WO2022143695A1 - Sulfonamide inhibitor, and preparation method therefor and application thereof - Google Patents

Sulfonamide inhibitor, and preparation method therefor and application thereof Download PDF

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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
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alkyl
substituted
cycloalkyl
compound
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吕彬华
崔大为
刘连军
庞旭东
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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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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    • 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
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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

Abstract

The present invention relates to a sulfonamide inhibitor, and a preparation method therefor and an application thereof. Specifically, the compound of the present invention has a structure as represented by formula (I). Also disclosed in the present invention are a preparation method for the compound and an application thereof as an AhR inhibitor. The compound of the present invention has a good selective inhibitory effect on AhR, and has better pharmacodynamic and pharmacokinetic properties, and lower toxic and side effects.

Description

磺酰胺类抑制剂及其制备方法和应用Sulfonamide inhibitor and preparation method and application thereof 技术领域technical field
本发明属于药物领域，具体涉及一种磺酰胺类抑制剂及其制备方法和应用。The invention belongs to the field of medicine, and in particular relates to a sulfonamide inhibitor and a preparation method and application thereof.
背景技术Background technique
芳基烃受体(Aryl Hydrocarbon Receptor，AhR)是一种配体激活的转录因子，参与多种细胞过程的调控，包括细胞增殖、新陈代谢和免疫调节等。AhR可以通过与各种调控和信号蛋白相互作用来影响细胞信号传导，包括PAS异二聚体伴侣ARNT(芳烃受体核转运蛋白)、伴侣和免疫样蛋白(例如HSP90)、AIP(芳烃受体-相互作用蛋白)、p23、CK2(酪蛋白激酶-2)、PKC(蛋白激酶-C)等。另外，AhR还与激素受体、低氧、NF-KappaB、Rb蛋白介导的信号通路、MAPK信号通路、EGFR信号通路等有相互作用。研究发现AhR在肺癌、结直肠癌及头颈部鳞癌等多种肿瘤中观察到AhR的高表达，而且在肿瘤微环境中能对免疫抑制的调节起到关键作用。临床前研究表明持续活化的小鼠会自发性的产生肿瘤。Aryl Hydrocarbon Receptor (AhR) 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. In addition, AhR also interacts with hormone receptors, hypoxia, NF-KappaB, Rb protein-mediated signaling pathways, MAPK signaling pathways, and EGFR signaling pathways. Studies have found that AhR is highly expressed in various tumors such as lung cancer, colorectal cancer, and head and neck squamous cell carcinoma, and plays a key role in the regulation of immunosuppression in the tumor microenvironment. Preclinical studies have shown that persistently activated mice develop tumors spontaneously.
AhR在免疫***的许多细胞中表达，包括树突状细胞(dendritic cells,DCs)、巨噬细胞、T细胞和NK细胞等。AhR在免疫调节中发挥重要作用：(1)如内源性AhR配体可能促进TME中Treg细胞的发育；(2)AhR通过多种机制促进Th17细胞的分化；另一方面，AhR通过与Th17启动子上的DRE位点结合来调控Th17的表达；AhR还可以协同Stat3诱导Ikaros家族成员Aiolos(IKZF3)的表达，降低IL-2的表达，同时促进Th17细胞的生成；(3)AhR和c-Maf之间的相互作用对小鼠和人类Tr1调节细胞的发育至关重要；(4)AhR通过对B细胞早期基因EBF1和PAX5的转录抑制调控B细胞分化等。免疫***中的细胞不断暴露于内源性和外源性AhR配体中，这些配体可干扰生理功能、改变免疫稳态并发展为炎症性疾病、自身免疫性疾病和癌症。AhR的抑制可以通过减轻免疫抑制使免疫治疗更加有效。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. Cells in the immune system are constantly exposed to endogenous and exogenous AhR 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.
外源性配体如PAH(多环芳烃)、二恶英(例如TCDD)和多氯联苯等是大多数毒性反应的罪魁祸首。与这些环境毒素结合后，AhR诱导代谢机制如细胞色素p450酶等(CYP1A1、CYP1A2和CYP1B1等)对环境毒素进行消除。研究表明外源性配体如TCDD等激活AhR已被证明在许多细胞过程中发挥作用，如胚胎发生、肿瘤发生和炎症等。Exogenous ligands such as PAHs (polycyclic aromatic hydrocarbons), dioxins (eg TCDD) and polychlorinated biphenyls are responsible for most toxic reactions. After binding to these environmental toxins, AhR induces metabolic mechanisms such as cytochrome p450 enzymes (CYP1A1, CYP1A2 and CYP1B1, etc.) to eliminate environmental toxins. Studies have shown that activation of AhR by exogenous ligands such as TCDD has been shown to play a role in many cellular processes, such as embryogenesis, tumorigenesis, and inflammation.
除了外源性配体外，AhR还可以结合色氨酸降解的代谢产物。色氨酸代谢物如kynurenine和kynurenic acid是内源性AhR配体，可以在生理条件下激活AhR。kynurenine和色氨酸降解的免疫抑制特性已经被充分证明，并涉及癌症相关的免疫 抑制。在色氨酸降解途径中，吲哚胺-2,3-双加氧酶1和2(1DO1/1DO2)以及色氨酸-2,3-双加氧酶2(TDO2)负责催化色氨酸代谢的第一步和限速步骤。在动物模型中，降低抗肿瘤免疫反应和抑制IDO可以抑制肿瘤的形成。在癌症中TDO2也有强表达，可导致产生免疫抑制的kynurenine。在胶质瘤中，kynurenine激活AhR，通过介导色氨酸降解的下游抑制抗肿瘤免疫反应，并直接促进肿瘤细胞存活和活性，从而促进肿瘤生长。因此，肿瘤细胞产生的AhR配体分别以自分泌和旁分泌方式作用于肿瘤细胞和淋巴细胞，促进肿瘤生长。In addition to exogenous ligands, 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. In the tryptophan degradation pathway, 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. In animal models, reducing antitumor immune responses and inhibiting IDO inhibited tumor formation. TDO2 is also strongly expressed in cancer, leading to the production of immunosuppressive kynurenine. In glioma, 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.
由于AhR靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的AhR抑制剂用于临床治疗。高选择性高活性的AhR抑制剂可以对AhR异常介导的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。Since 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.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一类新型的对AhR有选择性抑制作用和/或更好药效学性能的化合物及其用途。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.
本发明第一方面，提供一种具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：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:
Figure PCTCN2021142177-appb-000001
Figure PCTCN2021142177-appb-000001
式中：where:
X选自取代或未取代的下组基团：C 2-C 6亚烷基、C 3-C 10亚环烷基、4-10元亚杂环基、C 1-C 6亚烷基C 3-C 10亚环烷基或C 1-C 6亚烷基4-10元亚杂环基，其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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选自：NH或NR 4，其中，R 4选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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选自：O、NH、NCN、NR 9，其中，R 9选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 8环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基；其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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选自：N或CR 10，其中，R 10选自：H、D或卤素； U is selected from: N or CR 10 , wherein, R 10 is selected from: H, D or halogen;
R 1选自取代或未取代的下组基团：NH 2、NR 11R 11'、C 1-C 6烷基、C 3-C 10环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基，其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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和R 11'各自独立地选自取代或未取代的下组基团：H、C 1-C 6烷基、C 3-C 10环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基，且R 11和R 11'不同时为H，其中，所述取代是指 被一个或多个(如2、3或4)Ra取代； 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选自取代或未取代的下组基团：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基； 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选自取代或未取代的下组基团：C 6-C 14芳基、5-14元杂芳基，其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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和R 8各自独立地选自取代或未取代的下组基团：氢、氘、卤素、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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选自取代或未取代的下组基团：氢、氘、卤素、CF 3、CHF 2、OCF 3、OCHF 2、C 1-C 6烷基、C 3-C 8环烷基、4-10元杂环基、C 6-C 14芳基、5-14元杂芳基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，所述取代是指被一个或多个(如2、3或4)Ra取代； 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选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基，其中，Ra中所述取代是指被一个或多个(如2、3或4)选自下组的基团取代：氘、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 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 membered Heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or ureido.
