WO2020140894A1 - 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 - Google Patents

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 Download PDF

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WO2020140894A1
WO2020140894A1 PCT/CN2019/130605 CN2019130605W WO2020140894A1 WO 2020140894 A1 WO2020140894 A1 WO 2020140894A1 CN 2019130605 W CN2019130605 W CN 2019130605W WO 2020140894 A1 WO2020140894 A1 WO 2020140894A1
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compound
group
pharmaceutically acceptable
alkyl
substituted
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PCT/CN2019/130605
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English (en)
French (fr)
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张翱
耿美玉
丁春勇
谢作权
丁健
张燕
沈安成
王玺渊
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中国科学院上海药物研究所
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Priority to BR112021013099-3A priority Critical patent/BR112021013099A2/pt
Priority to EP19907455.0A priority patent/EP3907221A4/en
Priority to US17/420,389 priority patent/US20220089561A1/en
Priority to CA3125505A priority patent/CA3125505C/en
Priority to AU2019419663A priority patent/AU2019419663B2/en
Priority to KR1020217024365A priority patent/KR102606167B1/ko
Priority to JP2021539037A priority patent/JP7329052B2/ja
Publication of WO2020140894A1 publication Critical patent/WO2020140894A1/zh

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    • 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
    • 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
    • C07D333/56—Radicals substituted by oxygen atoms
    • 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
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • 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
    • 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
    • C07D333/58—Radicals substituted by nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicine, in particular to a class of fluorine-substituted benzothiophene compounds and their pharmaceutical compositions and applications.
  • interferon gene stimulating protein As a regulator of cytokine signaling pathway, interferon gene stimulating protein is closely related to the pathology and clinical symptoms of various diseases, including infectious diseases, cancer and autoimmune diseases.
  • the protein is a transmembrane protein, usually in the region of 152-173 junction to form a dimer and is in a state of self-inhibition.
  • the molecular configuration When stimulated by a partial ligand, such as cyclic dinucleotide, the molecular configuration changes and is activated, recruiting TANK-binding kinase 1 (TBK1) in the cytoplasm, mediating the phosphorylation of IRF3 by TBK1 Chemical conversion, leading to the formation of interferon (IFN)- ⁇ and various other cytokines, and through a series of cascade reactions, activate the adaptive immune system and activate T cells.
  • a partial ligand such as cyclic dinucleotide
  • TAE tumor microenvironment
  • TIL tumor infiltrating lymphocyte
  • type I IFN plays a key role in the activation of tumor activated T cells.
  • STING agonists not only induce the expression of type I interferon genes, but also play an important role in the natural immune signaling pathway; it can also activate immune stimulating cells including dendritic cells, change the tumor microenvironment and induce tumor-specific T cells Generation, which in turn kills tumor cells.
  • cyclic guanylate-adenylate synthase (cGAS)/STING signaling pathway can not only induce the production of cytokines, activate tumor-targeted T cells, but also trigger the body's immune response to tumor cells, thereby enhancing tumors.
  • the efficacy of radiochemotherapy, such as cGAS can sense the DNA released by the killed tumor cells to activate STING to induce dendritic cells to produce type I interferon, which in turn activates the potential anti-tumor immune response and enhances radiochemotherapy Efficacy.
  • Interferon gene-stimulating protein agonists have shown some potential in combination with other immune checkpoint inhibitors. Although two monoclonal antibody drugs have been successfully marketed for the immune checkpoint PD-1/PD-L1, the overall efficiency of such drugs is relatively low, only about 20-30%. PD-1/L1 inhibitors can relieve the inhibition of T cell activation, but if there are no T cells in/near the tumor, it is difficult for these drugs to exert their efficacy, which is part of the reason for the overall low efficiency of these drugs. In this way, patients need to have an immune response before using such drugs so that checkpoint suppression can work. The innate immune system happens to be able to accomplish this task. Therefore, the activated interferon gene stimulation protein can provide the basis for the activation and proliferation of T cells, and then the use of checkpoint inhibitors can make T cells have sufficient ability to clear tumor cells in the body.
  • interferon gene stimulating protein agonists that have been reported to be effective for human and mouse sources are mainly cyclic dinucleotide (CDN) compounds, such as ADU-S100, MK-1454, etc. have entered the first phase of clinical research, but The compound has a complex structure and is not easy to synthesize. More importantly, it has the disadvantages of metabolic instability and high adverse reaction rate. As a result, the current drug administration method is mainly intratumoral injection, which greatly limits its clinical application.
  • CDN cyclic dinucleotide
  • the object of the present invention is to provide a compound represented by formula I, its preparation method and its use in anti-tumor.
  • a compound of formula I or an isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from the group consisting of substituted or unsubstituted: H, halogen, amino, hydroxy, carboxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S, containing 1-3 3-8 membered heterocyclic alkoxy group from hetero atom of N, O, S, C6-C10 aryl group, 3-10 membered heteroaryl group containing 1-3 hetero atoms selected from N, O, S; Or R 1 and R 2 together with the carbon atom to which they are attached form a 5-14 membered heterocyclic group;
  • substitution in R 1 and R 2 means independently substituted by one or more substituents selected from the group consisting of halogen, amino, hydroxy, carboxy, C1-C6 alkyl, C3-C8 cycloalkyl, C1- C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, C6-C10 aryl, containing 1-3 selected 3-10 membered heteroaryl of hetero atom of N, O, S;
  • X 1 and X 2 are independently selected from the group consisting of H, D, halogen, unsubstituted or halogen-substituted C1-C6 alkyl, unsubstituted or halogen-substituted C1-C6 alkoxy, and nitrile;
  • X 3 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy;
  • n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;
  • Y is selected from the group: -OR 3 , -N(X 4 R 4 )R 5 ,
  • X 4 is selected from the group: O, S, NH;
  • R 3 is selected from the group consisting of substituted or unsubstituted: H, carboxyl, sulfonate, phosphoryl, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, containing 1-3 choices 3-10 membered heteroaryl group from hetero atom of N, O, S, 3-8 membered heterocycloalkyl group containing 1-3 hetero atoms selected from N, O, S;
  • R 4 and R 5 are independently selected from the group consisting of substituted or unsubstituted: H, carboxyl, sulfonate, phosphoryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C6-C10 aryloxy, C6-C10 aryl, 3 to 3 heteroatoms selected from N, O, S -8 membered heterocycloalkyl, 3-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S;
  • substitution in R 3 , R 4 and R 5 means independently substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, carboxy, C1-C6 alkyl, C3-C8 cycloalkyl , C1-C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, C6-C10 aryl, containing 1-3 A 3-10 membered heteroaryl group selected from heteroatoms of N, O, S.
  • the 5-14 membered heterocyclic group is a heterocyclic group containing 1-4 O , Is preferably a heterocyclic group containing 2 O.
  • the "5-14 membered heterocyclic group” is a cycloalkoxy group containing 2 O.
  • X 3 is halogen
  • X 3 is fluorine
  • X 2 is hydrogen or fluorine.
  • n is an integer selected from 0, 1, and 2.
  • Y is selected from the group: -OR 3 , -N(X 4 R 4 )R 5 ,
  • X 4 is selected from the group: O, NH;
  • R 3 is selected from the group consisting of substituted or unsubstituted: H, carboxyl, sulfonate, phosphoryl, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, containing 1-3 choices 3-10 membered heteroaryl group from hetero atom of N, O, S, 3-8 membered heterocycloalkyl group containing 1-3 hetero atoms selected from N, O, S;
  • R 4 and R 5 are independently selected from the group consisting of substituted or unsubstituted: H, carboxyl, sulfonate, phosphoryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C6-C10 aryloxy, C6-C10 aryl, 3 to 3 heteroatoms selected from N, O, S -8 membered heterocycloalkyl, 3-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S;
  • substitution in R 3 , R 4 and R 5 means independently substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, carboxy, C1-C6 alkyl, C3-C8 cycloalkyl , C1-C6 alkoxy, C3-C8 cycloalkoxy, 3--8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, C6-C10 aryl, containing 1-3 A 3-10 membered heteroaryl group selected from heteroatoms of N, O, S.
  • the compound is selected from the compounds listed in Table 1.
  • a method for preparing a compound according to the first aspect of the present invention or an isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof, The method is selected from the following group:
  • R 1 , R 2 , X 1 , X 2 , n, Y, X 3 are as defined in the first aspect of the present invention
  • R 1 , R 2 , X 1 , X 2 , X 3 , n, R 3 , X 4 , R 4 and R 5 are as defined in the first aspect of the present invention.
  • the compound of formula A is subjected to a reduction treatment before reacting with DAST.
  • the reduction treatment refers to reducing the carbonyl group connected to the benzothiophene structure in the compound of formula A to a hydroxyl group.
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition is an injection, sachet, tablet, pill, powder or granule.
  • the pharmaceutical composition further includes one or more second therapeutic agents, and the second therapeutic agent is a drug for preventing and/or treating cancer.
  • the second therapeutic agent is a traditional cytotoxic chemotherapy drug or other anti-tumor immune drugs.
