WO2012130160A1 - Aminopyridine derivatives containing acridine ring and use thereof - Google Patents

Abstract

Provided are aminopyridine derivatives containing acridine ring, particularly compounds represented by formula I or formula II, preparation method thereof and use thereof in the preparation of a medicament for inhibiting excessive cell proliferation. Also disclosed are compositions comprising the compounds according to the present invention. The compounds can be used for treating hyperproliferative diseases such as cancers, neuropathic pain, inflammations and the like.

Description

 Aminopyridine derivative containing azetidine ring and use thereof

 The present invention relates to an acridine ring-containing aminopyridine derivative, and more particularly to a compound represented by Formula I or Formula II, a process for the preparation thereof, and use thereof for the preparation of a medicament for inhibiting cell hyperproliferation. Background technique

 Cancer is a disease that poses a serious threat to human health. Since the advent of the first anticancer drug in the 1940s, scientists have isolated and extracted a number of natural products with potential cytotoxic activity from plants. Based on this, a variety of clear anti-tumor have been obtained through structural modification. Active compounds in which vinblastine, etoposide, paclitaxel, etc. are successively approved for clinical treatment of cancer. However, these natural product drugs have limited resources, their molecular structures are complex, chemical synthesis is difficult, and it is difficult to scale production. Therefore, it is necessary to find a small molecule antitumor drug with a simple structure. Summary of the invention

 The present invention is directed to an acridine ring-containing aminopyridine derivative having an activity of inhibiting cell hyperproliferation.

 The first aspect of the invention provides a compound of formula I, hydrazine or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof.

 I Π

 among them:

In Formula II, one represents an optional bond, provided that one and only one nitrogen atom in the ring is a double R! R ₂ , R ₃ , R ₄ , R ₅ , R ₇ or R ₈ are each independently selected from hydrogen , hydroxyl, halogen, Amino, nitro, nitrile, trifluoromethyl, -OR ₉ , -C(O)R ₁₀ , -C(0)OR ₉ , -NR ₁₀ C(O)OR ₉ , -OC(0)R ₉ -NR ₁₀ SO ₂ R ₉ , -SO ₂ NR ₁₀ R ₉ , -NR ₁₀ C(O)R ₉ NR oR C - C o J3⁄4^3⁄4^, C2 - C 10 Women^^, C - C o Block ^^, C3-C10 ring^ _3⁄4 > _3⁄4 ^, C ₃ -C _1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycloalkane base;

R _{6 is} selected from the group consisting of hydrogen, trifluoromethyl, d-do alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C _1Q cycloalkyl, C ₃ -C _1Q cycloalkyl An alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group;

W selects ll -OR ₉ , - NR ₁₀ OR ₉ , - NR ₁₀ SO ₂ R ₉ , - NR ₁₀ R ₉ ;

R ₉ , . Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ block, C ₃ -C ₁₀ cycloalkyl, C ₃ - C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkane The aryl, aryl, heteroaryl and heterocyclyl are optionally substituted by one to five (e.g., 1, 2, 3, 4, 5) groups independently selected from the group consisting of: hydroxy, hydroxy , amino, nitro and trifluoromethyl;

 Preferred compounds have the structure of formulae IV, IV:

 III IV

 Wherein each substituent group is as defined above;

 More preferred compounds have the structure of formula V, VI:

其中， 各个取代基团如上所定义；

Wherein each substituent group is as defined above;

Preferably, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , 11 _{8 are} selected from the group consisting of hydrogen, halogen, nitro, nitrile, trifluoromethyl;

Preferably, W is -NR ₁₍₎ OR ₉ or -NR ₁₀ R ₉ .

 In an embodiment of the invention, the compound is selected from the group consisting of:

 1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl hydrazide }-3-carboxylic acid acridine;

 N-(cyclohexyldecyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-indol-2-pyridyl)amino]benzoyl}-3-carboxamide Acridine

N-( ² _ morpholineethyl) -1-{ ³ , ⁴ , ⁵ _trifluoro- ² _[( ³曱 _ _ ⁵ _ iodine ² _pyridyl)amino] benzoyl}-3- Carboxamide acridine;

 N-(benzomethoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl}-3-carboxamide Acridine

 N-[(2,2-Mercapto-1,3-dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2-[(3-indolyl_5-捵-2-pyridyl)amino]benzoyl}-3-carboxyamide acridine;

 (R)-N-[(2,2-mercapto-1,3-dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2-[(3-曱) 5-amino-2-pyridyl)amino]benzoyl}-3-carboxyamide acridine;

N-( ² , ³ _ dihydroxypropoxy) -1-{ ³ , ⁴ , ⁵ _ trifluoro- ² _[( ³曱 _ _ ⁵ _捵_ ² _pyridyl) amino] benzoyl} -3-carboxyamide acridine;

 1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridinyl)amino]benzoyl hydrazide }-3-carboxylic acid acridine;

 N-(cyclohexyldecyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridinyl)amino]benzoyl}-3-carboxamide Acridine

N- ⁽² - morpholinoethyl) -1- ^{{3, 4, 5-trifluoromethyl} _ _ ² _ [(Yue-yl ³ _ _ _ ² _ ⁵ _ bromo-pyridinyl) amino] phenyl} -3-acyloxy Yue Carboxamide acridine;

N-(benzomethoxy)-1-{ ³ , ⁴ , ⁵ _trifluoro _ ² _[( ³曱 _ _ ⁵ _ bromo ² _pyridyl)amino]benzoyl}-3-carboxamide Acridine

(R)-N-( ² , ³ _ dihydroxypropoxy) -1-{ ³ , ⁴ , ⁵ _trifluoro- ² _[( ³曱 _ _ ⁵ _ _ ² _pyridyl)amino] Benzoyl}-3-carboxyamide acridine;

 N-[2-(piperidin-1-yl)ethyl]-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzene Decanoyl-3-carboxyamide acridine;

N-(cyclopropoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino] Benzoyl}-3-carboxyamide acridine;

 (S)-N-(2,3-dihydroxypropoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridinyl)amino] Benzoyl}-3-carboxyamide acridine;

1-{5-[(5-But-3-indolyl- ² -pyridyl)amino] ^-4 -fluoro-1H-benzimidazole-6-decanoyl-3-carboxylic acid acridine;

N-[ ² _(thiophene- ² -yl)ethyl] -1{ ⁵ _[( ⁵ _iodo_ ³曱indolyl ² _pyridyl)amino] _ ⁴ -fluoro-1H-benzimidazole-6-曱 amide}-3-carboxyamide acridine;

N-[ ² _ (piperidin-1-yl)ethyl b 1{5-[(5-resor-3-indolyl ² _pyridyl)amino] _ ⁴ -fluoro-1H-benzimidazole-6-曱 amide}-3-carboxyamide acridine.

 In another aspect, the invention relates to a compound of formula I, II or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide synthesis thereof.

