxyl group and a halogen.
  • each R g is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy, and n is 0, 1, 2 or 3; preferably, each R g is the same or different and is independently halogen or C 1-6 alkyl, and n is 0, 1 or 2; more preferably, each R g is the same or different and is independently halogen, and n is 0 or 1.
  • the compound represented by the general formula (II) or (II-1) or a pharmaceutically acceptable salt thereof wherein: X1 , X2 and X3 are not nitrogen atoms at the same time; preferably, one of X1 , X2 and X3 is a nitrogen atom.
  • the compound represented by the general formula (II) or (II-1) or a pharmaceutically acceptable salt thereof wherein: X1 , X2 and X3 are not nitrogen atoms at the same time; preferably, two of X1 , X2 and X3 are nitrogen atoms, and X2 and X3 are not nitrogen atoms at the same time.
  • the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof wherein: Selected from R g and n are as defined in general formula (II); preferably, Selected from Each Rg is the same or different and is independently halogen or C1-6 alkyl, and n is 0, 1, 2 or 3; more preferably, Selected from More preferably, Selected from Most preferably, Selected from
  • Ring A is a 6-membered heteroaryl group containing 1 or 2 nitrogen atoms
  • G1 is CRg1
  • G2 is CRg2
  • G3 is CRg3
  • G4 is CRg4
  • Rg1 , Rg2 , Rg3 and Rg4 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, a C1-6 alkoxy group, a halogenated C1-6 alkyl group and a halogenated C1-6 alkoxy group
  • each R4 is the same or different and is each independently halogen or C1-6 alkyl group, and m is 0, 1 or 2
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen and a C1-6 alkyl group
  • R1 is selected from a hydrogen atom
  • Ring A is a 6-membered heteroaryl group containing 1 or 2 nitrogen atoms
  • G1 is CR g1
  • G2 is CR g2
  • G3 is CR g3
  • G4 is CR g4
  • R g1 , R g2 , R g3 and R g4 are the same or different and are each independently selected from a hydrogen atom, a halogen and
  • m is 0
  • R 2 and R 3 are the same or different and are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl
  • R 1 is selected from a hydrogen atom, a hydroxyl group and a halogen.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein: Selected from Each Rg is the same or different and is independently halogen or C1-6 alkyl, and n is 0, 1, 2 or 3; R2 and R3 are the same or different and are independently selected from hydrogen atom, halogen and C1-6 alkyl; and R1 is selected from hydrogen atom, deuterium atom, hydroxyl, amino, cyano, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein: Selected from Each Rg is the same or different and is independently halogen or C1-6 alkyl, and n is 0 or 1; R2 and R3 are the same or different and are independently hydrogen or halogen; and R1 is selected from hydrogen, hydroxyl and halogen.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:
  • R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NRn8Rn9 , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R is C1-6 alkyl;
  • Ring A, G1 , G2 , G3, G4 , R1 , R2 , R3 , R4 , Rn8 , Rn9 and m are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof:
  • R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NRn8Rn9 , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R is C1-6 alkyl;
  • X1 , X2 , X3 , Rg , R1 , R2 , R3 , Rn8 , Rn9 and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IA) or its salt undergoes a deprotection reaction to obtain a compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof;
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, a cyano group, an amino group, a C1-6 alkylcyano group, a C1-6 alkylamino group, a C2-6 alkenyl group and a C2-6 alkynyl group;
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, cyano, amino, C 1-6 alkylcyano, C 1-6 alkylamino, C 2-6 alkenyl and C 2-6 alkynyl;
  • step 2 R1 is -OR
  • R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NRn8Rn9 , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R is C1-6 alkyl;
  • Ring A, G 1 , G 2 , G 3 , G 4 , R 4 , R n8 , R n9 and m are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, a cyano group, an amino group, a C1-6 alkylcyano group, a C1-6 alkylamino group, a C2-6 alkenyl group and a C2-6 alkynyl group;
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, cyano, amino, C 1-6 alkylcyano, C 1-6 alkylamino, C 2-6 alkenyl and C 2-6 alkynyl;
  • step 2 R1 is -OR
  • R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NRn8Rn9 , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R is C1-6 alkyl;
  • X 1 , X 2 , X 3 , R g , R n8 , R n9 and n are as defined in the general formula (II).