  • a compound according to the first aspect of the present invention or an isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof, or a third aspect of the present invention
  • the use of the pharmaceutical composition is for preparing a preparation, and the preparation is used for preventing and/or treating diseases related to type I interferon.
  • the type I interferon is IFN- ⁇ .
  • the disease associated with type I interferon is 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.
  • an interferon gene stimulating protein agonist comprising one or more compounds according to the first aspect of the present invention, or isomers thereof, prodrugs, solvates, hydrates Or a pharmaceutically acceptable salt thereof.
  • a method for preventing and/or treating diseases associated with type I interferon comprising the steps of: applying a therapeutically effective amount of one or more compounds of the first aspect of the present invention, Or an isomer, prodrug, solvate, hydrate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the third aspect of the present invention is administered to a desired patient.
  • the inventor unexpectedly prepared a compound of formula I with simple structure, convenient synthesis, stable metabolism, and high safety.
  • the compound has excellent activation properties for interferon gene stimulating protein. This activates T cells and significantly promotes the expression of interferon factor IFN- ⁇ , thereby achieving effective treatment of tumors and their complications.
  • the inventor completed the present invention.
  • 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, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, tert-amyl group, hexyl group or the like.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, cycloheptyl, cyclooctyl, etc.
  • aromatic ring or "aryl” has the same meaning, preferably “C6-C10 aryl”.
  • C6-C10 aryl refers to an aromatic ring group having 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, and the like.
  • heterocyclic aryl or “heteroaryl” has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms.
  • C3-C10 heteroaryl refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms.
  • Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic group or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • halo means substituted by halogen.
  • C2-C6 alkenyl refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl , Isobutenyl, pentenyl and hexenyl.
  • C2-C6 alkynyl refers to a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms containing a triple bond, and includes, without limitation, ethynyl, propynyl, butyn Group, isobutynyl, pentynyl and hexynyl.
  • C1-C6 alkoxy refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, Isopropoxy and butoxy etc. It is preferably C1-C4 alkoxy.
  • substituted means that one or more hydrogen atoms on a specific group are replaced with a specific substituent.
  • the specific substituents are the substituents described correspondingly in the foregoing, or the substituents appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example (but not limited to): halogen, hydroxyl, 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 and the like.
  • sulfonic acid group has the following structure:
  • phosphoryl has the following structure:
  • the present invention provides a compound represented by formula I, or an isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , X 1 , X 2 , X 3 , n, Y are as defined above.
  • any one of R 1 , R 2 , X 1 , X 2 , X 3 , n, and Y is a corresponding group in the specific compound described in Table 1, respectively.
  • the compound is preferably the compound prepared in the examples.
  • the compound is selected from the compounds listed in Table 1.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention formed with an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One type of preferred salts are the salts of the compounds of the invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as 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; Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
  • salts of the compounds of the present invention are the salts of the compounds of the present invention with bases, such as alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as magnesium or calcium salts), and ammonium salts (such as lower alkanolammonium) Salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl Base amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trishydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • bases such as alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as magnesium or calcium salts), and ammonium salts (such as lower alkanolammonium) Salts and other
  • solvate refers to a compound of the present invention that coordinates with a solvent molecule to form a complex in a specific ratio.
  • Hydrophilate refers to a complex formed by coordination of a compound of the present invention and water.
  • prodrug includes itself which may be biologically active or inactive, and when taken by an appropriate method, it undergoes a metabolic or chemical reaction in the human body to be converted into a compound of formula I, or formula I
  • the salt or solution of a compound include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not limit the present invention in any way.
  • the compound of the present invention can also be optionally prepared by combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a person skilled in the art to which the present invention belongs.
  • the preparation process of the compound of the present invention is as follows, where the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the preparation method of the compound is selected from the following group:
  • the 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 to treat, prevent, and alleviate tumor-related diseases.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier in a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the therapeutically effective amount is determined according to the age, condition, course of treatment, etc. of the treatment subject.
  • the pharmaceutical composition contains 1-2000 mg of the compound/dose of the present invention, and more preferably, 10-1000 mg of the compound/dose of the present invention.
  • the "one dose" is a capsule or tablet.
  • the “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 sufficiently low toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts are sugar (such as glucose, sucrose, lactose, etc.), starch (such as corn starch, potato starch, etc.), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose Sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as Propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, no heat Raw water, etc.
  • sugar such as glucose, sucrose, lactose, etc.
  • starch such as corn starch, potato starch, etc.
  • 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and g
  • Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner.
  • coatings and shell materials such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner.
  • embedding components that can be used are polymeric substances and waxy substances.
  • the active compound can also be formed in the form of microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • the liquid dosage form may contain inert diluents commonly 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.
  • inert diluents commonly 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,
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, 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 alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the benzothiophene derivatives represented by the above general formula I and their pharmaceutically acceptable salts in the present invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, especially in combination with traditional cytotoxicity Combination of chemotherapy drugs and tumor immune checkpoint inhibitors.
  • the pharmaceutically acceptable therapeutic agents include, but are not limited to, other acceptable therapeutic agents used in combination with the benzothiophene derivative represented by Formula I, for example, immune checkpoint inhibitor monoclonal antibody drugs Opdivo and Keytruda , Directly acting on the PD-1 protein on the surface of T cells, interrupting the binding of PD-1/PD-L1; and traditional cytotoxic chemotherapy small molecule drugs, such as the antitumor drug methotrexate (MTX) that affects nucleic acid synthesis, 5 -Fluorouracil (5FU), etc., antitumor drugs that affect nucleic acid transcription such as doxorubicin, epirubicin, clarithromycin, glaucomycin, etc., antitumor drugs that act
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or treatment drugs.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose when administered is a pharmaceutically effective dose, for a person of 60 kg body weight, daily
  • the dose to be administered is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
  • the present invention has the following main advantages:
  • the compound has the characteristics of simple structure, easy synthesis, stable metabolism, high safety, and various administration methods;
  • the compound has excellent activation properties for interferon gene-stimulating protein, thereby activating T cells and significantly promoting the expression of interferon factor IFN- ⁇ , thereby achieving effective treatment of tumors and their complications;
  • TW201817723A discloses compound 1a, the compound has a significantly improved agonistic activity on interferon gene stimulating protein, which is about 2-2.5 times enhanced; in addition, the pharmacokinetic properties of the patented compound S2 It is also significantly better than the compound 1a disclosed in TW201817723A (US20180093964), especially the plasma exposure during intravenous injection is about 4.4 times that of 1a.
  • the nuclear magnetic resonance hydrogen spectrum was measured with a Mercury-300MHz nuclear magnetic resonance instrument, deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • the chromatography column generally uses 200-300 mesh silica gel as a carrier.
  • RT room temperature
  • DIPEA is N,N-diisopropylethylamine
  • THF is tetrahydrofuran
  • TBTU is O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid
  • DAST is diethylaminosulfur trifluoride.
  • Step 1 Weigh succinic anhydride (1.55g, 15.44mmol) and aluminum trichloride (2.75g, 20.6mmol) in 10mL 1,2-dichloroethane, and stir at minus 10°C; mix 5,6 -Dimethoxybenzo[b]thiophene (2.0g, 10.30mmol) was dissolved in 40mL 1,2-dichloroethane and dropped into the above reaction solution drop by drop for 30min; after the drop was completed, stirring was continued for 10min Then transfer to 45°C oil bath and react overnight.
  • Step 2 Compound 1a (1 eq) was dissolved in methanol, and thionyl chloride (5 eq) was added dropwise at 0°C, and then moved to room temperature for 4 hours. After the reaction, the solvent was spin-dried, a small amount of water was added and the pH was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was collected and purified through the column to obtain compound 1b;
  • Step 3 Dissolve compound 1b (1eq) in dichloromethane, add DAST (5eq) in an ice bath. After about 10 minutes, warm to 45°C for two hours. After the reaction solution is cooled to room temperature, use saturated in ice bath The sodium bicarbonate solution was quenched, extracted with ethyl acetate, and purified by column separation to obtain compound S1.
  • Step 1 Dissolve compound 1b (1eq) in acetonitrile, add selective fluoride reagent Selectfluor at room temperature, and react overnight. After the reaction was completed, it was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and then the organic phase was collected and purified by column to obtain compound 19a;
  • Step 2 Dissolve compound 19a (1eq) in dichloromethane, add DAST (5eq) under ice bath, warm to 45°C for two hours after about 10 minutes, and wait for the reaction solution to cool to room temperature, then use saturated in ice bath Quenched with sodium bicarbonate solution, extracted with ethyl acetate, and purified by column separation to obtain compound 19b;
  • Step 3 Dissolve compound 19b (1 eq) in dichloromethane, add DAST (5 eq) under ice bath. After about 10 minutes, warm to 45°C for two hours. After the reaction solution is cooled to room temperature, saturate under ice bath The sodium bicarbonate solution was quenched, extracted with ethyl acetate, and purified through column separation to obtain the difluoro intermediate. The difluoro intermediate was dissolved in 1,4-dioxane, and then an appropriate amount of 6N hydrochloric acid was added, and refluxed overnight. After the reaction, after the reaction solution was cooled to room temperature, the solvent was spin-dried and recrystallized from ethanol to obtain compound S19.
