WO2023036195A1 - Dérivé de benzothiophène substitué par du deutérium, sa préparation et son utilisation - Google Patents

Dérivé de benzothiophène substitué par du deutérium, sa préparation et son utilisation Download PDF

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WO2023036195A1
WO2023036195A1 PCT/CN2022/117613 CN2022117613W WO2023036195A1 WO 2023036195 A1 WO2023036195 A1 WO 2023036195A1 CN 2022117613 W CN2022117613 W CN 2022117613W WO 2023036195 A1 WO2023036195 A1 WO 2023036195A1
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group
substituted
alkyl
hydrogen
compound
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PCT/CN2022/117613
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Chinese (zh)
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张翱
沈安成
宋子兰
肖若璇
丁春勇
马静
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上海交通大学
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    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to the field of biomedicine, in particular to a class of deuterium-substituted benzothiophene derivatives and their preparation and use.
  • Stimulator of interferon genes is an important signaling protein in the cGAS-STING signaling pathway of innate immunity.
  • cGAS recognizes the 2', 3'-cGAMP catalyzed by endogenous or exogenous dsDNA, it can bind and activate STING, promotes the transport of STING from the endoplasmic reticulum to the Golgi apparatus, thereby recruiting and phosphorylating TBK1 to activate IRF3 or NF- ⁇ B, and then induce the secretion of type I interferon and other inflammatory factors, and finally produce the effect of inhibiting tumor growth .
  • activating STING can be used as one of the strategies for anti-tumor immunotherapy.
  • STING agonists At present, there are a number of STING agonists in clinical trials, but most of their structural types are cyclic dinucleoside derivatives of the endogenous ligand 2',3'-cGAMP. These compounds have large molecular weight and poor stability. , Most of them can only be administered by intratumoral injection, which greatly limits the clinical application and development of STING agonists. The development of STING agonists with good pharmacokinetic properties and good biological activity is one of the urgent tasks in this field.
  • deuterium atoms In the process of drug development, the introduction of deuterium atoms usually helps to optimize the pharmacokinetic properties of drug molecules and prolong the drug action time, or can reduce the toxicity of drug molecules, enhance the biological activity of drug molecules, and increase the stability of molecules And so on.
  • many domestic and foreign pharmaceutical companies such as BMS, Concert, Suzhou Zelgen, etc.
  • deuterium-containing drugs such as deuterated tetrabenazine, donafenib.
  • deuterated drugs are in clinical trials (such as BMS-986165, VX-984, CTP-656, AVP-786, etc.). It can be seen that deuterated drugs have extensive research value and broad application prospects.
  • the object of the present invention is to provide a compound represented by formula I and its preparation method and application.
  • the first aspect of the present invention provides a compound represented by formula I, or its isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof,
  • X is selected from the group consisting of C(O), CF 2 ;
  • Y is selected from the group consisting of OR a , NHR b , N(R b ) 2 ;
  • R 1 and R 4 are independently selected from the following group: hydrogen, halogen;
  • R 2 and R 3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, C1-C4 alkyl;
  • R a is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, the substitution means being substituted by 1-4 substituents selected from the group consisting of deuterium, C1-C4 Alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);
  • R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, the substitution means being selected from the group 1-4 substituents: hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl;
  • the additional proviso is that at least one of R 2 , R 3 , Ra, R b contains deuterium.
  • X is C(O);
  • Y is selected from the group consisting of OR a , NHR b , N(R b ) 2 ;
  • R 1 and R 4 are independently selected from the following group: hydrogen, halogen;
  • R 2 and R 3 are independently deuterium-substituted C1-C4 alkyl
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, C1-C4 alkyl;
  • R a is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, the substitution means being substituted by 1-4 substituents selected from the group consisting of deuterium, C1-C4 Alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);
  • R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, the substitution means being selected from the group Substitution of 1-4 substituents: hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl.
