[go: up one dir, main page]

WO2018137614A1 - Dérivé d'hétéroarothiadiazide-2,2-dioxyde, son procédé de préparation et application de celui-ci dans un médicament - Google Patents

Dérivé d'hétéroarothiadiazide-2,2-dioxyde, son procédé de préparation et application de celui-ci dans un médicament Download PDF

Info

Publication number
WO2018137614A1
WO2018137614A1 PCT/CN2018/073815 CN2018073815W WO2018137614A1 WO 2018137614 A1 WO2018137614 A1 WO 2018137614A1 CN 2018073815 W CN2018073815 W CN 2018073815W WO 2018137614 A1 WO2018137614 A1 WO 2018137614A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
formula
cycloalkyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/073815
Other languages
English (en)
Chinese (zh)
Inventor
张国宝
陈一千
贺峰
陶维康
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN201880004318.3A priority Critical patent/CN109937205B/zh
Publication of WO2018137614A1 publication Critical patent/WO2018137614A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medicine, and relates to a novel heteroarylthiathiadiazine-2,2-dioxide derivative represented by the general formula (I), a preparation method thereof and a pharmaceutical composition containing the same And its use as a therapeutic, especially as a TLR7 agonist.
  • TLRs Toll-like receptors
  • TLRs are important protein molecules involved in innate immunity.
  • TLRs are non-catalytic receptors for monomeric transmembranes, usually expressed in sentinel cells such as macrophages and dendritic cells, and can recognize structurally conserved molecules produced by microorganisms. Once these microorganisms break through physical barriers such as the skin or intestinal mucosa, they are recognized by TLRs, which in turn activate immune cell responses (Mahla, R S. et al., Front Immunol. 4:248 (2013)). The ability of the immune system to broadly recognize pathogenic microorganisms is due in part to the widespread presence of Toll-like immunoreceptors.
  • TLR7 is a member of a subset of TLRs (TLRs 3, 7, 8, and 9) and is restricted to the endosomal compartment of cells that specifically detect non-hexucleic acids. TLR7 plays a key role in recognizing ssRNA antiviral defense (Diebold S.S. et al, Science, 2004: 303, 1529-1531; and Lund J. M. et al, PNAS, 2004: 101, 5598-5603).
  • TLR7 has a limited expression profile in humans and is expressed primarily by B cells and plasmacytoid dendritic cells (pDC), but to a lesser extent by monocytes.
  • Plasmacytoid DCs are the only population of lymphoid-derived dendritic cells (0.2-0.8% of peripheral blood mononuclear cells (PBMCs)) that secrete high levels of interferon- ⁇ (IFN ⁇ ) and interferon in response to viral infections.
  • PBMCs peripheral blood mononuclear cells
  • IFN ⁇ interferon- ⁇
  • the first type I interferon-producing cell of ⁇ (IFN ⁇ ) Liu YJ, Annu. Rev. Immunol., 2005: 23, 275-306).
  • TLRs diseases and disorders are associated with abnormalities in TLRs such as melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD). ), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV, RSV, SARS, HIV or influenza virus infection. Therefore, the use of agonists for TLRs to treat related diseases is promising.
  • TLR7 and TLR8 are highly homologous, the TLR7 ligand, in most cases, is also a TLR8 ligand.
  • TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines.
  • TNF-alpha tumor necrosis factor alpha
  • Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C
  • TNF- ⁇ is a pro-inflammatory cytokine, and excessive secretion may cause serious side effects. Therefore, selectivity for TLR7 and TLR8 is critical for the development of TLR7 agonists for the treatment of viral infectious diseases.
  • TLR7 agonist patent applications such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO2012080730.
  • TLR7 agonists there are currently related TLR7 agonist patent applications, such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO2012080730.
  • TLR7 agonists such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO2012080730.
  • the present invention is directed to the above technical problems, and provides a drug compound having a lower incineration concentration, a better selectivity, and a more effective activation effect, and is a safer and more effective TLR7 agonist.
  • Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • G is selected from N and CR 6 ;
  • X 1 is selected from an alkylene group or S(O) m , wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, and nitrate Substituted by one or more substituents of a group, a cycloalkyl group and a heterocyclic group;
  • L 1 is selected from -NR 7 -, -O-, -S-, -C(O)-, -S(O) m -, -N(R 7 )C(O)-, -C(O)N (R 7 )-, -N(R 7 )S(O) 2 -, -S(O) 2 N(R 7 )- and a covalent bond;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, and the cycloalkyl group are selected.
  • a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;
  • R is the same or different and are each independently selected from hydrogen, halo, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl a base, a heteroaryl group, -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 and -C(O)NR 9 R 10 , wherein
  • the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitrate Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • L 2 is selected from an alkylene group or a covalent bond, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, Substituting one or more substituents of a cycloalkyl group and a heterocyclic group;
  • R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C (O) R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 and -C(O)NR 9 R 10 wherein the cycloalkyl group, heterocyclic group And the aryl and heteroaryl are each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl group, a heteroaryl group, -