在另一优选例中，Ra选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 8环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-8元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基，其中，Ra中所述取代是指被一个或多个(如2、3或4)选自下组的基团取代：氘、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred embodiment, 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 6 ring Alkyl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(II)所示结构：In another preferred example, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates substance or prodrug, which has the structure represented by the general formula (II):
Figure PCTCN2021142177-appb-000002
Figure PCTCN2021142177-appb-000002
X、Y、Z、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(III)所示结构：In another preferred example, 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 general formula (III):
Figure PCTCN2021142177-appb-000003
Figure PCTCN2021142177-appb-000003
X、Y、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 X, Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式IV所示结构：In another preferred example, 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:
Figure PCTCN2021142177-appb-000004
Figure PCTCN2021142177-appb-000004
X、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 X, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式V或V'所示结构：In another preferred example, 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':
Figure PCTCN2021142177-appb-000005
Figure PCTCN2021142177-appb-000005
式中，In the formula,
x为1、2、3或4；x is 1, 2, 3 or 4;
R e、R f、R m和R n各自独立地选自：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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;
或者R e和R f、R f和R m、R m和R n与其连接的C原子共同形成取代或未取代的下组基团：C 3-C 6亚环烷基、4-6元亚杂环基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Or 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, amido, sulfo amide group or urea group;
R 12选自取代或未取代的下组基团：CN、C 1-C 6烷基、C 3-C 6环烷基、C 6-C 14芳基或5-14元杂芳基；其中，所述取代是指被所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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和R 10的定义如上所述。 R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式VI所示结构：In another preferred example, 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:
Figure PCTCN2021142177-appb-000006
Figure PCTCN2021142177-appb-000006
式中，In the formula,
环A为取代或未取代的下组基团：C 3-C 6亚环烷基、4-6元亚杂环基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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和R 10的定义如上所述。 R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
在另一优选例中，环A选自：
Figure PCTCN2021142177-appb-000007
Figure PCTCN2021142177-appb-000008
其中，R b选自：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred embodiment, ring A is selected from:
Figure PCTCN2021142177-appb-000007
Figure PCTCN2021142177-appb-000008
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.
在另一优选例中，上述各式中，R 1选自取代或未取代的下组基团：NR 11R 11'、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、苯基或5-6元杂芳基；R 11和R 11'各自独立地选自取代或未取代的下组基团：H、C 1-C 6烷基、C 3-C 6环烷基，且R 11和R 11'不同时为H，其中，R 1、R 11和R 11'中所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred example, in the above formulas, 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 -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.
在另一优选例中，在另一优选例中，上述各式中，R 1选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基、卤代C 1-C 3烷基羟基、C 1-C 3烷氧基、氘代C 1-C 3烷氧基、卤代C 1-C 3烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred example, in the above formulas, 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.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，R 3选自取代或未取代的下组基团：苯基或5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、 卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred example, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates compound or prodrug, 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, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido.
在另一优选例中，
Figure PCTCN2021142177-appb-000009
部分选自：
Figure PCTCN2021142177-appb-000010
其中，R 7的定义如上所述，优选地，R 7为卤素，更优选地为Cl。 In another preferred embodiment,
Figure PCTCN2021142177-appb-000009
Partially selected from:
Figure PCTCN2021142177-appb-000010
Wherein, R 7 is defined as above, preferably, R 7 is halogen, more preferably Cl.
在另一优选例中，R 3为取代或未取代的
Figure PCTCN2021142177-appb-000011
其中所述取代是指被C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基取代，更优选地被甲基、CD 3取代。 In another preferred embodiment, R 3 is substituted or unsubstituted
Figure PCTCN2021142177-appb-000011
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 .
在另一优选例中，R 3为
Figure PCTCN2021142177-appb-000012
In another preferred embodiment, R 3 is
Figure PCTCN2021142177-appb-000012
在另一优选例中，R 1、R 2、R 3、R 5、R 6、R 7、R 8、R 10、R e、R f、R m、R n、X、Y、Z、U、x、R 12、环A为实施例中各具体化合物所对应基团。 In another preferred example, 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.
在另一优选例中，所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，所述化合物选自下组：In another preferred example, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates drug or prodrug selected from the group consisting of:
Figure PCTCN2021142177-appb-000013
Figure PCTCN2021142177-appb-000013
Figure PCTCN2021142177-appb-000014
Figure PCTCN2021142177-appb-000014
在另一优选例中，所述化合物选自实施例中所示化合物。In another preferred embodiment, the compound is selected from the compounds shown in the Examples.
本发明第二方面，提供一种制备通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，所述方法包括步 骤：In the second aspect of the present invention, there is provided a sulfonamide compound of general formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate and solvate or a method for a prodrug, the method comprising the steps of:
Figure PCTCN2021142177-appb-000015
Figure PCTCN2021142177-appb-000015
(i)在碱存在下，式(P-1)化合物与式(Q)化合物反应，得到式(P-2)化合物；(i) reacting the compound of formula (P-1) with the compound of formula (Q) in the presence of a base to obtain the compound of formula (P-2);
(ii)在铜盐存在下，式(P-2)化合物发生脱氢反应，得到式(P-3)化合物；(ii) in the presence of copper salt, the compound of formula (P-2) undergoes a dehydrogenation reaction to obtain the compound of formula (P-3);
(iii)在碱存在下，式(P-3)化合物水解得到式(P-4)化合物；(iii) in the presence of a base, the compound of formula (P-3) is hydrolyzed to obtain the compound of formula (P-4);
(iv)式(P-4)化合物与胺(R)反应，得到式(I)化合物；(iv) the compound of formula (P-4) is reacted with amine (R) to obtain the compound of formula (I);
式中，In the formula,
X、Y、Z、U、R 1、R 2、R 3、R 5、R 6、R 7、和R 8定义如上所述。 X, Y, Z, U, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 are as defined above.
本发明第三方面，提供一种药物组合物，其包含i)一种或多种第一方面所述通式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。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.
在另一优选例中，所述药物组合物还包含选自下组的药物：PD-1抑制剂(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非 尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)，或其组合。In another preferred embodiment, 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, tositumumab, 131I-tositumumab, tiimumab, 90Y - tiimumab, 90In-tiimumab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172 , SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocartinib) Nitrogen), PI3K inhibitors (such as Idelaris, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, acalatinib, zabrutinib, Vecabrutinib) etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, sapritinib, Naquotinib, Pyrotinib, Roletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Seletinib, Ningetinib, Cabozantinib, Suni tinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, vorinostat, Fimepinostat, Droxinostat, entinostat, darxilast, Quisinostat, tycodinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1) 120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or its combination.
本发明第四方面，提供一种第一方面所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或第三方面所述的药物组合物的用途，用于制备预防和/或治疗与AhR介导的疾病的药物组合物。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.
在另一优选例中，所述的疾病是肿瘤或失调性疾病。In another preferred embodiment, the disease is a tumor or a disordered disease.
在另一优选例中，所述疾病选自下组：肺癌、乳腺癌、***癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、白血病、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。In another preferred embodiment, 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.
在本发明的第五方面，提供了一种抑制AhR的方法，其包括步骤：向所需患者施用有效量的本发明第一方面所述的通式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用本发明第三方面所述的药物组合物。In the fifth aspect of the present invention, there is provided 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.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，意外地发现了一类新型的对AhR有选择性抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。After long-term and in-depth research, 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.
术语the term
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.
