WO2022143695A1 - Inhibiteur de sulfonamide, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de sulfonamide, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2022143695A1
WO2022143695A1 PCT/CN2021/142177 CN2021142177W WO2022143695A1 WO 2022143695 A1 WO2022143695 A1 WO 2022143695A1 CN 2021142177 W CN2021142177 W CN 2021142177W WO 2022143695 A1 WO2022143695 A1 WO 2022143695A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
substituted
cycloalkyl
compound
Prior art date
Application number
PCT/CN2021/142177
Other languages
English (en)
Chinese (zh)
Inventor
吕彬华
崔大为
刘连军
庞旭东
Original Assignee
苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州泽璟生物制药股份有限公司, 上海泽璟医药技术有限公司 filed Critical 苏州泽璟生物制药股份有限公司
Publication of WO2022143695A1 publication Critical patent/WO2022143695A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a sulfonamide inhibitor and a preparation method and application thereof.
  • Aryl Hydrocarbon Receptor is a ligand-activated transcription factor involved in the regulation of various cellular processes, including cell proliferation, metabolism, and immune regulation. AhR can affect cell signaling by interacting with a variety of regulatory and signaling proteins, including the PAS heterodimeric chaperone ARNT (Arylene Receptor Nuclear Transporter), chaperones and immune-like proteins (e.g. HSP90), AIP (Arylene Receptor - interacting protein), p23, CK2 (casein kinase-2), PKC (protein kinase-C), etc.
  • PAS heterodimeric chaperone ARNT Allene Receptor Nuclear Transporter
  • AIP Arylene Receptor - interacting protein
  • p23 CK2
  • CK2 casein kinase-2
  • PKC protein kinase-C
  • AhR also interacts with hormone receptors, hypoxia, NF-KappaB, Rb protein-mediated signaling pathways, MAPK signaling pathways, and EGFR signaling pathways.
  • hormone receptors hypoxia, NF-KappaB, Rb protein-mediated signaling pathways, MAPK signaling pathways, and EGFR signaling pathways.
  • AhR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells, and NK cells.
  • AhR plays an important role in immune regulation: (1) For example, endogenous AhR ligands may promote the development of Treg cells in the TME; (2) AhR promotes the differentiation of Th17 cells through various mechanisms; The DRE site on the promoter is combined to regulate the expression of Th17; AhR can also cooperate with Stat3 to induce the expression of Aiolos (IKZF3), a member of the Ikaros family, reduce the expression of IL-2, and promote the generation of Th17 cells; (3) AhR and c The interaction between -Maf is crucial for the development of mouse and human Tr1 regulatory cells; (4) AhR regulates B cell differentiation through transcriptional repression of the early B cell genes EBF1 and PAX5.
  • IKZF3 Aiolos
  • AhR Ah receptor ligands that interfere with physiological functions, alter immune homeostasis, and develop inflammatory diseases, autoimmune diseases, and cancer. Inhibition of AhR may make immunotherapy more effective by alleviating immunosuppression.
  • Exogenous ligands such as PAHs (polycyclic aromatic hydrocarbons), dioxins (eg TCDD) and polychlorinated biphenyls are responsible for most toxic reactions.
  • AhR induces metabolic mechanisms such as cytochrome p450 enzymes (CYP1A1, CYP1A2 and CYP1B1, etc.) to eliminate environmental toxins.
  • cytochrome p450 enzymes CYP1A1, CYP1A2 and CYP1B1, etc.
  • AhR can also bind metabolites of tryptophan degradation.
  • Tryptophan metabolites such as kynurenine and kynurenic acid are endogenous AhR ligands that can activate AhR under physiological conditions.
  • the immunosuppressive properties of kynurenine and tryptophan degradation are well documented and implicated in cancer-related immunosuppression.
  • indoleamine-2,3-dioxygenases 1 and 2 (1DO1/1DO2) and tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalyzing tryptophan The first and rate-limiting step of metabolism.
  • kynurenine activates AhR, suppresses antitumor immune responses by mediating downstream of tryptophan degradation, and directly promotes tumor cell survival and activity, thereby promoting tumor growth. Therefore, AhR ligands produced by tumor cells act on tumor cells and lymphocytes in an autocrine and paracrine manner, respectively, to promote tumor growth.
  • AhR target proteins are pathologically associated with a variety of diseases, there is a need for novel AhR inhibitors for clinical treatment.
  • Highly selective and highly active AhR inhibitors can be more effective in treating diseases such as cancer mediated by abnormal AhR, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on AhR and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, and solvates or prodrug:
  • X is selected from the group consisting of substituted or unsubstituted groups: C 2 -C 6 alkylene, C 3 -C 10 cycloalkylene, 4-10 membered heterocyclylene, C 1 -C 6 alkylene C 3 -C 10 cycloalkylene or C 1 -C 6 alkylene 4-10 membered heterocyclylene, wherein the substitution refers to being substituted by one or more (such as 2, 3 or 4) Ra;
  • Y is selected from: NH or NR 4 , wherein R 4 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl; Wherein, the substitution refers to being substituted by one or more (such as 2, 3 or 4) Ra;
  • Z is selected from: O, NH, NCN, NR 9 , wherein, R 9 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-10 membered Heterocyclyl, C 6 -C 14 aryl or 5-14 membered heteroaryl; wherein, the substitution refers to being substituted by one or more (such as 2, 3 or 4) Ra;
  • U is selected from: N or CR 10 , wherein, R 10 is selected from: H, D or halogen;
  • R 1 is selected from the group consisting of substituted or unsubstituted groups: NH 2 , NR 11 R 11 ′, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 14 -aryl or 5-14-membered heteroaryl, wherein the substitution refers to being substituted by one or more (such as 2, 3 or 4) Ra;
  • R 11 and R 11 ′ are each independently selected from the group consisting of substituted or unsubstituted groups: H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 14 aryl or 5-14-membered heteroaryl, and R 11 and R 11 ' are not H at the same time, wherein the substitution refers to one or more (such as 2, 3 or 4) Ra is substituted;
  • R 2 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14-membered heteroaryl, wherein the substitution refers to being replaced by one or more (such as 2, 3 or 4) Ra replaces;
  • R 5 , R 6 and R 8 are each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered Heterocyclic group, cyano group, ester group, amine group, amide group, sulfonamide group or ureido group; wherein, the substitution refers to being substituted by one or more (such as 2, 3 or 4) Ra;
