TWI402066B - Novel 1,2-disubstituted amido-anthraquinone derivatives, preparation method and application thereof - Google Patents

Description

Novel 1,2-disubstituted guanamine hydrazine derivative, preparation method thereof and application thereof

The present invention relates to the technical field of cancer drug development, and in particular to novel 1,2-disubstituted guanamido fluorene derivatives, their anticancer activity applications and evaluation.

Telomeres

The tail of the chromosome, also known as telomere, has a completely different structure and function from the rest of the chromosome. Telomeres are used to protect chromosome integrity and prevent chromosomal recombination, degradation, and end-to-end fusion. If the structure is lost, the chromosome cannot be completely replicated. Telomeres are usually composed of short, but repeating sequences. This sequence contains a high ratio of Guanine (G) from the 5' end to the 3' end. The telomeres of all vertebrates, including humans, are composed of very many repeats of TTAGGG.

In normal somatic cells, a part of the RNA primer is reduced at each end of the chromosome, and after each cell division, the telomere is shortened by about 50-60 bp, when the telomere is shortened to a certain extent. After the degree, the cells will apoptosis, which is the cell's end-replication problem.

Telomerase

In most organisms, the replication and maintenance of telomere length must be dependent on telomerase. Telomerase is a ribonuclease that is a complex of RNA and protein subunits. At present, some important telomerase subunits have been identified, including human telomerase reverse transcriptase (hTERT) with reverse transcriptase activity, and as a human telomerase composition. The human telomerase RNA component of the template, and some proteins that bind to telomerase, such as human telomerase-associated protein, p23, hsp90, hsp40, hsp70, and the like.

Many studies have pointed out that human telomerase activity exists only in some highly proliferating cells, such as germ cells, hematopoietic cells, part of stem cells, most immortalized cells, and Most of the tumor cells. In general somatic cells, since telomerase activity is not contained, telomeres are gradually reduced as the number of cell divisions increases, which can be regarded as a mitotic clock for cells to calculate the number of divisions. When the telomere is short to a certain extent, the cell will stop dividing and enter the aging stage, and the cell will stay at this stage for a period of time, and then go to death, this period is called the M1 phase (mortality stage 1); if in the M1 phase Mutations in the tumor suppressor gene, such as p53 and Rb, cause the cell to escape the aging phase and continue cell division, which is called the M2 phase (mortality stage 2). During this period, due to the absence of telomerase activity, the telomere length will still be shortened. At this time, telomeres can not protect the integrity of the chromosome ends, which leads to chromosomal instability, and the cells cannot completely transmit the genetic information. Death, so M2 is also called crisis; most of the cells will die in M2 phase, only a few cells will survive due to the expression of telomerase activity, and this cell can be unrestricted and persistently divided. Become an undead cell (or cancer cell).

Therefore, it is generally believed that activation of telomerase can maintain telomere length to prevent cells from entering replicative senescence, or to remove telomerase activity and inhibit its activity to limit the division of cancer cells, both of which can be cell-oriented and cancerous. The key to development. In summary, since normal human somatic cells do not have telomerase activity, a drug capable of inhibiting telomerase activity does not affect the physiological state of normal cells when inhibiting telomerase activity. However, this active inhibitory drug can attenuate the proliferative ability of cancer cells, so if telomerase activity inhibitors can be found, the development of cancer therapeutic drugs has great potential through the discussion of anticancer mechanisms.

In view of the importance of the development of cancer therapeutic drugs, the inventor of this case has innovated and developed, and finally successfully developed the novel 1,2-disubstituted guanamine hydrazine derivative, its preparation method and its application.

The object of the present invention is to provide a series of novel 1,2-disubstituted guanamido fluorene derivatives, chemical modification and synthesis steps, to obtain 1,2-disubstituted guanamine hydrazine derivatives having the structural formula of formula I. And R _a and R _{b are} as defined herein.

A second object of the present invention is to provide a novel 1,2-disubstituted guanamido fluorene derivative having the structural formula of Formula I, wherein R _a , R _{b are} as defined herein.

Another object of the present invention is to provide a pharmaceutical composition comprising a novel 1,2-disubstituted quinone oxime derivative, the pharmaceutical composition comprising a compound having the structural formula of Formula I for use in the treatment of cancer, wherein R _a , R _{b are} as defined herein.

In order to achieve the above object, the inventors of the present invention used a commercially available 1,2-diaminoanthraquinone as a reaction starting material, and used a chemical synthesis reaction to modify different functional groups. A novel 1,2-disubstituted quinone oxime derivative is produced, which are compounds CC-01 ^to CC-50, respectively.

In addition, the present invention further explores and evaluates the pharmacological results of the derivatives in the examples as biased target drugs or chemotherapeutic drugs for inhibiting the growth of tumor cells or cancer cells, thereby treating cancer.

The present invention provides a series of novel 1,2-disubstituted quinone oxime derivatives, processes for their preparation, and uses thereof, wherein the use comprises the preparation of the derivatives as a component of a pharmaceutical composition for the treatment of cancer. Wherein the pharmaceutical composition comprises at least one of the group of compounds having the structural formula of Formula I, wherein R _a , R _{b are} as defined herein:

And a pharmaceutically acceptable excipient.

The pharmaceutical composition is for treating cancer, inhibiting tumor growth, and cancer cells, wherein the cancer includes, but is not limited to, leukemia, Non-Small Cell Lung Cancer, Colon Cancer. Cancers such as CNS Cancer, Melanoma, Ovarian Cancer, Renal Cancer, Prostate Cancer, Breast Cancer, and the like.

Such excipients include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, and the like. Wherein the excipient includes, but is not limited to, microcrystalline cellulose, polyvinylpyrrolidone (PVP), corn starch, modified starches, sodium starch glycolate, resin, gelatinization Gelatinized starches, saccharides, polyethylene glycol (PEG), polyvinyl alcohol, hydroxypropyl cellulose, methylcellulose, hydroxymethylcellulose (hydroxymethyl cellulose), hydroxypropyl methylcellulose, and the like.

The term " therapeutically effective amount " means a compound or compound that treats a disease, ameliorates, attenuates or eliminates one or more symptoms of a particular disease (eg, cancer), or inhibits or delays the onset of one or more symptoms of cancer cell growth. The amount of combination. The term " pharmaceutically acceptable " means that the substance or composition must be compatible with the other ingredients of the formulation and not deleterious to the patient.

The present invention is exemplified by the following examples, but the present invention is not limited by the following examples.

Example 1 Source of reagent

The drugs and materials used in the present invention are commercially available and are readily available. The following are merely examples of available pipelines.

Purchased from Merck, Germany:

TLC 60 F ₂₅₄ , methanol, dichloromethane, chloroform (Chloroform-d ₁ ), dimethyl sulfoxide-d ₆ 99.8%, DMSO-d ₆ ).

Purchased from Aldrich, USA:

1,2-diaminoanthraquinone, N , N -Diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine , dimethylformamide ( N, N- dimethylformamide anhdrous 99.8%, DMF), tetrahydrofuran anhdrous 99.9%, THF, chloroacetyl chloride, 3-chloropropionyl chloride ), 4-chlorobutyryl chloride, 2-chloropropionyl chloride, 5-chlorovaleroyl chloride, benzoyl chloride, 4-toluoyl chloride, 3-toluoyl chloride, 2-toluoyl chloride, 4-fluorobenzol 4-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, 2-fluorobenzoyl chloride, 4-chlorobenzoyl chloride , 3-chlorobenzoyl chloride, 2-chlorobenzoyl chloride, 4-(trifluoromethyl) benzoyl chloride , 3-trifluoromethylbenzimidium chloride (3-(trifluoromethy) l) benzoyl chloride), 2-(trifluoromethyl) benzoyl chloride, 2,5-(trifluoromethyl) benzoyl chloride , phenylacetyl chloride), cyclopropane carbonyl chloride, cyclohexanecarbonyl chloride, 2-furoyl chloride, 2-thiophenecarbonyl Chloride), isoxazole-5-carbonyl chloride, 2,5-dimethylfuran-3-carbonyl chloride, phenoxy acetyl chloride (phenoxyacetyl chloride), phenylthio acetyl chloride ((phenylthio) acetyl chloride), N- phenyl-piperazine (N -phenylpiperazine), 1- (2- fluorophenyl) piperazine (1- (2- Fluorophenyl) piperazine), dimethylamine, 2-methylaminomethyl-1,3 dioxolane, 2-(2-methylaminoethyl- 2-(2-methylaminoethyl pyridine), piperididine, 1,4-dioxo-8-azaspiro[4.5]decane (1,4-dioxa-8-azaspiro[4.5]decane ), morpholine (morpholine), thiomorpholine (thiomorpholine), N - methyl-piperazine (N -methylpiperazine), 2- 2-(piperazin-1-yl)ethanol, 1-(2-cyanophenyl) piperazine, 1-(2-methoxyphenyl) 1-(2-methoxyphenyl) piperazine, 1-(2-pyridyl) piperazine, 1-(2-pyrimidinyl)pyridazine (1-(2-) Pyrimidyl) piperazine).

Purchased from Mallinckrodt (J.T. Baker), USA:

Ethyl acetate (Ethyl acetate), hexane (n-Hexane), N, N- dimethylacetamide (N, N -dimethyl acetamide), diethyl ether (Ether), anhydrous sodium sulfide (Sodium sulfate anhydrous, Na ₂ SO ₄ ), magnesium sulfate (Magnessium sulfate, MgSO ₄ )

Purchased from Taiwan Liuhe Company:

Acetone (Acetone, technical grade), ethanol (Ethanol, industrial grade 95%)

Example 2 Chemical Synthesis Reaction Summary I (Scheme I), see Figure 1: 1. Synthesis procedure General A (General procedure A)

The compound 1,2-diaminoanthraquinone is dissolved in DMF, and then pyridine (pyridine) is added to a series of acyl chloride to stir, and the reaction mixture is mixed. The liquid was cooled, filtered to remove the precipitate, and finally the precipitate was washed with alcohol to give compounds CC-01 to CC-03.

2. Synthesis procedure General B (General procedure B)

The compound 1,2-diaminoanthraquinone is dissolved in DMF, stirred with chloroacetyl chloride, the reaction mixture is cooled, the precipitate is filtered, and finally The precipitate was rinsed with alcohol to give compound CC-05.

3. Synthesis procedure general C (General procedure C)

Compound CC-05 was dissolved in DMF, and (1) pyridine and 2-chloropropionyl chloride, (2) pyridine and 3-chloropropionyl chloride were added, respectively. -chloropropionyl chloride) or (3) pyridine and 4-chlorobutyryl chloride are stirred, the reaction mixture is cooled, the precipitate is filtered, and finally the precipitate is washed with alcohol and recrystallized. That is, compounds CC-06, CC-07 and CC-08 can be obtained respectively.

Reaction Summary II (Scheme II), please refer to Figure 2: 1. Synthesis procedure General A (General procedure A)

The compound 1,2-diaminoanthraquinone is dissolved in THF, and then pyridine (pyridine) and 4-toluoyl chloride are added and stirred. mixture was stirred in an oil bath at a temperature of 120-130 deg.] C, the reaction was complete the mixture was filtered, whichever filtrate was concentrated under reduced pressure drained with ethyl acetate (ethyl acetate) was extracted, and then through over magnesium sulfate (MgSO ₄₎ After removing the water and concentrating under reduced pressure, the crude product was washed with ethyl acetate/hexane, and the crude product was recrystallized from alcohol to afford compound CC-04.

