WO2009049492A1 - N-substituted aromatic hydrocarbon aniline and multi-substituted diarylether compounds, the preparation and the use of antitumor thereof - Google Patents

Abstract

The invention provides N-substituted aromatic hydrocarbon aniline and multi-substituted diarylether compounds of formula (I) or their pharmaceutically acceptable salts, wherein X, Y, Z and R1-R4 are defined as in the claims. The invention also provides the preparation of such compounds, the pharmaceutical composition containing the said compounds, and the use of such compounds in preparation of medicaments for antitumor.

Description

 N-substituted arene aniline / polysubstituted diaryl ether compounds,

 Preparation method and anti-tumor application Technical field:

 The present invention relates to an N-substituted arene aniline/polysubstituted diaryl ether compound having various anticancer activities, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition containing the same, and an antitumor drug thereof Application in . Background technique:

 Malignant tumors are common and frequently-occurring diseases that seriously threaten human health. According to the World Health Organization, about 9 million new cases occur in the world's 5 billion people, and 7 million people die from cancer, and there is an increasing trend every year. In the three major therapies for malignant tumors (surgery, chemotherapy, radiotherapy), drug therapy plays an important role. In recent years, with the development of molecular biology and the further understanding of the molecular level mechanisms of cancer occurrence and development, anti-tumor drug research is shifting from traditional cytotoxic drugs to novel anti-tumor drugs targeting multiple mechanisms of mechanism. Inhibitors targeting cell signaling molecules or targets of neovascularization, anti-metastatic or anti-drug resistant drugs, differentiation inducers, targeted therapy, improving or regulating immune function, and gene therapy have become The focus of research and development of new anticancer drugs. Gefet inib, a protein tyrosine kinase inhibitor targeting cell signaling molecules, has been successful and has become the first non-small cell lung cancer drug on the market.

Although there are more than 60 kinds of anti-tumor drugs commonly used in clinical practice, the treatment of solid tumors that are the most serious for human life and account for more than 90% of malignant tumors have not achieved satisfactory results. Therefore, it is still a hot spot in the field of drug research to continue to search for new high-efficiency and low-toxic anti-tumor drugs. Summary of the invention

 The present inventors discovered a series of N-substituted aromatic anilines and polysubstituted diaryl ether compounds by investigating the anticancer activity of small molecule synthetic compounds in vitro in the research process of searching for new anticancer drugs. The cancer cells have strong inhibitory activities and exhibit a certain structure-activity relationship, and accordingly, the inventors conducted intensive studies on the compounds. The anticancer activity of this class of compounds has not been reported.

 Accordingly, a first aspect of the invention relates to N-substituted arene anilines and polysubstituted diaryl ether compounds having the structure of the following general formula (I): or a pharmaceutically acceptable salt thereof:

 among them,

 Z is CH or N;

 X is a hormone or hydrogen;

 Y is -0- or - NR,-;

R, R ₂ , R ₃ are each independently H, halogen, -N0 ₂ , -CN, -NH ₂ , d- ₆ alkyl, C! _-6 alkoxy, 0H, -0CH ₂ 0-, - CF ₃ ,, -C00H, -S0 ₃ H, -C0NH ₂ , -C0NHR' or - C00R,;

Alternatively, and R ₂ or R ₂ and R ₃ may together form -CHCH ₂ 0-;

R ₄ is -CN, -N0 ₂ , -CH=CH ₂ , -C≡CH, -CH ₃ , d- ₆ alkyl, d- ₆ alkoxy, halogen, -NH ₂ , -0H, -C00H, - S0 ₃ H, -C≡CR" or - CH-CHR", and R ₄ is mono- (o-, m-, para-) or polysubstituted;

R, an H, d- ₄ hydrocarbyl-substituted aromatic ring, a five- or six-membered heteroaryl ring, optionally a d-aliphatic hydrocarbon group containing a double or triple bond, or optionally a double or triple bond Fatty acyl group;

R" is a d- ₄ hydrocarbon group optionally containing a double bond or a triple bond;

 The condition is that the following compounds are not included:

 5-chloro-2,4-dinitro-(4,-methylphenyl)-aniline

 5-chloro-2,4-dinitro-N-(4,-methoxyphenyl)-aniline;

 6-Chloro-2-(N-anilino)-3-nitropyridine. A second aspect of the invention relates to a process for the preparation of a compound of formula I above.

 A third aspect of the invention relates to a pharmaceutical composition comprising a compound of formula I above and one or more pharmaceutically acceptable carriers or excipients.

 A fourth aspect of the invention relates to the use of a compound of formula I for the preparation of an anti-tumor drug.

 The term "hydrocarbyl" as used in the present invention includes alkyl, alkenyl and alkynyl groups. The term "Cw.aromatic ring" as used in the present invention means a single or fused aromatic ring system having 6 to 10 carbon atoms, including but not limited to phenyl, naphthyl.