  • R 7 is selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, CF 3 , CHF 2 , OCF 3 , OCHF 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4 -10-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group, cyano group, ester group, amine group, amide group, sulfonamide group or ureido group; wherein, the substitution refers to being replaced by One or more (eg 2, 3 or 4) Ra substitutions;
  • Ra is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, halo C 1 - C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 -aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group, wherein, in Ra The substitution refers to substitution with one or more (eg 2, 3 or 4) groups selected from the group consisting of deuterium, C1 - C6 alkyl, C3 - C6 cycloalkyl, 4-6 member
  • Ra is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy oxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamido or Urea group, wherein, the substitution in Ra refers to being substituted by one or more (such as 2, 3 or 4) groups selected from the group consisting of: deuterium, C 1 -C 6 alkyl, C 3 -C
  • X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • X, Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates substance or prodrug, it has the structure shown in formula IV:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates substance or prodrug, it has the structure shown by formula V or V':
  • x is 1, 2, 3 or 4;
  • R e , R f , R m and R n are each independently selected from the group consisting of: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo Substituted C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido;
  • R e and R f , R f and R m , R m and R n together with the C atom to which they are attached form a substituted or unsubstituted group of the following groups: C 3 -C 6 cycloalkylene, 4-6 membered Heterocyclyl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 - C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine
  • R 12 is selected from the group consisting of substituted or unsubstituted groups: CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl or 5-14 membered heteroaryl; wherein , the substitution means being substituted by the substitution means being substituted by one or more groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates substance or prodrug, it has the structure shown in formula VI:
  • Ring A is a substituted or unsubstituted group of the following group: C 3 -C 6 cycloalkylene, 4-6 membered heterocyclic group, wherein the substitution refers to one or more groups selected from the group Group substitution: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 6 ring Alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • ring A is selected from: wherein, R b is selected from: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido.
  • R 1 is selected from the group consisting of substituted or unsubstituted groups: NR 11 R 11 ', C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • R 11 and R 11 ' are each independently selected from the group consisting of substituted or unsubstituted groups: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and R 11 and R 11 ' are not H at the same time, wherein the substitution described in R 1 , R 11 and R 11 ' refers to substitution by one or more groups selected from the group consisting of : deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -
  • R 1 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halo Substituted C 1 -C 3 alkyl, halogenated C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, deuterated C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy , halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea.
  • R 3 is selected from substituted or unsubstituted groups of the following group: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to substitution by one or more groups selected from the group of : deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl , C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl, 4- 6-membered heterocyclyl, halogen, nitro
  • R 7 is defined as above, preferably, R 7 is halogen, more preferably Cl.
  • R 3 is substituted or unsubstituted Wherein the substitution refers to substitution by C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, more preferably by methyl, CD 3 .
  • R 3 is
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 10 , Re , R f , R m , R n , X, Y, Z, U , x, R 12 and ring A are the groups corresponding to the specific compounds in the examples.
  • the compound is selected from the compounds shown in the Examples.
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 are as defined above.
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises i) one or more compounds of the general formula (I) described in the first aspect, its stereoisomers, tautomers, crystal forms , a pharmaceutically acceptable salt, hydrate, solvate or prodrug; and ii) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, Atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab,
  • the fourth aspect of the present invention provides a sulfonamide compound having the structure of general formula (I) according to the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, Use of the hydrate, solvate or prodrug, or the pharmaceutical composition described in the third aspect, for preparing a pharmaceutical composition for preventing and/or treating diseases mediated by AhR.
  • the disease is a tumor or a disordered disease.
  • the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia , blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • a method for inhibiting AhR which comprises the steps of: administering an effective amount of the compound of general formula (I), its stereoisomer, Tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administer the pharmaceutical compositions described in the third aspect of the present invention.
  • the present inventors unexpectedly discovered a new class of compounds with selective inhibitory effect on AhR and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl groups, including from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl n-butyl, tert-butyl, isobutyl (such as ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • alkylene refers to a group formed by removing one hydrogen atom from “alkyl”, such as methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as )Wait.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group comprising 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaromatic ring), fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclic or fused aryl ring, the above cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted. Any two or more atoms on the ring can be further cyclolinked with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • cycloalkylene refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as:
  • heterocyclyl refers to fully saturated or partially unsaturated cyclic groups (including, but not limited to, such as 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic systems), At least one heteroatom is present in a ring having at least one carbon atom.
  • Each heterocyclic ring containing a heteroatom may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur may be oxidized or the nitrogen may Quaternized.
  • a heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepanyl gene, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms on the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further cyclically connected; the heterocyclic group can be substituted or unsubstituted, and when substituted,
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate, where
  • heterocyclylene refers to a group formed by removing two or more hydrogen atoms from a heterocyclyl group, such as: Wait.
  • H of NH can be further substituted; when substituted, the substituents are preferably alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl.
  • C1-C6 alkylene C3-C10 cycloalkylene or "C3-C10 cycloalkylene C1-C6 alkylene” have the same meaning and refer to the removal of a cycloalkylalkyl or alkylcycloalkyl A group formed by two hydrogen atoms, such as Wait.
  • C1-C6 alkylene 4-10 membered heterocyclylene or “4-10 membered heterocyclylene C1-C6 alkylene” have the same meaning and refer to heterocyclylalkyl or alkylheterocycle A group formed by removing two hydrogen atoms from a radical, such as, Wait.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclyl or fused ring aryl, the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo refers to substitution with halogen.
  • deuterated refers to substitution with deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2.
  • cyano refers to a group with the structure CN.
  • esters refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • amino refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • Amido refers to a group with the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • sulfonamido refers to a group with the structure -SO2NRR ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclo Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • ureido refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.
  • alkylaminoalkyl refers to a group with the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.
  • heterocyclylalkyl refers to a group bearing the structure -RR', where R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R' represents heterocycle or substituted heterocycle.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, and stereoisomers of compounds of formula I. Solvates or prodrugs.
  • the compound of formula I has the following structure:
  • X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and U are as defined above.
  • the compound has the structure represented by the general formula (II):
  • X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • the compound has the structure represented by the general formula (III):
  • X, Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • the compound has the structure shown in formula IV:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • the compound has a structure represented by formula V or V':
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 10 , R 12 , Re , R f , R m and R n are as defined above.
  • the compound has the structure shown in formula VI:
  • Ring A, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
  • ring A is selected from:
  • R b is selected from: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido.
  • R 7 is selected from: hydrogen, deuterium, halogen, CF 3 , CHF 2 , OCF 3 , OCHF 2 , C 1 -C 6 alkyl, N(CH 3 ) 2 .
  • R 5 , R 6 and R 8 are each independently selected from: hydrogen, deuterium, halogen, C 1 -C 6 alkyl, cyano, ester, amine, amido, sulfonic Amido or ureido, more preferably, R 5 , R 6 and R 8 are each independently selected from: hydrogen, deuterium, halogen, C 1 -C 6 alkyl, cyano.
  • R 1 is selected from the group consisting of substituted or unsubstituted groups: NR 11 R 11 ', C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered Heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • R 11 and R 11 ' are each independently selected from the group consisting of substituted or unsubstituted groups: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and R 11 and R 11 ' are not H at the same time, wherein the substitution in R 1 , R 11 and R 11 ' refers to substitution by one or more groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxy, C 3 -C 6 cycloal
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 -alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl, 4-6-membered heterocyclic , halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea;
  • R 7 is selected from: hydrogen, deuterium, halogen, CF 3 , CHF 2 , OCF 3 , OCHF 2 , C 1 -C 6 alkyl, N(CH 3 ) 2 ;
  • R 5 , R 6 and R 8 are each independently selected from: hydrogen, deuterium, halogen, C 1 -C 6 alkyl, cyano, ester, amine, amide, sulfonamide, or ureido.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • the term "stable" refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • reaction solvent the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc.
  • reaction solvent the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting AhR.
  • the present invention has the following main advantages:
  • the compound of the present invention has a good selective inhibitory effect on AhR;
  • the compounds of the present invention have better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • the first step preparation of (S)-tert-butyl(2-((tert-butoxycarbonyl)amino)propyl(methylsulfonyl)carbamate
  • the second step the preparation of (S)-N-(2-aminopropyl) methanesulfonamide hydrochloride
  • Example 1-1 According to the method of Example 1-1, the following compounds were synthesized with different starting materials:
  • the third step preparation of 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
  • Breeding medium Opti-MEM, 5% FBS, 1uM sodium Pyruvate, 0.1mM NEAA, stored at 4°C.
  • 15K cells/well put 15K cells into each well with 30uL of culture medium;
  • Wavelength Excitation Filter 400 Emission Filter 1 460 Emission Filter 2 535 Dichroic Mirror Beta lactamase D425/490