2. Synthesis procedure General B (General procedure B)

The compound CC-05 is dissolved in THF, and then pyridine (pyridine) and a series of benzoyl chloride are added to stir, and the mixture is stirred at an oil bath temperature of 120-130 ° C to complete the reaction. the mixture is filtered, whichever the filtrate was concentrated under reduced pressure drained with ethyl acetate (ethyl acetate) was extracted, and then through magnesium sulfate (MgSO ₄₎ and concentrated after addition of water, under reduced pressure, ethyl acetate / n-hexane (ethyl The crude product is washed with acetate/hexane, and finally the crude product is recrystallized from alcohol to give compounds CC-09 to CC-22.

3. Synthesis procedure general C (General procedure C)

The compound CC-05 is dissolved in THF, and then pyridine (pyridine) is added to a series of acetyl chloride to stir, and the mixture is stirred at an oil bath temperature of 120-130 ° to complete the reaction. the mixture is filtered, whichever the filtrate was concentrated under reduced pressure drained with ethyl acetate (ethyl acetate) was extracted, and then through magnesium sulfate (MgSO ₄₎ and concentrated after addition of water, under reduced pressure, ethyl acetate / n-hexane (ethyl The crude product is washed with acetate/hexane, and finally the crude product is recrystallized from alcohol to give the compound CC-23 to CC-32.

Reaction Summary III (Scheme III), please refer to Figure 3: 1. Synthesis procedure General A (General procedure A)

The compound CC-09 was dissolved in THF, and N , N -diisopropylethylamine (DIPEA) was added successively with a series of piperazine to stir, and the mixture was heated under reflux to complete the reaction mixture. The liquid is filtered, the crude product is chromatographed, and finally the crude product is recrystallized from alcohol to give compounds CC-33 and CC-34.

2. Synthesis procedure General B (General procedure B)

The compound CC-12 was dissolved in THF, and N , N -diisopropylethylamine (DIPEA) was added successively with a series of secondary amines, and the mixture was heated under reflux to complete the reaction. the mixture is filtered, whichever the filtrate was concentrated under reduced pressure drained with ethyl acetate (ethyl acetate) was extracted, and then through over magnesium sulfate (MgSO ₄₎ and concentrated after addition of water, under reduced pressure, ethyl acetate / n-hexane (ethyl The crude product is washed with acetate/hexane, and finally the crude product is recrystallized from alcohol to give compounds CC-35 to CC-50.

Example 3 Pharmacological activity test

In the pharmacological test, chemically synthesized compound structures CC-01 to CC-50 (fifty compounds) were tested for pharmacological activity in the following three parts: 3-1. Telomeric repeat method (Telomeric repeat) Amplification protocol, TRAP); 3-2. Secreted alkaline phosphatase assay (SEAP assay), and MTT assay to detect cell viability of cancer cells; 3-3. American Cancer Research Center (NCI) Five compound structures were screened and a toxicity test of fifty to sixty cancer cell lines was performed against the five compounds.

3-1. Telomeric repeat amplification protocol (TRAP):

The telomere sequence replication method is currently used to detect telomerase activity. The analysis method is as follows: First, commercially available 2nM CX primer (0.05μM, 2μl), 1nM NT primer (0.05μM, 1μl) ), 4 nM oligonucleic acid TSNT was placed in the bottom of the tube, and a wax block (PERKIN ELMER Ampli Wax PCR Gem 50) was placed in a test tube, and a PCR thermo cycle machine (PERKIN ELMER 9700) was used at 90 ° C, 5 minutes, 72 ° C, After 3 minutes, 50 ° C, 1 minute, 20 ° C, 1 minute, the temperature was lowered to 4 ° C, and the tube in which the wax block was sealed was taken out. The protein concentration of the cell extract (about 0.5-2 μl of cell extract total protein content) to be analyzed is diluted to about 0.5 mg/ml, and 4 μl (equivalent to 10 ³ -10 ⁴ cell extracts) is taken. Place in 50 μl of reaction mix reagent. The cell extract and the reaction reagent were placed in a 0.2 ml PCR-specific test tube, and reacted at 30 ° C for 30 minutes to extend the TS primer in the cell extract, and then the entire reaction mixture was heated to 94 ° C for 3 minutes to terminate. Telomerase reaction, and dissolve the wax block (mixed into the primer CX required for the PCR reaction), and then heat the entire reaction mixture to 94 ° C, 3 minutes, and then 94 ° C, 30 seconds, 50 ° C, 30 seconds, 72 ° C, The PCR thermocycling reaction was carried out 34 times under 1 minute, and finally the reaction was allowed to proceed completely at 72 ° C for 7 minutes, and the entire reaction was terminated by dropping to 4 ° C. Positive control group in TRAP analysis (no synthetic drug added, 5 μl mg/ml 0.1% DEPC water); negative control group in TRAP analysis (no synthetic drug added, and 5 μl mg/ml RNase A added) ). The reaction mixture after the appropriate amount of PCR reaction was subjected to colloidal electrophoresis (10% acrylamide gel), and development was carried out under UV light, and the effect of telomerase activity was judged by the development result.

3-2. Secreted alkaline phosphatase analysis and MTT assay 3-2-1. Secreted alkaline phosphatase assay (SEAP Assay) Test cell line:

H1299 is a non-small cell lung cancer cell line with telomerase activity, so it is suitable as a model cell strain for screening telomerase inhibitors. And the cell line contains human telomerase reverse transcriptase (hTERT, telomerase activity is mainly determined by the expression of hTERT), therefore, H1299 is suitable for screening the compounds of the present invention, thereby evaluating the telomerase activity of the compounds. Ability. However, hTERT is not easy to detect, so another plastid with the hTERT promoter (P _hTERT ) with the SEAP communication gene (easy to detect) and transfection into the H1299 cell line. This system is used to assess the ability of a compound to inhibit the hTERT promoter (P _hTERT ).

Secretion of the alkaline phosphatase assay (SEAP Assay) process:

Take 2×10 ³ hTERT-H1299+P _TERT (3.4)-SEAP cells in a 96 well cell culture dish, 4:1 DMEM (GIBCO BRL) + Glucose: Medium 199 (GIBCO BRL) + 10% FBS +1 mM sodiumpyruvate (GIBCO BRL) + 4 mM L-glutamine (GIBCO BRL) was incubated at 37 ° C for 24 hours, followed by a series of different concentrations (final concentrations of 100, 10, 1 μM, respectively) CC-01 to CC-50 compound, cells were treated for 24 hours without addition of drug-treated cells as P _TERT -SEAP control group. After 24 hours of drug treatment, the culture solution was collected for SEAP activity analysis (the rate of increase in absorbance at 405 nm indicates the activity of SEAP), and the cells were subjected to MTT assay to compare the relative toxicity or effect of the drug on cell proliferation and activity.

3-2-2. MTT assay

MTT assay is commonly used to determine cell viability or proliferation. The method is briefly described as follows: The above cells are cultured in 96 well, 25 μl of MTT solution is added, placed in a 37 ° C carbon dioxide incubator for 4 hours, and then 100 μl of Lysis buffer is added. The °C carbon dioxide incubator was used overnight to measure the absorbance of optical densitry (OD) at 550 nm using an ELISA reader (Bio-Rad Model 450).

3-3. Toxic test of cancer cells of the National Cancer Institute

The results of this part of the test are from the structure of the fifty compounds provided by the National Cancer Research Center (NCI) from the present invention, and five compound structures (and the existing certification number) are selected (Fig. 4), and sixty A poisoning test of a cancer cell line.

Synthesis and analysis of each compound

According to the chemical synthesis step of the 1,2-disubstituted guanamine hydrazine derivative disclosed in Example 2, the preparation method of each derivative compound and the analysis result thereof are further disclosed in the following examples.

Testing equipment:

Melting point determination is to use B Chi 545 melting point tester. The instrument used for IR (KBr) is the Perkin-Elmer 983G spectrometer. MS commissioned the National Transportation University Guiyi Center to take the test. ^{The 1} H-NMR and ¹³ C-NMR were measured using a Varian GEMINI-300 (300 MHz) or a BRUKER AV 500 MHz.

Example 4 1,2-bis-(chloroethylamino)-oxime (1,2- Bis -(chloroacetamido)-anthraquinone)(CC-01)

The compound 1,2-diaminoanthraquinone (0.92 g, 4 mmole) was dissolved in anhydrous N , N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, followed by the addition of pyridine (0.5 ml) and chlorine. Chlorochloro chloride (1 ml, 1.2 mmole), stirred at room temperature for 24 hours; the reaction mixture was poured into an ice water bath (200 ml), and allowed to stand for 10 to 20 minutes, at which time precipitation occurred. The precipitate was taken, and finally the precipitate was washed with ethanol to obtain a khony compound CC-01 . Mol. Wt.: 391.2049 (C ₁₈ H ₁₂ Cl ₂ N ₂ O ₄ ); R _f : 0.27 (ethyl acetate: n-hexane = 1:2); Yield (Yield): 56%; Mp.: 254- 255 ° C (EtOH); HRMS (EI) m / z : calcd [M] ⁺ , 390.0174 (C ₁₈ H ₁₂ Cl ₂ N ₂ O ₄ ⁺ ); found, 390.0170; ¹ H-NMR (300 MHz, DMSO-d ₆ )d(ppm): 4.43 (s, 2H, -CH ₂ Cl), 4.45 (s, 2H, -CH ₂ Cl), 7.90-7.93 (m, 2H, Ar-H), 8.12-8.18 (m, 2H) , Ar-H), 8.22 (d, J = 8.1 Hz, 1H, Ar-H), 8.38 (d, J = 9.0 Hz, 1H, Ar-H), 9.83 (s, 1H, Ar-NH-), 10.29 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 43.25, 126.20, 126.93, 128.14, 130.33, 132.28, 134.25, 134.42, 134.63, 139.77, 165.61 (NCO), 166.02 (NCO), 181.60 (CO), 183.25 (CO),

Example 5 1,2-bis-(3-chloropropionamido)-oxime (1,2- Bis -(3-chloropropionamido)-anthraquinone)(CC-02)

The compound 1,2-diaminoanthraquinone (0.92 g, 4 mmole) was dissolved in anhydrous N,N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, followed by the addition of triethylamine (TEA) (0.5 ml). , 3-chloropropionyl chloride (1.2 ml, 12 mmole), stirred at room temperature for 24 hours; the reaction mixture was poured into an ice water bath (200 ml), and allowed to stand for 10 to 20 minutes. At this time, precipitation will occur, and the precipitate will be taken by filtration. Finally, the precipitate is washed with ethanol to obtain a khony compound CC-02 . Mol. Wt.: 419.2580 (C ₂₀ H ₁₆ Cl ₂ N ₂ O ₄ ); R _f : 0.23 (ethyl acetate: n-hexane = 1:2); Yield: 51%; Mp.: 179-180 ° C (EtOH) HRMS(EI) m/z :calcd[M] ⁺ , 418.0487 (C ₂₀ H ₁₆ Cl ₂ N ₂ O ₄ ⁺ ); found, 418.0494; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 2.94-3.03 (m, 4H, -CH ₂ -), 3.86-3.94 (m, 4H, -CH ₂ Cl), 7.88-7.90 (m, 2H, Ar-H), 8.10-8.15 (m, 2H) , Ar-H), 8.08 (d, J = 8.1 Hz, 1H, Ar-H), 8.42 (d, J = 8.7 Hz, 1H, Ar-H), 9.50 (s, 1H, Ar-NH-), 10.02 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 40.20, 40.26, 125.94, 126.29, 126.87, 127.61, 127.79, 128.33, 129.79, 132.27, 134.26 , 134.36, 134.52, 140.28, 168.86 (NCO), 169.43 (NCO), 181.63 (CO), 183.22 (CO).