 The synthesis scheme of the compound of formula I is as follows:

L表示离去集团， 可以为卤素； The substituted benzoic acid containing the leaving group L is used as a starting material, and the carboxyl group is thiolated by reacting with a thiolation reagent; and the oxime ester is converted into an amide group by reacting with ammonia water; under the action of P0C1 ₃ Removing a portion of water to convert the ugly amine bond to a cyano group; the substituted phenyl phthalocyanine containing the leaving group L is subjected to a base (for example, lithium amide) to remove the group-derived and substituted aminopyridine compound. Condensation reaction; hydrolysis of a cyano group to give a carboxyl group. Reacting with a 3-carboxy acridine ring, the carboxyl group on the acridine ring is reacted with the corresponding side chain to give a compound of formula I;

L represents the leaving group and can be halogen;

 The synthesis scheme of the compound of formula II is as follows;

 The substituted benzoic acid containing the leaving group L is used as a starting material, and after the nitration reaction, a nitro group is introduced on the benzene ring; under the action of a base (for example, lithium), the group is removed and the substituted amino group is removed. The pyridine compound undergoes a condensation reaction; under the action of ammonia water, an amino group is introduced into the benzene ring; after reacting with a thiolation reagent, the carboxyl group is thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out, and the decarboxylated ester is obtained. a key intermediate of a carboxy group, which is then reacted with a 3-carboxy acridine ring to give a compound of formula II;

L represents the leaving group and can be halogen;

Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , W, R ₉ and R _{10 are} as defined in the first aspect of the invention.

 The invention further provides a pharmaceutical composition comprising a Formula I of the invention, a guanidine compound, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier.

The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for inhibiting cell hyperproliferation. The cell hyperproliferation includes diseases such as leukemia, glioblastoma, lymphoma, melanoma, cancer, neuropathic pain, inflammation, and the like. In one embodiment of the invention, the inhibiting cell hyperproliferation means inhibiting tumor cell proliferation.

 The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament against tumors and/or cancer.

 The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for the prevention and/or treatment of a cell hyperproliferative disorder.

 The invention also relates to a method of preventing and/or treating a tumor and/or cancer comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.

 The invention also relates to a method of preventing and/or treating a cell hyperproliferative disorder comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.

 In the present invention, the cell hyperproliferative diseases include tumors (benign or malignant tumors) and/or diseases such as cancer, neuropathic pain, inflammation, and the like.

 In the present invention, the tumor and/or cancer described therein may be any tumor and/or cancer known in medicine. Preferably, the tumor and/or cancer includes but is not limited to:

 Malignant tumors, including but not limited to bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer (including small cell lung, non-small cell carcinoma), head and neck cancer, esophageal cancer, biliary cancer, stomach cancer, cervical cancer, Sickle adenocarcinoma, prostate cancer and skin cancer (including squamous cell carcinoma);

 Hematopoietic tumors of the lymphatic system, including but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair Cellular lymphoma, mantle cell lymphoma, myeloma, and Burketfs' lymphoma;

 Hematopoietic tumors of the myeloid system, including but not limited to acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;

 Tumors of interstitial origin, including but not limited to fibrosarcoma and rhabdomyosarcoma;

 Centrally occurring tumors, including but not limited to fibrosarcoma and rhabdomyosarcoma;

 Tumors of the central and peripheral nervous system, including astrocytoma, fibrosarcoma, neuroglioma, and schwannomas;

Other tumors, including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, Shielded cell tumor, xenoderoma pigmentosum, squamous cell carcinoma and Kaposi's sarcoma.

 The -CH) alkyl group in the present invention means an alkyl or branched fluorenyl group having 1 to 10 carbon atoms, such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group or a sec-butyl group. Base, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-decylpentyl, heptyl, octyl and the like. Preferred alkyl groups are d-alkyl groups. More preferred alkyl groups are - alkyl groups;

C ₂ -C _1Q alkenyl means an alkenyl group having 2 to 10 carbon atoms and at least one double bond, and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl , 1-hex-5-alkenyl, and the like. More preferred are lower alkenyl groups having 2 or 3-5 carbon atoms;

The C ₂ -C _1Q block group means a hydrocarbon group having 2 to 10 carbon atoms and at least one triple bond, and includes, for example, an ethynyl group, a propynyl group, a butynyl group, a pentyn-2-yl group and the like. More preferred is a block group having 3-5 carbon atoms;

 Halogen means fluorine, chlorine, bromine and germanium atoms;

 An aryl group means a fused ring having a single ring (such as a phenyl group), a polycyclic ring (such as a biphenyl group), or at least one of which is aromatic (for example, 1, 2, 3, 4-tetrahydronaphthyl, An anthranyl carbocyclyl group optionally substituted by, for example, a sulfonyl group, a lower alkyl group (for example, an alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, or an aryl group. , heteroaryl and hydroxy, mono, di or trisubstituted.

 Heteroaryl refers to one or more aromatic ring systems of a 5, 6 or 7 membered ring comprising a 5-10 atom fused ring system (wherein at least one ring is aromatic), said ring system containing At least one and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, iso Thiazolyl, pyrrole ring, quinoline ring, isoquinoline ring, anthracene ring, benzimidazole, benzofuran ring, benzothiophene ring, benzothiazole ring, pyridazine ring and the like. It is optionally, for example, a pharmaceutically acceptable group, a lower alkyl group (for example, a d-alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, an aryl group, a heteroaryl group, and a hydroxy group. Three substitutions.

Carbocyclic, carbocyclic, cycloalkyl, C ₃ -C _IE cycloalkyl refers to a saturated carbocyclic group having 3 to 10 carbon atoms. The cycloalkyl group can be a monocyclic or polycyclic fused system and can be fused to the aromatic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group herein may be unsubstituted or as detailed, in one Or a plurality of substitutable positions are substituted by various groups. For example, these cycloalkyl groups may be optionally substituted by the following groups: d-alkyl, d-Ce alkoxy, nitrile, halogen, hydroxy, amino, nitro, mono(d-Ce)alkylamino, di (d-)alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, dC ₆ haloalkyl, dC ₆ halo alkoxy;

Heterocyclic or heterocyclic group means one or more carbocyclic ring systems of a 5, 6 or 7 membered ring comprising a fused ring system of 4 to 10 atoms, said ring system containing at least one and up to four selected A hetero atom from nitrogen, oxygen or sulfur, provided that the ring of the group does not contain two adjacent O or S atoms. The fused ring system may be a heterocyclic ring fused to an aromatic group. Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholine, cyclohexyl, pyrazine ring, dioxolane (eg 1, 3) - Dioxolane) and the like, which may be substituted by the following groups: d-Ce alkyl, d-Ce alkoxy, nitrile, halogen, hydroxy, amino, nitro, mono(d-Ce)alkyl Amino group, di(d-)alkylamino group, C ₂ -C ₆ fluorenyl group, C ₂ -C ₆ alkynyl group, d-Ce halogenated pit group, d-Ce halogenated pit oxy group;

 Arylalkyl means an alkyl group (as defined above) substituted by one or more aryl groups (as defined above). A more preferred arylalkyl group is an aryl-d-alkyl group. Examples include benzyl, phenylethyl and the like;

 Heteroarylalkyl means an alkyl group (as defined above) substituted by a heteroaryl group (as defined above). More preferred heteroarylalkyl groups are 5- or 6-membered heteroaryl-d-alkyl groups. Examples include pyridylethyl and the like;

Heterocyclylalkyl means an alkyl group (as defined above) substituted by a heterocyclyl group (as defined above). More preferred heterocyclylalkyl is a 5 or 6-membered heterocyclic group -C rC ₃ - alkyl group. Examples include tetrahydropyranyl fluorenyl;

 Cycloalkylalkyl refers to an alkyl group (as defined above) substituted by a cycloalkyl group (as defined above). A more preferred heterocyclic group is a 5- or 6-membered cycloalkyl-Cr-alkyl group. Examples include cyclopropyl fluorenyl;

The compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates. Physiologically acceptable salts of the compounds of Formula I or Formula II include the conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, terephthalic acid, sulfonate Salts of acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroquinone, malic acid, steroic, citric acid and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-decyl glucosamine and procaine salt.

