Sulfonamide inhibitors and methods of making and using the same

Abstract

This invention relates to sulfonamide inhibitors, their preparation methods, and applications. Specifically, the compounds of this invention have the structure shown in formula (I). This invention also discloses the preparation method of the compounds and their use as AhR inhibitors. The compounds of this invention exhibit excellent selective inhibition of AhR and possess better pharmacodynamic and pharmacokinetic properties, as well as lower toxicity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a sulfonamide inhibitor, its preparation method, and its application. Background Technology

[0002] Aryl hydrocarbon receptors (AhRs) are ligand-activated transcription factors involved in the regulation of various cellular processes, including cell proliferation, metabolism, and immune regulation. AhRs can influence cell signaling by interacting with various regulatory and signaling proteins, including the PAS heterodimer chaperone ARNT (aryl hydrocarbon receptor nuclear transporter), chaperones and immune-like proteins (such as HSP90), AIP (aryl hydrocarbon receptor-interacting protein), p23, CK2 (casein kinase-2), and PKC (protein kinase-C). Furthermore, AhRs interact with hormone receptors, hypoxia, NF-κB, Rb protein-mediated signaling pathways, the MAPK signaling pathway, and the EGFR signaling pathway. Studies have shown high expression of AhRs in various tumors, including lung cancer, colorectal cancer, and head and neck squamous cell carcinoma, and it plays a crucial role in regulating immunosuppression in the tumor microenvironment. Preclinical studies have shown that continuously activated mice spontaneously generate tumors.

[0003] 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) endogenous AhR ligands may promote the development of Treg cells in the TME; (2) AhR promotes the differentiation of Th17 cells through multiple mechanisms; on the other hand, AhR regulates the expression of Th17 cells by binding to the DRE site on the Th17 promoter; AhR can also synergistically induce the expression of Aiolos (IKZF3), a member of the Ikaros family, by Stat3, reduce the expression of IL-2, and promote the generation of Th17 cells; (3) the interaction between AhR and c-Maf is crucial for the development of Tr1-regulated cells in mice and humans; (4) AhR regulates B cell differentiation by inhibiting the transcription of early B cell genes EBF1 and PAX5. Cells in the immune system are constantly exposed to endogenous and exogenous AhR ligands, which can interfere with physiological functions, alter immune homeostasis, and develop into inflammatory diseases, autoimmune diseases, and cancer. Inhibition of AhR can make immunotherapy more effective by reducing immunosuppression.

[0004] Exogenous ligands such as PAHs (polycyclic aromatic hydrocarbons), dioxins (e.g., TCDD), and polychlorinated biphenyls (PCBs) are the culprits behind most toxic reactions. Upon binding to these environmental toxins, AhR induces metabolic mechanisms such as cytochrome p450 enzymes (CYP1A1, CYP1A2, and CYP1B1) to eliminate these toxins. Studies have shown that activation of AhR by exogenous ligands such as TCDD has been demonstrated to play a role in many cellular processes, such as embryogenesis, tumorigenesis, and inflammation.

[0005] In addition to exogenous ligands, AhR can also bind to tryptophan degradation metabolites. 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 have been well-documented and are involved 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 the first and rate-limiting steps of tryptophan metabolism. In animal models, reducing antitumor immune responses and inhibiting IDO can suppress tumor formation. TDO2 is also strongly expressed in cancer, leading to the production of immunosuppressive kynurenine. In gliomas, kynurenine activates AhR, inhibiting antitumor immune responses by mediating downstream tryptophan degradation and directly promoting tumor cell survival and activity, thereby promoting tumor growth. Therefore, AhR ligands produced by tumor cells act on tumor cells and lymphocytes in both autocrine and paracrine modes, promoting tumor growth.

[0006] Because AhR targets are pathologically associated with a variety of diseases, there is a current need for novel AhR inhibitors for clinical treatment. Highly selective and highly active AhR inhibitors have the potential to more effectively treat diseases such as cancer mediated by AhR abnormalities, and also reduce off-target effects, thus creating a more urgent clinical need. Summary of the Invention

[0007] The purpose of this invention is to provide a novel class of compounds that selectively inhibit AhR and / or have better pharmacodynamic properties, and their uses.