  • X is C(O);
  • Y is selected from the group consisting of OR a , NHR b , N(R b ) 2 ;
  • R 1 and R 4 are independently selected from the following group: hydrogen, halogen;
  • R 2 and R 3 are independently deuterium-substituted C1-C4 alkyl
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, C1-C4 alkyl;
  • R a is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, the substitution means being substituted by 1-4 substituents selected from the group: C1-C4 alkyl , C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);
  • R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, the substitution means being selected from the group Substitution of 1-4 substituents: hydrogen, halogen, C1-C4 alkyl, C6-C10 aryl.
  • X is CF 2 ;
  • Y is selected from the group consisting of OR a , NHR b , N(R b ) 2 ;
  • R 1 and R 4 are independently selected from the following group: hydrogen, halogen;
  • R 2 and R 3 are independently deuterium-substituted C1-C4 alkyl
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, C1-C4 alkyl;
  • R a is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, the substitution means being substituted by 1-4 substituents selected from the group consisting of deuterium, C1-C4 Alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);
  • R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, the substitution means being selected from the group Substitution of 1-4 substituents: hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl.
  • X is CF 2 ;
  • Y is selected from the group consisting of OR a , NHR b , N(R b ) 2 ;
  • R 1 and R 4 are independently selected from the following group: hydrogen, halogen;
  • R 2 and R 3 are independently deuterium-substituted C1-C4 alkyl
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, C1-C4 alkyl;
  • R a is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, the substitution means being substituted by 1-4 substituents selected from the group: C1-C4 alkyl , C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);
  • R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, the substitution means being selected from the group Substitution of 1-4 substituents: hydrogen, halogen, C1-C4 alkyl, C6-C10 aryl.
  • R 1 and R 4 are independently selected from the group consisting of hydrogen and halogen.
  • R 2 and R 3 are independently deuterated or fully deuterated C1-C4 alkyl groups one or more times.
  • R 2 and R 3 are each independently one or more deuterated or fully deuterated groups selected from the following group: methyl, ethyl, propyl, isopropyl, butyl , tert-butyl.
  • R 2 and R 3 are independently selected from the following group: perdeuteromethyl, perdeuteroethyl, perdeuteropropyl, perdeuteroisopropyl, perdeuterobutyl , All deuterated tert-butyl.
  • both R 2 and R 3 are perdeuteromethyl.
  • R 5 and R 6 are independently selected from the following group: hydrogen, C1-C4 alkyl.
  • R a is selected from the group consisting of hydrogen, substituted or unsubstituted amino, said substitution means being substituted by 1-4 substituents selected from the group consisting of deuterium and C1-C4 alkyl.
  • each occurrence of R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxyl, substituted or unsubstituted C1-C4 alkoxy, said Substitution refers to being substituted by 1-4 substituents selected from the group consisting of deuterium, C1-C4 alkyl, and C6-C10 aryl.
  • R a is not deuterated.
  • R b is not deuterated.
  • the compound is selected from the following group:
  • a second aspect of the present invention provides a pharmaceutical composition comprising:
  • the third aspect of the present invention provides a compound described in the first aspect of the present invention, or its isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof or the second aspect of the present invention
  • the use of the pharmaceutical composition is used for preparing a preparation, and the preparation is used for preventing and/or treating diseases related to type I interferon.
  • the type I interferon-related diseases are selected from the group consisting of infectious diseases, cancer, and autoimmune diseases.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer, and gastric cancer.
  • Figure 1 is the result of tumor inhibition by compound S1 of Example 3.
  • halogen refers to F, Cl, Br or I.
  • C1-C6 alkyl refers to a linear or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl group, neopentyl group, tertyl group, or similar groups.
  • C1-C4 alkyl has a similar meaning.
  • C2-C6 alkenyl refers to a straight chain or branched alkenyl group with 2-6 carbon atoms containing a double bond, including non-limiting ethenyl, propenyl, butenyl , Isobutenyl, Pentenyl and Hexenyl etc.
  • C2-C6 alkynyl refers to a straight-chain or branched-chain alkynyl group with 2-6 carbon atoms containing a triple bond, including without limitation ethynyl, propynyl, butynyl, group, isobutynyl, pentynyl and hexynyl, etc.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, cyclooctyl, etc.