  • R 4 and R 5 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a heterocyclic ring.
  • Base aryl and heteroaryl;
  • R 4 and R 5 together form an oxo group
  • R 6 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 9 and R 10 are the same or different and are each independently selected from hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, cycloalkyl,
  • the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aromatic Substituted with one or more substituents in the heteroaryl group;
  • R 9 and R 10 together with a nitrogen atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms which are the same or different from N, O and S, and
  • the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by a plurality of substituents;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • the compound of the formula (I), wherein the ring A is selected from the group consisting of a phenyl group and a pyridyl group.
  • the compound of the formula (I), wherein the X 1 is an alkylene group is an alkylene group.
  • the compound of the formula (I) is a compound of the formula (II):
  • G, L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III):
  • R 9 and R 10 together with a nitrogen atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group contains 1 to 2 hetero atoms which are the same or different and are selected from N, O and S, and the heterocyclic ring
  • the group is optionally substituted with one or more selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted, preferably 5-6 membered heterocyclic group, more preferably pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or tetrahydropyranyl;
  • G, L 1 to L 2 and R 1 are as defined in the formula (I).
  • the compound of the formula (I), wherein the L 2 is an alkylene group, preferably a C 1-6 alkylene group, more preferably a methylene group. 1,2-ethylene, 1,1-ethylene or 1,3-propylene.
  • Typical compounds of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • a compound of the formula (IB) is an intermediate for the preparation of a compound of the formula (I):
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • X is a halogen
  • S is 1 or 2;
  • Rings A, G, X 1 , L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • the compound represented by the formula (IB) includes, but is not limited to:
  • a compound of the formula (IC) is used as an intermediate for the preparation of a compound of the formula (I):
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • S is 1 or 2;
  • Rings A, G, X 1 , L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • Compounds of the formula (IC) include, but are not limited to:
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (IB) which comprises:
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • X is a halogen;
  • S is 1 or 2;
  • Rings A, G, X 1 , L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (IC), the process comprising:
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • X is a halogen;
  • S is 1 or 2;
  • Rings A, G, X 1 , L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • S is 1 or 2;
  • Rings A, G, X 1 , L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same in the manufacture of a medicament for a TLR7 agonist.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of a medicament for treating an infection caused by a virus selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus , ⁇ ⁇ encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV , SARS and influenza viruses.
  • a virus selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus , ⁇ ⁇ encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encepha
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for use in the treatment or prevention of melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD Use in drugs for ulcerative colitis and liver fibrosis.
  • the invention further relates to a method of agonizing TLR7 comprising the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer
  • a method of agonizing TLR7 comprising the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer
  • the invention further relates to a method of treating an infection caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, ink Dementia encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza viruses, the method comprising administering A therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, is required. Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, ink
  • the invention further relates to a treatment or prevention of melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, autoimmune diseases a method of plaque psoriasis, systemic lupus erythematosus, actinic keratosis, and liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, A meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a compound of the formula (I) or a tautomer thereof A meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same, which is used as a medicament.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same, which is for use in a TLR7 agonist.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same for use in the treatment or prevention of an infection caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, rumor Encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and flu virus.
  • a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, rumor Encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemo
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same for use in the treatment or prevention of melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis and liver fibrosis.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavor.