[0008] In a first aspect, the present invention provides a sulfonamide compound having the general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs:

[0009]

[0010] In the formula:

[0011] X is selected from the following group, whether substituted or unsubstituted: C2-C6 alkylene, C3-C6 alkylene, C4-C6 alkylene, C5-C6 alkylene, C6 ... 10 Cycloalkylene, 4-10 membered heterocyclic alkylene, C1-C6 alkylene, C3-C 10 Cycloalkylene or C1-C6 alkylene 4-10-membered heterocyclic alkylene, wherein the substitution refers to substitution by one or more (e.g., 2, 3 or 4) Ra;

[0012] Y is selected from: NH or NR 4 , where R 4 Selected from the following group of substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more (such as 2, 3 or 4) Ra;

[0013] Z is selected from: O, NH, NCN, NR 9 , where R 9 Selected from the following groups, whether substituted or unsubstituted: C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclic groups, C6-C 14 Aryl or 5-14 heteroaryl; wherein, the substitution refers to substitution by one or more (e.g., 2, 3 or 4) Ra;

[0014] U is selected from: N or CR 10 , where R 10 Selected from: H, D, or halogens;

[0015] R 1 Selected from the following groups, substituted or unsubstituted: NH2, NR 11 R 11 ', C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 14 Aryl or 5-14 heteroaryl, wherein the substitution refers to being substituted by one or more (e.g., 2, 3 or 4) Ra;

[0016] R 11 and R 11 Each group is independently selected from the following group: substituted or unsubstituted: H, C1-C6 alkyl, C3-C6 alkyl. 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 14 Aryl or 5-14 heteroaryl, and R 11 and R 11 'Not simultaneously H, wherein the substitution refers to being replaced by one or more (e.g., 2, 3 or 4) Ra;

[0017] R 2 Selected from the following groups, whether substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl;

[0018] R 3 Selected from the following group of substituent or unsubstituted groups: C6-C 14 Aryl, 5-14 heteroaryl, wherein the substitution refers to being substituted by one or more (e.g., 2, 3 or 4) Ra;

[0019] R 5 R 6 and R 8 Each group is independently selected from the following group, whether substituted or unsubstituted: hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, cyano, ester, amino, amide, sulfonamide, or urea; wherein, the substitution refers to being substituted by one or more (e.g., 2, 3, or 4) Ra.

[0020] R 7 Selected from the following groups, whether substituted or unsubstituted: hydrogen, deuterium, halogen, CF3, CHF2, OCF3, OCHF2, C1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclic groups, C6-C 14 Aryl, 5-14 heteroaryl, cyano, ester, amino, amide, sulfonamide, or urea; wherein the substitution refers to being substituted by one or more (e.g., 2, 3, or 4) Ra.

[0021] Ra is selected from the following group of groups, whether substituted or unsubstituted: hydrogen, deuterium, C1-C. 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl hydroxyl, C3-C 20 cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C6-C 14 Aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea, wherein the substitution described in Ra refers to substitution by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6-membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0022] In another preferred embodiment, Ra is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C8 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C 10Aryl, 5-10-membered heteroaryl, 4-8-membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea, wherein the substitution described in Ra refers to substitution by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6-membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0023] In another preferred embodiment, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in general formula (II):

[0024]

[0025] X, Y, Z, R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0026] In another preferred embodiment, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in general formula (III):

[0027]

[0028] X, Y, R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0029] In another preferred embodiment, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula (IV):

[0030]

[0031] X, R 1 R 2 R 3 R 5 R 6 R7 R 8 and R 10 The definition is as described above.

[0032] In another preferred embodiment, the sulfonamide compound having the general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula V or V':

[0033]

[0034] In the formula,

[0035] x is 1, 2, 3 or 4;

[0036] R e R f R m and R n Each is independently selected from: hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide or urea;

[0037] Or R e and R f R f and R m R m and R n The C atom attached to it forms a substituted or unsubstituted group from the following group: C3-C6 cycloalkylene, 4-6 membered heterocyclic alkylene, wherein the substitution refers to substitution by one or more groups selected from the following group: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxyl, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide or urea;

[0038] R 12 Selected from the following groups, whether substituted or unsubstituted: CN, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 14Aryl or 5-14 heteroaryl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea;

[0039] R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0040] In another preferred embodiment, the sulfonamide compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula (VI):

[0041]

[0042] In the formula,

[0043] Ring A is a substituted or unsubstituted group from the following group: C3-C6 cycloalkylene, 4-6 membered heterocyclic alkylene, wherein the substitution refers to being substituted by one or more groups selected from the following group: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide or urea;

[0044] R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0045] In another preferred embodiment, ring A is selected from: Among them, R bSelected from: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0046] In another preferred embodiment, in the above formulas, R 1 Selected from the following group of substituent or unsubstituted groups: NR 11 R 11 ', C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl; R 11 and R 11 Each group is independently selected from the following group, either substituted or unsubstituted: H, C1-C6 alkyl, C3-C6 cycloalkyl, and R 11 and R 11 'Not both H, where R 1 R 11 and R 11 The substitution referred to herein means substitution by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0047] In another preferred embodiment, in the above formulas, R 1 The group is selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to being substituted by one or more groups selected from the following group: deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkyl hydroxyl, C1-C3 alkoxy, deuterated C1-C3 alkoxy, halo-C1-C3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide or urea.