  • Step 1 Suspend compound 1b (1eq) in methanol, then add palladium hydroxide/carbon (20%), and react at room temperature under a hydrogen atmosphere of 1.1 atm for 6 hours. After the reaction, the reaction solution was filtered through celite, dried by spin-drying, and purified through a column to obtain compound 23a.
  • Step 2 Dissolve compound 23a (1 eq) in dichloromethane, add DAST (5 eq) under ice bath. After about 10 minutes, warm to room temperature and react for two hours. After the reaction solution is completed, use saturated sodium bicarbonate under ice bath The solution was quenched, extracted with ethyl acetate, and purified through column separation to obtain compound 23b.
  • Step 3 Dissolve compound 23b (1eq) in a mixed solvent of tetrahydrofuran: water (1:1), then add lithium hydroxide monohydrate (3eq), react at room temperature for half an hour, and adjust the pH to 5 with 1N hydrochloric acid ⁇ 6, extracted with chloroform, the organic phase was collected and purified through column to obtain compound S23.
  • Step 1 Weigh succinic anhydride (1eq) and aluminum trichloride (1.5eq) and dissolve in 1,2-dichloroethane, stir at minus 10°C; mix methylenedioxybenzo[b]thiophene (1.1eq) was dissolved in 1,2-dichloroethane, and dropped into the above reaction solution drop by drop for 30min; after the drop was completed, stirring was continued for 10min and then transferred to a 45°C oil bath to react overnight. After TLC detected the reaction, the reaction solution was poured into ice water, 15% hydrochloric acid solution was added, the product was precipitated by stirring, and the crude product was obtained by suction filtration. After recrystallization from dichloromethane, pure product 26a was obtained.
  • Step 2 Compound 26a (1 eq) was dissolved in methanol, and thionyl chloride (5 eq) was added dropwise at 0°C, and then moved to room temperature for 4 hours. After the reaction, the solvent was spin-dried, a small amount of water was added and the pH was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was collected and purified through column to obtain compound 26b;
  • Step 3 Dissolve compound 26b (1eq) in dichloromethane, add DAST (5eq) under ice bath. After about 10 minutes, warm to 45°C and react for two hours. After the reaction solution is cooled to room temperature, use saturated in ice bath The sodium bicarbonate solution was quenched, extracted with ethyl acetate, and purified through column separation to obtain compound 26c.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.32 (s, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 5.87 (s, 2H), 3.64 (s, 3H), 2.64-2.57 ( m, 4H); MS (EI): 314.
  • Step 4 Dissolve compound 26c (1eq) in a mixed solvent of tetrahydrofuran: water (1:1), then add lithium hydroxide monohydrate (3eq), react at room temperature for half an hour, and adjust the pH to 5 with 1N hydrochloric acid ⁇ 6, extracted with chloroform, the organic phase was collected and purified through column to obtain compound S26.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.31 (s, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 5.83 (s, 2H), 2.72–263 (m, 4H); MS ( EI): 300.
  • Step 1 Dissolve compound 5,6-dimethoxybenzo[b]thiophene (1eq) in methylene chloride, and slowly add 1.0M boron tribromide in methylene chloride solution (6eq) at -78°C ), and react at -78°C for half an hour, then move to room temperature for about half an hour. After the reaction was completed, water was slowly added dropwise under ice bath to quench, and then extracted with dichloromethane, and purified through the column to obtain intermediate 27a.
  • Step 2 Weigh succinic anhydride (1eq) and aluminum trichloride (1.5eq) and dissolve in 1,2-dichloroethane, stir at minus 10°C; dissolve 27b (1.1eql) in 1,2- In dichloroethane, drop by drop into the above reaction solution for 30 min; after the drop, continue stirring for 10 min and then transfer to a 45°C oil bath for overnight reaction. After TLC detected the reaction, the reaction solution was poured into ice water, 15% hydrochloric acid solution was added, the product was precipitated by stirring, and the crude product was obtained by suction filtration. After recrystallization from dichloromethane, pure product 27c was obtained.
  • Step 3 Dissolve compound 27c (1 eq) in methanol, add sulfoxide chloride (5 eq) dropwise at 0°C, and then move to room temperature for 4 hours. After the reaction, the solvent was spin-dried, a small amount of water was added and the pH was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was collected and purified through the column to obtain compound 27d;
  • Step 4 Dissolve compound 27d (1 eq) in dichloromethane, add DAST (5 eq) in an ice bath. After about 10 minutes, warm to 45°C for two hours. After the reaction solution is cooled to room temperature, use saturated in ice bath The sodium bicarbonate solution was quenched, extracted with ethyl acetate, and purified through column separation to obtain compound 27e.
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.35 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 4.32 (m, 4H), 3.64 (s, 3H), 2.63-2.57 ( m, 4H); MS (EI): 328.
  • Step 5 Dissolve compound 27e (1eq) in a mixed solvent of tetrahydrofuran: water (1:1), then add lithium hydroxide monohydrate (3eq), react at room temperature for half an hour, and adjust the pH to 5 with 1N hydrochloric acid ⁇ 6, extracted with chloroform, the organic phase was collected and purified through column to obtain compound S27.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 7.38 (s, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 4.36 (m, 4H), 2.61–2.56 (m, 4H); MS ( EI): 314.
  • Step 1 Dissolve 6-methoxybenzothiophene (1eq) in dichloromethane, add NBS (1.1eq), and continue to stir the reaction solution for 6 hours. After the reaction is completed by TLC, spin off the solvent and pass through the column Purification gave compound 28a.
  • Step 2 Weigh succinic anhydride (1eq) and aluminum trichloride (1.5eq) and dissolve in 1,2-dichloroethane, stir at minus 10°C; dissolve 28a (1.1eq) in 1,2- In dichloroethane, drop by drop into the above reaction solution for 30 min; after the drop, continue stirring for 10 min and then transfer to a 45°C oil bath for overnight reaction. After TLC detected the reaction was completed, the reaction solution was poured into ice water, 15% hydrochloric acid solution was added, the product was precipitated by stirring, and the crude product was obtained by suction filtration. After recrystallization from dichloromethane, pure product 28b was obtained.
  • Step 3 Dissolve compound 28b (1 eq) in methanol, add sulfoxide chloride (5 eq) dropwise at 0°C, and then move to room temperature for 4 hours. After the reaction was completed, the solvent was spin-dried, a small amount of water was added and the pH was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was collected and purified by column to obtain compound 28c;
  • Step 4 Dissolve compound 28c (1 eq) in dichloromethane, add DAST (5 eq) under ice bath. After about 10 minutes, warm to 45°C and react for two hours. After the reaction solution is cooled to room temperature, saturate under ice bath The sodium bicarbonate solution was quenched, extracted with ethyl acetate, and purified by column separation to obtain compound 28d.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.81 (s, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 3.94 (s, 3H), 3.64 (s, 3H), 2.61-2.54 ( m,4H);.
  • Step 5 Dissolve compound 28d (1 eq) in a mixed solvent of tetrahydrofuran: water (1:1), then add lithium hydroxide monohydrate (3 eq), react at room temperature for half an hour, and adjust the pH to 5 with 1N hydrochloric acid ⁇ 6, extracted with chloroform, the organic phase was collected and purified through column to obtain compound S28.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.83 (s, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 3.99 (s, 3H), 2.62–2.53 (m, 4H); MS ( EI): 363.
  • Step 1 Dissolve 28d (1eq), alkenyl borate (1.1eq), catalyst Pd 2 (dba) 3 (0.05eq), ligand X-Phos (0.05eq) and Cs2CO3 (1eq) in dry toluene After reaction at 110°C for 12 hours, after completion of TLC detection, ethyl acetate was added for dilution, washed with saturated brine, the organic phase was dried over anhydrous Na 2 SO 4, concentrated under reduced pressure and purified through column to obtain compound 29a.
  • Step 2 Dissolve compound 29a (1eq) in a mixed solvent of tetrahydrofuran: water (1:1), then add lithium hydroxide monohydrate (3eq), react at room temperature for half an hour, and adjust the pH to 5 with 1N hydrochloric acid ⁇ 6, extracted with chloroform, the organic phase was collected and purified through column to obtain compound S29.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.55 (s, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 6.49 (m, 1H), 5.25-5.43 (m, 2H), 3.95 ( s, 3H), 2.60–2.54 (m, 4H); MS (EI): 312.
  • the compound activates the interferon gene stimulating protein and promotes IFN- ⁇ expression in cell screening experiments
  • Detection method and principle Human-derived THP1-Blue-ISG cells, which have a reporter system containing IFN- ⁇ , which can induce the expression of downstream alkaline phosphatase, when alkaline phosphatase is secreted out of the cell , OD650 can reflect its content by color reaction.
  • the compound is added to the cell, if the interferon gene stimulating protein is activated, it can promote the expression of IFN- ⁇ , thereby promoting the increase of downstream alkaline phosphorylation secretion and the increase of the absorbance of the color reaction.
