WO2011095027A1

WO2011095027A1 - Pyridyl cyanoguanidine derivatives

Info

Publication number: WO2011095027A1
Application number: PCT/CN2010/078868
Authority: WO
Inventors: 张和胜; 陈鑫; 陈英伟; 从俊杰; 李幸稳
Original assignee: 天津和美生物技术有限公司; 天津米雪儿科技发展有限公司
Priority date: 2010-02-04
Filing date: 2010-11-18
Publication date: 2011-08-11

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof, and use for treating cancer thereof are disclosed, wherein, the definitions of X, Y, R₁, R₂ and n are described in description.

Description

Pyridyl cyanoguanidine derivatives

This application relates to terpenoids and their use, and in particular to pyridyl-containing cyanoguanidine derivatives and their use. Background technique

It has been reported in the prior art that pyridyl cyanoguanidine compounds have antitumor activity. Such as US patents

A series of pyridylguanidine compounds having activity against cancer cells is disclosed in U.S. Patent 5,563,160. However, this patent document only gives experimental data for several compounds in the formula.

The inventors of the present application conducted studies on pyridyl cyanoguanidine compounds and found that certain specific structures of pyridyl cyanoguanidine compounds have unexpected biological activities. Thus, the present application is filed. Summary of invention

In one aspect, the present invention is a compound of the following formula (I) or a pharmaceutically acceptable salt thereof,

Where: X is N or CH;

n is an integer from 3 to 10;

Y is -0-, -S-, -N; -OC(O)- or -NR ₃ C(O)-, wherein R ₃ is H or C alkyl;

R! is a decyloxy group substituted by one or more F or C1, preferably a decyloxy group substituted by at least two F or C1 at the 2- or 3-position of the phenyl ring;

R ₂ is H, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, decanoylamino, aminosulfonyl, halogen, any alkyl substituted by halogen or optionally substituted by halogen Alkoxy group.

In another aspect, the present application is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a further aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.

In yet another aspect, the present application relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, including, preferably, a compound of formula (II) in the presence of a base

Reacting with a compound of formula (III)

(πι),

Wherein R is a C _1-6 alkyl or aryl group or an aryl group substituted by a halogen, a C _1-6 alkyl group, X, Y, η, and

R _{2 is} defined as before, and

Optionally, the resulting compound of formula (I) is formulated into a pharmaceutically acceptable salt thereof.

In another aspect, the present application relates to a method of inhibiting tumor cell growth comprising administering an inhibitory effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, to said tumor cell.

In another aspect, the present application is also directed to a method of treating a tumor in an individual comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

The inventors have found through research that, for the compound of the formula (I), if the terminal benzene ring has at least one decyloxy group substituted by at least one F or C1, it is preferably at the 2- or 3-position thereof, particularly At the 2-position, these compounds have unexpectedly high cell viability compared to other substituted compounds. In addition, the compounds of the formula of the present application have improved hydrophilicity and are advantageous in forming corresponding formulations. Detailed description of the invention

In the above definition of the compound of the formula (I) and the embodiments described below, the terms used herein have the following meanings:

The term "d- ₆ pit group" means a straight or branched saturated hydrocarbon group having one to six carbon atoms, preferably a C _M alkyl group having one to four carbon atoms. Examples of the Ci- ₆ alkyl group specifically include But not limited to: mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, 1-mercaptopropyl, tert-butyl, pentyl, isopentyl, 1,2-dimercaptopropyl Base, 2,2-dimercaptopropyl, hexyl, isohexyl, and the like.

The term "d- ₆ alkoxy" means a straight or branched saturated alkoxy group having one to six carbon atoms, preferably a CM alkoxy group having one to four carbon atoms. Specifically, but not limited to: decyloxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 1-mercaptopropoxy, tert-butoxy, pentyloxy, iso Pentyloxy, 1,2-dimercaptopropoxy, 2,2-dimercaptopropoxy, hexyloxy, isohexyloxy and the like.

The term "aryl" means a monocyclic or fused aromatic ring containing from 6 to 20 carbon atoms. Non-limiting examples include benzene Base, naphthyl.

The term "halogen" means fluoro, chloro, bromo or iodo.

As used herein, "pharmaceutical composition" refers to a formulation of a compound of the present application and a medium which is generally accepted in the art for delivery of a biologically active compound to a mammal such as a human. Such media include all pharmaceutically acceptable carriers.

As used herein, "pharmaceutically acceptable carrier," includes, but is not limited to, any adjuvant, excipient, or helper that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or animals. Agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, disintegrating agents, solvents or Emulsifiers and the like have various forms of carriers which do not have side effects in constituting the pharmaceutical composition.

As used herein, "inhibitory effective amount" and "therapeutically effective amount" are used interchangeably, meaning that the compound of the present application is sufficient to effectively inhibit tumor cells or treatment when administered to a human, preferably a mammal, more preferably to a human. The amount of tumor. The amount of the compound of the present application which constitutes an "inhibitory effective amount, or a therapeutically effective amount" will vary depending on the state of the selected compound or the subject to be administered, but those skilled in the art will, based on their own knowledge and the disclosure of the present application. An effective amount of a compound of the present application can be determined according to common knowledge in the art.

The term "treating" means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing a disease or disease state from occurring in a mammal, particularly when such a mammal is susceptible to the disease state, but has not been diagnosed as having the disease state;

(ii) inhibiting the disease or disease state, ie, curbing its development;

(iii) alleviating the disease or condition, even if the disease or condition resolves.

"Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base additions"

3⁄4- ".

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids. The inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and the organic acid is, for example but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, Aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexyl Alkyl sulfamic acid, dodecyl sulphate, ethane-1,2-disulfonic acid, ethane sulfonic acid, 2-hydroxyethane sulfonic acid, citric acid, fumaric acid, mucic acid, gentisic acid, Glucose, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactulic acid, Lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, decanesulfonic acid, naphthalene-1,5 -disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-carotonic acid, nicotinic acid, oleic acid, orotic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid , salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like.