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un inhibiteur de sulfonamide, son procédé de préparation et son utilisation. Plus particulièrement, le composé selon la présente invention a une structure telle que représentée par la formule (I). La présente invention concerne également un procédé de préparation du composé et son utilisation en tant qu'inhibiteur de l'AhR. Le composé selon la présente invention a un bon effet d'inhibition sélective sur l'AhR, et de meilleures propriétés pharmacodynamiques et pharmacocinétiques, une toxicité inférieure et de très faibles effets secondaires.
PCT/CN2021/142177 2020-12-28 2021-12-28 Inhibiteur de sulfonamide, son procédé de préparation et son utilisation WO2022143695A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011580707.6A CN114685426A (zh) 2020-12-28 2020-12-28 磺酰胺类抑制剂及其制备方法和应用
CN202011580707.6 2020-12-28

Publications (1)

Publication Number Publication Date
WO2022143695A1 true WO2022143695A1 (fr) 2022-07-07

Family

ID=82129430

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/142177 WO2022143695A1 (fr) 2020-12-28 2021-12-28 Inhibiteur de sulfonamide, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN114685426A (fr)
WO (1) WO2022143695A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114835687B (zh) * 2021-04-02 2023-09-05 北京华森英诺生物科技有限公司 AhR抑制剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019101642A1 (fr) * 2017-11-21 2019-05-31 Bayer Aktiengesellschaft 3-oxo-2,3-dihydropyridazine-4-carboxamides substitués par du soufre
WO2019101643A1 (fr) * 2017-11-21 2019-05-31 Bayer Aktiengesellschaft 3-oxo-6-hétéroaryl-2-phényl-2,3-dihydropyridazine-4-carboxamides
CN109863140A (zh) * 2016-05-25 2019-06-07 拜耳医药股份有限公司 3-氧代-2,6-二苯基-2,3-二氢哒嗪-4-甲酰胺
CN110678459A (zh) * 2017-02-09 2020-01-10 拜耳股份公司 用于治疗癌症的2-杂芳基-3-氧代-2,3-二氢哒嗪-4-甲酰胺
CN111592528A (zh) * 2019-02-20 2020-08-28 苏州泽璟生物制药股份有限公司 氘代的哒嗪酮及其衍生物和药物组合物
WO2020201825A2 (fr) * 2019-03-29 2020-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Signature d'activation de récepteur d'hydrocarbures aryliques (ahr) et procédés de détermination d'état de signalisation d'ahr