Example 6 1,2-bis-(4-chlorobutylidene)-ruthenium (1,2- Bis -(4-chlorobutyramido)-anthraquinone)(CC-03)

The compound 1,2-diaminoanthraquinone (0.92 g, 4 mmole) was dissolved in anhydrous N , N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, followed by the addition of pyridine (0.5 ml) and 4-chloropyridinium. 4-chlorobutyryl chloride (1.4 ml, 12 mmole), stirred at room temperature for 24 hours; the reaction mixture was poured into an ice water bath (200 ml), and allowed to stand for 10 to 20 minutes, at which time precipitation occurred. The precipitate was taken by filtration, and finally the precipitate was washed with ethanol to give chloro compound CC-03 . Mol. Wt.: 447.3112 (C ₂₂ H ₂₀ Cl ₂ N ₂ O ₄ ); R _f : 0.37 (ethyl acetate: n-hexane = 1:2); Yield: 45%; Mp.: 154-155 ° C (EtOH) HRMS(EI) m/z :calcd[M] ⁺ , 446.0800 (C ₂₂ H ₂₀ Cl ₂ N ₂ O ₄ ⁺ ); found, 446.0793; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 2.04-2.12 (m, 4H, -CH ₂ -), 2.57-2.66 (m, 4H, -CH ₂ -), 3.71 (t, J = 6.6 Hz, 2H, -CH ₂ -), 3.78 (t , J = 6.6 Hz, 2H, -CH ₂ -), 7.88-7.91 (m, 2H, Ar-H), 8.08-8.16 (m, 3H, Ar-H), 8.36 (d, J = 8.7 Hz, 1H , Ar-H), 9.52 (s, 1H, Ar-NH-), 9.82 (s, 1H, Ar-NH-); ¹³ C-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 27.68, 27.76 , 33.11, 33.37, 44.75, 44.99, 125.55, 126.28, 126.85, 127.88, 128.21128.40, 129.57, 132.28, 134.23, 134.47, 134.53, 140.45, 171.12 (NCO), 171.60 (NCO), 181.71 (CO), 183.46 (CO) .

Example 7 1,2-bis-(4-methylbenzamide)-oxime (1,2- Bis -(4-methylbenzamido)-anthraquinone)(CC-04)

The compound 1,2-diaminoanthraquinone (0.92 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 4-toluoyl chloride were added thereto at room temperature. 1.6 ml, 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, and the filtrate was taken, concentrated under reduced pressure, and extracted with ethylacetate, and then extracted with a magnessium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane; Recrystallization from hot ethanol gives the brownish compound CC-04 . Mol. Wt.: 474.5067 (C ₃₀ H ₂₂ N ₂ O ₄ ); R _f : 0.51 (ethyl acetate: n-hexane = 1:2); Yield: 62%; Mp.: 227-229 ° C (EtOH); HRMS (EI) m/z : Calcd [M] ⁺ , 474.1580 (C ₃₀ H ₂₂ N ₂ O ₄ ⁺ ); found, 474.1572; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.36 ( s, 3H, -CH ₃ ), 2.42 (s, 3H, -CH ₃ ), 7.33 (d, J = 8.4 Hz, 2H, Ar-H), 7.42 (d, J = 8.4 Hz, 2H, Ar-H ), 7.79 (d, J = 8.1 Hz, 2H, Ar-H), 7.90-7.93 (m, 2H, Ar-H), 8.01 (d, J = 8.1 Hz, 1H, Ar-H), 8.13-8.16 (m, 1H, Ar-H), 8.18-8.20 (m, 1H, Ar-H), 8.42 (d, J = 8.7 Hz, 1H, Ar-H), 10.06 (s, 1H, Ar-NH-) , 10.90 (s, 1H, Ar-NH-); ¹³ C-NMR (300MHz, DMSO-d ₆ )d (ppm): 20.37, 20.48, 125.02, 125.90, 126.61, 126.90, 127.45, 128.88, 128.92, 129.28, 129.70, 129.99, 130.39, 130.57, 131.79, 133.85, 134.00, 134.14, 138.94, 142.12, 142.20, 164.50 (NCO), 165.85 (NCO), 181.21 (CO), 183.84 (CO).

Example 8 1-(Amino)-2-(chloroethylammonium)-oxime (1-(amino)-2-(chloroacetamido)-anthraquinone)(CC-05)

The compound 1,2-diaminoanthraquinone (1.19 g, 5 mmole) was dissolved in anhydrous N,N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, and chloroacetyl chloride (0.5 ml, 6 mmole) was added and placed in the chamber. After stirring for 2 hours, the reaction mixture was poured into an ice water bath (200 ml), and allowed to stand for 10 to 20 minutes. At this time, precipitation occurred, and the precipitate was collected by filtration. Finally, the precipitate was washed with hot ethanol to obtain a red compound CC. -05 . Mol. Wt.: 314.7231 (C ₁₆ H ₁₁ N ₂ O ₃ ); R _f : 0.82 (ethyl acetate: n-hexane = 1:4); Yield: 65%; Mp.: 193-194 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 314.0458 (C ₁₆ H ₁₁ N ₂ O ₃ ⁺ ); found, 314.0455; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 4.38 ( s, 2H, -CH ₂ Cl), 7.48 (d, J = 7.8 Hz, 1H, Ar-H), 7.74 (d, J = 8.1 Hz, 1H, Ar-H), 7.84 (dd, J = 8.1 Hz) , J = 1.8 Hz, 1H, Ar-H), 7.88 (t, J = 1.5 Hz, 1H, Ar-H), 7.91 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H, Ar-H), 7.96 (br, 2H, Ar-NH ₂ ), 8.14 (dd, J = 7.2 Hz, J = 1.8 Hz, 1H, Ar-H), 8.22 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H, Ar -H), 9.80 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 43.25, 112.98, 115.62, 126.69, 126.55, 129.88, 128.88, 128.92, 130.25 , 131.01, 132.64, 133.65, 134.37, 165.72 (NCO), 182.28 (CO), 184.38 (CO).

Example 9 1-[(2-Chloropropanin)amino]-2-(chloroethylammonium)-oxime (1-[(2-chloropropanyl)amido]-2-(chloroacetamido)-anthraquinone)(CC-06)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous N , N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, followed by the addition of pyridine (0.5 ml) and 2-chloropropionyl chloride ( 2-chloropropanoyl chloride) (1.32 ml, 12 mmole), stirred at room temperature for 1 hour; the reaction mixture was poured into an ice water bath (200 ml), and allowed to stand for 10 to 20 minutes. Precipitation, and finally the precipitate was washed with ethanol and recrystallized to obtain the khony compound CC-06 . Mol. Wt.: 405.2315 (C ₁₉ H ₁₄ Cl ₂ N ₂ O ₄ ); R _f : 0.61 (ethyl acetate: n-hexane = 1:2); Yield: 28%; Mp.: 175-176 ° C (EtOH) HRMS(EI) m / z :calcd[M] ⁺ , 404.0331 (C ₁₉ H ₁₄ Cl ₂ N ₂ O ₄ ⁺ ); found, 404.0339; ¹ H-NMR (300MHz, CDCl ₃ )d (ppm): 1.92(s,3H,-CH ₃ ), 4.23 (s, 2H, -CH ₂ Cl), 4.67-4.74 (m, 1H, -CH ₂ -), 7.79-7.86 (m, 2H, Ar-H), 8.27-8.37 (m, 4H, Ar-H), 9.50 (s, 1H, Ar-NH-), 11.930 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ )d (ppm): 21.35, 43.04, 54.64, 125.99, 126.29, 126.84, 128.53, 128.68, 130.59, 132.21, 134.19, 134.32, 134.52, 139.18, 165.27 (NCO), 168.58 (NCO), 181.51 (CO), 183.34 (CO) ).

Example 10 1-[(3-Chloropropyl)amino]-2-(chloroethinyl)-hydrazine (1-[(3-chloropropanyl)amido]-2-(chloroacetamido)-anthraquinone)(CC-07)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous N,N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, followed by the addition of pyridine (0.5 ml) and 3-chloropropionyl chloride ( 3-chloropropionyl chloride) (1.2ml, 12mmole), stirred at room temperature for 24 hours; poured the reaction mixture into an ice water bath (200ml), let stand for 10 to 20 minutes, precipitation will occur, filter Precipitation, and finally the precipitate was washed with ethanol and recrystallized to obtain a khony compound CC-07 . Mol. Wt.: 405.2315 (C ₁₉ H ₁₄ C ₁₂ N ₂ O ₄ ); R _f : 0.43 (ethyl acetate: n-hexane = 1:2); Yield: 33%; Mp: 182-183 ° C (EtOH) ;HRMS(EI) m/z :calcd[M] ⁺ , 404.0331 (C ₁₉ H ₁₄ C ₁₂ N ₂ O ₄ ⁺ ); found, 404.0334; ¹ H-NMR (300MHz, CDCl ₃ )d (ppm): 3.13 (t, J = 6.3 Hz, 2H, -CH ₃ ), 3.96 (t, J = 6.6 Hz, 2H, -CH ₃ ), 4.21 (s, 2H, -CH ₂ Cl), 7.81 - 7.84 (m, 2H) , Ar-H), 8.25-8.34 (m, 4H, Ar-H), 9.73 (s, 1H, Ar-NH-), 11.51 (s, 1H, Ar-NH-); ¹³ C-NMR (125 MHz, DMSO-d ₆ )d (ppm): 43.33, 125.92, 126.28, 126.46, 122.82, 126.97, 127.90, 128.00, 128.92, 130.28, 132.18, 134.19, 134.28, 134.52, 139.56, 164.50 (NCO), 165.85 (NCO), 183.09 (CO), 183.09 (CO).

Example 11 1-[(4-Chlorobutyryl)amino]-2-(chloroethylammonium)-oxime (1-[(4-chlorobutanyl)amido]-2-(chloroacetamido)-anthraquinone)(CC-08)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous N,N- dimethylformamide (30 ml), and nitrogen was introduced into the reaction flask at room temperature, followed by pyridine (0.5 ml) and 4-chlorobutyric chloride ( 4-chlorobutyryl chloride) (1.4ml, 12mmole), after stirring at room temperature for 24 hours; pour the reaction mixture into an ice water bath (200ml), let stand for 10 to 20 minutes, precipitation will occur, filter Precipitation, and finally the precipitate was washed with ethanol and recrystallized to obtain a khony compound CC-08 . Mol. Wt.: 419.2580 (C ₂₀ H ₁₆ Cl ₂ N ₂ O ₄ ); R _f : 0.52 (ethyl acetate: n-hexane = 1:2); Yield: 38%; Mp: 163-164 ° C (EtOH) HRMS (EI) m/z : calcd [M] ⁺ , 418.0487 (C ₂₀ H ₁₆ Cl ₂ N ₂ O ₄ ⁺ ); found, 418.0494; ¹ H-NMR (300MHz, CDCl ₃ )d (ppm): 2.28 -2.34(m,2H,-CH ₂ -), 3.13 (t, J = 6.3 Hz, 2H, -CH ₃ ), 2.88 (t, J = 7.2 Hz, 2H, -CH ₂ -), 3.73 (t, J = 6.3 Hz, 2H, -CH ₂ -), 4.22 (s, 2H, -CH ₂ Cl), 7.81 - 7.83 (m, 2H, Ar-H), 8.26 - 8.34 (m, 4H, Ar-H) , 9.84 (s, 1H, Ar-NH-), 11.46 (s, 1H, Ar-NH-); ¹³ C-NMR (125MHz, DMSO-d ₆ ) d (ppm): 44.99, 125.67, 126.26, 126.79, 127.91, 128.01, 128.73, 130.21, 132.16, 134.23, 134.26, 134.52, 165.34 (NCO), 171.81 (NCO), 181.49 (CO), 183.21 (CO).