[0048] In another preferred embodiment, the sulfonamide compound having the general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, R 3Selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0049] In another preferred embodiment, Partially selected from: Among them, R 7 The definition is as described above.

[0050] In another preferred embodiment, 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 Ring A represents the functional group corresponding to each specific compound in the examples.

[0051] In another preferred embodiment, the sulfonamide compound having the general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs are selected from the group consisting of:

[0052]

[0053]

[0054] In another preferred embodiment, the compound is selected from the compounds shown in the examples.

[0055] In a second aspect, the present invention provides a method for preparing sulfonamide compounds of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, the method comprising the steps of:

[0056]

[0057] (i) In the presence of a base, compound (P-1) reacts with compound (Q) to give compound (P-2);

[0058] (ii) In the presence of copper salt, compound (P-2) undergoes a dehydrogenation reaction to give compound (P-3);

[0059] (iii) In the presence of a base, the compound of formula (P-3) is hydrolyzed to give the compound of formula (P-4);

[0060] (iv) The compound of formula (P-4) reacts with an amine (R) to give the compound of formula (I);

[0061] In the formula,

[0062] X, Y, Z, U, R 1 R 2 R 3 R 5 R 6 R 7 and R 8 Defined as described above.

[0063] In a third aspect, the present invention provides a pharmaceutical composition comprising i) one or more compounds of the general formula (I) described in the first aspect, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs; and ii) a pharmaceutically acceptable carrier.

[0064] 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), PD-L1 inhibitors (such as duvamarab, 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, olibutuzumab, veltuzumab, etc.),Tosimomab, 131I-Tosimomab, Tiimomab, 90Y-Tiimomab, 90In-Tiimomab, Tiimomab (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, oxcarbatinib), PI3K inhibitors (such as ederaris, duvelisib, dactolisib, Tas Elisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, cannatinib, saprotinib, naquotinib, pyrotinib, roximateb, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, bimiralisib, omepatinib, dacomitinib, icotinib, cannatinib, saprotinib, naquotinib, pyrotinib, roximateb, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, tebu ... (Examples of inhibitors include: fenofib, pazopanib, regorafenib, stratinib, ningetinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entenotide, dacistar, quisinostat, tebuconazole, etc.), and CDK inhibitors (such as palbociclib, ribociclib, abemaciclib, milciclib, triamcinolone, etc.). Inhibitors include laciclib, lerociclib, MEK inhibitors (such as selmetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), mTOR inhibitors (such as vistusertib), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155), or combinations thereof.

[0065] In a fourth aspect, the present invention provides the use of a sulfonamide compound having the general formula (I) of the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition of the third aspect, for the preparation of a pharmaceutical composition for the prevention and / or treatment of AhR-mediated diseases.

[0066] In another preferred embodiment, the disease is a tumor or a disorder.

[0067] 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, stomach cancer, liver cancer, colon cancer, melanoma, lymphoma, leukemia, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

[0068] In a fifth aspect of the invention, a method for inhibiting AhR is provided, comprising the steps of: administering to a desired patient an effective amount of a compound of general formula (I) of the first aspect of the invention, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering a pharmaceutical composition of the third aspect of the invention. Attached Figure Description

[0069] none Detailed Implementation

[0070] Through long-term and in-depth research, the inventors unexpectedly discovered a new class of compounds that selectively inhibit AhR and / or have better pharmacodynamic properties. Based on this, the inventors completed this invention.

[0071] the term

[0072] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0073] The term "alkyl" refers to a straight-chain, branched, or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, with a particular emphasis on 1-18 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. Amyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.

[0074] The term "C1-C18 alkyl" refers to straight-chain, branched, or cyclic alkyl groups, including those with 1-18 carbon atoms, such as methyl, ethyl, propyl, and isopropyl. n-Butyl, tert-Butyl, isobutyl (e.g.) ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "Substituted alkyl" refers to an alkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)Re S(=O)2R e P(=O)2R e S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR 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)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings, can be optionally substituted.

[0075] The term "alkylene" refers to a group formed by removing one hydrogen atom from an alkyl group, such as methylene, ethylene, propylene, and isopropylene (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as )wait.

[0076] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group comprising 1-4 rings, each containing 3-8 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, 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 b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR 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)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2Re R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e The group can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings. The aforementioned typical substituents can be optionally substituted. Typical substitutions also include spirocyclic, bridged-cyclic, or fused-ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocyclic (excluding heteroaromatic rings), bridged-cyclic alkyl, bridged-cyclic alkenyl, bridged-cyclic heterocyclic (excluding heteroaromatic rings), fused-cyclic alkyl, fused-cyclic alkenyl, fused-cyclic heterocyclic, or fused-cyclic aromatic rings, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted. Any two or more atoms on the ring can be further cyclically linked with other cycloalkyl, heterocyclic, aryl, and heteroaromatic groups.