术语“烷基”是指直链或支链或环状烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2021142177-appb-000016
戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等等。 The term "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,
Figure PCTCN2021142177-appb-000016
Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
术语“C1-C18烷基”指的是直链或支链或环状烷基，包括从1-18个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2021142177-appb-000017
正丁基、叔丁基、异丁基(如
Figure PCTCN2021142177-appb-000018
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷 基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。 The term "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
Figure PCTCN2021142177-appb-000017
n-butyl, tert-butyl, isobutyl (such as
Figure PCTCN2021142177-appb-000018
), 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. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ), nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 Re , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O) R a , OC(=O) NR b R c , NR b C(=O) OR e , NR d C (=O) NRbRc , NRdS (=O) 2NRbRc , NRdP ( =O ) 2NRbRc , NRbC ( =O ) Ra , or NRbP ( =O) 2 R e , wherein R a appearing here may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with N atom can form a heterocycle; R e can independently represent hydrogen, alkyl, cycloalkane alkenyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
术语“亚烷基”是指“烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2021142177-appb-000019
)、亚丁基(如
Figure PCTCN2021142177-appb-000020
)、亚戊基(如
Figure PCTCN2021142177-appb-000021
)、亚己基(如
Figure PCTCN2021142177-appb-000022
)、亚庚基(如
Figure PCTCN2021142177-appb-000023
)等。 The term "alkylene" refers to a group formed by removing one hydrogen atom from "alkyl", such as methylene, ethylene, propylene, isopropylidene (such as
Figure PCTCN2021142177-appb-000019
), butylene (such as
Figure PCTCN2021142177-appb-000020
), pentylene (such as
Figure PCTCN2021142177-appb-000021
), ahexyl (such as
Figure PCTCN2021142177-appb-000022
), heptidene (such as
Figure PCTCN2021142177-appb-000023
)Wait.
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选被取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。 The term "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 substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, a monohalogen substituent or a polyhalogen substituent such as trifluoromethyl or an alkyl group containing Cl ), nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 Re , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O) R a , OC(=O) NR b R c , NR b C(=O) OR e , NR d C (=O) NRbRc , NRdS (=O) 2NRbRc , NRdP ( =O ) 2NRbRc , NRbC ( =O ) Ra , or NRbP ( =O) 2 R e , wherein R a appearing here may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c together with N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned 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.
术语“亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2021142177-appb-000024
The term "cycloalkylene" refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as:
Figure PCTCN2021142177-appb-000024
Figure PCTCN2021142177-appb-000025
等。
Figure PCTCN2021142177-appb-000025
Wait.
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环，6-11元双环，或8-16元三环***)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、***啉基、硫代***啉基、硫代***啉亚砜基、硫代***啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基，其中，环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。The term "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, wherein the ring Any two or more atoms may be further co-linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
术语“亚杂环基”是指杂环基脱掉两个及两个以上氢原子所形成的基团，如：
Figure PCTCN2021142177-appb-000026
Figure PCTCN2021142177-appb-000027
Figure PCTCN2021142177-appb-000028
等。其中，NH的H可以被进一步取代；当被取代时，取代基优选为烷基、氘代烷基、卤代烷基、烯基、炔基、、环烷基、杂环基、芳基、杂芳基、烷氧基烷基、羟基烷基、胺基烷基、环烷基烷基、杂环基烷基、芳基烷基、杂芳基烷基。 The term "heterocyclylene" refers to a group formed by removing two or more hydrogen atoms from a heterocyclyl group, such as:
Figure PCTCN2021142177-appb-000026
Figure PCTCN2021142177-appb-000027
Figure PCTCN2021142177-appb-000028
Wait. Wherein, 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.
术语“C1‐C6亚烷基C3‐C10亚环烷基”或“C3‐C10亚环烷基C1‐C6亚烷基”具有相同含义，是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，如
Figure PCTCN2021142177-appb-000029
Figure PCTCN2021142177-appb-000030
等。 The terms "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
Figure PCTCN2021142177-appb-000029
Figure PCTCN2021142177-appb-000030
Wait.
术语“C1‐C6亚烷基4-10元亚杂环基”或“4-10元亚杂环基C1‐C6亚烷基”具有相同含义，是指杂环基烷基或烷基杂环基脱掉两个氢原子所形成的基团，，如,
Figure PCTCN2021142177-appb-000031
Figure PCTCN2021142177-appb-000032
等。 The terms "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,
Figure PCTCN2021142177-appb-000031
Figure PCTCN2021142177-appb-000032
Wait.
术语“芳基”是指芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环 烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。 The term "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 substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ), nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 Re , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O) R a , OC(=O) NR b R c , NR b C(=O) OR e , NR d C (=O) NRbRc , NRdS (=O) 2NRbRc , NRdP ( =O ) 2NRbRc , NRbC ( =O ) Ra , or NRbP ( =O) 2 R e , wherein R a appearing here may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c together with N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned 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.
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。The term "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.
术语“卤素”或“卤”是指氯、溴、氟、碘。The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
术语“卤代”是指被卤素取代。The term "halo" refers to substitution with halogen.
术语“氘代”是指被氘取代。The term "deuterated" refers to substitution with deuterium.
术语“羟基”是指带有结构OH的基团。The term "hydroxyl" refers to a group with the structure OH.
术语“硝基”是指带有结构NO 2的基团。 The term "nitro" refers to a group with the structure NO2.
术语“氰基”是指带有结构CN的基团。The term "cyano" refers to a group with the structure CN.
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。The term "ester" 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.
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。The term "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.
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。The term "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.
术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。 The term "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.
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。The term "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.
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'可以相同或不同。The term "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.
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。The term "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.
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷 基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。The term "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.
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, 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.
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has enough hydrogen atoms to replenish its valence state.
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。When 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.
活性成分Active ingredient
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药。As used herein, "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.
所述式I化合物具有如下结构：The compound of formula I has the following structure:
Figure PCTCN2021142177-appb-000033
Figure PCTCN2021142177-appb-000033
式中，In the formula,
X、Y、Z、R 1、R 2、R 3、R 5、R 6、R 7、R 8和U的定义如上所述。 X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and U are as defined above.
优选地，所述化合物具有通式(II)所示结构：Preferably, the compound has the structure represented by the general formula (II):
Figure PCTCN2021142177-appb-000034
Figure PCTCN2021142177-appb-000034
其中，in,
X、Y、Z、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
优选地，所述化合物具有通式(III)所示结构：Preferably, the compound has the structure represented by the general formula (III):
Figure PCTCN2021142177-appb-000035
Figure PCTCN2021142177-appb-000035
其中，in,
X、Y、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 X, Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
优选地，所述化合物具有式IV所示结构：Preferably, the compound has the structure shown in formula IV:
Figure PCTCN2021142177-appb-000036
Figure PCTCN2021142177-appb-000036
其中，in,
X、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 X, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
优选地，所述化合物具有式V或V'所示结构：Preferably, the compound has a structure represented by formula V or V':
Figure PCTCN2021142177-appb-000037
Figure PCTCN2021142177-appb-000037
其中，in,
x、R 1、R 2、R 3、R 5、R 6、R 7、R 8、R 10、R 12、R e、R f、R m和R n的定义如上所述。 x, 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.
优选地，所述化合物具有式VI所示结构：Preferably, the compound has the structure shown in formula VI:
Figure PCTCN2021142177-appb-000038
Figure PCTCN2021142177-appb-000038
其中，in,
环A、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如上所述。 Ring A, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined above.
优选地，式VI中，环A选自：
Figure PCTCN2021142177-appb-000039
Figure PCTCN2021142177-appb-000040
其中，R b选自：氘、C 1-C 6烷基、氘代C 1-C 6烷基、 卤代C 1-C 6烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 Preferably, in formula VI, ring A is selected from:
Figure PCTCN2021142177-appb-000039
Figure PCTCN2021142177-appb-000040
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.
优选地，式I-VI中，R 7选自：氢、氘、卤素、CF 3、CHF 2、OCF 3、OCHF 2、C 1-C 6烷基、N(CH 3) 2。 Preferably, in formulae I-VI, 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 .
优选地，式I-VI中，R 5、R 6和R 8各自独立地选自：氢、氘、卤素、C 1-C 6烷基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基，更优选，R 5、R 6和R 8各自独立地选自：氢、氘、卤素、C 1-C 6烷基、氰基。 Preferably, in formulas I-VI, 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.