Example 121-(Benzamethylene)-2-(chloroacetamido)-oxime (1-(benzamido)-2-(chloroacetamido)-anthraquinone)(CC-09)

Compound CC-05 (1.28g, 4mole) was dissolved in anhydrous tetrahydrofuran (30ml), and pyridine (0.5ml), benzoyl chloride (1.23ml, 12mmole) was added successively at room temperature, stirring 5 The mixture was stirred for 3 hours in a mini-reactor at an oil bath temperature of 120-130 ° C for 10 minutes. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the khaki compound CC-09 . Mol. Wt.: 418.8292 (C ₂₃ H ₁₅ ClN ₂ O ₄ ); R _f : 0.83 (ethyl acetate: n-hexane = 1:1); Yield: 67%; Mp.: 203-204 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 418.0720 (C ₂₃ H ₁₅ ClN ₂ O ₄ ⁺ ); found, 418.0716; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 4.42 ( s, 2H, -CH ₂ Cl), 7.57-7.67 (m, 2H, Ar-H), 7.78-7.92 (m, 2H, Ar-H), 8.09-8.18 (m, 4H, Ar-H), 8.24 (d, J = 8.7 Hz, 1H, Ar-H), 8.40 (d, J = 8.7 Hz, 1H, Ar-H), 9.86 (s, 1H, Ar-NH-), 10.58 (s, 1H, Ar -NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 43.19, 125.76, 126.28, 126.95, 127.79, 127.95, 128.40, 128.51, 129.56, 130.43, 132.00, 132.22, 133.97, 134.23, 134.34, 134.50, 139.44, 165.42 (NCO), 166.35 (NCO), 181.55 (CO), 183.77 (CO).

Example 13 1-(2-methylbenzamideamino)-2-(2-methylbenzamido-2-(chloroacetamido)-anthraquinone) (CC-10 )

Compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2-toluoyl chloride (1.62 ml) were added successively at room temperature. , 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the terrane compound CC-10 . Mol. Wt.: 432.8558 (C ₂₄ H ₁₇ ClN ₂ O ₄ ); R _f : 0.47 (ethyl acetate: n-hexane = 1:2); Yield: 47%; Mp.: 179-180 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 432.0877 ( C ₂₄ H ₁₇ ClN ₂ O ₄ ⁺ ); found, 432.0877; ¹ H-NMR (300 MHz, CDCl ₃ ) d (ppm): 2.52 (s, 3H, -CH ₃ ), 4.20 (s, 2H, -CH ₂ Cl), 7.48-7.50 (m, 2H, Ar-H), 7.79-7.83 (m, 2H, Ar-H), 7.99-8.01 (m , 2H, Ar-H), 8.26-8.33 (m, 4H, Ar-H), 10.08 (s, 1H, Ar-NH-), 12.35 (s, 1H, Ar-NH-); ¹³ C-NMR ( 75 MHz, CDCl ₃ )d (ppm): 21.39, 43.12, 124.08, 125.16, 125.16, 125.60, 127.24, 127.63, 128.91, 128.91, 129.06, 131.71, 132.07, 132.91, 133.32, 133.81, 134.35, 134.83, 136.53, 139.15165. 44 (NCO), 168.03 (NCO), 181.68 (CO), 187.58 (CO).

Example 14 1-(3-Methylbenzimidino)-2-(chloroacetamido)-oxime (1-(3-methylbenzamido)-2-(chloroacetamido)-anthraquinone)(CC-11)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 3-toluoyl chloride (1.62 ml) were added thereto at room temperature. 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the terrane compound CC-11 . Mol. Wt.: 432.8558 (C ₂₄ H ₁₇ ClN ₂ O ₄ ); R _f : 0.62 (ethyl acetate: n-hexane = 1:2); Yield: 56%; Mp.: 202-203 ° C (EtOH); HRMS(EI) m/z calcd [M] ⁺ , 432.0877 ( C ₂₄ H ₁₇ ClN ₂ O ₄ ⁺ ); found, 432.0873; ¹ H-NMR (300MHz, CDCl ₃ )d (ppm): 2.52 (s, 3H , -CH ₃ ), 4.20 (s, 2H, -CH ₂ Cl), 7.48-7.50 (m, 2H, Ar-H), 7.80-7.83 (m, 2H, Ar-H), 7.99-8.01 (m, 2H, Ar-H), 8.26-8.32 (m, 4H, Ar-H), 10.08 (s, 1H, Ar-NH-), 12.36 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz , CDCl ₃ )d (ppm): 21.39, 43.12, 124.07, 125.15, 125.60, 127.24, 127.63, 128.91, 128.91, 129.06, 131.70, 132.08, 132.91, 133.30, 133.81, 134.29, 134.36, 136.84, 136.51, 139.15, 165.45 (NCO), 168.03 (NCO), 181.69 (CO), 187.58 (CO).

Example 15 1-(4-Methylbenzamideamino)-2-(chloromethylbenzamide)-2-(chloroacetamido-anthraquinone) (CC-12 )

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 4-toluoyl chloride (1.62 ml) were added successively at room temperature. , 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the khony compound CC-12 . Mol. Wt.: 432.8558 (C ₂₄ H ₁₇ ClN ₂ O ₄ ); R _f : 0.76 (ethyl acetate: n-hexane = 1:2); Yield: 66%; Mp.: 198-199 ° C (EtOH); HRMS(EI) m/z : calcd [M] ⁺ , 432.0877 (C ₂ 4H ₁₇ ClN ₂ O ₄ ⁺ ); found, 432.0881; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.43 ( s, 3H, -CH ₃ ), 4.43 (s, 2H, -CH ₂ Cl), 7.41 (d, J = 7.8 Hz, 2H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.01 (d, J = 8.1 Hz, 2H, Ar-H), 8.10-8.13 (m, 1H, Ar-H), 8.16-8.19 (m, 1H, Ar-H), 8.24 (d, J = 8.7 Hz) , 1H, Ar-H), 8.39 (d, J = 9.0 Hz, 1H, Ar-H), 9.84 (s, 1H, ArNH-), 10.58 (s, 1H, Ar-NH-); ¹³ C-NMR (300MHz, CDCl ₃ )d (ppm): 20.90, 43.53, 123.99, 125.52, 127.23, 127.60, 128.24, 129.87, 130.52, 131.66, 132.02, 132.94, 133.01, 134.29, 134.33, 136.80, 136.51, 143.22, 164.83 (NCO ), 167.15 (NCO), 181.07 (CO), 187.00 (CO).

Example 16 1-(2-Fluorobenzylamino)-2-(chloroethylamino)-indole (1-(2-fluorobenzamido)-2-(chloroacetamido)-anthraquinone)(CC-13)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2-fluorobenzoyl chloride (1.42 ml) were added thereto at room temperature. 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, and the filtrate was taken, concentrated under reduced pressure, and extracted with ethylacetate, and then extracted with a magnessium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane; Recrystallization from hot ethanol gives the khaki compound CC-13 . Mol. Wt.: 436.8197 (C ₂₃ H ₁₄ ClFN ₂ O ₄ ); R _f : 0.62 (ethyl acetate: n-hexane = 1:2); Yield: 31%; Mp.: 245-246 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 436.0626 ( C ₂₃ H ₁₄ ClFN ₂ O ₄ ⁺ ); found, 436.0630; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 4.41 ( s, 2H, -CH ₂ Cl), 7.40-7.47 (m, 2H, Ar-H), 7.65-7.72 (m, 1H, Ar-H), 7.86-7.93 (m, 2H, Ar-H), 8.03 -8.19 (m, 3H, Ar-H), 8.24 (d, J = 8.4 Hz, 1H, Ar-H), 8.37 (d, J = 8.7 Hz, 1H, Ar-H), 9.83 (s, 1H, Ar-NH-), 10.48 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 43.11, 116.43, 116.65, 124.71, 125.86, 126.29, 126.94, 127.83 , 128.50, 128.96, 130.98, 132.23, 133.80, 133.92, 134.24, 134.35, 134.51, 139.27, 162.97 (NCO), 165.41 (NCO), 181.55 (CO), 183.82 (CO).

Example 17-(3-Chomobenzoguanamine)-2-(chloroacetamido)-oxime (1-(3-fluorobenzamido)-2-(chloroacetamido)-anthraquinone)(CC-14)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 3-fluorobenzoyl chloride (1.42 ml) were added thereto at room temperature. 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the terrane compound CC-14 . Mol. Wt.: 436.8197 (C ₂₃ H ₁₄ ClFN ₂ O ₄ ); R _f : 0.48 (ethyl acetate: n-hexane = 1:2); Yield: 47%; Mp.: 197-198 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 436.0626 ( C ₂₃ H ₁₄ ClFN ₂ O ₄ ⁺ ); found, 436.0623; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 4.43 ( s, 2H, -CH ₂ Cl), 7.48-7.55 (m, 1H, Ar-H), 7.63-7.70 (m, 1H, Ar-H), 7.86-7.96 (m, 4H, Ar-H), 8.10 -8.13 (m, 1H, Ar-H), 8.15-8.19 (m, 1H, Ar-H), 8.26 (d, J = 8.7 Hz, 1H, Ar-H), 8.44 (d, J = 8.7 Hz, 1H, Ar-H), 9.85 (s, 1H, Ar-NH-), 10.49 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 43.21. 114.61, 114.91, 118.63, 118.90, 124.18, 126.12, 126.30, 126.96, 128.14, 128.24, 128.84, 130.37, 130.64, 130.74, 132.23, 134.23, 134.35, 134.54, 136.55, 140.00, 162.97 (NCO), 165.54 (NCO), 181.55 (CO), 183.41 (CO).

Example 18 1-(4-Fluorobenzylamino)-2-(chloroethylamino)-indole (1-(4-fluorobenzamido)-2-(chloroacetamido)-anthraquinone)(CC-15)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 4-fluorobenzoyl chloride (1.42 ml) were added thereto at room temperature. 12 mmo, e), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the green brown compound CC-15. Mol. Wt.: 436.8197 (C ₂₃ H ₁₄ ClFN ₂ O ₄ ); R _f : 0.72 (ethyl acetate: n-hexane = 1:2); Yield: 62%; Mp.: 184-185 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 436.0626 (C ₂₃ H ₁₄ ClFN ₂ O ₄ ⁺ ); found, 436.0625; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 4.42 ( s, 2H, -CH ₂ Cl), 7.44 (t, J = 9.0 Hz, 2H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.09-8.18 (m, 4H, Ar-H ), 8.25 (d, J = 8.7 Hz, 1H, Ar-H), 8.42 (d, J = 8.7 Hz, 1H, Ar-H), 9.84 (s, 1H, Ar-NH-), 10.51 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 43.21, 114.61, 114.91, 118.63, 118.90, 124.18, 126.12, 126.30, 126.96, 128.14, 128.24, 128.84, 130.37 , 130.64, 130.74, 132.23, 134.23, 134.35, 134.54, 136.55, 140.00, 162.97 (NCO), 165.54 (NCO), 181.55 (CO), 183.41 (CO).

Example 19 1-(2-Chomobenzoguanamine)-2-(chloroacetamido)-oxime (1-(2-chlorobenzamido)-2-(chloroacetamido)-anthraquinone)(CC-16)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2-chlorobenzoyl chloride (1.42 ml) were added thereto at room temperature. 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-16 . Mol. Wt.: 453.2743 (C ₂₃ H ₁₄ Cl ₂ N ₂ O ₄ ); R _f : 0.47 (ethyl acetate: n-hexane = 1:2); Yield: 46%; Mp.: 193-194 ° C (EtOH HRMS(EI) m/z :calcd[M] ⁺ , 452.0331 (C ₂₃ H ₁₄ Cl ₂ N ₂ O ₄ ⁺ ); found, 436.0325; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 4.43 (s, 2H, -CH ₂ Cl), 7.57-7.60 (m, 3H, Ar-H), 7.89-7.94 (m, 2H, Ar-H), 8.08-8.19 (m, 3H, Ar-) H), 8.26 (d, J = 8.7 Hz, 1H, Ar-H), 8.37 (d, J = 8.7 Hz, 1H, Ar-H), 9.76 (s, 1H, Ar-NH-), 10.44 (s , 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 43.16, 126.16, 126.32, 126.93, 127.19, 128.37, 128.53, 129.49, 130.14, 130.63, 130.76, 131.73, 134.24, 134.34, 134.56, 135.29, 139.44, 165.36 (NCO), 165.54 (NCO), 181.55 (CO), 183.44 (CO).

