TWI419894B - 4-anilinofuro[2,3-b]quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same - Google Patents

Description

4-anilinofuran[2,3-b]quinoline derivative, preparation method thereof and pharmaceutical composition containing the same

This invention relates to novel 4-anilinofuran[2,3- b ]quinoline derivatives which have been shown to possess a broad and effective anticancer activity. The invention also relates to methods of preparing such derivatives, and their use in the preparation of pharmaceutical compositions.

Acridine derivatives are a group of compounds having a tricyclic acridine plane. The acridine derivative can inhibit the topoisomerase II by inserting DNA through the tricyclic acridine plane. Thereby blocking DNA replication or transcription. Therefore, acridine derivatives, particularly 9-anilinoacridine derivatives, have been extensively studied as potential chemotherapeutic agents (Denny WA et al . (1987), J. Med. Chem ., 30: 658-663; Gamage SA et al . (1994), J. Med. Chem ., 37: 1486-1494; and Gamage SA et al . (1997), J. Med. Chem ., 40:2634-2642).

In order to develop new potent anticancer drugs, in the previous study, the inventors synthesized a series by replacing a benzene moiety of 9-anilinoacridine with a furan ring. structurally related derivative 9- anilinoacridone 4-anilino-furo [2,3- b] quinoline derivative (4-anilinofuro [2,3- b] quinoline derivatives) (US 6,750,223 B2; Chen IL et al . (2002), Helv. Chem. Acta ., 85:2214-2221; Zhao YL et al . (2005), Chem. Biodiver ., 2:205-214; Chen YL et al . (2005), J. Med . Chem ., 40: 928-934; and Chen YL et al . (2008), Chem . Biodiver ., 4:267-278).

From the experimental results of the inventors, it was found that among the 4-anilinofuran [2,3- b ]quinoline derivatives synthesized, 1-(4-(furan[2,3-) having the following chemical formula (I) b ]quinolin-4-ylamino)phenyl)ethanone {1-(4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone} (Compound 1 ) is resistant in vitro In vitro anticancer assay has been shown to be more effective than amsacrine ( m- AMSA) [a 9-anilinoacridine derivative clinically used to treat leukemia and lymphoma The substance has a higher antiproliferative potency:

Further, a hydroxyimino derivative of Compound 1 {i.e., ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone肟}{ (E) -1-(4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone oxime} (Compound 2 ) and methoxyimino derivative { That is, ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -methyloxime}{ (E) -1-(4- (furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- methyloxime} (Compound 3 ) has also been shown to have antiproliferative effects comparable to those of ampicillin. In a subsequent study, the inventors further discovered that Compound 1 induces mitotic arrest and apoptosis by binding to tubulin and inhibiting tubulin polymerization ( Huang YT et al . (2005), J. Med. Chem ., 280:2771-2779).

Although Compounds 1 , 2, and 3 have satisfactory antiproliferative effects, they still have disadvantages such as lower water solubility and poor oral bioavailability (according to the inventors' Previous studies, unpublished data).

Low water solubility is an intrinsic property of many natural or synthetic drug candidates and is often associated with poor absorption and bioavailability. In fact, low water solubility and low oral bioavailability during drug development are common problems, particularly in the field of anticancer drugs, and as a result, many researchers are now working to improve drug candidates. Water solubility and oral bioavailability in order to develop more anticancer drugs for clinical use. For example, camptothecin having anticancer activity is obtained by introducing aminoalkyl functionalities to give camptothecin derivatives having higher water solubility [ie, topotecan and Irinotecan], in addition, the anti-cancer activity of combistatin A-4 (CA-4) is obtained by introducing a phosphate group. Solubility of CA-4 phosphate (combretastatin A-4 phosphate, CA-4P).

Upon investigation, the inventors have unexpectedly discovered that the introduction of an aminoalkyl side chain to a 4-anilinofuran[2,3- b ]quinoline derivative enhances 4-anilinofuran [2] , 3- b ] the water solubility of the quinoline derivative improves oral bioavailability.

Summary of invention

Thus, in a first aspect, the invention provides a compound of the following formula (I):

Or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of S, O and NH; R ¹ and R ² may be the same or different and are independently selected since in the following from the group consisting of: hydrogen, halo (halogen), a C ₁ -C ₄ alkyl group _{(C 1 -C 4 alkyl group)} , a hydroxyl group (hydroxy), a C ₁ -C ₄ alkoxy a group (C ₁ -C ₄ alkoxyl group), a nitro group, and an amino group; and one of R ³ and R ⁴ is hydrogen, and the other is Wherein: R ⁵ is a mono-C ₂ -C ₈ alkyl group; and R ⁶ is hydrogen or a C ₁ -C ₄ alkyl group.

In a second aspect, the present invention provides a process for the preparation of a compound of formula (I) as described above, which comprises a compound having the following formula (A):

R ⁵ O-NH ₂ HCl (A)

Wherein the R ⁵ group has the same definition as defined above for the compound of formula (I) and reacts with a compound of the formula (B):

Wherein the R ¹ and R ² groups and X have the same definitions as those defined above for the compound of formula (I), and one of R ⁹ and R ¹⁰ is hydrogen, and the other is Wherein the R ⁶ group has the same definition as defined above for the compound of formula (I).

In a third aspect, the present invention provides a pharmaceutical composition for treating cancer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above.

In a fourth aspect, the present invention provides a method for treating an individual having or suspected of having a cancer disease, comprising administering to the individual a compound of formula (I) or a compound thereof as described above Pharmaceutically acceptable salts.

Detailed description of the invention

It is to be understood that if any of the previous publications is quoted here, the prior publication does not constitute an acknowledgement that in Taiwan or any other country, the pre-existing publication forms a common general knowledge in the art. Part of it.

For the purposes of this specification, it will be clearly understood that the term "comprising" means "including but not limited to" and the term "comprises" has a corresponding meaning.

All technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains, unless otherwise defined. A person skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used to practice the invention. Of course, the invention is in no way limited by the methods and materials described. For clarity, the following definitions are used herein.

In a previous study, the inventors attempted to synthesize a series of 4-anilino-furo [2,3- b] quinoline derivative (4-anilinofuro [2,3- b] quinoline derivatives), found by the experimental results: 1- (4- (furo [2,3- b] quinolin-4-yl) phenyl) ethanone {1- (4- (furo [2,3- b] quinolin-4-ylamino) phenyl Ethanone} (Compound 1 ), ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone oxime { (E) -1-(4) -(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone oxime} (Compound 2 ) and ( E )-1-(4-(furan[2,3- b ]quinolin-4-yl Amino)phenyl)ethanone O -methyloxime { (E) -1-(4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- methyloxime} (compound 3 ) Inhibits a variety of cancer cells [including non-small-cell lung cancer cells, breast cancer cells, central nervous system cancer cells, leukemia cancer cells] ), colon cancer cells, melanoma cancer cells, ovarian cancer cells, renal cancer cells Cells) and the effects of growth of prostate cancer cells. Although Compounds 1 , 2, and 3 have satisfactory antiproliferative effects, they still have disadvantages such as lower water solubility and poor oral bioavailability.

In order to overcome the above disadvantages, the inventors have found through various studies that an aminoalkyl group is introduced into the oxime moiety of the 4-anilinofuran[2,3- b ]quinoline derivative. The water solubility of the 4-anilinofuran[2,3- b ]quinoline derivative can be enhanced to further improve the oral bioavailability of such derivatives.

Thus, the present invention provides a compound of the following formula (I):

Or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of S, O and NH; R ¹ and R ² may be the same or different and are independently selected From the group consisting of hydrogen, halogen, a C ₁ -C ₄ alkyl group, a hydroxyl group, a C ₁ -C ₄ alkoxy group, a nitro group, and an amine group; and R ³ and R ^{One of the four} is hydrogen, and the other is Wherein: R ⁵ is a mono-C ₂ -C ₈ alkyl group; and R ⁶ is hydrogen or a C ₁ -C ₄ alkyl group.

As used herein, the term "halogen" means fluoro, chloro, bromo and iodo.

As used herein, the term "alkyl group" means saturated monovalent hydrocarbon groups having a straight chain or branched chain moieties. In general, an alkyl group, by itself or as part of another group, includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Sec -butyl, tert -butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, heptyl, isoheptyl, octyl, And their various branched chain isomers and the like.

As used herein, the term "alkoxy group" means a group of the formula -OR' wherein R' is an alkyl group as described above. Alkoxy groups, including but not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, di-butoxy, tertiary - Butoxy and the like. In a preferred embodiment of the invention, the alkoxy group is a C ₁ -C ₄ alkoxy group. In a more preferred embodiment of the invention, the alkoxy group is a methoxy group.

As used herein, the term "aminoalkyl group" means an alkyl group substituted with an amine group, wherein the amine group may be a primary amine or a secondary amine. (secondary amine) or tertiary amine, and the alkyl group has a definition as described above. In a preferred embodiment of the invention, the aminoalkyl group is an amine C ₂ -C ₈ alkyl group. In another preferred embodiment of the invention, the aminoalkyl group is an amine C ₂ -C ₄ alkyl group. In a more preferred embodiment of the invention, the aminoalkyl group is an aminoethyl group.

According to the invention, the compounds of formula (I) have the following chemical formula (II):

Wherein: R ¹ is hydrogen or a C ₁ -C ₄ alkoxy group; R ² is hydrogen or halogen; R ⁵ is an amino C ₂ -C ₈ alkyl group; and R ⁶ is a C ₁ - C ₄ alkyl group.

Representative examples of such compounds of formula (I) include, but are not limited to, ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)benzene according to the present invention. Ethyl ketone O -2-aminoethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2- Aminoethyl hydrazine hydrochloride; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethyl Amino)ethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropyl hydrazine; E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine; ( E )- 1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethylanthracene; ( E )-1- (4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4) -(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-oxalinoline ethyl hydrazide; ( E )-1-(4-(furan[2, 3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(3-chlorofur) [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(3-chloro Furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4-(3-chlorofuran[2,3 - b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine; ( E )-1-(4-(3-chlorofuran [2,3] - b ] quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-(3-chlorofuran [2, 3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2 ,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b] Quinoline-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinoline -4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ] Quinoline-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinoline- 4-aminoamino)phenyl)B O -3- (dimethylamino) propyl oxime; (E) -1- (4- ( 7- methoxy-furo [2,3- b] quinolin-4-yl) phenyl) Ethyl ketone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamino) Phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-yl Amino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamine Phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinoline-4 -ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinoline- 4-aminoamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran [2,3] - b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran [2, 3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine; ( E )-1-(4-(3-chloro-7-- Oxyfuran [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-( 3-chloro-7-methoxyfur [2,3- b] quinolin-4-yl) phenyl) ethanone O -2- (piperidin-1-yl) ethyl oxime; (E) -1- (4- ( 3- chloro -7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine-ethyl hydrazine; and ( E )-1-(4- (3-Chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine.

According to the invention, the compounds of formula (I) may be in the form of their free form or a pharmaceutically acceptable salt thereof. Furthermore, the compound of formula (I) according to the invention may also be present as a stereoisomer or as a solvate represented by a hydrate. Therefore, it is expected that such stereoisomers and solvates will fall within the technical concept of the present invention.

Exemplary pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; with organic acids such as acetic acid, maleate , salts of tartrate, methanesulfonate; and salts with amino acids such as arginine, aspartic acid, and glutamic acid.

The present invention also provides a process for the preparation of a compound of formula (I) as described above, which comprises a compound having the following chemical formula (A):

R ⁵ O-NH ₂ HCl (A)

Wherein the R ⁵ group has the same definition as defined above for the compound of formula (I) and reacts with a compound of the formula (B):

Wherein the R ¹ and R ² groups and X have the same definitions as those defined above for the compound of formula (I), and one of R ⁹ and R ¹⁰ is hydrogen, and the other is Wherein the R ⁶ group has the same definition as defined above for the compound of formula (I).

The compound of formula (I) according to the present invention has been shown to have excellent tumor/cancer cell inhibition (especially breast cancer cells, human gastric adenocarcinoma cells, human prostate cancer cells, human cervical epithelial cancer cells, human esophageal cancer cells, The activity of growth of human lung adenocarcinoma cells, non-small cell lung cancer cells, renal cell cancer cells, hepatocyte cancer cells, human oral squamous carcinoma cells, central nervous system cancer cells, and dividing lung adenocarcinoma cells. Therefore, it is expected that the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used for the treatment of a cancer disease/tumor.

Thus, the present invention provides a method for treating an individual having or suspected of having a cancer disease/tumor comprising administering to the individual a compound of formula (I) or a pharmaceutical thereof as described above Acceptable salts.

The term "treating" or "treatment" as used herein means administering to a subject a pharmaceutical composition of the invention having one of the above cancers, a symptom toward a cancer. Or a predisposition for the purpose of administering a therapeutic effect, for example, cure, relieve, alter, affect, or ameliorate the cancer.

The invention also contemplates the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention for the preparation of a pharmaceutical composition for the treatment of cancer. Accordingly, the present invention provides a pharmaceutical composition for treating a cancer comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as described above.

The pharmaceutical compositions according to the present invention may additionally comprise a pharmaceutically acceptable carrier which is conventionally used in the art to prepare pharmaceutical compositions. For example, the pharmaceutically acceptable carrier can include one or more of the following agents: solvents, emulsifiers, suspending agents, decomposers, binding agents, Excipients, stabilizing agents, chelating agents, diluents, gelling agents, preservatives, lubricants, disintegrants Disintegrating agents, absorption delaying agents, and the like.

The pharmaceutical composition according to the present invention may be administered parenterally or orally in a suitable pharmaceutical form. Suitable pharmaceutical forms include sterile aqueous solutions or dispersions, sterile powders, tablets, troches, pills, capsules, and the like. Similar things.

