CN114685426A - Sulfonamide inhibitor and preparation method and application thereof - Google Patents

Abstract

The invention relates to a sulfonamide inhibitor, a preparation method and application thereof. The compound has a structure shown in a formula (I), and also discloses a preparation method of the compound and application of the compound as an AhR inhibitor.

Description

Sulfonamide inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a sulfonamide inhibitor, and a preparation method and application thereof.

Background

Aryl Hydrocarbon receptors (AhR) are ligand-activated transcription factors involved in the regulation of various cellular processes, including cell proliferation, metabolism, and immune regulation. AhR can affect cell signaling by interacting with various regulatory and signaling proteins, including PAS heterodimer chaperone ARNT (arene receptor nuclear transport protein), chaperone and immune-like proteins (e.g., HSP90), AIP (arene receptor-interacting protein), p23, CK2 (casein kinase-2), PKC (protein kinase-C), and the like. In addition, AhR also interacts with hormone receptors, hypoxia, NF-kappaB, Rb protein mediated signaling pathways, MAPK signaling pathways, EGFR signaling pathways, and the like. Researches find that the AhR is high in expression in various tumors such as lung cancer, colorectal cancer, head and neck squamous cell carcinoma and the like, and plays a key role in regulating immunosuppression in a tumor microenvironment. Preclinical studies have shown that mice that are continuously activated spontaneously develop tumors.

AhR is expressed in many cells of the immune system, including Dendritic Cells (DCs), macrophages, T cells, NK cells, and the like. AhR plays an important role in immune regulation: (1) for example, endogenous AhR ligands may promote the development of Treg cells in TME; (2) AhR promotes differentiation of Th17 cells through multiple mechanisms; on the other hand, AhR regulates expression of Th17 by binding to DRE site on Th17 promoter; the AhR can also cooperate with Stat3 to induce the expression of Ikaros family member Aiolos (IKZF3), 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 mouse and human Tr1 regulatory cells; (4) AhR regulates B-cell differentiation and the like through transcriptional inhibition of B-cell early genes EBF1 and PAX 5. Cells in the immune system are constantly exposed to endogenous and exogenous AhR ligands, which can interfere with physiological functions, alter immune homeostasis, and progress to inflammatory diseases, autoimmune diseases, and cancer. Inhibition of AhR may make immunotherapy more effective by reducing immunosuppression.

Exogenous ligands such as PAH (polycyclic aromatic hydrocarbons), dioxins (e.g. TCDD) and polychlorinated biphenyls are among the main culprits for most toxic reactions. After binding to these environmental toxins, AhR induces metabolic mechanisms such as cytochrome p450 enzymes and the like (CYP1a1, CYP1a2, CYP1B1 and the like) to eliminate the environmental toxins. Studies have shown that exogenous ligands such as TCDD and the like activate AhR and have been shown to play a role in many cellular processes such as embryogenesis, tumorigenesis, inflammation and the like.

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 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 step of tryptophan metabolism. In animal models, reduction of the anti-tumor immune response and inhibition of IDO can inhibit tumor formation. TDO2 is also strongly expressed in cancer, leading to the production of immunosuppressive kynurenines. In glioma, kynurenine activates AhR, inhibits anti-tumor immune response by mediating the 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.

Since AhR target proteins are pathologically associated with a variety of diseases, there is also a need for novel AhR inhibitors for clinical treatment. The high-selectivity and high-activity AhR inhibitor can be used for more effectively treating diseases such as cancer mediated by AhR abnormality and reducing the potential of off-target effect, so that the AhR inhibitor has more urgent clinical requirements.

Disclosure of Invention

The invention aims to provide a novel compound with selective AhR inhibition effect and/or better pharmacodynamic property and application thereof.

In a first aspect of the present invention, there is provided a sulfonamide compound having a structure of general formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula:

x is selected from the group consisting of substituted or unsubstituted groups: c₂-C₆Alkylene radical, C₃-C₁₀Cycloalkylene, 4-10 membered heterocyclylene, C₁-C₆Alkylene radical C₃-C₁₀Cycloalkylene or C₁-C₆Alkylene 4-10 membered heterocyclylene, wherein said substitution is with one or more (e.g. 2,3 or 4) Ra;

y is selected from: NH or NR⁴Wherein R is⁴Selected from the group consisting of substituted or unsubstituted: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or 4-6 membered heterocyclyl; wherein said substitution is by one or more (e.g., 2,3, or 4) Ra;

z is selected from: o, NH, NCN, NR⁹Wherein R is⁹Selected from the group consisting of substituted or unsubstituted: c₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₄Aryl or 5-14 membered heteroaryl; wherein said substitution is by one or more (e.g., 2,3, or 4) Ra;

u is selected from: n or CR¹⁰Wherein R is¹⁰Selected from: H. d or halogen;

R¹selected from the group consisting of substituted or unsubstituted: NH (NH)₂、NR¹¹R¹¹'、C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, 4-to 10-membered heterocyclic group, C₆-C₁₄Aryl or 5-14 membered heteroaryl, wherein said substitution is by one or more (e.g. 2,3 or 4) Ra;