Example 201-(3-Chomobenzoguanamine)-2-(chloroacetamido)-oxime (1-(3-chlorobenzamido)-2-(chloroacetamido)-anthraquinone)(CC-17)

Compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 3-chlorobenzoyl chloride (1.42 ml) were added at room temperature. 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the terrane compound CC-17 . Mol. Wt.: 453.2743 (C ₂₃ H ₁₄ Cl ₂ N ₂ O ₄ ); R _f : 0.53 (ethyl acetate: n-hexane = 1:2); Yield: 51%; Mp.: 188-189 ° C (EtOH HRMS(EI) m/z :calcd[M] ⁺ , 452.0331 (C ₂₃ H ₁₄ Cl ₂ N ₂ O ₄ ⁺ ); found, 436.0330; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 4.43 (s, 2H, -CH ₂ Cl), 7.72 - 7.64 (m, 2H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.02-8.19 (m, 4H, Ar-) H), 8.26 (d, J = 8.4 Hz, 1H, Ar-H), 8.45 (d, J = 8.4 Hz, 1H, Ar-H), 9.79 (s, 1H, Ar-NH-), 10.49 (s , 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 43.28, 126.11, 126.24, 126.36, 126.79, 127.01, 127.88, 128.01, 128.37, 128.74, 130.36, 130.53, 131.73, 132.27, 133.33, 134.17, 134.26, 134.41, 134.60, 136.28, 165.23 (NCO), 165.64 (NCO), 181.61 (CO), 183.36 (CO).

Example 211-(4-Chomobenzoguanamine)-2-(chloroacetamido)-oxime (1-(4-chlorobenzamido)-2-(chloroacetamido)-anthraquinone)(CC-18)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 4-chlorobenzoyl chloride (1.44 ml) were added thereto at room temperature. 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 3 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the khaki compound CC-18 . Mo1. Wt.: 453.2743 (C ₂₃ H ₁₄ Cl ₂ N ₂ O ₄ ); R _f : 0.64 (ethyl acetate: n-hexane = 1:2); Yie 1d: 67%; Mp.: 224-225 ° C (EtOH) HRMS(EI) m/z : caLcd[M] ⁺ , 452.0331 (C ₂₃ H ₁₄ Cl ₂ N ₂ O ₄ ⁺ ); found, 436.0333; ¹ H-NMR (300MHz, DMso-d ₆ )d (ppm) ): 4.42 (s, 2H, -CH ₂ Cl), 7.68-7.71 (m, 2H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.08-8.18 (m, 4H, Ar-) H), 8.25 (d, J = 8.4 Hz, 1H, Ar-H), 8.43 (d, J = 8.7 Hz, 1H, Ar-H), 9.86 (s, 1H, Ar-NH-), 10.52 (s , 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 43.23, 126.06, 126.33, 126.96, 128.21, 128.61, 129.06, 129.93, 130.40, 132.25, 132.92, 134.38, 134.56, 136.91, 139.87, 165.50 (NCO), 165.53 (NCO), 181.58 (CO), 183.51 (CO).

Example 22 1-[2-(Trifluoromethyl)benzimidamide]-2-(chloroethylammonium)-oxime (1-[2-(trifluoromethyl)benzamido]-2-(chloroacetamido)-anthraquinone)(CC-19)

Compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2-trifluoromethylbenzoyl chloride (2-(trifluoromethyl)benzoylchl) were added successively at room temperature. Oride) (1.78 ml, 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 4 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-19 . Mol. Wt.: 486.8272 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ); R _f : 0.42 (ethyl acetate: n-hexane = 1:2); Yield: 32%; Mp.: 248-250 ° C (EtOH) HRMS(EI) m / z :calcd[M] ⁺ , 486.0594 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ⁺ ); found, 486.0587; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 4.38 (s, 2H, -CH ₂ Cl), 7.80 (t, J = 7.4 Hz, 1H, Ar-H), 7.90-7.97 (m, 4H, Ar-H), 8.13-8.29 (m, 4H) , Ar-H), 8.37 (d, J = 8.4 Hz, 1H, Ar-H), 9.72 (s, 1H, Ar-NH-), 10.49 (s, 1H, Ar-NH-); ¹³ C-NMR (125MHz, DMSO-d ₆ )d (ppm): 43.32, 126.27, 126.33, 126.63, 126.87, 128.13, 128.64, 129.01, 130.66, 130.76, 132.18, 132.59, 134.23, 134.35, 134.58, 139.39, 165.31 (NCO), 166.00 (NCO), 181.45 (CO), 183.24 (CO).

Example 23 1-[3-(Trifluoromethyl)benzimidamide]-2-(chloroethylammonium)-oxime (1-[3-(trifluoromethyl)benzamido]-2-(chloroacetamido)-anthraquinone)(CC-20)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 3-trifluoromethylbenzoyl chloride (3-(trifluoromethyl)benzoyl) were added successively at room temperature. Chloride) (1.78 ml, 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred for 4 hours in a mini-reactor at an oil bath temperature of 120-130 °C. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the golden compound CC-20 . Mol. Wt.: 486.8272 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ); R _f : 0.52 (ethyl acetate: n-hexane = 1:2); Yield: 48%; Mp.: 190-191 ° C (EtOH) HRMS(EI) m / z :calcd[M] ⁺ , 486.0594 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ⁺ ); found, 486.0596; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 4.38 (s, 2H, -CH ₂ Cl), 7.84 - 7.93 (m, 3H, Ar-H), 8.04 (d, J = 7.5 Hz, 1H, Ar-H), 8.08-8.11 (m, 1H) , Ar-H), 8.16-8.19 (m, 1H, Ar-H), 8.27 (d, J = 9.0 Hz, 1H, Ar-H), 8.38-8.49 (m, 3H, Ar-H), 9.90 ( s, 1H, Ar-NH-), 10.58 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 43.25, 124.66, 126.32, 126.96, 127.98, 128.39 , 128.48, 128.55, 129.82, 130.34, 132.07, 132.25, 134.22, 134.37, 134.55, 135.27, 140.30, 165.24 (NCO), 165.63 (NCO), 181.56 (CO), 183.25 (CO).

Example 24 1-[4-(Trifluoromethyl)benzimidamide]-2-(chloroethylammonium)-oxime (1-[4-(trifluoromethyl)benzamido]-2-(chloroacetamido)-anthraquinone)(CC-21)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 4-trifluoromethylbenzoyl chloride (4-trifluoromethyl) benzoylchloride were added successively at room temperature. (1.78 ml, 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 4 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the brown brown compound CC-21 . Mol. Wt.: 486.8272 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ); R _f : 0.63 (ethyl acetate: n-hexane = 1:2); Yield: 57%; Mp.: 203-204 ° C (EtOH) HRMS(EI) m / z :calcd[M] ⁺ , 486.0594 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ⁺ ); found, 486.0597; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm) ): 4.43 (s, 2H, -CH ₂ Cl), 7.88-7.91 (m, 2H, Ar-H), 8.01 (d, J = 8.4 Hz, 2H, Ar-H), 8.08-8.11 (m, 1H) , Ar-H), 8.16-8.19 (m, 1H, Ar-H), 8.25-8.32 (m, 3H, Ar-H), 8.45 (d, J = 8.3 Hz, 1H, Ar-H), 9.90 ( s, 1H, Ar-NH-), 10.60 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 43.25, 122.15, 125.48, 125.53, 125.77, 126.27 , 126.34, 126.95, 128.11, 128.39, 128.66, 128.93, 130.37, 131.56, 131.99, 132.26, 134.24, 134.39, 134.57, 138.02, 140.12, 165.42 (NCO), 165.61 (NCO), 181.77 (CO), 183.35 (CO) .

Example 25 1-[2,5-Bis-(trifluoromethyl)benzamideamino]-2-(chloroethylammonium)-oxime (1-[2,5- Bis - (trifluoromethyl)benzamido]-2-(chloroacetamido)-anthraquinone)(CC-22)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2,5-bis-trifluoromethylbenzhydrin chloride (2, 5- bis - (trifluoromethyl) benzoyl chloride ) (1ml, 6mmole), stirred for 5 to 10 minutes, and then this mixture was stirred for mini-reactor temperature of 120-130 deg.] C oil bath for 4 hours was placed. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the terrane compound CC-22 . Mol. Wt.: 554.8251 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ); R _f : 0.63 (ethyl acetate: n-hexane = 1:2); Yield: 42%; Mp.: 187-188 ° C (EtOH) HRMS(EI) m/z :calcd[M] ⁺ , 554.0468 (C ₂₄ H ₁₄ ClF ₃ N ₂ O ₄ ⁺ ); found, 554.0468; ¹ H-NMR (300 MHz, DMSO-d ₆ )d (ppm) ): 4.38 (s, 2H, -CH ₂ Cl), 7.90-7.95 (m, 2H, Ar-H), 8.11 - 8.22 (m, 5H, Ar-H), 8.29 (d, J = 8.4 Hz, 1H) , Ar-H), 8.40 (d, J = 8.7 Hz, 1H, Ar-H), 8.69 (s, 1H, Ar-H), 9.85 (s, 1H, Ar-NH-), 10.69 (s, 1H) , Ar-NH-); ¹³ C-NMR (300MHz, DMSO-d ₆ )d (ppm): 42.94, 126.35, 126.59, 126.83, 127.77, 127.90, 128.21, 128.27, 128.68, 128.75, 130.75, 134.21, 134.42, 134.63, 136.22, 139.90, 164.63 (NCO), 165.39 (NCO), 181.50 (CO), 183.26 (CO).

Example 261-[2-(Phenyl)acetamido]-2-(chloroacetamido)-oxime (1-[2-(phenyl)acetylamino]-2-(ch1oroacetamido)-anthraquinone)(CC-23)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and phenylacetyl chloride (1.6 ml, 12 mmole) were added thereto at room temperature, and stirred. The mixture was stirred for 4 hours in a mini-reactor at an oil bath temperature of 120-130 ° C for 10 minutes. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the brown compound CC-23 . Mol. Wt.: 432.8558 (C ₂₄ H ₁₇ ClN ₂ O ₄ ); R _f : 0.46 (ethyl acetate: n-hexane = 1:2); Yield: 34%; Mp.: 184-185 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 432.0877 ( C ₂₄ H ₁₇ ClN ₂ O ₄ ⁺ ); found, 432.0885; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 3.86 ( s, 2H, -CH ₂ -), 4.36 (s, 2H, -CH ₂ Cl), 7.23 - 7.93 (m, 5H, Ar-H), 7.89 - 7.93 (m, 2H, Ar-H), 8.11 8.20 (m, 3H, Ar-H), 8.31 (d, J = 8.7 Hz, 1H, Ar-H), 9.66 (s, 1H, Ar-NH-), 10.25 (s, 1H, Ar-NH-) ¹³ C-NMR (125 MHz, DMSO-d ₆ ) d (ppm): 25.08, 42.51, 43.20, 43.34, 66.97, 125.59, 126.26, 126.53, 126.83, 127.92, 128.15, 128.86, 129.30, 129.66, 128.75, 130.30, 132.16, 134.22, 134.29, 134.52, 135.35, 142.78, 145.07, 165.25 (NCO), 170.57 (NCO), 181.51 (CO), 183.25 (CO).