  • C1-C6 alkoxy refers to a straight-chain or branched alkoxy group with 1-6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc. Preference is given to C1-C4 alkoxy.
  • aromatic ring or “aryl” has the same meaning, preferably “C6-C10 aryl”.
  • C6-C10 aryl refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl and the like.
  • halo refers to substitution by halogen.
  • deuterated refers to substitution by deuterium.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • the substituents are for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have a similar meaning.
  • amino is -NH2.
  • the present invention provides the compound represented by formula I, or its isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof,
  • each group is as defined above.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid
  • salts of the compounds of the present invention with bases such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g.
  • lower alkanolammonium salts and other pharmaceutically acceptable amine salts such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • methylamine salts such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salt
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination between the compound of the present invention and water.
  • the compounds of the present invention also include prodrugs of the compounds represented by formula I.
  • prodrug includes itself may be biologically active or inactive, when administered in an appropriate manner, it undergoes metabolism or chemical reactions in the human body to convert into a class of compounds of formula I, or formula I A salt or solution of a compound.
  • the prodrugs include (but are not limited to) carboxylates, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds of the compounds , phosphoramide, glucoside, ether, acetal and other forms.
  • compositions and methods of administration are provided.
  • the present invention also provides a pharmaceutical composition, comprising:
  • the compound of the present invention has excellent antitumor activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and drugs containing the compound of the present invention as the main active ingredient
  • the composition can be used for the treatment, prevention and alleviation of tumor-related diseases.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount range.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents 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 non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antineoplastic drugs).
  • other pharmaceutically acceptable compounds such as antineoplastic drugs.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention has the following main advantages:
  • the compound has excellent pharmacokinetic properties
  • Step 1 Dissolve compound 1a (1eq) in N,N-dimethylformamide, add potassium hydroxide (2eq) and deuteroiodomethane (2.5eq), and react at room temperature for about 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 1b.
  • Step 2 Suspend succinic anhydride (1.5eq) in 1,2-dichloroethane, add aluminum chloride (2eq) at 0°C, and then add compound 1b (1eq) to 1,2-dichloro After adding the ethane solution in about 15 minutes, the temperature of the reaction was raised to 45° C. for about 8 hours. After the reaction is complete, slowly pour the reaction solution into water, then neutralize the reaction solution with 4N hydrochloric acid aqueous solution with 3 times the equivalent of aluminum chloride, and filter after stirring for about 30 minutes. The obtained filter cake is beaten with ethanol, and the filtered cake Compound S1 was obtained by drying.
  • Step 1 Suspend compound 2a (1eq) in dichloromethane, slowly add aluminum chloride (5eq), heat up to 45°C and react for about 1.5 hours. After the reaction is complete, slowly pour the reaction solution into water, neutralize the reaction solution with 4N hydrochloric acid aqueous solution of 3 times equivalent to aluminum chloride, fully stir until the solution is clear, extract with dichloromethane, collect the organic phase and pass through column purification to obtain Compounds 2b and 2c.
  • aluminum chloride 5eq
  • Step 2 Dissolve compound 2b (1eq) in N,N-dimethylformamide, add potassium hydroxide (1.5eq) and deuteroiodomethane (1.5eq), and react at room temperature for about 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 2d.
  • Step 3 Suspend compound 2d (1eq) in tetrahydrofuran, add lithium hydroxide monohydrate (3eq) in water, and react at room temperature for about 2 hours. After the reaction is complete, spin off most of the organic solvents, then slowly add 1N aqueous hydrochloric acid solution dropwise to the remaining solution, adjust the pH to 5-6, filter after the solid is fully separated, beat the obtained filter cake with ethanol, filter and dry the filter cake Compound S2 was obtained.
  • Step 1 Suspend compound S1 (1eq) in methanol, add thionyl chloride (10eq) dropwise under ice-cooling, and react at room temperature for about 8 hours. After the reaction was complete, the reaction solution was spin-dried, the solid was dissolved in ethyl acetate and the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 4a.