  • Oil suspensions can be formulated by suspending the active ingredient in vegetable oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of the active ingredient and dispersion or dispersing or suspending agents or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt
  • the type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpent
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently selected from alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 and -C(O Substituting one or more substituents in NR 9 R 10 .
  • alkylene refers to a saturated straight or branched aliphatic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
  • alkylene examples include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 ) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently selected from alkyl, alkenyl, alkynyl groups.
  • alkenyl refers to a hydrocarbon group formed by one or more hydrogen atoms in the olefin molecule.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a hydroxyl group, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 8, -C (O) OR 8, -S (O) m R Substituting one or more substituents of 8- , -NR 9 R 10 and -C(O)NR 9 R 10 .
  • alkynyl refers to a hydrocarbon containing a carbon-carbon triple bond in the molecule.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a hydroxyl group, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 8 , -C(O)OR 8 , -S(O) m R Substituting one or more substituents of 8- , -NR 9 R 10 and -C(O)NR 9 R 10 .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 10 The carbon atom, more preferably contains 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • amino protecting group is intended to keep the amino group unchanged during the reaction of other parts of the molecule, and to protect the amino group with a group which is easily removed.
  • Non-limiting examples include t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with from 1 to 3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably p-methoxybenzyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, High piperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • alkylthio alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, oxo, -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 and -C(O)NR Substituting one or more substituents in 9 R 10 .
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, One of a heterocycloalkylthio group, -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 and -C(O)NR 9 R 10 or Substituted by a plurality of substituents.
  • the substituent is preferably one or more of the following groups, which are independently optionally selected from the group consisting of alky
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio
  • One of a heterocycloalkylthio group, -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 and -C(O)NR 9 R 10 Or substituted with multiple substituents.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group.
  • a hydroxyl group substituted by one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • a method for preparing a medicinal salt comprising the steps of:
  • a compound of the formula (I-1) and NH(W) s are subjected to a nucleophilic substitution reaction under basic conditions to obtain a compound of the formula (I-2);
  • a compound of the formula (I-2) and a compound of the formula (I-3) are subjected to a nucleophilic substitution reaction under basic conditions to obtain a compound of the formula (I-4);
  • the compound of the formula (I-4) is subjected to a reduction reaction in the presence of a reducing reagent to obtain a compound of the formula (IA);
  • the fourth step the compound of the formula (IA) and a nucleophilic substitution reaction under basic conditions to give a compound of the formula (IB);
  • the compound of the formula (IB) is subjected to ring closure in the presence of iodide under basic conditions to obtain a compound of the formula (IC);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and n-butyl.
  • organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and n-butyl.
  • said inorganic bases including but not limited to sodium hydride, Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf;
  • the reducing reagents include, but are not limited to, iron powder, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH, B 2 H 5 . , Li(Et) 3 BH, Pd/C/H 2 and Raney Ni/H 2 ;
  • Iodide includes, but is not limited to, iodine, iodinated ketone, potassium iodide, and cesium iodide;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof;
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • X is a halogen, preferably chlorine
  • S is 1 or 2;
  • Rings A, G, X 1 , L 1 to L 2 , R 1 to R 5 and n are as defined in the formula (I).
  • the fourth step the compound of the formula (II-A) and a nucleophilic substitution reaction under basic conditions to give a compound of the formula (II-B);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and n-butyl.
  • organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and n-butyl.
  • said inorganic bases including but not limited to sodium hydride, Potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the reducing agents include, but are not limited to: iron, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH (Ot -Bu) 3, AlH 3, NaCNBH 3, Na (AcO) 3 BH, B 2 H 5 , Li(Et) 3 BH, Pd/C/H 2 and Raney Ni/H 2 ;
  • Iodide includes, but is not limited to, iodine, iodinated ketone, potassium iodide, and cesium iodide;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof;
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • G, n, L 1 to L 2 and R 1 to R 5 are as defined in the formula (II).