R¹¹and R¹¹' each is independently selected from the group consisting of substituted or unsubstituted: H. c₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₄Aryl or 5-14 membered heteroaryl, and R¹¹And R¹¹' is not both H, wherein said substitution is with one or more (e.g., 2,3, or 4) Ra;

R²selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

R³selected from the group consisting of substituted or unsubstituted: c₆-C₁₄Aryl, 5-14 membered heteroaryl, wherein said substitution is by one or more (e.g. 2,3 or 4) Ra;

R⁵、R⁶and R⁸Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, cyano, ester, amine, amide, sulfonamide, or urea; wherein said substitution is by one or more (e.g., 2,3, or 4) Ra;

R⁷selected from substituted or unsubstitutedThe following groups: hydrogen, deuterium, halogen, CF₃、CHF₂、OCF₃、OCHF₂、C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₄Aryl, 5-14 membered heteroaryl, cyano, ester, amine, amide, sulfonamide, or urea; wherein said substitution is by one or more (e.g., 2,3, or 4) Ra;

ra is selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl hydroxy, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide or ureido, wherein substitution in Ra means substitution with one or more (e.g., 2,3 or 4) groups selected from the group consisting of: deuterium, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, Ra is selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₈Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide or ureido, wherein substitution in Ra means substitution with one or more (e.g., 2,3 or 4) groups selected from the group consisting of: deuterium, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the sulfonamide compound having the structure of formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has the structure of formula (II):

X、Y、Z、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

In another preferred embodiment, the sulfonamide compound having the structure of formula (I), or the stereoisomer, the tautomer, the crystal form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has the structure of formula (III):

X、Y、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

In another preferred embodiment, the sulfonamide compound having the structure of formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has the structure shown in formula IV:

X、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Definition of (1)As described above.

In another preferred embodiment, the sulfonamide compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, has a structure represented by formula V or V':

in the formula,

x is 1, 2,3 or 4;

R_e、R_f、R_mand R_nEach independently selected from: hydrogen, deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

or R_eAnd R_f、R_fAnd R_m、R_mAnd R_nTogether with the C atom to which they are attached form a substituted or unsubstituted group of: c₃-C₆Cycloalkylene, 4-6 membered heterocyclylene, wherein the substitution means substitution with one or more groups selected from: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

R¹²selected from the group consisting of substituted or unsubstituted: CN, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₆-C₁₄Aryl or 5-14 membered heteroaryl; wherein said substitution means being substituted by one or more groups selected from the group consisting of: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea;

R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

In another preferred embodiment, the sulfonamide compound having the structure of formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has the structure of formula VI:

in the formula,

ring a is a substituted or unsubstituted group of: c₃-C₆Cycloalkylene, 4-6 membered heterocyclylene, wherein the substitution means substitution with one or more groups selected from: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl,4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

In another preferred embodiment, ring a is selected from:

wherein R is_bSelected from: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, in the above formulas, R¹Selected from the group consisting of substituted or unsubstituted: NR¹¹R¹¹'、C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; r¹¹And R¹¹' each is independently selected from the group consisting of substituted or unsubstituted: H. c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, and R¹¹And R¹¹' not simultaneously H, wherein R¹、R¹¹And R¹¹The substitution in' means substitution with one or more groups selected from the group consisting of: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocycleA group, a halogen, a nitro group, a hydroxyl group, a cyano group, an ester group, an amine group, an amide group, a sulfonamide group, or a urea group.

In another preferred embodiment, in the above formulas, R¹Selected from the group consisting of substituted or unsubstituted: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, wherein said substitution means substitution by one or more groups selected from the group consisting of: deuterium, C₁-C₃Alkyl, deuterated C₁-C₃Alkyl, halo C₁-C₃Alkyl, halo C₁-C₃Alkyl hydroxy, C₁-C₃Alkoxy, deuterated C₁-C₃Alkoxy, halo C₁-C₃Alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the sulfonamide compound with the structure of the general formula (I), or the stereoisomer, the tautomer, the crystal form, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof, R³Selected from the group consisting of substituted or unsubstituted: phenyl or 5-6 membered heteroaryl, wherein said substitution means substitution by one or more groups selected from the group consisting of: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido.

In a further preferred embodiment of the method,

moieties are selected from:

wherein R is⁷Is as defined above.

In another preferred embodiment, R¹、R²、R³、R⁵、R⁶、R⁷、R⁸、R¹⁰、R_e、R_f、R_m、R_n、X、Y、Z、U、x、R¹²And ring A is a group corresponding to each specific compound in the examples.

In another preferred embodiment, the sulfonamide compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof is selected from the group consisting of:

in another preferred embodiment, the compound is selected from the compounds shown in the examples.

