WO2019232665A1 - 一类具有抗癌活性的硫代吲嗪类化合物及其衍生物 - Google Patents

一类具有抗癌活性的硫代吲嗪类化合物及其衍生物 Download PDF

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WO2019232665A1
WO2019232665A1 PCT/CN2018/000246 CN2018000246W WO2019232665A1 WO 2019232665 A1 WO2019232665 A1 WO 2019232665A1 CN 2018000246 W CN2018000246 W CN 2018000246W WO 2019232665 A1 WO2019232665 A1 WO 2019232665A1
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cancer
substituted
unsubstituted
pharmaceutically acceptable
stereoisomer
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PCT/CN2018/000246
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English (en)
French (fr)
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曹华
李彬
陈伟鑫
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广东药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a class of thioindazines, or stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof.
  • the present invention further relates to a pharmaceutical composition containing at least the aforementioned compound for use in the treatment of cancer.
  • Cancer is one of the important diseases that seriously threaten human health, and its treatment and prevention have attracted widespread attention.
  • the current treatment methods include surgical resection, radiation therapy, and chemical drug treatment.
  • chemical drug treatment is still the main method.
  • chemical drugs used in the clinical treatment of cancer such as platinums, nitrogen mustards, triazoles, etc., but most drugs are limited in their application due to their high toxicity, many adverse reactions, and low bioavailability. Therefore, finding effective and low-toxic anticancer drugs has become one of the key research topics in the field of medicinal chemistry.
  • the invention relates to a new class of indazine compounds, which can effectively inhibit various types of cancers or tumors.
  • the invention provides a thioindazine compound and its derivative with anticancer activity.
  • the purpose of the present invention is to use the compound for treating various cancers or tumors, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • the invention also provides methods and intermediates for preparing the compounds of the invention or their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the present invention also provides a method for treating a tumor or cancer, which comprises administering to a host a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable Salts, solvates or prodrugs thereof.
  • a preferred embodiment is the treatment of various tumors or cancers.
  • the invention also provides the compound or a stereoisomer, tautomer, medicament for use in therapy
  • the invention also provides the compound or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, for preparing a medicine for treating cancer.
  • the present invention provides a compound of general formula selected from the compounds of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, as shown below:
  • R 1 -R 3 are independently selected from hydrogen, deuterium, halogen, -CN, -C (O) -OEt, -SR 0 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1- 6 haloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or substituted or substituted containing 1-4 heteroatoms selected from N, O and S Unsubstituted 5-10 membered heteroaryl;
  • R 0 is independently selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 haloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted containing 1-4 heteroatoms selected from N, O and S 5-10 membered heterocyclic ring, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
  • said substituted means that the corresponding group is replaced by halogen, NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10
  • halogen NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10
  • One or more of cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S are substituted.
  • the aryl group is selected from phenyl, naphthyl, anthracenyl or phenanthryl.
  • the heteroaryl group is selected from the group consisting of indolyl, benzothiazolyl, pyrazolopyridyl, benzoisothiazolyl, triazolopyridyl, indazopyridyl, benzoxazolyl, Triazolopyridyl, indazinopyridyl, pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazyl, benzothiadiazolyl, benzoindazinyl.
  • the invention also provides a method for preparing the compound, which includes the following steps:
  • Substituted nitrogen indene and substituted mercaptans are prepared in an oil bath
  • composition comprising the above-mentioned compound as shown in I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable adjuvant, carrier or diluent.
  • the dosage form of the composition is selected from plain tablets, film-coated tablets, sugar-coated tablets, enteric-coated tablets, dispersible tablets, capsules, granules, oral solutions or oral suspensions.
  • the compound represented by I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used for preparing a medicine for treating tumors or cancers.
  • the tumors or cancers are gastric cancer, cervical adenocarcinoma, Colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, bowel cancer, nasopharyngeal cancer, breast cancer, lymphoma, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer , Melanoma, tongue cancer, laryngeal cancer, blood cancer, prostate cancer, brain tumor, squamous cell carcinoma, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.
  • the invention also provides methods and intermediates for preparing the compounds of the invention, their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs.
  • the present invention also provides a method for treating tumors or cancers (or a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof for use in the preparation of a medicament for treating these diseases Use), including administering to a host a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, according to a therapeutic need.
  • the invention also provides methods of treating diseases (or the use of a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for treating these diseases) Including administering to a patient a therapeutically effective amount of a compound of formula I, wherein the disease is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, bowel cancer, nasopharyngeal cancer, breast Cancer, lymphoma, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, blood cancer, prostate cancer, brain tumor, squamous cell carcinoma, Skin cancer, hemangiomas, lipomas, cervical cancer and thyroid cancer.
  • the disease is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer,
  • the invention also provides a method for treating a disease, which comprises administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with other therapeutic agents.
  • the invention also provides the compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs for use in therapy.
  • the compound of formula I is selected from an exemplary compound or a combination of exemplary compounds or other specific embodiments herein.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and one or more active ingredients.
  • alkyl as used herein includes both branched and straight chain saturated hydrocarbon groups having a specific number of carbon atoms.
  • C 1-10 alkyl (or alkylene) is intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl.
  • C 1-6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • An alkyl group may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced by other chemical groups.
  • alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl) , Pentyl (such as n-pentyl, isopentyl, neopentyl) and their analogs.
  • alkenyl is a hydrocarbon that includes both a straight or branched chain structure and has one or more carbon-carbon double bonds that occur at any stable point in the chain.
  • C 2-6 alkenyl (or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl , 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
  • alkynyl is a hydrocarbon that includes both a linear or branched structure and has one or more carbon-carbon triple bonds that occur at any stable point in the chain.
  • C 2-6 alkynyl (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and Its analog.
  • alkenyl, alkynyl, alkylene, alkenylene or alkynylene these groups are substituted with one to three alkyl substituents as described above.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom or group with a selected specified group, provided that the general valence of the specified atom is not exceeded.
  • 2 hydrogen atoms on the atom are replaced.
  • Ketone substituents are not present on the aromatic fragments.
  • substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety.
  • a stable compound or stable structure implies that the compound is sufficiently stable when isolated from the reaction mixture with useful purity, and is subsequently formulated to form an effective therapeutic agent.
  • the present compound does not comprise N- halogen, S (O) 2 H, or S (O) H group.
  • cycloalkyl refers to cycloalkyl and includes mono-, bi- or polycyclic systems.
  • C 3-7 cycloalkyl is intended to include C3, C4, C5, C6 and C7 cycloalkyl.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, butyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • carbocycle or “carbocycle residue” refers to any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13- Two-membered bi- or tricyclic, which may be saturated, partially unsaturated, unsaturated or aromatic.
  • carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, Cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, Fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (naphthyl).
  • bridged rings are also included in the definition of carbocyclic rings (such as [2.2.2] bicyclooctane). Unless otherwise stated, preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term “carbocycle” is used, it is intended to include “aryl”. Bridged rings occur when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is pointed out that the bridge always converts a single ring into a double ring. When the ring is bridged, the substituents of the ring also exist on the bridge.
  • aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
  • halogen refers to chlorine, bromine, fluorine and iodine.
  • haloalkyl refers to a substituted alkyl group having one or more halogen substituents.
  • haloalkyl includes mono, bis and trifluoromethyl.
  • heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups having at least one ring in at least one ring One heteroatom (O, S or N), said heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N.
  • Each ring of a heteroaryl-containing heteroaryl group may contain one or two oxygen or sulfur atoms and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each Each ring has at least one carbon atom.
  • Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazoline, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, oxadiazolyl , Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
  • Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxenyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinyl Phenyl, benzimidazolyl, benzopyranyl, indolazinyl, benzofuranyl, chromone, coumarin, benzopyranyl, fluorinyl, quinoxalinyl, indazole Group, pyrrolopyridyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
  • salt refers to the formation of acidic and / or basic salts with inorganic and / or organic acids and bases.
  • salt may include zwitterions (internal salts), such as when the compound of formula I contains a basic fragment such as an amine or pyridine or an imidazole ring, and an acid fragment such as a carboxylic acid.
  • Pharmaceutically acceptable (ie, non-toxic, physiological (Acceptable) salts are preferred, such as acceptable metal and amine salts, where the cations do not significantly contribute to toxicity or the biological activity of the salt.
  • the salts of the compound of formula I can be formed as a compound of formula I with a certain amount of acid or base, such as an equivalent amount, in a medium such as where the salt can be precipitated or in its aqueous medium, and then frozen. Dry action.
  • Exemplary acid addition salts include acetates (such as with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipic acid salts, alginates, ascorbates, aspartates, benzoates , Benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor, camphor sulfonate, cyclopentanoate, digluconate, dodecyl sulfate, Ethylsulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrobromic acid) , Hydroiodate, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), mesylate (formed with methanesulfonic acid), 2-naphthal
  • Exemplary basic salts include ammonium, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (such as organic amines) such as trioxane Based amines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-diphenylhydroxymethylamine, N, N′-bisbenzylethylenediamine, dehydroabietylamine , N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like.
  • organic bases such as organic amines
  • trioxane Based amines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-diphenyl
  • Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (such as methyl, ethyl, propyl and butyl chloride, bromine and iodide), dialkyl sulfates (such as dimethyl, Diethyl, dibutyl and dipentyl sulfate), long-chain halides (e.g. decyl, dodecyl, tetradecyl and octadecyl chloride, bromine and iodide), aralkyl halides Substances (such as benzyl and phenethyl bromide) and other substances.
  • Preferred salts include monohydrochloride, bisulfate, mesylate, phosphate or nitrate.
  • phrases "pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical evaluation, are suitable for use in contact with human and animal tissues without additional toxicity, irritation, An allergic reaction or other problem or complication with a reasonably reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a derivative of a disclosed compound in which the parent compound is modified with an acid or a basic salt thereof.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and base or organic salts of acid groups such as carboxylic acids.
  • Pharmaceutically acceptable salts include traditional non-toxic salts or parent compounds that form quaternary ammonium salts, such as from non-toxic inorganic or organic acids.
  • these traditional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, and glycolic acid , Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- Ethoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic fragment by conventional chemical methods.
  • these salts can be prepared from a suitable base or acid in the free acid or base form and stoichiometric ratio of these compounds in water or an organic solvent, or a mixture of both; typically, non-aqueous vehicles such as ether, ethyl acetate , Ethanol, isopropanol or acetonitrile are preferred.
  • Stereoisomers can include compounds of substituted optical isomers through one or more chiral atoms, and optical isomer compounds through restricted rotation of one or more bonds (atropisomers).
  • the definition of the compounds of the invention includes all possible stereoisomers and mixtures thereof. These include, in particular, racemic forms and isolated optical isomers with particular activity. Racemic forms are resolved by physical methods, such as distributed crystallization, separation or crystallization of stereoisomeric derivatives, or by chiral column chromatography. Independent optical isomers such as salts with optically active acids are obtained from racemic salts by conventional methods and then crystallized.
  • Prodrugs and solvates of the compounds of the invention are also contemplated.
  • the term "prodrug” refers to a compound that undergoes a chemical reaction through metabolic or chemical methods based on the administered receptor to produce a compound of formula I, and / or a salt and / or a solvate thereof. Any compound that is transformed in vivo to provide a biologically active agent (ie, a compound of Formula I) is a prodrug within the scope and spirit of the invention.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester as a prodrug, which is hydrolyzed in vivo to produce a compound of formula I itself.
  • prodrugs are preferably administered orally, since hydrolysis under many conditions occurs substantially under the influence of digestive enzymes.
  • Parenteral administration can be used, and the esters are themselves active, in those instances, hydrolysis occurs in the blood.
  • physiologically hydrolyzed esters of compounds of formula I include C 1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C 1-6 alkanoyloxy -C 1-6 alkyl such as acetoxymethyl, pivaloyloxymethyl or propoxymethyl, C 1-6 alkoxycarbonyloxy-C 1-6 alkyl, such as methoxycarbonyl-oxymethyl Or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolene-4-yl ) -Methyl and other well-known physiologically hydrolyzed esters, such as in the fields of pen
  • “Pharmaceutically acceptable carrier” generally refers to those generally accepted in the art that can deliver biologically active agents to animals, especially mammals. Formulating a pharmaceutically acceptable carrier is based on a number of factors well known to those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the recipient to which the agent-containing composition is administered; the route of administration of the composition; and targeted therapy instructions. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid vehicles, as well as a variety of solid and semi-solid dosage forms. These carriers include many different components and additives. In addition to the active agent, these additional components are included in the formulation for a variety of reasons, such as the stability of active agents, adhesives, etc., which are well known to those of ordinary skill in the art. of.
  • the compounds of formula I of the invention may be administered in any suitable manner for the treatment of symptoms, depending on the amount of site-specific treatment or delivery of drug. Local administration is usually preferred for systemic treatment of skin-related diseases, cancerous or precancerous symptoms, but other modes of delivery are also considered.
  • the compounds are administered orally, such as in the form of tablets, capsules, granules, powders or liquid formulations including syrups; topically, such as in solutions, suspensions, gels or ointments; sublingual administration; cheek ground; parenteral administration Medicines such as by subcutaneous, intravenous, intramuscular or intrasternal injection or perfusion (such as sterile water or non-aqueous solution or suspension); nasal, such as by inhalation spray; topically, such as in the form of an emulsion or ointment; Such as in the form of suppositories; or liposomes.
  • Dosage unit formulations containing non-toxic, pharmaceutically acceptable excipients or diluents can be administered.
  • the compounds may be administered in an immediate or delayed release form. Immediate or delayed release can be obtained with suitable pharmaceutical compositions, in the case of partially delayed release, using equipment such as a subcutaneous graft or an osmotic pump.
  • compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for transmission, alginic acid or sodium alginate as a suspending agent, methyl cellulose as a viscosity enhancer, and the prior art Known sweeteners or flavors; immediate release tablets may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders Bulking agents, disintegrating agents, diluents and lubricants are those known in the art.
  • the compounds of the present invention can also be delivered orally by sublingual and / or buccal administration, such as compression molding, compressed or lyophilized tablets.
  • compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrins. Included in these formulations can also be high molecular weight excipients such as cellulose Or polyethylene glycol (PEG); excipients that aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or Maleic anhydride copolymer (e.g. ); And controlled release agents such as polyacrylic acid copolymers (such as ). Lubricants, glidants, perfumes, colorants and stabilizers can also be added to aid preparation and use.