  • compositions which contains a therapeutically effective amount of a compound of the present disclosure represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of compounds represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for regulating AhR protein; preferably in the preparation of drugs for agonizing or antagonizing AhR protein.
  • the present disclosure further relates to the use of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of an AhR modulator, preferably in the preparation of an AhR agonist or an AhR antagonist.
  • the present disclosure further relates to the use of compounds represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and/or AhR protein-mediated diseases or conditions. way.
  • the present disclosure further relates to the use of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing a disease or condition mediated by AhR protein, wherein the disease or condition is selected from cancer, ophthalmological diseases, autoimmune diseases, viral infectious diseases, immune diseases, central nervous system diseases, inflammatory or obstructive respiratory diseases, inflammatory diseases and other conditions or discomforts with immunological factors.
  • the present disclosure further relates to compounds of formula (I), formula (I-1), formula (II), formula (II-1) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same for use in the preparation of a pharmaceutical composition for treating and/or preventing skin diseases, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis,
  • the skin disease is selected from the group consisting of psoriasis, acne, vitiligo and atopic dermatitis; preferably, the use of the compound in the preparation of a drug for the treatment and/or prevention of a skin disease; more preferably, the use of the compound in the preparation of a drug for the treatment and/or prevention of a skin
  • the present disclosure further relates to a method for regulating AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for antagonizing (inhibiting) AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for agonizing AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for treating and/or preventing diseases or conditions mediated by AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for treating and/or preventing a disease or condition mediated by AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from cancer, ophthalmological diseases, autoimmune diseases, viral infectious diseases, immune diseases, central nervous system diseases, inflammatory or obstructive respiratory diseases, inflammatory diseases and other conditions or discomforts with immunological factors.
  • the present disclosure further relates to a method for treating and/or preventing skin diseases, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eyes, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colon cancer and colorectal cancer; the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for treating and/or preventing skin diseases; the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for treating and/or preventing psoriasis, acne, vitiligo and atopic dermatitis; the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.
  • the present disclosure further relates to a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an AhR protein modulator.
  • the present disclosure further relates to a compound shown in formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an AhR protein antagonist (inhibitor).
  • the present disclosure further relates to a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an AhR protein agonist.
  • the present disclosure further relates to a compound shown in formula (I), formula (I-1), formula (II), formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and/or preventing diseases or conditions mediated by AhR protein.
  • the present disclosure further relates to a compound shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and/or preventing diseases or conditions mediated by AhR protein, wherein the diseases or conditions are selected from cancer, ophthalmological diseases, autoimmune diseases, viral infectious diseases, immune diseases, central nervous system diseases, inflammatory or obstructive respiratory diseases, inflammatory diseases and other diseases or discomforts with immunological factors.
  • the present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and/or preventing skin diseases, acute lung injury, adult/acute respiratory distress syndrome, chronic obstructive pulmonary disease, eye allergies, conjunctivitis, dry eyes, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colon cancer and colorectal cancer; preferably, it is used for treating and/or preventing skin diseases; more preferably, it
  • aryl hydrocarbon receptor (AHR) modulator refers to an agent that causes or promotes a qualitative or quantitative change, alteration or modification of one or more processes, mechanisms, effects, reactions, functions, activities or pathways mediated by the AHR receptor.
  • AHR modulators such as inhibitors or non-constitutive agonists of AHR described herein
  • AHR modulators can refer to a decrease or increase in AHR activity or function, such as a decrease, inhibition or shift in AHR constitutive activity.
  • AHR antagonists refer to AHR inhibitors that do not induce a biological response themselves when specifically binding to an AHR polypeptide or a polynucleotide encoding an AHR, but block or inhibit agonist-mediated or ligand-mediated responses, i.e., AHR antagonists can bind to but not activate an AHR polypeptide or a polynucleotide encoding an AHR, and the binding disrupts the interaction, displaces an AHR agonist, and/or inhibits the function of an AHR agonist. Therefore, as used herein, when bound to AHR, AHR antagonists do not act as inducers of AHR activity, i.e., they act as pure AHR inhibitors.