 The term "five- or six-membered heteroaryl ring" as used in the present invention means a five- or six-membered aromatic ring system containing at least one hetero atom selected from 0, S or N in the ring system, including but not limited to Pyrrole, pyrazole, furan, thiophene, pyridine, and the like.

 According to one embodiment of the present invention, the present invention relates to N-substituted arene anilines and polysubstituted diaryl ether compounds having the following general formula (I):

 among them,

Z is CH or N; X is! 3⁄4 prime or hydrogen;

 Y is -0- or -NR,-;

R ₂ and R ₃ are each independently H, halogen, -N0 ₂ , -CN, -NH ₂ , alkyl, C ₁₆ alkoxy, OH, - 0CH ₂ 0-, -CF ₃ , -C00H, -S0 ₃ H, - C0NH ₂ , -C0NHR' or -C00R,;

Alternatively, and R ₂ or R ₂ and R ₃ may together form - 0CH ₂ 0-;

R ₄ is -CN, -N0 ₂ , -CH=CH ₂ , -C≡CH, -CH ₃ , d- ₆ alkyl, (^ ₆ alkoxy, -, -NH ₂ , -0H, -C00H, - S0 ₃ H, -C≡CR" or -CH=CHR" , and

^ is single-(neighbor, meta, para) or multiple substitution;

R, is an H, d- ₄ hydrocarbyl-substituted (.. aromatic ring, five- or six-membered heteroaryl ring, optionally containing a double or triple bond CH. an aliphatic hydrocarbon group, or optionally containing a double or triple bond D—monthly fat ugly base;

 R" is a hydrocarbon group optionally containing a double bond or a triple bond;

 The condition is that the following compounds are not included:

 5-Chloro-2,4-dinitro-indole (4,-methylphenyl)-aniline

 5-chloro-2,4-dinitro-indole-(4,-methoxyphenyl)-aniline;

 6-Chloro-2-(indolyl-anilino)-3-nitropyridine. According to a preferred embodiment of the invention, wherein Ζ is CH.

 According to another preferred embodiment of the invention, wherein ∑ is 1^.

According to another preferred embodiment of the invention, wherein R ₄ is a para substitution. According to another preferred embodiment of the invention, wherein Y is -NH-. According to another preferred embodiment of the present invention, wherein

RR _{3 is} each independently halogen, -N0 ₂ , -CN, -NH ₂ , -CH ₃ , -0CH ₃ , 0H, -0CH ₂ 0-, -CF ₃ , -C00H, -S0 ₃ H, -C0NH ₂ ;

R ₂ is H. According to another preferred embodiment of the present invention, wherein

! ^ is halogen, -N0 ₂ , -CN, -NH ₂ , -CH ₃ , -0CH ₃ , 0H, -0CH ₂ 0-, -CF ₃ , - C00H, -S0 ₃ H, -C0NH ₂ ;

R ₂ and R ₃ are H. According to another preferred embodiment of the present invention, wherein

R ₂ is halogen, -N0 ₂ , —CN, —NH ₂ , —CH ₃ , —0CH ₃ , 0H, —0CH ₂ 0-, —CF ₃ , —C00H, —S0 ₃ H, —CONH ₂ ;

RR ₃ is H. According to another preferred embodiment of the present invention, wherein

^ and R ₃ are each independently halogen, -N0 ₂ , -CN, -NH ₂ , -CH ₃ , - 0CH ₃ ,

0H, -0CH ₂ 0-, -CF ₃ , - C00H, -S0 ₃ H, -C0NH ₂ ;

R ₂ is H. According to another preferred embodiment of the present invention, wherein

R ₃ is independently halogen, -N0 ₂ , -CN, -NH ₂ , -CH ₃ , - 0CH ₃ , 0H, - 0CH ₂ 0-, -CF ₃ , - C00H, -S0 ₃ H, -C0NH ₂ ;

! ^ and 11 ₂ are H;

Alternatively, it may form -0CH ₂ 0- together with R ₂ or R ₂ and R ₃ . The following compounds are more preferred in the present invention:

 N-( zz hydroxyphenyl ) -5-chloro -2, 4-dinitroaniline;

 5-chloro-(4,-aminophenyl)-2,4-dinitroaniline;

 5-chloro-2,4-dinitro-N-(4,-decyloxyphenyl)-aniline;

5-chloro-N-(4,-nitrophenyl)-2,4-dinitroaniline; 5-chloro-N-(4,-cyanophenyl)-2-nitroaniline;

 5-chloro-N-(4,-aminophenyl)-3-nitroaniline;

 4,-cyanophenoxy-5-chloro-2,4-dinitrophenyl ether;

 (4,-A-,2,6-xylyleneoxy)-5-chloro-2,4-dinitrophenyl ether;

 (4,-cyano-2,6-xylyleneoxy)-5-chloro-2,4-dinitrophenyl ether;

 5-( 4,-cyanophenoxy)-2-nitrophenyl ether;