  • the concentration of the compound was 100 ⁇ M, and 2 replicate wells were set up.
  • the positive control compound was ADU-S100 at a concentration of 100 ⁇ M.
  • the non-medicated control group added 20 ⁇ L of saline containing 1% DMSO.
  • THP1-Blue-ISG cell count adjust the cell concentration to 5 ⁇ 10 5 /mL, and add 180 ⁇ l of cells to each well for incubation. Therefore, the final volume of each test well is 200 ⁇ L, the content of DMSO is 0.1%, and the test concentration of the compound is 10 ⁇ M.
  • the positive control compound was ADU-S100 with a final concentration of 10 ⁇ M, which was tested after incubation for 24 hours; another blank control group was added with 180 ⁇ L culture medium.
  • Compound OD650 is the OD650 value of the compound of the present invention
  • Blank OD650 is the OD650 value of the culture medium
  • Control OD650 is the OD650 value of the control group without adding the compound (only cells and 0.1% DMSO).
  • Table 2 The ability of some compounds to activate human interferon gene-stimulating protein in THP1 cells at a concentration of 10 ⁇ M and promote the expression of type I interferon
  • CON represents the control without compound (ie only cells and 0.1% DMSO).
  • the tested compounds can significantly activate the interferon gene stimulating protein and promote the expression of interferon factor IFN- ⁇ ; among them, the agonistic activity of most of the compounds is similar to the ring II in phase I clinical research.
  • the nucleoside compound ADU-S100 is equivalent, even better, and has further application prospects.

Abstract

本发明涉及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。具体地，本发明化合物具有式I所示结构，其中各基团和取代基的定义如说明书中所述。本发明还公开了所述化合物的制备方法及其在抗肿瘤方面的用途。（I）

Description

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 技术领域
本发明涉及医药领域，具体地涉及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。
背景技术
作为细胞因子信号通路的调节者，干扰素基因刺激蛋白与多种疾病的病理及临床表症密切相关，包括感染性疾病、癌症和自身免疫病。该蛋白是一种跨膜蛋白，通常在152-173位区域交接形成二聚体并处于自我抑制状态。当受到部分配体，如环二核苷酸的刺激后，分子构型发生变化并被激活，招募细胞质中的TANK结合激酶1(TANK-binding kinase 1，TBK1)，介导TBK1对IRF3的磷酸化，导致干扰素(interferon，IFN)-β和其它多种细胞素的形成，并通过一系列的级联反应，激活适应性免疫***，活化T细胞。一般情况下，干扰素基因刺激蛋白的正常活性维持免疫***的正常功能，其活性缺失导致免疫缺陷，而过度活化会导致免疫过激。
肿瘤微环境(TME)天然免疫的信号传导是肿瘤特异性T细胞的激活和肿瘤浸润性淋巴细胞(TIL)浸润的关键步骤。其中I型IFN对肿瘤激活的T细胞活化起着关键作用。STING激动剂不仅诱导Ⅰ型干扰素基因的表达，在天然免疫信号通路中起着重要作用；它还能激活包括树突状细胞等免疫刺激细胞，改变肿瘤微环境并诱导了肿瘤特异性T细胞的产生，进而杀死肿瘤细胞。
环鸟苷酸-腺苷酸合成酶(cGAS)/STING信号通路的正常活化不光可以诱导细胞因子的生成、活化靶向肿瘤的T细胞，还可引发机体对肿瘤细胞的免疫应答，进而增强肿瘤放化射疗法的疗效，如cGAS可感知被杀死的肿瘤细胞释放的DNA，来活化STING来诱导树突状细胞产生I型干扰素，进而激活潜在的抗肿瘤免疫反应，增强放化射疗法疗效。
干扰素基因刺激蛋白激动剂在与其他免疫检查点抑制剂联合用药方面显示出一定潜力。尽管目前针对免疫检查点PD-1/PD-L1已经有两个单克隆抗体药物成功上市，但是这类药物总体存在效率相对较低，大约只有20–30％。PD-1/L1抑制剂能够解除T细胞的活化抑制，但是如果肿瘤内部/附近并不存在T细胞，那么该类药物也很难发挥疗效，这也是该类药物总体存在效率低的部分原因。这样，患者需要在使用该类药物之前就存在免疫反应，这样检查点抑制才能发挥作用。而固有免疫***恰好能够完成这一任务。因此，活化干扰素基因刺激蛋白能够为T细胞的活化和增殖提供基础，然后再使用检查点抑制剂就可以使T细胞有足够的能力清除体内的肿瘤细胞。
综上所述，活化干扰素基因刺激蛋白，诱导Ⅰ型干扰素的产生，成为抗肿瘤免疫领域中极具潜力的研究方向。目前已报道的对人源和鼠源都有效的干扰素基因刺激蛋白激动剂主要为环二核苷酸(CDN)类化合物，如ADU-S100、MK-1454等已经进入一期临床研究，但该类化合物结构复杂、不易合成，更重要的是存在代谢不稳定、不良反应率高等缺点，导致目前该药的给药方式主要为瘤内注射，极大地限制其临床应用。
因此，需要进一步开发结构简单、合成方便、代谢稳定、安全性高的新型小分子，激活干扰素基因刺激蛋白，诱导Ⅰ型干扰素IFN-β的产生。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和其在抗肿瘤方面的用途。
本发明的第一方面，提供了一种式I所示化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，
Figure PCTCN2019130605-appb-000001
其中，
R 1和R 2独立地选自取代或未取代的下组基团：H、卤素、氨基、羟基、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、含1-3个选自N、O、S的杂原子的3-8元杂环烷基、含1-3个选自N、O、S的杂原子的3-8元杂环烷氧基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；或者R 1和R 2与它们连接的碳原子一起形成5-14元杂环基；
所述R 1和R 2中的取代指独立地被选自下组的一个或多个取代基取代：卤素、氨基、羟基、羧基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、含1-3个选自N、O、S的杂原子的3-8元杂环基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；
X 1和X 2独立地选自下组：H、D、卤素、未取代的或卤素取代的C1-C6烷基、未取代的或卤素取代的C1-C6烷氧基、腈基；
X 3选自下组：氢、卤素、羟基、C1-C3烷基、C1-C3烷氧基；
n为选自0、1、2、3、4、5、6、7、8的整数；
Y选自下组：-OR 3、-N(X 4R 4)R 5，
其中，
X 4选自下组：O、S、NH；
R 3选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1‐C6烷基、C3‐C8环烷基、C6‐C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、含1‐3个选自N、O、S的杂原子的3‐8元杂环烷基；
R 4和R 5独立地选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、C6-C10芳氧基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-8元杂环烷基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；
所述R 3、R 4和R 5中的取代指独立地被选自下组的一个或多个取代基取代：卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、含1-3个选自N、O、S的杂原子的3-8元杂环基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基。
在另一优选例中，当R 1和R 2与它们连接的碳原子一起形成5-14元杂环基时，所述5-14元杂环基为含1-4个O的杂环基，优选为含2个O的杂环基。
在另一优选例中，所述“5-14元杂环基”为含2个O的环烷氧基。
在另一优选例中，X 3为卤素。
在另一优选例中，X 3为氟。
在另一优选例中，X 2为氢或氟。
在另一优选例中，n为选自0、1、2的整数。
在另一优选例中，Y选自下组：-OR 3、-N(X 4R 4)R 5，
其中，
X 4选自下组：O、NH；
R 3选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1‐C6烷基、C3‐C8环烷基、C6‐C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、含1‐3个选自N、O、S的杂原子的3‐8元杂环烷基；
R 4和R 5独立地选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1-C6 烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、C6-C10芳氧基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-8元杂环烷基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；
所述R 3、R 4和R 5中的取代指独立地被选自下组的一个或多个取代基取代：卤素、羟基、氨基、羧基、C1‐C6烷基、C3‐C8环烷基、C1‐C6烷氧基、C3‐C8环烷氧基、含1‐3个选自N、O、S的杂原子的3‐8元杂环基、C6‐C10芳基、含1‐3个选自N、O、S的杂原子的3‐10元杂芳基。
在另一优选例中，所述化合物选自表1所列化合物。
本发明的第二方面，提供了一种本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐的制备方法，所述方法选自下组：
方法一：
Figure PCTCN2019130605-appb-000002
将式A化合物与DAST反应，得到B；
其中，R 1、R 2、X 1、X 2、n、Y、X 3如本发明第一方面所定义；
方法二：
Figure PCTCN2019130605-appb-000003