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109863140A (zh) * 2016-05-25 2019-06-07 拜耳医药股份有限公司 3-氧代-2,6-二苯基-2,3-二氢哒嗪-4-甲酰胺
CN110678459A (zh) * 2017-02-09 2020-01-10 拜耳股份公司 用于治疗癌症的2-杂芳基-3-氧代-2,3-二氢哒嗪-4-甲酰胺
WO2019101642A1 (fr) * 2017-11-21 2019-05-31 Bayer Aktiengesellschaft 3-oxo-2,3-dihydropyridazine-4-carboxamides substitués par du soufre
WO2019101643A1 (fr) * 2017-11-21 2019-05-31 Bayer Aktiengesellschaft 3-oxo-6-hétéroaryl-2-phényl-2,3-dihydropyridazine-4-carboxamides
CN111592528A (zh) * 2019-02-20 2020-08-28 苏州泽璟生物制药股份有限公司 氘代的哒嗪酮及其衍生物和药物组合物
WO2020201825A2 (fr) * 2019-03-29 2020-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Signature d'activation de récepteur d'hydrocarbures aryliques (ahr) et procédés de détermination d'état de signalisation d'ahr

Also Published As

Publication number Publication date
CN114685426A (zh) 2022-07-01

Similar Documents

Publication Publication Date Title
WO2021078285A1 (fr) Inhibiteurs à base de groupes cycloalkyle et hétéroalkyle, procédé de préparation associé et utilisation associée
WO2021228161A1 (fr) Inhibiteur hétérocyclique substitué par alkyle, son procédé de préparation et son utilisation
WO2021143693A1 (fr) Dérivé de pyridone ou de pyrimidine aryle ou hétéroaryle, son procédé de préparation et son utilisation
WO2022161480A1 (fr) Inhibiteur amine hétérocyclique bicyclo-aromatique substitué, son procédé de préparation et son utilisation
WO2022017533A1 (fr) Composé utile en tant qu'inhibiteur de kinase cdk7 et son utilisation
RU2633694C2 (ru) Дейтерированный фениламинопиримидин и фармацевтическая композиция, содержащая такое соединение
TW202035370A (zh) Mdm2抑制劑之製備方法及結晶型
WO2022199586A1 (fr) Inhibiteur de pyrimidopyridine, son procédé de préparation et son utilisation
WO2021249563A1 (fr) Dérivé de pyridone ou de pyrimidone aryle ou hétéroaryle, son procédé de préparation et son utilisation
WO2022166592A1 (fr) Inhibiteur de pyrimidopyridone substitué, son procédé de préparation et son utilisation
AU2019249560B2 (en) Heteroaryl-substituted pyrazole compound and medicinal use thereof
WO2022188819A1 (fr) Modulateur de protéolyse sos1, son procédé de préparation et son application
WO2021098859A1 (fr) Inhibiteur à cycle aza à sept chaînons, et son procédé de préparation et utilisation associée
CA2901770A1 (fr) Cyanoethylpyrazolo pyridones acycliques en tant qu'inhibiteurs de janus kinase
WO2022083657A1 (fr) Inhibiteur d'amine benzo ou pyridopyrimidine substitué, son procédé de préparation et son application
WO2021078274A1 (fr) Composé de pyridazinone ou de pyridazine et dérivé et composition pharmaceutique de celui-ci
TWI832539B (zh) 用作ｃｄｋ７激酶抑制劑的化合物及其應用
WO2022095910A1 (fr) Composé servant d'inhibiteur de kinase et son utilisation
WO2022143695A1 (fr) Inhibiteur de sulfonamide, son procédé de préparation et son utilisation
WO2022111708A1 (fr) Inhibiteur de 2-arylhétérocycle-3-oxo-2,3-dihydropyridazine-4-carboxamide deutéré, son procédé de préparation et son utilisation
WO2021129841A1 (fr) Composé utilisé comme inhibiteur de kinase ret et son application
WO2022135591A1 (fr) Dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application
CN117003737A (zh) 取代的咪唑苯基甲酮类化合物及其衍生物和药物组合物
CN115215844A (zh) 取代嘧啶并环类抑制剂及其制备方法和应用
CN114380805A (zh) 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21914429

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21914429

Country of ref document: EP

Kind code of ref document: A1