 4-(4,-cyanophenoxy)nitrophenyl ether;

 2-(4,-cyanophenoxy)nitrobenzene;

 6-chloro-2-(4,-methoxyanilino)-3-nitropyridine;

 6-chloro-2-(4,-cyanoanilino)-3-nitropyridine;

 2-(4,-methylanilino)-3-nitropyridine;

 2-(4,-cyanoanilino)-3-nitropyridine;

 6-Chloro-2-(2,,4,, 6,-tridecylanilino)-3-nitropyridine. The compounds of formula I according to the invention can be prepared by the following reaction scheme:

W = CI, Br, IY = NH ₂ or OH X = halogen or hydrogen

 X = halogen or hydrogen Y = H O NR'

 Z = C, N Z = C, N

Wherein R ₂ , R ₃ and R ₄ are as defined above for formula I.

 The halogenated benzene or halopyridine substituted by the formula II is reacted with a substituted aniline or a substituted phenolic compound of the formula III under the action of a base to form a compound of the formula I.

More specifically, in the presence of potassium t-butoxide, sodium hydride, triethylamine, pyridine, N,N-diguanamine pyridine, or potassium carbonate, a halogenated benzene with a nitro group or 3⁄4 pyridine (formula II) with substituted aniline or substituted phenolic compound (formula III) In DMF, acetonitrile, THF or DMSO solvent, room temperature or 130. Below C, 5 minutes to 24 hours, the reactant Π / Ι Π feed molar ratio is 1: 1. 1 - 1: 2.

 The coupling reaction can also be carried out under microwave conditions, and the ratio of the base to the reactants is the same as described above, and the reaction is carried out at 150 to 180 ° C for 10 to 30 minutes using DMF or DMS0 as a solvent.

 The compounds of the invention exhibit potent inhibitory activity in a variety of cancer cell tests. As described below, the compounds showed positive inhibition with the positive control drug [Homoharr ingtonine] in lung cancer cells (A549), breast cancer cells (MCF-7) and nasopharyngeal carcinoma cells (KB). Etopos ide (VP-16) is equivalent or better inhibitory activity. Of particular note is that some of these compounds also show potent inhibitory activity against resistant KB-VIN cells. Therefore, intensive research on the compounds of the present invention is expected to develop new anticancer drugs.

 The compound of the present invention can be used either in its own form or in the form of a pharmaceutically acceptable salt or solvate thereof. Pharmaceutically acceptable salts of the compounds of formula I include the conventional salts formed with pharmaceutically acceptable inorganic or organic acids, or inorganic or organic bases. Examples of suitable acid addition salts include with 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, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid a salt formed of benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like. Examples of suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. a salt formed by a diamine, N-methylglucamine, and procaine. When reference is made herein to a compound of the invention, a compound of formula I, and pharmaceutically acceptable salts or solvates thereof, are included.

In accordance with the present invention, the compounds of formula I of the present invention may be combined with conventional pharmaceutical carriers or excipients to form a pharmaceutical composition. The pharmaceutical composition can be administered orally or parenterally. The pharmaceutical compositions of the present invention can be prepared into a variety of dosage forms according to conventional methods in the art, including However, it is not limited to tablets, gelatine, solutions, suspensions, granules or injections, and the like, and is administered orally or parenterally.

 It should also be noted that the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician. The preferred dosage is between 0.01 and 100 mg/kg body weight per day. detailed description

 The following examples are intended to further illustrate the invention, but are not intended to limit the invention thereto. Example 1: hydroxyphenyl)-5-chloro-2,4-dinitroaniline (A1) 1,5-dichloro-2,4-dinitrobenzene (237 mg 1.0 mmol) and m-aminophenol (230 mg, 2.11 awake) Dissolved in DMF (0.5 mL), placed directly in an oil bath of 1201:, stirred for 2 minutes, the reaction solution turned red, then cooled to room temperature, water was added, and the pH was adjusted to 3 with dilute HC1. The solid was filtered, and the title compound wasjjjjjjj NMR NMR (DMS0) δ ppm 6.77 ( 1H, s, ArH-2' ), 6.78 ( 1H, d, J = 8.4 Hz, ArH-4' ), 6.81 ( 1H, t, J = 8.4 Hz, ArH-5 ' ),