  • AhR-mediated diseases and/or disorders of the present disclosure refer to any disease or other deleterious condition in which AhR or a mutant thereof is known to play a role. Therefore, another embodiment of the present invention is directed to treating or lessening the severity of one or more diseases in which AhR or a mutant thereof is known to play a role.
  • cancer includes but is not limited to the following cancers:
  • Epidermoid oral cavity oral cavity, lips, tongue, mouth, pharynx;
  • sarcomas angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma
  • myxoma rhabdomyoma
  • fibrosarcoma tumors lipomas, and teratomas
  • Lung bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, rectum;
  • Kidney adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);
  • liver cancer hepatocellular carcinoma
  • bile duct cancer hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • bile duct liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bile duct;
  • Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor;
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma
  • multiple myeloma malignant giant cell tumor chordoma
  • osteochondroma benign enchondroma
  • chondroblastoma chondromyxofibroma
  • osteoid osteoma giant cell tumor
  • Nervous system skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, spinal neurofibromas;
  • Gynecology uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), breast;
  • Blood myeloid leukemias (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma hairy cell, lymphatic diseases;
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;
  • Thyroid papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and neuroblastoma.
  • Neurodegenerative diseases described in the present disclosure can affect many activities of the body, such as balance, movement, speech, breathing and heart function.
  • Neurodegenerative diseases can be genetic diseases or caused by medical diseases, such as alcoholism, tumors, stroke, toxins, chemicals and viruses.
  • Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease or ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.
  • ALS amyotrophic lateral sclerosis
  • ALS Lou Gehrig's disease or ALS
  • Friedreich's ataxia Huntington's disease
  • Lewy body disease Lewy body disease
  • Parkinson's disease and spinal muscular atrophy.
  • Non-limiting examples of central nervous system (CNS) diseases or disorders described in the present disclosure include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, and prion disease.
  • CNS central nervous system
  • disease or “disorder” refers broadly to any of the above diseases or disorders that can be treated and/or prevented by administering to a patient a compound or an aryl hydrocarbon receptor modulator (antagonist or agonist) described herein.
  • the compounds of the present disclosure or their compositions can be used to treat and/or prevent inflammatory or obstructive airway diseases, reducing, for example, tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression.
  • Inflammatory or obstructive airway diseases to which the present disclosure is applicable include asthma of any type or cause, including intrinsic (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection.
  • Treatment of asthma should also be understood to cover treatment of subjects, for example, less than 4 or 5 years of age who exhibit wheezing symptoms and are diagnosed or diagnosable as "wheezing infants", which is an established patient category of major medical problems and is now often identified as an incipient or early asthma patient.
  • inflammatory or obstructive airway diseases and/or conditions to which the present disclosure is applicable include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung disease including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airway hyperresponsiveness caused by other drug therapies, particularly other inhaled drug therapies.
  • ALI acute lung injury
  • ARDS adult/acute respiratory distress syndrome
  • chronic obstructive pulmonary disease airway or lung disease including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airway hyperresponsiveness caused by other drug therapies, particularly other inhaled drug therapies.
  • the present disclosure can also be used to treat inflammatory or allergic conditions of the skin and other diseases or conditions, such as those with an inflammatory component, such as treating eye diseases and conditions, such as ocular allergies, conjunctivitis, dry eyes, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having an autoimmune component or etiology.
  • an inflammatory component such as treating eye diseases and conditions, such as ocular allergies, conjunctivitis, dry eyes, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having an autoimmune component or etiology.
  • Inflammatory diseases that can be treated according to the methods of the present disclosure are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryptopyrin-associated periodic syndrome (CAPS), and osteoarthritis.
  • SJIA systemic juvenile idiopathic arthritis
  • CAS cryptopyrin-associated periodic syndrome
  • the inflammatory diseases that can be treated according to the methods of the present disclosure are selected from TH17-mediated diseases.
  • TH17-mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).
  • Subject and “patient” as used herein refer to an organism, such as a human, that is receiving treatment for a particular disease or condition described herein.
  • the terms subject or patient as used herein may refer to a mammal, such as a dog, cat, horse, cow, pig, guinea pig, etc.
  • a patient such as a human patient, in need of an aryl hydrocarbon receptor antagonist may receive a treatment comprising an aryl hydrocarbon receptor antagonist to treat a disease or condition described herein, such as cancer, an autoimmune disease, or an inflammatory disease.