优选地，式I-VI中，R 1选自取代或未取代的下组基团：NR 11R 11'、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、苯基或5-6元杂芳基；R 11和R 11'各自独立地选自取代或未取代的下组基团：H、C 1-C 6烷基、C 3-C 6环烷基，且R 11和R 11'不同时为H，其中，R 1、R 11和R 11'中所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Preferably, in formulas I-VI, 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 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 heteroaryl Cyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups;
R 3选自取代或未取代的下组基团：苯基或5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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选自：氢、氘、卤素、CF 3、CHF 2、OCF 3、OCHF 2、C 1-C 6烷基、N(CH 3) 2； 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和R 8各自独立地选自：氢、氘、卤素、C 1-C 6烷基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 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.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。The 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. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when 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". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process. The compounds 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.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸 盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等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, mesylate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salts, pectates, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonates, dodecanoates, etc.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。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.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。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.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。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.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, 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.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。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.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义 的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。 Specific functional groups and chemical term definitions are detailed below. For the purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。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.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. 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.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。 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. Examples of 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. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the aforementioned compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioisotopes of3H and14C , are also among them and are useful in drug and substrate tissue distribution experiments. Tritium, ie 3 H and carbon-14, ie 14 C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie 2 H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. 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.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If a synthesis of a particular enantiomer of a compound of the present invention is desired, it 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. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, 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.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明 中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. Generally, whether the term "substituted" appears before or after the term "optional", 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. When multiples of a particular structure are substituted at positions with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, the heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence. Furthermore, 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. As used herein, 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.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.
制备方法Preparation
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。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.
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。Typically, 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.
Figure PCTCN2021142177-appb-000041
Figure PCTCN2021142177-appb-000041
(i)在碱(如醋酸钠)存在下，式(P-1)化合物与式(Q)化合物反应，得到式(P-2)化合物；(i) reacting the compound of formula (P-1) with the compound of formula (Q) in the presence of a base (such as sodium acetate) to obtain the compound of formula (P-2);
(ii)在铜盐(如CuCl 2)存在下，式(P-2)化合物发生脱氢反应，得到式(P-3)化合物； (ii) in the presence of copper salt (such as CuCl 2 ), the compound of formula (P-2) undergoes a dehydrogenation reaction to obtain the compound of formula (P-3);
(iii)在碱(如LiOH)存在下，式(P-3)化合物水解得到式(P-4)化合物；(iii) in the presence of a base (such as LiOH), the compound of formula (P-3) is hydrolyzed to obtain the compound of formula (P-4);
(iv)式(P-4)化合物与胺(R)反应，得到式(I)化合物；(iv) the compound of formula (P-4) is reacted with amine (R) to obtain the compound of formula (I);
式中，X、Y、Z、U、R 1、R 2、R 3、R 5、R 6、R 7、和R 8定义如上所述。 In the formula, X, Y, Z, U, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 are as defined above.
上述反应步骤中，反应溶剂、反应催化剂、反应所用的碱、反应温度、反应时间等， 本领域技术人员可以根据具体的反应物进行选择。In the above reaction steps, the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc., can be selected by those skilled in the art according to the specific reactants.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。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.
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When co-administered, the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently. When the compound of formula I is administered concomitantly with one or more other drugs, 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. When a compound of formula I is administered in pharmaceutical combination with one or more other drugs, 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.
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003,KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622,OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。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, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX -148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocaltinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Caboza ntinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib , Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 Inhibitors (eg, RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。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.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。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. Usually, 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. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021142177-appb-000042
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "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)
Figure PCTCN2021142177-appb-000042
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。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 .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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 monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。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.
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, 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. Of course, 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.
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。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.
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制AhR。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.
与现有技术相比，本发明具有以下主要优点：Compared with the prior art, the present invention has the following main advantages:
(1)本发明化合物对AhR具有很好的选择性抑制作用；(1) The compound of the present invention has a good selective inhibitory effect on AhR;
(2)本发明化合物具有更好的药效学、药代动力学性能和更低的毒副作用。(2) The compounds of the present invention have better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental method of unreceipted specific conditions in the following examples, usually according to conventional conditions such as Sambrook et al., molecular cloning: conditions described in laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer the proposed conditions. Percentages and parts are by weight unless otherwise indicated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。 NMR was detected using a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was determined to include deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc., tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in units of parts per million (ppm).
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100x 3.0mm色谱柱)。Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. The HPLC assay was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。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.
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。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.
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。Unless otherwise specified, all the reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.
实施例Example
实施例1中间体的制备The preparation of embodiment 1 intermediate
实施例1-1(S)-N-(2-氨基丙基)甲磺酰胺盐酸盐的合成Example 1-1 (S)-N-(2-aminopropyl) methanesulfonamide hydrochloride synthesis
Figure PCTCN2021142177-appb-000043
Figure PCTCN2021142177-appb-000043
第一步：(S)-叔丁基(2-((叔丁氧羰基)氨基)丙基(甲磺酰基)氨基甲酸酯的制备The first step: preparation of (S)-tert-butyl(2-((tert-butoxycarbonyl)amino)propyl(methylsulfonyl)carbamate
将(S)-叔丁基(1-羟丙基-2-基)氨基甲酸酯(3.76g，21.49mmol)、甲基磺酰氨基甲酸叔丁酯(4.61g，23.63mmol)和三苯基膦(7.32g，27.93mmol)溶于75毫升无水四氢呋喃中，冰浴冷却后缓慢滴加偶氮二甲酸二异丙酯(5.5mL,27.93mmol)，维持内温不高于10度。滴加完毕后，反应液室温搅拌16小时后浓缩。残留物以硅胶柱纯化(石油醚：乙酸乙酯＝20：1到10：1)，得目标产物(5.76g，收率：76％)。Combine (S)-tert-butyl(1-hydroxypropyl-2-yl)carbamate (3.76 g, 21.49 mmol), tert-butyl methylsulfonylcarbamate (4.61 g, 23.63 mmol) and triphenyl Phosphine (7.32 g, 27.93 mmol) was dissolved in 75 mL of anhydrous tetrahydrofuran, and after cooling in an ice bath, diisopropyl azodicarboxylate (5.5 mL, 27.93 mmol) was slowly added dropwise to maintain the inner temperature not higher than 10 degrees. After the dropwise addition, the reaction solution was stirred at room temperature for 16 hours and then concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=20:1 to 10:1) to obtain the target product (5.76 g, yield: 76%).
第二步：(S)-N-(2-氨基丙基)甲磺酰胺盐酸盐的制备The second step: the preparation of (S)-N-(2-aminopropyl) methanesulfonamide hydrochloride
将(S)-叔丁基(2-((叔丁氧羰基)氨基)丙基(甲磺酰基)氨基甲酸酯(5.76g，16.36mmol)溶解在12毫升二氯甲烷中，加入氯化氢/乙酸乙酯溶液(约5M，80mL)。反应液室温搅拌4小时后旋干。残留物冷冻干燥，得到目标产物(2.9g，收率：94％)。(S)-tert-Butyl(2-((tert-butoxycarbonyl)amino)propyl(methylsulfonyl)carbamate (5.76 g, 16.36 mmol) was dissolved in 12 mL of dichloromethane, and hydrogen chloride/ Ethyl acetate solution (about 5M, 80 mL). The reaction solution was stirred at room temperature for 4 hours and then spin-dried. The residue was freeze-dried to obtain the target product (2.9 g, yield: 94%).
LC-MS：m/z 153(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.21(brs,3H),7.46(t,J＝6.0Hz,1H),3.30-3.05(m,3H),2.96(s,3H),1.20(d,J＝6.8Hz,3H). LC-MS: m/z 153 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (brs, 3H), 7.46 (t, J=6.0 Hz, 1H), 3.30-3.05 (m, 3H), 2.96 (s, 3H), 1.20 (d, J=6.8Hz, 3H).