7.04 ( 1H, s, ArH-6 ), 7.31 ( 1H, d, J = 8.4 Hz, ArH-6' ),

8.90 ( 1H, s, ArH-3 ), 9.83 ( 1H, s, OH ), 10.04 ( 1H, s, NH ) ₀ Example 2: 5-chloro-^ ( 4,-cyanophenyl) -2, 4-Dinitroaniline (A2) 2,4-dichloro-1,5-dinitrobenzene (1.2 g, 5 mmol) and p-nitrile aniline (0.59 g, 5 mmol) dissolved in N,N-dioxin Base amide (DMF, 10 mL). Put in water Potassium tert-butoxide (1.4 g, 12.5 leg ol) was added portionwise in a bath and then stirred at room temperature for 45 minutes. The reaction solution was poured into ice water, and the pH was adjusted to neutral with dilute HC1. The precipitated solid was filtered, evaporated, evaporated,jjjjjjjj ^ NMI CDCIJ δ ppm, 7.41 (1H, s, ArH-6), 7.57 (2H, d, J = 8.8 Hz, ArH-3', 5, ), 7.91 (2H, d, J = 8.8 Hz, ArH- 2', 6, ), 8.90 (1H, s, ArH-3), 10.07 (1H, s, NH). Example 3: 5-Chloro-2,4-dinitro-N-(4,-methoxyphenyl)-aniline (A3) 2,4-Dichloro-1,5-dinitrobenzene ( 0.5 g, 2.11 mmol ) and p-nonylaniline (0.26 g, 2.11 mmol) dissolved in DMSO (5 mL), K ₂ C0 ₃ (0.58 g, 4.22 mmol) and a catalytic amount of metal Cu, under nitrogen , 115 X: Stir for 2 hours. It was poured into ice water, and the solid was filtered, washed with EtOAc EtOAcjjjjjjj ^NMR (CDC1 ₃ ) δ ppm 3.88 (3H, s, 0CH ₃ ), 7.02 (1H, s, ArH-6), 7.03 (2H, d, J = 8.96 Hz, ArH-3', 5, ), 7.21 (2H, d, J = 8.96 Hz, ArH-2', 6, ), 9.07 (1H, s, ArH-3), 9.73 (1H, s, NH). Example 4: 5-Chloro-2,4-dinitro-indole 4,-nonylphenyl)-aniline (A4) 1, 5-dichloro-2,4-dinitrobenzene (370^, 1 Methyl aniline (128 mg, 1.2 mmol) and potassium t-butoxide (224 mg, 2 mmol) were stirred in DMF (3 mL) 40 min. The mixture was poured into water, EtOAc (EtOAc m. . 'HNMR (CDCls) δ ppm 52.43 (3H, s, CH ₃ ), 7.12 (1H, s, ArH-6), 7.17 (2H, d, J - 8.4 Hz, ArH-3', 5, ), 7.32 ( 2H, d, J = 8.4 Hz, ArH-2', 6, ), 9.08 ( 1H, s, ArH-3) , 9.79 (1H, s, NH) Example 5: 5-Chloro-N-(4,-methoxyphenyl)-1,2,4-benzenetriamine (A5) Compound A4 (128 mg, 0.4 mmol) Dissolve in 2.5 mL of THF and add a solution of nickel chloride hexahydrate ( 28.3 mg, 0.12 mmol) in methanol (1 mL) to THF. The mixture was cooled with a water bath, stirred, and sodium borohydride (75.6 mg, 2 mmol). The reaction mixture was poured into ice water, and the pH was adjusted to about 5, and the mixture was stirred at room temperature, and the mixture was evaporated to dryness. . ^l NMR (CDC1 ₃ ) δ ppm 3.78 (3H, s, 0CH ₃ ) 5.81 (1H, s, ArH-3), 6.18 (1H, s, ArH-6), 6.71 (2H, d, J = 8.8 Hz, ArH-3', 5, ), 6.77 (2H, d, J = 8.8 Hz, ArH-2', 6, ). Example 6: 5-Chloro-N-(4,-nitrophenyl)-2,4-dinitroaniline (A6) 1, 5-dichloro- 2,4-dinitrobenzene (237 mg, l mmol), p-Nitroaniline (166 mg, 1.2 mmol) and potassium t-butoxide (236 mg, 2.1 mmol) in DMF (3 mL). Work-up with A5 gave the title compound 280 mg, m. ^ NMR (DMS0) δ ppm 7.55 (1H, s, ArH-6), 7.60 (2H, d, J = 9.0 Hz, ArH-2', 6, ), 8.29 (2H, d, J = 9.0 Hz, ArH -3', 5, ), 8.90 (1H, s, ArH-3), 10.19 (1H, s, NH). Example 7: 5-Chloro-N-(4,-cyanophenyl)-2-nitroaniline (A7)

2, 4-Dichloronitrobenzene (576 mg, 3 mmol), p-cyanoaniline (425 mg, 3.6 mmol) and potassium t-butoxide (672 mg, 6 mmol) in 4 mL DMF, stirred at room temperature for 20 h. The workup was followed by A5 to give the title compound as a red-yellow solid, 583 mg, yield 71%. Melting point 123Ό; ^ NMR ( DMS0 ) δ ppm 7.17 (1H, d, J = 9.2 Hz, ArH-4), 7.40 (2H, d, J = 8.8 Hz, ArH-3', 5, ), 7.45 (1H, s, ArH-6), 7, 79 ( 2H, d, J = 8.8 Hz, ArH-2', 6, ), 8.14 (1H, d, J = 9.2 Hz, ArH-3), 9.48 (1H, s, NH). Example 8: 5-Chloro-N-(4,-cyanophenyl)-3-nitroaniline (A8)

 3, 5-Dichloronitrobenzene (192 mg, 1 mmol) and p-aniline aniline (118 mg, 1 mmol) and potassium t-butoxide (224 mg, 2 mmol) in DMF (3 mL). The title compound was obtained as a red-yellow solid, 223 mg, yield 82%.