将式C化合物和式D化合物或其盐酸盐反应，得到E；
其中，R 1、R 2、X 1、X 2、X 3、n、R 3、X 4、R 4和R 5如本发明第一方面所定义。
在另一优选例中，方法一中，所述式A化合物在与DAST反应前经还原处理。
在另一优选例中，所述还原处理是指将式A化合物中与苯并噻吩结构连接的羰基还原为羟基。
本发明的第三方面，提供了一种药物组合物，包含：
(i)一种或多种治疗有效量的本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐；和
(ii)药学上可接受的载体。
在另一优选例中，所述药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中，所述药物组合物还包含一种或多种第二治疗剂，所述第二治疗剂为预防和/或治疗癌症的药物。
在另一优选例中，所述第二治疗剂为传统细胞毒化疗药物或其他抗肿瘤免疫药物。
本发明的第四方面，提供了一种本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐或本发明第三方面所述的药物组合物的用途，用于制备制剂，所述制剂用于预防和/或治疗与I型干扰素相关的疾病。
在另一优选例中，所述I型干扰素为IFN-β。
在另一优选例中，所述与I型干扰素相关的疾病选自下组：感染性疾病、癌症、自身免疫病。
在另一优选例中，所述癌症选自下组：乳腺癌、卵巢癌、肝癌、黑色素瘤、***癌、结肠癌、胃癌。
本发明的第五方面，提供了一种干扰素基因刺激蛋白激动剂，包含一种或多种本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐。
本发明的第六方面，提供了一种预防和/或治疗与I型干扰素相关的疾病的方法，包括步骤：将治疗有效量的一种或多种本发明第一方面所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐或本发明第三方面所述的药物组合物施用于所需患者。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种结构简单、合成方便、代谢稳定、安全性高的式I所示化合物，所述化合物对干扰素基因刺激蛋白具有优异的活化性能，从而活化T细胞并显著促进干扰素因子IFN-β的表达，进而实现对肿瘤及其并发症的有效治疗。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、特戊基、已基或类似基团。
在本发明中，术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“杂环芳基”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基 所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语“磺酸基”具有如下结构：
Figure PCTCN2019130605-appb-000004
在本发明中，术语“磷酰基”具有如下结构：
Figure PCTCN2019130605-appb-000005
化合物
本发明提供了一种式I所示化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，
Figure PCTCN2019130605-appb-000006
其中，R 1、R 2、X 1、X 2、X 3、n、Y如上文所定义。
在另一优选例中，所述的化合物中，R 1、R 2、X 1、X 2、X 3、n、Y中任一个分别为表1中所述具体化合物中所对应的基团。
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
在另一优选例中，所述化合物选自表1所列化合物。
表1
Figure PCTCN2019130605-appb-000007
Figure PCTCN2019130605-appb-000008
Figure PCTCN2019130605-appb-000009
盐型
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式I的一类化合物，或式I的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
示例性地，所述化合物的制备方法选自下组：
方法一：
Figure PCTCN2019130605-appb-000010
将苯并噻吩与环酸酐反应得到酸A，然后进行甲酯化得B，再进行羰基硫化得C，进一步在二氟化试剂条件下得D，甲酯水解得E，最后与HY缩合得F；其中，R 1、R 2、X 1、X 2、n、Y如上文中所限定；
方法二：
Figure PCTCN2019130605-appb-000011
将B与选择性氟试剂Selectfluor反应得G，再与劳森试剂反应得H，再进一步与DAST反应得I，水解得J，最后与HY缩合得K；其中，X 2＝H、R 1、R 2、X 1、n、Y如上文中所限定；
方法三：
Figure PCTCN2019130605-appb-000012
B在Pd/C条件下进行氢化还原得L，再与DAST反应得到M，进一步水解得N，最后与HY进行缩合得O；其中，R 1、R 2、X 1、X 2、n、Y如上文中所限定。
药物组合物和施用方法
本发明还提供了一种药物组合物，包含：
(i)一种或多种治疗有效量的所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐；和
(ii)药学上可接受的载体。
由于本发明化合物具有优异的抗肿瘤活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肿瘤相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。治疗有效量根据治疗对象的年龄、病情、疗程等来确定。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
所述的“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容 性”在此指的是组合物中各组分能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有糖(如葡萄糖、蔗糖、乳糖等)，淀粉(如玉米淀粉、马铃薯淀粉等)，纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)，明胶，滑石，固体润滑剂(如硬脂酸、硬脂酸镁)，硫酸钙，植物油(如豆油，芝麻油，花生油，橄榄油等)，多元醇(如丙二醇、甘油、甘露醇、山梨醇等)，乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)，着色剂，调味剂，稳定剂，抗氧化剂，防腐剂，无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明中的上述通式I所示的苯并噻吩衍生物和其药学上可接受的盐可以单独给药，或者与其他药学上可接受的治疗剂联合给药，特别是与传统的细胞毒化疗药物、肿瘤免疫检查点抑制剂的药物组合。所述药学上可接受的治疗剂包括但不限于，同通式I所示的苯并噻吩衍生物联合用药的其他可接受的治疗剂，例如，免疫检查点抑制剂单克隆抗体药物Opdivo和Keytruda，直接作用于T细胞表面PD-1蛋白，中断PD-1/PD-L1相互结合的；以及传统细胞毒化疗小分子药物，如影响核酸合成的抗肿瘤药物甲氨蝶呤(MTX)、5-氟尿嘧啶(5FU)等，影响核酸转录的抗肿瘤药物如阿霉素、表阿霉素、阿克拉霉素、光辉霉素等，作用于微管蛋白合成的抗肿瘤药物如紫杉醇、长春瑞滨等，芳香化酶抑制剂如氨鲁米特等，细胞信号通路抑制剂如表皮生长因子受体抑制剂伊马替尼(Imatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)等。该组合的各成分可同时或顺序地给予，以单一制剂形式或以不同制剂的形式给予。所述组合不仅包括本发明的化合物和一种其它活性剂的组合，而且包括本发明的化合物和两种或更多种其它活性剂的组合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物具有结构简单、易于合成、代谢稳定、安全性高、给药方式多样的特点；
(2)所述化合物对干扰素基因刺激蛋白具有优异的活化性能，从而活化T细胞并显著促进干扰素因子IFN-β的表达，进而实现对肿瘤及其并发症的有效治疗；
(3)相对于TW201817723A(US20180093964)公开化合物1a，所述化合物对干扰素基因刺激蛋白具有显著提高的激动活性，约有2-2.5倍的增强；此外，本专利化合物S2在药物代谢动力学性质方面亦明显优于TW201817723A(US20180093964)公开化合物1a，特别是静脉注射时的血浆暴露量约为1a的4.4倍。
下面结合具体实施例对本发明作进一步阐述，但这些实施例并不限制本发明的范围。
对于以下实施例，可以使用本领域技术人员已知的标准操作和纯化方法。除非另有规定，否则原料通常是从市售来源可获得的，比如Aldrich Chemicals Co.和Acros Organics。商购的溶剂和试剂一般在不进一步纯化的情况下使用，无水溶剂均通过标准方法处理，其他试剂为市售分析纯。除非另有说明，所有温度以℃(摄氏度)表示，室温或环境温度是指20～25℃。化合物的结构通过核磁共振谱(NMR)来确定的。核磁共振氢谱位移(δ)以百万分之一(ppm)的单位给出。核磁共振氢谱用Mercury-300MHz型核磁共振仪测定，氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)为溶剂，四甲基硅烷(TMS)为内标。
层析柱一般使用200～300目硅胶为载体。
在上述讨论和下述实施例中，下列缩写具有如下含义。如果某一缩写没有定义，则它具有通常被接受的含义。
RT为室温；
DIPEA为N，N-二异丙基乙胺；
THF为四氢呋喃；
TBTU为O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸；
Selectfluor为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐；
DAST为二乙胺基三氟化硫。
一、化合物制备例部分
以下制备例示例性的制备了本发明的部分式I化合物，各化合物分别以S1至S33表示。
1.化合物S1的合成
Figure PCTCN2019130605-appb-000013
步骤1：称取丁二酸酐(1.55g,15.44mmol)、三氯化铝(2.75g,20.6mmol)溶于10mL 1,2-二氯乙烷中，置零下10℃搅拌；将5,6-二甲氧基苯并[b]噻吩(2.0g,10.30mmol)溶于40mL 1,2-二氯乙烷中，逐滴滴入上述反应液中，持续30min；滴毕，继续搅拌10min中后转移至45℃油浴锅中反应过夜。TLC检测反应完毕后，将反应液倒入冰水中，加入60mL 15％盐酸溶液，搅拌使产物析出，抽滤得粗产品。二氯甲烷重结晶后得纯品1a(2.35g,产率77.6％)。 1H NMR(400MHz,DMSO)δ12.18(s,1H),8.19(s,1H),7.58(s,1H),7.46(s,1H),3.85(s,3H),3.82(s,3H),3.25(t,t,J＝6.4Hz,2H),2.58(t,J＝6.4Hz,2H).
步骤2：将化合物1a(1eq)溶于甲醇中，于0℃下滴加氯化亚砜(5eq)，而后移至室温反应4小时。反应结束后将溶剂旋干，加入少量水并用饱和碳酸氢钠溶液调节pH至8左右，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物1b；
步骤3：将化合物1b(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至45℃反应两小时，待反应液冷却至室温后，冰浴下用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得化合物S1。 1H NMR(400MHz,CDCl 3)δ7.34(s,1H),7.25(s,1H),7.20(s,1H),3.95(s,3H),3.94(s,3H),3.67(s,3H),2.72–2.61(m,2H),2.61–2.55(m,2H)；MS(EI):330.0。.