Detailed description of the preferred embodiment

The invention will be described in more detail with reference to the accompanying drawings, which are not to be construed as limiting the scope of the invention.

The compound of formula (I) according to the present invention can be prepared according to the following exemplary reaction route and procedure.

Alkylation of benzophenone oxime (compound 7 ) with an aminoalkyl chloride, as shown in Reaction Scheme 1, gives diphenyl ketone aminoalkyl hydrazine (benzophenone aminoalkyloxime) (Compound 8 ). Compound 8 was then hydrolyzed with 3N HCl to give the aminoalkoxyamine hydrochloride (Compound 9 ). Next, the compound with 4-9-yl acetanilide furo [2,3- b] quinoline (4-acetylanilinofuro [2,3- b] quinoline) ( Compound 1) to thereby obtain a formula (I), Compound 13 . Compound 9 can also be combined with 1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone {1-(4-(3-chlorofuro[2, 3- b] quinolin-4-ylamino ) phenyl) ethanone} ( compound 10), 1- (4- (7-methoxy-furo [2,3- b] quinolin-4-yl) phenyl) {1-(4-(7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone} (Compound 11 ) or 1-(4-(3-chloro-7-methoxyfuran) [2,3- b ]quinolin-4-ylamino)phenyl)ethanone {1-(4-(3-chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl) Ethanone} (Compound 12 ) is reacted, and correspondingly, compound 14 , 15 or 16 having the formula (I) is obtained.

Representative compounds of formula (I) according to the invention are shown in Table 1 below.

General operating procedures:

The general thin layer chromatography (TLC) is performed by using pre-coated silica gel 60 F254 plates (E. Merck and Co.), and by It was detected using a UV light (254 nm).

Flash column chromatography is a solid phase using a silicone 60 [sieve mesh 0.040-0.063 mm, manufactured by E. Merck and Co.] and combined for use. It is carried out in a suitable eluent for separation and purification.

The melting point of each of the compounds synthesized in the following examples was examined by an uncorrected Electrothermal IA9100 melting point apparatus.

The IR spectrum was detected using a Perkin-Elmer System-2000 infrared spectrophotometer.

The UV spectrum was detected using a Shimadzu UV-160A UV-VIS spectrometer with methanol (MeOH) as the solvent and λ _max in nm.

¹ H-NMR and ¹³ C-NMR spectra were detected using a Varian Unity-400 (400 MHZ) nuclear magnetic resonance spectrometer, and chemical shifts expressed in δ (in ppm). ) is the use of TMS (0 ppm) as an internal standard, and the coupling constant is expressed in J (in Hz).

Elemental analysis was performed using a Heraeus CHN-O-Rapid elemental analyzer.

High-resolution mass spectra (HRMS) were detected using a Bruker APEX II (ESI) mass spectrometer.

Synthesis Example 1. ( E )-1-(4-(furan[2,3] -b Quinoline-4-ylamino)phenyl)ethanone O -2-aminoethyl hydrazine {( E )-1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethyl oxime} (compound 13a)

First, 1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone {1-] was prepared according to the method disclosed in Example 4 of the inventors of US 6,750,223 B2. (4-Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone} (Compound 1 ). Next, the obtained Compound 1 (0.30 g, 1 mmol), 2-aminoethoxyamine hydrochloride (0.28 g, 2.5 mmol) and K ₂ CO ₃ (0.69 g, 5.0) were obtained. A mixture of ethanol (EtOH) (10 mL) gave a mixture which was refluxed for 4 hours (TLC) and then evaporated. The residue formed is dissolved in CH ₂ Cl ₂ (50 mL), followed by water, followed by brine to be washed. After drying with Na ₂ SO ₄ , the organic phase was evaporated and the residue formed was purified by flash column chromatography (MeOH/CH ₂ Cl ₂ = 1/50). The title compound 13a (0.45 g, yield 96%) was obtained as a pale yellow solid.

The nature of the title compound was measured:

Mp: 112-113 °C. IR (KBr): 3216, 1578, 1517. UV (MeOH): 372 (4.22), 260 (4.52), 208 (4.53). ¹ H NMR (400 MHz, DMSO- d ₆ ): 2.29 (s, 3H, CH ₃ ), 3.17 (m, 2H, OCH ₂ CH ₂ N), 4.35 (t, 2H, J = 5.0 Hz, O CH ₂ CH ₂ N), 5.94 (d, 1H, J = 2.8 Hz, 3-H), 7.33 - 7.35 (m, 2H, ArH), 7.57-7.61 (m, 1H, 6-H), 7.78-7.88 (m , 4H, 2-, 7-H, ArH), 8.00 (d, 1H, J = 8. 0 Hz, 5-H), 8.23 (br s, 2H, NH ₂ ), 8.60 (d, 1H, J = 8.4 Hz, 8-H), 10.37 (br s, 1H, NH). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 12.63, 38.27, 69.78, 103.86, 106.07, 117.21, 122.75 (2C), 123.76, 123.95, 125.02, 127.01 (2C), 130.81, 131.82, 141.60, 141.98, 143.07 , 144.76, 155.14, 160.44. For C ₂₁ H ₂₀ N ₄ O ₂ ‧0.6 H ₂ O δ 0.5 HCl calc.: C, 64.77; H, 5.62; N, 14.39; Found: C, 64.88; H, 5.97; N, 14.17. About HRMS _{C 21 H 21 N 4 O 2} [M + H] + of (ESI) calcd: 361.1664; Found: 361.1663.

The hydrochloride salt of the title compound

A mixture of compound 13a (0.38 g) and 6 N HCl (2 mL) in EtOH (20 mL) was stirred at room temperature for 2 hours. The precipitate formed was collected and then recrystallized from EtOH to give the hydrochloride salt of compound 13a . For C ₂₁ H ₂₀ N ₄ O ₂ ‧0.6 H ₂ O </ RTI></RTI> HCl calc.: C, 57.74; H, 5.31; N, 12.

Synthesis Example 2. ( E )-1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine {( E )-1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyloxime} (compound 13b)

Compound 13b was prepared substantially according to the procedure described in Synthesis Example 1 above, except that 2-dimethylaminoethoxyamine HCl was used instead. - Aminoethoxyamine hydrochloride, and does not require a step of recrystallization. The title compound 13b was obtained as a dark brown liquid (yield: 90%).

The nature of the title compound was measured:

IR (KBr): 3221, 1578, 1519. UV (MeOH): 372 (4.18), 260 (4.48), 208 (4.50). ¹ H NMR (400 MHz, CDCl ₃ ): 2.27 (s, 3H, CH ₃ ), 2.37 (s, 6H, N (CH ₃ ) ₂ ), 2.74 (t, 2H, J = 5.8 Hz, OCH ₂ CH ₂ N), 4.35 (t, 2H, J = 5.8 Hz, O CH ₂ CH ₂ N), 6.19 (d, 1H, J = 2.8 Hz, 3-H), 6.90 (br s, 1H, NH), 7.15- 7.17 (m, 2H, ArH), 7.47-7.52 (m, 2H, 2-H, 6-H), 7.67-7.74 (m, 3H, 7-H, ArH), 8.04 (dd, 1H, J = 8.8 , 1.2 Hz, 5-H), 8.09 (dd, 1H, J = 8.8, 2.4 Hz, 8-H). ^{13 C NMR (100 MHz, CDCl} 3): 12.74,45.91 (2C), 58.20,72.29,105.73,106.09,118.31,120.61,120.92 (2C), 123.86,127.10 (2C), 129.21,129.23,132.12,140.27, 141.68, 142.84, 145.99, 154.00, 163.28. About _{C 23 H 24 N 4 O 2} ‧2.0 H Analysis calculated value of _{2 O‧1.1} HCl: C, 59.46; H, 6.31 ; N, 12.06; Found: C, 59.68; H, 6.40 ; N, 11.77. About _{C 23 H 25 N 4 O 2} [M + H] + of HRMS (ESI) calcd: 389.1977; Found: 389.1979.

Synthesis Example 3. ( E )-1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O - 3-aminopropyl hydrazine { ( E ) -1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-aminopropyl oxime} (compound 13c)

Compound 13c was prepared essentially according to the procedure described in Synthesis Example 1 above, except that 3-aminopropoxyamine HCl was used instead of 2-aminoethoxyamine. Hydrochloride. The title compound 13c was obtained as a pale yellow solid (yield: 96%).

The nature of the title compound was measured:

Mp: 83-85 ° C. IR (KBr): 3237, 1578, 1517. UV (MeOH): 366 (4.20), 258 (4.48), 210 (4.50). ¹ H NMR (400 MHz, CDCl ₃ ): 1.90 (quin, 2H, J = 6.4 Hz, OCH ₂ CH ₂ CH ₂ N), 2.25 (s, 3H, CH ₃ ), 2.88 (t, 2H, J = 6.8 Hz, OCH ₂ CH ₂ CH ₂ N), 4.30 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ CH ₂ N), 6.17 (d, 1H, J = 2.8 Hz, 3-H), 7.03 ( Br s,1H,NH),7.14-7.17(m,2H,ArH), 7.46-7.50(m,2H,2-H,6-H), 7.66-7.73(m,3H,7-H,ArH) , 8.04-8.10 (m, 2H, 5-H, 8-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.54, 33.25, 39.34, 72.01, 105.74, 106.01, 118.31, 120.69, 120.98 (2C), 123.79, 127.01 (2C), 129.16, 129.18, 132.14, 140.39, 141.67, 142.76 , 145.97, 153.72, 163.27. Analysis calculated values for _{C 22 H 22 N 4 O 2} ‧0.9 H 2 O of: C, 67.64; H, 6.14 ; N, 14.34; Found: C, 67.97; H, 6.32 ; N, 14.02. About _{C 22 H 23 N 4 O 2} [M + H] + of HRMS (ESI) calcd: 375.1821; Found: 375.1823.

Synthesis Example 4. ( E )-1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine { ( E ) -1-(4-(Furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl oxime} (compound 13d)

Compound 13d was prepared essentially according to the procedure described in Synthesis Example 1 above, except that 3-dimethylaminopropoxyamine HCl was used instead of 2-amino B. Oxyoxamine hydrochloride. The title compound 13d was obtained as a yellow solid (yield: 75%).

Standard The nature of the test compound:

Mp: 83-85 ° C. IR (KBr): 3219, 1578, 1519. UV (MeOH): 368 (4.26), 258 (4.53), 210 (4.53). ¹ H NMR (400 MHz, CDCl ₃ ): 1.99-2.06 (m, 2H, OCH ₂ CH ₂ CH ₂ N), 2.25 (s, 3H, CH ₃ ), 2.39 (s, 6H, N ( CH ₃ ) ₂ ), 2.59 (t, 2H, J = 7.6 Hz, OCH ₂ CH ₂ CH ₂ N), 4.26 (t, 2H, J = 6.2 Hz, O CH ₂ CH ₂ CH ₂ N), 6.19 (d, 1H, J) = 2.8 Hz, 3-H), 6.93 (br s, 1H, NH), 7.14 - 7.17 (m, 2H, ArH), 7.47-7.52 (m, 2H, 2-H, 6-H), 7.67-7.74 (m, 3H, 7-H, ArH), 8.04-8.10 (m, 2H, 8-H, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.52, 26.93, 44.93 (2C), 56.34, 71.99, 105.74, 106.07, 118.34, 120.75, 120.96 (2C), 123.81, 127.03 (2C), 129.14, 129.19, 132.07, 140.40, 141.75, 142.77, 145.97, 153.92, 163.27. Analysis calculated values for _{C 24 H 26 N 4 O 2} ‧0.5 H 2 O of: C, 67.43; H, 6.39 ; N, 13.11; Found: C, 67.35; H, 6.69 ; N, 12.94. About _{C 24 H 27 N 4 O 2} [M + H] + of HRMS (ESI) calcd: 403.2134; Found: 403.2136.

Synthesis Example 5. ( E )-1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine{ ( E ) -1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl oxime} (compound 13e)

Compound 13e was prepared essentially according to the procedure described in Synthesis Example 1 above, except that 2-pyrrolidine-1-ylethoxyamine hydrochloride (2-pyrrolidin-1-ylethoxyamine) was used. HCl) replaces 2-aminoethoxyamine hydrochloride and does not require a recrystallization step. The title compound 13e was obtained as a brown liquid (yield: 61%).

The nature of the title compound was measured:

IR (KBr): 3217, 1577, 1519. UV (MeOH): 372 (4.22), 260 (4.56), 208 (4.51). ¹ H NMR (400 MHz, CDCl ₃ ): 2.06-2.10 (m, 4H, Pyr-H), 2.26 (s, 3H, CH ₃ ), 3.24 (br s, 4H, Pyr-H), 3.35 (t, 2H, J = 4.8 Hz, OCH ₂ CH ₂ N), 4.60-4.63 (m, 2H, O CH ₂ CH ₂ N), 6.23 (d, 1H, J = 2.8 Hz, 3-H), 7.15-7.18 ( m, 2H, ArH), 7.29 (br s, 1H, NH), 7.46-7.51 (m, 2H, 2-H, 6-H), 7.63-7.66 (m, 2H, ArH), 7.69-7.73 (m , 1H, 7-H), 8.07-8.14 (m, 2H, 8-H, 5-H). ^{13 C NMR (100 MHz, CDCl} 3): 12.87,23.27 (2C), 53.80,54.27 (2C), 69.56,105.71,106.51,118.65,120.44 (2C), 121.11,123.86,127.10 (2C), 129.10,129.24 , 130.76, 140.15, 142.48, 142.92, 146.00, 155.58, 163.22. For C ₂₅ H ₂₆ N ₄ O ₂ ‧1.0 H ₂ O 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 About _{C 25 H 27 N 4 O 2} [M + H] + of HRMS (ESI) calcd: 415.2134; Found: 415.2135.