NMR (CDC1 ₃ ) δ ppm 6.25 (1H, s, ArH-6), 6.78 (2H, d, J = 8.8 Hz, ArH-3', 5, ), 7.55 (2H, d, J = 8.8 Hz, ArH -2', 6, ), 7.83 (1H, s, ArH-2), 8.02 (1H, s, ArH-4) ₀ Example 9: 4,-cyanophenoxy-5-chloro-2, 4 -dinitrophenyl ether (A9) 1, 5-dichloro-2,4-dinitrobenzene (237 mg, 1 mmol), p-cyanobenzoquinone (143 mg, 1.2 mmol) and potassium carbonate (276 mg, 2 mmol) Microwave reaction at 192 V for 10 minutes in DMS0 (2 mL). The reaction mixture was poured into water, stirred for 10 minutes, and extracted with diethyl ether. The organic phase was washed sequentially with 10% aqueous sodium hydroxide, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crystallite crystallite NMR (DMS0) δ 5.98 (1H, s, ArH-6), 7.12 (2H, d, J = 8.8 Hz, ArH-2', 6, ), 7.80 (2H, d, J = 8.8 Hz, ArH-3 ' , 5' ), 8.73 (1H, s, ArH-3). Example 10: (4,-Bromo-2,6-dioxaphenoxy)-5-chloro-2,4-dinitrophenyl ether (A10)

Dissolve 1,5-dichloro-2,4-dinitrobenzene (250 mg, 1.05 mmol) and 2,6-dimethyl-4-bromophenol (250 mg, 1.2 mmol) in DMF (3 mL) Add potassium carbonate (180 mg, 1.3 mmol) and react with microwave for 10 minutes. The reaction solution After pouring into water, the solid was filtered, washed with EtOAc EtOAcjjjjjjj

!H NMR (CDC) 6ppm2.15 (6H, s, 2 χ CH ₃ ) , 5.85 (1Η, s, ArH-6) , 7.31 (2Η, s, ArH - 3, , 5, ), 8, 79 ( 1H, s, ArH-3) Example 11: (4,-Cyano-2,6,-xylyleneoxy)-5-chloro-2,4-dinitrophenyl ether (All)

1, 5-dichloro-2,4-dinitrobenzene (71 mg, 0, 3 mmol) and 2,6-dimethyl-4-cyanophenol (59 mg, 0.4 mmol), anhydrous potassium carbonate ( 83 mg, 0.6 mmol) In 3 mL DMF, the temperature was 180 and the microwave was reacted for 10 minutes. Work-up as before, the title compound was obtained as a yellow solid, 73 mg, yield 70%. 'HNMR (CDC1 ₃ ) δ ppm 2.17 (6H, s, 2xCH3), 5.88 (1H, s, ArH-6), 7.45 (2H, s, ArH-3', 5, ), 8.79 (1H, s, ArH -3) „ Example 12: 5-(4,-Cyanophenoxy)-2-nitrophenyl ether (A12)

5-Chloro-2-nitroaniline (172.5 mg, 1 mmol) and p-cyanophenol (143 mg, 1.2 mmol), mp. ^J H NMR (CDCI3) δ ppm 6.16 (2H, s, NH ₂ ), 6.33 (1H, d, J = 2.4 Hz, ArH-6), 6.36 (2H, dd, Jl - 9.2 & 2· 4 Hz, ArH -4) , 7.15 (2H, d, J = 8.8 Hz, ArH-2', 6, ), 7.71 (2H, d, J = 8.8 Hz, ArH-3', 5, ), 8.17 (1H, d, J = 9.2 Hz, ArH-3). Example 13: 4-(4,-Cyanophenoxy)nitrophenyl ether (A13)

The method is the same as in Example 12. 158 mg (1 mmol) of p-chloronitrobenzene and 143 mg (1.2 mmol) of p-cyanophenol were obtained to give the title compound as a pale yellow solid, 130 mg, yield 54%. NMR (CDC1 ₃ ) δ ppm 7.11 (2H, d, J = 9.0 Hz, ArH-2', 6, ), 7.15 (2H, d, J = 9.2 Hz, ArH-3, 5), 7.72 (2H, d, J = 9.0 Hz, ArH-3, , 5, ), 8.28 (2H, d, J = 9.2 Hz, ArH-2, 6). Example 14: 2-(4,-Cyanophenoxy)nitrobenzene (A14)