In a second aspect of the present invention, there is provided a method for preparing sulfonamide compounds having the structure of general formula (I), stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, the method comprising the steps of:

(i) reacting a compound of formula (P-1) with a compound of formula (Q) in the presence of a base to obtain a compound of formula (P-2);

(ii) in the presence of copper salt, carrying out dehydrogenation reaction on the compound of the formula (P-2) to obtain a compound of the formula (P-3);

(iii) hydrolyzing the compound of formula (P-3) in the presence of a base to obtain a compound of formula (P-4);

(iv) reacting the compound of formula (P-4) with an amine (R) to obtain a compound of formula (I);

in the formula,

X、Y、Z、U、R¹、R²、R³、R⁵、R⁶、R⁷and R⁸As defined above.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising I) one or more compounds of the structure of formula (I) according to the first aspect, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and ii) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or the like biologically similar to the above drugs), PD-L1 inhibitors (e.g., Duvalimab, alemtuzumab, Avelumab (avelumab), CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR, MSB2311, or the like biologically similar to the above drugs), CD20 antibodies (e.g., rituximab, otuzumab, ofatumumab, otuzumab, tututemumab, tositumumab, 131I-tositumomab, ibritumomab, Y-90, Y-itumomab, Y-90, In-5932, or the like), and the like, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01, ALK inhibitors (e.g., Ceritinib, Aleptinib, Bugatinib, Laratinib, Ocatinib), PI3K inhibitors (e.g., Idiranib, Duvelisib, Dactlisib, Taselisib, Bimiralisib, Omipalisib, Bupalisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acatinib, Zabritinib, Vebrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, erlotinib, Lapatinib, Darkatinib, Icotinib, Netinib, Sapatinib, Napatinib, pyrroltinib, Hirtitinib, HDAC, erlotinib, Galatinib, e, Galatinib, e, vorinostat, fimepinastat, drosrinostat, entinostat, daciclast, Quisinostat, tacrine, etc.), CDK inhibitors (e.g., palbociclib, ribbociclib, Abemaciclib, micciib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (e.g., semetinib (AZD6244), trametinib (GSK1120212), PD0325901, seru 0126, pimatiib (AS-703026), PD184352(CI-1040), etc.), mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.

In a fourth aspect of the present invention, there is provided a use of the sulfonamide compound having the structure of general formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition according to the third aspect, for preparing a pharmaceutical composition for preventing and/or treating AhR-mediated diseases.

In another preferred embodiment, the disease is a tumor or a dysregulated disease.

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, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

In a fifth aspect of the invention, there is provided a method of inhibiting AhR comprising the steps of: administering to a patient in need thereof an effective amount of a compound of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to the first aspect of the invention, or a pharmaceutical composition according to the third aspect of the invention.

Drawings

Is free of

Detailed Description

The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a novel class of compounds having selective inhibitory effects on AhR and/or better pharmacodynamic properties. On the basis of this, the inventors have completed the present invention.

Term(s) for

In the present invention, unless otherwise specified, the terms used have the ordinary meaning known to those skilled in the art.

The term "alkyl" refers to straight or branched chain or cyclic alkyl groups containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-butyl,

Pentyl, isopentyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.

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

N-butyl, t-butyl, isobutyl (e.g. butyl, isobutyl)

) N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "substituted alkyl" means an alkyl group which is substituted at one or more positions, especially 1 to 4 substituents, and 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 (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl₃Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, 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_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_aOr NR_bP(＝O)₂R_eWherein R is present therein_aMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R_b、R_cAnd R_dMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R_bAnd R_cTogether with the N atom may form a heterocyclic ring; r_eMay independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.

The term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, such as methylene, ethylene, propylene, isopropylene (e.g.

) Butylene (e.g. butyl oxide)

) Pentylene (e.g. ethylene)

) Hexamethylene (e.g. hexamethylene)

) Heptylene (e.g. ethylene)

) And the like.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings each containing 3 to 8 carbon atoms. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 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 (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl₃Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, 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_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_aOr NR_bP(＝O)₂R_eWherein R is present therein_aMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R_b、R_cAnd R_dMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R_bAnd R_cTogether with the N atom may form a heterocyclic ring; r_eMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spiroalkenylSpirocyclic heterocycles (excluding heteroaryl rings), endocyclic alkyls, endocyclic alkenyls, endocyclic heterocycles (excluding heteroaryl rings), fused ring alkyls, fused ring alkenyls, fused ring heterocyclyls, or fused ring aromatic ring groups, which cycloalkyl, cycloalkenyl, heterocyclyl, and heterocyclylaryl groups may be optionally substituted. Any two or more atoms on the ring may be further ring-connected with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

The term "cycloalkylene" refers to a group formed by a cycloalkyl group minus two hydrogen atoms, such as:

and the like.

The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, e.g., a 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring system) in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocyclic ring may carry 1, 2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may 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, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate groups, wherein any two or more atoms on the ring may be further ring-connected to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

The term "heterocyclylene" refers to a group formed by a heterocyclyl group with two or more hydrogen atoms removed, such as:

and the like. Wherein H of NH may be further substituted; when substituted, the substituents are preferably alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl.

The term "C1-C6 alkylene C3-C10 cycloalkylene" or "C3-C10 cycloalkylene C1-C6 alkylene" has the same meaning and refers to a cycloalkylalkyl or alkylcycloalkyl group which has two hydrogen atoms removed, e.g.

And the like.

The term "C1-C6 alkylene 4-10 membered heterocyclylene" or "4-10 membered heterocyclylene C1-C6 alkylene" has the same meaning and refers to a group formed by a heterocyclylalkyl or alkylheterocyclyl group minus two hydrogen atoms, e.g.,

and the like.