Synthesis Example 6. ( E ) -1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine { (E) -1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl Oxime} (compound 13f)

Compound 13f was prepared essentially according to the procedure described in Synthesis Example 1 above, except that 2-piperidin-1-ylethoxyamine hydrochloride (2-piperidin-1-ylethoxyamine) was used. HCl) replaces 2-aminoethoxyamine hydrochloride and does not require a recrystallization step. The title compound 13f was obtained as a brown liquid (yield: 85%).

The nature of the title compound was measured:

IR (KBr): 3221, 1579, 1519. UV (MeOH): 368 (4.15), 260 (4.51), 206 (4.51). ¹ H NMR (400 MHz, CDCl ₃ ): 1.44-1.48 (m, 2H, Pip-H), 1.57-1.65 (m, 4H, Pip-H), 2.25 (s, 3H, CH ₃ ), 2.53-2.78 (m, 4H, Pip-H), 3.81 (t, 2H, J = 5.6 Hz, OCH ₂ CH ₂ N), 4.37 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ N), 6.18 (d , 1H, J = 2.4 Hz, 3-H), 7.02 (br s, 1H, NH), 7.14 - 7.17 (m, 2H, ArH), 7.46-7.50 (m, 2H, 2-H, 6-H) , 7.66-7.73 (m, 3H, 7-H, ArH), 8.05-8.10 (m, 2H, 8-H, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.65, 24.13, 25.79, 25.87, 54.89, 54.93, 57.85, 72.18, 105.72, 106.06, 118.34, 120.72, 120.94 (2C), 123.78, 127.04 (2C), 129.17 (2C ), 132.11, 140.38, 141.71, 142.77, 145.99, 153.83, 163.28. About _{C 26 H 29 N 4 O 2} [M + H] + of HRMS (ESI) calcd: 429.2290; Found: 429.2292.

Synthesis Example 7. (E)-1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine { (E) - 1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholinoethyl oxime} (compound 13g)

Compound 13g was prepared essentially according to the procedure described in Synthesis Example 1 above, except that 2-morpholinoethoxyamine hydrochloride (2-morpholinoethoxyamine HCl) was used instead of 2-aminoethyl ethoxylate. Amine hydrochloride. The title compound 13g was obtained as a pale yellow solid (yield: 73%).

The nature of the title compound was measured:

Mp 59-62 ° C. IR (KBr): 3269, 1578, 1518. UV (MeOH): 372 (4.33), 260 (4.67), 208 (4.62). ¹ H NMR (400 MHz, CDCl ₃ ): 2.25 (s, 3H, CH ₃ ), 2.58-2.60 (m, 4H, Mor-H), 2.78 (t, 2H, J = 5.6 Hz, OCH ₂ CH ₂ N ), 3.73-3.76 (m, 4H, Mor-H), 4.37 (t, 2H, J = 5.6 Hz, O CH ₂ CH ₂ N), 6.18 (d, 1H, J = 2.8 Hz, 3-H), 6.97 (br s, 1H, NH), 7.14 - 7.17 (m, 2H, ArH), 7.46-7.50 (m, 2H, 2-H, 6-H), 7.66-7.73 (m, 3H, 7-H, ArH), 8.04-8.10 (m, 2H, 8-H, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.70, 54.05 (2C), 57.61, 60.95 (2C), 72.03, 105.70, 106.13, 118.36, 120.66, 120.88 (2C), 123.84, 127.06 (2C), 129.19 (2C ), 131.97, 140.28, 141.78, 142.83, 145.98, 154.02, 163.26. For C ₂₅ H ₂₆ N ₄ O ₃ ‧0.5 H ₂ O: C, 68.32; H, 6.19; N, 12.75; found: C, 68.20; H, 6.21.; N, 12.78. About _{C 25 H 27 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 431.2083; Found: 431.2080.

Synthesis Example 8. ( E ) -1-(4-(furan[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -4-morphophene butyl hydrazine { (E) -1-(4-(Furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholinobutyl oxime} (compound 13h)

Compound 13h was prepared essentially according to the procedure described in Synthesis Example 1 above, except that 4-morpholinobutoxyamine hydrochloride (4-morpholinobutoxyamine HCl) was used instead of 2-aminoethyl ethoxylate. Amine hydrochloride. The title compound 13h was obtained as a pale yellow solid (yield: 73%).

The nature of the title compound was measured:

Mp: 87-88 ° C. IR (KBr): 3263, 1579, 1518. UV (MeOH): 368 (4.23), 260 (4.60), 208 (4.57). ¹ H NMR (400 MHz, CDCl ₃ ): 1.62-1.79 (m, 4H, OCH ₂ ( CH ₂ ) ₂ CH ₂ N), 2.25 (s, 3H, CH ₃ ), 2.38-2.46 (m, 6H, OCH ₂ (CH ₂ ) ₂ CH ₂ N,Mor-H), 3.72-3.74 (m, 4H, Mor-H), 4.23 (t, 2H, J = 5.6 Hz, O CH ₂ (CH ₂ ) ₂ CH ₂ N ), 6.16 (d, 1H, J = 2.8 Hz, 3-H), 7.06 (br s, 1H, NH), 7.14-7.16 (m, 2H, ArH), 7.45-7.46 (m, 2H, 2-H) , 6-H), 7.66-7.70 (m, 3H, 7-H, ArH), 8.04-8.09 (m, 2H, 8-H, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.54, 23.07, 27.18, 53.68 (2C), 58.82, 66.93 (2C), 73.94, 105.72, 105.99, 118.30, 120.69, 121.00 (2C), 123.78, 126.99 (2C) , 129.14, 129.18, 132.23, 140.42, 141.64, 142.74, 145.96, 153.60, 163.27. For C ₂₇ H ₃₀ N ₄ O ₃ ‧ 0.8 H ₂ O: C, 68.56; H, 6.73; N, 11.84; Found: C, 68.47; H, 6.94; N, 11.81. About _{C 27 H 31 N 4 O 3} [M + H +] of HRMS (ESI) calcd: 459.2396; Found: 459.2399.

Synthesis Example 9. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-aminoethyl hydrazine {( E ) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethyl oxime} (compound 14a)

First, 1-(4-(3-chlorofuran[2,3- b ]quinoline-) was prepared according to the method described in Chen YL et al . (2005), J. Med. Chem ., 40:928-934. 4-Aminoamino)phenyl)ethanone (Compound 10 ). Next, the obtained compound 10 (0.30 g, 1 mmol), 2-aminoethoxyamine hydrochloride (0.28 g, 2.5 mmol) and K ₂ CO ₃ (0.69 g, 5.0 mmol) were combined with EtOH ( A mixture was obtained in 10 mL), which was refluxed for 4 hours (TLC) and then evaporated under reduced pressure. The residue formed is dissolved in CH ₂ Cl ₂ (50 mL), followed by water, followed by brine to be washed. After that, it was dried over Na ₂ SO ₄ , then the organic phase was evaporated and the residue formed was purified by flash column chromatography (MeOH/CH ₂ Cl ₂ = 1/50), followed by EtOH The title compound 14a (yield 95%) was obtained as a yellow solid.

The nature of the title compound was measured:

Mp: 169-172 °C. IR (KBr): 3146, 1580, 1514. UV (MeOH): 382 (4.09), 264 (4.32), 236 (4.53), 208 (4.52). ¹ H NMR (400 MHz, CDCl ₃ ): 2.22 (s, 3H, CH ₃ ), 3.04 (t, 2H, J = 5.2 Hz, OCH ₂ CH ₂ N), 4.22 (t. 2H, J = 5.2 Hz, O CH ₂ CH ₂ N), 6.86-6.89 (m, 2H, ArH), 7.18 (br s, 1H, NH), 7.29-7.34 (m, 1H, 6-H), 7.53-7.56 (m, 2H, ArH), 7.66-7.70 (m, 2H, 2-H, 7-H), 7.81 (dd, 1H, J = 8.8, 0.8 Hz, 5-H), 8.06 (d, J = 8.8 Hz, 8-H) ). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.56, 41.55, 75.66, 107.99, 110.11, 118.09 (2C), 120.05, 123.99, 124.41, 127.11 (2C), 129.09, 129.89, 130.68, 140.65, 141.53, 144.62, 146.77 , 154.44, 160.73. For C ₂₁ H ₁₉ ClN ₄ O ₂ ‧0.4 H ₂ O: C, 62.74; H, 4.96; N, 13.94; Found: C, 62.40; H, 5.17; N, 13.76. About _{C 21 H 20 ClN 4 O 2} [M + H] + of HRMS (ESI) calcd: 395.1275; Found: 395.1274.

Synthesis Example 10. ( E ) -1-(4-(3-chlorofuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine {( E ) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl oxime} (compound 14b)

Compound 14b was prepared essentially according to the procedure described in Synthesis Example 9 above, except that 2-dimethylaminoethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. . The title compound 14b was obtained as a yellow solid (yield: 97%).

The nature of the title compound was measured:

Mp: 118-122 ° C. IR (KBr): 3398, 1578, 1520. UV (MeOH): 382 (4.12), 264 (4.33), 234 (4.50), 210 (4.48). ¹ H NMR (400 MHz, CDCl ₃ ): 2.22 (s, 3H, CH ₃ ), 2.51 (s, 6H, N (CH ₃ ) 2 ₎ , 2.94 (t, 2H, J = 5.4 Hz, OCH ₂ CH ₂ N), 4.42 (t, 2H, J = 5.4 Hz, O CH ₂ CH ₂ N), 6.86-6.90 (m, 2H, ArH), 7.19 (br s, 1H, NH), 7.32-7.36 (m, 1H) ,6-H),7.53-7.56(m,2H,ArH), 7.67-7.71(m,2H,2-H,7-H),7.83-7.86(m,1H,5-H),8.07-8.09 (m, 1H, 8-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.78, 45.10 (2C), 57.48, 70.87, 110.10, 117.10, 118.01 (2C), 120.09, 124.02, 124.39, 127.14 (2C), 129.10, 129.91, 130.38, 140.70, 141.44, 144.75, 146.75, 154.77, 160.72. For C ₂₃ H ₂₃ ClN ₄ O ₂ ‧1.5 H ₂ O: C, 61.40; H, 5.83; N, 12.45; found: C, 61.17; H, 5.98; N, 12.09. About _{C 23 H 24 ClN 4 O 2} [M + H] + of HRMS (ESI) calcd: 423.1588; Found: 423.1587.

Synthesis Example 11. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O 3-aminopropyl hydrazine { ( E ) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-aminopropyl oxime} (compound 14c)

Compound 14c was prepared essentially according to the procedure described in the above Synthesis Example 9, except that 3-aminopropoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 14c was obtained as a dark brown solid (yield 98%).

The nature of the title compound was measured:

Mp: 114-116 ° C. IR (KBr): 3143, 1579, 1512. UV (MeOH): 382 (4.11), 264 (4.32), 234 (4.50), 210 (4.49). ¹ H NMR (400 MHz, CDCl ₃ ): 1.92 (quin, 2H, J = 6.4 Hz, OCH ₂ CH ₂ CH ₂ N), 2.19 (s, 3H, CH ₃ ), 2.90 (t, 2H, J = 6.8 Hz, OCH ₂ CH ₂ CH ₂ N), 4.26 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ CH ₂ N), 6.87-6.90 (m, 2H, ArH), 7.19 (br s, 1H, NH), 7.30-7.34 (m, 1H, 6-H), 7.53-7.56 (m, 2H, ArH), 7.66-7.70 (m, 2H, 2-H, 7-H), 7.82 (dd, 1H, J = 8.4, 1.0 Hz, 5-H), 8.06 (d, 1H, J = 8.4 Hz, 8-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.55, 32.43, 39.09, 71.75, 107.94, 110.13, 118.16 (2C), 120.04, 123.98, 124.43, 127.09 (2C), 129.08, 129.90, 130.83, 140.63, 141.61, 144.56 , 146.78, 154.02, 160.75. About _{C 22 H 22 ClN 4 O 2} [M + H] + of HRMS (ESI) calcd: 409.1431; Found: 409.1430.

Synthesis Example 12. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine { (E) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl oxime} (compound 14d)

Compound 14d was prepared essentially according to the procedure described in Synthesis Example 9 above, except that 3-dimethylaminopropoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. . The title compound 14d was obtained as a yellow solid (yield: 96%).

The nature of the title compound was measured:

Mp: 104-106 ° C. IR (KBr): 3147, 1578, 1520. UV (MeOH): 382 (4.17), 266 (4.45), 236 (4.62), 208 (4.59). ¹ H NMR (400 MHz, CDCl ₃ ): 1.87-1.94 (m, 2H, OCH ₂ CH ₂ CH ₂ N), 2.20 (s, 3H, CH ₃ ), 2.26 (s, 6H, N (CH ₃ ) ₂ ), 2.39-2.42 (m, 2H, OCH ₂ CH ₂ CH ₂ N), 4.21 (t, 2H, J = 6.4 Hz, O CH ₂ CH ₂ CH ₂ N), 6.87-6.90 (m, 2H, ArH) , 7.18 (br s, 1H, NH), 7.30-7.34 (m, 1H, 6-H), 7.54-7.57 (m, 2H, ArH), 7.66-7.70 (m, 2H, 2-H, 7-H ), 7.82 (dd, 1H, J = 8.6, 1.0 Hz, 5-H), 8.06 (d, 1H, J = 8.4 Hz, 8-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.49, 27.52, 45.44 (2C), 56.52, 72.29, 107.86, 110.11, 118.18 (2C), 119.99, 123.94, 124.46, 127.06 (2C), 129.08, 129.87, 131.04, 140.58, 141.65, 144.43, 146.80, 153.75, 160.74. Analysis calculated values for _{C 24 H 25 ClN 4 O 2} ‧0.5 H 2 O of: C, 64.64; H, 5.88 ; N, 12.56; Found: C, 64.41; H, 6.03 ; N, 12.77. About _{C 24 H 26 ClN 4 O 2} [M + H]] + of HRMS (ESI) calcd: 437.1744; Found: 437.1747.