  • PEG cellulose Or polyethylene glycol
  • HPMC hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • SCMC sodium carboxymethyl cellulose
  • compositions for spray or inhalation administration include solutions which may contain benzyl alcohol or other suitable preservatives, absorption enhancers that enhance absorption and / or biological activity, and / or other soluble or dispersing agents Such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Green's solution , Isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids including oleic acid.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Green's solution , Isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids including oleic acid.
  • compositions for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides or polyvinyl glycols, which are solid at ordinary temperatures, but dissolve and / Or dissolve into the stomach and release the drug.
  • suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyvinyl glycols, which are solid at ordinary temperatures, but dissolve and / Or dissolve into the stomach and release the drug.
  • a therapeutically effective amount of a compound of the invention can be determined by one of ordinary skill in the art and includes, for mammals, exemplary doses from about 0.05 to 1000 mg / kg; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg 250-1000 mg / kg, depending on the amount of active compound per kilogram of body weight per day, which can be administered in a single dose or in separate divided doses, such as from 1 to 4 times per day.
  • the particular dosage level and frequency of the agent for a particular receptor can alter the disease depending on a number of factors, including the activity of the particular compound used, the metabolic stability and length of the effect of the compound, race, age, weight, general health Condition, recipient gender and diet, mode and timing of administration, excretion rate, drug combination, and severity of particular disease.
  • Preferred recipients for treatment include animals, most preferably mammals such as humans and poultry animals such as dogs, cats, horses and the like.
  • a stirrer was added to a 25 mL test tube, and 0.4 mmol of 2-phenylindolizine (1a), 0.2 mmol of propyl mercaptan (2a), 0.04 mmol of HOAc, 0.01 mmol of CuI, 0.4 mmol of TBHP, and 2 mL of DMSO were added.
  • the reaction was stirred in a 60 ° C oil pan, and the reaction was monitored by a thin layer chromatography plate until 1a was consumed and the reaction was stopped.
  • the reaction mixture was then diluted with ethyl acetate and water, and extracted, and the ethyl acetate layer was taken. The organic layer was washed with brine, dried over Mg 2 SO 4 and evaporated under reduced pressure.
  • the crude mixture was purified by thin-layer chromatography on a silica gel plate.
  • Example 2 In a manner similar to the preparation of Example 1, the following compounds were prepared using only different raw materials.
  • mice Healthy Kunming mice were selected and provided by the Experimental Center of Guangdong Pharmaceutical University. Mice were housed in non-toxic plastic boxes of five females and males in separate cages. They changed litter once a day, fed and drank freely, kept at room temperature of 18-20 ° C, and exposed to natural light. The drug was dissolved in a 0.9% sodium chloride aqueous solution, and the dose of the test substance was expressed in mg / kg. The following doses are administered intraperitoneally, with a volume of 0.1 mL / 10g, and the doses are as follows: 50, 100, 150, 200, 300 mg / kg.
  • mice After the administration, the animals' appearance, spirit, diet, sleep, activity and daily death distribution were observed and recorded daily for 10 consecutive days, and the LD50 was calculated according to the Bliss method. After administration in the high-concentration group, the mice were debilitated, their feces were not formed before death, they were thin, their hairs were vertical, and their clumps atrophied.
  • the compounds of formula I according to the invention have lower toxicity.