[0077] The term "cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as:

[0078] wait.

[0079] The term "heterocyclic group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic rings, 6-11 membered bicyclic rings, or 8-16 membered tricyclic systems) in which at least one heteroatom is present in a ring containing at least one carbon atom. Each heterocycle containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon residue in a ring or cyclic molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups, wherein any two or more atoms on the ring can be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0080] The term "subheterocyclic group" refers to a group formed by removing two or more hydrogen atoms from a heterocyclic group, such as: etc. Among them, the H in NH can be further substituted; when substituted, the substituents are preferably alkyl, deuteralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl.

[0081] The terms "C1-C6 alkylene C3-C10 cycloalkylene" or "C3-C10 cycloalkylene C1-C6 alkylene" have the same meaning, referring to groups formed by removing two hydrogen atoms from cycloalkyl or alkylcycloalkyl groups, such as... wait.

[0082] The terms "C1-C6 alkylene 4-10 heterocyclic alkylene" or "4-10 heterocyclic C1-C6 alkylene" have the same meaning, referring to a heterocyclic alkyl group or an alkyl heterocyclic group formed by removing two hydrogen atoms, such as... wait.

[0083] The term "aryl" refers to an aromatic cyclic hydrocarbon compound group having 1-5 rings, particularly monocyclic and bicyclic groups such as phenyl, biphenyl, or naphthyl. Any aryl group containing two or more aromatic rings (bicyclic, etc.) can have its aromatic rings linked by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). "Substituted aryl" refers to an aryl group where one or more positions are substituted, particularly 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogens (e.g., monohalogenated or polyhalogenated substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, 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 b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR 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)NR b R c NR d S(=O)2NR b R c NR dP(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings. The above-mentioned typical substituents can be optionally substituted. Typical substitutions also include fused-ring substituents, especially fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aromatic rings, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0084] The term "heteroaryl" refers to a heteroaryl system comprising 1-4 heteroatoms and 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. Heteroaryl groups are preferably 5- to 10-membered rings, more preferably 5- or 6-membered, such as pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0085] The term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0086] The term "halogenation" refers to the replacement of a substance with a halogen.

[0087] The term "deuteration" refers to being replaced by deuterium.

[0088] The term "hydroxyl group" refers to a group containing the structure OH.

[0089] The term "nitro" refers to a group containing the structure NO2.

[0090] The term "cyano" refers to a group containing the structure CN.

[0091] The term "ester group" 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, heterocyclic or substituted heterocyclic.

[0092] The term "amine" refers to a group with 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, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0093] The term "amide group" 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, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0094] The term "sulfonamide group" refers to a group with the structure -SO2NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0095] The term "ureido" refers to a group with 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, heterocyclic or substituted heterocyclic, as defined above. R, R', and R" can be the same or different in dialkylamine segments.

[0096] 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, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different.

[0097] 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, heterocyclic or substituted heterocyclic, as defined above. R, R', and R" can be the same or different in the dialkylamine segment.

[0098] The term "heterocyclic alkyl" refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, a cycloalkyl or substituted cycloalkyl, a cycloalkenyl or substituted cycloalkenyl, an aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.

[0099] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureyl groups, etc.

[0100] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0101] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0102] Active ingredients

[0103] As used herein, “compound of the present invention” refers to a compound of formula I, and also includes stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of a compound of formula I.

[0104] The compound of formula I has the following structure:

[0105]

[0106] In the formula,

[0107] X, Y, Z, R 1 R 2 R 3 R 5 R 6 R 7 R 8 The definitions of U are as described above.

[0108] Preferably, the compound has the structure shown in general formula (II):

[0109]

[0110] in,

[0111] X, Y, Z, R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0112] Preferably, the compound has the structure shown in general formula (III):

[0113]

[0114] in,

[0115] X, Y, R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0116] Preferably, the compound has the structure shown in Formula IV:

[0117]

[0118] in,

[0119] X, R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0120] Preferably, the compound has the structure shown in formula V or V':

[0121]

[0122] in,

[0123] x、R 1 R 2 R 3 R 5 R6 R 7 R 8 R 10 R 12 R e R f R m and R n The definition is as described above.

[0124] Preferably, the compound has the structure shown in Formula VI:

[0125]

[0126] in,

[0127] Rings A and R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 10 The definition is as described above.

[0128] Preferably, in formula VI, ring A is selected from: Among them, R b Selected from: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0129] Preferably, in formulas I-VI, R 7 Selected from: hydrogen, deuterium, halogen, CF3, CHF2, OCF3, OCHF2, C1-C6 alkyl, N(CH3)2.