  • a compound of the formula (I-1) and NH-(W) s are subjected to a nucleophilic substitution reaction under basic conditions to obtain a compound of the formula (I-2);
  • a compound of the formula (I-2) and a compound of the formula (III-1) are subjected to a nucleophilic substitution reaction under basic conditions to obtain a compound of the formula (III-2);
  • the fourth step the compound of the formula (III-A) and a nucleophilic substitution reaction under basic conditions to give a compound of the formula (III-B);
  • the compound of the formula (III-B) is subjected to ring closure in the presence of iodide under basic conditions to obtain a compound of the formula (III-C);
  • Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf;
  • the reducing reagents include, but are not limited to, iron powder, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH, B 2 H 5 . , Li(Et) 3 BH, Pd/C/H 2 and Raney Ni/H 2 ;
  • Iodide includes, but is not limited to, iodine, iodinated ketone, potassium iodide, and cesium iodide;
  • W is an amino protecting group, preferably t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl;
  • S is 1 or 2;
  • G, L 1 to L 2 , R 1 and R 9 to R 10 are as defined in the formula (III).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • TLC thin layer chromatography
  • A Methylene chloride/methanol system
  • B n-hexane/ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • Determination of the compounds of the present invention adopts the following experimental method hTLR7 protein activation HEK-Blue TM hTLR7 expression in stably transfected cell lines of:
  • PBS Phosphate buffer pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320).
  • HEK-Blue assay medium Take a bag of HEK-Blue dry powder, add 50ml to endotoxin water to dissolve, then put it into the 37 °C incubator, and then sterile filtration after 10 minutes.
  • the compound was first formulated into a 20 mM stock solution; it was diluted with pure DMSO to a maximum concentration of 6 x 106 nM and diluted by a 3-fold gradient for a total of 10 points.
  • the above-prepared compound was diluted 20-fold with a medium, and then 20 ⁇ l of the diluted compound was added to each well.
  • the cells were resuspended in HEK-Blue assay medium at a concentration of 2.2 ⁇ 10 5 cells/ml, and 180 ⁇ l of the cells were added to the above 96-well cell culture plate to which 20 ⁇ l of the drug had been added, and cultured at 37 ° C for 6-16 hours.
  • the microplate reader reads at a wavelength of 620 nm. Corresponding OD values obtained by Graphpad Prism calculated EC 50 value of the drug.
  • the activation of human TLR7 by the compounds of the present invention can be determined by the above test, and the measured EC 50 values are shown in Table 1.
  • Table 1 Compound of the present invention to the human EC TLR7 50.
  • the compounds of the present invention have a good activation effect on human TLR7.
  • Test Example 2 Determination of agonistic activity of human TLR8 by the compound of the present invention
  • Determination of the compounds of the present invention adopts the following experimental method hTLR8 protein activation HEK-Blue TM hTLR8 expression in stably transfected cell lines of:
  • PBS Phosphate buffer pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320).
  • HEK-Blue assay medium Take a bag of HEK-Blue dry powder, add 50ml to endotoxin water to dissolve, then put it into the 37 °C incubator, and then sterile filtration after 10 minutes.
  • Compound is first formulated as a 20mM stock solution; neat DMSO and then diluted to a maximum concentration of 6 ⁇ 10 6 nM, and then diluted 3 fold gradient, a total of 10 points; first compound is diluted 20-fold with medium and then diluted with 20 ⁇ l added per well After the compound.
  • HEK-Blue TM hTLR8 cells Take HEK-Blue TM hTLR8 cells, first remove the supernatant, add 2-5 ml of pre-warmed PBS, put into the incubator for 1-2 minutes, gently pipe the cells, and trypan blue staining. The cells were resuspended in HEK-Blue assay medium at a concentration of 2.2 ⁇ 10 5 cells/ml, and 180 ⁇ l of the cells were added to the above 96-well cell culture plate to which 20 ⁇ l of the drug had been added, and cultured at 37 ° C for 6-16 hours.
  • the microplate reader reads at a wavelength of 620 nm.
  • the corresponding OD value can be obtained, and the EC 50 value of the drug is calculated by Graphpad Prism.
  • Table Compound 2 of the present invention to human TLR8, EC 50.
  • the compounds of the present invention have weak activation on human TLR8, indicating that the compounds of the present invention are selective for TLR7.
  • RMPI 1640 medium containing 10% FBS Resuspend and count with RMPI 1640 medium containing 10% FBS, adjust the amount of PBMC to 3.33 ⁇ 10 6 cells/ml, take 150 ⁇ l to the cell culture plate to which the compound has been added, and incubate at 37 ° C, 5.0% CO 2 The medium was cultured for 24 hours.
  • the cell culture plate was placed in a centrifuge, centrifuged at 1200 rpm for 10 minutes at room temperature. 150 ⁇ l of the supernatant was taken out per well.
  • the reagent in the human IFN- ⁇ kit is firstly equilibrated to room temperature, and anti-IFN- ⁇ -Eu 3+ - Cryptate conjugate and anti-IFN- ⁇ - are prepared according to the kit instructions in the dark.
  • the d2-conjugate both mixed in a 1:40 ratio with a conjugate buffer. Then, 16 ⁇ l of the supernatant obtained by centrifugation was added to each well.
  • the HTRF mode is read on the PHERAStar.
  • MEC Minimum Effective Concentration
  • Test Example 4 Inhibition of the Enzymatic Activity of the Compound of the Invention on the Metabolite of the Metabolite of CYP3A4 Midazolam in Human Liver Microsomes