  • Step 2 Compound 4a (1eq) was dissolved in dichloromethane, then 1-fluoro-2,6-dichloropyridine tetrafluoroborate (3eq) was added, and the temperature was raised to reflux for about 2 hours. After the reaction was complete, the reaction solution was spin-dried and purified by column to obtain compound 4b.
  • Step 3 Suspend compound 4b (1eq) in tetrahydrofuran, add an aqueous solution of lithium hydroxide monohydrate (3eq), and react at room temperature for about 2 hours. After the reaction is complete, spin off most of the organic solvents, then slowly add 1N aqueous hydrochloric acid solution dropwise to the remaining solution, adjust the pH to 5-6, filter after the solid is fully separated, beat the obtained filter cake with ethanol, filter and dry the filter cake Compound S4 was obtained.
  • Step 1 Dissolve compound 5a (1eq) in dichloromethane under nitrogen atmosphere, add boron tribromide (1.0M solution in dichloromethane, 6eq) dropwise at -78°C, stir for 1 hour and then rise to The reaction was continued at room temperature for about 3 hours. After the reaction was complete, ice water was slowly added to quench, extracted with dichloromethane, and the organic phase was collected and purified by column to obtain compound 5b.
  • boron tribromide 1.0M solution in dichloromethane, 6eq
  • Step 2 Dissolve compound 5b (1eq) in N,N-dimethylformamide, add potassium hydroxide (2eq) and deuteroiodomethane (2.5eq), and react at room temperature for about 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 5c.
  • Step 3 Compound 5c (1eq) was dissolved in acetonitrile, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (1.1eq ), heated to 45°C and reacted overnight. After the reaction was complete, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 5d.
  • Step 4 Suspend compound 5d (1eq) in tetrahydrofuran, add lithium hydroxide monohydrate (3eq) in water, and react at room temperature for about 3 hours. After the reaction is complete, spin off most of the organic solvents, then slowly add 1N aqueous hydrochloric acid solution dropwise to the remaining solution, adjust the pH to 5-6, filter after the solid is fully separated, beat the obtained filter cake with ethanol, filter and dry the filter cake Compound 5e was obtained.
  • Step 5 Dissolve compound 5e (1eq) in N-methylpyrrolidone, add silver carbonate (1.2eq), heat up to 170°C and react for about 1 hour. After the reaction was complete, the reaction solution was cooled and filtered, the filtrate was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 5f.
  • Step 6 Suspend (S)-3-methylsuccinic anhydride (1.5eq) in 1,2-dichloroethane, add aluminum chloride (2eq) at 0°C, and then add compound 5f (1eq ) in 1,2-dichloroethane solution, after about 15 minutes, the reaction temperature was raised to 45°C for about 6 hours. After the reaction is complete, slowly pour the reaction solution into water, then neutralize the reaction solution with 3 times the equivalent of 4N hydrochloric acid aqueous solution in aluminum chloride, fully stir for about 30 minutes, extract with ethyl acetate, collect the organic phase and pass through the column for purification. Compound S5 was obtained.
  • step 6 of compound S5 replace compound 5f with compound 1b, and perform the same operations to obtain compound S6.
  • Step 1 Dissolve compound S1 (1eq) in N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (2eq), N,N-diisopropylethylamine (3eq) and methoxyamine hydrochloride (1.5eq) were reacted at room temperature for about 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound S7.
  • Step 1 Under an inert gas atmosphere, dissolve compound 8a (1eq) in N,N-dimethylformamide, add sodium hydride (60%, 1.5eq) in batches under ice bath, and react at 0°C for about After half an hour, deuterated methyl iodide (1.5 eq) was added dropwise at this temperature, and then the temperature was raised to 70° C. for about 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate and washed with saturated sodium bicarbonate solution, and the organic phase was collected and purified by column to obtain compound 8b.
  • Step 2 Dissolve compound 8b in glacial acetic acid/concentrated hydrochloric acid (volume ratio: 2:1), and heat up to reflux for about 3 hours. After the reaction was complete, the reaction solution was spin-dried to obtain a crude product of compound 8c, which was directly used in the next step without purification.
