WO2019232665A1 - Thiolized indolizine compound having anticancer activity and derivative thereof - Google Patents

Abstract

Probided are a hiolized indolizine compound having anticancer activity and a derivative thereof. Said compound and derivative thereof shown in formula (I) have an inhibitory effect on a purality of cancers and tumors.

Description

A class of thioindazine compounds and their derivatives with anticancer activity Technical field

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.

Background technique

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. However, chemical drug treatment is still the main method. At present, there are many types of 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.

In view of the potential application of indazine anticancer drugs in cancer treatment, and the author has not seen domestic and foreign literature specifically reporting the development of indazine derivatives in the entire field of anticancer drugs, combined with the research work in this laboratory, this article reviews Azine compounds are used as anticancer drugs in radiosensitizers, farnesyl transferase inhibitors, cytochrome P450 inhibitors, angiogenesis inhibitors, topoisomerase inhibitors, cyclin-dependent protein kinase inhibitors and tumor resistance. Recent research and development progress in drug reversal agents.

The invention relates to a new class of indazine compounds, which can effectively inhibit various types of cancers or tumors.

Summary of the Invention

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 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

An acceptable salt, solvate, or prodrug thereof.

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.

These and other features of the invention will continue to be explained in a more detailed manner.

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:

among them

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.

Preferably, 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 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.

Preferably, the aryl group is selected from phenyl, naphthyl, anthracenyl or phenanthryl.

Preferably, 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.

Preferably, it is selected from the following compounds:

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;

A 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.

Preferably, 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 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.

In another specific embodiment, the compound of formula I is selected from an exemplary compound or a combination of exemplary compounds or other specific embodiments herein.

In another specific embodiment, the invention is directed to a pharmaceutical composition comprising a compound of formula (I) and one or more active ingredients.

The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having a specific number of carbon atoms. For example "C _1-10 alkyl" (or alkylene) is intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "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. Examples of alkyl 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.

An "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. For example "C _2-6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl. Examples of 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.

An "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. For example, "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.

When referring to substituted alkenyl, alkynyl, alkylene, alkenylene or alkynylene, these groups are substituted with one to three alkyl substituents as described above.

The term "substituted" as used herein 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. When the substituent is oxygen or ketone (ie = O), then 2 hydrogen atoms on the atom are replaced. Ketone substituents are not present on the aromatic fragments. Unless otherwise specified, 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. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (eg, C = C, C = N, or N = N).

Combinations of substituents and or variables are permissible only if these combinations result in stable compounds or useful synthetic intermediates. 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. Preferably, the present compound does not comprise N- halogen, S (O) ₂ H, or S (O) H group.

The term "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. As used herein, "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. Examples of these 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). As mentioned above, 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.

The term "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.

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

The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example "haloalkyl" includes mono, bis and trifluoromethyl.

The term "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. Fused rings that complete bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms can be optionally oxidized and nitrogen atoms can be optionally quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and other fused rings of nitrogen may be aromatic or non-aromatic. Heteroaryl groups can be attached at any available nitrogen or carbon atom of any ring. When the valence allows, if the other ring is a cycloalkyl or heterocyclic ring, it is additionally optionally substituted with = 0 (oxy).

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.

Unless otherwise stated, the compounds of the present invention are understood to include the free form and its salts. The term "salt" refers to the formation of acidic and / or basic salts with inorganic and / or organic acids and bases. In addition, the term "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. However, other salts may be useful, such as using isolation or purification steps in the preparation process, It is therefore also included in the scope of the present invention. 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-naphthalenesulfonate, smoke Acid salt, nitrate, oxalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate Salts, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned here), tartrate, thiocyanate, tosylate such as tosylate, undecylate, and the like Thing.

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-β-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. 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.

The phrase "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.

As used herein, "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. Examples of 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. For example, 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.

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. Generally, 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.

All stereoisomers of the compounds of the invention are considered, both as mixtures or in pure or substantially pure form. 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. For example, 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. These 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. Examples of 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 penicillin and cephalogensporin. These esters can be prepared by conventional techniques known in the art. Many forms of prodrugs are well known in the art.

"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. For example, 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.

Exemplary 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. Exemplary 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.

Exemplary 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.

Exemplary 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.

Exemplary 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.