"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In the present application, salts derived from inorganic bases are preferred, including but not limited to sodium, potassium, A compound of the invention I) or a pharmaceutically acceptable salt thereof

(I)

Where: X is N or CH;

n is an integer from 3 to 10;

Y is -0-, -S-, -NR ₃ -, -OC(O)- or -NR ₃ C(O)-, wherein R ₃ is H or C _1-6 ;

Ri is a decyloxy group substituted by one or more F or C1, preferably a decyloxy group substituted by at least two F or C1 at the 2- or 3-position of the phenyl ring;

R ₂ is H, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, decanoylamino, aminosulfonyl, halogen, any d- ₆ alkyl substituted by halogen or optionally Halogen substituted d- ₆ alkoxy.

In some preferred embodiments of the compounds of formula (I) in relation to various aspects of the present application, are methoxy groups substituted with at least two F or C1, preferably a decyloxy group substituted by two F, most preferably It is a trifluoromethoxy group.

In some preferred embodiments, the 2-position of the phenyl ring.

In other preferred embodiments, X is N, more preferably, N is in the para position of the thiol group.

In other embodiments, Y is _{-0-, -S -, -NR 3 -} , -OC (O) - or -NR ₃ C (O) -, wherein R ₃ is H or Yue group; preferably, Y is -O-, -NR ₃ -, -OC(O)- or -NR ₃ C(O)-, wherein R ₃ is H or a fluorenyl group; more preferably, Y is -0-, -NH- or -OC(O)-; Most preferably, Y is -0-.

In other embodiments, n is an integer from 4-8.

In still other embodiments, is 11, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, formylamino, halogen, any alkyl substituted by halogen or any d_ substituted by halogen ₆ alkoxy; preferably, an alkyl group, a nitro group, a halogen or an alkyl group optionally substituted by halogen; more preferably, 11, C _M alkyl group, nitro group, halogen; most preferably, 11 , C _M alkyl, F, C1 or Br. In some aspects of the compounds of formula (I) in the various aspects of the invention described above,

X is N;

n is an integer of 4-8;

Y is -O-, -S -, -NR ₃ -, -OC(O)- or -NR ₃ C(O)-, wherein R ₃ is H or C _1-6 alkyl;

i is a decyloxy group substituted by at least two F, preferably a methoxy group substituted by at least two F at the 2-position of the phenyl ring;

It is 11, C alkyl, nitro, halogen or any C ₆ alkyl substituted by halogen. In other aspects of the compounds of formula (I) in the above various aspects of the present application, X is N;

n is an integer of 4-8;

γ is -0-, -NH- or -OC(O)-;

i is a methoxy group substituted by at least two F, preferably a decyloxy group substituted by at least two F at the 2-position of the phenyl ring;

It is 11, d- ₄ alkyl, nitro, halogen.

In other aspects of the compounds of formula (I) in the various aspects of the invention described above,

X is N;

n is an integer of 4-8;

Y is -0-, -NH- or -OC(O)-;

Ri is OCF ₃ or OCHF _2, preferably located at the 2-position of the phenyl ring OCF ₃ or OCHF _{_2;} 1 ₂ to 11, C _1-4 alkyl, F, C1 or Br.

X is N;

n is an integer of 4-8;

Y is -O-;

In another embodiment, the application provides the following compound of formula (I) or a pharmaceutically acceptable salt thereof:

N- cyano -N, - (6- (2- Yue-difluoro-5-chlorophenoxy) hexyl) -N ,, - (4- pyrazol ^a guanidine;

N-cyano-N,-(6-(o-trifluoromethoxyphenoxy)hexyl)-! ^,,- -pyridyl ¹ ^)胍;

N-cyano-N,-(6-(m-trifluoromethoxyphenoxy)hexyl)^,-(pyridin ¹ ) hydrazine;

N-cyano-N,-(6-(p-trifluoromethoxyphenoxy)hexyl)^,-(pyridin ¹ ) hydrazine;

N-cyano-N,-(5-(o-trifluoromethoxyphenoxy)pentyl)-N,,-(4-pyridyl)anthracene;

N-cyano-N,-(8-(o-trifluoromethoxyphenoxy)octyl)-N,,-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-trifluorodecyloxy-4-bromophenoxy)hexyl)-N"-(4-pyridyl)indole;

N- cyano -N, - (6- (o-trifluoromethyl phenylamino Yue yloxy) hexyl) -N ,, - (4- pyrazol ^ ¹⁾ guanidine;

N-cyano-N,-(6-(o-trifluorodecyloxybenzoyloxy)hexyl)-N,,-(4-pyridyl)anthracene;

N-cyano-N,-( ^6- ( ² -difluoromethoxy) ^-5 -tert-butylphenoxy)hexyl)-1^"-( ⁴ -pyridinium);

N-cyano-N,-(6-(o-trifluoromethoxyphenoxy)hexyl)^,-(pyridin ¹ ) hydrazine;

N-cyano-N,-(6-(2-difluorodecyloxy-4-chlorophenoxy)hexyl)-N,,-(4-pyridyl)indole;

N-cyano-N,-(6-(2-trifluoromethoxy-4-chlorophenoxy)hexyl)-N"-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-trifluoromethoxy-4-nitrophenoxy)hexyl)-N"-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-trifluoromethoxy-4-fluorophenoxy)hexyl)-N"-(4-pyridyl)indole;

N-cyano-N,-(6-(5-methyl-2-difluoromethoxyphenoxy)hexyl)-N"-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-difluoromethoxyphenoxy)hexyl)-indole, -(4)胍; N-cyano-N,-(6-(2-difluoromethoxy-5-fluorophenoxy)hexyl)-N"-(4-pyridyl)anthracene. The present application also provides a pharmaceutical composition comprising A therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is for use in treating cancer.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present application can inhibit mammalian, preferably human, tumor cells. Such tumors include, but are not limited to, pancreatic cancer, acute lymphocytic leukemia, lung cancer such as lung adenocarcinoma, pharyngeal squamous cell carcinoma, lymphoma, gastric cancer, breast cancer, melanoma, neuroendocrine tumor, intestinal cancer, multiple myeloma, fibrosarcoma , prostate cancer or liver cancer. Therefore, the compound of the formula (I) of the present application or a pharmaceutically acceptable salt thereof can be expected as a drug for treating the above tumor (cancer).