[0130] Preferably, in formulas I-VI, R 5 R 6 and R 8 Each group is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, cyano, ester, amino, amide, sulfonamide, or urea, more preferably, R 5 R 6 and R 8 Each is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, cyano.

[0131] Preferably, in formulas I-VI, R 1 Selected from the following group of substituent or unsubstituted groups: NR 11 R 11', C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl; R 11 and R 11 Each group is independently selected from the following group, either substituted or unsubstituted: H, C1-C6 alkyl, C3-C6 cycloalkyl, and R 11 and R 11 'Not both H, where R 1 R 11 and R 11 The substitution referred to herein means substitution by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide or urea;

[0132] R 3 Selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amino, amide, sulfonamide or urea;

[0133] R 7 Selected from: hydrogen, deuterium, halogen, CF3, CHF2, OCF3, OCHF2, C1-C6 alkyl, N(CH3)2;

[0134] R 5 R 6 and R 8 Each group is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, cyano, ester, amino, amide, sulfonamide, or urea.

[0135] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0136] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0137] Some compounds of this invention may contain acidic fragments, 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, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0138] The prodrugs and solvates of the compounds in this invention are also included within the scope of this invention. The term "prodrug" here refers to a compound that, in the course of treatment of a related disease, undergoes a chemical transformation through metabolism or a chemical process to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0139] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0140] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0141] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0142] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0143] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0144] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0145] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0146] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0147] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0148] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0149] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0150] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0151] Preparation method

[0152] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on 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, such combinations being readily performed by those skilled in the art.

[0153] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0154]

[0155] (i) In the presence of a base (such as sodium acetate), compound (P-1) reacts with compound (Q) to give compound (P-2);

[0156] (ii) In the presence of a copper salt (such as CuCl2), compound (P-2) undergoes a dehydrogenation reaction to give compound (P-3);

[0157] (iii) In the presence of a base (such as LiOH), the compound of formula (P-3) is hydrolyzed to give the compound of formula (P-4);

[0158] (iv) The compound of formula (P-4) reacts with an amine (R) to give the compound of formula (I);

[0159] In the formula, X, Y, Z, U, R 1 R 2 R 3 R 5 R 6 R 7 and R 8 Defined as described above.

[0160] 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 based on the specific reactants.

[0161] Pharmaceutical Compositions and Administration

[0162] The pharmaceutical compositions described in this invention are used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0163] The compound of formula (I) can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I is preferred. Drug combination also includes taking the compound of formula I with one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of either drug alone.

[0164] Drugs or active ingredients that can be used in combination with compounds of general 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, CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, etc.),OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocalatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Ti... EGFR inhibitors (such as afatinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), and CDK inhibitors (such as palbociclib, ribociclib, A...). bemaciclib, 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), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.

[0165] The dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release or nano-formulations.

[0166] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0167] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0168] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0169] 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 the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0170] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0171] 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 used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0172] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0173] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0174] 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.

[0175] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0176] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0177] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0178] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound of general formula (I) or its crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate of the present invention, thereby forming a pharmaceutical composition.

[0179] The present invention also provides a treatment method comprising the steps of: administering to a subject requiring treatment a compound of general formula (I) as described in the present invention, or a crystal form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, or administering a pharmaceutical composition as described in the present invention for selectively inhibiting AhR.

[0180] Compared with the prior art, the present invention has the following main advantages:

[0181] (1) The compounds of the present invention have a good selective inhibitory effect on AhR;

[0182] (2) The compounds of the present invention have better pharmacodynamic and pharmacokinetic properties and lower toxic side effects.

[0183] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0184] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0185] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0186] NMR was performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the determination included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

[0187] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC determinations were performed using an Agilent 1100 high-performance chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).

[0188] Thin-layer chromatography (TLC) uses Qingdao GF254 silica gel plates, with a thickness of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative TLC. Column chromatography typically uses Qingdao 200-300 mesh silica gel as the support.

[0189] The starting materials used in the embodiments of the present invention are all known and commercially available, or can be synthesized using or in accordance with literature reported in the field.

[0190] Unless otherwise specified, all reactions in this invention are carried out under the protection of a dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature is [degrees Celsius].

[0191] Example

[0192] Example 1: Preparation of intermediates

[0193] Example 1-1 Synthesis of (S)-N-(2-aminopropyl)methanesulfonamide hydrochloride

[0194]

[0195] Step 1: Preparation of (S)-tert-butyl(2-((tert-butoxycarbonyl)amino)propyl(methanesulfonyl)carbamate

[0196] (S)-tert-butyl(1-hydroxypropyl-2-yl)carbamate (3.76 g, 21.49 mmol), tert-butyl methanesulfonylcarbamate (4.61 g, 23.63 mmol), and triphenylphosphine (7.32 g, 27.93 mmol) were dissolved in 75 mL of anhydrous tetrahydrofuran. After cooling in an ice bath, diisopropyl azodicarbonate (5.5 mL, 27.93 mmol) was slowly added dropwise, maintaining the internal temperature no higher than 10 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to give the target product (5.76 g, yield: 76%).