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. It can be understood that 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.

Examples

The present invention is further described below through examples. It should be understood that the methods described in the embodiments of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Simple improvements to the preparation method of the present invention under the premise of the present invention belong to the scope of protection of the present invention. All raw materials and solvents used in the examples were purchased from Sigma Biochemical and Organic Compounds for Research and Diagnostic Clinical Agents.

Example 1: 2-phenyl-3- (propylsulfide) indazine (yield 84%)

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.

44.9 mg. IR (KBr): 3048, 2965, 1609, 756, 712 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 7.2 Hz, 1 H), 7.84 (d, J = 9.6 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 7.2 Hz, 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). ¹³ C NMR ( 100MHz, CDCl ₃ ) δ 135.8, 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 ₁₇ H ₁₇ NS C, 76.36; H, 6.41; N, 5.24; Found: C, 76.48; H, 6.43; N, 5.22.

In a manner similar to the preparation of Example 1, the following compounds were prepared using only different raw materials.

Example 2: 3- (ethylsulfide) -2-phenylindazine (yield 86%)

43.5 mg. IR (KBr): 3047, 2897, 1608, 774, 708 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (d, J = 7.2 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 6.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 6.8 Hz, 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). ¹³ C 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 ₁₆ H ₁₅ NS C, 75.85; H, 5.97; N, 5.53; Found: C, 75.67; H, 5.98; N, 5.52.

Example 3: 3- (butylsulfide) -2-phenylindazine (yield 76%)

42.7mg.IR (KBr): 3077, 2880, 1588, 786, 719cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ 8.53 (d, J = 7.2Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 6.8 Hz, 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 = 11, 7.2Hz , 2H), 0.74 (t, J = 7.2Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 135.8, 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. Calcd for C ₁₈ H ₁₉ NS C, 76.82; H, 6.81; N, 4.98; Found : C, 76.97; H, 6.83; N, 4.99.

Example 4: 3- (isopropylsulfide) -2-phenylindazine (yield 60%)

32.1 mg. IR (KBr): 3031, 2904, 1507, 753, 689 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 7.2 Hz, 1 H), 7.85 (d, J = 9.6 Hz, 2H), 7.43 (t, J = 6.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 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). ¹³ C 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 ₁₇ H ₁₇ NS C, 76.36; H, 6.41; N, 5.24; Found: C, 76.49; H, 6.40; N, 5.23.

Example 5: 3- (benzylsulfide) -2-phenylindazine (yield 41%)

25.8 mg.IR (KBr): 3073, 2952, 1603, 786, 707 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J = 7.2 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 8.8 Hz, 2H), 7.09 (d, J = 6.4 Hz, 3H), 6.90 (d, J = 7.2 Hz, 2H), 6.79-6.73 (m, 1H), 6.65 (s, 1H), 6.48 (t, J = 6.8Hz, 1H), 3.73 (s, 2H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 137.5 , 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 ₂₁ H ₁₇ NS C, 79.96; H, 5.43; N, 4.44; Found: C, 79.84; H, 5.44; N, 4.43.

Example 6: 3-((4-fluorophenyl) sulfide) -2-phenylindazine (yield 48%)

30.6 mg.IR (KBr): 3047, 2973, 1603, 846, 775, 713 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 7.6 Hz, 1 H), 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 = 6.8 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.3 (J = 243.1 Hz), 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.

Example 7: 3- (propylsulfide) -2- (p-tolyl) indazine (73% yield)

41.0mg.IR (KBr): 3073, 2952, 1603, 1484, 842cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ 8.49 (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). ¹³ C NMR (100MHz, CDCl ₃ ) δ 136.3, 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 ₁₈ H ₁₉ NS C, 76.82; H, 6.81; N, 4.98; Found: C, 76.64; H, 6.83; N, 4.99.

Example 8: 2- (4-methoxyphenyl) -3- (propylsulfide) indazine (93% yield)

55.24 mg.IR (KBr): 3083, 2942, 1603, 1434, 837 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 20.0 Hz, 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). ¹³ C NMR (100MHz, CDCl ₃ ) δ 159.3, 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 ₁₈ H ₁₉ NOS C, 72.69; H, 6.44; N, 4.71; Found: C, 72.56; H, 6.43; N, 4.73 .