The pharmaceutical composition contains a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. One skilled in the art can determine the particular therapeutically effective amount of the composition based on the selected compound, the subject being administered. In some embodiments, the effective amount may range from 0.01 to 99.99%, preferably from 0.1 to 75%, more preferably from 0.5 to 50% by weight of the composition.

The pharmaceutical compositions referred to in the present application can be formulated into various preparations for various routes of administration for therapeutic administration. For example, it is prepared in a form suitable for topical administration, a form for oral administration, a form for intravenous administration, and a form for intramuscular administration. The preparation may be administered to an individual or a patient in need of the drug by various routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, and the like.

The topical preparation may be in the form of a transdermal patch, a suppository, a paste, a lotion, a paste, a gel, or the like. Topical formulations may include one or more penetrants, thickeners, diluents, emulsifiers, dispersing agents or binding agents. When the composition is prepared for transdermal delivery, the composition can be used with or with the penetration enhancer. The penetration enhancer includes a chemical penetration enhancer and a physical penetration enhancer that facilitates transport of the composition through the skin.

When the composition is in association with a chemical permeation enhancer, the permeation enhancer is selected from the group that is compatible with the compound and is present to promote delivery of the compound through the skin of the individual, for example, for the compound The transmission of the individual's systemic circulation.

For oral preparations, the compounds may be prepared alone or in combination with suitable additives to prepare tablets, powders, granules and capsules, for example, with conventional additives such as lactose, mannitol, corn starch or potato starch; , such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; and lubricants such as talc or magnesium stearate; If necessary, combine with diluents, buffers, wetting agents, preservatives and flavoring agents. It is especially advantageous that the combination of the compound and buffer provides the protection of the compound against the low pH gastric acid environment. It may also be preferred to provide an enteric coating to avoid precipitation of the compound when passed through the stomach. A similar oil, synthetic fatty acid glyceride, higher fatty acid ester or propylene glycol) is dissolved, suspended or emulsified into the injection formulation. If desired, it can be combined with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. Particularly beneficial solubilizers include Vitamin E TPGS (da-tocopherol polyethylene glycol 1000 succinate), cyclodextrin, and the like.

In still another aspect, the present application relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (II)

Reacting with a compound of formula (III)

(ΠΙ),

R _{2 is} defined as before, and

The compound of the formula (II) and the formula (III) may be used in a molar ratio of 1:1, but it is understood that one of the excess will favor the yield of the final product. Generally, the molar ratio of the compound of the formula (II) to the compound of the formula (III) may be from 1.2 to 1.5:1.

In some preferred embodiments of the preparation process of the present application, the reaction is carried out in the presence of a base. The base may be an organic base, preferably a tertiary amine such as triethylamine or pyridine. The molar ratio of the amount to the reference reactant may be from 1.5 to 2.5:1.

The reaction can be carried out in a polar organic solvent which is inert to the reaction, preferably in a solvent having a relatively high polarity. As a non-limiting example, it is preferred that the reaction be carried out in the following solvents: lower alkyl alcohols such as decyl alcohol, ethanol, propanol, amides such as dimethylformamide, dimercaptoacetamide, sulfones such as dimethyl sulfoxide, Sulfolane, ethers such as tetrahydrofuran, and acetonitrile.

The reaction temperature of the above reaction is not limited, and it can be generally carried out at normal temperature. It is preferred to place the reaction system under inert gas protection.

In another aspect, the present application is also directed to a method of treating a tumor in an individual comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. Detailed ways:

The non-limiting specific embodiments provided below are intended to make the person skilled in the art more aware. The invention is understood and implemented. They should not be considered as limiting the scope of the invention. Preparation of intermediates

La. 5-Chloro-2-difluoromethoxyphenol

Under argon protection and stirring, sodium chlorodifluoroacetate 723 mg (5.0 mmol), sodium hydroxide 220 mg (5.5 mmol) and 4-chlorocatechol 838 mg (5.5 mmol) were added to N, N. In a mixture of dimethylformamide 7.0 mL and water 0.1 mL, the temperature was slowly raised to 125 ° C for 1.0 hour. Stop the reaction and drop to room temperature. 10 mL of 1.0 mol/L hydrochloric acid was added to the reaction solution, and the solution was adjusted to be acidic, and then 50 mL of water and 20 mL of ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate 20 mL. The organic layer was combined, washed with 50 mL of water and 50 mL of brine, and dried over anhydrous magnesium sulfate. Filtration, concentration and preparation of a thin layer of silica gel (mobile phase: petroleum ether: ethyl acetate = 4:1) eluted to afford pale yellow oil 189 mg, yield 19.4%. MS ([M-Hr): 193.

The lb compound (5-tert-butyl-2-difluoromethoxyphenol) and the lc compound (5-mercapto-2-difluoromethoxyphenol) were prepared in a similar manner to the preparation of la.

Id. 4-Nitro-2-trifluoromethoxyphenol

Under an argon atmosphere and stirring, 3.0 g (7.5 mmol) of anhydrous cerium nitrate was added to a solution of 2-trifluoromethoxyphenol 891 mg (5.0 mmol) in tetrahydrofuran (re-distilled) in 20 mL, and slowly warmed to 50 °. C, reaction for 10 min. Stop the reaction and cool down. After suction filtration, the filter cake was washed with 20 mL of tetrahydrofuran. The filtrate was concentrated, and 40 mL of water and 45 mL of ethyl acetate were added to the residue. The organic layer was separated and the aqueous layer was extracted with ethyl acetate 40 mL. The organic layers were combined, washed with water (110 mL) and saturated brine (110 mL) and dried over anhydrous magnesium sulfate. Filtration, concentration and column chromatography silica gel (mobile phase: petroleum ether: ethyl acetate = 15:1) eluted to afford 356 mg of y.