  • the active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration.
  • the compounds of the present disclosure can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose.
  • the unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.
  • Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil.
  • the oil suspension may contain a thickener.
  • the above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, or a mineral oil or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.
  • compositions disclosed herein may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injectable solution or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound.
  • a continuous intravenous drug delivery device may be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.
  • compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents.
  • Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents.
  • sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used.
  • fatty acids can also be used to prepare injections.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.
  • alkyl refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C1-12 alkyl), and more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 alkyl).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methyl pentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C1-12 alkylene), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C1-6 alkylene).
  • Non-limiting examples include: -CH2- , -CH( CH3 )-, -C( CH3 ) 2- , -CH2CH2-, -CH( CH2CH3 )-, -CH2CH ( CH3 ) - , -CH2C ( CH3 ) 2- , -CH2CH2CH2- , -CH2CH2CH2- , -CH2CH2CH2CH2- , etc.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkenyl).
  • the alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., C2-6 alkenyl).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.
  • the alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkynyl).
  • the alkynyl group preferably has an alkynyl group of 2 to 6 carbon atoms (i.e., C2-6 alkynyl).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.
  • Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl).
  • the cycloalkyl preferably has 3 to 12 ring atoms.
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 12-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group), or preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group).
  • Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -O-O-, -O-S- or -S-S-), provided that at least one all-carbon ring is contained and the connection point is on the all-carbon ring, and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl).
  • nitrogen may be optionally oxidized, i.e., to form nitrogen oxides
  • the spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl).
  • the spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 7-yuan/5-yuan or 7-yuan/6-yuan monospiro
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl).
  • the fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl).
  • the condensed cycloalkyl includes bicyclic condensed cycloalkyl and polycyclic condensed cycloalkyl (such as tricyclic condensed cycloalkyl, tetracyclic condensed cycloalkyl, etc.), preferably bicyclic condensed cycloalkyl or tricyclic condensed cycloalkyl, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yu
  • bridged cycloalkyl refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl).
  • the bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl).
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl.
  • Non-limiting examples include:
  • connection point can be at any position.
  • the cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl).
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group) or preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).
  • Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.
  • the polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the rings, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur in the rings (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl).
  • the spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl), more preferably a spiroheterocyclyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroheterocyclyl).
  • the spiro heterocyclic group includes a monospiro heterocyclic group and a polyspiro heterocyclic group (such as a bispiro heterocyclic group, etc.), preferably a monospiro heterocyclic group or a bispiro heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-member
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring
  • the fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably has a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 6-yuan/3-yuan, 6-yu
  • bridged heterocyclic group refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S-, or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups).
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups.
  • Non-limiting examples include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated ⁇ electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 6 to 14-membered aromatic group).
  • the aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group), and more preferably an aromatic group having 8 to 10 ring atoms (i.e., 8 to 10-membered polycyclic aromatic group).
  • the monocyclic aromatic group is, for example, phenyl.
  • Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc.
  • the polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or the naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:
  • the aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated ⁇ electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl).
  • a monocyclic heteroaromatic ring i.e., a monocyclic heteroaryl
  • the heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl), or preferably a heteroaryl having 8 to 10 ring atoms (i.e., an 8- to 10-membered polycyclic heteroaryl).
  • the monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2,4]triazolo[1,5-a]pyridinyl, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • Non-limiting examples include:
  • the heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • amino protecting group refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxy protecting group refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to an aryl-O- group in which aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to an alkyl-S- group in which alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.
  • the disclosed compounds may exist in specific stereoisomeric forms.
  • stereoisomer refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers).
  • the substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques.
  • An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers.
  • the separation of enantiomers and diastereoisomers is usually completed by chromatography.
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or both Two configurations.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses.
  • isotopes that can be introduced into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I , etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • the position when a position is specifically designated as “deuterium” or “D,” the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • alkyl optionally substituted by halogen or cyano includes the case where alkyl is substituted by halogen or cyano and the case where alkyl is not substituted by halogen and cyano.
  • substitution means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are replaced independently by a corresponding number of substituents.