Synthesis Example 13. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine {( E ) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl oxime} (Compound 14e)

Compound 14e was prepared essentially according to the procedure described in Synthesis Example 9 above, except that 2-pyrrolidin-1-ylethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. salt. The title compound 14e was obtained as a yellow solid (yield: 92%).

The nature of the title compound was measured:

Mp: 208-210 °C. IR (KBr): 3241, 1578, 1513. UV (MeOH): 382 (4.15), 286 (4.31), 264 (4.37), 236 (4.58). ¹ H NMR (400 MHz, CDCl ₃ ): 2.12 (br s, 4H, Pyr-H), 2.22 (s, 3H, CH ₃ ), 3.32-3.40 (m, 6H, Pyr-H, OCH ₂ CH ₂ N ), 4.62-4.65 (m, 2H, O CH ₂ CH ₂ N), 6.87-6.90 (m, 2H, ArH), 7.19 (br s, 1H, NH), 7.33 - 7.37 (m, 1H, 6-H ), 7.53 - 7.56 (m, 2H, ArH), 7.68 - 7.73 (m, 2H, 2-H, 7-H), 7.84 - 7.87 (m, 1H, 5-H), 8.08-8.10 (m, 1H) , 8-H). ^{13 C NMR (100 MHz, CDCl} 3): 12.86,23.26 (2C), 53.66,54.20 (2C), 69.26,108.36,110.10,117.80 (2C), 120.27,124.12,124.28,127.20 (2C), 129.16,129.68 , 129.94, 140.85, 141.21, 145.15, 146.75, 155.76, 160.72. For C ₂₅ H ₂₅ ClN ₄ O ₂ ‧0.2H ₂ O ‧ 1.0 H ₂ O: C, 61.40; H, 5.44; N, 11.46; found: C, 61.61; H, 5.64; N, 11.16 . About _{C 25 H 26 ClN 4 O 2} [M + H] + of HRMS (ESI) calcd: 449.1744; Found: 449.1746.

Synthesis Example 14. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine {( E )-1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl oxime} (compound 14f)

Compound 14f was prepared essentially according to the procedure described in Synthesis Example 9 above, except that 2-piperidin-1-ylethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. salt. The title compound 14f was obtained as a yellow solid (yield 69%).

The nature of the title compound was measured:

Mp: 136-138 °C. IR (KBr): 3386, 1578, 1516. UV (MeOH): 382 (4.17), 266 (4.49), 236 (4.62), 206 (4.66). ¹ H NMR (400 MHz, CDCl ₃ ): 1.41-1.65 (m, 6H, Pip-H), 2.20 (s, 3H, CH ₃ ), 2.52 (br s, 4H, Pip-H), 2.75 (t, 2H, J = 6.0 Hz, OCH ₂ CH ₂ N), 4.23 (t, 2H, J = 6.2 Hz, O CH ₂ CH ₂ N), 6.86-6.90 (m, 2H, ArH), 7.18 (br s, 1H) , NH), 7.30-7.35 (m, 1H, 6-H), 7.54-7.57 (m, 2H, Ar-H), 7.67-7.57 (m, 2H, 2-H, 7-H), 7.82-7.86 (m, 1H, 5-H), 8.06-8.09 (m, 1H, 8-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.65, 24.08, 25.80 (2C), 54.88 (2C), 57.78, 72.01, 107.91, 110.10, 118.13 (2C), 120.00, 123.95, 124.44, 127.08 (2C), 129.08 , 129.87, 130.86, 140.61, 141.99, 144.49, 146.77, 153.96, 160.73. Analysis calculated values for _{C 26 H 27 ClN 4 O 2} ‧1.1 H 2 O‧1.0HCl of: C, 60.14; H, 5.86 ; N, 10.79; Found: C, 59.92; H, 6.12 ; N, 10.47. About _{C 26 H 28 ClN 4 O 2} [M + H] + of HRMS (ESI) calcd: 463.1901; Found: 463.1904.

Synthesis Example 15. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O - 2-morpholine and ethyl hydrazine { (E) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholinoethyl oxime} (compound 14g)

Compound 14g was prepared essentially according to the procedure described in the above Synthesis Example 9, except that 2-morpholine and ethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 14g was obtained as a pale yellow solid (yield: 96%).

The nature of the title compound was measured:

Mp: 118-121 °C. IR (KBr): 3391, 1579, 1514. UV (MeOH): 382 (4.11), 264 (4.34), 234 (4.50), 210 (4.49). ¹ H NMR (400 MHz, CDCl ₃ ): 2.19 (s, 3H, CH ₃ ), 2.54-2.57 (m, 4H, Mor-H), 2.75 (t, 2H, J = 5.6 Hz, OCH ₂ CH ₂ N ), 3.72-3.74 (m, 4H, Mor-H), 4.33 (t, 2H, J = 5.6 Hz, O CH ₂ CH ₂ N), 6.86-6.89 (m, 2H, ArH), 7.18 (br s, 1H, NH), 7.28-7.33 (m, 1H, 6-H), 7.52-7.56 (m, 2H, ArH), 7.67-7.70 (m, 2H, 2-H, 7-H), 7.81 (dd, 1H, J = 8.8, 0.8 Hz, 5-H), 8.06 (dd, 1H, J = 8.6, 0.6 Hz, 8-H). ^{13 C NMR (100 MHz, CDCl} 3): 12.63,53.98 (2C), 57.54,66.90 (2C), 71.87,107.97,110.06,117.97 (2C), 120.03,123.91,124.33,127.03 (2C), 129.00,129.82 , 130.60, 140.60, 141.44, 144.56, 146.67, 154.03, 160.66. For C ₂₅ H ₂₅ ClN ₄ O ₃ ‧1.0 H ₂ O δ 0.5 HCl calcd.: C, 59.91; H, 5.53; N, 11.18; Found: C, 60.05; H, 5.68; N, 10.88. About _{C 25 H 26 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 465.1693; Found: 465.1695.

Synthesis Example 16. ( E )-1-(4-(3-chlorofuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -4-morphophene butyl hydrazine {( E ) -1-(4-(3-Chlorofuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholinobutyl oxime} (compound 14h)

Compound 14h was prepared essentially according to the procedure described in the above Synthesis Example 9 except that 4-morpholine-butoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 14h was obtained as a yellow solid (yield 86%).

The nature of the title compound was measured:

Mp: 112-113 ° C. IR (KBr): 3138, 1614, 1580, 1512. UV (MeOH): 382 (4.14), 266 (4.45), 236 (4.58), 206 (4.56). ¹ H NMR (400 MHz, CDCl ₃ ): 1.60-1.77 (m, 4H, OCH ₂ ( CH ₂ ) ₂ CH ₂ N), 2.20 (s, 3H, CH ₃ ), 2.40 (t, 2H, J = 7.6 Hz, OCH ₂ (CH ₂ ) ₂ CH ₂ N), 2.46 (br s, 4H, Mor-H), 3.72-3.74 (m, 4H, Mor-H), 4.19 (t, 2H, J = 6.4 Hz, O CH ₂ (CH ₂ ) ₂ CH ₂ N), 6.86-6.90 (m, 2H, ArH), 7.17 (br s, 1H, NH), 7.30-7.34 (m, 1H, 6-H), 7.53-7.57 (m, 2H, ArH), 7.66-7.71 (m, 2H, 2-H), 7.82 (dd, 1H, J = 8.4, 1.2 Hz, 5-H), 8.06 (dd, 1H, J = 8.4, 0.4 Hz, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.53, 23.04, 27.17 (2C), 53.67 (2C), 58.82, 66.90, 73.84, 107.90, 110.12, 118.19 (2C), 120.01, 123.95, 124.45, 127.06 (2C) , 129.11, 129.87, 131.04, 140.61, 141.33, 144.46, 144.81, 153.70, 160.75. For C ₂₇ H ₂₉ ClN ₄ O ₃ ‧0.3 H ₂ O: C, 65.06; H, 5.99; N, 11.24; Found: C, 64.96; H, 6.25; N, 11.07. About _{C 27 H 30 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 493.2006; Found: 493.2004.

Synthesis Example 17. ( E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O - 2-aminoethyl hydrazine { (E) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethyl oxime} (compound 15a)

First, 1-(4-(7-methoxyfuran[2,3- b ]quina) was prepared according to the method described in Chen YL et al. (2005), J. Med. Chem. , 40:928-934. Polin-4-ylamino)phenyl)ethanone (Compound 11 ). Next, the obtained compound 11 (0.33 g, 1 mmol), 2-aminoethoxyamine hydrochloride (0.28 g, 2.5 mmol) and K ₂ CO ₃ (0.69 g, 5.0 mmol) were combined with EtOH ( A mixture was obtained in 10 mL), which was refluxed for 4 hours (TLC) and then evaporated under reduced pressure. The residue formed is dissolved in CH ₂ Cl ₂ (50 mL), followed by water, followed by brine to be washed. After drying with Na ₂ SO ₄ , the organic phase was evaporated and the residue formed was purified by flash column chromatography (MeOH/CH ₂ Cl ₂ = 1/50). The title compound 15a (0.26 g, yield 66%) was obtained as a dark green solid.

The nature of the title compound was measured:

Mp: 91-93 ° C. IR (KBr): 3219, 1581, 1517. UV (MeOH): 358 (4.22), 248 (4.44), 212 (4.48). ¹ H NMR (400 MHz, DMSO- d ₆ ): 2.22 (s, 3H, CH ₃ ), 2.88 (t, 2H, J = 5.8 Hz, OCH ₂ CH ₂ N), 3.92 (s, 3H, OCH ₃ ) , 4.12 (t, 2H, J = 5.8 Hz, O CH ₂ CH ₂ N), 6.08 (d, 1H, J = 2.4 Hz, 3-H), 7.13-7.19 (m, 3H, 6-H, ArH) , 7.29 (d, 1H, J = 2.4 Hz, 2-H), 7.66-7.69 (m, 2H, ArH), 7.74 (d, 1H, J = 2.8 Hz, 8-H), 8.27 (d, 1H, J = 9.6 Hz, 5-H), 9.48 (br s, 1H, NH). ^{13 C NMR (100 MHz, DMSO-} d 6): 12.20,40.72,55.35,75.17,103.70,105.72,106.75,113.14,115.49,120.69 (2C), 124.39,126.59 (2C), 130.28,141.47,142.06,142.73 , 147.70, 153.70, 160.09, 163.44. About _{C 22 H 23 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 391.1770; Found: 391.1769.

Synthesis Example 18. ( E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine { (E) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl oxime} (compound 15b)

Compound 15b was prepared essentially according to the procedure described in the above Synthesis Example 17, except that 2-dimethylaminoethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. . The title compound 15b was obtained as a pale yellow solid (yield: 88%).

The nature of the title compound was measured:

Mp: 150-152 °C. IR (KBr): 3256, 1580, 1518. UV (MeOH): 360 (4.26), 250 (4.47), 210 (4.50). ¹ H NMR (400 MHz, CDCl ₃ ): 2.26 (s, 3H, CH ₃ ), 2.36 (s, 6H, N (CH ₃ ) ₂ ), 2.75 (t, 2H, J = 5.8 Hz, OCH ₂ CH ₂ N), 3.95 (s, 3H, OCH ₃ ), 4.34 (t, 2H, J = 5.8 Hz, O CH ₂ CH ₂ N), 6.16 (d, 1H, J = 2.4 Hz, 3-H), 6.95 ( Br s, 1H, NH), 7.10-7.15 (m, 3H, 6-H, ArH), 7.39 (d, 1H, J = 2.4 Hz, 2-H), 7.40 (d, 1H, J = 2.8 Hz, 8-H), 7.65-7.68 (m, 2H, ArH), 7.92 (d, 1H, J = 9.2 Hz, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.70, 45.85 (2C), 55.48, 58.17, 72.21, 104.80, 105.74, 107.20, 113.24, 116.74, 120.72 (2C), 122.04, 127.04 (2C), 131.86, 140.47, 141.80, 141.87, 148.04, 154.04, 160.57, 163.85. Analysis calculated values for _{C 24 H 26 N 4 O 3} ‧0.5 H 2 O of: C, 67.43; H, 6.37 ; N, 13.11; Found: C, 67.43; H, 6.58 ; N, 12.83. About _{C 24 H 27 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 419.2083; Found: 419.2086.

Synthesis Example 19. ( E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O 3-aminopropyl hydrazine { (E) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-aminopropyloxime} (compound 15c)

Compound 15c was prepared essentially according to the procedure described in Synthesis Example 17 above, except that 3-aminopropoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. Salt, and does not require the step of recrystallization. The title compound 15c was obtained as a pale yellow liquid (yield 68%).