Example 27 1-[2-(4-Fluorophenyl)acetamido]-2-(chloroethylammonium)-oxime (1-[2-(4-fluorophenyl)acetylamino]-2-(chloroacetamido)-anthraquinone)(CC-24)

The compound CC05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 4-fluorophenylacetyl chloride (1.7 ml, 12 mmole) were added at room temperature. Stir for 5 to 10 minutes, and then mix the mixture in a mini-reactor at an oil bath temperature of 120-130 ° C for 4 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the khaki compound CC-24 . Mol. Wt.: 450.8462 (C ₂₄ H ₁₆ ClFN ₂ O ₄ ); R _f : 0.37 (ethyl acetate: n-hexane = 1:2); Yield: 37%; Mp.: 213-214 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 450.0783 (C ₂₄ H ₁₆ ClFN ₂ O ₄ ⁺ ); found, 450.0782; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 3.86 ( s, 2H, -CH ₂ -), 4.37 (s, 2H, -CH ₂ Cl), 7.17 (t, J = 9.0 Hz, 1H, Ar-H), 7.42 - 7.47 (m, 2H, Ar-H) , 7.90-7.93 (m, 2H, Ar-H), 8.11 - 8.23 (m, 3H, Ar-H), 8.32 (d, J = 8.7 Hz, 1H, Ar-H), 9.64 (s, 1H, Ar -NH-), 10.20 (s, 1H, Ar-NH-); ¹³ C-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 41.48, 43.03, 114.69, 114.97, 125.67, 126.26, 126.79, 127.79, 128.15, 128.28, 129.14, 130.45, 131.42, 131.53, 132.23, 134.27, 134.50, 139.18, 165.23 (NCO), 170.70 (NCO), 181.54 (CO), 183.46 (CO).

Example 281-[(Cyclopropylcarbamimidino)amino]-2-(chloroacetamido)-oxime (1-[(cyclopropanecarbonyl)amino]-2-(chloroacetamido)-anthraquinone)(CC-25)

The compound CC - 05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and cyclopropanecarbonyl chloride (0.6 ml, 6 mmole) were added at room temperature. After stirring for 5 to 10 minutes, the mixture was stirred in a mlni-reactor at an oil bath temperature of 120-130 ° C for 4 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the tan compound CC-25 . Mol. Wt.: 382.7971 (C ₂₀ H ₁₅ ClN ₂ O ₄ ); R _f : 0.43 (ethyl acetate: n-hexane = 1:2); Yield: 27%; Mp.: 191-192 ° C (EtOH); HRMS(EI) m/z : calcd [M] ⁺ , 382.0720 (C ₂₀ H ₁₅ ClN ₂ O ₄ ⁺ ); found, 382.0712; ¹ H-NMR (300MHz, CDCl ₃ )d (ppm): 1.02-1.08 ( m, 2H, -CH ₂ -), 1.26-1.80 (m, 2H, -CH ₂ -), 1.92-1.97 (m, 1H, -CH ₂ -), 4.20 (s, 2H, -CH ₂ Cl), 7.80-7.85 (m, 2H, Ar-H), 8.26-8.33 (m, 4H, Ar-H), 10.01 (s, 1H, Ar-NH-), 11.75 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, CDCl ₃ ) d (ppm): 0.86, 9.16, 16.15, 43.14, 123.55, 125.35, 127.21, 127.53, 131.49, 131.80, 132.61, 132.94, 134.33, 134.75, 136.41, 165.29 (NCO), 175.30 (NCO), 181.79 (CO), 187.40 (CO).

Example 29 1-[(cyclohexylmethylindenyl)amino]-2-(chloroethylammonium)-oxime (1-[(cyclohexanecarbonyl)amino]-2-(chloroacetamido)-anthraquinone)(CC-26)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and cyclohexanecarbonyl chloride (0.88 ml, 6 mmole) were added thereto at room temperature, followed by stirring. The mixture was stirred for 5 to 10 minutes in a mini-reactor at an oil bath temperature of 120-130 ° C for 4 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to give the khaki compound CC-26 . Mol. Wt.: 424.8768 (C ₂₃ H ₂₁ ClN ₂ O ₄ ); R _f : 0.47 (ethyl acetate: n-hexane = 1:2); Yield: 52%; Mp.: 216-217 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 424.1190 (C ₂₃ H ₂₁ ClN ₂ O ₄ ⁺ ); found, 424.1194; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 1.20- 1.49(m,6H,-CH ₂ -),1.67-1.83 (m,2H,-CH ₂ -), 2.06 (d, J = 11.4 Hz, 2H, -CH ₂ -), 4.43 (s, 2H, - CH ₂ Cl), 7.89-7.92 (m, 2H, Ar-H), 8.13-8.19 (m, 3H, Ar-H), 8.28 (d, J = 8.7 Hz, 1H, Ar-H), 9.57 (s , 1H, Ar-NH-), 10.12 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 25.03, 25.32, 28.68, 43.15, 44.36, 125.34, 126.30, 126.92, 127.27, 128.74, 129.89, 130.61, 132.22, 134.29, 134.32, 134.55, 138.65, 165.16 (NCO), 175.60 (NCO), 181.61 (CO), 183.80 (CO).

Example 30 1-[(2-Furanylmethyl)amino]-2-(chloroethylamino)-indole (1-[(2-furoyl)amino]-2-(chloroacetamido)-anthraquinone)(CC-27)

Compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2-furoyl chloride (1.22 ml, 12 mmole) were added at room temperature. The mixture was stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 2 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the brown compound CC-27 . Mol. Wt.: 408.7913 (C ₂₁ H ₁₃ ClN ₂ O ₅ ); R _f : 0.57 (ethyl acetate: n-hexane = 1:2); Yield: 63%; Mp.: 211-212 ° C (EtOH); HRM S(EI) m / z :calcd[M] ⁺ , 408.0513 (C ₂₁ H ₁₃ ClN ₂ O ₅ ⁺ ); found, 408.0518; ¹ H-NMR (300MHz, DMSO-d ₆ )d (ppm): 4.43 (s, 2H, -CH ₂ Cl), 6.77-6.79 (m, 2H, -HC=CH-), 7.38 (d, J = 3.0 Hz, 1H, -HC=CH-), 7.88-7.92 (m, 2H, Ar-H), 8.06 (d, J = 0.9 Hz, 1H, -HC=CH-), 8.22 (d, J = 8.7 Hz, 1H, Ar-H), 8.39 (d, J = 8.7 Hz, 1H, Ar-H), 9.93 (s, 1H, Ar-NH-), 10.60 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 43.26, 112.51, 115.71, 125.74, 126.37, 127.05, 127.56, 128.59, 128.82, 130.37, 132.27, 134.26, 134.47, 134.61, 139.34, 157.15 (NCO), 165.60 (NCO), 181.60 (CO), 184.03 (CO).

Example 31 1-[(2-Thienylmethyl)amino]-2-(chloroacetamido)-oxime (1-[(2-thiophenecarbonyl)amino]-2-(chloroacetamido)-anthraquinone)(CC-28)

Compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2-thiophenecarbonyl chloride (1.28 ml, 12 mmole) were added successively at room temperature. The mixture was stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 2 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the reddish brown compound CC-28 . Mol. Wt.: 424.8569 (C ₂₁ H ₁₃ ClN ₂ O ₄ S); R _f : 0.52 (ethyl acetate: n-hexane = 1:2); Yield: 55%; Mp.: 190-191 ° C (EtOH) HRMS (EI) m/z : calcd [M] ⁺ , 424.0285 (C ₂₁ H ₁₃ ClN ₂ O ₄ S ⁺ ); found, 424.0288; ¹ H-NMR (300 MHz, DMSO-d ₆ )d (ppm): 4.45 (s, 2H, -CH ₂ Cl), 7.30-7.33 (m, 1H, -HC=CH-), 7.88-7.94 (m, 1H, -HC=CH-), 7.88-7.94 (m, 3H, Ar-H), 8.10-8.20 (m, 1H, -HC=CH-), 8.10-8.20 (m, 1H, Ar-H), 8.24 (d, J = 8.4 Hz, 1H, Ar-H), 8.42 (d, J = 6.9 Hz, 1H, Ar-H), 9.45 (s, 1H, Ar-NH-), 10.53 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆₎ )d(ppm): 43.25, 125.95, 126.36, 127.01, 128.04, 128.24, 128.37, 128.88, 130.36, 132.26, 134.26, 134.42, 134.60, 139.08, 139.79, 161.77 (NCO), 165.60 (NCO), 181.55, 181.61 ( CO), 183.59 (CO).

Example 321-[(5-Isooxazolylmethyl)amino]-2-(chloroacetamido)-oxime (1-[(5-isoxazolecarbonyl)amino]-2-(chloroacetamido)-anthraquinone)(CC-29)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and isoxazole-5-carbonium chloride (isoxazole-5-carbonyl) were added successively at room temperature. Chloride) (1.14 ml, 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 2 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the brown compound CC-29 . Mol. Wt.: 409.7794 (C ₂₀ H ₁₂ ClN ₃ O ₅ ); R _f : 0.43 (ethyl acetate: n-hexane = 1:2); Yield: 52%; Mp.: 212-213 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 409.0465 (C ₂₀ H ₁₂ ClN ₃ O ₅ ⁺ ); found, 409.0472; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 4.43 (s, 2H, -CH ₂ Cl), 7.31 (d, J = 1.8 Hz, 1H, -HC=CH-), 7.88-7.94 (m, 1H, -HC=CH-), 7.88-7.92 (m, 2H, Ar-H), 8.08-8.11 (m, 1H, Ar-H), 8.15-8.18 (m, 1H, Ar-H), 8.27 (d, J = 8.7 Hz, 1H, Ar-H), 8.49 (d, J = 8.7 Hz, 1H, Ar-H), 8.88 (d, J = 1.8 Hz, 1H, -HC = N-), 10.03 (s, 1H, Ar-NH-), 10.69 (s, 1H) , Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) δ (ppm): 43.25, 107.12, 126.35, 126.66, 126.82, 126.98, 127.84, 128.56, 130.17, 132.24, 134.18, 134.42, 134.59 , 140.46, 151.99, 155.50, 162.77 (NCO), 165.79 (NCO), 181.50 (CO), 183.06 (CO).

Example 33 N -[2-(2-Chloroacetamido)-9,10-dioxo-9,10-dihydroindol-1-yl]-2,5-dimethylfuran-3- Formamide ( N -[2-(2-chloroacetamido)-9,10-dioxo-9,10-dihydroanthracen-1-yl]-2,5-dimethylfuran-3-carboxamide)(CC-30)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and 2,5-dimethyl-3-furoylpyridinium chloride (2, 5-dimethylfuran-3-carbonyl chloride) (1.51 ml, 12 mmole), stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 2 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow compound CC-30 . Mol. Wt.: 436.8445 (C ₂₃ H ₁₇ ClN ₂ O ₅ ); R _f : 0.54 (ethyl acetate: n-hexane = 1:2); Yield: 63%; Mp.: 207-208 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 436.0826 ( C ₂₃ H ₁₇ ClN ₂ O ₅ ⁺ ); found, 436.0832; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.33 ( s, 3H, -CH ₃ ), 2.52 (s, 3H, -CH ₃ ), 4.44 (s, 2H, -CH ₂ Cl), 6.70 (s, 1H, -HC=CCH ₃ ), 7.89-7.92 (m , 2H, Ar-H), 8.13-8.19 (m, 2H, Ar-H), 8.21 (d, J = 8.7 Hz, 1H, Ar-H), 8.34 (d, J = 8.7 Hz, 1H, Ar- H), 9.83 (s, 1H, Ar-NH-), 10.29 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 12.74, 13.04, 43. 105.21, 116.20, 125.29, 126.29, 126.98, 128.82, 129.93, 130.50, 132.23, 134.23, 134.39, 134.52, 138.67, 149.74, 156.05, 162.99 (NCO), 165.30 (NCO), 181.55 (CO), 184.22 (CO).