The term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 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 (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl₃Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, 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_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_aOr NR_bP(＝O)₂R_eWherein R is present therein_aMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R_b、R_cAnd R_dMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R_bAnd R_cTogether with the N atom may form a heterocyclic ring; r_eMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring groups, which can be optionally substituted.

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. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

The term "halo" means substituted with halogen.

The term "deuterated" refers to substitution by deuterium.

The term "hydroxy" refers to a group with the structure OH.

The term "nitro" refers to a group with the structure NO₂A group of (1).

The term "cyano" refers to a group with the structure CN.

The term "ester group" refers to a group with the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.

The term "amine" refers to a group having the structure-NRR ', where R and R' may 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' may be the same or different in the dialkylamine fragment.

The term "amido" refers to a group with the structure-CONRR ', where R and R' may 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' may be the same or different in the dialkylamine fragment.

The term "sulfonamide" refers to a sulfonamide group having the structure-SO₂NRR 'wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic as hereinbefore defined. R and R' may be the same or different in the dialkylamine fragment.

The term "ureido" refers to a group having the structure — NRCONR 'R ", where R, R' and R" may 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 "may be the same or different in the dialkylamine fragment.

The term "alkylaminoalkyl" refers to a group having the structure-RNHR ', wherein R and R' may 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' may be the same or different.

The term "dialkylaminoalkyl" refers to a group having 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, a heterocycle or a substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "heterocyclylalkyl" refers to a group having the structure-RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; r' represents a heterocycle or a substituted heterocycle.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, a certain substituted group may have one substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such 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 heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido, and the like.

Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.

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, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.

Active ingredient

As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, of compounds of formula I.

The compounds of formula I have the following structure:

in the formula,

X、Y、Z、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and U is as defined above.

Preferably, the compound has a structure represented by general formula (II):

wherein,

X、Y、Z、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

Preferably, the compound has a structure represented by general formula (III):

wherein,

X、Y、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

Preferably, the compound has the structure shown in formula IV:

wherein,

X、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined above.

Preferably, the compound has a structure represented by formula V or V':

wherein,

x、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸、R¹⁰、R¹²、R_e、R_f、R_mand R_nIs as defined above.

Preferably, the compound has the structure shown in formula VI:

wherein,

ring A, R¹、R²、R³、R⁵、R⁶、R⁷、R⁸And R¹⁰Is as defined above.

Preferably, in formula VI, ring a is selected from:

wherein R is_bSelected from: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy, halogen, nitro, hydroxyCyano, ester, amine, amide, sulfonamide, or urea groups.

Preferably, in the formulae I-VI, R⁷Selected from: hydrogen, deuterium, halogen, CF₃、CHF₂、OCF₃、OCHF₂、C₁-C₆Alkyl, N (CH)₃)₂。

Preferably, in the formulae I-VI, R⁵、R⁶And R⁸Each independently selected from: hydrogen, deuterium, halogen, C₁-C₆Alkyl, cyano, ester, amine, amide, sulfonamide or urea groups, more preferably, R⁵、R⁶And R⁸Each independently selected from: hydrogen, deuterium, halogen, C₁-C₆Alkyl, cyano.

Preferably, in the formulae I-VI, R¹Selected from the group consisting of substituted or unsubstituted: NR (nitrogen to noise ratio)¹¹R¹¹'、C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; r¹¹And R¹¹' each is independently selected from the group consisting of substituted or unsubstituted: H. c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, and R¹¹And R¹¹' not simultaneously being H, wherein R¹、R¹¹And R¹¹The substitution in' means substitution with one or more groups selected from the group consisting of: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

R³selected from the group consisting of substituted or unsubstituted: phenyl or 5-6 membered heteroaryl, wherein said substitution means substitution by one or more groups selected from the group consisting of: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

R⁷selected from: hydrogen, deuterium, halogen, CF₃、CHF₂、OCF₃、OCHF₂、C₁-C₆Alkyl, N (CH)₃)₂；

R⁵、R⁶And R⁸Each independently selected from: hydrogen, deuterium, halogen, C₁-C₆Alkyl, cyano, ester, amine, amide, sulfonamide, or urea groups.

The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may form are included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps during manufacture. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and salting out in a medium, or lyophilizing in an aqueous solution.

The compounds of the invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetates (e.g. with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglycolates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g. 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionates), phosphates, propionates, citrates, and the like, Picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, e.g., p-toluenesulfonate, dodecanoate, and the like

Acidic moieties that certain compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (salt with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. The basic nitrogen-containing groups may be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound, salt, or solvate of the present invention when used 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 invention may exist in tautomeric forms (e.g. amides and imino ethers). All of these tautomers are part of the present invention.

All stereoisomers of the compounds (e.g., those asymmetric carbon atoms that may exist due to various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated within the invention. The individual stereoisomers of the compounds of the invention may not be present in combination with the other isomers (e.g. as a pure or substantially pure optical isomer having a particular activity), or may be present as a mixture, e.g. as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the invention has two S or R configurations, and is defined by the International Union of theory and applied chemistry (IUPAC) proposed in 1974. The racemic forms can be resolved by physical methods such as fractional crystallization, or by separation of the crystals by derivatization into diastereomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

The compounds of the present invention, which are obtained by preparing, isolating and purifying the compound in order to obtain the compound in an amount of 90% by weight or more, for example, 95% by weight or more, or 99% by weight or more ("very pure" compounds), are listed in the text description. Such "very pure" compounds of the invention are also part of the invention herein.