The nature of the title compound was measured:

IR (KBr): 3220, 1582, 1518. UV (MeOH): 362 (4.12), 260 (4.35), 210 (4.40). ¹ H NMR (400 MHz, DMSO- d ₆ ): 1.82 (quin, 2H, J = 6.6 Hz, OCH ₂ CH ₂ CH ₂ N), 2.20 (s, 3H, CH ₃ ), 2.73 (t, 2H, J = 6.8 Hz, OCH ₂ CH ₂ CH ₂ N), 3.92 (s, 1H, OCH ₃ ), 4.19 (t, 2H, J = 6.4 Hz, O CH ₂ CH ₂ CH ₂ N), 6.08 (d, 1H, J = 2.4 Hz, 3-H), 7.12-7.18 (m, 3H, 6-H, ArH), 7.28 (d, 1H, J = 2.4 Hz, 2-H), 7.66-7.69 (m, 2H, ArH ), 7.74 (d, 1H, J = 2.8 Hz, 8-H), 8.28 (d, 1H, J = 9.6 Hz, 5-H), 9.50 (br s, 1H, NH). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 12.11, 31.28, 37.87, 55.34, 71.14, 103.68, 105.72, 106.74, 113.14, 115.46, 120.68 (2C), 124.40, 126.54 (2C), 130.29, 141.47, 142.05 , 142.71, 147.70, 153.36, 160.08, 163.33. About _{C 23 H 25 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 405.1927; Found: 405.1926.

Synthesis Example 20. E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine { (E) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl Oxime} (compound 15d)

Compound 15d was prepared essentially according to the procedure described in the above Synthesis Example 17, except that 3-dimethylaminopropoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. . The title compound 15d was obtained as a pale yellow solid (yield: 79%).

The nature of the title compound was measured:

Mp: 95-97 ° C. IR (KBr): 3327, 1580, 1516. UV (MeOH): 364 (4.32), 264 (4.60), 206 (4.61). ¹ H NMR (400 MHz, DMSO- d ₆ ): 1.82 (quin, 2H, J = 6.6 Hz, OCH ₂ CH ₂ CH ₂ N), 2.18 (s, 6H, N( CH ₃ ) ₂ ), 2.19 (s , 3H, CH ₃ ), 2.37 (t, 2H, J = 7.2 Hz, OCH ₂ CH ₂ CH ₂ N), 3.92 (s, 1H, OCH ₃ ), 4.15 (t, 2H, J = 6.4 Hz, O CH ₂ CH ₂ CH ₂ N), 6.08 (d, 1H, J = 2.8 Hz, 3-H), 7.13-7.19 (m, 3H, 6-H, ArH), 7.29 (d, 1H, J = 2.4 Hz, 2-H), 7.66-7.68 (m, 2H, ArH), 7.74 (d, 1H, J = 2.8 Hz, 8-H), 8.27 (d, 1H, J = 9.2 Hz, 5-H), 9.47 ( Br s, 1H, NH). ^{13 C NMR (100 MHz, DMSO-} d 6): 12.11,26.81,44.97 (2C), 55.34,55.67,71.60,103.68,105.72,106.75,113.13,115.46,120.69 (2C), 124.38,126.54 (2C), 130.33, 141.47, 142.05, 142.68, 147.70, 153.31, 160.08, 163.33. For C ₂₅ H ₂₈ N ₄ O ₃ ‧1.2 H ₂ O: C, 66.12; H, 6.75; N, 12.34; Found: C, 66.28; H, 6.82; N, 12.08. About _{C 25 H 29 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 433.2240; Found: 433.2243.

Synthesis Example 21. ( E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine{ (E) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O - 2-(pyrrolidin-1-yl)ethyl oxime} (Compound 15e)

Compound 15e was prepared essentially according to the procedure described in the above Synthesis Example 17, except that 2-pyrrolidin-1-ylethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. salt. The title compound 15e was obtained as a pale yellow solid (yield 81%).

The nature of the title compound was measured:

Mp: 123-124 °C. IR (KBr): 3244, 1585, 1525. UV (MeOH): 362 (4.28), 260 (4.50), 210 (4.54). ¹ H NMR (400 MHz, DMSO- d ₆ ): 1.69-1.72 (m, 4H, Pyr-H), 2.20 (s, 3H, CH ₃ ), 2.60 (br s, 4H, Pyr-H), 2.83 ( t, 2H, J = 5.6 Hz, OCH ₂ CH ₂ N), 3.91 (s, 3H, OCH ₃ ), 4.24 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ N), 6.08 (d, 1H) , J = 2.8 Hz, 3-H), 7.13-7.18 (m, 3H, 6-H, ArH), 7.28 (d, 1H, J = 2.8 Hz, 2-H), 7.66-7.68 (m, 2H, ArH), 7.74 (d, 1H, J = 2.4 Hz, 5-H), 8.25 (d, 1H, J = 9.2 Hz, 8-H), 9.47 (br s, 1H, NH). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 12.33, 23.11 (2C), 54.13 (2C), 54.28, 55.40, 72.39, 103.73, 105.77, 106.75, 113.147, 115.56, 120.69 (2C), 124.42, 126.65 ( 2C), 130.21, 141.47, 142.13, 142.78, 147.73, 153.64, 160.12, 163.46. Analysis calculated values for _{C 26 H 28 N 4 O 3} ‧1.2 H 2 O of: C, 66.99; H, 6.57 ; N, 12.02; Found: C, 67.12; H, 6.73 ; N, 11.73. About _{C 26 H 29 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 445.2240; Found: 445.2241.

Synthesis Example 22. E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine {( E ) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl oxime} (compound 15f)

Compound 15f was prepared essentially according to the procedure described in the above Synthesis Example 17, except that 2-piperidin-1-ylethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. salt. The title compound 15f was obtained as a pale yellow solid (yield: 72%).

The nature of the title compound was measured:

M .p:. 116-119 ℃. IR (KBr): 3221, 1618, 1585, 1526. UV (MeOH): 362 (4.35), 260 (4.57), 210 (4.59). ¹ H NMR (400 MHz, DMSO- d ₆ ): 1.35-1.50 (m, 6H, Pip-H), 2.18 (s, 3H, CH ₃ ), 2.42 (m, 4H, Pip-H), 2.62 (t , 2H, J = 5.8 Hz, OCH ₂ CH ₂ N), 3.92 (s, 3H, OCH ₃ ), 4.22 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ N), 6.07 (d, 1H, J = 2.8 Hz, 3-H), 7.12-7.17 (m, 3H, 6-H, ArH), 7.29 (d, 1H, J = 2.8 Hz, 2-H), 7.65-7.68 (m, 2H, ArH ), 7.74 (d, 1H, J = 2.8 Hz, 5-H), 8.25 (d, 1H, J = 9.2 Hz, 8-H), 9.46 (br s, 1H, NH). ^{13 C NMR (100 MHz, DMSO-} d 6): 12.26,23.86,25.54 (2C), 54.40 (2C), 55.36,57.34,71.57,103.70,105.73,106.75,113.14,115.49,120.68 (2C), 124.37, 126.59 (2C), 130.24, 141.45, 142.07, 142.72, 147.70, 153.48, 160.09, 163.44. About _{C 27 H 31 N 4 O 3} [M + H] + of HRMS (ESI) calcd: 459.2396; Found: 459.2395.

Synthesis Example 23. E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine { ( E ) -1-(4-(7-Methoxyfuro[2,3- b ] Quinolin-4-ylamino)phenyl)ethanone O -2-morpholinoethyl oxime} (compound 15g)

Compound 15g was prepared essentially according to the procedure described in the above Synthesis Example 17, except that 2-morpholine and ethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 15g was obtained as a white solid (yield: 80%).

The nature of the title compound was measured:

Mp: 148-149 ° C. IR (KBr): 3208, 1617, 1578, 1524. UV (MeOH): 362 (4.32), 262 (4.56), 246 (4.53), 206 (4.61). ¹ H NMR (400 MHz, DMSO- d ₆ ): 2.18 (s, 3H, CH ₃ ), 2.43 - 2.46 (m, 4H, Mor-H), 2.64 (t, 2H, J = 6.0 Hz, OCH ₂ CH ₂ N), 3.57 (m, 4H, Mor-H), 3.91 (s, 3H, OCH ₃ ), 4.24 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ N), 6.07 (d, 1H, J = 2.8 Hz, 3-H), 7.137.18 (m, 3H, 6-H, ArH), 7.28 (d, 1H, J = 2.4 Hz, 2-H), 7.65-7.68 (m, 2H, ArH ), 7.74 (d, 1H, J = 2.8 Hz, 5-H), 8.25 (d, 1H, J = 9.6 Hz, 8-H), 9.46 (br s, 1H, NH). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 12.33, 53.72 (2C), 55.40, 57.10, 66.24 (2C), 71.43, 103.72, 105.77, 106.75, 113.16, 115.56, 120.70 (2C), 124.41, 126.63 ( 2C), 130.24, 141.47, 142.12, 142.75, 147.73, 153.60, 160.12, 163.46. Analysis calculated values for C ₂₆ H ₂₈ N ₄ O ₄ is: C, 67.81; H, 6.13 ; N, 12.16; Found: C, 67.98; H, 6.27 ; N, 11.71. About HRMS _{C 26 H 29 N 4 O 4} [M + H] + of (ESI) calcd: 461.2189; Found: 461.2187.

Synthesis Example 24. E )-1-(4-(7-methoxyfuran[2,3- b Quinoline-4-ylamino)phenyl)ethanone O -4-morphophene butyl hydrazine { (E) -1-(4-(7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholinobutyl oxime} 15h)

Compound 15h was prepared essentially according to the procedure described in the above Synthesis Example 17, except that 4-morpholine-butoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 15h was obtained as a white solid (yield: 71%).

The nature of the title compound was measured:

Mp: 100-102 ° C. IR (KBr): 3211, 1578, 1519. UV (MeOH): 362 (4.35), 260 (4.56), 210 (4.57). ¹ H NMR (400 MHz, CDCl ₃ ): 1.60-1.86 (m, 2H, OCH ₂ ( CH ₂ ) ₂ CH ₂ N), 2.25 (s, 3H, CH ₃ ), 2.39-2.46 (m, 6H, Mor -H, OCH ₂ (CH ₂ ) ₂ CH ₂ N), 3.72-3.74 (m, 4H, Mor-H), 3.95 (s, 3H, OCH ₃ ), 4.22 (t, 2H, J = 6.4 Hz, O CH ₂ (CH ₂ ) ₂ CH ₂ N), 6.15 (d, 1H, J = 2.8 Hz, 3-H), 6.90 (br s, 1H, NH), 7.10 (d, 1H, J = 2.4 Hz, 6 -H), 7.12-7.15 (m, 2H, ArH), 7.39 (d, 1H, J = 2.8 Hz, 2-H), 7.40 (d, 1H, J = 2.4 Hz, 5-H), 7.65-7.68 (m, 2H, ArH), 7.91 (d, 1H, J = 9.6 Hz, 8-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.55, 23.06, 27.18, 53.68 (2C), 55.48, 58.82, 66.91 (2C), 73.92, 104.70, 105.74, 107.18, 113.17, 116.73, 120.79 (2C), 121.98, 126.98(2C), 132.05, 140.48, 141.74, 141.77, 148.02, 153.63, 160.56, 163.85. For C ₂₈ H ₃₂ N ₄ O ₄ : C, 68.83; H, 6.60; N, 11.47; Found: C, 68.94; H, 6.81; N, 11.04. About _{C 28 H 33 N 4 O 4} [M + H] + of HRMS (ESI) calcd: 489.2502; Found: 489.2503.

Synthesis Example 25. ( E ) -1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamine Phenyl)ethanone O -2-aminoethyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl) ethanone O -2-aminoethyl Oxime} (compound 16a)

First, 1-(4-(3-chloro-7-methoxyfuran [2,3] was prepared according to the method described in Chen YL et al . (2005), J. Med. Chem ., 40:928-934. - b ] Quinoline-4-ylamino)phenyl)ethanone (Compound 12 ). Next, the obtained compound 12 (0.37 g, 1 mmol), 2-aminoethoxyamine hydrochloride (0.28 g, 2.5 mmol) and K ₂ CO ₃ (0.69 g, 5.0 mmol) were combined with EtOH ( A mixture was obtained in 10 mL), which was refluxed for 4 hours (TLC) and then evaporated under reduced pressure. The residue formed is dissolved in CH ₂ Cl ₂ (50 mL), followed by water, followed by brine to be washed. After drying with Na ₂ SO ₄ , the organic phase was evaporated and the residue formed was purified by flash column chromatography (MeOH/CH ₂ Cl ₂ = 1/50). The title compound 16a (yield 98%) was obtained as a yellow solid.

The nature of the title compound was measured:

Mp: 108-110 ° C. IR (KBr): 3133, 1580, 1520. UV (MeOH): 374 (4.15), 246 (4.49), 210 (4.47). ¹ H NMR (400 MHz, DMSO- d ₆ ): 2.14 (s, 3H, CH ₃ ), 2.81 (t, 2H, J = 6.4 Hz, OCH ₂ CH ₂ N), 3.94 (s, 3H, OCH ₃ ) , 4.05 (t, 2H, J = 5.8 Hz, O CH ₂ CH ₂ N), 6.85-6.87 (m, 2H, ArH), 7.20 (dd, 1H, J = 9.2, 2.4 Hz, 6-H), 7.37 (d, 1H, J = 2.4 Hz, 8-H), 7.49-7.52 (m, 2H, ArH), 8.11 (d, 1H, J = 9.2 Hz, 5-H), 8.24 (s, 1H, 2- H), 9.12 (br s, 1H, NH). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 12.12, 41.00, 55.57, 75.65, 106.72, 107.53, 109.95, 115.74 (2C), 116.64, 117.26, 124.84, 126.80 (2C), 127.76, 140.67, 141.13, 147.02 , 148.01, 153.59, 160.81, 161.35. About _{C 22 H 22 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 425.1380; Found: 425.1382.

Synthesis Example 26. ( E )-1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl oxime} (Compound 16b)

Compound 16b was prepared essentially according to the procedure described in Synthesis Example 25 above, except that 2-dimethylaminoethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. . The title compound 16b was obtained as a dark yellow solid (yield: 88%).