The method is the same as in Example 12. The title compound was obtained as a white solid (yield: 54%, mp. ^ NMR (CDC1 ₃ ) δ ppm 7.04 (2H, d, J = 8.8 Hz, ArH-2', 6, ), 7.20 (1H, d, J = 8.4 Hz, ArH-3), 7.40 (1H, t, J = 8.4 Hz, ArH-4), 7.65 (3H, m, ArH-5, ArH-3', 5, ), 8.04 (1H, d, J = 8.4 Hz, ArH-6). Example 15: 6-Chloro-2-(N-anilino)-3-nitropyridine (B1)

2,6-Dichloro-3-nitropyridine (553.3 mg, 2.867 mmol), aniline (266.6 mg, 286.7 mg) and NaHC0 ₃ (240.8 mg, 2, 867 mmol) in absolute ethanol (15 mL) at room temperature After stirring for 40 h, a large amount of red solid precipitated. 1N of HCl was added to the reaction solution to adjust the pH to about 3. The solid was filtered, washed with EtOAc EtOAc (EtOAc) TLC (ethyl acetate / petroleum ether) showed a single point HNMR (CDC13) δ ppm 6.81 (1H d, J = 8.4 Hz, H-5), 7.21 (1H, t, J = 8.0 Hz, H-4'), 7.42 (2H, t, J = 8.0 Hz, H-3', 5, ), 7.66 (2H, d, J = 8.0 Hz, H-2, ,6, ) , 8.47 (1H, d, J = 8.4 Hz , H-4), 10.28 (1H, bs, NH). Example 16: 6-Chloro-2-(4,-methoxyanilino)-3-nitropyridine (B2) 2,6-dichloro-3-nitropyridine (193 mg, 1 匪ol), p-anisidine (123 mg, 1 mmol) and _{NaHC0 3 (84 mg, 1 mmol} ) in absolute ethanol (10 mL) are stirred at room temperature for 4 days to give the title compound as a red solid, 212 mg, yield rate: 75.7% ₀ Ή NMR (CDC1 ₃ ) δ 3.84 (3H, s, 0CH ₃ ) , 6.75 (1H, d, J = 8.8 Hz, H-5) , 6.95 (2H, d, J = 8.8 Hz, H-3 ' ,5, ), 7.53 (2H, d, J = 8.8 Hz, H-2, ,6, ), 8. 5 (1H, d, J = 8.8 Hz, H-4) , 10.17 (1H, bs, NH). Example 17: 6-Chloro-2-(4,-cyanoanilino)-3-nitropyridine (B3) 2,6-dichloro-3-nitropyridine (193 mg, 1 sa ol), pair Cyanoaniline (354 mg, 3 mmol) and Na ₂ C0 ₃ (168 mg, 2 mmol) were refluxed in t-butanol (10 mL) under N ₂ for 2 days. TLC (ethyl acetate/petroleum ether) showed that there was still a starting material. The crude product was isolated with EtOAc (EtOAc): _{^{! H NMR (CDC1 3) δ}} ppm 6.96 (1H, d, J = 8.4 Hz, H-5), 7.70 (2H, d, J = 8.8 Hz, H-3 ', 5,), 7.86 (2H, d , J = 8.8 Hz, H-2', 6,), 8.53 (1H, d, J = 8.4 Hz, H-4), 10.47 (1H, bs, NH). Example 18: 6-Chloro-2-(2,4,6,3-trimethylanilino)-3-nitropyridine (B4)