Le. 4-yl-2-trifluoromethoxyphenol

Under argon protection and mechanical stirring, 223 mg (1.0 mmol) of 4-nitro-2-trifluoromethoxyphenol, 224 mg (4.0 mmol) of reduced iron powder and 321 mg (6.0 mmol) of chlorination were added in sequence. In a mixture of 20 mL of ethanol and 6.0 mL of water, the temperature was slowly raised to 50 ° C, and the reaction was 1.5 h, and the solution was brown. Stop the reaction and cool naturally. Filter by suction and wash the cake with 10 mL of ethyl acetate. 20 mL of water and 20 mL of ethyl acetate were added to the filtrate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate 20 mL. The organic layers were combined, washed with 50 mL of water and 50 mL of brine, and dried over anhydrous magnesium sulfate. Filtration and concentration gave a dark red solid 144 mg, yield 74.4%.

If. 4-fluoro-2-trifluoromethoxyphenol

Under argon protection and stirring, the temperature of the external bath was controlled to 0~5 °C, and sodium nitrite 33 mg (0.48 mmol) was added to the solution of 4-amino-2-trifluoromethoxyphenol 77 mg (0.4 mmol). % (w/w) pyridine fluoride solution in 0.8 mL. The bath was raised to 5~10 °C, and it was shed for 30 min. The solution was brownish red. To the above reaction solution, stannous chloride dihydrate 90 mg (0.4 mmol) and tetrabutylammonium fluoride trihydrate 105 mg (0.4 mmol) were successively added, and the temperature was slowly raised to 100. C, the reaction was 3.0 h, and the solution was dark brown. Stop the reaction and cool naturally. The reaction solution was poured into ice water, ethyl acetate (15 mL) was evaporated, and the organic layer was evaporated. The organic layers were combined and washed with 30 mL of water and 30 mL of brine, dried over anhydrous magnesium sulfate Dry. Filtration, concentration, and preparation of a thin layer of silica gel (mobile phase: petroleum ether: ethyl acetate = 2:1) afforded a pale yellow oil, 14 mg, yield 17.9%.

Lg. p-chloro-trifluoromethoxyphenol

1.78 g of o-trifluoromethoxyphenol was dissolved in 5 mL of toluene and stirred in an ice water bath for 20 min. 1.485 g of sulfonyl chloride was added dropwise to the reaction system within 10 min, and the mixture was stirred for 20 min, then transferred to a 30 ° C water bath, and stirring was continued for 1 h. 200 mL of 5% sodium carbonate aqueous solution and 50 mL of toluene were added to the system, and the mixture was shaken well (the pH of the aqueous layer was 10). The aqueous layer was adjusted to pH 2 with 2 N aqueous hydrochloric acid and extracted again with 50 mL of toluene. The toluene layers were combined twice, washed successively with 100 mL of water, 100 mL of a saturated aqueous solution of sodium chloride, and dried over 5 g of anhydrous magnesium sulfate for 30 min. Concentration by rotary evaporation gave a white solid. MS negative ion peak (M-H: 213). Under an ice bath, 5.85 g (0.05 mol) of 6-aminohexanol was added to 30 mL of dichloromethane (molecular sieve treatment), and the solid was not completely dissolved. A solution of 12.0 g (0.055 mol) of dichloromethane (molecular sieve treated) 20 mL of di-tert-butyl dicarbonate was dropped into the above solution. The white turbid liquid was obtained by dropping. After reacting at room temperature for 2.5 h, the reaction was stopped, 50 mL of water was added to the reaction mixture, and the organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined and washed with 125 mL of a 5.0% aqueous citric acid solution, 125 mL of a saturated aqueous sodium hydrogen carbonate solution and 125 mL of saturated brine, and dried over anhydrous magnesium sulfate. Filtration and concentration gave a pale yellow oil, 10.9 g,.

The product of the previous step (0.05 mol) and p-toluenesulfonyl chloride 11.4 g (0.06 mol) were added to 50 mL of dichloromethane (molecular sieve treatment) with stirring in a water bath, and the solid was completely dissolved. 12.1 mL (0.15 mol) of pyridine was added dropwise to the above solution. After the dropwise addition, the mixture was stirred at room temperature overnight. The reaction was stopped, 50 mL of water was added to the reaction mixture, and the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 125 mL of a 5.0% aqueous citric acid solution, 125 mL of water and 125 mL of a saturated brine, and dried with anhydrous magnesium sulfate. Filtration, concentration and drying in vacuo gave a white solid (13.9 g).

The compound of 2b (6-(tert-butoxycarbonylamino)hexyl 2-(trifluorophosphonio)benzoate) was synthesized in a similar manner to the preparation of 2a.

3a. 6-(5-Chloro-2-difluoromethoxy-phenoxy)hexylaminodecanoic acid tert-butyl ester

5-Chloro-2-difluoromethoxyphenol 189 mg (0.97 mmol) and sodium hydride 47 mg (1.94 mmol) were added to N,N-dimercaptoamide 3.0 mL with argon protection and ice-bath stirring. Medium, stirring for 1.0 h. A solution of 721 mg (1.94 mmol) of 6-aminodecanoic acid-tert-butylbenzenesulfonate in N,N-dimercaptoamide (3.0 mL) was added dropwise to the above solution. After the dropwise addition, the mixture was stirred at room temperature overnight. The reaction was stopped, and 40 mL of ethyl acetate and 100 mL of water were added to the mixture, and the organic layer was separated. The organic layer was combined and washed with a saturated aqueous solution of sodium hydrogen carbonate (120 mL), water (120 mL) Filtration, concentration, column chromatography silica gel (mobile phase: petroleum ether: ethyl acetate = 15:1). MS ([M+Na] ⁺ ): 416.

The compound of 3b (t-butyl 6-(2-(trifluorodecyloxy)phenylamino)hexyl decanoate) was synthesized in a similar manner to the preparation of 3a.