All configurational isomers of the compounds of the invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of compounds in the present invention encompasses both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are detailedAs described in detail below. For purposes of the present invention, the chemical Elements are compatible with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75^thD. as defined in. The definition of a particular functional group is also described herein. In addition, the basic principles of Organic Chemistry, as well as specific functional groups and reactivities are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomer, (L) isomer, racemic mixtures and other mixtures thereof. Further the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are encompassed by the present invention.

According to the present invention, the mixture of isomers may contain a variety of isomer ratios. For example, in a mixture of only two isomers there may be 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 invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, are readily understood by those of ordinary skill in the art to be within the scope of this invention.

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein for the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight or mass number. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. The compound of the present invention, or an enantiomer, diastereomer, isomer, or pharmaceutically acceptable salt or solvate thereof, wherein the compound contains the above compoundIsotopes and other isotopic atoms of matter are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g.³H and¹⁴among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.³H and carbon-14, i.e.¹⁴C, their preparation and detection are relatively easy. Is the first choice among isotopes. Furthermore, heavier isotopes such as deuterium are substituted, i.e.²H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples.

If it is desired to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary agents, separation of the resulting diastereomeric mixture and removal of the chiral auxiliary agent to give 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, a diastereomeric salt thereof can be formed with an appropriate optically active acid or base, and the resulting salt can be separated by a conventional means such as fractional crystallization or chromatography to obtain a pure enantiomer.

As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. 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 nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.

Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.

Preparation method

The following describes more specifically the processes for the preparation of the compounds of formula (I) according to the invention, but these particular processes do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

Typically, the process for the preparation of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available without specific reference.

(i) Reacting the compound of formula (P-1) with the compound of formula (Q) in the presence of a base (e.g., sodium acetate) to obtain a compound of formula (P-2);

(ii) in the presence of copper salts (e.g. CuCl)₂) In the presence of the catalyst, carrying out dehydrogenation reaction on the compound shown in the formula (P-2) to obtain a compound shown in a formula (P-3);

(iii) hydrolyzing the compound of formula (P-3) in the presence of a base (e.g., LiOH) to obtain a compound of formula (P-4);

(iv) reacting the compound of formula (P-4) with an amine (R) to obtain a compound of formula (I);

in the formula, X, Y, Z, U, R¹、R²、R³、R⁵、R⁶、R⁷And R⁸As defined above.

In the above reaction steps, a reaction solvent, a reaction catalyst, a base used for the reaction, a reaction temperature, a reaction time, and the like may be selected by those skilled in the art according to a specific reactant.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, and metabolic disease.

The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may be maintained unchanged while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. The pharmaceutical combination also includes administration of the compound of formula I in an overlapping time period with one or more other known drugs. When a compound of formula I is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose at which they are administered alone.

Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obiumumab, ofutatumab, NI, tositumomab, 131-tositumomab, moylb, MOVITAb, MOXIB 483, TSM-90, TSI-52, TSI-102, TSI-35, TSI-102, TSI-35, TSI-102, TSI-II, TSI-10, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI-II, TSI, alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotininib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimicinib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Leutinib 6265, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF, Lipocinib, etc.), inhibitors (e, Lipocinib, etc.), inhibitors, Lipocinib, VEGF, etc. (e, Lipocinib, etc.), inhibitors, Lipocinib, e, etc. (e, etc.), inhibitors, e, Lipocinib, e, etc. (e, e.g., Nonocitinib, Lipocinib, e, e.g., Nonocitinib, VEGF-10-III inhibitors, VEGF-III inhibitors, e, e.g., Nonocitinib, e, e.g., Lipocinib, e.g., Nonocitinib, e, e.g., Lipocinib, VEGF-III inhibitors, e.g., Lipocinib, e, VEGF-III inhibitors (e.g., Lipocinib, VEGF-III inhibitors, e, e.g., Lipocinib, VEGF-III inhibitors, e.g., Lipocinib, e, e.g., Lipocinib, VEGF-III inhibitors, e, e.g., Lipocinib, VEGF-III inhibitors (e.g., Lipocinib, VEGF-III inhibitors, VEGF-10-III inhibitors, VEGF-III inhibitors, e, e.g., Lipocinib, III inhibitors (e, III inhibitors, III-III inhibitors, III.

Dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, topical liniment, controlled release type or delayed release type 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 in a safe and effective amount range. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, suitable for use inIs suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

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. 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 ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells 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 delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. 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. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain 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 as, for example, 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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present 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 which may be required if necessary.

The treatment methods of the present invention can be administered alone or in combination with other therapeutic means or agents.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.

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

Compared with the prior art, the invention has the following main advantages:

(1) the compound has good selective inhibition effect on AhR;

(2) the compound of the invention has better pharmacodynamics and pharmacokinetic performance and lower toxic and side effects.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS).

NMR was detected using a Bruker AVANCE-400 nuclear magnetic instrument, and the assay solvent contained deuterated dimethylsulfoxide (DMSO-d)₆) Deuterated acetone (CD)₃COCD₃) Deuterated chloroform (CDCl)₃) And deuterated methanol (CD)₃OD), and internal standards are Tetramethylsilane (TMS), chemical shifts are measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18100X 3.0mm column).

Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC is 0.15-0.20mm, and preparative thin layer chromatography is 0.4-0.5 mm. 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 known and commercially available or may be used or synthesized according to literature reports in the art.

All reactions of the present invention are carried out under continuous magnetic stirring under the protection of a dry inert gas (e.g., nitrogen or argon) except for the specific indications, and the reaction temperatures are all in degrees centigrade.

Examples

EXAMPLE 1 preparation of the intermediate

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

The first step is as follows: preparation of (S) -tert-butyl (2- ((tert-butoxycarbonyl) amino) propyl (methylsulfonyl) carbamate

(S) -tert-butyl (1-hydroxypropyl-2-yl) carbamate (3.76g, 21.49mmol), tert-butyl methylsulfonylcarbamate (4.61g, 23.63mmol) and triphenylphosphine (7.32g, 27.93mmol) were dissolved in 75 mL of anhydrous tetrahydrofuran, cooled in an ice bath and diisopropyl azodicarboxylate (5.5mL,27.93mmol) was slowly added dropwise while maintaining an internal temperature of not higher than 10 ℃. After the completion of the dropwise addition, the reaction solution was stirred at room temperature for 16 hours and then concentrated. The residue was purified with a silica gel column (petroleum ether: ethyl acetate: 20: 1 to 10: 1) to obtain the objective product (5.76g, yield: 76%).

The second step is that: preparation of (S) -N- (2-aminopropyl) methanesulfonamide hydrochloride

(S) -tert-butyl (2- ((tert-butoxycarbonyl) amino) propyl (methylsulfonyl) carbamate (5.76g, 16.36mmol) was dissolved in 12 mL of dichloromethane, a hydrogen chloride/ethyl acetate solution (about 5M, 80mL) was added, the reaction was stirred at room temperature for 4 hours and then spun dry, and the residue was lyophilized to give the objective product (2.9g, yield: 94%).

LC-MS：m/z 153(M+H)⁺。¹H 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).

The following compounds were synthesized according to the procedure of example 1-1, starting from different starting materials:

EXAMPLE 1 Synthesis of 2(S) -N- (2-aminopropyl) cyclopropylsulfonamide hydrochloride

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).

EXAMPLE 2 preparation of (S) -6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -N- (1- (methanesulfonamido) propan-2-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

The first step is as follows: preparation of methyl 6- (4-chlorophenyl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -3-oxo-2, 3,4, 5-tetrahydropyridazine-4-carboxylate

Dimethyl 2- (2- (4-chlorophenyl) -2-oxoethyl) malonate (350.0mg,1.23mmol) was added to acetic acid (7mL), followed by the addition of sodium acetate (504.2mg,6.15mmol) and 4-hydrazino-1-methyl-1H-pyrazole (500.5mg,2.21mmol) in that order. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour and then at 50 ℃ overnight. The resulting reaction was concentrated, and then an excess amount of sodium bicarbonate solution was added to adjust the pH to 8, followed by extraction with ethyl acetate (3 × 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 (275mg, 64% yield).

LC-MS：m/z 347(M+H)⁺。

The second step is that: preparation of methyl 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxylate

Methyl 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3,4, 5-tetrahydropyridazine-4-carboxylate (275mg, 0.79mmol) was added to acetonitrile (15mL), and anhydrous copper chloride (405.6mg,2.38mmol) was added. After the addition, the reaction is heated to 90 ℃ and stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue is filtered after addition of 10mL of water, and the filter cake is washed three times with water and dried in vacuo. The obtained target product is directly used for the next reaction without further purification.

LC-MS：m/z 345(M+H)⁺。

The third step: preparation of 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxylic acid

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 (5.0mL), and LiOH. H.₂An aqueous solution (1.0mL) of O (120.0mg,2.87mmol) was added dropwise to the reaction system. The resulting reaction solution was stirred at room temperature for 1.0h, then filteredInsoluble matter was removed by filtration, and the solid was washed with THF. The combined filtrates were concentrated and adjusted to pH 3-4 with aqueous HCl (1M) and then extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the objective product (146mg, 55.8% yield in two steps). The product was used in the next reaction without further purification.

LC-MS：m/z 331(M+H)⁺。

The fourth step: preparation of (S) -6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -N- (1- (methanesulfonamido) propan-2-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxylic acid (70.0mg, 0.21mmol) was dissolved in DMF (2.0mL), and (S) -N- (2-aminopropyl) methanesulfonamide hydrochloride (79mg,0.42mmol), DIPEA (0.1mL,0.63mmol) and HATU (160.9mg,0.42mmol) were added in this order. The reaction was stirred at room temperature for 15min, then quenched by addition of water (5mL) and extracted with ethyl acetate (3X 5 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was separated by liquid phase separation to obtain the objective product (5.0mg, 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).

Following the procedure of example 2, the following compounds were synthesized from different starting materials:

EXAMPLE 3 preparation of (S) -6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-5-yl) -N- (1- (methanesulfonamido) propan-2-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

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).

EXAMPLE 4 preparation of (S) -6- (4-chlorophenyl) -N- (1- (cyclopropylsulfonamido) propan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

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).