2.化合物S2的合成
Figure PCTCN2019130605-appb-000014
将化合物S1(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S2。 1H NMR(400MHz,CDCl 3)δ7.35(s,1H),7.25(s,1H),7.20(s,1H),3.96(s,3H),3.94(s,3H),2.70–2.58(m,4H)；MS(EI):316.
3.化合物S3的合成
Figure PCTCN2019130605-appb-000015
将化合物S2(1eq)溶于异丙醇中，于0℃下滴加氯化亚砜(5eq)，而后移至室温反应4小时。反应结束后将溶剂旋干，加入少量水并用饱和碳酸氢钠溶液调节pH至8左右，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S3。 1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.22(s,1H),7.19(s,1H),3.97(s,3H),3.94(s,3H),3.68(m,1H),3.31(t,2H,J＝6.8Hz),2.78(t,2H,J＝6.8Hz),1.13(d,6H,J＝4.0Hz)；MS(EI):358.
4.化合物S4的合成
Figure PCTCN2019130605-appb-000016
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入肼盐酸盐(1.0eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S4。H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.10(s,1H),7.53(s,1H),7.44(s,1H),3.89(s,3H),3.86(s,3H),2.62–2.53(m,4H)；MS(EI):330.
5.化合物S5的合成
Figure PCTCN2019130605-appb-000017
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入盐酸羟胺(1.0eq)，缩合剂TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S5。 1H NMR(400MHz,CDCl 3+CD 3OD)δ7.39(s,1H),7.26(s,1H),7.21(s,1H),3.95(s,3H),3.93(s,3H),2.59–2.50(m,4H)；MS(EI):331.
6.化合物S6的合成
Figure PCTCN2019130605-appb-000018
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-甲基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S6。 1H NMR(400MHz,DMSO)δ7.79(s,1H),7.26(s,1H),7.24(s,1H),3.97(s,3H),3.95(s,3H),3.28(s,3H),2.67–2.53(m,4H)；MS(EI):345.
7.化合物S7的合成
Figure PCTCN2019130605-appb-000019
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-二氟甲基羟胺(1.0eq)，缩合剂TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S7。 1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.25(s,1H),7.24(s,1H),7.20(m,1H),3.95(s,3H),3.93(s,3H),3.38(t,2H,J＝8.0Hz),2.97(t,2H,J＝8.0Hz)；MS(EI):381.
8.化合物S8的合成
Figure PCTCN2019130605-appb-000020
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-烯丙基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S8。 1H NMR(400MHz,CDCl 3)δ8.10(brs,1H),7.72(s,1H),7.35(s,1H),7.13(s,1H),5.61(m,1H),5.33(m,2H),3.96(s,3H),3.92(s,3H),3.70(d,2H,J＝6.2Hz),2.65–2.54(m,4H)；MS(EI):371。
9.化合物S9的合成
Figure PCTCN2019130605-appb-000021
将化合物S8(1eq)溶于1，4-二氧六环中，而后加入二羟化混合物试剂AD-Mix-β(1.5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用二氯甲烷萃取，收集有机相并过柱纯化得化合物S9。 1H NMR(400MHz,CD 3OD)δ8.30(brs,1H),7.99(s,1H),7.37(s,1H),7.22(s,1H),4.01(m,1H),3.96(s,3H),3.94(s,3H),3.84(m,2H),3.65(m,2H),2.62–2.55(m,4H)；MS(EI):405。
10.化合物S10的合成
Figure PCTCN2019130605-appb-000022
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-异丙基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得 化合物S10。 1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.28(brs,1H),7.23(s,1H),7.20(s,1H),3.99(s,3H),3.97(s,3H),3.23(m,1H),2.65–2.60(m,4H),1.10(d,6H,J＝4.0Hz)；MS(EI):373。
11.化合物S11的合成
Figure PCTCN2019130605-appb-000023
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-苄基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S11。 1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.73(brs,1H),7.37-7.3(m,5H),7.23(s,1H),7.20(s,1H),4.14(s,2H),3.99(s,3H),3.97(s,3H),2.59–2.53(m,4H),MS(EI):421.
12.化合物S12的合成
Figure PCTCN2019130605-appb-000024
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-二氟苄基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S12。 1H NMR(400MHz,CDCl 3)δ7.90(s,1H),7.76(brs,1H),7.59-7.52(m,5H),7.38(s,1H),7.29(s,1H),3.95(s,3H),3.93(s,3H),2.68–2.62(m,4H),MS(EI):457.
13.化合物S13的合成
Figure PCTCN2019130605-appb-000025
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-吡啶亚甲基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S13。 1H NMR(400MHz,CDCl 3)δ8.45(s,1H),8.17(d,1H,J＝7.5Hz),7.82(s,1H),7.79(d,1H,J＝7.5Hz),7.70(brs,1H),7.28(m,1H),7.25(s,1H),7.20(s,1H),4.21(s,2H),3.97(s,3H),3.95(s,3H),2.66–2.59(m,4H),MS(EI):422.
14.化合物S14的合成
Figure PCTCN2019130605-appb-000026
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-苯基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S14。 1H NMR(400MHz,CDCl 3)δ8.00(s,1H),7.79(brs,1H),7.50-7.42(m,5H),7.29(s,1H),7.22(s,1H),3.99(s,3H),3.97(s,3H),2.62–2.54(m,4H)；MS(EI):407.
15.化合物S15的合成
Figure PCTCN2019130605-appb-000027
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-环丙基羟胺盐酸盐(1.0eq)，缩合剂TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱 纯化得化合物S15。 1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.28(s,1H),7.24(s,1H),3.96(s,3H),3.95(s,3H),3.28(m,1H),2.61–2.52(m,4H),0.94(m,4H)；MS(EI):371.
16.化合物S16的合成
Figure PCTCN2019130605-appb-000028
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入磺酸羟胺盐酸盐(1.0eq)，缩合剂TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S16。 1H NMR(400MHz,CDCl 3+CD 3OD)δ11.89(brs,1H,),7.40(s,1H),7.24(s,1H),7.19(s,1H),3.97(s,3H),3.96(s,3H),2.67–2.58(m,4H)；MS(EI):411.
17.化合物S17的合成
Figure PCTCN2019130605-appb-000029
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入甲氧基胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S17。 1H NMR(400MHz,CDCl 3)δ8.54(brs 1H),7.87(s,1H),7.20(s,2H),3.97(s,3H),3.96(s,3H),3.79(s,3H),2.69–2.60(m,4H)；MS(EI):345。
18.化合物S18的合成
Figure PCTCN2019130605-appb-000030
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入O-苯基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S18。 1H NMR(400MHz,CDCl 3)δ8.33(s,1H),7.65(s,1H),7.24–6.95(m,6H),3.96(s,3H),3.95(s,3H),2.67–2.59(m,4H)；MS(EI):407.
19.化合物S19的合成
Figure PCTCN2019130605-appb-000031
步骤1：将化合物1b(1eq)溶于乙腈中，于室温下加入选择性氟试剂Selectfluor，反应过夜。反应结束后用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，而后收集有机相过柱纯化得化合物19a；
步骤2：将化合物19a(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至45℃反应两小时，待反应液冷却至室温后，冰浴下用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得化合物19b；
步骤3：将化合物19b(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至45℃反应两小时，待反应液冷却至室温后，冰浴下用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得二氟中间体。将该二氟中间体溶于1，4-二氧六环中，而后加入适量6N盐酸，回流过夜。反应结束后，待反应液冷却至室温，旋干溶剂，用乙醇重结晶，得化合物S19。 1H NMR(400MHz,CDCl 3)δ12.09(s,1H),8.12(s,1H),7.48(s,1H),3.94(s,3H),3.89(s,3H),2.90–2.58(m, 4H)；MS(EI):334.
20.化合物S20的合成
Figure PCTCN2019130605-appb-000032
将化合物S19(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入盐酸羟胺(1.0eq)，缩合剂TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S20。 1H NMR(400MHz,CDCl 3+CD 3OD)δ8.19(s,1H),7.58(s,1H),3.98(s,3H),3.93(s,3H),2.88-2.62(m,4H)；MS(EI):349.
21.化合物S21的合成
Figure PCTCN2019130605-appb-000033
将化合物S19(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-异丙基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S21。 1H NMR(400MHz,CDCl 3)δ7 1H NMR(400MHz,CDCl 3)δ8.25(s,1H),7.61(s,1H),3.99(s,3H),3.97(s,3H),3.34(m,1H),2.93–2.89(m,4H),1.13(d,J＝4.0Hz,6H)；MS(EI):391.
22.化合物S22的合成
Figure PCTCN2019130605-appb-000034
将化合物S19(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-苄基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得 化合物S22。 1H NMR(400MHz,CDCl 3)δ 1H NMR(400MHz,CDCl 3)δ8.25(s,1H),7.61(s,1H),3.99(s,3H),3.97(s,3H),2.78(m,4H)；MS(EI):439.