  • inhibition rate (%) (absorbance value of control group-absorbance value of administration group) / (absorbance value of control group-absorbance value of blank group) x 100%.
  • the IC 50 calculation software (China Pharmaceutical University) was used to calculate the half inhibitory concentration (IC 50 ).
  • the unit of data in the table is ⁇ mol / L.
  • Experimental tumor strains include human gastric cancer cells BGC, human cervical adenocarcinoma cells HeLa, human colon cancer cells HCT116, human lung adenocarcinoma cells A549, human lung cancer cells NCI-H460, human prostate cancer cells DU-145, and human breast cancer cells MDA- MB-231. Cells were purchased from the cell bank of the Guangdong Provincial Center for Microbial Strains. The experimental results are shown in the following table.

Abstract

提供一类具有抗癌活性的硫代吲嗪类化合物及其衍生物。其以如下（I）所示：所述化合物及其衍生物对多种癌症及肿瘤都有抑制作用。

Description

一类具有抗癌活性的硫代吲嗪类化合物及其衍生物 技术领域
本发明涉及一类硫代吲嗪类化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物。本发明进一步涉及含有至少上述化合物的药物组合物，其用于治疗癌症。
背景技术
癌症是当前严重威胁人类健康的重要疾病之一，其治疗和预防引起广泛重视。目前的治疗方法有手术切除、放射治疗、化学药物治疗等，但仍主要以化学药物治疗为主。当前临床用于治疗癌症的化学药物种类较多，如铂类、氮芥类、***类等，但大多数药物由于毒性大、不良反应多、生物利用度低而使其应用受到了限制。因此，寻找高效、低毒的抗癌药物已成为当前药物化学领域重点研究课题之一。
鉴于吲嗪类抗癌药物在癌症治疗中的潜在应用，且作者未见国内外文献专门报道吲嗪衍生物在整个抗癌药物领域的研发概况，结合本实验室的研究工作，在此综述吲嗪类化合物作为抗癌药物在放射增敏剂、法尼基转移酶抑制剂、细胞色素P450抑制剂、血管生成抑制剂、拓扑异构酶抑制剂、周期素依赖型蛋白激酶抑制剂及肿瘤耐药逆转剂等方面的最新研究与开发进展。
本发明涉及一类新的吲嗪类化合物，其可有效的抑制各类癌症或肿瘤。
发明内容
本发明提供了一种具有抗癌活性的硫代吲嗪类化合物及其衍生物。
本发明目的是所述化合物用于治疗各种癌症或肿瘤，或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或其前药。
本发明也提供了制备本发明化合物或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或其前药的方法和中间体。
本发明也提供了包括药物上可接受的载体和至少一种本发明化合物或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或其前药的药物组合物。
本发明也提供了***或癌症的方法，包括根据治疗需要，向寄主施予治疗有效量的至少一种本发明化合物，或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或其前药。
优选的具体实施方式是治疗各种肿瘤或癌症。
本发明也提供了用于治疗的所述化合物或其立体异构体、互变异构体、药物上
可接受的盐、溶剂化物或其前药。
本发明也提供了所述化合物或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或其前药，用于制备治疗癌症的药物。
本发明的这些和其它特征将以更详细的方式继续说明。
本发明提供了选自式I化合物的一个通式化合物，或其立体异构体、或其药物上可接受的盐或其溶剂化物，如下所示：
Figure PCTCN2018000246-appb-000001
其中
R 1-R 3独立的选自氢、氘、卤素、-CN、-C(O)-OEt、-S-R 0、取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 6-10芳基、含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂环，或含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂芳基；
R 0独立的选自取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 6-10芳基、含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂环，或含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂芳基。
优选地，其中所述的取代的，指的是相应的基团被卤素、NH 2、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、含有1-4个选自N、O和S中杂原子的5-10元杂芳基中的一个或多个所取代。
优选地，所述芳基选自苯基、萘基、蒽基或菲基。
优选地，所述杂芳基选自吲哚满基、苯并噻唑基、吡唑并吡啶基、苯并异噻唑基、***并吡啶基、吲嗪并吡啶基、苯并噁唑基、***并吡啶基、吲嗪并吡啶基、吡啶并吡嗪基、喹唑啉基、吡啶并吡嗪基、苯并噁二唑基、苯并噻二唑基、苯并吲嗪基。
优选地，选自下述化合物：
Figure PCTCN2018000246-appb-000002
Figure PCTCN2018000246-appb-000003
Figure PCTCN2018000246-appb-000004
本发明还提供了所述的化合物的制备方法，其包括下述步骤：
取代氮茚和取代硫醇在油浴锅反应制备得到；
一种组合物，其包括上述如I所示的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，和药学上可接受的助剂、载体或稀释剂。
优选地，所述组合物的剂型选自素片、薄膜包衣片、糖衣片、肠衣片、分散片、胶囊、颗粒剂、口服溶液或口服混悬液。
所述的如I所示的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物可用于制备***或癌症药物，所述肿瘤或癌症为胃癌、***、结肠癌、肺癌、肝癌、胶质瘤、食道癌、肠癌、鼻咽癌、乳腺癌、淋巴癌、肾癌、胰腺癌、膀胱癌、卵巢癌、子宫癌、骨癌、胆囊癌、唇癌、黑素瘤、舌癌、喉癌、血癌、***癌、脑瘤、鳞癌、皮肤癌、血管瘤、脂肪瘤、***和甲状腺癌。
本发明也提供了制备本发明化合物、其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或前药的方法和中间体。
本发明也提供了***或癌症的方法(或本发明的化合物或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或前药用于制备治疗这些疾病药物的用途)，包括根据治疗需要，向寄主施予治疗有效量的至少一种本发明化合物，或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或其前药。
本发明也提供了治疗疾病的方法(或本发明的化合物或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或前药用于制备治疗这些疾病药物的用途)，包括根据治疗需要向患者施予治疗有效量的式I化合物，其中所述疾病是胃癌、***、结肠癌、肺癌、肝癌、胶质瘤、食道癌、肠癌、鼻咽癌、乳腺癌、淋巴癌、肾癌、胰腺癌、膀胱癌、卵巢癌、子宫癌、骨癌、胆囊癌、唇癌、黑素瘤、舌癌、喉癌、血癌、***癌、脑瘤、鳞癌、皮肤癌、血管瘤、脂肪瘤、***和甲状腺癌。
本发明也提供了治疗疾病的方法，包括根据治疗需要向患者施予治疗有效量的式I化合物或其药物上可接受的盐，与其它治疗试剂联合使用。
本发明也提供了所述化合物或其立体异构体、互变异构体、药物上可接受的盐、溶剂化物或前药用于治疗。
在另一具体实施方式中，式I化合物选自示例化合物或示例化合物的组合或此处的其它具体实施方式。
在另一具体实施方式中，本发明目的在于包括式(I)化合物和一种或多种活性组分的药物组合物。
此处用到的术语“烷基”是包括具有特定数目碳原子的支链和直链饱和烃基。例如“C 1-10烷基”(或亚烷基)目的是C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外，例如“C 1-6烷基”表示具有1到6个碳原子的烷基。烷基可为非取代或取代的，以使一个或多个其氢原子被其它化学基团取代。烷基的实施例包括但不限于甲基(Me)、乙基(Et)、丙基(如正丙基和异丙基)、丁基(如正丁基、异丁基、叔丁基)、戊基(如正戊基、异戊基、新戊基)及其类似物。