 Some of the compounds in the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed. The present invention includes those stoichiometric solvates, such as hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.

 Thus, when referring to a compound of the invention, a compound of formula I or formula II, and pharmaceutically acceptable salts and solvates thereof, are included.

 The present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I or formula II. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", Η Bund Saard, Elsevier, ed., 1985.

 The invention also includes active metabolites of the compounds of the invention.

 Another aspect of the invention relates to a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible. The pharmaceutical composition can be prepared in various forms depending on the route of administration. The compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.

 The pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula I or formula II of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants. Partial glyceride mixture of fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fiber Substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.

The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: Oral, Spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or input or by means of a Explant storage. Among them, oral, intraperitoneal or intravenous administration is preferred.

 When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule preparation generally comprises lactose and dried corn starch. Aqueous suspension formulations are usually those in which the active ingredient is admix If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.

 In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs. The form is as follows:

 When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution preparation, the carrier used is an isotonic pH of sterile saline, with or without preservatives such as chlorination. Benzyl alkoxide. For ophthalmic use, the compound can also be formulated into a cream such as a vaseline cream.

 When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers which can be used for cartilage preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which can be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

 The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride. Advantageous effects of the invention

The compounds of the present invention are effective for inhibiting excessive proliferation of cells, and are useful for treating hyperproliferative diseases such as various tumors, cancers, neuropathic pain, inflammation, and the like in mammals. detailed description

 The embodiments of the present invention are described in detail below with reference to the accompanying drawings. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained commercially. The melting point of the compound was determined by a RY-1 melting point apparatus and the temperature was not corrected. The iH NMR spectrum was measured by a Bruker ARX 400 type nuclear magnetic instrument. Example 1 1-{3,4,5-Trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)J^]benzoyl hydrazide }-3-carboxylic acid acridine

Step 1, 2, 3, 4, 5-tetrafluorobenzene

2,3,4,5-Tetrafluorobenzoic acid (48.5 g, 0.25 mol) was dissolved in 130 mL of anhydrous decyl alcohol, and trimethyl chlorosilane (63 mL, 0.50 mol) was slowly added dropwise. After the addition was completed, reflux was carried out for 12 h. The pump is distilled off under reduced pressure and excess trimethyl chlorosilane to obtain a pale yellow liquid. Dichloromethane (200 mL) is added and washed with 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with the organic layer. The organic layer was dried over anhydrous sodium sulfate overnight. Filtration the next day, and the solvent was evaporated under reduced pressure to give EtOAc (3,3,4,5-tetrafluorobenzoic acid decyl ester (30.52 g, 97.8 %), ^-NMR (400 MHz, CDC1 ₃ ) δ ppm: 7.65-7.60 (m, 1H), 3.97 (s, 1H). Step 2, 2, 3, 4, 5-tetrafluorobenzamide

Add 2,3,4,5-tetrafluorobenzoic acid decyl ester (29.5 g, 0.147 mol) and concentrated ammonia water (244 mL, 3.24 mol) to the eggplant-shaped flask. The system is a two-phase system. , white insolubles appeared, mechanically stirred overnight, filtered to give white solid 2,3,4,5-tetrafluorobenzamide (21.2 g, 74.7 %), ^-NMR (400 MHz, DMSO-D ₆ ) δ ppm : 7.93 (br s, 1H), 7.91 (br s, 1H), 7.63-7.61 (m, 1H), ESI-MS m/z: 194.0 [M+l]+. Step 3, 2,3,4,5-tetrafluorobenzonitrile Add 2,3,4,5-tetrafluorobenzamide (5 g, 0.026 mol) to 20 mL of anhydrous acetonitrile, add phosphorus oxychloride (16.6 g, 0.11 mol), and warm to 70 °C. 1.5 h. The reaction solution was slowly added dropwise to a 200 mL water-water mixture. The process was strongly exothermic. The temperature was controlled to 30 ° C by controlling the dropping rate. After the completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 h, and extracted with ethyl acetate. After drying overnight, the solvent was evaporated under reduced pressure over the next day to yield 2,3,4,5-tetrafluorobenzonitrile ( 4.21 g, 92.5 %). iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 10.01 (br s, 1H), 7.35-7.28 (m, 1H), ¹⁹ F-NMR (400 MHz, CDC1 ₃ ) δ ppm: -130.04. - 130.06 (m,lH), -134.62-134.66 (m, 1H), -143.48-143.60 (m, 1H), -150.60-150.62 (m, 1H), ESI-MS m/z: 176.0[M+1 ] ⁺ . Step 4, 2-J.-3 mercapto-5-purine pyridine

2-J^-3hydrazinylpyridine (5.5 g, 0.05 mol), hydrazine (5.1 g, 0.02 mol), periodic acid dihydrate (2.88 g, 0.01 mol) were added to the reaction flask, followed by acetic acid ( 30 mL), water (60 mL) and fefe acid (0.9 mL), the system exothermed and the temperature in the system rose from room temperature to 25. C, get a dark brown solution and heat to 80. C, reaction for 4 h. The system was naturally cooled to room temperature, and a 10% aqueous solution of Na ₂ S _{2 4 4} (150 mL) was added thereto, and the mixture was stirred for 30 min, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium hydroxide. The organic layer was dried overnight without sodium sulfate. Filtration the next day, and the solvent was evaporated under reduced pressure to give pale-yellow solid 2-amino-3 decyl-5-pyridylpyridine (10.76 g, 92.0%), ^-NMR (400 MHz, CDC1 ₃ ) δ ppm: 8.11 (s , 1H), 7.53 (s, 1H), 4.85-4.80 (br s, 2H), 2.01 (s, 3H), ESI-MS m/z: 235.8 [M+l]+. Step 5, 3,4,5-Trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzonitrile

2-J^-3 mercapto-5-indole pyridine (23.10 g, 0.0986 mol) and lithium amide (7.99 g, 0.343 mol) were added to 170 mL of diphenylbenzene under nitrogen to heat to 100. C, stir the reaction for 2 h. Naturally cooled to room temperature, 2,3,4,5-tetrafluorobenzonitrile (15 g, 0.0857 mol) was added and heated to 126. C, reaction 3.5 h. The black solid obtained in the reaction was filtered, and the product was sandwiched between black solids, washed several times with ethyl acetate, and ultrasonicated for 5 min. The obtained ethyl acetate layer and the reaction mixture were washed with aq. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale-yellow solid 3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl) J^]benzonitrile (8.9 g, 27 %), 匪R (400 MHz, CDC1 ₃ ) δ ppm: 8.24-8.23 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H ), 5.99 (s, 1H), 2.31 (s, 3H), 1V F-NMR (400 MHz, CDC1 3) δ ppm: -122.29 (s, 1H), -133.63 ~-133.72(m, 1H), -135.71-135.76 (m, 1H), ESI-MS m/z: 390.0 [M+l]+. Step 6, 3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzoic acid

3,4,5-Trifluoro-2-[(3-indolyl-5-bromo-2-pyridinonitrile ( 8.90 g, 0.023 mol) was dissolved in absolute ethanol: distilled water: THF = 150 mL: 75 In a mixed solvent of 22.5 mL, potassium hydroxide (6.44 g, 0.115 mol) was added, and the mixture was heated under reflux for 30 h. The solvent was evaporated under reduced pressure to give an oil, which was adjusted to pH 1 with 10% aqueous hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate. 2-pyridyl) benzoic acid ( 8.72 g, yield 92.9 %), mp 103-105 ° C. ^-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 13.61 (br s, 1H), 8.38 (s, 1H), 8.11-8.09 (d, 1H), 7.85-7.84 (d, 1H),