[0197] Step 2: Preparation of (S)-N-(2-aminopropyl)methanesulfonamide hydrochloride

[0198] (S)-tert-butyl(2-((tert-butoxycarbonyl)amino)propyl(methanesulfonyl)carbamate (5.76 g, 16.36 mmol) was dissolved in 12 mL of dichloromethane, and a solution of hydrogen chloride / ethyl acetate (approximately 5 M, 80 mL) was added. The reaction mixture was stirred at room temperature for 4 hours and then evaporated to dryness. The residue was lyophilized to give the target product (2.9 g, yield: 94%).

[0199] LC-MS: m / z 153 (M+H) + . 1 H NMR (400MHz, CDCl3) 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).

[0200] Following the method of Example 1-1, the following compounds were synthesized using different starting materials:

[0201] Example 1-2 Synthesis of (S)-N-(2-aminopropyl)cyclopropylsulfonamide hydrochloride

[0202]

[0203] 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).

[0204] Example 2: Preparation of (S)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(methanesulfonyl)propane-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0205]

[0206] Step 1: Preparation of methyl 6-(4-chlorophenyl)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0207] 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 additions, the reaction mixture was stirred at room temperature for 1 h, then stirred overnight at 50 °C. The resulting reaction mixture was concentrated, and the pH was adjusted to 8 with excess sodium bicarbonate solution, followed by extraction with ethyl acetate (3 x 30 mL). The combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was separated by preparative HPLC to give the target product (275 mg, 64% yield).

[0208] LC-MS: m / z 347 (M+H) + .

[0209] Step 2: Preparation of methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0210] Methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (275 mg, 0.79 mmol) was added to acetonitrile (15 mL), followed by anhydrous copper chloride (405.6 mg, 2.38 mmol). After the addition was complete, the reaction mixture was heated to 90 °C and stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was filtered after adding 10 mL of water, and the filter cake was washed three times with water and dried under vacuum. The resulting target product did not require further purification and was used directly in the next reaction.

[0211] LC-MS: m / z 345 (M+H) + .

[0212] Step 3: Preparation of 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0213] The methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate obtained in the previous step was dissolved in THF (5.0 mL), and then an aqueous solution of LiOH·H₂O (120.0 mg, 2.87 mmol) (1.0 mL) 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 the pH was adjusted to 3-4 with an aqueous solution of HCl (1 M), and 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 give the target product (146 mg, two-step yield 55.8%). No further purification was required, and it was used directly in the next reaction.

[0214] LC-MS: m / z 331 (M+H) + .

[0215] Step 4: Preparation of (S)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(methanesulfonyl)propane-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0216] 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-carboxylic acid (70.0 mg, 0.21 mmol) was dissolved in DMF (2.0 mL), followed by the addition of (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 mixture was stirred at room temperature for 15 min, then quenched with 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 residue was separated by liquid chromatography to give the target product (5.0 mg, 5% yield).

[0217] 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=8.6H z,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).

[0218] Following the method of Example 2, the following compounds were synthesized using different starting materials:

[0219] Example 3: Preparation of (S)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-5-yl)-N-(1-(methanesulfonyl)propane-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0220]

[0221] 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).

[0222] Example 4: Preparation of (S)-6-(4-chlorophenyl)-N-(1-(cyclopropylsulfonamido)propane-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0223]

[0224] 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=8.8Hz,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).

[0225] Example 5: Preparation of (S)-6-(4-chlorophenyl)-N-(1-(cyclopropylsulfonamido)propane-2-yl)-2-(1-methyl-1H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0226]

[0227] 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).

[0228] Example 6: Preparation of (S)-6-(4-chlorophenyl)-N-(1-(cyclopropylsulfonamido)propane-2-yl)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0229]

[0230] 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=8.6Hz,2 H),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).

[0231] Example 7: Preparation of (S)-6-(4-chlorophenyl-2,3,5,6-d4)-N-(1-(cyclopropylsulfonamido)propane-2-yl)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0232]

[0233] LC-MS: m / z 498 (M+H) + .

[0234] Example 8: Preparation of (S)-6-(4-chlorophenyl)-N-(1-(methanesulfonamido)propane-2-yl)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0235]

[0236] LC-MS: m / z 468 (M+H) + .