The nature of the title compound was measured:

Mp: 102-104 ° C. IR (KBr): 3130, 1581, 1518. UV (MeOH): 374 (4.19), 248 (4.55), 210 (4.55). ¹ H NMR (400 MHz, CDCl ₃ ): 2.21 (s, 3H, CH ₃ ), 2.33 (s, 6H, N (CH ₃ ) ₂ ), 2.70 (t, 2H, J = 6.0 Hz, OCH ₂ CH ₂ N), 3.95 (s, 3H, OCH ₃ ), 4.30 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ N), 6.87-6.89 (m, 2H, ArH), 6.96 (dd, 1H, J = 9.4, 2.6 Hz, 6-H), 7.12 (br s, 1H, NH), 7.36 (d, 1H, J = 2.6 Hz, 8-H), 7.54 - 7.56 (m, 2H, ArH), 7.61 ( s, 1H, 2-H), 7.68 (d, 1H, J = 9.4 Hz, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.71, 45.94 (2C), 55.51, 58.22, 72.26, 106.14, 106.86, 110.11 (2C), 114.80, 117.19, 118.11, 125.66, 127.11 (2C), 130.83, 139.40, 141.64, 144.48, 149.04, 154.05, 161.00, 161.38. Analysis calculated values for _{C 24 H 25 C1N 4 O 3} ‧0.2 H 2 O of: C, 63.12; H, 5.62 ; N, 12.27; Found: C, 62.94; H, 5.64 ; N, 12.07. About _{C 24 H 26 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 453.1693; Found: 453.1691.

Synthesis Example 27. E )-1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O 3-aminopropyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O - 3-aminopropyl oxime} (compound 16c)

Compound 16c was prepared essentially according to the procedure described in the above Synthesis Example 25, except that 3-aminopropoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 16c was obtained as a yellow solid (yield: 43%).

The nature of the title compound was measured:

Mp: 115-116 °C. IR (KBr): 3386, 1584, 1513. UV (MeOH): 374 (4.02), 344 (4.02), 246 (4.42), 206 (4.46). ¹ H NMR (400 MHz, CDCl ₃ ): 1.90 (quin, 2H, J = 6.8 Hz, OCH ₂ CH ₂ CH ₂ N), 2.14 (s, 3H, CH ₃ ), 2.83 (t, 2H, J = 7.2 Hz, OCH ₂ CH ₂ CH ₂ N), 3.94 (s, 3H, OCH ₃ ), 4.16 (t, 2H, J = 6.4 Hz, O CH ₂ CH ₂ CH ₂ N), 6.84-6.77 (m, 2H, ArH), 7.21 (dd, 1H, J = 9.6, 2.4 Hz, 6-H), 7.37 (d, 1H, J = 2.4 Hz, 8-H), 7.47-7.52 (m, 2H, ArH), 8.14 ( d, 1H, J = 9.6 Hz, 5-H), 8.24 (s, 1H, 2-H), 9.18 (br s, 1H, NH). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.10, 28.68, 36.91, 55.56, 70.39, 106.71, 107.56, 109.92, 115.69 (2C), 116.68, 117.55, 124.85, 126.43, 126.83 (2C), 140.63, 141.14, 147.13 , 148.03, 153.81, 160.82, 161.34. About _{C 23 H 24 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 439.1537; Found: 439.1535.

Synthesis Example 28. ( E )-1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl oxime} (compound 16d)

Compound 16d was prepared essentially according to the procedure described in the above Synthesis Example 25, except that 3-dimethylaminopropoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. . The title compound 16d was obtained as a dark yellow solid (yield: 79%).

The nature of the title compound was measured:

Mp: 96-98 ° C. IR (KBr): 3247, 1615, 1583, 1523. UV (MeOH): 374 (4.20), 346 (4.17), 248 (4.55), 210 (4.56). ¹ H NMR (400 MHz, CDCl ₃ ): 1.85-1.96 (m, 2H, OCH ₂ CH ₂ CH ₂ N), 2.20 (s, 3H, CH ₃ ), 2.28 (s, 6H, N ( CH ₃ ) ₂ ), 2.44 (t, 2H, J = 7.6 Hz, OCH ₂ CH ₂ CH ₂ N), 3.95 (d, 3H, OCH ₃ ), 4.22 (t, 2H, J = 6.4 Hz, O CH ₂ CH ₂ CH ₂ N), 6.86-6.90 (m, 2H, ArH), 6.96 (dd, 1H, J = 9.6, 2.6 Hz, 6-H), 7.12 (br s, 1H, NH), 7.36 (d, 1H, J = 2.6 Hz, 8-H), 7.54-7.56 (m, 2H, ArH), 7.61 (s, 1H, 2-H), 7.69 (d, 1H, J = 9.6 Hz, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.48, 27.40, 45.33 (2C), 55.50, 56.49, 72.20, 106.11, 106.89, 110.13, 114.80, 117.18, 118.15 (2C), 125.66, 127.08 (2C), 130.95, 139.38, 141.88, 144.43, 149.06, 153.80, 161.01, 161.39. Analysis calculated values for _{C 24 H 25 ClN 4 O 3} ‧1.0 H 2 O of: C, 61.91; H, 6.03 ; N, 11.55; Found: C, 61.61; H, 6.34 ; N, 11.57. About _{C 25 H 28 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 467.1850; Found: 467.1851.

Synthesis Example 29. ( E )-1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine{ (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl oxime} (Compound 16e)

Compound 16e was prepared essentially according to the procedure described in the above Synthesis Example 25, except that 2-pyrrolidin-1-ylethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. salt. The title compound 16e was obtained as a yellow solid (yield 98%).

The nature of the title compound was measured:

Mp: 116-117 ° C. IR (KBr): 3137, 1617, 1580, 1520. UV (MeOH): 374 (4.14), 344 (4.13), 246 (4.52), 206 (4.58). ¹ H NMR (400 MHz, CDCl ₃ ): 1.67-1.70 (m, 4H, Pyr-H), 2.13 (s, 3H, CH ₃ ), 2.50-2.55 (m, 4H, Pyr-H), 2.76-2.79 (m, 2H, OCH ₂ CH ₂ N), 4.19 (t, 2H, J = 6.0 Hz, O CH ₂ CH ₂ N), 6.84-6.88 (m, 2H, ArH), 7.20 (dd, 1H, J = 9.4, 2.6 Hz, 6-H), 7.37 (d, 1H, J = 2.6 Hz, 8-H), 7.48-7.52 (m, 2H, ArH), 8.12 (d, 1H, J = 9.6 Hz, 5- H), 8.24 (s, 1H, 2-H), 9.13 (br s, 1H, NH). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.22, 23.09 (2C), 54.07 (2C), 54.31, 55.57, 72.33, 106.72, 107.57, 109.94, 115.70 (2C), 116.66, 117.28, 124.84, 126.84 (2C) , 127.62, 140.65, 141.16, 147.08, 148.04, 153.59, 160.82, 161.34. For C ₂₆ H ₂₇ ClN ₄ O ₃ ‧0.1 HCl: C, 64.70; H, 5.66; N, 11.61; found: C, 64.75; H, 6.28; N, 11.29. About _{C 26 H 28 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 479.1850; Found: 479.1852.

Synthesis Example 30. ( E ) -1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl oxime} (compound 16f)

Compound 16f was prepared essentially according to the procedure described in the above Synthesis Example 25, except that 2-piperidin-1-ylethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. salt. The title compound 16f was obtained as a yellow solid (yield 98%).

The nature of the title compound was measured:

Mp: 126-127 °C. IR (KBr): 3135, 1617, 1580, 1521. UV (MeOH): 374 (4.13), 346 (4.12), 246 (4.47), 210 (4.47). ¹ H NMR (400 MHz, CDCl ₃ ): 1.34-1.38 (m, 2H, Pip-H), 1.44-1.51 (m, 4H, Pip-H), 2.11 (s, 3H, CH ₃ ), 2.37-2.46 (br s, 4H, Pip-H), 3.60 (t, 2H, J = 5.6 Hz, OCH ₂ CH ₂ N), 3.93 (s, 3H, OCH ₃ ), 4.17 (t, 2H, J = 2.6 Hz, O CH ₂ CH ₂ N), 6.83-6.87 (m, 2H, ArH), 7.20 (dd, 1H, J = 9.4, 2.6 Hz, 6-H), 7.36 (d, 1H, J = 2.6 Hz, 8- H), 7.48-7.51 (m, 2H, ArH), 8.11 (d, 1H, J = 9.4 Hz, 5-H), 8.24 (s, 1H, 2-H), 9.12 (br s, 1H, NH) . ¹³ C NMR (100 MHz, CDCl ₃ ): 12.24, 23.86, 25.52 (2C), 54.40 (2C), 55.60, 57.39, 71.39, 106.73, 107.58, 109.96, 115.72 (2C), 116.67, 117.31, 124.86, 126.86 ( 2C), 127.67, 140.67, 141.18, 147.08, 148.06, 153.59, 160.84, 161.36. For C ₂₇ H ₂₉ ClN ₄ O ₃ ‧0.4 H ₂ O: C, 64.83; H, 6.00; N, 11.20; Found: C, 64.78; H, 6.31; N, 11.08. About _{C 27 H 30 ClN 4 O 3} [M + H] + of HRMS (ESI) calcd: 493.2006; Found: 493.2005.

Synthesis Example 31. ( E )-1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholinoethyl oxime} (compound 16g)

Compound 16g was prepared essentially according to the procedure described in the above Synthesis Example 25, except that 2-morpholine and ethoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 16g was obtained as a pale yellow solid (yield: 99%).

The nature of the title compound was measured:

Mp: 99-101 ° C. IR (KBr): 3149, 1613, 1582, 1522. UV (MeOH): 374 (4.12), 344 (4.11), 248 (4.55), 206 (4.63). ¹ H NMR (400 MHz, CDCl ₃ ): 2.13 (s, 3H, CH ₃ ), 2.52-2.63 (br s, 4H, Mor-H), 2.72 (br s, 2H, OCH ₂ CH ₂ N), 3.54 -3.68 (m, 4H, Mor-H), 4.24 (m, 2H, O CH ₂ CH ₂ N), 6.85-6.87 (m, 2H, ArH), 7.21. (dd, 1H, J = 9.4, 2.6 Hz, 6-H), 7.37 (d, 1H, J = 2.6 Hz, 8-H), 7.50-7.52 (m, 2H, ArH), 8.12 (d, 1H, J = 9.4 Hz, 5-H), 8.24 ( s, 1H, 2-H), 9.15 (br s, 1H, NH). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.26, 53.42 (2C), 55.58, 56.78, 65.84 (2C), 71.26, 106.73, 107.60, 109.94, 115.70 (2C), 116.68, 117.27, 124.85, 126.88 (2C) , 127.55, 140.65, 141.16, 147.13, 148.04, 153.89, 160.83, 161.34. For C ₂₆ H ₂₇ ClN ₄ O ₄ ‧ 2.0 H ₂ O: C, 58.81; H, 5.88; N, 10.55; Found: C, 58.55; H, 6.15; N, 10.36. About _{C 26 H 28 ClN 4 O 4} [M + H] + of HRMS (ESI) calcd: 495.1799; Found: 495.1801.

Synthesis Example 32. ( E ) -1-(4-(3-chloro-7-methoxyfuran [2,3- b Quinoline-4-ylamino)phenyl)ethanone O -4-morphophene butyl hydrazine { (E) -1-(4-(3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholinobutyl oxime} (compound 16h)

Compound 16h was prepared essentially according to the procedure described in the above Synthesis Example 25, except that 4-morpholine-butoxyamine hydrochloride was used instead of 2-aminoethoxyamine hydrochloride. The title compound 16h was obtained as an orange solid (yield 98%).

The nature of the title compound was measured:

Mp: 124-126 ° C. IR (KBr): 3142, 1614, 1585, 1515. UV (MeOH): 374 (4.06), 344 (4.06), 246 (4.48), 206 (4.51). ¹ H NMR (400 MHz, CDCl ₃ ): 1.54-1.78 (m, 4H, OCH ₂ (CH ₂ ) ₂ CH ₂ N), 2.20 (s, 3H, CH ₃ ), 2.33 - 2.46 (m, 6H, OCH ₂ (CH ₂ ) ₂ CH ₂ N, Mor-H), 3.72-3.74 (m, 4H, Mor-H), 3.95 (s, 3H, OCH ₃ ), 4.19 (t, 2H, J = 6.4 Hz, O CH ₂ (CH ₂ ) ₂ CH ₂ N), 6.86-6.89 (m, 2H, ArH), 6.96 (dd, 1H, J = 9.4, 2.6 Hz, 6-H), 7.12 (br s, 1H, NH) , 7.36 (d, 1H, J = 2.6 Hz, 8-H), 7.54 - 7.56 (m, 2H, ArH), 7.61 (s, 1H, 2-H), 7.70 (d, 1H, J = 9.4 Hz, 5-H). ¹³ C NMR (100 MHz, CDCl ₃ ): 12.54, 23.02, 27.16, 53.65 (2C), 55.51, 58.81, 66.88 (2C), 73.82, 106.11, 106.86, 110.11, 114.78, 117.18, 118.16 (2C), 125.65, 127.06(2C), 130.95, 139.39, 141.66, 144.43, 149.04, 153.72, 161.00, 161.38. For C ₂₈ H ₃₁ ClN ₄ O ₄ ‧0.7 H ₂ O: C, 62.78; H, 6.10; N, 10.46; Found: C, 62.66; H, 6.40; N, 10.51. About _{C 28 H 31 ClN 4 O 4} [M + H] + of HRMS (ESI) calcd: 523.2112; Found: 523.2115.

Pharmacological Examples

In order to determine the biological activity of the compounds 13a-16h according to the invention, the following analysis was carried out.

Experimental Materials:

1. The type, source and registration number of the cell strain used in the following examples are shown in Table 2 below.