Example 9: 4- (3- (propylsulfide) indazin-2-yl) benzonitrile (88% yield)

51.4 mg. IR (KBr): 3045, 2897, 2247, 1606, 833 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 8.0 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 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). ¹³ C NMR (100MHz, CDCl ₃ ) δ 140.5, 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 ₁₈ H ₁₆ N ₂ S C, 73.94; H, 5.52; N, 9.58; Found: C, 73.67; H, 5.51; N, 9.54.

Example 10: 2- (4-fluorophenyl) -3- (propylsulfide) indazine (87% yield)

49.6mg.IR (KBr): 3033, 2957, 1583, 1491, 836cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ 8.53 (d, J = 8.0 Hz, 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). ¹³ C NMR (100MHz, CDCl ₃ ) δ 163.2 (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 ₁₇ H ₁₆ FNS C, 71.55; H, 5.65; N, 4.91; Found: C, 71.36; H, 5.66; N, 4.92.

Example 11: 2- (4-nitrophenyl) -3- (propylsulfide) indazine (52% yield)

32.4mg.IR (KBr): 3056, 2893, 1592, 1463, 848cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ 8.51 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 8.8 Hz, 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). ¹³ C 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 ₁₇ H ₁₆ N ₂ O ₂ S C, 65.36; H, 5.16; N, 8.97; Found: C, 65.60; H, 5.17; N, 8.99.

Example 12: 2- (3,4-dichlorophenyl) -3- (propylsulfide) indazine (yield 87%)

58.5 mg. IR (KBr): 3075, 2946, 1611, 1481, 764 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 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). ¹³ C 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 ₁₇ H ₁₅ Cl ₂ NS C, 60.72; H, 4.50; N, 4.17; Found: C, 60.53; H, 4.51; N, 4.19.

Toxicity test:

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. 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.

As can be seen from the table above, the compounds of formula I according to the invention have lower toxicity.

Inhibitory effect of compounds of formula I on tumor cells:

Take the cells in the logarithmic growth phase, digest and count them, and inoculate them into a 96-well culture plate with 100 μL per well. After 24 hours in culture, tumor cells were treated with different concentrations of the complex. After 72 hours of drug action, the supernatant was removed, and 100 μL of MTT (1 mg / mL) was added to each well, and the culture was continued for 4 hours. The supernatant was discarded, 100 μL of DMSO was added to each well, and the mixture was shaken and mixed. The absorbance was measured at 570 nm using a microplate reader. Calculate the inhibition rate. Calculation formula: 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 μmol / 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.

Claims (9)

1. A compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof is characterized by the following:

   

   among them

   R ₁ -R _{3 are} independently selected from hydrogen, deuterium, halogen, -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, containing 1-4 selected from N Substituted or unsubstituted 5-10 membered heterocyclic rings of heteroatoms in O, O and S, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;

   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.
2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein 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 cycloalkyl, C _6-10 aryl, containing 1-4 selected from N, One or more of the 5-10 membered heteroaryl groups of the heteroatoms in O and S are substituted.
3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the aryl group is selected from the group consisting of phenyl, naphthyl, anthracenyl, or Fiki.
4. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the heteroaryl group is selected from the group consisting of indolyl and benzothiazole , Pyrazolopyridyl, benzoisothiazolyl, triazolopyridyl, indazinopyridyl, benzoxazolyl, triazolopyridyl, indazinopyridyl, pyridopyrazinyl, Quinazolinyl, pyridopyrazinyl, benzooxadiazolyl, benzothiadiazolyl, benzoindazinyl.
5. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that it is selected from the following compounds:

   

   

   
6. The method for preparing a compound according to any one of claims 1-5, comprising the following steps:

   Substituted middle indene and substituted thiol are prepared in an oil bath.
7. A composition, comprising the compound represented by any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable Accepted auxiliaries, carriers or diluents.
8. The composition according to claim 7, characterized in that its dosage form is selected from the group consisting of plain tablets, film-coated tablets, sugar-coated tablets, enteric-coated tablets, dispersible tablets, capsules, granules, oral solutions or oral suspensions.
9. Use of the compound represented by any one of 1-6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the preparation of a medicament for treating a tumor or cancer, said tumor or cancer For gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, colon 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, lipoma, cervical cancer and thyroid cancer.