Example 34 1-[2-(Phenoxy)acetamido]-2-(chloroethylamino) _- 蒽醌 ( 1-[2-(phenoxy)acetylamino]-2-(chloroacetamido)-anthraquinone)(CC-31)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml), phenoxyacetyl chloride (1.65 ml, 12 mmole) was added thereto at room temperature, followed by stirring. After 5 to 10 minutes, the mixture was placed in a mini-reactor at an oil bath temperature of 120-130 ° C for 2 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-31 . Mol. Wt.: 448.8552 (C ₂₄ H ₁₇ ClN ₂ O ₅ ); R _f : 0.61 (ethyl acetate: n-hexane = 1:2); Yield: 55%; Mp.: 217-218 ° C (EtOH); HRMS (EI) m / z: calcd [m] +, 448.0826 (C 24 H 17 ClN 2 O 5 +); found, 448.0824; 1 H-NMR (300MHz, DMSO-d 6) (ppm) d: 4.40 ( s, 2H, -CH ₂ Cl), 4.82 (s, 2H, -CH ₂ O-), 7.02 (t, J = 6.0 Hz, 1H, Ar-H), 7.16 (d, J = 7.5 Hz, 1H, Ar-H), 7.35-7.40 (m, 2H, Ar-H), 7.90-7.93 (m, 2H, Ar-H), 8.13-8.18 (m, 2H, Ar-H), 8.20 (d, J = 8.7 Hz, 1H, Ar-H), 8.33 (d, J = 8.4 Hz, 1H, Ar-H), 9.86 (s, 1H, Ar-NH-), 10.58 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 43.12, 67.24, 114.94, 118.49, 121.48, 125.60, 126.29, 126.89, 127.44, 128.64, 129.54, 132.22, 134.21, 134.37, 134.52, 135.11, 138.87 , 157.66, 165.41 (NCO), 168.03 (NCO), 181.50 (CO), 181.94 (CO).

Example 35 1-[2-(phenylthio)acetamido]-2-(chloroethylammonium)-oxime ( 1-[2-(phenylsulfanyl)acetyla mino]-2-(chloroacetamido)-anth raquinone)(CC-32)

The compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and pyridine (0.5 ml) and phenylthio(acetyl) chloride (1.79 ml, 12 mmole) were added successively at room temperature. The mixture was stirred for 5 to 10 minutes, and the mixture was stirred in a mini-reactor at an oil bath temperature of 120-130 ° C for 2 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the brown compound CC-32 . Mol. Wt.: 464.9208 (C ₂₄ H ₁₇ ClN ₂ O ₄ S); R _f : 0.57 (ethyl acetate: n-hexane = 1:2); Yield: 59%; Mp.: 161-162 ° C (EtOH) HRMS (EI) m/z : calcd [M] ⁺ , 464.0598 (C ₂₄ H ₁₇ ClN ₂ O ₄ S ⁺ ); found, 464.0602; ¹ H-NMR (300 MHz, DMSO-d ₆ )d (ppm): 4.10(s, 2H, -CH ₂ S-), 4.43 (s, 2H, -CH ₂ Cl), 7.33 (td, J = 6.6 Hz, J = 1.8 Hz, 2H, Ar-H), 7.45 (d, J = 7.2 Hz, 2H, Ar-H), 7.86-7.93 (m, 2H, Ar-H), 8.08-8.16 (m, 2H, Ar-H), 8.21 (d, J = 8.7 Hz, 1H, Ar -H), 8.30 (d, J = 8.7 Hz, 1H, Ar-H), 9.71 (s, 1H, Ar-NH-), 10.46 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz) , DMSO-d ₆ )d (ppm): 43.82, 126.43, 126.58, 127.00, 127.51, 128.56, 129.20, 129.52, 129.66, 131.16, 132.93, 134.96, 135.23, 136.69, 139.82, 166.05 (NCO), 168.92 (NCO) , 182.23 (CO), 184.16 (CO).

Example 36 1-(Benzamethylene)-2-[2-(4-phenylpyridazine)acetamido]-oxime (1-(benzamido)-2-[2-(4-phenylpiperazino) acetylamino]-anthraquinone)(CC-33)

Compound CC-09 (0.83 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), N-phenylpiperazine (1.22 ml, 8 mmole) was added successively at room temperature. The mixture was stirred for 5 to 10 minutes and the mixture was heated to reflux for 16 hours. The reaction mixture is filtered, and the crude product is chromatographed; finally, the crude product is recrystallized from hot ethanol to give the yellow-green compound CC-33 . Mol. Wt.: 544.5998 (C ₃₃ H ₂₈ N ₄ O ₄ ); R _f : 0.33 (ethyl acetate: n-hexane = 1:2); Yield: 57%; Mp.: 225-226 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 544.2111 (C ₃₃ H ₂₈ N ₄ O ₄ ⁺ ); found, 544.2119; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.56 ( Br, 4H, -CH ₂ -), 2.78 (br, 4H, -CH ₂ -), 3.23 (s, 2H, -CH ₂ N-), 6.25 (d, J = 7.8 Hz, 2H, Ar-H) , 6.78 (t, J = 7.2 Hz, 1H, Ar-H), 7.18 (t, J = 8.7 Hz, 2H, Ar-H), 7.37 (t, J = 7.5 Hz, 2H, Ar-H), 7.47 (t, J = 7.5 Hz, 1H, Ar-H), 7.87-7.93 (m, 2H, Ar-H), 8.10 (d, J = 6.0 Hz, 2H, Ar-H), 8.16-8.19 (m, 2H, Ar-H), 8.30 (d, J = 8.7 Hz, 1H, Ar-H), 8.79 (d, J = 8.7 Hz, 1H, Ar-H), 10.06 (s, 1H, Ar-NH-) , 10.58 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 47.81, 52.74, 61.47, 115.56, 118.87, 125.38, 126.29, 126.65, 126.91, 127.72, 127.91, 128.03, 128.48, 128.62, 129.35, 132.14, 132.31, 133.10, 134.12, 134.44, 140.53, 150.77, 166.36 (NCO), 169.06 (NCO), 181.42 (CO), 183.64 (CO).

Example 37 1-(Benzamethylene)-2-[2-[4-(2-fluorophenyl)pyridazine]ethylamino]-indole (1-(benzamido)-2-[2-[4-(2-fluorophenyl)piperazino]acetylamino]-anthraquinone)(CC-34)

Compound CC-09 (0.83 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole) and 1-(2-fluorophenyl)pyridazine (1-(2) were added successively at room temperature. -fluorophenyl)piperazine) (1.26 ml, 8 mmole), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture is filtered to obtain the crude product of the upper layer; finally, the crude product is recrystallized from hot ethanol to obtain an orange-red compound CC-34 . Mol. Wt.: 562.5903 (C ₃₃ H ₂₇ FN ₄ O ₄ ); R _f : 0.37 (ethyl acetate: n-hexane = 1:2); Yield: 65%; Mp.: 228-229 ° C (EtoH); HRMS (EI) m/z : calcd [M] ⁺ , 562.2016 (C ₃₃ H ₂₇ FN ₄ O ₄ ⁺ ); found, 562.2012; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.59 ( Br, 4H, -CH ₂ -), 2.61 (br, 4H, -CH ₂ -), 3.23 (s, 2H, -CH ₂ N-), 6.41 (t, J = 8.1 Hz, 1H, Ar-H) , 6.95-7.10 (m, 3H, Ar-H), 7.48-7.60 (m, 3H, Ar-H), 7.87-7.93 (m, 2H, Ar-H), 8.09-8.20 (m, 4H, Ar- H), 8.30 (d, J = 8.7 Hz, 1H, Ar-H), 8.80 (d, J = 9.0 Hz, 1H, Ar-H), 10.06 (s, 1H, Ar-NH-), 10.62 (s , 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ )d (ppm): 49.53, 52.81, 61.50, 114.20, 115.51, 115.78, 119.13, 119.17, 122.24, 122.35, 124.47, 124.51, 125.31,126.30,126.67,126.92,127.69,128.01,128.66,129.34,132.28,133.27,134.11,134.44,139.32,139.43,140.50,153.20,156.44,166.38 (NCO),169.03 (NCO),181.41(CO),183.68 (CO).

Example 38 1-(4-Methylbenzimidino)-2-[2-(dimethylamino)acetamido]-indole (1-(4-methylbenzamido)-2-[2- (dimethylamino)acetylamino]-anthraquinone)(CC-35)

The compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml), and DIPEA (1ml, 6mmole), dimethylamine (0.8ml, 8mmole) was added successively at room temperature, stirring 5 The mixture was heated to reflux for 16 hours for 10 minutes. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the tan compound CC-35 . Mol. Wt.: 441.4785 (C ₂₆ H ₂₃ N ₃ O ₄ ); R _f : 0.33 (ethyl acetate: n-hexane = 1:2); Yield: 54%; Mp.: 190-191 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 441.1 ^< /RTI> (C ₂₆ H ₂₃ N ₃ O ₄ ⁺ ); found, 441.1689; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.11 ( s,6H,-NCH ₃ ), 2.44 (s,3H,-CH ₃ ), 3.09 (s, 2H, -CH ₂ N-), 7.43 (d, J = 8.1 Hz, 1H, Ar-H), 7.88 -7.91 (m, 2H, Ar-H), 8.11-8.19 (m, 2H, Ar-H), 8.26 (d, J = 8.7 Hz, 1H, Ar-H), 8.64 (d, J = 8.4 Hz, 1H, Ar-H), 10.16 (s, 1H, Ar-NH-), 10.54 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 20.86, 45.16,62.82,125.73,126.30,126.47,127.79,127.99,128.12,128.89,129.09,129.39,130.93,132.32,134.13,134.36,134.43,140.34,142.23,166.35 (NCO),169.14(NCO),181.45(CO) , 183.63 (CO).

Example 39 1-(4-Methylbenzimidino)-2-[2-[(1,3-dioxolan-2-ylmethyl)(methyl)amino]acetamido ]-蒽醌 (1-(4-methylbenzamido)-2-[2-[(1,3-dioxolan-2-ylmethyl)(methyl)amino]acetylamino]-anthraquinone)(CC-36)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), 2-methylaminemethyl-1,3-diox was added successively at room temperature. 2-methylaminomethyl-1,3 dioxolane (0.91 ml, 8 mmole) was stirred for 5 to 10 minutes and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-36 . Mol.Wt.: 513.5412 (C ₂₉ H ₂₇ N ₃ O ₆ ); R _f : 0.31 (ethyl acetate: n-hexane = 1:2); Yield: 43%; Mp.: 156-157 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 513. 1900 (C ₂₉ H ₂₇ N ₃ O ₆ ⁺ ); found, 513.1902; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.18 (s, 3H, -CH ₃ ), 2.44 (s, 3H, -CH ₃ ), 2.54 (d, J = 8.7 Hz, 2H, -NCH ₂ -), 3.26 (s, 2H, -CH ₂ N-) , 3.52-3.55 (m, 2H, -OCH ₂ -), 3.72-3.77 (m, 2H, -OCH ₂ -), 4.58 (t, J = 4.5 Hz, 1H, -OCHO-), 7.43 (d, J = 7.8 Hz, 2H, Ar-H), 7.88-7.92 (m, 2H, Ar-H), 8.04 (d, J = 8.1 Hz, 2H, Ar-H), 8.10-8.19 (m, 2H, Ar- H), 8.27 (d, J = 8.4 Hz, 1H, Ar-H), 8.70 (d, J = 8.7 Hz, 1H, Ar-H), 10.15 (s, 1H, Ar-NH-), 10.53 (s , 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 20.87, 43.49, 59.43, 61.73, 63.91, 102.61, 125.50, 126.31, 126.48, 126.90, 127.89, 128.06 , 129.06, 129.31, 130.75, 132.33, 134.16, 134.38, 134.45, 140.42, 142.29, 166.25 (NCO), 169.59 (NCO), 181.46 (CO), 183.70 (CO).