[0237] Example 9: Preparation of (S)-6-(4-chlorophenyl-2,3,5,6-d4)-N-(1-(cyclopropylsulfonamido)propane-2-yl)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0238]

[0239] LC-MS: m / z 472 (M+H) + .

[0240] Example 10 Biological Test Evaluation

[0241] The following biological test examples further illustrate the invention, but these examples are not intended to limit the scope of the invention.

[0242] AhRβ-lactamase antagonism experiment

[0243] Preparation of reagents

[0244] (1) Breeding medium: Opti-MEM, 5% FBS, 1uM sodium Pyruvate, 0.1 mM NEAA, stored at 4℃.

[0245] (2) Experimental culture medium: Opti-MEM, 0.1% BSA, 1uM sodium Pyruvate, 0.1mM NEAA, stored at 4℃.

[0246] Experimental steps:

[0247] Day 1:

[0248] Coating test panel (one day before the test)

[0249] 1) Dissolve 25 mg of poly-L-lysine in 500 mL of DPBS;

[0250] 2) Add 20 μL / well, incubate at 37°C with 5% CO2 for 1-2 hours;

[0251] 3) Pour out the solution completely and rinse once with 50 μL MEM.

[0252] Cells planted on a plate

[0253] 1) Remove the CYP1A1-bla LS-180 cell line from the incubator;

[0254] 2) Remove the culture medium and add 2 mL of TrypLE / flask;

[0255] 3) Place the flask at 37°C and let it stand for 5-8 minutes to allow the cells to separate;

[0256] 4) Add 10 mL of seeding medium / flask;

[0257] 5) Transfer the cell mixture to a 50 ml sterile centrifuge tube and mix well;

[0258] 6) Cell counting and dispersing of cells into a cell plate;

[0259] 7) 15K cells / well: Add 15K cells to each well using 30 μL of culture medium;

[0260] 8) Sow the seeds in the wells using 30 μL of breeding medium, and use the Combi standard model of 384-well TC-treated microplates with biofilm poly-D-lysine per well.

[0261] 9) Incubate overnight at 37℃ with 5% CO2.

[0262] the next day:

[0263] Compound drug delivery

[0264] a) Preparation of reference compounds

[0265] A 20-dose reference CH-223191 was prepared in an LDV plate using DMSO. The maximum working solution of CH-223191 was a 10 mM DMSO solution. It was serially diluted 2-fold using Bravo.

[0266] b) Max and Min Wells

[0267] Maximum hole size: 10mM DMSO standard CH-223191 on LDV plate;

[0268] Minimum hole: DMSO in LDV plate.

[0269] c) Use ECHO to transfer 80 nL from the LDV board to the composite board (PE6008590) according to the board mapping.

[0270] d) Using Combi Stand mode, add 20 μL of detection medium to each well and centrifuge at 2000 rpm for 2 minutes to ensure thorough mixing.

[0271] e) Cell starvation

[0272] 29 μL of culture medium was transferred into the wells of the cell plate using Bravo.

[0273] Using the Combi vertical mode, add 20 μL of warm test solution to each well and centrifuge at 300 rpm for 1 minute; incubate at 37°C with 5% CO2 for 1 hour.

[0274] f) Compound addition

[0275] Transfer 10 μL of the diluted solution or DMSO (4x working solution) from the composite plate (PE6008590) to the cell plate using Bravo. Incubate at 37°C with 5% CO2 for 1 hour.

[0276] g) Addition of receptor agonists

[0277] 10 μL of 4X ITE working solution (2 nM) was added to all wells of the cell plate using Bravo. The total assay volume was 40 μL / well. Incubation was performed at 37°C with 5% CO2 for 4 hours.

[0278] Allow the plate to stand at room temperature for 10 minutes before adding the loading reagent.

[0279] h) Final determination conditions

[0280] Final hole: 15k / hole

[0281] Minimum value: 0.1% DMSO solution

[0282] Max: 10µM CH-223191

[0283] CH-223191CRC: Diluted 2x to 10µM, 20 points

[0284] Final ITE concentration: 0.5 nM

[0285] Day 2: Add detection buffer and read the plate.

[0286] A. Substrate loading and plate reading

[0287] a) Store and prepare each reagent according to the kit instructions.

[0288] b) Remove solutions A and D from the -20°C freezer. After complete thawing, prepare the following mixed solution.

[0289] c) Add solution A to solution B, and vortex.

[0290] d) When solution C is added to the mixture of A and B, good eddy current is generated.

[0291] e) Add solution D to solutions A, B, and C, and vortex.

[0292] f) Add 9.5 μL of final solution to each plate using the Combi small mode.

[0293] g) Incubate at room temperature in the dark for at least 1 hour, then read the plate. The signal should be operational for at least 3 hours.

[0294] B. Use Envision to read the board.