“烯基”是既包括直链或支链结构的烃，且具有一个或多个出现在链中任何稳定点的碳-碳双键。例如“C 2-6烯基”(或亚烯基)目的是包括C2、C3、C4、C5和C6烯基。烯基的实例包括但不限于乙烯基、1-丙烯基，2-丙烯基、2-丁烯基、3-丁烯基、 2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基及其类似物。
“炔基”是既包括直链或支链结构的烃，且具有一个或多个出现在链中任何稳定点的碳-碳叁键。例如“C 2-6炔基”(或亚炔基)目的是包括C2、C3、C4、C5和C6炔基；如乙炔基、丙炔基、丁炔基、戊炔基、己炔基及其类似物。
当提到取代烯基、炔基、亚烷基、亚烯基或亚炔基，这些基团以如上所述的一到三个取代烷基的取代基。
此处用到的术语“取代的”指的是在指定原子或基团上的任意一个或多个氢原子以选择的指定基团取代，前提是不超过指定原子的一般化合价。当取代基是氧或酮(即＝O)，那么原子上的2个氢原子被取代。酮取代基不存在芳香片段上。如果没有其它说明，取代基命名至中心结构。例如，可以理解的是当(环烷基)烷基是可能的取代基，该取代基至中心结构的连接点是在烷基部分中。此处使用的环双键是形成于两个临近环原子之间的双键(如C＝C、C＝N或N＝N)。
取代基和或变量的组合是允许的，仅当这些组合产生稳定的化合物或有用的合成中间体。稳定的化合物或稳定结构暗示所述化合物以有用的纯度从反应混合物分离出来时是足够稳定的，随之配制形成有效的治疗试剂。优选地，目前所述化合物不包含N-卤素、S(O) 2H或S(O)H基。
术语“环烷基”指的是环烷基，包括单-、双-或多环体系。C 3-7环烷基目的是包括C3、C4、C5、C6和C7环烷基。环烷基实例包括但不限于环丙基、还丁基、环戊基、环己基、降冰片基及其类似物。此处用到的“碳环”或“碳环残余”指的是任何稳定3、4、5、6或7-元单环或双环或7、8、9、10、11、12或13-元双或三环，其可为饱和、部分不饱和、不饱和或芳香性的。这些碳环实例包括但不限于环丙基、环丁基、环丁烯基、环戊基、戊烯基、环己基、环己烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯、[3.3.0]双环辛烷、[4.3.0]双环壬烷、[4.4.0]双环癸烷、[2.2.2]双环辛烷、芴基、苯基、萘基、茚满基、金刚烷基、蒽基和四氢萘基(萘满)。如上所述，桥环也包含于碳环(如[2.2.2]双环辛烷)的定义中。如果没有其它说明，优选的碳环是环丙基、环丁基、环戊基、环己基和苯基。当使用术语“碳环”，目的是包括“芳基”。当一个或多个碳原子连接两个非临近碳原子出现桥环。优选的桥是一个或两个碳原子。指出的是桥总是将单环转化为双环。当环是桥连的，环的取代基也存在于桥上。
术语“芳基”指的是在环部分具有6到12个碳原子的单环或双环芳香烃基，如苯基和萘基，每个可被取代的。
术语“卤素”或“卤素”指的是氯、溴、氟和碘。
术语“卤代烷基”指的是具有一个或多个卤素取代基的取代烷基。例如“卤代烷基”包括单、双和三氟甲基。
术语“杂芳基”指的是取代和非取代芳香5或6元单环基团，9-或10-元双环基团，和11到14元三环基团，在至少一个环中具有至少一个杂原子(O，S或N)，所述含杂原子的环优选具有1、2或3个选自O、S和N中的杂原子。含杂原子的杂芳基的每个环可含一个或两个氧或硫原子和/或由1到4个氮原子，前提是每个环中杂原子的总数是4或更少，且每个环具有至少一个碳原子。完成双环和三环基团的稠合环可仅含有碳原子，并可以是饱和、部分饱和或不饱和。氮和硫原子可任选被氧化且氮原子可任选被季铵化。双环或三环的杂芳基必须包括至少一个全芳香环，氮其它稠合环可为芳香性或非芳香性的。杂芳基可在任何环的任何可利用氮或碳原子上连接。当化合价允许，如果所述其它环是环烷基或杂环，其另外任选以＝O(氧)取代。
示例性单环杂芳基包括吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑 基、噻唑基、噻二唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基及其类似物。
示例性双环杂芳基包括吲哚基、苯并噻唑基、苯并二氧杂环戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲哚嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、氟代吡啶基、二氢异吲哚基、四氢喹啉基及其类似物。
如果没有其它说明，本发明的化合物理解为包括游离态和其盐。术语“盐”表示以无机和/或有机酸和碱形成酸式和/或碱式盐。另外，术语“盐可包括两性离子(内盐)，如当式I化合物含有碱性片段如胺或吡啶或咪唑环，和酸式片段如羧酸。药物上可接受的(即非毒性、生理学上可接受的)盐是优选的，如可接受的金属和胺盐，其中阳离子没有显著贡献毒性或盐的生物活性。然而，其它盐可是有用的，如在制备过程中采用分离或纯化步骤，因此也包含于本发明范围中。式I化合物的盐可以如式I化合物与一定量的酸或碱形成，如等量，在媒介中如在其中盐可沉淀或其水媒介中，然后进行冻干作用。
示例性的酸式加成盐包括乙酸盐(如与乙酸或三卤素乙酸形成，如三氟乙酸)、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊丙酸盐、双葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(与盐酸形成)、氢溴酸盐(与氢溴酸形成)、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐(与马来酸形成)、甲磺酸盐(与甲磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的那些)、磺酸盐(如此处提及的那些)、酒石酸盐、硫氰酸盐、甲苯磺酸盐如甲苯磺酸盐、十一酸盐及其类似物。
示例性碱式盐包括铵盐、碱金属盐如钠、锂和钾盐；碱土金属盐如钙和镁盐；钡、锌和铝盐；与有机碱形成的盐(如有机胺)如三烷基胺如三乙胺、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺、N，N′-双苄乙二胺、去氢枞胺、N-乙基哌啶、苄胺、二环己胺或类似药物上可接受的胺和与氨基酸的盐如精氨酸、赖氨酸及其类似物。碱式含氮基团可与试剂季铵化如低级烷基卤化物(如甲基、乙基、丙基和丁基氯、溴和碘化物)、二烷基硫酸盐(如二甲基、二乙基、二丁基和二戊基硫酸盐)、长链卤化物(如癸基、十二烷基、十四烷基和十八烷基氯、溴和碘化物)、芳烷基卤化物(如苄基和苯乙基溴化物)和其它物质。优选的盐包括单盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
短语“药物上可接受的”指的是那些化合物、材料、组合物和/或剂型，在完好的医疗评价范围内，适合用于与人类和动物的组织接触，而没有额外的毒性、刺激、过敏反应或其它问题或并发症，具有相称的合理收益/风险比例。
此处用到的“药物上可接受的盐”指的是公开化合物的衍生物，其中父系化合物是以酸或其碱式盐修饰。药物上可接受盐的实例包括但不限于碱式基团如胺的无机或有机酸式盐；和酸式基团如羧酸的碱或有机盐。药物上可接受的盐包括传统的非毒性盐或父系化合物形成季铵盐，如由非毒性无机或有机酸。例如，这些传统的非毒性盐包括那些衍生自无机酸如盐酸、氢溴酸、硫磺酸、氨基磺酸、磷酸和硝酸；和由有机酸制备的盐如乙酸、丙酸、琥珀酸、羟基乙酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、帕莫酸、马来酸、羟基马来酸、苯基乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙氧苯甲酸、反丁烯二酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸和羟乙磺酸及其类似物。
本发明药物上可接受的盐可由含有碱式或酸式片段的父系化合物，通过常规化学方法合成。通常地，这些盐可由这些化合物的游离酸或碱形式与化学计量比的适合碱或酸在水或有机溶剂，或其两种混合物中进行制备；通常地，非水媒介如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。
本发明化合物的所有立体异构体是被考虑的，既以混合物或纯或基本纯的形式。立体异构体可包括通过一个或多个手性原子的取代的光学异构体的化合物，以及通过限制旋转一个或多个键(阻转异构体)的光学异构体化合物。本发明化合物的定义包括所有可能立体异构体和其混合物。其尤其包括外消旋形式和具有特别活性的分离光学异构体。通过物理方法拆分外消旋形式，例如分布结晶、分离或立体异构衍生物的结晶或通过手性柱色谱分离。通过常规方法由外消旋盐得到独立的光学异构体如与光学活性的酸形成的盐，然后结晶。