7.56-7.52 (m, 1H), 2.49 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-D ₆ ) δ ppm: ■12193~- 121.99 (m, 1H), -133.82~- 133.88 (m , 1H), -139.86-139.97 (m, 1H), ESI-MS m/z: 409.1 [M+l]+. Step 7. 1-{3,4,5-Trifluoro-2-[(3-indolyl-5-indol-2-pyridyl)amino]benzoyl}-3-carboxylic acid acridine

3,4,5-Trifluoro-2-[(3-indolyl-5-e-2-pyridyl)amino]benzoic acid (0.20 g, 0.49 mmol), 1-ethyl-(3-di Mercaptoaminopropyl) carbodiimide hydrochloride (EDCI) (0.14 g, 0.73 mmol), 1-hydroxy-benzo-triazole (HOBT) (0.07 g, 0.49 mmol) was added to DMF (5 mL) The mixture was stirred at room temperature for 30 min, then 3-carboxylic acid acridine (0.07 g, 0.73 mmol). After adding 30 mL of ethyl acetate, the mixture was washed with EtOAc EtOAc. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale-yellow solid 1-{3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyr) J^] Benzoyl}-3-carboxylic acid acridine (0.19g, 79.2%) ^-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 13.61 (br s, 1H), 8.38 (s, 1H), 8.11- 8.09 (d, 1H), 7.85-7.84 (d, 1H),

7.56-7.52 (m, 1H), 4.22-4.02 (m, 4H), 2.95-2.92 (m, 1H), 2.49 (s, 3H).

ESI-MS m/z: 492.0 [M+l]+. Example 2 N-(cyclohexyldecyl)-l-{3,4,5-trifluoro-2-[(3-indolyl-5-branche-2-pyridyl) J.]benzoyl}-3-carboxamide

1-{3,4,5-Trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)J^benzoyl}-3-carboxylate acridine obtained in Example 1. (0.23 g, 0.47 mmol) dissolved in DMF (5 mL), benzotriazole-^^^,^-tetradecylurea hexafluorophosphate (1181 ¹ 11 ) (0.54 8, 1.41 mmol), After being removed at room temperature for 30 min, phenylhydrazine (O.ll g, 0.94 mmol) and N-decylmorpholine (0.52 mL, 4.7 mmol) were added to the mixture, and the mixture was stirred at room temperature for 3 d. 30 mL of dichloromethane was added to the reaction system, and the organic phase was washed with water, and the aqueous phase was back-extracted with dichloromethane, and the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate overnight. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a yellow solid solid N-(cyclohexylmethyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-捵-2-pyr^) J^]benzoyl}-3-carboxyamide acridine (0.12 g, 43.7 %). iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 8.23 (s, 1H), 8.08-8.07 (m, 1H), 8.00-7.97 (m, 1H), 7.82-7.81 (m, 1H), 7.31 -7.30 (m, 1H), 4.22-4.02 (m, 4H), 2.95-2.92 (m, 2H), 2.69(s, 1H), 2.25(s, 3H), 1.66-1.63 (m, 5H), 1.38 -1.12 (m, 6H).

ESI-MS m/z: 587.2 [M+l]+. Example 3 N-(2-morpholinylethyl)-l-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridinyl ¹ ^)benzoyl}- 3-carboxyamide oxime

方法同实施例 2, 得淡黄色色固体 N-(2-吗啉乙基) -1-{3，4，5-三氟 -2-[(3-曱基 -5-捵 -2-吡啶基 ) J^】苯曱酰 }-3-^J^酰胺吖啶。 iH-NMR (400 MHz, DMSO-D₆) δ ppm: 10.97 (br s, 1H), 8.51-8.50 (m, 1H), 8.26(s, 1H)， 8.08-8.07 (m, 1H), 7.82-7.81 (m, 1H), 7.31-7.30(m, 1H), 4.25-4.08(m, 4H), 3.96-3.80 (m, 4H)， 3.51-3.38 (m, 3H)， 3.19-3.03 (m, 4H)， 2.89(s, 1H)， 2.73 (s, 1H)， 2.25(s, 3H)， ESI-MS m/z: 604.2 [M+l]⁺。 实施例 4 N- (苯曱氧基) -l-{3，4，5-三氟 -2-[(3-曱基 -5-捵 -2-吡 )氨 基】苯曱酰 }-3- 酰胺吖啶

The same procedure as in Example 2 gave N-(2-morpholinethyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridine) as a pale yellow solid. Base) J^]benzoyl}-3-^J^amide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 10.97 (br s, 1H), 8.51-8.50 (m, 1H), 8.26 (s, 1H), 8.08-8.07 (m, 1H), 7.82- 7.81 (m, 1H), 7.31-7.30 (m, 1H), 4.25-4.08 (m, 4H), 3.96-3.80 (m, 4H), 3.51-3.38 (m, 3H), 3.19-3.03 (m, 4H ), 2.89 (s, 1H), 2.73 (s, 1H), 2.25 (s, 3H), ESI-MS m/z: 604.2 [M+l] ⁺ . Example 4 N-(Phenyloxy)-l-{3,4,5-trifluoro-2-[(3-indolyl-5-indol-2-pyridylamino)benzoyl}-3- Amide acridine

The same procedure as in Example 2 gave N-(benzomethoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridyl) J as a pale yellow solid. ^] benzoyl}-3-^^amide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 11.54-11.52 (br s, 0.21H), 11.26-11.24 (br s, 0.87H), 8.25 (s, IH), 8.08-8.07 (m, IH), 7.82-7.81 (m, IH), 7.40-7.36 (m, 7H), 4.82 (s, 2H), 4.22-4.11 (m, 4H), 3.28-3.25 (m, 1H), 2.25(s, 3H), ESI-MS m/z: 597.2 [M+l]+. Example 5 N-[(2,2-Mercapto-1,3dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2-[(3-indenyl) -5-indole-2-pyridyl) J^benzoyl}-3-carboxyamide acridine

The same procedure as in Example 2 gave a dark yellow solid N-[(2,2-indolyl-1,3-dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2 -[(3-indolyl-5-indol-2-pyridyl)amino]benzoyl}-3-^^amide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 11.34 (br s, 1H), 8.26 (s, IH), 8.08 (s, IH), 7.96 (m, IH), 7.82 (m, IH) , 7.35-7.32 (m, IH), 4.26-4.15 (m, 4H), 3.82-3.80 (m, 2H), 3.71-3.68 (m, 1H), 3.28-3.25(m, 1H), 2.89(s, IH), 2.73 (s, IH), 2.25 (s, 3H), 1.34-1.23 (m, 6H), ESI-MS m/z: 621.3 [M+l]+. Example 6 (R)-N-[(2,2-Mercapto-1,3dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2-[( 3-mercapto-5-iodo-2-pyridin ¹ ^ ) phenyl benzoyl}-3-^^amide acridine