  • substituents Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect.
  • the determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
  • the method for preparing the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IA) or its salt undergoes a deprotection reaction under the protection of an inert gas to obtain a compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof;
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, a cyano group, an amino group, a C1-6 alkylcyano group, a C1-6 alkylamino group, a C2-6 alkenyl group and a C2-6 alkynyl group;
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, cyano, amino, C 1-6 alkylcyano, C 1-6 alkylamino, C 2-6 alkenyl and C 2-6 alkynyl;
  • step 2 R1 is -OR
  • R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NRn8Rn9 , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R is C1-6 alkyl;
  • Ring A, G 1 , G 2 , G 3 , G 4 , R 4 , R n8 , R n9 and m are as defined in the general formula (I).
  • the present invention discloses a method for preparing a compound represented by general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound represented by the general formula (IIA) or a salt thereof undergoes a deprotection reaction under the protection of an inert gas to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, a cyano group, an amino group, a C1-6 alkylcyano group, a C1-6 alkylamino group, a C2-6 alkenyl group and a C2-6 alkynyl group;
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, cyano, amino, C 1-6 alkylcyano, C 1-6 alkylamino, C 2-6 alkenyl and C 2-6 alkynyl;
  • step 2 R1 is -OR
  • R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NRn8Rn9 , hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R is C1-6 alkyl;
  • X 1 , X 2 , X 3 , R g , R n8 , R n9 and n are as defined in the general formula (II).
  • the reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • the LC-MS instruments used were Waters 2695+ZQ2000, Shimadzu MS-2020+LC-20AB and Shimadzu LC-40D XR+MS-2020.
  • High performance liquid chromatography (HPLC) analyses were performed using Shimadzu LC-20AB, Shimadzu LC-20ADXR, and Shimadzu LC-40D XR HPLC instruments.
  • HPLC High performance liquid chromatography
  • the chiral preparation uses Waters 150Mgm and Waters SFC 350 preparative chromatographs.
  • the CombiFlash rapid preparation instrument used was CH-200P (Agela & Phenomenex).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses 200-300 mesh silica gel from Yantai Huanghai or Titan Technology as the carrier.
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Haohong Biotechnology, and Bid Pharmaceuticals.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the reaction is carried out under hydrogen conditions, and the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: petroleum ether/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • compounds were purified using preparative HPLC.
  • Dissolve compound 1a (21.0 g, 83.6 mmol) in methanol (200 mL), continue to add sodium methoxide (9.94 g, 184 mmol), and then stir at 80 ° C for 12 h. Concentrate the reaction mixture, dilute with ethyl acetate (200 mL), and wash with water (200 mL) and saturated brine (200 mL) respectively. Separate the organic phase, dry it with anhydrous sodium sulfate, and filter it. Concentrate the filtrate to obtain the title product 1b.
  • the reaction mixture was added to a saturated aqueous ammonium chloride solution (100 mL) cooled in an ice-water bath, and extracted with ethyl acetate (50 mL ⁇ 2).
  • the organic phases were combined and washed with saturated brine (50 mL).
  • the organic phase was separated, dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain the title product 1e.
  • the reaction mixture was quenched with a saturated aqueous sodium thiosulfate solution (900 mL) and extracted with petroleum ether (600 mL).
  • the organic phase was separated and washed with water (300 mL) and saturated brine (300 mL) respectively.
  • the organic phase was separated, dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain the title product 2c.
  • the reaction mixture was cooled to room temperature, poured into a saturated potassium fluoride aqueous solution (1000 mL), and extracted with ethyl acetate (200 mL ⁇ 2).
  • the organic phases were combined and concentrated.
  • the residue was added to a mixed solution of tetrahydrofuran (150 mL) and hydrochloric acid aqueous solution (150 mL, 3 M), stirred at room temperature for 0.5 h, and extracted with ethyl acetate (150 mL ⁇ 2).
  • the organic phases were combined and washed with water (100 mL) and saturated brine (100 mL) respectively.
  • the organic phase was separated, dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain the title product 2e.
  • the title product 2h was prepared from the intermediate 2g.
  • the title product 2i was prepared from the intermediate 2h and 3-bromoisoquinoline.