本发明化合物的前药和溶剂化物也是被考虑的。术语“前药”表示化合物，基于施予受体，通过代谢性或化学方法经历化学反应生成式I化合物，和/或盐和/或其溶剂化物。在体内转化以提供生物活性试剂(即式I化合物)的任何化合物是本发明范围和精神内的前药。例如，含有羧基的化合物可形成作为前药的生理学可水解酯，通过在体内水解生成式I化合物自身。这些前药优选口服施予，由于许多条件下的水解基本出现在消化酶的影响下。可使用肠胃外施予，酯自身是活性的，在那些实例中，水解出现在血液中。式I化合物的生理学水解酯实例包括C 1-6烷基苄基、4-甲氧基苄基、茚满基、邻苯二甲酰基、甲氧基甲基、C 1-6链烷酰氧基-C 1-6烷基如乙酰氧甲基、特戊酰氧甲基或丙氧甲基、C 1-6烷氧羰氧基-C 1-6烷基，如甲氧羰基-氧甲基或乙氧基羰氧甲基、甘氨酰氧甲基、苯基甘氨酰氧甲基、(5-甲基-2-氧-1，3-二氧杂环戊烯-4-基)-甲基和其它使用的熟知的生理学水解酯，例如在盘尼西林和cephalogensporin领域中。这些酯可通过现有技术中已知的常规技术进行制备。多种形式的前药是现有技术中熟知的。
“药物上可接受的载体”一般指的是通常在该领域中接受的，可传递生物活性试剂至动物，尤其是哺乳动物。配制药物上可接受载体，根据本领域普通技术人员所熟知的许多因素。这些包括没有限制被配制的活性试剂的类型和特性；含试剂组合物施予的受体；组合物施予途径；和定向治疗指示。药物上可接受的载体包括水性和非水性液态媒介，以及多种固态和半固态剂型。这些载体包括许多不同组分和添加剂，除了活性试剂之外，这些额外组分由于多种原因包含于配方中，如活性试剂、粘合剂等的稳定性，这是本领域普通技术人员所熟知的。
本发明式I化合物可以治疗症状的任何适合方式施予，取决于位点专一治疗或传递药物的量。局部投药通常优选皮肤相关疾病，癌性或癌性前症状的***性治疗，但其它传递模式也是考虑的。例如口服施予化合物，如以片剂、胶囊、颗粒、粉末或包括糖浆剂的液体配方形式；局部如以溶液、悬浮液、凝胶或软膏；舌下给药；脸颊地；胃肠外给药如通过皮下、静脉注射、肌肉注射或胸骨内注射或灌注术(如无菌水或非水溶液或悬浮液)；经鼻的如通过吸入喷雾；局部地如以乳液或软膏形式；经直肠地如以栓剂形式；或脂质体地。可施予含非毒性、药物上可接受赋形剂或稀释剂的剂量单位配方。可以立即释放或延缓释放的形式施予所述化合物。立即释放或延缓释放可以适合的药物组合物获得，在部分延缓释放的实例中，使用设备如皮下移植或渗透泵。
口服施予的示例性组合物包括悬浮液，其可含有如用于传输的微晶纤维素、作为悬浮剂的海藻酸或海藻酸钠、作为粘度增强剂的甲基纤维素和现有技术中已知的那些甜味剂或调味剂；立即释放的片剂可含有如微晶纤维素、磷酸二钙盐、淀粉、硬脂酸镁和/或乳糖和/或其它赋形剂、粘合剂、膨胀剂、崩解剂、稀释剂和润滑剂 如现有技术中已知的那些。本发明化合物也可通过舌下和/或颊部施予进行口服传递，如压模、压缩或冻干片剂。示例性组合物可包括快速溶解的稀释剂如甘露醇、乳糖、蔗糖和/或环糊精类。包含在这些配方中也可以是高分子量赋形剂如纤维素
Figure PCTCN2018000246-appb-000005
或聚乙烯二醇(PEG)；有助于粘膜附着的赋形剂如羟丙基纤维素(HPC)、羟丙甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)和/或马来酸酐共聚物(如
Figure PCTCN2018000246-appb-000006
)；和控制释放的试剂如聚丙烯酸共聚物(如
Figure PCTCN2018000246-appb-000007
)。也可加入润滑剂、助流剂、香料、着色剂和稳定剂有助于制备和使用。
喷雾法或吸入施予的示例性组合物包括溶液，所述溶液可含有苄基醇或其它适合防腐剂、提高吸收性和/或生物活性的吸收促进剂、和/或其它可溶性或分散性试剂如现有技术中已知的那些。
肠胃外施药的示例性组合物包括注射溶液或悬浮液，其可含有如适合的非毒性、肠胃可接受稀释剂或溶剂，如甘露醇、1，3-丁二醇、水、格林氏溶液、等渗氯化钠溶液，或其它适合的分散或润湿和悬浮试剂，包括合成的单或甘油二酯类，和脂肪酸包括油酸。
直肠给药的示例性组合物包括栓剂，其可含如适合的非刺激性赋形剂，如可可脂、合成甘油酯类或聚乙烯二醇类，在普通温度下为固体，但溶解和/或溶入肠胃内释放药物。
治疗有效量的本发明化合物可由本领域普通技术人员确定，并对哺乳动物而言包括示例性剂量约从0.05至1000mg/kg；1-1000mg/kg；1-50mg/kg；5-250mg/kg；250-1000mg/kg，按照每天每千克体重的活性化合物量，其可以单一剂量或以单独的分开剂量形式施予，如每天从1到4倍。可以理解的是，对于特别受体的特殊剂量水平和药剂频率可改变病取决于多种因素，包括使用的特殊化合物活性、所述化合物代谢稳定性和作用长度、种族、年龄、体重、一般健康状况、受体性别和饮食、施予模式和时间、***速率、药物组合和特殊疾病的严重程度。用于治疗的优选受体包括动物，最优选哺乳种族如人类和家禽动物如狗、猫、马及其类似物。
实施例
下面通过实施例对本发明作进一步说明。应该理解的是，本发明实施例所述方法仅仅是用于说明本发明，而不是对本发明的限制，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。实施例中用到的所有原料和溶剂均购自Sigma Biochemical and Organic Compounds for Research and Diagnostic Clinical Reagents公司。
实施例1：2-苯基-3-(丙基硫醚)吲嗪(产率84％)
Figure PCTCN2018000246-appb-000008
在25mL的试管中加入一个搅拌子，再加入0.4mmol 2-苯基中氮茚(1a)，0.2mmol丙硫醇(2a)，0.04mmol HOAc，0.01mmol CuI，0.4mmol TBHP，2mL DMSO。反应置于60℃油锅搅拌反应，通过薄层层析板监测反应直到1a被消耗完全即停止反应。然后将反应混合物用乙酸乙酯和水稀释，萃取，取乙酸乙酯层。将有机层用盐水洗涤，经Mg 2SO 4干燥，减压蒸发。粗混合物通过薄层色谱硅胶板纯化。
44.9mg.IR(KBr)：3048，2965，1609，756，712cm -1； 1H NMR(400MHz，CDCl 3)δ8.53(d，J＝7.2Hz，1H)，7.84(d，J＝9.6Hz，2H)，7.45(t，J＝7.6Hz，2H)，7.40(d，J＝8.8Hz，1H)，7.34(t，J＝7.2Hz，1H)，6.84-6.80(m，1H)，6.69(s，1H)，6.67-6.63(m，1H)， 2.56-2.51(m，2H)，1.42-1.35(m，2H)，0.83(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ135.8，135.4，134.9，129.1，128.1，126.7，123.8，118.8，118.7，110.7，109.3，99.7，37.7，22.8，13.1.ESI-MS m/z(％)267(100)[M+H] +；Anal.Calcd for C 17H 17NS C，76.36；H，6.41；N，5.24；Found：C，76.48；H，6.43；N，5.22.
以类似于实施例1的制备方法，仅用不同的原料制备下述化合物.
实施例2：3-(乙硫醚)-2-苯基吲嗪(产率86％)
Figure PCTCN2018000246-appb-000009
43.5mg.IR(KBr)：3047，2897，1608，774，708cm -1； 1H NMR(400MHz，CDCl 3)δ8.55(d，J＝7.2Hz，1H)，7.86(d，J＝8.0Hz，2H)，7.46(t，J＝6.8Hz，2H)，7.41(d，J＝8.8Hz，1H)，7.35(t，J＝6.8Hz，1H)，6.85-6.79(m，1H)，6.71(s，1H)，6.65(t，J＝6.8Hz，1H)，2.61(q，J＝7.2Hz，2H)，1.05(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ135.8，135.5，134.9，129.1，128.1，126.7，123.9，118.9，118.7，110.7，109.0，99.7，29.8，14.6.ESI-MS m/z(％)253(100)[M+H] +；Anal.Calcd for C 16H 15NS C，75.85；H，5.97；N，5.53；Found：C，75.67；H，5.98；N，5.52.
实施例3：3-(丁基硫醚)-2-苯基吲嗪(产率76％)
Figure PCTCN2018000246-appb-000010
42.7mg.IR(KBr)：3077，2880，1588，786，719cm -1； 1H NMR(400MHz，CDCl 3)δ8.53(d，J＝7.2Hz，1H)，7.83(d，J＝8.4Hz，2H)，7.45(t，J＝7.6Hz，2H)，7.40(d，J＝8.8Hz，1H)，7.34(t，J＝6.8Hz，1H)，6.87-6.77(m，1H)，6.69(s，1H)，6.65(t，J＝7.2Hz，1H)，2.56(t，J＝7.2Hz，2H)，1.36-1.30(m，2H)，1.26(dd，J＝14.8，7.2Hz，2H)，0.74(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ135.8，135.4，134.9，129.1，128.1，126.7，123.8，118.8，118.7，110.7，109.3，99.7，35.4，31.3，21.6，13.5.ESI-MS m/z(％)281(100)[M+H] +；Anal.Calcdfor C 18H 19NS C，76.82；H，6.81；N，4.98；Found：C，76.97；H，6.83；N，4.99.