  • PBS Phosphate buffer
  • CYP probe substrate (15 ⁇ M midazolam, SIGMA UC429) and positive control inhibitor (ketoconazole, SIGMA K1003).
  • the compound of the present invention has no inhibitory effect on the midazolam metabolic site of human liver microsome CYP3A4, and shows better safety, suggesting that metabolites based on CYP3A4 metabolism of midazolam metabolite sites do not occur. effect.
  • the activity of the compound of the present invention on human liver microsome CYP2D6 enzyme activity was determined by the following experimental method:
  • PBS Phosphate buffer
  • CYP probe substrate (20 ⁇ M dextromethorphan, SIGMA Q0750) and positive control inhibitor (Quinidine, SIGMA D9684).
  • Test Example 6 Inhibition of Enzyme Activity of Testosterone Metabolism Site of Human Liver Microsome CYP3A4 by Human Compound Microsomes
  • the enzymatic activity of the compound of the present invention on the testosterone metabolism site of human liver microsome CYP3A4 was determined by the following experimental method:
  • PBS Phosphate buffer
  • CYP probe substrate testosterone / 100 ⁇ M, SIGMA K1003
  • positive control inhibitor ketoconazole, Dr. Ehrenstorfer GmbH, C17322500
  • the compound of the present invention has no inhibitory effect on the testosterone metabolism site of human liver microsome CYP3A4, and shows better safety, suggesting that metabolic drug interaction based on CYP3A4-based testosterone metabolism site does not occur.
  • the blocking effect of the compounds of the invention on hERG potassium current was tested using a fully automated patch clamp on a stable cell line transfected with hERG potassium channels.
  • the HEK293-hERG stable cell line was passaged at a density of 1:4 in MEM/EBSS medium (10% FBS, 400 ⁇ g/ml G418, 1% MEM non-essential amino acid solution (100 ⁇ ), 1% sodium pyruvate solution). Culture, culture within 48-72 hours for automated patch-clamp experiments.
  • the instrument When the whole cell mode is formed, the instrument will get the hERG current according to the set hERG current voltage program, and then the instrument will automatically perfuse the compound from low to high concentration.
  • the currents at each concentration of the compounds and the blank control current were analyzed by HEAK Patchmaster, HEAK EPC10 patch clamp amplifiers (Nanion) and Pathlinersoftware and data analysis software provided by Pathcontrol HTsoftware.
  • the compounds of the present invention have a weak inhibitory effect on hERG and can reduce side effects caused by the hERG pathway.
  • Test Example 8 Mouse pharmacokinetic test of the compound of the present invention
  • mice Using mice as test animals, the concentration of the drug in plasma at different times after administration of the compound of Example 1 by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in mice was investigated and their pharmacokinetic characteristics were evaluated.
  • a certain amount of the drug was weighed, and 5% by volume of DMSO, 5% by volume of tween 80, and 90% physiological saline were set to 1 mg/ml of a colorless clear liquid.
  • mice were intragastrically administered overnight after fasting, and the dose was 20.0 mg/kg, and the administration volume was 20 ml/kg.
  • Example 1 The compound of Example 1 was administered by gavage in mice, and 0.1 ml of blood was collected before administration and after 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration, and placed in a heparinized test tube, 3500 rpm. The plasma was separated by centrifugation for 10 minutes at /min and stored at -20 °C.
  • the content of the test compound in the plasma of the mice after the intragastric administration of different concentrations of the drug was determined: 25 ⁇ l of the mouse plasma at each time after administration, 50 ⁇ l (100 ng/mL) of the internal standard solution, and 200 ⁇ l of acetonitrile were added. The mixture was vortexed for 5 minutes, centrifuged for 10 minutes (3600 rpm), and 10 ⁇ l of the supernatant was taken for LC/MS/MS analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the compounds of the present invention have better pharmacological absorption and have pharmacokinetic advantages.
  • Test sample Test Example 8 Pharmacokinetics The mice of Example 1 were administered intragastrically, and blood was collected before administration and at 0, 2.0, 4.0 and 8.0 hours after administration.
  • I.g. is administered by intragastric administration.
  • the compound of Example 1 was administered with 20 mpk in mice for 2 hours and had a strong ability to stimulate IFN- ⁇ expression.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'hétéroarothiadiazide-2,2-dioxyde, son procédé de préparation et une application de celui-ci dans un médicament. L'invention concerne particulièrement, un nouveau dérivé d'hétéroarothiadiazide-2,2-dioxyde représenté par la formule (I), son procédé de préparation, une composition pharmaceutique contenant le dérivé, et une utilisation en tant qu'agent thérapeutique, en particulier en tant qu'agoniste TLR7. Selon la présente invention, chaque groupe substituant dans la formule (I) est tel que défini dans la description.
PCT/CN2018/073815 2017-01-24 2018-01-23 Dérivé d'hétéroarothiadiazide-2,2-dioxyde, son procédé de préparation et application de celui-ci dans un médicament Ceased WO2018137614A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880004318.3A CN109937205B (zh) 2017-01-24 2018-01-23 杂芳基并噻二嗪-2,2-二氧化物类衍生物、其制备方法及其在医药上的应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710059379.7 2017-01-24
CN201710059379 2017-01-24