2,6-Dichloro-3-nitropyridine (193 mg, 1 mmol), 2,4,6-trimethylaniline (0.5 mL, 3.56 mmol) and K ₂ C0 ₃ (276 mg, 2 mmol) In i^uOH (4 mL), the reaction was carried out under microwave conditions for 30 min, and the reaction mixture was dark brown. TLC (ethyl acetate/petroleum ether) showed new point generation. 1 N of HCl was added to the reaction solution to adjust the pH to 4-5 to precipitate a yellow solid. Filtered, washed with water to give the crude product, after preparation chromatography to give title compound as a red solid, 123 mg, 42.2% yield, m.p. _{123-124.7 ^ HNMR (CDC1 3) δ} ppm 2.07 (6H, s, 2 x CH ₃ -2, , 6, ) , 2.27 (3H, s, CH3-4' ), 6.85 (1H, d, J = 8.4 Hz, H-5), 6.95 (2H, s, H-3' , H- 5'), 8.50 (1H, d, J = 8.4 Hz, H-4), 9.75 (1H, brs, NH). Example 19: 2-(4,-Methylanilino)-3-nitropyridine (B5)2-bromo-3-nitropyridine (101.5 mg, 0.5 mmol), p-methylaniline (53.5 mg, 0.5 Methyl) and K ₂ C0 ₃ (69 mg, 0.5 mmol) in DMSO (1.5 mL) with N2 protection and external bath. The reaction was carried out for 4 h under C conditions. The reaction was monitored by TLC (ethyl acetate / petroleum ether). The reaction solution was poured into distilled water, and the precipitate was filtered. The resulting solid was dissolved with acetone, the product was isolated TLC plate 47 mg, red solid, yield 40.0%, ^{mp: 176-177 ° (: J H NMR} (CDC1 3) δ ppm 10.04 (1H, br s, NH);. 8.46-8.53 (2H, m, H-4, H-6); 7.49 (2H, d, J = 8.4 Hz, H-2,, H-6'); 7.21 (2H, d, J = 8.4 Hz, H-3', H-5,); 6.80 (1H, dd, J = 8.0 Hz, 4.0 Hz, H-5); 2, 36 (3H, s, CH ₃ ). Example 20: 2- ( 4 , -cyanoanilino)-3-nitropyridine (B6)2-bromo-3-nitropyridine (203 mg, 1 mmol), 4-cyanoaniline (354 mg, 3 mmol) and potassium tert-butoxide (112 mg, 1 mmol) in t-BuOH (4 ml), reacted for 10 min at 110 ° C under microwave conditions. The reaction was monitored by TLC (ethyl acetate / petroleum ether). dilute HC1 pH was adjusted to acidic, and the precipitated solid was chromatographed crude product was purified by column to give a yellow solid 18 mg, ^{yield:. 7.5%:. H NMR} (CDC1 3) δρρπι 10.37 (1H, br s, NH), 8.58 ( 2H, m, H-4, H-6), 7.90 (2H, d, J = 8.4 Hz, H-3', H-5,), 7.67 (2H, d, J = 8.8 Hz, H-2, , H-6'), 7.00 (1H, dd, J = 8.4 Hz, 4.4 Hz, H-5) Example 21. Inhibition of cancer cell growth assay

The human cancer cells (A549, MCF-7, KB, KB-VIN, etc.) used were placed in a single medium PMI-16 ⁴⁰ containing 10% (v/v) calf serum), and the cells were cultured in a microscope. The morphological characteristics and growth conditions in the liquid were examined. The cells were placed in a 2.5 cm ² Petri dish, 37. C, cultured in 5% CO ₂ humidified air. Cell line sticker Wall growth. The process of sample preparation and dilution and inoculation into the cell fluid should be aseptic. Test samples are usually dissolved in DMS0 and stored at -70 °C. In a 96-well culture plate, each well was placed at different concentrations of the test sample and approximately 5,000-20,000 cells were placed for 72 hours. ED _{5 that} inhibits cancer cell growth. The value is determined by the SRB (sulforhodamine B) method. The anticancer drugs homoharringtonine and VP16 served as positive controls.

A549: lung cancer cells; MCF-7: breast cancer cells; KB: nasopharyngeal carcinoma cells; KB-VIN: drug-resistant nasopharyngeal carcinoma cells. ED ₅ . The value is an effective dose that inhibits the growth of half of cancer cells, indicating anticancer activity. The test results of partial anticancer activity of the compounds of the present invention are shown in Table 1. Compounds of formula I and their anticancer activity data

 EDso g/mL

Compound Ri R ₂ R ₃ XY A549 MCF7 KB KBVIN

A1 N0 ₂ H N0 ₂ fl-OH CI NH 5. 41 1. 22 0. 76 0. 83

A2 N0 ₂ H N0 ₂ ^-CN CI NH 1. 13 0. 38 0. 77 0. 098

A3 N0 ₂ H NO2 H)CH ₃ CI NH 3. 45 2. 37 1. 08 1. 67

A4 N0 ₂ H NO2 ^CH ₃ CI NH 9. 57 3. 94 1. 82 1. 92

A5 NH ₂ H NH ₂ p-ocn ₃ CI NH 7. 09 7. 69

A6 Ν0 ₂ H N0 ₂ CI NH 0. 87 0. 71 6. 76 5. 61

A7 Ν0 ₂ HH CI NH NA NA NA NA

A8 Η N0 ₂ H p-CN CI NH 8. 36 8. 35 9. 21 7. 33

A9 Ν0 ₂ H N0 ₂ CI 0 0. 98 0. 76 0. 59 0. 49

B1 Ν0 ₂ HHH CI NH 5. 96 3. 46 5. 19 4. 41

B2 Ν0 ₂ HH p-OC , CI NH 3. 78 3. 24 2. 01 0. 67

B3 Ν0 ₂ HH ^-CN CI NH 1. 68 3. 25 0. 75 0. 58

B4 Ν0 ₂ HH 0, p- t T i - CI NH 1. 45 2. 22 3. 61 0. 74

Homoharringtonine 0. 014 0. 021 0. 002 0. 28 Etoposide, VP-16 5. 88 NA 8. 33 NA Description: A549: lung cancer cells; MCF-7: breast cancer cells; KB: nasopharyngeal carcinoma cells; B-VIN: drug-resistant nasopharyngeal carcinoma cells. An effective dose (ED ₅ ) which inhibits the growth of half of cancer cells indicates anticancer activity. NA: no inhibitory activity