4a. 6-(5-Chloro-2-difluoromethoxy-phenoxy)hexylamine Add 0.6 mL (8.0 mmol) of trifluoroacetic acid to tert-butyl 6-(5-chloro-2-difluoromethoxy-phenoxy)hexylcarbamate 198 mg with argon and ice-cooling. (0.5 mmol) of dichloromethane (molecular sieve treatment) 5.0 mL of solution, bubbles were generated and stirred for 3.0 h. The reaction was stopped, the solvent was evaporated, and 10 mL of 5.0 mol/L sodium hydroxide was added to the residue. The solution was adjusted to basic, ethyl acetate (15 mL) was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate 15 mL. The organic layer was combined and washed with 40 mL of water and 40 mL of brine, and dried over anhydrous magnesium sulfate. Filtration and concentration gave 144 mg (yield: EtOAc)

A 4b-4t compound was synthesized in a similar manner:

4b. 6-(2-(Trifluoromethoxy)phenoxy)hexyl-1-amine

4c. 6-(3-(Trifluoromethoxy)phenoxy)hexyl-1-amine

4d. 6-(4-(Trifluoromethoxy)phenoxy)hexyl-1-amine

4e. 5-(2-(Trifluoromethoxy)phenoxy)pentyl-1-amine

4f. ⁶ -( ⁴ -Bromo- ^2- (trifluoromethoxy)phenoxy)hexyl-1-amine

4g. N-(6-Aminohexyl)-2-(trifluoromethoxy)aniline

4h. 6-aminohexyl 2-(trifluoromethoxy)benzoate

4i. 6-(3-tert-Butyl-2-(difluoromethoxy)phenoxy)hexylamine

4j. 6-(4-Chloro-2-(difluoromethoxy)phenoxy)hexyl-1-amine

4k. 6-(4-Chloro-2-(trifluoromethoxy)phenoxy)hexyl-1-amine

41. 6-(4-Nitro-2-(trifluoromethoxy)phenoxy)hexyl-1-amine

4m. 6-(4-Fluoro-2-(trifluoromethoxy)phenoxy)hexyl-1-amine

4n. 6-(3-Mercapto-2-(difluoromethoxy)phenoxy)hexyl-1-amine

4o. 6-(2-(Difluorodecyloxy)phenoxy)hexyl-1-amine

4p. 6-(3-Fluoro-2-(difluoromethoxy)phenoxy)hexyl-1-amine

4q. 5-(2-(decyloxy)phenoxy)pentyl-1-amine

4r. 6-(4-Chlorophenoxy)hexyl-1-amine

4s. 6-( ² -Chlorophenoxy)hexyl-1-amine

4t. 6-(2-(Methoxy)phenoxy)hexyl-1-amine

5a. Phenyl-3-(pyridin-4-yl)-isourea

Under argon gas protection and stirring, diphenyl-N-cyanocarbonate 10.0 g (0.042 mol) and 4-aminopyridine 2.44 g (0.026 mol) were sequentially added to tetrahydrofuran (re-distilled) 10 mL, and the temperature was slowly raised to At 50 ° C, the reaction was carried out for 2.5 h, and the solid was completely dissolved. Stir at room temperature overnight. The reaction was stopped and the reaction solution was placed in a water tank for 20 min. After suction filtration, a solid of 4.7 g was obtained, and the yield was 75.9 %.

5b (1-cyano-2-phenyl-3-(pyridin-3-yl)-isourea) was synthesized by the synthesis method of Preparation 5a.

6. 2-(7-Hydroxyheptyl)isoindole-1,3-dione

585 mg of 7-bromoheptanol was dissolved in 5 mL of DMF, and 833 mg of phthalimide clock salt was added and stirred for 4 h. Add 50 mL of water and 50 mL of DCM to the system, shake well and separate. The aqueous layer was extracted again with 50 mL of DCM. The organic layers were combined twice, washed successively with 100 mL of water and 100 mL of saturated aqueous sodium chloride, and dried over 5 g of anhydrous magnesium sulfate for 30 min. Concentrated by rotary evaporation to give a pale yellow transparent oily liquid. 7. 7-(l,3-Dioxoisoindol-2-yl)heptyl-4-indenyl]

783 mg of 2-(7-hydroxyheptyl)isoindole-1,3-dione was added to 40 mL of DCM, 800 mg of p-benzenesulfonyl chloride was added, and pyridine was added dropwise with stirring, and stirred overnight. After 24 h, 100 mL of water was added to the reaction system, and the mixture was shaken well, and the aqueous layer was extracted once with 50 mL of DCM. The organic phases were combined, washed successively with 100 mL of 5% aqueous citric acid solution, 100 mL of saturated aqueous sodium carbonate, 100 mL of saturated aqueous sodium chloride, and dried over 5 g of magnesium sulfate for 30 min.

8. 2-(7-(2-decyloxyphenyl)heptyl)isoindole-1,3-dione

O-methoxyphenol 745 mg, dissolved in 10 mL DMF, 144 mg sodium hydride, stirred for 20 min, 7-(1,3-dioxoisoindol-2-yl)heptyl 4-methyl 1.25 g of benzoic acid ester was added to the reaction system. Stir the reaction overnight. After 16 h, 50 mL of water and 50 mL of ethyl acetate were added to the system, and the mixture was shaken well, and then separated. The aqueous layer was extracted with 50 mL of ethyl acetate and then combined with organic layer. The sodium aqueous solution was washed with 100 mL of water, dried over 5 g of magnesium sulfate for 30 min, and evaporated to give a yellow brown oil. Flash column chromatography, eluent ethyl acetate: n-hexane 1:2. Made of yellow transparent oil, 500 mg o

9a. 7-(2-decyloxyphenylheptamine

500 mg of 2-(7-(2-decyloxyphenoxy)heptyl)isoindole-1,3-dione, dissolved in 0.5 mL of THF, and 0.5 mL aqueous solution of guanamine. After stirring for 20 h overnight, 50 mL of water and 50 mL of ethyl acetate were added, and the mixture was shaken well and separated. The ethyl acetate layer was washed successively with 100 mL of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous sodium chloride and dried over 3 g of magnesium sulfate. Spin thousands, get a light yellow oil.