The same procedure as in Example 2 gave a dark yellow solid (R)-N-[(2,2-indolyl-1,3-dioxolan-4-yl) decyloxy]-1-{3,4,5- Trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzoyl}-3-carboxyamide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 11.34 (br s, 1H), 8.26 (s, IH), 8.08 (s, IH), 7.96 (m, IH), 7.82 (m, IH) , 7.35-7.32 (m, IH), 4.26-4.15 (m, 4H), 3.82-3.80 (m, 2H), 3.71-3.68 (m, IH), 3.28-3.25(m, IH), 2.89(s, IH), 2.73 (s, IH), 2.25 (s, 3H), 1.32-1.26 (m, 6H). ESI-MS m/z: 621.4 [M+l]+. Example 7, N-(2,3-dihydroxypropoxy)-l-{3,4,5-trifluoro-2-[(3-indolyl-5-reef-2-pyridyl)]benzene Decanoyl-3-yl amide acridine

Ν-[(2,2-Mercapto-1,3dioxolan-4-yl)decyloxy] -1-{3,4,5-trifluoro-2-[() prepared in Example 5 3-mercapto-5-indole-2-pyridyl)amino]benzoyl}-3-carboxamide acridine (0.27 g, 0.45 mmol) in sterol (5 mL) and water (0.5 mL) To the solvent, p-citric acid monohydrate ( 0.008 g, 0.042 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was concentrated, EtOAc EtOAc EtOAc. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale yellow solid N-(2,3-dihydroxypropoxy)-1-{3,4,5-trifluoro-2-[(3- Base-5- 捵-2-pyridyl)amino]benzoyl 3-carboxyamide acridine (0.16 g, 56.3 %), mp 110-112. C.匪R (400 MHz, DMSO-D ₆ ) δ ppm: 11.34 (br s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.82 (m, 1H), 7.35-7.32 (m, 1H ), 4.24-4.15 (m, 4H), 3.85-3.83 (m, 1H), 3.68-3,66 (m, 1H), 3.36-3.34(m, 2H), 2.89(s, 1H), 2.73(s , 1H), 2.25 (s, 3H), ESI-MS m/z: 581.3 [M+l]+. Example 8 l-{3,4,5-Trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)J^benzoyl}-3-

 Step 1. 2-J^-3-Chloro-5-bromopyridine

2-Amino-5-bromopyridine (3.0 g, 17.34 mmol) was dissolved in DMF (10 mL)EtOAc The mixture was cooled to 0 ° C, added NCS ( 2.40 g, 18.03 mmol), and reacted at 0 ° C for 1 h. 30 mL of water was added to the reaction mixture, and the mixture was extracted with anhydrous diethyl ether. Filtration the next day, the solvent was evaporated under reduced pressure to give a white solid (2.72 _g , 75.6%), ESI-MS m/z: 207.9 [M+l]+. Step 2, 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyrrole) J^]benzonitrile

2-J^-3-chloro-5-bromopyridine (10.30 g, 0.050 mol) and lithium amide (4.58 g, 0.20 mol) were added to 150 mL of diphenylbenzene under nitrogen atmosphere and heated to 100 °C. , stir the reaction for 2 h. Naturally, the temperature was lowered to room temperature, 2,3,4,5-tetrafluorobenzonitrile (7.33 g, 0.042 mol) was added, and the mixture was heated to 126 ° C for 3.5 h. The reaction solution was added to 100 mL of ethyl acetate and stirred for 10 min to yield a large white solid. The product was sandwiched between black solids, washed in small portions with ethyl acetate, and sonicated for 5 min. The obtained ethyl acetate layer and the reaction mixture were washed with 1N aqueous hydrochloric acid, and the organic layer was combined, and the organic layer was dried overnight. The solvent was evaporated under reduced pressure. [(3-Chloro-5-bromo-2-pyridinyl)amino]benzonitrile ( 4.5 g, 29.6 %), ^-NMR (400MHz, CDC1 ₃ ) δ ppm: 8.16-8.13 (m, 1H), 7.82 -7.81 (m, 1H), 7.24-7.23 (m, 1H), 6.57 (br s, 1H), ¹⁹ F-NMR (400MHz, CDC1 ₃ ) δ ppm: -123.65—123.71 (m, 1H), -136.9 1-136.50 (m, 1H), -138.60-138.74 (m, 1H), ESI-MS m/z: 363.9 [M+l]+. Step 3, 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyrrole) J^]benzoic acid

3,4,5-Trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzonitrile (4.50 g, 12.4 mmmol) was dissolved in absolute ethanol: distilled water: THF = 100 In a mixed solvent of mL: 50 mL: 15 mL, a hydrogenation clock (3.48 g) was added, and the mixture was heated under reflux for 30 h. The solvent was evaporated under reduced pressure to give crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Fluor-2-[(3- Chloro-5-bromo-2-pyridyl)amino]benzoic acid (4.27 g, 90.2%). Step 4, 1-{3,4,5-Trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)J^benzoyl}-3-carboxylic acid acridine

3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)J^]benzoic acid (3.0 g, 8.31 mmol), EDCI ( 2.39 g, 12.46 mmol), HOBT (1. 16 g, 8.31 mmol) was added to DMF (5 mL). EtOAc. The mixture was washed with water and aq. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale yellow solid of 1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyrazine)J^benzene Acrylyl-3-carboxylic acid acridine (3.02 g, 82.1%) ^-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 13.67 (br s, 1H), 8.26 (s, 1H), 8.06-8.04 (d, 1H), 7.83-7.81(d, 1H),

7.56-7.52 (m, 1H), 4.16-4.02 (m, 4H), 2.95-2.92 (m, 1H), 2.49 (s, 3H).

ESI-MS m/z: 444.1 [M+l] ⁺ „ Example 9. N-(cyclohexyldecyl)-l-{3,4,5-trifluoro-2-[(3-indolyl-5) -Bromo-2-pyrrole^) J^benzoyl}-3-carboxyamide acridine

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The same procedure as in Example 2 gave (R)-N-(2,3-dihydroxypropoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5). -iodo-2-pyridyl) J^]benzoyl}-3-carboxyamide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 8.42 (m, 1H), 8.27 (s, 1H), 7.96 (m, IH), 7.72 (m, 1H), 7.35-7.32 (m, 1H) ), 3.59-3.57 (m, 4H), 3.40-3.37 (m, 2H), 2.49-2.42 (m, 6H), 2.28 (s, 3H). ESI-MS m/z: 534.3 [M+l] ⁺ . Example 13, N-[2-(piperidin-1-yl)ethyl]-l-{3,4,5-trifluoro-2-[(3-indolyl-5-branche-2-pyridyl) 】 benzoyl}-3-carboxyamide acridine

The same procedure as in Example 2 gave a dark-yellow solid of Ν-[2-(pyridin-1-yl)ethyl]-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodine -2-pyridyl) J^]benzoyl}-3-carboxyamide acridine, iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 10.22 (br s, 1H), 8.56 (s, 1H) , 8.29(s, 1H), 8.09 (m, 1H), 7.83 (m, 1H), 7.35-7.32 (m, 1H), 4.25-4.08(m, 4H), 3.10-3.09(m, 3H), 2.90 - 2.80 (m, 4H), 273 (s, 2H), 2.25 (s, 3H), 1.84-1.67 (m, 6H), ESI-MS m/z: 602.3 [M+l] ⁺ . Example 14, N-(cyclopropoxy)-l-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl} -3-carboxyamide acridine