  • Step 3 Dissolve compound 8d (1eq) in N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (2eq), N,N-diisopropylethylamine (3eq) and crude compound 8c (1.5eq) were reacted at room temperature for about 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound S8.
  • step 3 of compound S8 replace compound 8d with compound S1, and perform the same operations to obtain compound S9.
  • 1 H NMR 400MHz, CD 3 OD
  • 3.39(d, J 6.7Hz, 2H)
  • 2.49(t, J 6.7Hz, 2H).
  • Step 1 Dissolve compound 4a (1eq) in dichloromethane under an inert gas atmosphere, add 1,3-propanedithiol (2eq) and boron trifluoride diethyl ether (48%, 1eq) under ice bath , after reacting at 0° C. for about 1 hour, the reaction was continued at room temperature for about 4 hours. After the reaction was complete, the reaction solution was poured into saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was collected and purified by column to obtain compound 10a.
  • Step 2 Dissolve compound 10a (1eq) in dichloromethane, add diethylaminosulfur trifluoride (20eq) at room temperature, and react for about 1 hour. After the reaction was complete, the reaction solution was slowly poured into saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was collected and purified by column to obtain compound 10b.
  • Step 3 Suspend compound 10b (1eq) in tetrahydrofuran, add an aqueous solution of lithium hydroxide monohydrate (3eq), and react at room temperature for about 3 hours. After the reaction was complete, most of the organic solvent was spun off, and then 1N hydrochloric acid aqueous solution was slowly added dropwise to the remaining solution to adjust the pH to 5-6, extracted with dichloromethane, and the organic phase was collected and purified by column to obtain compound S10.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 7.35(s,1H),7.25(s,1H),7.20(s,1H),2.71–2.63(m,4H).
  • Step 1 Synthetic steps refer to compound S7: O-(tert-butyldiphenylsilyl)-N-methylhydroxylamine was used to replace methoxylamine hydrochloride, and other operations were the same to obtain compound 15a.
  • Step 2 Dissolve compound 15a (1eq) in tetrahydrofuran, add pyridine hydrofluoride (3eq) under ice-cooling, and react for about 2 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected for column purification to obtain compound S15.
  • Step 1 Under an inert gas atmosphere, add hydroxylamine hydrochloride (3eq) to potassium hydroxide (3eq) solution in methanol, react for about 30 minutes, then add compound 4a (1eq), and continue the reaction for about 6 hours. After the reaction was complete, it was directly purified by column to obtain compound S16.
  • Step 1 Synthetic steps refer to compound 4a: Compound S1 is replaced by compound S5, and other operations are the same to obtain compound 17a.
  • Step 2 Synthetic steps refer to compound S10: replace compound 4a with compound 17a, and perform the same operations to obtain compound S17.
  • Step 1 Dissolve compound S1 (1eq) in N,N-dimethylformamide, add 2-(1H-benzotrisazoL-1-yl)-1,1,3,3-tetramethyl Urea tetrafluoroborate (2eq), N,N-diisopropylethylamine (3eq) and N-isopropylhydroxylamine hydrochloride (1.5eq) were reacted at room temperature for about 2 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound S18.
  • the present invention discloses the pharmacokinetics of compound IA without deuterium atom substitution in patent CN111393404A and deuterium-substituted compounds S7, S8, and S9 described in the present invention in rats academic properties were compared.
  • mice 12 male SD rats, body weight 223-254g, were randomly divided into 4 groups, 3 rats in each group, given IA/S7/S8/S9 intravenously, and the dosage was 1mg/kg. Fasted overnight before administration, ate food 4 hours after administration, and drank water freely. At 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 h, 60 ⁇ L blood samples were collected from rats through the jugular vein into micro K 2 EDTA tubes, centrifuged at 8000 rpm for 6 min, separated from plasma, and frozen in a -20°C refrigerator.
  • the concentration of IA, S7, S8, and S9 in rat plasma was determined by LC-MS/MS, and the pharmacokinetic parameters after administration were calculated using the non-compartmental model of WinNonlin 8.2.0 software (Pharsight, USA).