The 9b compound (8-(2-(trifluoromethoxy)phenoxy)octyl-1-amine) was synthesized in a similar manner to the compound 9a. Preparation of the compounds of the invention

EXAMPLE 1. N-Cyano-N,-(6-(2-difluorodecyloxy-5-chlorophenoxy)hexyl)-N"-(4-3⁄4b-yl)anthracene

Triethylamine 0.17 mL (1.2 mmol) and 1-cyano-2-phenyl-3-(pyridin-4-yl)-isourea 140 mg (0.59 mmol) were sequentially added to 6 under argon atmosphere with stirring. -(5-Chloro-2-difluoromethoxy-phenoxy)hexyl-1-amine 144 mg (0.49 mmol) in ethanol (steamed) in 5.0 mL. Stir at room temperature for 2.0 h. The reaction was stopped, the solvent was evaporated, and ethyl acetate (25 mL) and water (20 mL). The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate (50 mL), 50 mL of water and 50 mL of brine and dried over anhydrous magnesium sulfate. Filtration, concentration, and preparation of a thin layer of silica gel (mobile phase: chloroform: decyl alcohol = 12:1) were separated to give a pale yellow, white, white solid, 115 mg, yield 53.5%. MS ([M _ H] — ): 436. The compounds of Example 2 - Example 18 and Control 1 - Control 4 were synthesized in a similar manner to Synthesis Example 1.

EXAMPLE 2. N-H^-N,-(6-(o-trifluorodecyloxyphenylhexyl)-N,,-(3-3⁄4b3⁄4^)胍

MS([M+H] ^T ): 422

Example 3. NH^-N,-(6-(m-trifluoromethoxyphenylhexyl)-N"-(4-pyridin ¹ ^)

MS ([M+H] ⁺ ): 422 Example 4. -Cyano-N,-(6-(p-fluorofluorophenylhexyl)-N"-(4-pyridyl)

MS ([M+H] ⁺ ): 422 Example 5. ) -N" -(4-pyridinium

MS ([M+H] ⁺ ): 408 Example 6. N-Cyano-N,-(8-(o-trifluorodecyloxyphenyloctyl)-N"-(4-pyryl ¹ 3⁄4)

MS ([M+H]卞): 450 Example 7. NH^-N,-(6-(2-trifluoromethoxy-4-bromophenyl)hexyl)-N"-(4-pyridyl) guanidine

MS ([M+H] 十): 501

1H NMR (600M, DMSO-d ₅ ) δ: 1.314-1.457 ( m, 4 Η, CiL ), 1.516-1.563 ( m, 2H, CH ₂ ), 1.704-1.750 ( m, 2H, CHs ), 3.265 ( q, 2H, NH-CHs, J ₂ =6.3),

4.062 ( t, 2H, O-CH ₂ , J = 12.6 ), 7.202-7.231 (m, 3H, phenyl, pyro ^1. 7.547 (q, 1H, phenyl), 7.591-7.602 (m, IH, phenyl) , 7.835 ( t, IH, NH ), 8.386 ( d, 2H, pyridyl), 9.353 ( bs, IH, NH ) ₀ Example 8. NH ^ -N, - (6- ( o-trifluorophenyl group ^ J Yue hexyl) -N ,, - (4- guanidino-pyrazol ¹

MS ([M+H] 十): 421 Example 9. (o-trifluorodecyloxybenzoylhexyl)-N"-(4-pyridinium)

MS ([M+H]卞): 450 Example 10. N-carbyl-N,-(6-(2-difluorodecyloxy-5-tert-butylphenoxy)hexyl)-N"- (4-pyridyl)胍

Example 11

MS([M+H]+): 422

1H NMR (600M, CDCI3) δ: 1.431-1.489 (m, 2H, CH ₂ ), 1.515-1.566 ( m, 2H, CH ₂ ), 1.630-1.676 ( m, 2H, Ci^ ), 1.802-1.848 ( m , 2H, ), 3.379 ( q, 2H, NH-CH ₂ ), 4.009 ( t, 2H, 0-CH ₂ ), 6.902-6.984 ( m, 3H ), 7.206-7.271 ( m, 4H ), 8.500 ( d , 2H).

,-(6-(2-difluorodecyloxy-4-chlorophenoxy)hexyl)-N,,-(4-pyridyl)indole

MS ([M - H]-): 436; MS ([M+H] ^† ): 438 Example 13. N-carbyl-N,-(6-(2-trifluoromethoxy-4-chloro) Phenoxy)hexyl)-N,,-(4-pyridyl)indole

Example 14. N-Cyano-N,-(6-(2-trifluoromethoxy-4-nitrophenoxy)hexyl)-N,,-(4-pyridyl)indole Example 15. N-^J^-N,-(6-(2-Trifluoromethoxy-4-fluorophenyliLi hexyl)-N"-(4-pyridinium)

MS([M+H] ⁺ ): 440

,-(6-(5-fluorenyl-2 phenoxy)hexyl)-N"-(4-pyridinium)

MS ([M - H] "): 416; MS ([M+H] ⁺ ): 418 Example 17. N-L^-N,-(6-(2-difluoro phenoxyphenoxy) Hexyl) -N"-(4-pyridinium

MS([M+H] ⁺ ): 404

Example 18. 3⁄4 胍

Comparative compound 1. N-gas group -N,-(5-(o-decyloxyphenoxy)pentyl)-N,,-(4-pyridyl)anthracene

MS([M - H]- ): 352; MS([M+H] 354

Control compound 2. N-^ LN,-(6-(4-chlorophenylfl^)hexyl)-1^"-(4-pyridyl)3⁄4_3⁄4 胍

Control compound 3. N-cyano-N,-(6-(2-chlorophenyl)hexyl)-N,,-(4-' is 3⁄4J胍

Control compound 4. ^^ -^-(6-(2-indolyloxy)hexyl)-^-(4-pyridinium)

MS([MH]-): 366; MS([M+H] ⁺ ): 368

Pharmacological activity test

The experiment is carried out by routine experimentation in the art, and the following materials and methods are specifically used:

Test compound

Examples 1, 2, 4-7, 10-12 and 16, Comparative Compounds 1-4.