按照实施例1-1的方法，以不同的起始原料合成了以下化合物：According to the method of Example 1-1, the following compounds were synthesized with different starting materials:
实施例1-2(S)-N-(2-氨基丙基)环丙基磺酰胺盐酸盐的合成Example 1-2 (S)-N-(2-aminopropyl) cyclopropylsulfonamide hydrochloride synthesis
Figure PCTCN2021142177-appb-000044
Figure PCTCN2021142177-appb-000044
LC-MS：m/z 179(M+H) +。 1H NMR(400MHz,DMSO)δ8.17(brs,3H),7.51(t,J＝5.9Hz,1H),3.29–3.16(m,2H),3.12(m,1H),2.65–2.56(m,1H),1.21(d,J＝6.1Hz,3H),1.02–0.84(m,4H). LC-MS: m/z 179 (M+H) + . 1 H NMR(400MHz, DMSO)δ8.17(brs,3H),7.51(t,J=5.9Hz,1H),3.29-3.16(m,2H),3.12(m,1H),2.65-2.56(m ,1H),1.21(d,J＝6.1Hz,3H),1.02–0.84(m,4H).
实施例2(S)-6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-N-(1-(甲磺酰胺基)丙烷-2-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 2(S)-6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(methanesulfonamido)propane-2- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000045
Figure PCTCN2021142177-appb-000045
第一步：6-(4-氯苯基)-2-(1-(甲基-d3)-1H-吡唑-4-基)-3-氧-2,3,4,5-四氢哒嗪-4-甲酸甲酯的制备The first step: 6-(4-chlorophenyl)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydro Preparation of methyl pyridazine-4-carboxylate
将2-(2-(4-氯苯基)-2-氧乙基)丙二酸二甲酯(350.0mg,1.23mmol)加入到乙酸(7mL)中，随后依次加入醋酸钠(504.2mg,6.15mmol)和4-肼基-1-甲基-1H-吡唑(500.5mg,2.21mmol)。加完后反应液在室温搅拌1h，然后50度搅拌过夜。得到的反应液浓缩后，加入过量碳酸氢钠溶液调pH为8，然后用乙酸乙酯(3x 30mL)萃取。合并的有机相用饱和氯化钠洗一次，然后用无水硫酸钠干燥后浓缩干。残余物用制备液相分离，得到目标产物(275mg，产率64％)。Dimethyl 2-(2-(4-chlorophenyl)-2-oxoethyl)malonate (350.0 mg, 1.23 mmol) was added to acetic acid (7 mL) followed by sodium acetate (504.2 mg, 6.15 mmol) and 4-hydrazino-1-methyl-1H-pyrazole (500.5 mg, 2.21 mmol). After the addition, the reaction solution was stirred at room temperature for 1 h, and then at 50°C overnight. After the resulting reaction solution was concentrated, excess sodium bicarbonate solution was added to adjust the pH to 8, and then extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated to dryness. The residue was separated by preparative liquid phase to give the desired product (275 mg, 64% yield).
LC-MS：m/z 347(M+H) +。 LC-MS: m/z 347 (M+H) + .
第二步：6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酸甲酯的制备The second step: 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester preparation
将6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-3-氧-2,3,4,5-四氢哒嗪-4-甲酸甲酯(275mg，0.79mmol)加入到乙腈(15mL)中，加入无水氯化铜(405.6mg,2.38mmol)。加完后反应升温至90℃搅拌2h。混合物降至室温，减压浓缩除去溶剂。残余物加入10mL水后过滤，滤饼用水洗三次后真空干燥。得到的目标产物无需进一步纯化，直接用于下一步反应。6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl The ester (275 mg, 0.79 mmol) was added to acetonitrile (15 mL) and anhydrous copper chloride (405.6 mg, 2.38 mmol) was added. After the addition, the reaction was heated to 90°C and stirred for 2h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was filtered by adding 10 mL of water, and the filter cake was washed three times with water and dried in vacuo. The obtained target product was directly used in the next reaction without further purification.
LC-MS：m/z 345(M+H) +。 LC-MS: m/z 345 (M+H) + .
第三步：6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酸的制备The third step: preparation of 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
将上一步得到的6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酸甲酯溶于THF(5.0mL)中，再将LiOH·H 2O(120.0mg,2.87mmol)的水溶液(1.0mL)滴加到反应体系中。得到的反应液在室温搅拌1.0h，然后过滤除去不溶物，用THF洗涤固体。合并的滤液浓缩后用HCl水溶液(1M)调节pH至3-4，然后用乙酸乙酯萃取(3x 10mL)。合并的有机相用饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，得到目标产物(146mg， 两步产率55.8％)。无需进一步纯化，直接用于下一步反应。 6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl obtained in the previous step The ester was dissolved in THF (5.0 mL), and an aqueous solution (1.0 mL) of LiOH·H 2 O (120.0 mg, 2.87 mmol) was added dropwise to the reaction system. The resulting reaction solution was stirred at room temperature for 1.0 h, then filtered to remove insoluble matter, and the solid was washed with THF. The combined filtrates were concentrated and adjusted to pH 3-4 with aqueous HCl (1 M), then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product (146 mg, 55.8% in two-step yield). It was used directly in the next reaction without further purification.
LC-MS：m/z 331(M+H) +。 LC-MS: m/z 331 (M+H) + .
第四步：(S)-6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-N-(1-(甲磺酰胺基)丙烷-2-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备The fourth step: (S)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(methanesulfonamido)propane-2 -yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide preparation
将6-(4-氯苯基)-2-(1-甲基-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酸(70.0mg，0.21mmol)溶于DMF(2.0mL)中，依次加入(S)-N-(2-氨基丙基)甲磺酰胺盐酸盐(79mg,0.42mmol)、DIPEA(0.1mL,0.63mmol)和HATU(160.9mg,0.42mmol)。反应液在室温搅拌15min，然后加入水(5mL)淬灭后用乙酸乙酯萃取(3x 5mL)。合并的有机相用饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩。得到的残余物用液相分离，得目标产物(5.0mg，产率5％)。6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (70.0 mg, 0.21 mmol) was dissolved in DMF (2.0 mL), followed by (S)-N-(2-aminopropyl)methanesulfonamide hydrochloride (79 mg, 0.42 mmol), DIPEA (0.1 mL, 0.63 mmol) and HATU ( 160.9 mg, 0.42 mmol). The reaction was stirred at room temperature for 15 min, then quenched by the addition of water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated by liquid phase to obtain the target product (5.0 mg, yield 5%).
LC-MS：m/z 465(M+H) +。 1H NMR(400MHz,DMSO)δ9.38(d,J＝8.0Hz,1H),8.56(d,J＝6.9Hz,2H),8.17–8.06(m,3H),7.60(d,J＝8.6Hz,2H),7.21(m,1H),4.21–4.07(m,1H),3.93(s,3H),3.12(m,2H),2.91(s,3H),1.21(t,J＝9.3Hz,3H). LC-MS: m/z 465 (M+H) + . 1 H NMR (400MHz, DMSO)δ9.38(d,J=8.0Hz,1H),8.56(d,J=6.9Hz,2H),8.17-8.06(m,3H),7.60(d,J=8.6 Hz, 2H), 7.21(m, 1H), 4.21–4.07(m, 1H), 3.93(s, 3H), 3.12(m, 2H), 2.91(s, 3H), 1.21(t, J=9.3Hz , 3H).
按照实施例2的方法，以不同的起始原料合成了以下化合物：According to the method of Example 2, the following compounds were synthesized with different starting materials:
实施例3(S)-6-(4-氯苯基)-2-(1-甲基-1H-吡唑-5-基)-N-(1-(甲磺酰胺基)丙烷-2-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 3 (S)-6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-5-yl)-N-(1-(methanesulfonamido)propane-2- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000046
Figure PCTCN2021142177-appb-000046
LC-MS：m/z 465(M+H) +。 1H NMR(400MHz,DMSO)δ9.11(d,J＝8.0Hz,1H),8.64(s,1H),7.97(d,J＝8.6Hz,2H),7.67–7.51(m,3H),7.20(t,J＝6.1Hz,1H),6.56(d,J＝2.0Hz,1H),4.12(dq,J＝13.0,6.5Hz,1H),3.73(s,3H),3.10(t,J＝5.8Hz,2H),2.89(s,3H),1.20(d,J＝6.7Hz,3H). LC-MS: m/z 465 (M+H) + . 1 H NMR(400MHz,DMSO)δ9.11(d,J=8.0Hz,1H),8.64(s,1H),7.97(d,J=8.6Hz,2H),7.67-7.51(m,3H), 7.20(t,J＝6.1Hz,1H),6.56(d,J＝2.0Hz,1H),4.12(dq,J＝13.0,6.5Hz,1H),3.73(s,3H),3.10(t,J ＝5.8Hz, 2H), 2.89(s, 3H), 1.20(d, J＝6.7Hz, 3H).