[0295] Envision Reader Settings

[0296] Wavelength Excitation Filter 400 Emission Filter 1 460 Emission Filter 2 535 Dichroic Mirror Beta lactamase D425 / 490

[0297] The antagonistic activity of the compounds in the embodiments of this invention against AhR is shown in Table 1.

[0298] Table 1 Inhibitory activity of compounds in the embodiments of the present invention

[0299]

[0300]

[0301] As can be seen from Table 1, the compounds in the embodiments of the present invention exhibited good antagonistic activity against AhR.

[0302] Rat pharmacokinetic evaluation

[0303] Male SD rats, weighing approximately 220g, were fasted overnight and then administered a solution of the compound of the present invention at a concentration of 2 mg / kg via gavage [using CMC / TW80 as a carrier]. Blood samples were 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, and the concentration of the compound of the present invention in plasma was determined by LC / MS / MS.

[0304] Evaluation of mouse pharmacokinetic assays

[0305] Male ICR mice, weighing approximately 20-30g, were fasted overnight and then administered a solution of the compound of the present invention at a concentration of 2 mg / kg via gavage [using CMC / TW80 as a carrier]. Blood samples were 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, and the concentration of the compound of the present invention in plasma was determined by LC / MS / MS.

[0306] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Sulfonamide compounds having the general formula (I) and their pharmaceutically acceptable salts: The compound has the structure shown in Formula V: In the formula, x is 1, 2, 3 or 4; R e R f R m and R n Each is independently selected from: hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkyl hydroxyl, C3 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen; R 1 Selected from the following groups, substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups, wherein, The substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkyl hydroxyl, C1-C3 alkoxy, deuterated C1-C3 alkoxy, halo-C1-C3 alkoxy, and halogen. R 2 It is hydrogen; R 3 for R 5 R 6 and R 8 Each is independently selected from: hydrogen and deuterium; R 10 Selected from: H, D; R 7 Selected from the following groups: halogen, CF3, CHF2, OCF3, OCHF2.

2. The sulfonamide compound having the general formula (I) structure as described in claim 1, and its pharmaceutically acceptable salt, characterized in that, R 1 Selected from the following groups, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, wherein the substitution refers to being substituted by one or more groups selected from the following group: deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkyl, halogen.

3. The sulfonamide compound having the general formula (I) structure as described in claim 1, and its pharmaceutically acceptable salt, characterized in that, R 7 It is a halogen.

4. The sulfonamide compound having the general formula (I) structure as described in claim 1, and its pharmaceutically acceptable salt, characterized in that, R 5 R 6 R 8 and R 10 Both are hydrogen.

5. The sulfonamide compound having the structure of general formula (I) as described in claim 1, and its pharmaceutically acceptable salt, characterized in that, x is 1, 2, 3 or 4; R e R f R m and R n Each is independently selected from: hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, and halo-C1-C6 alkyl; R 1 Selected from the following groups, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the substitution refers to being substituted by one or more groups selected from the following group: deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, halosubstituted C1-C3 alkyl; R 2 It is hydrogen; R 3 for R 5 R 6 and R 8 Each is independently selected from: hydrogen and deuterium; R 10 Selected from: H, D; R 7 Selected from the following group: halogen.

6. The sulfonamide compound having the structure of general formula (I) as described in claim 1, and its pharmaceutically acceptable salt, characterized in that, The compounds are selected from the group consisting of:

7. A method for preparing sulfonamide compounds of general formula (I) and their pharmaceutically acceptable salts, characterized in that, Including the following steps: (i) In the presence of CH3COONa, compound (P-1) reacts with compound (Q) to give compound (P-2); (ii) In the presence of CuCl2, compound (P-2) undergoes a dehydrogenation reaction to give compound (P-3); (iii) In the presence of LiOH, compound (P-3) is hydrolyzed to give compound (P-4); (iv) The compound of formula (P-4) reacts with an amine (R) to give the compound of formula (I); In the formula, X, Y, Z, U, R 1 R 2 R 3 R 5 R 6 R 7 and R 8 The definition is as described in claim 1.

8. A pharmaceutical composition, characterized in that, It comprises i) one or more compounds of general formula (I) according to any one of claims 1-6, or pharmaceutically acceptable salts thereof; and ii) pharmaceutically acceptable carriers.

9. Use of a sulfonamide compound having the structure of general formula (I) as described in any one of claims 1-6, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, characterized in that, Used to prepare pharmaceutical compositions for the prevention and / or treatment of AhR-mediated diseases.

10. The use as described in claim 9, characterized in that, The disease described is a tumor or a disorder.

11. The use as described in claim 9, characterized in that, The diseases mentioned are selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colon cancer, melanoma, lymphoma, leukemia, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

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