EXAMPLE 5 preparation of (S) -6- (4-chlorophenyl) -N- (1- (cyclopropylsulfonamido) propan-2-yl) -2- (1-methyl-1H-pyrazol-5-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

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).

EXAMPLE 6 preparation of (S) -6- (4-chlorophenyl) -N- (1- (cyclopropylsulfonamido) propan-2-yl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

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).

Example 7 preparation of (S) -6- (4-chlorophenyl-2, 3,5,6-d4) -N- (1- (cyclopropylsulfonamido) propan-2-yl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

LC-MS：m/z 498(M+H)⁺。

EXAMPLE 8 preparation of (S) -6- (4-chlorophenyl) -N- (1- (methanesulfonamido) propan-2-yl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

LC-MS：m/z 468(M+H)⁺。

Example 9 preparation of (S) -6- (4-chlorophenyl-2, 3,5,6-d4) -N- (1- (cyclopropylsulfonamido) propan-2-yl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

LC-MS：m/z 472(M+H)⁺。

Example 10 evaluation of biological assay

The following biological test examples further illustrate the present invention, but these examples are not meant to limit the scope of the present invention.

Antagonism experiment of AhR beta-lactamase

Preparation of reagents

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

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

The experimental steps are as follows:

the first day:

coating test board (day before test)

1) Dissolving 25mg of poly-L-lysine in 500mL of DPBS;

2) adding 20 uL/hole, incubating at 37 deg.C with 5% CO2 for 1-2 hr;

3) the solution was completely poured and washed once with 50uL MEM.

Plating cells on plates

1) Removing CYP1A1-bla LS-180 cell line cells from the incubator;

2) removing the culture medium by pumping, and adding 2mL of TrypLE/flash;

3) placing the flask at 37 ℃ and standing for 5-8 minutes to separate cells;

4) adding 10mL of seeding culture medium/flask;

5) transferring the cell mixture into a sterile 50 ml centrifuge tube and uniformly stirring;

6) counting cells, spreading the cells to a cell plate;

7)15K cells/well, 30uL of medium was added to each well;

8) seeding in wells with 30uL of a breeding medium, each well using a biofilm poly-D-lysine 384-well TC for processing the Combi standard pattern of the microplate;

9) incubate at 37 ℃ with 5% CO2 overnight.

The next day:

administration of Compounds

a) Reference compound preparation

A20-dose reference CH-223191 was prepared in LDV plates with DMSO. The largest working solution of CH-223191 was a 10mM DMSO solution. 2-fold serial dilutions were performed with Bravo.

b) Max and Min Wells

Maximum well 10mM DMSO standard CH-223191 on LDV plate;

the smallest hole is DMSO in LDV plate.

c) 80 nL's were transmitted from LDV panels to composite panels using ECHO according to panel mapping (PE 6008590).

d) Using the Combi Stand mode, 20uL of detection medium was added to each well and mixed well by centrifugation at 2000 rpm for 2 minutes.

e) Starvation treatment of cells

Transfer 29uL of medium to the wells of the cell plate using Bravo;

using Combi vertical mode, 20uL of warm test solution was added to each well and centrifuged at 300 rpm/min for 1 min; incubate 5% CO2 for 1 hour at 37 ℃.

f) Addition of the Compounds

From the composite plate (PE6008590) 10uL dilutions or DMSO (4 fold working solution) were transferred to the cell plate with Bravo. Incubate at 37 ℃ for 1 hour with 5% CO 2.

g) Receptor agonist addition

10uL of 4X ITE working solution (2nM) was added to all wells of the cell plate with Bravo. The total detection system is 40uL/Well and 5% CO2 incubated at 37 ℃ for 4 hours;

the plates were allowed to stand at room temperature for 10 minutes before adding the loading reagents

h) Final assay conditions

Final hole 15 k/hole

Minimum 0.1% DMSO solution

Max:10uM CH-223191

CH-223191CRC, 2-fold dilution to 10uM,20 points

Final concentration of ITE 0.5nM

The next day, add detection buffer and read plate

A. Substrate loading and reading plate

a) Storing and preparing each reagent according to kit instructions

b) Solution A and solution D were removed from a-20 ℃ freezer. After completely thawing, the following mixed solution was prepared

c) Adding the solution A into the solution B with good vortex

d) The solution C is added into the mixture of A and B, and the vortex is good

e) Adding the solution D into the solution A, B, C, and swirling well

f) Add 9.5uL of final solution to each plate using Combi mini-mode

g) Incubate at room temperature in the dark for at least 1 hour, read the plate. The signal can operate for at least 3 hours.

B. Reading the plate with Envision

Envision Reader settings

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

Antagonistic activity against AhR of the compounds of the examples of the invention is shown in table 1.

Table 1 inhibitory Activity of the Compounds of the examples of the present invention

As can be seen from table 1, the compounds of the examples of the present invention showed good antagonistic activity against AhR.

Evaluation of rat pharmacokinetic testing

Male SD rats, weighing around 220g, were fasted overnight and then gavaged with 2mg/kg of a solution of the compound of the invention [ CMC/TW80 as vehicle ]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24h 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, respectively.