实施例4(S)-6-(4-氯苯基)-N-(1-(环丙基磺酰胺基)丙烷-2-基)-2-(1-甲基-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 4 (S)-6-(4-Chlorophenyl)-N-(1-(cyclopropylsulfonamido)propan-2-yl)-2-(1-methyl-1H-pyrazole- Preparation of 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000047
Figure PCTCN2021142177-appb-000047
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ9.37(d,J＝8.0Hz,1H),8.57(d, J＝7.9Hz,2H),8.16–8.05(m,3H),7.59(t,J＝8.8Hz,2H),7.28(t,J＝6.2Hz,1H),4.21–4.06(m,1H),3.93(s,3H),3.16(m,2H),2.53(m,1H),1.23(d,J＝6.6Hz,3H),0.89(m,4H). LC-MS: m/z 491 (M+H) + . 1 H NMR(400MHz, DMSO)δ9.37(d,J=8.0Hz,1H),8.57(d,J=7.9Hz,2H),8.16-8.05(m,3H),7.59(t,J=8.8 Hz, 2H), 7.28(t, J＝6.2Hz, 1H), 4.21–4.06(m, 1H), 3.93(s, 3H), 3.16(m, 2H), 2.53(m, 1H), 1.23(d ,J=6.6Hz,3H),0.89(m,4H).
实施例5(S)-6-(4-氯苯基)-N-(1-(环丙基磺酰胺基)丙烷-2-基)-2-(1-甲基-1H-吡唑-5-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 5 (S)-6-(4-Chlorophenyl)-N-(1-(cyclopropylsulfonamido)propan-2-yl)-2-(1-methyl-1H-pyrazole- Preparation of 5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000048
Figure PCTCN2021142177-appb-000048
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ9.11(d,J＝8.0Hz,1H),8.64(s,1H),7.98(d,J＝8.6Hz,2H),7.65–7.52(m,3H),7.27(s,1H),6.55(d,J＝1.9Hz,1H),4.19–4.06(m,1H),3.72(s,3H),3.22–3.06(m,2H),2.60–2.52(m,1H),1.21(d,J＝7.6Hz,3H),0.98–0.81(m,4H). LC-MS: m/z 491 (M+H) + . 1 H NMR(400MHz, DMSO)δ9.11(d,J=8.0Hz,1H),8.64(s,1H),7.98(d,J=8.6Hz,2H),7.65-7.52(m,3H), 7.27(s, 1H), 6.55(d, J=1.9Hz, 1H), 4.19-4.06(m, 1H), 3.72(s, 3H), 3.22-3.06(m, 2H), 2.60-2.52(m, 1H), 1.21(d, J=7.6Hz, 3H), 0.98–0.81(m, 4H).
实施例6(S)-6-(4-氯苯基)-N-(1-(环丙基磺酰胺基)丙烷-2-基)-2-(1-(甲基-d3)-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 6(S)-6-(4-Chlorophenyl)-N-(1-(cyclopropylsulfonamido)propan-2-yl)-2-(1-(methyl-d3)-1H - Preparation of pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000049
Figure PCTCN2021142177-appb-000049
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ9.37(d,J＝8.0Hz,1H),8.56(d,J＝7.7Hz,2H),8.17–8.05(m,3H),7.60(d,J＝8.6Hz,2H),7.28(m,1H),4.22–4.06(m,1H),3.15(m,2H),2.56(m,1H),1.22(t,J＝7.4Hz,3H),1.00–0.86(m,4H). LC-MS: m/z 494 (M+H) + . 1 H NMR (400MHz, DMSO)δ9.37(d,J=8.0Hz,1H),8.56(d,J=7.7Hz,2H),8.17-8.05(m,3H),7.60(d,J=8.6 Hz, 2H), 7.28 (m, 1H), 4.22–4.06 (m, 1H), 3.15 (m, 2H), 2.56 (m, 1H), 1.22 (t, J=7.4Hz, 3H), 1.00–0.86 (m,4H).
实施例7(S)-6-(4-氯苯基-2,3,5,6-d4)-N-(1-(环丙基磺酰胺基)丙烷-2-基)-2-(1-(甲基-d3)-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 7(S)-6-(4-Chlorophenyl-2,3,5,6-d4)-N-(1-(cyclopropylsulfonamido)propan-2-yl)-2-( Preparation of 1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000050
Figure PCTCN2021142177-appb-000050
LC-MS：m/z 498(M+H) +。 LC-MS: m/z 498 (M+H) + .
实施例8(S)-6-(4-氯苯基)-N-(1-(甲磺酰胺基)丙烷-2-基)-2-(1-(甲基-d3)-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 8 (S)-6-(4-Chlorophenyl)-N-(1-(methanesulfonamido)propan-2-yl)-2-(1-(methyl-d3)-1H-pyridine Preparation of oxazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000051
Figure PCTCN2021142177-appb-000051
LC-MS：m/z 468(M+H) +。 LC-MS: m/z 468 (M+H) + .
实施例9(S)-6-(4-氯苯基-2,3,5,6-d4)-N-(1-(环丙基磺酰胺基)丙烷-2-基)-2-(1-(甲基-d3)-1H-吡唑-4-基)-3-氧-2,3-二氢哒嗪-4-甲酰胺的制备Example 9 (S)-6-(4-Chlorophenyl-2,3,5,6-d4)-N-(1-(cyclopropylsulfonamido)propan-2-yl)-2-( Preparation of 1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
Figure PCTCN2021142177-appb-000052
Figure PCTCN2021142177-appb-000052
LC-MS：m/z 472(M+H) +。 LC-MS: m/z 472 (M+H) + .
实施例10生物学测试评价Example 10 Biological Test Evaluation
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。The following biological test examples are further described to illustrate the present invention, but these examples are not meant to limit the scope of the present invention.
AhRβ-内酰胺酶的拮抗实验Antagonism experiment of AhRβ-lactamase
试剂的制备Preparation of reagents
(1)育种培养基：Opti-MEM,5％FBS,1uM sodium Pyruvate,0.1mM NEAA,4℃保存。(1) Breeding medium: Opti-MEM, 5% FBS, 1uM sodium Pyruvate, 0.1mM NEAA, stored at 4°C.
(2)实验培养基：Opti-MEM,0.1％BSA,1uM sodium Pyruvate,0.1mM NEAA,4℃保存.(2) Experimental medium: Opti-MEM, 0.1% BSA, 1uM sodium Pyruvate, 0.1mM NEAA, stored at 4°C.
实验步骤:Experimental steps:
第一天：first day:
涂覆试验板(试验前一天)Coated test panels (one day before test)
1)将25mg多聚-L-赖氨酸溶解于500mL DPBS中；1) 25mg poly-L-lysine was dissolved in 500mL DPBS;
2)加入20uL/孔，37℃，5％CO2孵育1-2小时；2) Add 20uL/well, incubate for 1-2 hours at 37°C, 5% CO2;
3)完全倾倒溶液，用50uL MEM清洗一次。3) Pour the solution completely and wash once with 50uL of MEM.