23.化合物S23的合成
Figure PCTCN2019130605-appb-000035
步骤1：将化合物1b(1eq)悬浮于甲醇中，而后加入氢氧化钯/碳(20％)，于室温下在1.1atm氢气环境下反应6小时。反应结束后将反应液用硅藻土过滤，并旋干，过柱纯化，得化合物23a。
步骤2：将化合物23a(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至室温反应两小时，待反应液结束后，冰浴下用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得化合物23b。 1H NMR(400MHz,CDCl 3)δ7.23(s,1H),7.14(s,1H),7.08(s,1H),5.06(t,J＝6.7Hz,1H),3.96(s,3H),3.94(s,3H),3.80(s,3H),2.55(s,2H),2.21(d,J＝6.5Hz,2H)；
步骤3：将化合物23b(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S23。 1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.31(s,1H),7.16(s,1H),5.16(m,1H),3.99(s,3H),3.96(s,3H),2.55(brs,2H),2.23(d,J＝6.5Hz,2H)；MS(EI):298
24.化合物S24的合成
Figure PCTCN2019130605-appb-000036
将化合物S23(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-异丙基羟 胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S24。 1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.30(brs,1H),7.21(s,1H),7.18(s,1H),5.24(m,1H),3.98(s,3H),3.96(s,3H),3.23(m,1H),2.57(brs,2H),2.29(d,J＝6.5Hz,2H),1.08(d,6H,J＝4.0Hz).MS(EI):355.
25.化合物S25的合成
Figure PCTCN2019130605-appb-000037
将化合物S23(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-苯基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S25。 1H NMR(400MHz,CDCl 3)δ8.23(s,1H),7.62-7.53(m,5H),7.35(s,1H),7.31(s,1H),5.31(m,1H),3.98(s,3H),3.97(s,3H),2.49(brs,2H),2.35(d,J＝6.5Hz,2H)；MS(EI):389.
26.化合物S26的合成
Figure PCTCN2019130605-appb-000038
步骤1：称取丁二酸酐(1eq)、三氯化铝(1.5eq)溶于1,2-二氯乙烷中，置零下10℃搅拌；将亚甲二氧基苯并[b]噻吩(1.1eq)溶于1,2-二氯乙烷中，逐滴滴入上述反应液中，持续30min；滴毕，继续搅拌10min中后转移至45℃油浴锅 中反应过夜。TLC检测反应完毕后，将反应液倒入冰水中，加入15％盐酸溶液，搅拌使产物析出，抽滤得粗产品。二氯甲烷重结晶后得纯品26a。 1H NMR(400MHz,DMSO)δ11.98(s,1H),8.04(s,1H),7.43(s,1H),7.36(s,1H),5.95(s,2H),3.23(t,t,J＝6.4Hz,2H),2.51(t,J＝6.4Hz,2H).
步骤2：将化合物26a(1eq)溶于甲醇中，于0℃下滴加氯化亚砜(5eq)，而后移至室温反应4小时。反应结束后将溶剂旋干，加入少量水并用饱和碳酸氢钠溶液调节pH至8左右，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物26b；
步骤3：将化合物26b(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至45℃反应两小时，待反应液冷却至室温后，冰浴下用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得化合物26c。 1H NMR(400MHz,CDCl 3)δ7.32(s,1H),7.21(s,1H),7.14(s,1H),5.87(s,2H),3.64(s,3H),2.64-2.57(m,4H)；MS(EI):314。
步骤4：将化合物26c(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S26。 1H NMR(400MHz,CDCl 3)δ7.31(s,1H),7.22(s,1H),7.18(s,1H),5.83(s,2H),2.72–263(m,4H)；MS(EI):300.
27.化合物S27的合成
Figure PCTCN2019130605-appb-000039
步骤1：将化合物5,6-二甲氧基苯并[b]噻吩(1eq)溶于二氯甲烷中，于-78℃下缓慢滴加1.0M三溴化硼的二氯甲烷溶液(6eq)，并在-78℃反应半小时，而后移至室温反应约半小时。反应结束后在冰浴下缓慢滴加水淬灭，而后用二氯甲烷萃取，并过柱纯化得中间体27a。将27a(1eq)溶于N,N-二甲基甲酰胺中，而已依次加入1，2-二溴乙烷(1eq)，碳酸钾(4.5eq)，于90℃下反应过夜，冷却至室温后倾入冰水中，用乙酸乙酯萃取并过柱纯化得化合物27b。
步骤2：称取丁二酸酐(1eq)、三氯化铝(1.5eq)溶于1,2-二氯乙烷中，置零下10℃搅拌；将27b(1.1eql)溶于1,2-二氯乙烷中，逐滴滴入上述反应液中，持续30min；滴毕，继续搅拌10min中后转移至45℃油浴锅中反应过夜。TLC检测反应完毕后，将反应液倒入冰水中，加入15％盐酸溶液，搅拌使产物析出，抽滤得粗产品。二氯甲烷重结晶后得纯品27c。
步骤3：将化合物27c(1eq)溶于甲醇中，于0℃下滴加氯化亚砜(5eq)，而后移至室温反应4小时。反应结束后将溶剂旋干，加入少量水并用饱和碳酸氢钠溶液调节pH至8左右，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物27d；
步骤4：将化合物27d(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至45℃反应两小时，待反应液冷却至室温后，冰浴下用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得化合物27e。 1H NMR(400MHz,CDCl 3)δ7.35(s,1H),7.23(s,1H),7.17(s,1H),4.32(m,4H),3.64(s,3H),2.63–2.57 (m,4H)；MS(EI):328。
步骤5：将化合物27e(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S27。 1H NMR(400MHz,CDCl 3)δ7.38(s,1H),7.28(s,1H),7.20(s,1H),4.36(m,4H),2.61–2.56(m,4H)；MS(EI):314。
28.化合物S28的合成
Figure PCTCN2019130605-appb-000040
步骤1:将6-甲氧基苯并噻吩(1eq)溶于二氯甲烷中，加入NBS(1.1eq),反应液持续搅拌6小时，TLC检测反应完毕后，将溶剂旋掉，并过柱纯化得化合物28a。
步骤2：称取丁二酸酐(1eq)、三氯化铝(1.5eq)溶于1,2-二氯乙烷中，置零下10℃搅拌；将28a(1.1eq)溶于1,2-二氯乙烷中，逐滴滴入上述反应液中，持续30min；滴毕，继续搅拌10min中后转移至45℃油浴锅中反应过夜。TLC检测反应完毕后，将反应液倒入冰水中，加入15％盐酸溶液，搅拌使产物析出，抽滤得粗产品。二氯甲烷重结晶后得纯品28b。
步骤3：将化合物28b(1eq)溶于甲醇中，于0℃下滴加氯化亚砜(5eq)，而后移至室温反应4小时。反应结束后将溶剂旋干，加入少量水并用饱和碳酸氢钠溶液调节pH至8左右，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物28c；
步骤4：将化合物28c(1eq)溶于二氯甲烷中，冰浴下加入DAST(5eq)，约10分钟后升温至45℃反应两小时，待反应液冷却至室温后，冰浴下用饱和碳 酸氢钠溶液淬灭，乙酸乙酯萃取，过柱分离纯化得化合物28d。 1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.36(s,1H),7.22(s,1H),3.94(s,3H),3.64(s,3H),2.61–2.54(m,4H)；。
步骤5：将化合物28d(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S28。 1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.38(s,1H),7.22(s,1H),3.99(s,3H),2.62–2.53(m,4H)；MS(EI):363。
29.化合物S29的合成
Figure PCTCN2019130605-appb-000041
步骤1:将28d(1eq)、烯基硼酸酯(1.1eq)、催化剂Pd 2(dba) 3(0.05eq)、配体X-Phos(0.05eq)和Cs2CO3(1eq)溶于干燥甲苯中，于110℃反应12小时，TLC检测反应完毕后，加入乙酸乙酯稀释，用饱和食盐水洗，有机相用无水Na2SO4干燥，减压浓缩并过柱纯化得化合物29a。 1H NMR(400MHz,CDCl 3)δ7.56(s,1H),7.30(s,1H),7.18(s,1H),6.52(m,1H),5.30-5.48(m,2H),3.96(s,3H),3.61(s,3H),2.65–2.58(m,4H)；
步骤2:将化合物29a(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S29。 1H NMR(400MHz,CDCl 3)δ7.55(s,1H),7.32(s,1H),7.20(s,1H),6.49(m,1H),5.25-5.43(m,2H),3.95(s,3H),2.60–2.54(m,4H)；MS(EI):312。
30.化合物S30的合成
Figure PCTCN2019130605-appb-000042
将化合物S2(1eq)溶于1，4-二氧六烷中，于0℃下滴加氯化亚砜(5eq)，而后加入苯酚(1.1eq),待反应结束，移至室温反应4小时。反应结束后将溶剂旋干， 加入少量水并用饱和碳酸氢钠溶液调节pH至8左右，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S30。 1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.19(s,1H),7.430-7.39(m,5H)，7.19(s,1H),3.97(s,3H),3.94(s,3H),2.79-2.68(m,4H)；MS(EI):358.