2. Cell line:

Human pancreatic cancer AsPC-1; human acute lymphoblastic leukemia cell line CCRF-CEM/T; human lung adenocarcinoma NCI-H1975; human squamous cell carcinoma Fadu; human B lymphoma BA25; human B lymphoma BA91; Human B lymphoma BA127; human gastric cancer NCI-N87; human non-small cell lung cancer A549; human liver cancer SK-Hep-1; human lung cancer NCI-H460; human prostate cancer PC-3.

3. Experimental method:

3.1 adherent cells

The following various cells were cultured under the following conditions:

AsPC-1 : 90% RPMI1640, 10% FBS;

NCI-H1975: 90% PMI1640, 10% FBS;

Fadu: 90% EMEM, 10% FBS;

NCI-N87: 90% RPMI1640, 10% FBS;

Incubate at 37 ° C, 5% CO ₂ , saturated humidity.

After the cells were cultured to the fusion, the cells were trypsinized, and a single cell suspension was prepared in complete medium. 96 well microplates were seeded with appropriate concentrations of cells (AsPC-1: 8000 cells/well; CI-H1975: 5000 cells/well; Fadu: 6000 cells/well; CI-N87: 15000 cells/well). The cells are attached.

The test compound was dissolved in DMSO to make a 2 mM stock solution, diluted to 20 μΜ or 2 μΜ of 10× working solution in basal medium (without serum), and diluted in 1/3 gradient to maintain the DMSO concentration during the dilution. No change, a total of 8 dose groups. 20 μM of lOx compound working solution was added to the experimental wells, and finally the volume per well was 200 μΐ, and the DMSO concentration was 1%. ; also set a solvent-free control group (PC) without compound and no A solvent control group (NC) containing cells and compounds. Continue to culture the cells for 72 h.

Then, the activity of the cells was measured by a tetrazolium salt reduction method (MTT method). The specific method was to aspirate the medium in the well, and add a basal medium containing 0.5 mg/ml MTT, 100 μΐ/well, and continue to culture 3 h, then remove the medium containing MTT, add DMSO 100 μΐ/well, dissolve the ΜΤΤ crystal, and measure the OD 490 nm value by enzyme microplate.

The inhibition rate of the compound was calculated by the following formula: Inhibition rate = [1 - (OD value of the administration group - NC OD value) / (PC OD value - NC OD value)] χ 100% Then the logarithm of the compound concentration is plotted on the abscissa, The inhibition rate is plotted on the ordinate, and the curve is fitted with the Logistic 4 parameter equation. The concentration of the compound corresponding to the 50% inhibition rate on the curve is the IC50 value.

3.2 Suspension cells

The cells were cultured under the following conditions:

Complete medium: 90% RPMI 1640, 10% FBS; C, 5% C0 ₂ , cultured in saturated humidity. After the cells are cultured to the end of logarithmic growth, the cells are diluted with the complete medium to the desired concentration.

96-well microtiter plates were seeded with appropriate concentrations of cells (CCRF-CEM/T: 20000 cells/well; BA25: 20000 cells/well; BA91: 60000 cells/well; BA127: 60000 cells/well).

The test compound was dissolved in DMSO to make a 2 mM stock solution, diluted to 20 μΜ or 2 μΜ of 10× working solution in basal medium (without serum), and diluted in 1/3 gradient to maintain the DMSO concentration during the dilution. No change, a total of 8 dose groups. Add 12 μL of lOx compound working solution to the well, which is 120 μl per well and 1% DMSO. A solvent control group (PC) containing no compound and a solvent control group (NC) containing no cells and compounds were also provided. Continue to culture the cells for 72 h.

Then, the activity of the cells was measured by the tetrazolium salt reduction method (MTT method) by adding 30 μl/well of PBS containing 2.5 mg/ml MTT, continuing to culture for 3 hours, and then adding triple lysate (10% SDS, 5%). Isobutanol, 0.012 M HC1) 100 μΐ/well, dissolved in ΜΤΤ crystal at room temperature, and measured by OD 570 nm.

4 test results

4.1 Table 1 below shows the in vitro growth inhibitory activity of some compounds against Aspc-1. Table 1. In vitro growth inhibitory activity of some compounds on Aspc-1 Compound number IC ₅₀ (nM) Compound number IC ₅₀ (nM) Control 2 19 Control 3 7.2 Control 4 7.3 Control 1 135 Example 11 2.1 Example 12 2.3 Example 16 0.9 As can be seen from Table 1, Examples 11 and 12 The in vitro growth inhibitory activity against 16 human pancreatic cancer AsPC-1 was significantly better than that of controls 1-4, indicating a significant effect of these compounds on pancreatic cancer.

4.2 Table 2 below shows the in vitro growth inhibitory activity of some compounds on CCRF-CEM-T. Table 2. In vitro growth inhibitory activity of some compounds on CCRF-CEM-T

As can be seen from Table 2, the growth inhibitory activities of Examples 1, 7, 11, 12 and 16 against human acute lymphoblastic leukemia cell line CCRF-CEM/T were significantly better than those of Control 1-4, indicating that these compounds are acute lymphoid. Significant efficacy of cell leukemia.

4.3 Table 3 below shows the in vitro growth inhibitory activity of some compounds on BA25. Table 3. In vitro growth inhibitory activity of some compounds on BA25

As can be seen from Table 3, IC _{5 of} Examples 2, 5-7 and 11. The value was significantly lower than the IC ₅₀ value of Example 4, indicating that the F-substituted decyloxy group has a better activity at the 2-position than the compound at the para-position to the human B lymphoblastic BA25.

4.4 Table 4 below shows the in vitro growth inhibitory activity of some compounds on FaDu. Table 4. In vitro growth inhibitory activity of some compounds on FaDu

It can be seen that the inhibitory activities of Examples 1, 7, 10-12 and 16 on human pharyngeal squamous cell carcinoma Fadu are significantly better than those in Fig. 2.