板上种植细胞seeding cells on plates
1)将CYP1A1-bla LS-180细胞系细胞从培养箱中取出；1) Remove the CYP1A1-bla LS-180 cell line cells from the incubator;
2)抽除培养基，加入2mL TrypLE/flask；2) Remove the culture medium and add 2 mL of TrypLE/flask;
3)将烧瓶置于37℃静置5-8分钟，使细胞分离；3) Place the flask at 37°C for 5-8 minutes to separate the cells;
4)加入10mL的播种培养基/烧瓶；4) Add 10 mL of seeding medium/flask;
5)将细胞混合物转移到50毫升无菌离心管中拌匀；5) Transfer the cell mixture to a 50 ml sterile centrifuge tube and mix well;
6)细胞计数，将细胞播散到细胞板；6) Cell counting, spreading the cells to the cell plate;
7)15K细胞/孔:每孔用30uL的培养基放入15K细胞；7) 15K cells/well: put 15K cells into each well with 30uL of culture medium;
8)用30uL的育种培养基在孔中播种，每孔采用生物膜多聚-D-赖氨酸384孔TC处理微板的Combi标准模式；8) Seed in the wells with 30uL of breeding medium, and each well adopts the Combi standard mode of biofilm poly-D-lysine 384-well TC-treated microplates;
9)37℃5％CO2孵育过夜。9) Incubate overnight at 37°C with 5% CO2.
第二天：the next day:
化合物给药Compound dosing
a)参比化合物准备a) Reference compound preparation
用DMSO在LDV平板中制备20剂量参比CH-223191。CH-223191的最大工作溶液为10mM的DMSO溶液。用Bravo进行2倍连续稀释。20 doses of reference CH-223191 were prepared in LDV plates with DMSO. The maximum working solution of CH-223191 is 10 mM in DMSO. 2-fold serial dilutions were performed with Bravo.
b)Max和Min Wellsb) Max and Min Wells
最大孔:10mM的DMSO标准CH-223191在LDV板；Largest well: 10mM DMSO standard CH-223191 in LDV plate;
最小孔:DMSO在LDV板。Smallest well: DMSO in LDV plate.
c)使用ECHO根据板映射将80个nL从LDV板传输到复合板(PE6008590)。c) Using ECHO to transfer 80 nL from LDV plate to composite plate (PE6008590) according to plate mapping.
d)使用Combi Stand模式，每孔加入20uL检测介质，按2000转/分离心2分钟，使其混合均匀。d) Using the Combi Stand mode, add 20uL of detection medium to each well, and centrifuge at 2000 rpm for 2 minutes to mix evenly.
e)细胞的饥饿处理e) starvation treatment of cells
利用Bravo将29uL的培养基转移到细胞板孔内；Use Bravo to transfer 29uL of medium into the cell plate wells;
使用Combi立式模式，每孔加入20uL的温试液，以300转/分离心1分钟；Using the Combi vertical mode, add 20uL of warm test solution to each well, and centrifuge at 300 rpm for 1 minute;
37℃5％CO2孵育1小时。Incubate for 1 hour at 37°C with 5% CO2.
f)化合物加入f) Compound addition
用Bravo将10uL稀释物或DMSO(4倍工作溶液)从复合板(PE6008590)转移至细胞板。10 uL of the dilution or DMSO (4x working solution) was transferred from the composite plate (PE6008590) to the cell plate using Bravo.
37℃5％CO2孵育1小时。Incubate for 1 hour at 37°C with 5% CO2.
g)受体激动剂加入g) Receptor agonist addition
用Bravo将10uL 4X ITE工作溶液(2nM)加到细胞板的所有孔。总检测体系为40uL/Well10 uL of 4X ITE working solution (2 nM) was added to all wells of the cell plate using Bravo. The total detection system is 40uL/Well
37℃5％CO2孵育4小时；Incubate for 4 hours at 37°C with 5% CO2;
在加入加载试剂之前，让板在室温下放置10分钟Allow the plate to sit at room temperature for 10 minutes before adding the loading reagent
h)最终测定条件h) Final assay conditions
最终孔:15k/孔Final hole: 15k/hole
最小值:0.1％DMSO溶液Minimum: 0.1% DMSO solution
Max:10uM CH-223191Max:10uM CH-223191
CH-223191 CRC:稀释2倍至10uM,20个点CH-223191 CRC: Dilute 2x to 10uM, 20 points
ITE终浓度:0.5nMITE final concentration: 0.5nM
第二天:添加检测缓冲液和读板Day 2: Add Assay Buffer and Read Plate
A.底物上载及读板A. Substrate upload and plate reading
a)按照试剂盒说明书存储和准备每种试剂a) Store and prepare each reagent according to the kit instructions
b)从-20℃冰箱中取出溶液A和溶液D。待完全解冻后，准备如下混合溶液b) Remove solution A and solution D from the -20°C refrigerator. After thawing completely, prepare the following mixed solution
c)将A溶液加到B溶液中，涡流好c) Add solution A to solution B, vortex well
d)将C溶液加入A和B混合物中，涡流良好d) Add solution C to A and B mixture, vortex well
e)将D溶液加入A、B、C溶液中，涡流好e) Add D solution to A, B, C solutions, vortex well
f)使用Combi小模式向每个板添加9.5uL最终溶液f) Add 9.5uL of final solution to each plate using Combi mini mode
g)室温下避光孵育至少1小时，读板。信号至少能工作3个小时。g) Incubate at room temperature for at least 1 hour in the dark, and read the plate. The signal can work for at least 3 hours.
B.用Envision读板B. Read the plate with Envision
Envision Reader设置Envision Reader settings
   WavelengthWavelength
Excitation FilterExcitation Filter 400400
Emission Filter 1Emission Filter 1 460460
Emission Filter 2Emission Filter 2 535535
Dichroic MirrorDichroic Mirror Beta lactamase D425/490Beta lactamase D425/490
本发明中实施例化合物对AhR的拮抗活性见表1。The antagonistic activities of the example compounds of the present invention to AhR are shown in Table 1.
表1本发明中实施例化合物抑制活性Table 1 Inhibitory activity of example compounds in the present invention
IC 50 IC50 (nM)(nM)
BAY-2416964BAY-2416964 6060
实施例2Example 2 8080
实施例3Example 3 >10000>10000
实施例4Example 4 4545
实施例5Example 5 28852885
实施例6Example 6 4949
从表1可以看出，本发明实施例化合物对于AhR显示出了很好的拮抗活性。It can be seen from Table 1 that the compounds of the examples of the present invention show good antagonistic activity against AhR.
大鼠药代动力学测试评价Evaluation of Pharmacokinetic Testing in Rats
雄性SD大鼠，体重220g左右，禁食过夜后，灌胃给予2mg/kg本发明化合物的溶液[CMC/TW80为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中本发明化合物的浓度。Male SD rats with a body weight of about 220 g were given a solution of 2 mg/kg of the compound of the present invention by gavage [CMC/TW80 as a carrier] after fasting overnight. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration of the compound of the present invention, respectively, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.