2. Male CD-1 (Crl.) mice (6 to 8 weeks old, weighing approximately 22 to 24 g) used in the following experiments were purchased from BioLasco Taiwan Co. , Ltd.), and Balb/C athymic nude mice (6 to 8 weeks old, weighing about 20 g) were purchased from the National Laboratory Animal Center (ROC). All experimental animals were housed in an independent air-conditioned animal room, and water and feed were adequately supplied. The breeding environment and experimental procedures of the experimental animals are in line with the international laboratory animal management standards.

Pharmacological Experiments 1. In Vitro Anticancer Analysis of Compounds of the Invention ( In In vitro Anticancer assay) A, evaluation of antiproliferative activity

Anti-proliferative activity was assessed by the method described in Tseng, CH et al. (2010), J. Med. Chem. , 53: 6164-6179. Briefly, three kinds of cancer cells (ie, breast cancer cell MCF7, non-small cell lung cancer cell NCI-H460, and central nervous system cancer cell SF-268) were inoculated to a density of 5×10 ³ cells/well, respectively. Dulbecco's Modified Eagle's Medium (DMEM) [containing 10% fetal bovine serum (FBS), 2 mM glutamine, 100 U/mL penicillin (penicillin) ) and wells of a 96-well culture dish of 100 g/mL streptomycin, and cultured at 37 ° C, 5% CO ₂ for 24 hours. Thereafter, the cells were treated with the compounds 13a-16h of the present invention [in dimethylsulfoxide (DMSO)] for 48 hours. In addition, DMSO-treated cells were used as a control group.

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [3-(4,5-dimethylthiazol-2) before and after treatment with the test compound -yl)-2,5-diphenyltetrazolium bromide, MTT] (2 mg/mL, 100 μL) was added to each well and cultured for 2 hours, and the formed formazan was dissolved by the addition of DMSO. The absorbance of each well was read at 570 nm using a microtiter plate reader (Dynex MRX-II). Cell growth (%) is calculated by substituting the measured absorbance value (OD ₅₇₀ ) into the following formula (1):

Formula (1): A = [(B'-B) / (C'-C)] × 100

Where: A = cell growth (%)

B = OD ₅₇₀ value measured before treatment with the test compound

B' = OD ₅₇₀ value measured after treatment with the test compound

C = OD ₅₇₀ value measured in the control group before treatment with DMSO

C' = OD ₅₇₀ value measured in the control group after treatment with DMSO

Further, for comparison, the inventors selected the compound 1 and ( E )-1-(4-furan[2,3- b ]quinolin-4-ylamino)phenyl)B disclosed in US 6,750,223 B2. Ketone oxime { (E) -1-(4-Furo[2,3- b ]quinolin-4-ylamino)phenyl}ethanone oxime} (disclosed in Example 7, Compound 2 ) and ( E )-1- (4-furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -methyloxime { (E) -1-(4-Furo[2,3- b ]quinolin- 4-ylamino)phenyl}ethanone O- methyloxime} (disclosed in Example 8, Compound 3 ) was subjected to the same experiment. The experimental results obtained are shown in Table 3 below.

As can be seen from Table 3, in terms of Compounds 1 to 3 , their antiproliferative activities did not significantly increase as the concentration increased. With respect to the compounds 13a-16h of the present invention, their antiproliferative activities are significantly increased as the concentration is increased. After considering the structure of each compound of the present invention and the evaluation results of the antiproliferative activity of Table 3, the inventors preliminarily selected compounds 13a , 13c , 14a , 14c , 15a and 16a and took them for the following experiments to further determine them. GI ₅₀ , selectivity index (SI), and water solubility.

B, GI ₅₀ And determination of the selectivity index (SI)

This experiment is generally carried out in accordance with the method described in Item A, "Evaluation of Antiproliferative Activity" above, except that: in addition to breast cancer cell MCF7, non-small cell lung cancer cell NCI-H460, and central nervous system cancer cell SF In addition to -268, the inventors also selected human lung fibroblast MRC-5 as a normal control.

GI ₅₀ means the concentration that causes 50% inhibition of cell growth by calculating the concentration of the treated cells to reduce the absorbance of the treated cells by 50% (compared to untreated control cells). It is determined from the linear part of the curve. The experiment was repeated 3 times and the experimental results obtained were expressed as mean ± standard deviation (SD).

As for the selection index, it is calculated by substituting the measured GI ₅₀ into the following formula (2):

Formula (2): D=E/F

Where: D = selection index

E = GI _{50 of the} test compound for normal control cells

F = GI _{50 of the} test compound for cancer cells

In addition, camptothecin and daunorubicin were used as a positive control group and the same experiment was performed. The experimental results obtained are summarized in Table 4 below.

As can be seen from Table 4, camptothecin and daunorubicin have lower GI ₅₀ for breast cancer cell MCF7, non-small cell lung cancer cell NCI-H460 and central nervous system cancer cell SF-268, respectively, but they all inhibit human lung. Growth of fibroblast MRC-5. In contrast, the compounds 13a , 13c , 14a , 14c , 15a and 16a of the present invention are less likely to inhibit the growth of human lung fibroblast MRC-5. In particular, although the GI _{50 of the} compounds 13a and 14a for non-small cell lung cancer cells NCI-H460 is higher than that of camptothecin and daunorubicin, respectively, they are extremely rare for non-small cell lung cancer cells NCI-H460. High selection index.

C. Determination of water solubility

To understand the effect of the aminoalkyl substitution at the oxime moiety on the water solubility of the compounds 13a-16h of the present invention, the following experiment was conducted. Further, for comparison, the hydrochloride of the compound 13a of the present invention was subjected to the same measurement.

The water solubility of the compound is determined by the method described in Vougogiannopoulou, K. et al . (2008), J. Med . Chem ., 51: 6421-6431. Briefly, excess compound was added to water, followed by sonication for 5 minutes and then stirred overnight at ambient temperature (25 ± 0.1 °C). After centrifugation at 4000 rpm for 5 minutes at 25 ° C, a part of the sample was taken out and the absorbance was measured with a UV-VIS spectrophotometer (JASCO UV-Visible V570) at a wavelength of 315-420 nm. The measured absorbance values were converted to water solubility (μg/mL) according to a standard curve previously prepared with compounds having different known concentrations relative to their own absorbance values, and the obtained experimental results were displayed. In Table 5 below.

As seen from Table 5, the compounds 13a , 13c , 14a , 14c , 15a and 16a of the present invention have a higher water solubility than the compounds 1 , 2 and 3 , and the compound 13a is the highest. In particular, as compared with the compound 2 below, the water solubility of the compound 13a than those compounds having two times higher than 6, which shows the introduction of amine group B (aminoethyl group) in the oxime moiety (oxime moiety) does have Helps increase water solubility. Further, the inventors have further found that when the compound 13a is reacted with HCl, the water solubility of the obtained hydrochloride is greatly increased to 1049 μg/mL, which is about 17 times higher than that of the compound 13a.

Based on the above experimental results, the compound of the present invention having the formula (I) is expected to be useful for the treatment of cancer. Among all the compounds of the formula (I), the inventors believe that the compounds 13a and 14a have the greatest development potential because of the high selection index and good water solubility, and they are used for the following pharmacological experiments.

Pharmacological Experiments 2. Single dose pharmacokinetic analysis of compounds 13a and 14a of the present invention experimental method:

A single dose pharmacokinetic analysis of compounds 13a and 14a of the present invention was commissioned by Rosetta Pharmamate Co., Ltd., ROC, Taiwan.

First, CD-1 mice were divided into 2 groups, of which group 1 mice (n=9) were used to evaluate single-dose pharmacokinetics of intravenous administration, while group 2 mice (n=9) were used. To evaluate single-dose pharmacokinetics for oral administration. From 4 hours before the start of the experiment, all mice were fasted until the 4th hour after administration.

Regarding the evaluation of single-dose pharmacokinetics of the test compound via intravenous administration, first, the first group of mice were randomly divided into three groups [ie, compound 13a group (n=3), compound 14a group). (n=3) and Compound 1 group (n=3)], wherein the mice of the compound 13a group, the compound 14a group, and the compound 1 group mice were respectively administered via the tail vein injection to the compound 13a , the compound 14a and Compound 1 [in a mixed solution of polyethylene glycol 400 (PEG 400), ethanol, and water (PEG 400/ethanol/water, 30/5/65, v/v In /v), the dose is 2 mg/kg]. 0.25 mL of blood was collected from mice by cardiac puncture before injection and at 2, 5, 15 and 30 minutes after injection and at 1, 1.5, 2, 4, 6, 9, 24 and 27 hours, respectively. Samples are ready for use.

Regarding the single-dose pharmacokinetic evaluation of the test compound via oral administration, first, the second group of mice were randomly divided into three groups [ie, the compound 13a group (n=3), the compound 14a group ( n=3) and Compound 1 (n=3)], wherein the mice of the compound 13a group, the compound 14a group, and the compound 1 group of mice were administered by tube feeding, respectively, with compound 13a , compound 14a. And Compound 1 [in 0.5% methylcellulose (MC) at a dose of 20 mg/kg]. 0.25 mL blood samples were collected from mice by cardiac puncture before administration, and at 15 and 30 minutes after the administration and at 1, 1.5, 2, 4, 6, 9, 24 and 27 hours.

The collected blood sample was added to a 0.5 mL Microtainer containing the anticoagulant EDTA-K ₂ (anticoagulant EDTA-K ₂ ) Tube (Microtainer The tube was mixed and homogenized, followed by centrifugation at 7,000 g for 5 minutes at 4 ° C, thereby obtaining plasma. The plasma obtained at different time points was mixed with an appropriate amount of acetonitrile and centrifuged. The supernatant was collected, injected into a reverse phase Biosil ODS column (reversed-phase Biosil ODS column) and the plasma of each compound at different time points was determined by LC-MS/MS (Waters 2795 LC and Micromass Quattro Ultima). Concentrations, as for the single dose pharmacokinetic parameters of each compound, were calculated from previously measured plasma concentrations using the WinNonlin Standard Program (version 3.1, Pharsight Corp).

result:

Figure 1 shows the concentration of Compound 1 measured by collecting plasma at different time points after intravenous administration of CD-1 mice and administration of Compound 1 orally. Figure 2 shows the concentration of Compound 13a measured by plasma in different time points after CD-1 mice were administered intravenously and orally administered with Compound 13a of the present invention. Figure 3 shows the concentration of compound 14a measured in plasma samples taken at different time points after intravenous administration of the CD-1 mice and oral administration of the compound 14a of the present invention.

As can be seen from Fig. 1, in the case of intravenous administration, Compound 1 was not able to be measured in plasma after the 1.5th hour after administration. For oral administration, Compound 1 could not be measured in plasma after 6 hours after administration.

As can be seen from Fig. 2, in the case of intravenous administration, the concentration of compound 13a in plasma rapidly decreases with time until the second hour after administration, and then the concentration of compound 13a in plasma is followed. The time was slowly reduced until the 27th hour after administration. In contrast to intravenous administration, Compound 13a was observed to have a first absorption peak ( _Tmax of 0.5 hours) at 0.5 hours after oral administration, and 1.5 and 9 after oral administration. The second and third absorption peaks were observed in the hour (the plasma concentration before administration was too low to be measured). The results of this experiment show that compound 13a can be rapidly absorbed after oral administration, and there may be several absorption sites for compound 13a in mice.

As can be seen from Fig. 3, in the case of intravenous administration, the concentration of compound 14a in plasma rapidly decreases with time until the fourth hour after administration, and then the concentration of compound 14a in plasma slowly decreases with time. Until the 27th hour. Compared with intravenous administration, compound 14a was observed to have a first absorption peak at 1.0 hour after oral administration ( _Tmax was 1.0 hour), and a second absorption peak was observed at the second hour. Then, the concentration of the compound 14a in the plasma was slowly lowered with time until the 9th hour, and the plasma concentration after the 9th hour could not be measured because the concentration was too low.

Based on each group of mice administration or oral administration respectively within intravenously at 1, 13a and single-dose pharmacokinetic parameters of the compound after 14a in the plasma concentration of the compound measured at different time points is calculated are summarized in the following Table 6 .

As can be seen from Table 6, for oral administration, Compound 13a had the highest half-life (t _1/2 ) (3.4 hours) and the highest bioavailability (57.1%). Further, the average _Cmax and AUC of the compound 13a of the present invention were 1905 ng/mL and 2072 ng×hr/mL, respectively, which were much higher than those of the compound 1 and the compound 14a , respectively.

From the above experimental results, it is understood that although the compounds 13a and 14a of the present invention exhibit comparable antiproliferative activity and selectivity to each other, since the compound 13a has superior bioavailability and a long half life, the compound 13a is added. The living body has multiple absorption peaks similar to those of sustained-released drugs, and therefore, the inventors believe that compound 13a is more suitable for developing an anticancer drug for oral administration than compound 14a .

Pharmacological Experiments 3. Evaluation of the selective antiproliferative activity of the compound 13a of the present invention

To understand whether the compound 13a of the present invention has selective antiproliferative activity against different types of cancer cells, the inventors selected renal cell carcinoma cell line RCC 786-O, human gastric adenocarcinoma AGS, human prostate cancer cell line PC-3, human breast cancer cell. BT483, human cervical epithelial cancer cell line HeLa, human oral squamous cell carcinoma SAS, hepatocellular carcinoma cell line SKHep, human esophageal cancer cell line CE81T, human lung adenocarcinoma cell line A549, non-small cell lung cancer cell line NCI-H1299, non-small cell lung cancer Cell NCI-H460, non-small cell lung cancer cell NCI-H611, and migrating lung adenocarcinoma cell line CL1-5, and were selected according to the method described in the above item A of the pharmacological experiment 1 "Assessment of anti-proliferative activity" Evaluation of anti-proliferative activity. The experimental results obtained are summarized in Table 7 below.