  • THP-1 cells were seeded in a 12-well plate at a density of 6*10 5 /mL, treated with 10 ⁇ M compound after 12 hours, collected by centrifugation at 500 g for 5 minutes after 8 hours, and lysed by adding 1 mL TRIzol to each cell pellet.
  • TRIzol operating instructions mRNA was extracted and its concentration was determined.
  • 500ng mRNA was used to reverse transcribe it into cDNA using PrimeScriptTM RT Master Mix Kit (TAKARA).
  • qPCR Mix Kit TOYOBO
  • 480 480
  • mice 16 4-6 week-old Balb/C female mice were injected with CT-26 cells (2.5*10 5 ), and the tumor volume grew to 50-100 mm 3 .
  • the mice were randomly divided into 2 groups, 8 mice in each group, and the compound S1 (10 mg/kg) was injected intratumorally on the 1st, 4th, and 7th day, respectively, for a total of 3 times.
  • Animals were randomly grouped and body weight was recorded, and each mouse in the group was marked after grouping; the body weight and tumor volume of the mice were measured every two days, and the state of the mice was observed and recorded at any time.
  • the compound S1 described in the present invention can effectively inhibit tumor growth in the CT26 mouse colorectal cancer model. After intratumoral injection of 10 mg/kg, after 3 administrations, the tumor growth inhibition rate reached 79.74%. .
  • the compounds substituted with deuterium described in the present invention have higher activation ability to STING, and the pharmacokinetic properties in rats are improved, which makes the compounds of the present invention enter the body with pharmacodynamics and safety. Its efficacy can be fully exposed during the sexual evaluation, and it has significant advantages and potential for further research and development compared with the STING agonists reported so far.

Abstract

La présente invention concerne un dérivé de benzothiophène substitué par du deutérium, sa préparation et son utilisation. En particulier, le composé selon la présente invention a la structure représentée par la formule I, les définitions de chaque groupe et substituant sont telle que décrite dans la description. Le composé a d'excellentes propriétés pharmacocinétiques et une activité agoniste de STING.
PCT/CN2022/117613 2021-09-08 2022-09-07 Dérivé de benzothiophène substitué par du deutérium, sa préparation et son utilisation WO2023036195A1 (fr)

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WO2019027857A1 (fr) * 2017-08-04 2019-02-07 Merck Sharp & Dohme Corp. Combinaisons d'antagonistes de pd-1 et d'agonistes de sting benzo[b]thiophéniques pour le traitement du cancer
CN110036001A (zh) * 2016-10-04 2019-07-19 默沙东公司 作为STING激动剂的苯并[b]噻吩化合物
CN111393404A (zh) * 2019-01-02 2020-07-10 中国科学院上海药物研究所 一类苯并噻吩类化合物及其药物组合物及应用
CN111971277A (zh) * 2018-04-03 2020-11-20 默沙东公司 作为sting激动剂的苯并噻吩及相关化合物
WO2021113679A1 (fr) * 2019-12-06 2021-06-10 Mersana Therapeutics, Inc. Composés dimères utilisés en tant qu'agonistes de sting
CN113518776A (zh) * 2019-04-30 2021-10-19 四川科伦博泰生物医药股份有限公司 苯并噻吩类化合物及其制备方法和用途

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CN111393405B (zh) * 2019-01-02 2022-11-25 中国科学院上海药物研究所 一类含氟取代的苯并噻吩类化合物及其药物组合物及应用

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CN110036001A (zh) * 2016-10-04 2019-07-19 默沙东公司 作为STING激动剂的苯并[b]噻吩化合物
WO2019027857A1 (fr) * 2017-08-04 2019-02-07 Merck Sharp & Dohme Corp. Combinaisons d'antagonistes de pd-1 et d'agonistes de sting benzo[b]thiophéniques pour le traitement du cancer
CN111971277A (zh) * 2018-04-03 2020-11-20 默沙东公司 作为sting激动剂的苯并噻吩及相关化合物
CN111393404A (zh) * 2019-01-02 2020-07-10 中国科学院上海药物研究所 一类苯并噻吩类化合物及其药物组合物及应用
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