Evaluation of mouse pharmacokinetic test

Male ICR mice, weighing about 20-30g, were fasted overnight and then gavaged with 2mg/kg of a solution of the compound of the present invention [ CMC/TW80 as vehicle ]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24h 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, respectively.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. Sulfonamide compounds having the structure of formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof:

in the formula:

x is selected from the group consisting of substituted or unsubstituted groups: c₂-C₆Alkylene radical, C₃-C₁₀Cycloalkylene, 4-10 membered heterocyclylene, C₁-C₆Alkylene radical C₃-C₁₀Cycloalkylene or C₁-C₆Alkylene 4-10 membered heterocyclylene, wherein said substitution is with one or more Ra;

y is selected from: NH or NR⁴Wherein R is⁴Selected from substituted or unsubstitutedThe following groups: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or 4-6 membered heterocyclyl; wherein said substitution is by one or more Ra;

z is selected from: o, NH, NCN, NR⁹Wherein R is⁹Selected from the group consisting of substituted or unsubstituted: c₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₄Aryl or 5-14 membered heteroaryl; wherein said substitution is by one or more Ra;

u is selected from: n or CR¹⁰Wherein R is¹⁰Selected from the group consisting of: H. d or halogen;

R¹selected from the group consisting of substituted or unsubstituted: NH (NH)₂、NR¹¹R¹¹'、C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₄Aryl or 5-14 membered heteroaryl, wherein said substitution is with one or more Ra;

R¹¹and R¹¹' each is independently selected from the group consisting of substituted or unsubstituted: H. c₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, 4-to 10-membered heterocyclic group, C₆-C₁₄Aryl or 5-14 membered heteroaryl, and R¹¹And R¹¹' is not simultaneously H, wherein said substitution means substitution by one or more Ra;

R²selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, cyano, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

R³selected from the group consisting of substituted or unsubstituted: c₆-C₁₄Aryl, 5-14 membered heteroaryl, wherein said substitution is with one or more Ra;

R⁵、R⁶and R⁸Each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, cyano, ester, amino, amido, sulphonylAn amine or urea group; wherein said substitution is by one or more Ra;

R⁷selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, halogen, CF₃、CHF₂、OCF₃、OCHF₂、C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₄Aryl, 5-14 membered heteroaryl, cyano, ester, amine, amide, sulfonamide, or urea; wherein said substitution is by one or more Ra;

ra is selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl hydroxy, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea, wherein said substitution in Ra means substitution by one or more groups selected from: deuterium, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

2. The sulfonamide compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystal form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein the sulfonamide compound has the structure of general formula (II):

wherein,

X、Y、Z、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined in claim 1.

3. The sulfonamide compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystal form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein the sulfonamide compound has the structure of general formula (III):

wherein,

X、Y、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined in claim 1.

4. The sulfonamide compound having the structure of formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof, according to claim 1, wherein the sulfonamide compound has the structure of formula IV:

wherein,

X、R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is as defined in claim 1.

5. The sulfonamide compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof according to claim 1, wherein the sulfonamide compound has the structure of formula V or V':

in the formula,

x is 1, 2,3 or 4;

R_e、R_f、R_mand R_nEach independently selected from: hydrogen, deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

or R_eAnd R_f、R_fAnd R_m、R_mAnd R_nTogether with the C atom to which they are attached form a substituted or unsubstituted group of: c₃-C₆Cycloalkylene, 4-6 membered heterocyclylene, wherein the substitution means substitution with one or more groups selected from: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, 4-to 6-membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea;

R¹²selected from the group consisting of substituted or unsubstituted: CN, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₆-C₁₄Aryl or 5-14 membered heteroaryl; wherein said substitution means being substituted by one or more groups selected from the group consisting of:deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea;

R¹、R²、R³、R⁵、R⁶、R⁷、R⁸and R¹⁰Is defined as in claim 1.

6. The sulfonamide compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof according to any one of claims 1 to 5, wherein R is³Selected from the group consisting of substituted or unsubstituted: phenyl or 5-6 membered heteroaryl, wherein said substitution means substitution by one or more groups selected from the group consisting of: deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkyl hydroxy, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido.

7. The sulfonamide compound of formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein the compound is selected from the group consisting of:

8. a process for the preparation of sulfonamides of formula (I), their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, comprising the steps of:

(i) reacting a compound of formula (P-1) with a compound of formula (Q) in the presence of a base to obtain a compound of formula (P-2);

(ii) in the presence of copper salt, carrying out dehydrogenation reaction on the compound of the formula (P-2) to obtain a compound of the formula (P-3);

(iii) hydrolyzing the compound of formula (P-3) in the presence of a base to obtain a compound of formula (P-4);

(iv) reacting the compound of formula (P-4) with an amine (R) to obtain a compound of formula (I);

in the formula,

X、Y、Z、U、R¹、R²、R³、R⁵、R⁶、R⁷and R⁸As defined in claim 1.

9. A pharmaceutical composition comprising I) one or more compounds of general formula (I) according to any one of claims 1 to 7, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof; and ii) a pharmaceutically acceptable carrier.

10. Use of a sulfonamide compound of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9, for producing a pharmaceutical composition for the prophylaxis and/or treatment of AhR-mediated diseases.