As can be seen from Table 7, among all the cell lines, the compound 13a of the present invention had the highest SI (NS.68.02) for the non-small cell lung cancer cell NCI-H460, and the non-small cell lung cancer cell NCI-H611 (SI was 43.72). There are also good selectivity for human lung adenocarcinoma A549, non-small cell lung cancer cell NCI-H1299 and dividing lung adenocarcinoma cell line CL1-5 (SI, 6.51, 13.91 and 8.27, respectively). The results of this experiment show that the compound 13a of the present invention has selective antiproliferative activity against lung cancer.

Pharmacological Experiment 4. Compound 13a of the present invention is in vivo ( In Vivo Effectiveness evaluation of inhibiting the growth of lung cancer cells NCI-H460

To understand whether the compound 13a according to the present invention can exert an anticancer effect on lung cancer cells NCI-H460 in vivo, a nude mouse was used in this experiment to perform an in vivo animal model test.

experimental method:

10 ⁶ non-small cell lung cancer cells, NCI-H460, were separately mixed with Matrigel (BD Biosciences), and the resulting mixture was subcutaneously injected into the dorsal side of the upper hind leg of the nude mouse. When a tumor having a volume of about 5 mm ³ was developed, the nude mice were taken for the following experiment.

Tumor-bearing nude mice were randomly divided into 2 groups, of which the first group (n=14) of nude mice were used for intraperitoneal injection test and further divided into 10 mg/kg group (n=4), 20 mg/ In the kg group (n=6) and the control group (n=4), the nude mice in the 10 mg/kg group and the 20 mg/kg group were administered with intraperitoneal injection of compound 13a [with DMSO/Tween 80/PBS]. In the doses of 1/1/8, v/v/v, 10 mg/kg and 20 mg/kg, respectively, while the nude mice of the control group were administered an equal volume of 5% dextrose via intraperitoneal injection. As for the second group (n=28), nude mice were used for oral administration test and further divided into 60 mg/kg group (n=10), 120 mg/kg group (n=10), and control group (n=8). ), in which the 60 mg/kg group and the 120 mg/kg group of nude mice were administered via tube feeding, respectively, with compound 13a [with 1% DMSO, 1.4% Tween 80, and 1% sodium carboxymethylcellulose ( Carboxymethyl cellulose) (Sigma) in the normal saline solution (as a carrier), the dose was 60 mg / kg and 120 mg / kg, 0.22 ~ 0.26 mL / only], while the control group of nude mice via The tube was fed with a carrier (dose of 10 mL/kg).

Each group was administered once a day for 6 consecutive days. Regarding the first group of nude mice, the survival rate of nude mice was recorded every 10 days from the first day after the first administration (day 1), and the nude mice were measured with caliper every 9 days. The tumor on the dorsal side lasted for 100 days. Regarding the second group of nude mice, the survival rate of nude mice was recorded every 10 days from the first day after the first administration (day 1) for 80 days, and the tumors on the dorsal side of nude mice were measured with calipers every 3 days. The size lasts for 32 days.

result:

Figure 4 shows the change in tumor volume in vivo in nude mice bearing tumors on the dorsal side after administration of Compound 13a of the present invention via intraperitoneal injection. Figure 5 shows the change in tumor volume in vivo in nude mice bearing tumors on the dorsal side after oral administration of Compound 13a of the present invention via tube feeding. As can be seen from Fig. 4 and Fig. 5, in comparison, the tumor volume in the nude mice of the control group rapidly increased with time, and the tumor volume in the nude mice administered with the compound 13a was over time. Increase more slowly. In particular, when the nude mice bearing the tumor on the dorsal side were orally administered with 120 mg/kg of Compound 13a for 16 days, the tumor volume in the body gradually decreased.

Figure 6 shows the survival rate of tumor-bearing nude mice on the dorsal side at various time points after oral administration of Compound 13a of the present invention via tube feeding. As can be seen from Fig. 6, the nude mice of the control group all died on the 80th day, while the survival rate of the nude mice of the 60 mg/kg group and the 120 mg/kg group was still 50%.

The results of this experiment show that the compound 13a of the present invention is effective in slowing the growth of tumors in vivo and improving the survival rate of nude mice. The inventors have inferred from this that the compound 13a of the present invention has a high potential for development into an anticancer drug.

All of the patents and documents cited in this specification are hereby incorporated by reference in their entirety. In the event of a conflict, the detailed description of the case (including definitions) will prevail.

While the invention has been described with respect to the specific embodiments of the invention, it will be understood that many modifications and changes can be made without departing from the scope and spirit of the invention. It is therefore intended that the invention be limited only by the scope of the appended claims.

Figure 1 shows the concentration of CD-1 mice compounds are administered intravenously and after oral administration to a compound, plasma was collected at different time points measured 1;

Figure 2 shows the concentration of compound 13a measured by collecting plasma at different time points after intravenous administration of the CD-1 mice and oral administration of the compound 13a of the present invention;

Figure 3 shows the concentration of compound 14a measured by collecting plasma at different time points after intravenous administration of the CD-1 mice and oral administration of the compound 14a of the present invention;

Figure 4 shows the change in tumor volume in vivo in nude mice bearing tumors on the dorsal side after administration of compound 13a of the present invention via intraperitoneal injection;

Figure 5 is a graph showing the change in tumor volume in vivo in nude mice bearing tumors on the dorsal side after oral administration of Compound 13a of the present invention via tube feeding;

Figure 6 shows the survival rate of tumor-bearing nude mice on the dorsal side at various time points after oral administration of Compound 13a of the present invention via tube feeding.

Claims (15)

a compound of the following formula (I): Or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of S, O and NH; R ¹ and R ² may be the same or different and are independently selected From the group consisting of hydrogen, halogen, a C ₁ -C ₄ alkyl group, a hydroxyl group, a C ₁ -C ₄ alkoxy group, a nitro group, and an amine group; and R ³ and R ^{One of the four} is hydrogen, and the other is Where: R ⁵ is Wherein: R ⁷ and R ⁸ may be the same or different and independently hydrogen or a C ₁ -C ₈ alkyl group; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 5 Or a 6-membered heterocyclic ring; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached and an intervening oxygen atom form a 6-membered heterocyclic ring; and t is an integer from 2 to 4; and R ⁶ is hydrogen Or a C ₁ -C ₄ alkyl group. For example, the compound of claim 1 has the following chemical formula (II): Wherein: R ¹ is hydrogen or a C ₁ -C ₄ alkoxy group; R ² is hydrogen or halogen; the R ⁵ group has the same definition as defined in item 1 of the scope of the patent application; and R ⁶ It is a C ₁ -C ₄ alkyl group. A compound according to claim 2, wherein R ⁵ is selected from the group consisting of: as well as A compound according to claim 1 which is selected from the group consisting of: ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino) Phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2 - hydrochloride of aminoethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethyl Ethylamino)ethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propylindole; ( E ) 1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethylanthracene; ( E )-1 -(4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-( 4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4-(furan[2] ,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b] quinolin-4-yl) phenyl) ethanone oxime O -2- aminoethyl; (E) -1- (4- ( 3- chloro furosemide [2,3- b] quinolin-4-yl) phenyl) ethanone O -2- (dimethylamino) ethyl oxime; (E) -1- (4- ( 3- chloro-furan [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-(dimethylamino)propylhydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethylanthracene; ( E )-1-(4-(3-chlorofuran[2,3 - b ] quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4-(3-chlorofuran [2, 3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b </RTI> quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ] Quinoline-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinoline- 4-aminoamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quina 4-yl) phenyl) ethanone oxime O -3- aminopropyl; (E) -1- (4- ( 7- methoxy-furo [2,3- b] quinolin-4 -ylamino)phenyl)B O -3- (dimethylamino) propyl oxime; (E) -1- (4- ( 7- methoxy-furo [2,3- b] quinolin-4-yl) phenyl) Ethyl ketone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamino) Phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-yl Amino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamine Phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinoline-4 -ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinoline- 4-aminoamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran [2,3] - b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran [2, 3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine; ( E )-1-(4-(3-chloro-7-- Oxyfuran [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-( 3-chloro-7-methoxyfur [2,3- b] quinolin-4-yl) phenyl) ethanone O -2- (piperidin-1-yl) ethyl oxime; (E) -1- (4- ( 3- chloro -7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine-ethyl hydrazine; and ( E )-1-(4- (3-Chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine. A pharmaceutical composition for treating a cancer, comprising a compound of formula (I) as defined in claim 1 of the scope of the patent application or a pharmaceutically acceptable salt. A pharmaceutical composition according to claim 5, wherein the compound of the formula (I) is selected from the group consisting of: ( E )-1-(4-(furan[2,3- b] Quinoline-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamine (6)Phenyl)ethanone O -2-aminoethylhydrazine hydrochloride; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl Ethylketone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethyl Amino)propyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl) Ethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl) ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E ) -1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4- (3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O - 2-aminoethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethyl Ethylamino)( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropyl ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propane ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl) Ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl) Ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )- 1-(4-(7-Methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1 -(4-(7-methoxyfuran) [2,3- b] quinolin-4-yl) phenyl) ethanone O -3- (dimethylamino) propyl oxime; (E) -1- (4- ( 7- methoxy [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7) -Methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4 -(7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4- (7-Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-( 3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4- (3-Chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E ) 1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-(dimethylamino) Propyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-( Pyrrolidin-1-yl)B Oxime; (E) -1- (4- ( 3- chloro-7-methoxy-furo [2,3- b] quinolin-4-yl) phenyl) ethanone O -2- (piperidine -1-yl)ethyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; and ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)benzene Ethyl ketone O -4-morphophene butyl hydrazine. The pharmaceutical composition according to claim 6, wherein the compound of the formula (1) is (E) -1-(4-(furan[2,3- b ]quinolin-4-ylamino)benzene Ethyl ketone O -2-aminoethyl hydrazine. The pharmaceutical composition according to claim 5, wherein the cancer is selected from the group consisting of breast cancer, gastric adenocarcinoma, prostate cancer, cervical cancer, esophageal cancer, lung adenocarcinoma, non-small cell lung cancer, renal cell carcinoma, and hepatocytes. Cancer, oral squamous cell carcinoma, central nervous system cancer, and lung adenocarcinoma. A pharmaceutical composition according to claim 8 wherein the cancer is non-small cell lung cancer. A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the preparation of a medicament for the treatment of a cancer. The use according to claim 10, wherein the compound of formula (I) is selected from the group consisting of: ( E )-1-(4-(furan[2,3- b ]quina 4-yl) phenyl) ethanone oxime O -2- aminoethyl; (E) -1- (4- (furo [2,3- b] quinolin-4-ylamino) Phenyl)ethanone O -2-aminoethylhydrazine hydrochloride; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl) Ketone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O - 3-aminopropyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-(dimethylamino) Propyl hydrazine; ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)B ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethylanthracene ( E )-1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine-ethyl hydrazine; ( E )-1 -(4-(furo[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(3 -chlorofuran [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-amino Ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino) Ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropyl hydrazine; E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine; E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethylanthracene; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethylanthracene ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine-ethyl hydrazine; ( E )-1-(4-(3-chlorofuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1 -(4-(7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4 -(7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1- (4-(7-Methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4- (7-methoxyfuran [2,3- b </RTI> quinolin-4-ylamino)phenyl)ethanone O -3-(dimethylamino)propyl hydrazine; ( E )-1-(4-(7-methoxyfuran [2,3] - b ] quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7-methoxyfuran [ 2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1-yl)ethyl hydrazine; ( E )-1-(4-(7-methoxy) [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-morpholine and ethyl hydrazine; ( E )-1-(4-(7-methoxy) Furan [2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -4-morpholine-butyl hydrazine; ( E )-1-(4-(3-chloro-7-) Methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-aminoethylhydrazine; ( E )-1-(4-(3-chloro-7) -Methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(dimethylamino)ethyl hydrazine; ( E )-1-(4- (3-Chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-aminopropylhydrazine; ( E )-1-(4 -(3-chloro-7-methoxyfuro[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O- 3-(dimethylamino)propylhydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(pyrrolidin-1-yl) Ethyl hydrazine; E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2-(piperidin-1- Ethyl hydrazine; ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl)ethanone O -2 - morphine and ethyl hydrazine; and ( E )-1-(4-(3-chloro-7-methoxyfuran[2,3- b ]quinolin-4-ylamino)phenyl) Ketone O -4-morphophene butyl hydrazine. The use according to claim 11, wherein the compound of formula (I) is (E) -1-(4-(furan[2,3- b ]quinolin-4-ylamino)phenyl) Ethyl ketone O -2-aminoethyl hydrazine. The use of the scope of claim 10, wherein the cancer is selected from the group consisting of: breast cancer, gastric adenocarcinoma, prostate cancer, cervical cancer, esophageal cancer, lung adenocarcinoma, non-small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, Oral squamous cell carcinoma, central nervous system cancer, and lung adenocarcinoma. The use of claim 13 wherein the cancer is non-small cell lung cancer. A process for the preparation of a compound of formula (I) as defined in claim 1 of the patent application, which comprises a compound of the formula (A): R ⁵ O-NH ₂ HCl (A) Wherein the R ⁵ group has the same definition as defined in claim 1 of the patent application and reacts with a compound of the following formula (B): Wherein the R ¹ and R ² groups and X have the same definitions as those defined in item 1 of the scope of the patent application, and one of R ⁹ and R ¹⁰ is hydrogen, and the other is Wherein the R ⁶ group has the same definition as defined in item 1 of the scope of the patent application.