Publications (1)

Publication Number Publication Date
WO2018137614A1 true WO2018137614A1 (fr) 2018-08-02

Family

ID=62978957

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/073815 Ceased WO2018137614A1 (fr) 2017-01-24 2018-01-23 Dérivé d'hétéroarothiadiazide-2,2-dioxyde, son procédé de préparation et application de celui-ci dans un médicament

Country Status (3)

Country Link
CN (1) CN109937205B (fr)
TW (1) TW201827442A (fr)
WO (1) WO2018137614A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202246260A (zh) * 2021-02-03 2022-12-01 大陸商江蘇恆瑞醫藥股份有限公司 稠合的氮雜三環類衍生物、其製備方法及其在醫藥上的應用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011031965A1 (fr) * 2009-09-14 2011-03-17 Gilead Sciences, Inc. Modulateurs des récepteurs de type toll (tlr)
CN102272134A (zh) * 2008-12-09 2011-12-07 吉里德科学公司 Toll样受体调节剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102272134A (zh) * 2008-12-09 2011-12-07 吉里德科学公司 Toll样受体调节剂
WO2011031965A1 (fr) * 2009-09-14 2011-03-17 Gilead Sciences, Inc. Modulateurs des récepteurs de type toll (tlr)

Also Published As

Publication number Publication date
CN109937205A (zh) 2019-06-25
CN109937205B (zh) 2021-12-21
TW201827442A (zh) 2018-08-01

Similar Documents

Publication Publication Date Title
JP7145854B2 (ja) ピラゾロ‐ヘテロアリール誘導体、その製造方法及び医学的用途
WO2018210298A1 (fr) Dérivés d'hétéroaryle pyrazole, leur procédé de préparation et leur application médicale
CN108794486B (zh) 稠环基酮类衍生物、其制备方法及其在医药上的应用
CN108948016B (zh) 嘌呤酮类衍生物、其制备方法及其在医药上的应用
TW200918528A (en) DNA-PK inhibitors
CN110317202B (zh) 氰基吡咯并杂芳基类衍生物、其制备方法及其在医药上的应用
WO2010082044A1 (fr) Dérivés hétérocycliques bicycliques insaturés utilisés comme antagonistes de smo
WO2018137614A1 (fr) Dérivé d'hétéroarothiadiazide-2,2-dioxyde, son procédé de préparation et application de celui-ci dans un médicament
WO2019057158A1 (fr) Dérivés hétéroaryles condensés, procédé de préparation de ceux-ci et leur application en médecine
TWI700281B (zh) 苯並氮雜䓬衍生物、其製備方法及其在醫藥上的應用
CN114502556B (zh) 一种联苯基氟代双键衍生物及其制备方法和在药学上的应用
JP2020504109A (ja) アザビシクロ置換トリアゾール誘導体、その調製方法、及びその医薬用途
HK1261626B (zh) 吡唑并杂芳基类衍生物、其制备方法及其在医药上的应用
TW202140009A (zh) ３－甲醯胺基－４－羥基納曲酮氘代衍生物、其製備方法及其在醫藥上的應用
JP2025521097A (ja) Ｌｒｒｋ２阻害剤
HK40013347A (en) Heteroaryl-pyrazole derivative, and preparation method therefor and medical application thereof
WO2022214009A1 (fr) Inhibiteur de la kinase hpk1 à haute activité

Legal Events

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

Ref document number: 18744842

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18744842

Country of ref document: EP

Kind code of ref document: A1