实施例4：3-(异丙基硫醚)-2-苯基吲嗪(产率60％)
Figure PCTCN2018000246-appb-000011
32.1mg.IR(KBr)：3031，2904，1507，753，689cm -1； 1H NMR(400MHz，CDCl 3)δ8.57(d，J＝7.2Hz，1H)，7.85(d，J＝9.6Hz，2H)，7.43(t，J＝6.8Hz，2H)，7.38(d，J＝8.8Hz，1H)，7.32(t，J＝7.6Hz，1H)，6.83-6.78(m，1H)，6.69(s，1H)，6.62(t，J＝6.8Hz，1H)，3.04(m，1H)，1.05(d，J＝6.8Hz，6H). 13C NMR(100MHz，CDCl 3)δ136.0，135.8，135.0，129.2，128.1，126.6，124.1，118.9，118.6，110.5，109.2，99.8，40.4，23.0，23.0.ESI-MS m/z(％)267(100)[M+H] +；Anal.Calcd for C 17H 17NS C，76.36；H，6.41；N，5.24；Found：C，76.49；H，6.40；N，5.23.
实施例5：3-(苄基硫醚)-2-苯基吲嗪(产率41％)
Figure PCTCN2018000246-appb-000012
25.8mg.IR(KBr)：3073，2952，1603，786，707cm -1； 1H NMR(400MHz，CDCl 3)δ8.24(d，J＝7.2Hz，1H)，7.71(d，J＝7.6Hz，2H)，7.41(t，J＝7.2Hz，2H)，7.34(t，J＝8.8Hz，2H)，7.09(d，J＝6.4Hz，3H)，6.90(d，J＝7.2Hz，2H)，6.79-6.73(m，1H)，6.65(s，1H)，6.48(t，J＝6.8Hz，1H)，3.73(s，2H). 13C NMR(100MHz，CDCl 3)δ137.5，135.9， 135.6，135.1，129.0，128.7，128.2，128.1，126.9，126.7，123.7，119.1，118.5，110.5，108.3，99.8，40.5.ESI-MS m/z(％)315(100)[M+H] +；Anal.Calcd for C 21H 17NS C，79.96；H，5.43；N，4.44；Found：C，79.84；H，5.44；N，4.43.
实施例6：3-((4-氟苯基)硫醚)-2-苯基吲嗪(产率48％)
Figure PCTCN2018000246-appb-000013
30.6mg.IR(KBr)：3047，2973，1603，846，775，713cm -1； 1H NMR(400MHz，CDCl 3)δ8.25(d，J＝7.6Hz，1H)，7.73(d，J＝8.0Hz，2H)，7.48(d，J＝8.8Hz，1H)，7.42(t，J＝7.6Hz，2H)，7.33(t，J＝6.8Hz，1H)，6.93-6.86(m，5H)，6.81(s，1H)，6.62(t，J＝6.8Hz，1H). 13C NMR(100MHz，CDCl 3)δ162.3(J＝243.1Hz)，136.9，135.9，135.0，132.1(J＝3.0Hz)，130.5，128.9，128.3，127.2，126.9(J＝7.8Hz)，119.9，118.8，116.4(J＝22.1Hz)，111.4，104.8，100.2.ESI-MS m/z(％)319(100)[M+H] +；Anal.Calcd for C20H14FNS C，75.21；H，4.42；N，4.39；Found：C，75.42；H，4.41；N，4.38.
实施例7：3-(丙基硫醚)-2-(p-甲苯基)吲嗪(产率73％)
Figure PCTCN2018000246-appb-000014
41.0mg.IR(KBr)：3073，2952，1603，1484，842cm -1； 1H NMR(400MHz，CDCl 3)δ8.49(d，J＝6.0Hz，1H)，7.77-7.68(m，2H)，7.39-7.32(m，1H)，7.26-7.22(m，2H)，6.81-6.73(m，1H)，6.67-6.57(m，2H)，2.55-2.48(m，2H)，2.41(s，3H)，1.42-1.34(m，2H)，0.85-0.78(m，3H). 13C NMR(100MHz，CDCl 3)δ136.3，135.3，134.8，132.8，128.9，128.9，123.8，118.7，118.6，110.5，109.1，99.5，37.7，22.8，21.2，13.2.ESI-MS m/z(％)281(100)[M+H] +；Anal.Calcd for C 18H 19NS C，76.82；H，6.81；N，4.98；Found：C，76.64；H，6.83；N，4.99.
实施例8：2-(4-甲氧基苯基)-3-(丙基硫醚)吲嗪(产率93％)
Figure PCTCN2018000246-appb-000015
55.24mg.IR(KBr)：3083，2942，1603，1434，837cm -1； 1H NMR(400MHz，CDCl 3)δ8.55(d，J＝8.0Hz，1H)，7.47(d，J＝20.0Hz，2H)，7.42-7.36(m，2H)，6.92(d，J＝8.8Hz，1H)，6.86-6.80(m，1H)，6.71(s，1H)，6.65(t，J＝6.8Hz，1H)，3.91(s，3H)，2.57(t，J＝7.2Hz，2H)，1.41(dt，J＝14.4，7.2Hz，2H)，0.86(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ159.3，137.1，135.0，134.8，129.0，123.8，121.5，118.8，118.7，114.5，112.3，110.7，109.3，99.7，55.2，37.7，22.8，13.2.ESI-MS m/z(％)297(100)[M+H] +；Anal.Calcd for C 18H 19NOS C，72.69；H，6.44；N，4.71；Found：C，72.56；H，6.43；N，4.73.
实施例9：4-(3-(丙基硫醚)吲嗪-2-基)苯腈(产率88％)
Figure PCTCN2018000246-appb-000016
51.4mg.IR(KBr)：3045，2897，2247，1606，833cm -1； 1H NMR(400MHz，CDCl 3)δ8.50(d，J＝8.0Hz，1H)，7.96(d，J＝8.4Hz，2H)，7.69(d，J＝8.4Hz，2H)，7.40(d，J＝8.8Hz，1H)，6.88-6.79(m，1H)，6.73-6.61(m，2H)，2.55-2.46(m，2H)，1.34(q，J＝7.2Hz，2H)，0.81(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ140.5，135.1，133.0，131.9，129.3，123.8，119.4，119.2，118.9，111.4，109.9，99.6，37.6，22.7，13.0.ESI-MS m/z(％)292(100)[M+H] +；Anal.Calcd for C 18H 16N 2S C，73.94；H，5.52；N，9.58；Found：C，73.67；H，5.51；N，9.54.