Claims

Rights request 1. An N-substituted arene aniline or polysubstituted diaryl ether compound of the formula I or a pharmaceutically acceptable salt thereof:

 among them,  Z is CH or N;  Is 3⁄4 or hydrogen;  Y is -0- or -NR,-; R, R ₂ , R ₃ are each independently H, halogen, -N0 ₂ , -CN, -NH ₂ , d- ₆ alkyl, d- ₆ alkoxy, 0H, -0CH ₂ 0-, -CF ₃ , -C00H, - S0 ₃ H, - C0NH ₂ , -C0NHR' or - C00R,; Alternatively, and R ₂ or R ₂ and R ₃ may together form -CHCH ₂ 0-; Is -CN, -N0 ₂ , -CH=CH ₂ , -C≡CH, d- ₆ alkyl, d- ₆ alkoxy, -CF ₃ , halogen, -NH ₂ , -OH , - C00H, - S0 ₃ H, -C≡CR" or - CH=CHR" , and R ₄ is mono- (o-, m-, para-) or polysubstituted; R is H, a hydrocarbyl-substituted C ₆ -i. An aromatic ring, a five- or six-membered heteroaryl ring, an aliphatic hydrocarbon group optionally containing a double bond or a triple bond, or a fatty acyl group optionally containing a double bond or a triple bond; R" is a d- ₄ hydrocarbon group optionally containing a double bond or a triple bond;  The condition is that the following compounds are not included:  5-Chloro-2,4-dinitro(4,-nonylphenyl)-aniline 5-chloro-2,4-dinitro-N-(4,-decyloxyphenyl)-aniline; 6-chloro-2-(N-anilino)-3-nitropyridine 2. The compound of claim 1 wherein R ₄ is para-substituted 3. The compound of claim 1 wherein Y is -NH-. 4. The compound of claim 1 wherein 1^ and R ₃ are each independently halogen, -N0 ₂ , -CN> -NH ₂ , -CH ₃ , - OCH 0H, - 0CH ₂ 0-, - CF ₃ , -C00H, - S0 ₃ H, -C0NH ₂ ; 11 ₂ is H. The compound of claim 1 wherein Is halogen, -N0 ₂ , -CN, -NH ₂ , -CH ₃ , - 0CH ₃ , 0H, - 0CH ₂ 0-,

-C00H, -S0 ₃ H, -C0NH ₂ ; R ₂ and R ₃ are H. 6. The compound of claim 1 wherein 1^ and 1 ₃ are each independently halogen, -N0 ₂ , -CN, -NH ₂ , -CH ₃ , -0CH ₃ , 0H, - 0CH ₂ 0-, - CF ₃ , - C00H, - S0 ₃ H, -C0NH ₂ ; R ₂ is H. 7. The compound of claim 1 selected from the group consisting of:  N-(^hydroxyphenyl)-5-chloro-2,4-dinitroaniline;  5-chloro(4,-cyanophenyl)-2,4-dinitroaniline;  5-chloro-2,4-dinitro-N-(4,-methoxyphenyl)-aniline;  5-chloro-N-(4,-nitrophenyl)-2,4-dinitroaniline; 5-chloro-N-(4,-nonylphenyl)-2-nitroaniline; 5-chloro-N-(4,-cyanophenyl)-3-nitroaniline;  4,-cyanophenoxy-5-chloro-2,4-dinitrophenyl ether;  (4,-bromo-2,6-dioxaphenoxy)-5-chloro-2,4-dinitrophenyl ether;  (4,-cyano-2,6-xylyleneoxy)-5-chloro-2,4-dinitrophenyl ether; 5-(4,-nonylphenoxy)-2-nitrophenyl ether;  4-(4,-cyanophenoxy)nitrophenyl ether;  2-(4,-cyanophenoxy)nitrobenzene;  6-chloro-2-(4,-methoxyanilino)-3-nitropyridine;  6-chloro-2-(4,-cyanoanilino)-3-nitropyridine;  2-( 4,-methylanilino)-3-nitropyridine;  2-( 4,-cyanoanilino)-3-nitropyridine;  6-Chloro-2-(2,,4,, 6,-tridecylanilino)-3-nitropyridine. 8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. 9. Process for the preparation of a compound according to any one of claims 1 to 7:

W = CI, Br, IY = NH ₂ or OH X = halogen or hydrogen  X = halogen or hydrogen Υ = ΝΗ, Ο, N '  Z = C, N Z = C, Ν Wherein Ri, R ₂ , R ₃ and R ₄ are as defined above for formula I, The halogenated benzene or pyridinyl substituted by the formula II is reacted with a substituted aniline or substituted phenolic compound of formula III under the action of a base to form a compound of formula I. 10. Use of a compound according to any one of claims 1 to 7 for the preparation of an anti-tumor drug, which does not comprise the exclusion conditions described in claim 1.