  • the title product 3b was prepared from the intermediate 3a.
  • the title product 3c was prepared from the intermediate 3b.
  • the title product 3e was prepared from intermediate 3d and 3-bromoisoquinoline.
  • the title product 4a was prepared from intermediate 3d and 3-bromoquinoline.
  • the title product 5a was prepared from intermediate 3d and 2-bromoquinoxaline.
  • the title product 6a was prepared from the intermediate 3d and 3-chlorocinnoline.
  • the title product 7c was prepared from the intermediate 7b.
  • the title product 7e was prepared from intermediate 7d and 2-bromonaphthalene.
  • the title product 8a was prepared from intermediate 7d and 3-chlorocinnoline.
  • the title product 9a was prepared from intermediate 7d and 2-bromoquinoxaline.
  • the title product 10f was prepared from intermediates 3d and 10e.
  • the title product 10 was prepared from the intermediate 10f.
  • the title product 11a was prepared from intermediates 7d and 10e.
  • the title product 12d was prepared from the intermediate 12c.
  • the title product 12e was prepared from the intermediate 12d.
  • the title product 12f was prepared from the intermediate 12e.
  • the title product 12g was prepared from the intermediate 12f and 2-bromoquinoxaline.
  • the title product 12 was prepared from the intermediate 12g.
  • the title product 13a was prepared from the intermediate 12f and 3-bromoisoquinoline.
  • the title product 13 was prepared from the intermediate 13a.
  • the title product 14a was prepared from the intermediate 12f and 3-chlorocinnoline.
  • the title product 14 was prepared from the intermediate 14a.
  • the title product 15c was prepared from the intermediate 15b.
  • the title product 15d was prepared from the intermediate 15c.
  • the title product 15e was prepared from the intermediate 15d.
  • compound 15f was prepared from intermediate 15e and 3-chlorocinnoline.
  • the title product 15 was prepared from the intermediate 15f.
  • the title product 16a was prepared from intermediate 15e and 2-bromoquinoxaline.
  • the title product 17a was prepared from the intermediate 15e and 3-bromoisoquinoline.
  • This test example is to use method 1 to perform a luciferase reporter gene test experiment to test the agonist activity of the disclosed compound and the control example (see WO2022015423A1 Example 1 compound for the control example) on the AHR protein.
  • the structure of the control example is as follows:
  • Human hepatoma cell HepG2-Lucia expressing AHR and luciferase was purchased from InvivoGen, catalog number hpgl-ahr;
  • Multifunctional ELISA reader model PHERAstar FSX, BMG LRBTECH.
  • Penicillin-streptomycin Gibco, catalog number 15140-122;
  • Fetal bovine serum Ausgenex, product number FBS500-S;
  • DMSO dimethyl sulfoxide
  • Solarbio catalog number D8371
  • FICZ (6-formyl indole [3,2-B] carbazole), MCE, product number HY-12451;
  • Zeocin (bleomycin), InvivoGen, catalog number ant-zn-1;
  • HepG2-Lucia AHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1 ⁇ NEAA, penicillin-streptomycin and 100 ⁇ g/ml Zeocin (bleomycin). The culture temperature was 37°C and the carbon dioxide concentration was 5%;
  • the 384-well plate with the added compound was cultured in an incubator for 24 hours;
  • AhR protein luciferase-labeled human liver cancer cell (HepG2-Lucia) AhR agonist EC 50 (nM)
  • Table 1 The data of the EC 50 of the activity of the disclosed compounds and control examples on AhR protein (luciferase-labeled human liver cancer cell (HepG2-Lucia) AhR agonist EC 50 (nM)) are summarized in Table 1 below.
  • This test example is a luciferase reporter gene test experiment conducted by method 2 to test the agonist activity of the disclosed compound and the control example (see Example 1 compound of WO2022015423A1 for the control example) on the AHR protein.
  • the structure of the control example is as follows:
  • Multifunctional microplate reader model LumiStation 1800, Flash Company.