31.化合物S31的合成
Figure PCTCN2019130605-appb-000043
将化合物S2(1eq)溶于1，4-二氧六烷中，于0℃下滴加氯甲酸甲酯(3eq)，而后加入Et3N(2eq),待反应结束，移至室温反应12小时。反应结束后将溶剂旋干，加入少量水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S31。 1H NMR(400MHz,DMSO-d6)δ11.18(brs,1H),7.39(s,1H),7.28(s,1H),7.22(s,1H),3.96(s,3H),3.94(s,3H),2.70–2.58(m,4H)；MS(EI):360.
32.化合物S32的合成
Figure PCTCN2019130605-appb-000044
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入N-乙酸甲酯羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得中间体；将中间体(1eq)溶于四氢呋喃：水(1：1)的混合溶剂中，而后加入氢氧化锂一水合物(3eq)，于室温下反应半小时，用1N盐酸调节pH至5～6，用氯仿萃取，将有机相收集并过柱纯化得化合物S32。 1H NMR(400MHz,CDCl 3)δ7.40(s,1H),7.29(s,1H),7.22(s,1H),4.13(s,2H),3.99(s,3H),3.97(s,3H),2.72–2.65(m,4H)；MS(EI):389.
33.化合物S33的合成
Figure PCTCN2019130605-appb-000045
将化合物S2(1eq)溶于N,N-二甲基甲酰胺中，而后依次加入O-羟乙基羟胺盐酸盐(1.5eq)，TBTU(3eq)，N,N-二异丙基乙胺(5eq)，于室温下反应过夜。反应结束后将反应液倾入冰水，用乙酸乙酯萃取，收集有机相并过柱纯化得化合物S33。 1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.32(s,1H),7.28(s,1H),3.97(s,3H),3.96(s,3H),3.72(t,2H,J＝8.4Hz),3.54(t,2H,J＝8.0Hz),2.84-2.65(m,4H).MS(EI):375.
二、化合物激活干扰素基因刺激蛋白，促进IFN-β表达的细胞筛选实验
检测方法及原理：人源的THP1-Blue-ISG细胞，该细胞内转有含IFN-β的报告***，报告***可诱导下游碱性磷酸酶的表达，当碱性磷酸酶分泌至细胞外时，可通过显色反应测定OD650可反应其含量。当细胞加入化合物后，若激活干扰素基因刺激蛋白，则可促进IFN-β的表达，进而促进下游的碱性磷酸化分泌增加及显色反应的吸光度增加。
试验方法：
1、加化合物：96孔细胞培养板中的每孔加入20μL用生理盐水稀释的化合物
化合物的浓度为100μM，设2个重复孔。阳性对照化合物为ADU-S100，浓度为100μM。不加药对照组加20μL含1％DMSO的生理盐水。
2、加细胞：THP1-Blue-ISG细胞计数，调整细胞浓度至5×10 5/mL，每孔加入180μl的细胞进行孵育。因此，每个测试孔的终体积为200μL，DMSO的含量为0.1％，化合物的测试浓度为10μM。阳性对照化合物为ADU-S100的终浓度为10μM，孵育24小时进行检测；另空白对照组加180μL培液。
3、检测显色反应：24小时后，每孔取20μL的培养液至新的96孔板中，加入显色液Quanti-Blue 200μL，放置37℃的培养箱，0.5-2小时后测定OD650值。
4、化合物的筛选浓度：10μM。
5、结果分析：
Figure PCTCN2019130605-appb-000046
其中Compound OD650为本发明化合物的OD650值，Blank OD650为培养基的OD650值，Control OD650为不加化合物(仅细胞和0.1％DMSO)的对照组的OD650值。
6、结果评定：激活倍数(Fold change)≥2时，有效。
实验结果：
表2部分化合物在10μM浓度时激活THP1细胞中人源干扰素基因刺激蛋白，促进Ⅰ型干扰素表达的能力
Figure PCTCN2019130605-appb-000047
其中，CON表示不加化合物(即仅细胞和0.1％DMSO)的对照。
以上结果表明，在10uM浓度时，所测化合物都能显著活化干扰素基因刺激蛋白，促进干扰素因子IFN-β的表达；其中，绝大部分化合物的激动活性与处于I期临床研究的环二核苷化合物ADU-S100相当，甚至更好，具有进一步应用前景。
此外，相对于TW201817723A(US20180093964)公开化合物1a(即已公开专利中化合物16)，化合物S1-3、S7、S10、S11-12、S15、S19、S21、S28-29具有2-2.5倍增强的激动活性。
三、化合物S2的药物代谢性质研究
表3.化合物S2与1a在大鼠中药物代谢动力学性质比较
Figure PCTCN2019130605-appb-000048
以上数据表明，本专利所述代表性化合物S2不管口服给药、还是静脉注射，其半衰期(T 1/2)、最大血药溶度(Cmax)、血浆暴露量(AUC)和平均驻留时间(MRT)等指标都要明显优于TW201817723A(US20180093964)公开化合物1a(即已公开专利中化合物16)，特别是静脉注射时的AUC，约为1a的4.4倍，显著提高。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，
    Figure PCTCN2019130605-appb-100001
    其中，
    R 1和R 2独立地选自取代或未取代的下组基团：H、卤素、氨基、羟基、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、含1-3个选自N、O、S的杂原子的3-8元杂环烷基、含1-3个选自N、O、S的杂原子的3-8元杂环烷氧基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；或者R 1和R 2与它们连接的碳原子一起形成5-14元杂环基；
    所述R 1和R 2中的取代指独立地被选自下组的一个或多个取代基取代：卤素、氨基、羟基、羧基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、含1-3个选自N、O、S的杂原子的3-8元杂环基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；
    X 1和X 2独立地选自下组：H、D、卤素、未取代的或卤素取代的C1-C6烷基、未取代的或卤素取代的C1-C6烷氧基、腈基；
    X 3选自下组：氢、卤素、羟基、C1-C3烷基、C1-C3烷氧基；
    n为选自0、1、2、3、4、5、6、7、8的整数；
    Y选自下组：-OR 3、-N(X 4R 4)R 5，
    其中，
    X 4选自下组：O、S、NH；
    R 3选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1‐C6烷基、C3‐C8环烷基、C6‐C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、含1‐3个选自N、O、S的杂原子的3‐8元杂环烷基；
    R 4和R 5独立地选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、C6-C10芳氧基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-8元杂环烷基、 含1-3个选自N、O、S的杂原子的3-10元杂芳基；
    所述R 3、R 4和R 5中的取代指独立地被选自下组的一个或多个取代基取代：卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、含1-3个选自N、O、S的杂原子的3-8元杂环基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基。
  2. 如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，其特征在于，X 3为卤素。
  3. 如权利要求2所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，其特征在于，X 2为氢或氟。
  4. 如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，其特征在于，n为选自0、1、2的整数。
  5. 如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，其特征在于，Y选自下组：-OR 3、-N(X 4R 4)R 5，
    其中，
    X 4选自下组：O、NH；
    R 3选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1‐C6烷基、C3‐C8环烷基、C6‐C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、含1‐3个选自N、O、S的杂原子的3‐8元杂环烷基；
    R 4和R 5独立地选自取代或未取代的下组基团：H、羧基、磺酸基、磷酰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基、C6-C10芳氧基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-8元杂环烷基、含1-3个选自N、O、S的杂原子的3-10元杂芳基；
    所述R 3、R 4和R 5中的取代指独立地被选自下组的一个或多个取代基取代：卤素、羟基、氨基、羧基、C1‐C6烷基、C3‐C8环烷基、C1‐C6烷氧基、C3‐C8环烷氧基、含1‐3个选自N、O、S的杂原子的3‐8元杂环基、C6‐C10芳基、含1‐3个选自N、O、S的杂原子的3‐10元杂芳基。
  6. 如权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐，其特征在于，所述化合物选自下组：
    Figure PCTCN2019130605-appb-100002
    Figure PCTCN2019130605-appb-100003
    Figure PCTCN2019130605-appb-100004
  7. 一种权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐的制备方法，其特征在于，所述方法选自下组：
    方法一：
    Figure PCTCN2019130605-appb-100005
    将式A化合物与DAST反应，得到B；
    其中，R 1、R 2、X 1、X 2、n、Y、X 3如权利要求1所定义；
    方法二：
    Figure PCTCN2019130605-appb-100006
    将式C化合物和式D化合物或其盐酸盐反应，得到E；
    其中，R 1、R 2、X 1、X 2、X 3、n、R 3、X 4、R 4和R 5如权利要求1所定义。
  8. 一种药物组合物，其特征在于，包含：
    (i)一种或多种治疗有效量的权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐；和
    (ii)药学上可接受的载体。
  9. 一种权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐或权利要求8所述的药物组合物的用途，其特征在于，用于制备制剂，所述制剂用于预防和/或治疗与I型干扰素相关的疾病。
  10. 一种干扰素基因刺激蛋白激动剂，其特征在于，包含一种或多种权利要求1所述的化合物、或其异构体、前药、溶剂合物、水合物或其药学上可接受的盐。
PCT/CN2019/130605 2019-01-02 2019-12-31 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 WO2020140894A1 (zh)

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