4.5 Table 5 below shows the in vitro growth inhibitory activity of some compounds against BA127.

4.7 Table 7 below shows the in vitro growth inhibitory activity of some compounds on tumor cells IC _:

Table 7. In vitro growth inhibitory activity of some compounds on tumor cells IC _5Q (nM)

The above table shows the in vitro growth inhibitory activity of Example 11 against six tumor cell models compared to Control 2 and 4 is much better.

It should be understood that the specific technical features, various constituent elements (such as compounds, compound structural units, groups, compositions, combinations) described in the present application are specific to a particular aspect, specific embodiment, and specific embodiments of the invention, and It is not limited to these specific aspects, specific embodiments, or specific embodiments. That is, it is highly understood by those skilled in the art, unless the specific technical features, the various constituent elements, and other aspects, embodiments, and specific technical features, and various constituent elements (such as compounds, compounds) in the present application. Structural units, groups, compositions, combinations) feature conflicts, otherwise they may be used in other aspects, embodiments, embodiments of the application.

Meanwhile, all technical features, constituent elements (including all steps in the method) disclosed in the present application may be combined in any form to form different technical solutions of the present invention unless they conflict with each other.

Claims

Claim

A compound of the formula (I) or a pharmaceutically acceptable salt thereof,

(I)

Where: X is N or CH;

n is an integer from 3 to 10;

Ri is a decyloxy group substituted by one or more F or CI, preferably a decyloxy group substituted by at least two F or C1 at the 2- or 3-position of the phenyl ring;

Is 11, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, nitro, decanoylamino, aminosulfonyl, halogen, any alkyl substituted by halogen or any halogen substituted by halogen Oxygen.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

X is N;

n is an integer of 4-8;

a methoxy group substituted by at least two F, preferably a methoxy group substituted by at least two F at the 2-position of the phenyl ring;

Is a C, ₆ alkyl group, a nitro group, a halogen or a C ₆ alkyl group optionally substituted by a halogen.

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein

X is N;

n is an integer of 4-8;

Y is -0-, NH- or -OC(O)-;

Ri is a methoxy group substituted by at least two F at the 2-position of the phenyl ring;

As 11, CM alkyl, nitro, halogen.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: X is N;

n is an integer of 4-8;

γ is — 0-, -ΝΗ- or -OC(O)-;

i is OCF ₃ or OCHF _{2 at the 2} -position of the phenyl ring;

1 ₂ is 11, C _M alkyl, F, CI or Br.

The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

X is N;

n is an integer of 4-8;

Y is -0-;

Ri is OCF ₃ or OCHF _{2 at the 2} -position of the phenyl ring;

1 ₂ is 11, C _1-4 alkyl, F, C1 or Br.

6. The following compounds or their pharmaceutically acceptable salts:

N- cyano -N, - (6- (2- difluoromethoxy-5-chlorophenoxy) hexyl) -N ,, - (4- pyrazol ^a guanidine;

N-cyano-N,-(6-(o-trifluoromethoxyphenoxy)hexyl)^,,--pyridyl ¹⁷ ^^)胍;

N-cyano-N,-(6-(m-trifluoromethoxyphenoxy)hexyl)^,-(pyridin ¹ ) hydrazine;

N-cyano-N,-(6-(p-trifluoromethoxyphenoxy)hexyl)^,-(pyridin ¹ ) hydrazine;

N-cyano-N,-(5-(o-trifluoromethoxyphenoxy)pentyl)-N"-(44t: ^p i 胍;

N-cyano-N,-(8-(o-trifluoromethoxyphenoxy)octyl)-N,,-(4-pyridyl ¹ ) fluorene;

N-cyano-N,-(6-(2-trifluorodecyloxy-4-bromophenoxy)hexyl)-N,,-(4-pyridyl)indole;

N-cyano-N,-(6-(o-trifluorodecyloxybenzoyloxy)hexyl)-N,,-(4-pyridyl)anthracene;

N-cyano-N,-( ^6- ( ² -difluorodecyloxy- ⁵ -t-butylphenoxy)hexyl)->1,,-( ⁴ -pyridinium);

N-cyano-N,-(6-(o-trifluoromethoxyphenoxy)hexyl)^,-(pyridin ¹ ) hydrazine;

N-cyano-N,-(6-(2-difluorodecyloxy-4-chlorophenoxy)hexyl)-N"-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-trifluorodecyloxy-4-chlorophenoxy)hexyl)-N,,-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-trifluorodecyloxy-4-nitrophenoxy)hexyl)-N,,-(4-pyridyl)indole;

N-cyano-N,-(6-(2-trifluorodecyloxy-4-fluorophenoxy)hexyl)-N"-(4-pyridyl)indole;

N-cyano-N,-(6-(5-fluorenyl-2-difluoromethoxyphenoxy)hexyl)-N,,-(4-pyridyl)anthracene;

N-cyano-N,-(6-(2-difluoromethoxyphenoxy)hexyl)-indole, -(4)胍;

Ν-Cyano-indole, -(6-(2-difluorodecyloxy-5-fluorophenoxy)hexyl)-indole, -(4-pyridyl)indole.

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is for treating cancer.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.

A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises, preferably, a compound of the formula (II) in the presence of a base

Reacting with a compound of formula (III)

(ΠΙ),

Wherein R is an alkyl group or an aryl group or an aryl group substituted by a halogen or an alkyl group, and X, Y, η, and R _{2 are} as defined above, and

A method of inhibiting the growth of a tumor cell, comprising administering an inhibitory effective amount of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 or Tumor cells.

12. The method according to claim 11, wherein the tumor is selected from the group consisting of pancreatic cancer, acute lymphocytic leukemia, lung cancer such as lung adenocarcinoma, pharyngeal squamous cell carcinoma, lymphoma, gastric cancer, breast cancer, melanoma, neuroendocrine tumor, intestinal cancer , multiple myeloma, fibrosarcoma, prostate cancer and liver cancer.