  • Penicillin-streptomycin Gibco, catalog number 15140-122;
  • Fetal bovine serum Gibco, catalog number 10100147C;
  • DMSO dimethyl sulfoxide
  • Solarbio catalog number D8370
  • FICZ (6-formyl indole [3,2-B] carbazole), MCE, product number HY-12451;
  • Zeocin (bleomycin), InvivoGen, catalog number ant-zn-05;
  • HepG2-Lucia AHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1 ⁇ NEAA, penicillin-streptomycin, 100 ⁇ g/ml Normocin, and 100 ⁇ g/ml Zeocin (bleomycin).
  • the culture temperature was 37°C and the carbon dioxide concentration was 5%.
  • the 96-well plate with the added compounds was cultured in an incubator for a further 24 h.
  • AhR protein luciferase-labeled human liver cancer cell (HepG2-Lucia) AhR agonist EC 50 (nM)
  • Table 2 The data of the EC 50 of the activity of the disclosed compounds and control examples on AhR protein (luciferase-labeled human liver cancer cell (HepG2-Lucia) AhR agonist EC 50 (nM)) are summarized in Table 2 below.

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Abstract

La présente invention concerne un composé cyclique fusionné, son procédé de préparation et son utilisation en médecine. En particulier, la présente invention concerne un composé cyclique fusionné représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le composé, et une utilisation du composé en tant que modulateur d'AhR, en particulier une utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention de maladies ou de troubles médiés par la protéine AhR.
PCT/CN2024/071902 2023-01-17 2024-01-12 Composé cyclique fusionné, son procédé de préparation et son utilisation en médecine Ceased WO2024152993A1 (fr)

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WO2025082312A1 (fr) * 2023-10-18 2025-04-24 德明药泰生物技术（深圳）有限公司 Composé modulateur de récepteur d'hydrocarbure aromatique, son procédé de préparation et son utilisation
CN120904199A (zh) * 2025-09-30 2025-11-07 上海泽德曼医药科技有限公司 具有稠环结构的化合物及其在医药上的应用
CN121005656A (zh) * 2025-10-24 2025-11-25 上海泽德曼医药科技有限公司 一种具有吡啶酮结构的化合物及其在医药上的应用

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WO2011156626A1 (fr) * 2010-06-09 2011-12-15 Rutgers, The State University Of New Jersey Agents antimicrobiens
WO2022015423A1 (fr) * 2020-07-16 2022-01-20 Dermavant Sciences GmbH Composés d'isoquinoléine et leur utilisation dans le traitement d'un déséquilibre du ahr
WO2023086428A2 (fr) * 2021-11-10 2023-05-19 Allianthera (Suzhou) Biopharmaceutical Co., Ltd. Nouveaux modulateurs du récepteur d'hydrocarbure aryle et leurs procédés d'utilisation
CN117229208A (zh) * 2023-11-13 2023-12-15 上海泽德曼医药科技有限公司 稠环类化合物、其制备方法及其在医药上的应用

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WO2010127307A1 (fr) * 2009-04-30 2010-11-04 Rutgers, The State University Of New Jersey Agents antimicrobiens
WO2011156626A1 (fr) * 2010-06-09 2011-12-15 Rutgers, The State University Of New Jersey Agents antimicrobiens
WO2022015423A1 (fr) * 2020-07-16 2022-01-20 Dermavant Sciences GmbH Composés d'isoquinoléine et leur utilisation dans le traitement d'un déséquilibre du ahr
WO2023086428A2 (fr) * 2021-11-10 2023-05-19 Allianthera (Suzhou) Biopharmaceutical Co., Ltd. Nouveaux modulateurs du récepteur d'hydrocarbure aryle et leurs procédés d'utilisation
CN117229208A (zh) * 2023-11-13 2023-12-15 上海泽德曼医药科技有限公司 稠环类化合物、其制备方法及其在医药上的应用

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* Cited by examiner, † Cited by third party
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WO2025082312A1 (fr) * 2023-10-18 2025-04-24 德明药泰生物技术（深圳）有限公司 Composé modulateur de récepteur d'hydrocarbure aromatique, son procédé de préparation et son utilisation
CN120904199A (zh) * 2025-09-30 2025-11-07 上海泽德曼医药科技有限公司 具有稠环结构的化合物及其在医药上的应用
CN121005656A (zh) * 2025-10-24 2025-11-25 上海泽德曼医药科技有限公司 一种具有吡啶酮结构的化合物及其在医药上的应用

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