The same procedure as in Example 9 gave N-(cyclopropoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridyl) J as a white solid. ^] benzoyl}-3-^^amide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 11.21 (br s, 1H), 8.31 (s, 1H), 7.99-7.98 (m, 1H), 7.74-7.73 (m, IH), 7.35-7.32 (m, IH), 4.24-4.02(m, 4H), 3.60-3.59 (m, 2H), 3.27-3.26 (m, IH), 2.28(s, 3H), 1.05-1.03(m, IH), 0.52-0.51(m, IH ), 0.23-0.21 (m, 2H), ESI-MS m/z: 513.2 [M+l] + Example 15. (S)-N-(2,3-dihydroxypropoxy)-l-{ 3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridinyl)J^benzoyl}-3-^amide acridine

方法同实施例 9, , 得白色固体 (S)-N-(2，3-二羟基丙氧基） -1-{3，4，5- 三氟 -2-[(3-曱基 -5-溴 -2-吡啶基) J^】苯曱酰 }-3-羧基酰胺吖啶。 iH-NMR (400 MHz, DMSO-D₆) δ ppm: 8.27(s, 1H)， 7.99-7.98(m, 1H)， 7.73(m， IH), 7.35-7.32 (m, 1H)， 4.24-4.02(m， 5H), 3.60-3.58 (m, 5H), 2.28(s, 3H)， ESI-MS m/z: 513.2 [M+l】+ 实施例 16、 l-{5-[(5-碘 -3-曱基 2-吡¹^ ) J^】-4-氟 -IH-苯并咪唑 -6- 曱酰 }-3-羧酸吖啶

The same procedure as in Example 9, gave (S)-N-(2,3-dihydroxypropoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5) as a white solid. -Bromo-2-pyridyl) J^]benzoyl}-3-carboxyamide acridine. iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 8.27 (s, 1H), 7.99-7.98 (m, 1H), 7.73 (m, IH), 7.35-7.32 (m, 1H), 4.24-4.02 (m, 5H), 3.60-3.58 (m, 5H), 2.28 (s, 3H), ESI-MS m/z: 513.2 [M+l] + Example 16, l-{5-[(5- -3-indolyl 2-pyridyl ¹ ^ ) J^]-4-fluoro-IH-benzimidazole-6-decanoyl-3-carboxylic acid acridine

步骤 1、 5-硝基 -2,3,4-三氟苯曱酸

Step 1, 5-nitro-2,3,4-trifluorobenzoic acid

The fuming nitric acid (37 mL, 0.78 mol) was slowly added dropwise to concentrated sulfuric acid (200 mL) in a water bath. In another reaction system, 2,3,4-trifluorobenzoic acid (109.4 g, 0.62) was added. Mol) and 330 mL of concentrated sulfuric acid. A concentrated sulfuric acid solution of fuming nitric acid was slowly added dropwise to the concentrated sulfuric acid solution of the reaction raw material under water bath conditions. The water bath was removed, and the temperature was naturally raised to room temperature, and the reaction was stirred for 5 hours. The reaction solution was slowly added dropwise to a 2000 mL aqueous solution under stirring, stirred at room temperature for 2 h, allowed to stand overnight, and filtered to give a white solid 5-nitro-2,3,4-trifluorobenzoic acid (123.7 g, 90.3%), ESI-MS m/z: 222.0 [M+1] ⁺ step 2, 5-nitro-3,4-difluoro-2-[(5-iodo-3-indolyl 2-pyridyl ¹ ^ Under a nitrogen-protective condition, 2-J^-3-mercapto-5-indole pyridine (10.61 g, 0.045 mol) was dissolved in 70 mL of anhydrous tetrahydrofuran (THF) and cooled to -70. (:. 2M of diisopropyl J ^ lithium (LDA) in THF solution (34 mL, 0.068 mol) was added to the reaction system, and reacted at -70 ° C for 1 h. Add 5-nitrate to the reaction system. A solution of bis- 2,3,4-trifluorobenzoic acid (5.01 g, 0.023 mol) in THF was added dropwise, and the reaction was carried out at -70 ° C for 1 h. The temperature was naturally raised to room temperature and stirred overnight at room temperature. The aqueous solution was washed with a saturated aqueous solution of sodium chloride, and the aqueous layer was evaporated to ethyl ether. The organic layer was dried overnight and then purified to give a yellow solid, 5-nitro-3, 4-difluoro-2-[(5- 2-pyridyl)^]-benzoic acid (4.788, 47.8%), ^-NMR (400 MHz, CDC1 ₃ ) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z: 436.0 [M+l]+. Step 3. 5-Nitro-4 -amino-3-fluoro-2-[(5-iodo-3-indolyl 2- Pyridyl) J^]-benzoic acid 5-nitro-3,4-difluoro-2-[(5-indol-3-yl-2-pyridyl)aminobenzoic acid ( 2.30 g, 5.29 Adding to 100 mL of distilled water, cooling to 0 ° (:. Concentrated aqueous ammonia ( 2.21 mL, 29.6 mmol) was added dropwise to the reaction system, and reacted at 0 ° C for 1 h. Naturally returned to room temperature, reacted for 4 h, filtered to give a yellow solid. 5-Nitro-4-J^-3-fluoro-2-[(5-iodo-3-indolyl-2-pyridinylbenzoic acid (1.82 g, 79.5%), ^-NMR (400 MHz, CDC1) ₃ ) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z: 433.1 [M+l] ⁺ . Step 4. 5-nitro-4-amino-3-fluoro-2-[(5-iodo-3-indolyl 2 -pyridyl) J^]-decyl benzoate

5-Nitro-4-amino-3-fluoro-2-[(5-iodo-3-indolyl 2-pyridyl)aminopropionic acid (1.82 g, 4.21 mmol) was dissolved in 20 mL of anhydrous hydrazine. Tridecylchlorosilane (1.06 mL, 8.42 mmol) was slowly added dropwise to the alcohol. After the addition was completed, reflux was carried out for 12 h. The pump is distilled off under reduced pressure and the excess trimethyl chlorosilane is obtained as a pale yellow liquid. 20 mL of dichloromethane is added and washed with a 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with dichloromethane. The organic layer was dried over anhydrous sodium sulfate overnight. Filtration the next day, and the solvent was evaporated under reduced pressure to give a yellow solid, 5-nitro-4-amino-3-fluoro-2-[(5-bromo-3-indolyl 2-pyridyl)J^]-benzoic acid Oxime ester ( 1.84 g, 97.9 % ), ^-NMR (400 MHz, CDCI3) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), ESI-MS m/z: 447.1 [M+l] ⁺ . Step 5, 5-[(5-iodo-3-indolyl 2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoate

5-Nitro-4-J^-3-fluoro-2-[(5-iodo-3-indolyl 2-pyridyl) J^]-benzoic acid decyl ester ( 1.84 g, 4.12 mmol), 曱The acid (25 mL) and 20% Pd(OH)/C (1.57 g, 2.95 mrnol) were heated to 95 ° C in 25 mL ethanol. After 16 hours, the reaction mixture was cooled to room temperature, and 0.5 g of 20% Pd(OH) 2 / C and 10 mL of decanoic acid were added. The reaction mixture was heated to 95 °C. After 16 hours, the reaction mixture was cooled to rt and filtered over EtOAc EtOAc. The filtrate was concentrated under reduced pressure, and a solid was precipitated, which was filtered to afford 5-[(5---- 3- </RTI> 2-pyridyl 2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoate. ( 1.35g, 76.7% ), ^-NMR (400 MHz, CDC1 ₃ ) δ ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), ESI-MS m/z: 427.1 [M+l] +. Step 6, 5-[(5-捵-3-indolyl-2-pyridyl)J^]-4-fluoro-1H-benzimidazole-6-decanoic acid 5-[(5-破-3 - mercapto 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoate ( 1.35 g 3.17 mmol) was suspended in methanol (30 mL) and 20% NaOH (8 mL) was added. After 16 h, the reaction mixture was cooled to 0 ° C, and 1 NHC1 solution was added dropwise until pH 2-3. The reaction mixture was diluted with ethyl acetate and water, and the layers were separated. The organic layer was washed, and the organic layer was dried over anhydrous sodium sulfate. The next day was filtered, and the solvent was evaporated under vacuo to give a dark-yellow solid 5-[(5- </RTI><RTIgt; 4-fluoro-1H-benzimidazole-6-decanoic acid (0.68g, 52.3%), ^-NMR (400 MHz, CDC1 ₃ ) δ ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H) , 6.21 (s, 1H), 5.99 (s, 1H), 2.31(s, 3H), ESI-MS m/z: 413.1 [M+l]+. Step 7, l-{5-[(5-broken -3-indolyl 2-pyridyl)) J^]-4-fluoro-1H-benzimidazole-6-decanoyl-3-carboxylic acid acridine