实施例10：2-(4-氟苯基)-3-(丙基硫醚)吲嗪(产率87％)
Figure PCTCN2018000246-appb-000017
49.6mg.IR(KBr)：3033，2957，1583，1491，836cm -1； 1H NMR(400MHz，CDCl 3)δ8.53(d，J＝8.0Hz，1H)，7.86-7.77(m，2H)，7.40(d，J＝8.8Hz，1H)，7.18-7.12(m，2H)，6.85-6.80(m，1H)，6.66(t，J＝7.6Hz，2H)，2.53(t，J＝7.2Hz，2H)，1.39(dt，J＝14.4，7.2Hz，2H)，0.84(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ163.2(J＝244.2Hz)，134.9(J＝44.7Hz)，131.8(J＝3.2Hz)，130.6(J＝7.7Hz)，123.8，118.9(J＝22.7Hz)，115.1(J＝21.1Hz)，110.8，109.1，99.5，37.6，22.7，13.1.ESI-MS m/z(％)285(100)[M+H] +；Anal.Calcd for C 17H 16FNS C，71.55；H，5.65；N，4.91；Found：C，71.36；H，5.66；N，4.92.
实施例11：2-(4-硝基苯基)-3-(丙基硫醚)吲嗪(产率52％)
Figure PCTCN2018000246-appb-000018
32.4mg.IR(KBr)：3056，2893，1592，1463，848cm -1； 1H NMR(400MHz，CDCl 3)δ8.51(d，J＝8.0Hz，1H)，8.27(d，J＝8.8Hz，2H)，8.02(d，J＝9.2Hz，2H)，7.41(d，J＝8.8Hz，1H)，6.90-6.81(m，1H)，6.72(s，1H)，6.68(d，J＝7.2Hz，1H)，2.57-2.49(m，2H)，1.35(q，J＝7.2Hz，2H)，0.81(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ146.3，142.7，135.2，132.6，129.4，123.9，123.5，119.6，119.1，111.6，110.2，99.8，37.7，22.7，13.1.ESI-MS m/z(％)312(100)[M+H] +；Anal.Calcd for C 17H 16N 2O 2S C，65.36；H，5.16；N，8.97；Found：C，65.60；H，5.17；N，8.99.
实施例12：2-(3，4-二氯苯基)-3-(丙基硫醚)吲嗪(产率87％)
Figure PCTCN2018000246-appb-000019
58.5mg.IR(KBr)：3075，2946，1611，1481，764cm -1； 1H NMR(400MHz，CDCl 3)δ8.51(d，J＝8.0Hz，1H)，7.99(d，J＝2.0Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.49(d，J＝8.4Hz，1H)，7.38(d，J＝8.8Hz，1H)，6.87-6.80(m，1H)，6.70-6.62(m，2H)，2.59-2.48(m，2H)，1.43-1.35(m，2H)，0.86(t，J＝7.2Hz，3H). 13C NMR(100MHz，CDCl 3)δ135.9，134.9，132.5，132.0，130.5，130.0，128.1，123.8，119.2，118.8，111.1，109.5，99.4，37.7，22.8，13.1.ESI-MS m/z(％)336(100)[M+H] +；Anal.Calcd for C 17H 15Cl 2NS C，60.72；H，4.50；N，4.17；Found：C，60.53；H，4.51；N，4.19.
毒性实验：
选用健康昆明种小鼠，由广东药科大学实验中心提供。小鼠饲养于无毒塑料盒内，每盒5只，雌、雄分笼，每天换1次垫料，自由摄食和饮水，室温保持18-20℃，自然光照。药物以0.9％氯化钠水溶液溶解，受试物剂量以mg/kg表示。按以下剂量腹腔注射给药，给药容积为0.1mL/10g，按照如下剂量给药：50、100、150、200、300mg/kg。给药后每天观察记录动物的外观、精神、饮食、睡眠、活动情况以及逐日死亡分布，连续观察10天，按Bliss法计算LD50。高浓度组给药后，小鼠精神萎靡，死前粪便不成形，消瘦，竖毛，抱团萎缩不动。
Figure PCTCN2018000246-appb-000020
由上表可以看出，本发明的式I化合物具有较低毒性。
式I化合物对肿瘤细胞的抑制作用：
取对数生长期细胞，消化、计数，接种于96孔培养板中，每孔100μL。培养24h后，以不同浓度复合物处理肿瘤细胞。药物作用72h后，去上清，每孔加入100μL MTT(1mg/mL)，继续培养4h，弃上清，每孔加入100μL DMSO，振荡混匀，用酶标仪在570nm处测定吸光度值。计算抑制率。计算公式：抑制率(％)＝(对照组吸光度值-给药组吸光度值)/(对照组吸光度值-空白组吸光度值)×100％。采用IC 50计算软件(中国药科大学)求出半数抑制浓度(IC 50)。表中数据的单位是μmol/L。
实验肿瘤株包括人胃癌细胞BGC、人***细胞HeLa、人结肠癌细胞HCT116、人肺腺癌细胞A549、人肺癌细胞NCI-H460、人***癌细胞DU-145，人乳腺癌细胞MDA-MB-231。细胞购自广东省微生物菌种保藏中心细胞库。实验结果如下表所示。
Figure PCTCN2018000246-appb-000021

Claims (9)

  1. 一种如式I所示的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，其特征在于如下所示：
    Figure PCTCN2018000246-appb-100001
    其中
    R 1-R 3独立的选自氢、氘、卤素、-S-R 0、取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 6-10芳基、含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂环，或含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂芳基；
    R 0独立的选自取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 6-10芳基、含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂环，或含有1-4个选自N、O和S中杂原子的取代或未取代的5-10元杂芳基。
  2. 根据权利要求1所述的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，其特征在于：其中所述的取代的，指的是相应的基团被卤素、NH 2、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、含有1-4个选自N、O和S中杂原子的5-10元杂芳基中的一个或多个所取代。
  3. 根据权利要求1或2所述的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，其特征在于：所述芳基选自苯基、萘基、蒽基或菲基。
  4. 根据权利要求1或2所述的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，其特征在于：所述杂芳基选自吲哚满基、苯并噻唑基、吡唑并吡啶基、苯并异噻唑基、***并吡啶基、吲嗪并吡啶基、苯并噁唑基、***并吡啶基、吲嗪并吡啶基、吡啶并吡嗪基、喹唑啉基、吡啶并吡嗪基、苯并噁二唑基、苯并噻二唑基、苯并吲嗪基。
  5. 根据权利要求1或2所述的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，其特征在于选自下述化合物：
    Figure PCTCN2018000246-appb-100002
    Figure PCTCN2018000246-appb-100003
    Figure PCTCN2018000246-appb-100004
  6. 权利要求1-5任一所述的化合物的制备方法，其特征在于包括下述步骤：
    取代中氮茚和取代硫醇在油浴锅反应制备得到。
  7. 一种组合物，其特征在于包括权利要求1-5任一所述的如I所示的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物，和药学上可接受的助剂、载体或稀释剂。
  8. 根据权利要求7所述的组合物，其特征在于：其剂型选自素片、薄膜包衣片、糖衣片、肠衣片、分散片、胶囊、颗粒剂、口服溶液或口服混悬液。
  9. 1-6任一所述的如I所示的化合物、或其立体异构体、或其药物上可接受的盐或其溶剂化物用于制备***或癌症药物的用途，所述肿瘤或癌症为胃癌、***、结肠癌、肺癌、肝癌、胶质瘤、食道癌、肠癌、鼻咽癌、乳腺癌、淋巴癌、肾癌、胰腺癌、膀胱癌、卵巢癌、子宫癌、骨癌、胆囊癌、唇癌、黑素瘤、舌癌、喉癌、血癌、***癌、脑瘤、鳞癌、皮肤癌、血管瘤、脂肪瘤、***和甲状腺癌。
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