小鼠药代动力学测试评价Evaluation of Pharmacokinetic Testing in Mice
雄性ICR小鼠，体重20-30g左右，禁食过夜后，灌胃给予2mg/kg本发明化合物的溶液[CMC/TW80为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中本发明化合物的浓度。Male ICR mice with a body weight of about 20-30 g were fasted overnight and then intragastrically administered a solution of 2 mg/kg of the compound of the present invention [CMC/TW80 as a carrier]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration of the compound of the present invention, respectively, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (12)

  1. 具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：Sulfonamide compounds with the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:
    Figure PCTCN2021142177-appb-100001
    Figure PCTCN2021142177-appb-100001
    式中：where:
    X选自取代或未取代的下组基团：C 2-C 6亚烷基、C 3-C 10亚环烷基、4-10元亚杂环基、C 1-C 6亚烷基C 3-C 10亚环烷基或C 1-C 6亚烷基4-10元亚杂环基，其中，所述取代是指被一个或多个Ra取代； 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 Ra;
    Y选自：NH或NR 4，其中，R 4选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；其中，所述取代是指被一个或多个Ra取代； 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 Ra;
    Z选自：O、NH、NCN、NR 9，其中，R 9选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 8环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基；其中，所述取代是指被一个或多个Ra取代； 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 Ra;
    U选自：N或CR 10，其中，R 10选自：H、D或卤素； U is selected from: N or CR 10 , wherein, R 10 is selected from: H, D or halogen;
    R 1选自取代或未取代的下组基团：NH 2、NR 11R 11'、C 1-C 6烷基、C 3-C 10环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基，其中，所述取代是指被一个或多个Ra取代； 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 Ra;
    R 11和R 11'各自独立地选自取代或未取代的下组基团：H、C 1-C 6烷基、C 3-C 10环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基，且R 11和R 11'不同时为H，其中，所述取代是指被一个或多个Ra取代； 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 being substituted by one or more Ra;
    R 2选自取代或未取代的下组基团：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基； 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选自取代或未取代的下组基团：C 6-C 14芳基、5-14元杂芳基，其中，所述取代是指被一个或多个Ra取代； 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 substituted by one or more Ra;
    R 5、R 6和R 8各自独立地选自取代或未取代的下组基团：氢、氘、卤素、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，所述取代是指被一个或多个Ra取代； 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 Ra;
    R 7选自取代或未取代的下组基团：氢、氘、卤素、CF 3、CHF 2、OCF 3、OCHF 2、C 1-C 6烷基、C 3-C 8环烷基、4-10元杂环基、C 6-C 14芳基、5-14元杂芳基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，所述取代是指被一个或多个Ra取代； 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 Ra substitutions;
    Ra选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、 胺基、酰胺基、磺酰胺基或脲基，其中，Ra中所述取代是指被一个或多个选自下组的基团取代：氘、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 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 groups selected from the group consisting of deuterium, C1 - C6 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl, halogen, nitro , hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups.
  2. 如权利要求1所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(II)所示结构：The sulfonamide compound having the structure of general formula (I) as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or pro Medicine, is characterized in that, it has the structure shown in general formula (II):
    Figure PCTCN2021142177-appb-100002
    Figure PCTCN2021142177-appb-100002
    其中，in,
    X、Y、Z、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如权利要求1所述。 X, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined in claim 1 .
  3. 如权利要求1所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(III)所示结构：The sulfonamide compound having the structure of general formula (I) as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or pro Medicine, is characterized in that, it has the structure shown in general formula (III):
    Figure PCTCN2021142177-appb-100003
    Figure PCTCN2021142177-appb-100003
    其中，in,
    X、Y、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如权利要求1所述。 X, Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined in claim 1 .
  4. 如权利要求1所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式IV所示结构：The sulfonamide compound having the structure of general formula (I) as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or pro Medicine, is characterized in that, it has the structure shown in formula IV:
    Figure PCTCN2021142177-appb-100004
    Figure PCTCN2021142177-appb-100004
    其中，in,
    X、R 1、R 2、R 3、R 5、R 6、R 7、R 8和R 10的定义如权利要求1所述。 X, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined in claim 1 .
  5. 如权利要求1所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式V或V'所示结构：The sulfonamide compound having the structure of general formula (I) as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or pro Medicine, it is characterized in that, it has the structure shown in formula V or V':
    Figure PCTCN2021142177-appb-100005
    Figure PCTCN2021142177-appb-100005
    式中，In the formula,
    x为1、2、3或4；x is 1, 2, 3 or 4;
    R e、R f、R m和R n各自独立地选自：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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;
    或者R e和R f、R f和R m、R m和R n与其连接的C原子共同形成取代或未取代的下组基团：C 3-C 6亚环烷基、4-6元亚杂环基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Or 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, amido, sulfo amide group or urea group;
    R 12选自取代或未取代的下组基团：CN、C 1-C 6烷基、C 3-C 6环烷基、C 6-C 14芳基或5-14元杂芳基；其中，所述取代是指被所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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和R 10的定义如权利要求1所述。 R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 10 are as defined in claim 1 .
  6. 如权利要求1-5中任一项所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R 1选自取代或未取代的下组基团：NR 11R 11'、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、苯基或5-6元杂芳基；R 11和R 11'各自独立地选自取代或未取代的下组基团：H、C 1-C 6烷基、C 3-C 6环烷基，且R 11和R 11'不同时为H，其中，R 1、R 11和R 11'中所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；优选地，R 1选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基、卤代C 1-C 3烷基羟基、C 1-C 3烷氧基、氘代C 1-C 3烷氧基、卤代C 1-C 3烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 The sulfonamide compound having the structure of general formula (I) according to any one of claims 1-5, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates , solvate or prodrug, characterized in that 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 -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 group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido; preferably, 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 C 1 -C 3 alkyl, halo C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, deuterated C 1 - C3alkoxy, halogenated C1 - C3alkoxy , halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido.
  7. 如权利要求1-6中任一项所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R 3选自 取代或未取代的下组基团：苯基或5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 The sulfonamide compound having the structure of general formula (I) according to any one of claims 1-6, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates , solvate or prodrug, characterized in that R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to a group selected from the group consisting of One or more groups substituted: 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 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, amido, sulfonamide or ureido.
  8. 如权利要求1-7中任一项所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，
    Figure PCTCN2021142177-appb-100006
    部分选自：
    Figure PCTCN2021142177-appb-100007
    其中，R 7的定义如权利要求1所述。     The sulfonamide compound having the structure of general formula (I) according to any one of claims 1-7, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates , solvate or prodrug, characterized in that,
    Figure PCTCN2021142177-appb-100006
    Partially selected from:
    Figure PCTCN2021142177-appb-100007
    Wherein, the definition of R 7 is as described in claim 1.
  9. 如权利要求1所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：The sulfonamide compound having the structure of general formula (I) as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or pro medicine, characterized in that the compound is selected from the group consisting of:
    Figure PCTCN2021142177-appb-100008
    Figure PCTCN2021142177-appb-100008
    Figure PCTCN2021142177-appb-100009
    Figure PCTCN2021142177-appb-100009
  10. 一种制备通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，其特征在于，包括步骤：A method for preparing a sulfonamide compound of the structure of general formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, its It is characterized in that it includes the steps:
    Figure PCTCN2021142177-appb-100010
    Figure PCTCN2021142177-appb-100010
    (i)在碱存在下，式(P-1)化合物与式(Q)化合物反应，得到式(P-2)化合物；(i) reacting the compound of formula (P-1) with the compound of formula (Q) in the presence of a base to obtain the compound of formula (P-2);
    (ii)在铜盐存在下，式(P-2)化合物发生脱氢反应，得到式(P-3)化合物；(ii) in the presence of copper salt, the compound of formula (P-2) undergoes dehydrogenation reaction to obtain the compound of formula (P-3);
    (iii)在碱存在下，式(P-3)化合物水解得到式(P-4)化合物；(iii) in the presence of a base, the compound of formula (P-3) is hydrolyzed to obtain the compound of formula (P-4);
    (iv)式(P-4)化合物与胺(R)反应，得到式(I)化合物；(iv) the compound of formula (P-4) is reacted with amine (R) to obtain the compound of formula (I);
    式中，In the formula,
    X、Y、Z、U、R 1、R 2、R 3、R 5、R 6、R 7、和R 8定义如权利要求1所述。 X, Y, Z, U, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 are as defined in claim 1 .
  11. 一种药物组合物，其特征在于，包含i)一种或多种权利要求1-9中任一项所述通式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。A pharmaceutical composition, characterized in that, comprising i) one or more compounds of the general formula (I) structure described in any one of claims 1-9, its stereoisomers, tautomers, A crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug; and ii) a pharmaceutically acceptable carrier.
  12. 一种如权利要求1-9中任一项所述的具有通式(I)结构的磺酰胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或权利要求11所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与AhR介导的疾病的药物组合物。A sulfonamide compound having general formula (I) structure as described in any one of claims 1-9, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, The hydrate, solvate or prodrug, or use of the pharmaceutical composition according to claim 11, characterized in that it is used to prepare a pharmaceutical composition for preventing and/or treating diseases mediated by AhR.
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