5-[(5-iodo-3-indolyl-2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoic acid (0.68 g, 1.65 mmol ), EDCI ( 2.39 g, 12.46 mmol ), HOBT ( 1.16 g, 8.31 mmol), added to DMF (5 mL), stirred at room temperature for 30 min, added 3-di-acid 1.26 g, 12.46 mmol), stirred at room temperature for 2 h . After adding 30 mL of ethyl acetate, the mixture was washed with water and aq. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give pale yellow solid 1-{5-[(5-iodo-3-indolyl 2-pyridyl) J^]-4-fluoro-1H-benzimidazole -6-decanoyl-3-carboxylic acid acridine (0.57 g, 70.3%), ^-NMR (400 MHz, CDC1 ₃ ) δ ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75(br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 4.16-4.02 (m, 4H), 2.95-2.92 (m , 1H), 2.49 (s, 3H). ESI-MS m/z: 496.0 [M+l] ⁺ „ Example 17. N-[2-(thiophen-2-yl)ethyl] -l{5- [(5-iodo-3-indolyl 2-pyridyl)aminobu 4-fluoro-1H-benzimidazole-6-amide}-3-^^amide acridine

1-{5-[(5-iodo-3-indolyl-2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoyl}-3-carboxylate obtained in Example 16 Acid acridine (0.28 g, 0.57 mol), 2-(thiophen-2-yl)ethylamine (0.13 g, 1.03 mmol), DIEA (0.12 mL, 0.68 mmol) dissolved in 20 mL of dichloromethane PyBOP (0.34 g, 0.65 mmol) was stirred at room temperature overnight. 40 mL of anhydrous diethyl ether was added to the reaction mixture, and the organic phase was washed with water and a saturated aqueous solution of sodium chloride. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale yellow solid N-[2-(thiophen-2-yl)ethyl] -1{5-[(5-iodo-3-indolyl 2-pyridyl) ¹ ^ ) J^]-4-fluoro-1H-benzimidazole-6-indoleamide}-3-^J^amide acridine (0.15 g, 44.1%), ^-NMR (400 MHz, CDC1 ₃ ) δ Ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.98-6.96 (m, 2H), 6.89 -6.88 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 6.75-6.78 (m, 1H), 4.16-4.02 (m, 4H), 3.78-3.75 (m, 2H), 3.18 -3.15 (t, 2H, J = 6.7 Hz), 2.95-2.92 (m, 1H), 2.31 (s, 3H), ESI-MS m/z: 605.1.0 [M+l]+. N-[2-(piperidin-1-yl)ethyl]-1{5-[(5-iodo-3-indolyl-2-pyridyl)aminobu-4-fluoro-1H-benzimidazole-6 -carboxamide}-3-^^amide acridine

The same procedure as in Example 17 gave N-[2-(piperidin-1-yl)ethyl]-5-[(5-redo-3-indolyl-2-pyridyl)amino-4-fluoro-1H as a yellow solid. -benzimidazole-6-indoleamide, iH-NMR (400 MHz, DMSO-D ₆ ) δ ppm: 8.41-8.39 (m, 1H), 8.19 ( ( s, 1H ) , 7.76-7-75 (br s , 1H), 6.89-6.88 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 6.75-6.78 (m, 1H), 4.16-4.02 (m, 4H), 3.36-3.34 (m , 2H), 2.95-2.92 (m, 1H), 2.43-2.38 (m, 6H), 2.31(s,3H), 1.51-1.49 (m, 6H), ESI-MS m/z: 606.1 [M+l 】 +. Example 19, activity test

 A preliminary activity test was performed on some of the compounds of Examples 1-18 to evaluate the activity of the compounds in tumor cell proliferation of myeloid leukemia cells (K562) and human colorectal cancer cells (HT-29) in vitro.

After the cultured tumor cells grow to a certain density, the adherent cells are digested with 0.25% trypsin for 2-5 min, and the suspension cells are centrifuged (1000 rpm/min), and the single cell suspension is prepared by using the corresponding culture medium to adjust the cell concentration to corresponding Density (lxlO ⁵ / mL), inoculated in 96-well culture plate, 100 μΐ well, cultured at 37 ° C, 5 % C0 ₂ for 24 h, then added the whole medium of the corresponding cells of 80 μ pupil, and then added different concentrations of the affected medium. Test compounds 20μΐ, each treatment set 3 replicates, continue to culture for 72h at 37°C, 5% C02, then aspirate the supernatant 每μΙ^ per well, then add 5mg/mL thiazolyl blue (MTT) solution lO L, 37 Incubate for 4 h at °C, finally add ΙΟΟμΙ^ 10% SDS per well, incubate for 24 h at 37 °C 5 % C0 ₂ to completely dissolve the MTT crystals. The absorbance per well was measured by an enzyme-linked immunosorbent assay at a wavelength of 570 nm. According to the formula:

Inhibition rate (%) = (1—the OD value of the test well/the average OD value of the solvent control well) χ100% Calculate the inhibition rate, and take the logarithm of the concentration of the test compound as the abscissa, and the average value of the cell inhibition rate as the ordinate. The dose-response curve was used and the half-cell inhibitor (IC ₅₀ ) was determined using the Origin analysis software.

The medium of K562 cells is 1640+10% FBS, and the medium of HT-29 is

The drug was dosed to the mother liquor concentration with DMSO (Sigma) before the test and diluted to the desired application concentration with whole medium without factor. Preliminary evaluation of compounds for tumor cell growth inhibition For the treatment, three dose groups of compound concentration of 3, 30, 300 μΜ, blank control group (no tumor cells and test compound, only culture medium), solvent control group (only solvent added without test compound) were used; Further, when half of the cytostatic amount (IC _5Q ) was obtained, six dose groups with a compound concentration of 1, 3, 10, 30, 100, 200, 300 μΜ, a blank control group (the same as before), and a solvent were selected according to the preliminary screening results. Control group (same as before). The specific results are shown in Table 1. Table 1 shows the inhibitory activity of some compounds on Κ562 and ΗΤ-29

IC ₅ o average (μΜ) IC _5e average (μΜ) No. Κ562 ΗΤ-29 No. 562 ΗΤ-29

 Example 2 30.43 10.81 Example 11 99.48 112.93

 Example 3 119.81 117.48 Example 12 233.33 >300

 Example 4 107.76 105.86 Example 13 119.50 131.79

 Example 5 136.13 120.11 Example 14 113.04 155.14

 Example 6 135.91 136.27 Example 17 56.32 72.36

 Example 7 15.95 22.70 Example 18 19.26 30.25

 Pdl98306 9.62 1.53

 Pdl98306 is a positive photo, and its structural formula is as follows:

 The experimental results show that the compound of the present invention has a remarkable inhibitory effect on tumor cells. Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and alterations may be made to those details in accordance with the teachings of the invention, which are within the scope of the invention. The full scope of the invention is indicated by the appended claims and any equivalents thereof.

Claims

Rights request A compound of the formula I or II, or a pharmaceutically acceptable salt, solvate optical isomer or N-oxide thereof.

II where:  In the formula π, - represents an optional bond, provided that there is one and only one nitrogen atom in the ring is double RL R ₂ , R ₃ , R ₄ , R ₅ , R ₇ or R ₈ are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, nitro, nitrile, trifluoromethyl, -OR ₉ , -C(O R ₁₀ , -C(0)OR ₉ , -NR ₁₀ C(O)OR ₉ , -OC(0)R ₉ , -NR ₁₀ SO ₂ R ₉ , -SO ₂ NR ₁₀ R ₉ , -NR ₁₀ C (O)R ₉ NR QR C - C o C2 - C 10 Women 3⁄4^, C-C o Block 3⁄4^, C-C. Ring J3⁄4^3⁄4^, c ₃ -c _1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; R _{6 is} independently selected from the group consisting of hydrogen, trifluoromethyl, d-do alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, <: ₃ -<: _{1 ()} cycloalkyl, C ₃ -C _1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is independently selected from -OR ₉ , -NR ₁₀ OR ₉ , -NR ₁₀ SO ₂ R ₉ and -NR ₁₀ R ₉ ; R ₉ , . Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkyl, C ₂ -C ₁₀ ), C ₂ -C ₁₀ block, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ ring pit base group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, heterocyclic group and heterocyclic group alkyl group; wherein each alkyl group, alkenyl group, alkynyl group, ring The alkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted with from 1 to 5 groups independently selected from the group consisting of hydroxy, pharmaceutically, amino, nitro and trifluoromethyl. 2. A compound according to claim 1 which is a combination of formula 式 or formula IV

 III IV  Wherein each substituent group is defined by the claims 3. A compound according to claim 2 which is a compound of formula V or formula VI:

 V VI  Wherein each substituent group is as defined in claim 1 The compound according to any one of claims 1 to 3, wherein Ri, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ or R ₈ are each independently hydrogen, halogen, nitro, Nitrile group, trifluoromethyl group, alkyl group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkylalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, hetero Cyclo or heterocyclylalkyl. The compound according to any one of claims 1 to 3, wherein W is -OR ₉ , -NR ₁₀ OR ₉ , -NR ₁₀ R ₉ , R ₉ , R ₁₀ are as defined in claim 1. . 6. A compound according to claim 1 selected from the group consisting of: 1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl}-3-carboxylic acid acridine; N-(cyclohexyldecyl)-l-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl}-3-carboxamide Acridine  N-(2-morpholinethyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl}-3- Carboxamide acridine;  N-(benzomethoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl}-3-carboxamide Acridine N-[(2,2-Mercapto-1,3dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2-[(3-indolyl_ ₅ _捵_2-pyridyl)amino]benzoyl}-3-carboxyamide acridine;  (R)-N-[(2,2-mercapto-1,3-dioxolan-4-yl)decyloxy]-1-{3,4,5-trifluoro-2-[(3-曱) 5-amino-2-pyridyl)amino]benzoyl}-3-carboxyamide acridine; N-( ² ,3-dihydroxypropoxy)-1-{3, ⁴ ,5-trifluoro-2- ² _[(3-indolyl-5-indole- ^2- pyridyl)amino]benzoyl} -3-carboxyamide acridine;  1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)amino]benzoyl}-3-carboxylic acid acridine;  N-(cyclohexyldecyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridinyl)amino]benzoyl}-3-carboxamide Acridine  N-(2-morpholinethyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridinyl)amino]benzoyl}-3- Carboxamide acridine; N-(benzomethoxy)-1-{ ³ , ⁴ , ⁵ _trifluoro _ ² _[( ³ _ fluorenyl- ^5- bromo- ² -pyridyl)amino]benzoyl}-3-carboxamide Acridine  (R)-N-(2,3-dihydroxypropoxy)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino] Benzoyl}-3-carboxyamide acridine; N-[ ² _ (piperidin-1-yl)ethyl]-1-{ ³ , ⁴ , ⁵ _trifluoro- ² _[( ³曱 _ _ ⁵ _捵_ ² _pyridyl) amino] benzene Decanoyl-3-carboxyamide acridine;  N-(cyclopropoxycarbonyl)-1-{3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzoyl}-3-carboxyl Amide acridine; (S)-N-( ² , ³ -dihydroxypropoxy)-1-{ ³ , ⁴ , ⁵ _trifluoro _ ² _[( ³曱 _ _ ⁵ _ bromo- ² -pyridyl)amino] Benzoyl}-3-carboxycarboxamide acridine; 1-{5-[(5-iodo-3-indolyl- ² -pyridyl)aminobu- ⁴ -fluoro-1H-benzimidazole-6-indoloyl 3-carboxylic acid acridine; N-[ ² -(thiophene- ² -yl)ethyl] -1{5-[(5-indole-3-indenyl- ² -pyridyl)aminobu- ⁴ -fluoro-1H-benzimidazole-6-oxime Amide}-3-carboxyamide acridine; N-[ ² -(piperidin-1-yl)ethyl] - 1{5-[(5-iodo-3-indolyl- ² -pyridyl)amino] _ ⁴ -fluoro-1H-benzimidazole-6 - oxime amide}-3-carboxyamide acridine. 7. A method of preparing the compound of claim 1  The synthesis scheme of the compound of formula I is as follows: The substituted benzoic acid containing the leaving group L is used as a starting material, and the carboxyl group is thiolated by reacting with a thiolation reagent; and the oxime ester is converted into an amide group by reacting with ammonia water; under the action of P0C1 ₃ Removing a portion of water to convert the amide bond to a cyano group; the substituted benzoquinone containing the leaving group L is condensed with a substituted aminopyridine compound by the action of a base such as lithium amide. Reaction; hydrolysis of a cyano group to give a carboxyl group. Reacting with a 3-carboxy acridine ring, the carboxyl group on the acridine ring is reacted with the corresponding side chain to give a compound of formula I;

 I  L represents the leaving group and can be halogen;  The synthesis scheme of the compound of formula II is as follows: The substituted benzoic acid containing the leaving group L is used as a starting material, and after the nitration reaction, a nitro group is introduced on the benzene ring; under the action of a base (for example, lithium), the group is removed and the substituted amino group is removed. a pyridine compound undergoes a condensation reaction; under the action of ammonia water, an amino group is introduced on the benzene ring; After reacting with a thiolation reagent, the carboxyl group is thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out, the decarboxylated ester is obtained to obtain a key intermediate containing a carboxyl group, and then reacted with a 3-carboxy acridine ring, acridine Obtaining a compound of formula II;

 L represents the leaving group and can be halogen; Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , W, R ₉ and R ₁₀ are as defined in claim 1.  A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier. 9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof for the manufacture of a medicament for the prevention and/or treatment of a cell hyperproliferative disorder. 10. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for antitumor and/or cancer. 11. A method of preventing and/or treating a tumor and/or cancer comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide. 12. A method of preventing and/or treating a cell hyperproliferative disorder, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.