Example 40 4-Methyl- N- (2-(2-methyl(2-(pyridyl-2-ethyl)amine)acetamido)-9,10-dioxo-9,10- Dihydroanthracene-1) benzoguanamine 4-methyl-N-(2-(2-(methyl(2-(pyridin-2-yl)ethyl)amino)acetamido)-9,10-dioxo-9,10-dihydroanthracen-1-yl)benzamide(CC) -37)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole) and 2-(2-methylaminoethyl-pyridine) were added at room temperature. 2-(2-methylaminoethyl pyridine)) (1.1 ml, 8 mmole), stirred for 5 to 10 min. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the bright yellow compound CC-37 . Mol. Wt.: 532.5891 (C ₃₂ H ₂₈ N ₄ O ₄ ); R _f : 0.29 (ethyl acetate: n-hexane = 1:2); Yield: 32%; Mp.: 166-167 ° C (EtOH); HRMS(EI) m/z : calcd [M] ⁺ , 532.2111 (C ₃₂ H ₂₈ N ₄ O ₄ ⁺ ); found, 532.2119; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.15 ( s, 3H, -CH ₃ ), 2.40 (s, 3H, -CH ₃ ), 2.68 (d, J = 7.2 Hz, 4H, -CH ₂ -), 3.20 (s, 2H, -CH ₂ N-), 7.03 (d, J = 7.0 Hz, 1H, Ar-H), 7.13-7.18 (m, 1H, Ar-H), 7.39 (d, J = 8.1 Hz, 2H, Ar-H), 7.60-7.65 (m , 1H, Ar-H), 7.89-7.93 (m, 2H, Ar-H), 8.03 (d, J = 8.1 Hz, 2H, Ar-H), 8.11-8.20 (m, 2H, Ar-H), 8.28 (d, J = 8.7 Hz, 1H, Ar-H), 8.40-8.42 (m, 1H, Ar-H), 8.69 (d, J = 8.7 Hz, 1H, Ar-H), 10.18 (s, 1H) , Ar-NH-), 10.54 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 20.81, 42.45, 56.92, 61.03, 63.91, 121.62, 122.81, 125.50,126.29,126.44,126.88,127.83,127.88,128.07,129.08,129.30,130.72,132.33,134.13,134.36,134.42,136.24,140.37,142.30,148.86,159.40,166.19(NCO),169.59(NCO),181.43( CO), 183.74 (CO).

Example 41 1-(4-Methylbenzylamino)-2-[2-(tetrahydro-1) H -1-pyrrolyl)ethinyl]-oxime (1-(4-methylbenzamido)-2-[2-(tetrahydro-1) H -1-pyrrolyl) acetylamino]-anthraquinone)(CC-38)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), pyrrolidine (0.8 ml, 8 mmole) was added successively at room temperature, stirring 5 to 10 The mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the dark brown compound CC-38 . Mol. Wt.: 467.5158 (C ₂₈ H ₂₅ N ₃ O ₄ ); R _f : 0.37 (ethyl acetate: n-hexane = 1:2); Yield: 39%; Mp.: 193-194 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 467.1845 (C ₂₈ H ₂₅ N ₂ O ₄ ⁺ ); found, 467.1840; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 1.31 ( Br, 10H, -CH ₂ -), 2.43 (s, 3H, -CH ₃ ), 3.27 (s, 2H, -CH ₂ N-), 7.42 (d, J = 8.1 Hz, 2H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.09-8.19 (m, 2H, Ar-H), 8.27 (d, J = 8.7 Hz, 1H, Ar-H), 8.73 (d, J = 8.4 Hz) , 1H, Ar-H), 10.12 (s, 1H, Ar-NH-), 10.54 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 20.86 , 23.20, 53.65, 59.09, 126.30, 126.54, 126.88, 127.80, 127.88, 127.92, 129.05, 129.25, 130.59, 132.33, 134.12, 134.38, 134.42, 136.24, 140.44, 142.43, 166.26 (NCO), 169.56 (NCO), 181.42 (CO), 183.86 (CO).

Example 42 1-(4-Methylbenzimidino)-2-[(2-acridinyl)amino]-oxime ( 1-(4-methylbenzamido)-2-[(2-piperidinoacetyl) amino]-anthraquinone)(CC-39)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), piperidine (0.79 ml, 8 mmole) was added successively at room temperature, stirring 5 to 10 The mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-39 . Mol. Wt.: 481.5424 (C ₂₉ H ₂₇ N ₃ O ₄ ); R _f : 0.36 (ethylacetate: n-hexane = 1:2); Yield: 43%; Mp.: 213-214 ° C (EtOH); HRMS (EI) m/z :calcd [M] ⁺ , 481.2002 (C ₂₉ H ₂₇ N ₃ O ₄ ⁺ ); found, 481.2000; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 1.08 (d) , J = 3.6 Hz, 2H, -CH ₂ -), 1.19 (br, 4H, -CH ₂ -), 2.33 (br, 4H, -CH ₂ -), 2.43 (s, 3H, -CH ₃ ), 3.07 (s, 2H, -CH ₂ N-), 7.43 (d, J = 7.8 Hz, 1H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.07-8.19 (m, 4H, Ar -H), 8.27 (d, J = 8.7 Hz, 1H, Ar-H), 8.78 (d, J = 8.7 Hz, 1H, Ar-H), 10.13 (s, 1H, Ar-NH-), 10.52 ( s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 20.85, 22.80, 24.79, 54.13, 62.39, 125.19, 126.27, 126.53, 126.89, 127.84, 127.92, 128.02 , 129.00, 129.22, 130.57, 132.31, 134.13, 134.36, 134.42, 140.63, 142.40, 166.25 (NCO), 169.55 (NCO), 181.42 (CO), 183.67 (CO).

Example 43 1-(4-Methylbenzylideneamino)-2-[2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)ethinylamino] -蒽醌 (1-(4-methylbenzamido)-2-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl) acetylamino]-anthraquinone)(CC-40)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), 1,4-dioxo-8-azaspiro[4.5] Alkane (1,4-dioxa-8-azaspiro [4.5] decane) (1.03 ml, 8 mmole) was stirred for 5 to 10 min then the mixture was heated to reflux for 16 h. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the brown compound CC-40 . Mol. Wt.: 539.5785 (C ₃₁ H ₂₉ N ₃ O ₆ ); R _f : 0.34 (ethyl acetate: n-hexane = 1:2); Yield: 55%; Mp.: 197-198 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 539.2056 (C ₃₁ H ₂₉ N ₃ O ₆ ⁺ ); found, 539. 2051; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 1.39 ( d, J = 5.4 Hz, 8H, -CH ₂ -), 2.43 (s, 3H, -CH ₃ ), 3.15 (s, 2H, -CH ₂ N-), 3.77 (s, 4H, -CH ₂ -) , 7.41 (d, J = 7.8 Hz, 1H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.06 (d, J = 8.1 Hz, 2H, Ar-H), 8.10-8.19 ( m, 2H, Ar-H), 8.26 (d, J = 8.7 Hz, 1H, Ar-H), 8.70 (d, J = 8.7 Hz, 1H, Ar-H), 10.03 (s, 1H, Ar-NH) -), 10.60 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 20.88, 33.68, 51.35, 61.29, 63.34, 63.52, 105.58, 125.90, 126.28, 126.32, 126.91, 127.75, 127.86, 128.18, 129.18, 129.40, 130.44, 132.29, 134.13, 134.38, 134.44, 140.32, 142.46, 166.29 (NCO), 169.31 (NCO), 181.44 (CO), 183.81 (CO).

Example 44 1-(4-Methylbenzimidino)-2-[(2-(morpholinyl)amino]-indole (1-(4-methylbenzamido)-2-[(2-morpholinoacetyl) amino]-anthraquinone)(CC-41)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), morpholine (0.69 ml, 8 mmole) was added successively at room temperature, stirring 5 to 10 The mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-41 . Mol. Wt.: 483.5152 (C ₂₈ H ₂₅ N ₃ O ₅ ); R _f : 0.38 (ethyl acetate: n-hexane = 1:2); Yield: 47%; Mp.: 225-226 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 483.1794 (C ₂₈ H ₂₅ N ₃ O ₅ ⁺ ); found, 483.1793; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.39 ( Br, 4H, -CH ₂ -), 2.45 (s, 3H, -CH ₃ ), 3.15 (s, 2H, -CH ₂ N-), 3.22 (br, 4H, -CH ₂ -), 7.45 (d, J = 7.8 Hz, 2H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.07-8.12 (m, 3H, Ar-H), 8.27 (d, J = 8.7 Hz, 1H, Ar -H), 8.73 (d, J = 8.7 Hz, 1H, Ar-H), 9.99 (s, 1H, Ar-NH-), 10.61 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz , DMSO-d ₆ ) d (ppm): 20.95, 53.17, 61.94, 65.59, 125.73, 126.37, 126.53, 126.98, 127.82, 128.05, 129.28, 129.46, 130.55, 132.35, 134.16, 134.53, 140.31, 142.66, 166.32 (NCO ), 168.97 (NCO), 181.50 (CO), 183.84 (CO).

Example 45 1-(4-Methylbenzimidino)-2-[2-(thiomorpholin-4-yl)acetamido]-oxime (1-(4-methylbenzamido)-2-[2-(1,4-thiazinan-4-yl) acetylamino]-anthraquinone)(CC-42)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole), thiomorpholine (0.80 ml, 8 mmole) was added successively at room temperature, stirring 5 The mixture was heated to reflux for 16 hours to 10 minutes. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-42 . Mol. Wt.: 499.5808 (C ₂₈ H ₂₅ N ₃ O ₄ S); R _f : 0.43 (ethyl acetate: n-hexane = 1:2); Yield: 51%; Mp.: 210-211 ° C (EtOH) ;HRMS(EI) m/z :calcd[M] ⁺ , 499.1566 (C ₂₈ H ₂₅ N ₃ O ₄ S ⁺ ); found, 499.1570; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.39 (br, 4H, -CH ₂ -), 2.45 (s, 3H, -CH ₃ ), 3.15 (s, 2H, -CH ₂ N-), 3.23 (br, 4H, -CH ₂ -), 7.45 ( d, J = 8.1 Hz, 2H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.07-8.19 (m, 4H, Ar-H), 8.27 (d, J = 8.4 Hz, 1H) , Ar-H), 8.73 (d, J = 8.4 Hz, 1H, Ar-H), 10.00 (s, 1H, Ar-NH-), 10.61 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 20.89, 26.48, 53.13, 54.62, 61.92, 65.54, 127.72, 126.30, 126.40, 126.92, 127.69, 127.92, 127.98, 129.22, 129.43, 130.53, 132.30, 134.12, 134.41 , 134.45, 140.21, 142.61, 166.27 (NCO), 168.89, 169.15 (NCO), 181.42 (CO), 183.84 (CO).

Example 46 1-(4-Methylbenzimidino)-2-[2-(4-methylpyridazine)acetamido]-oxime (1-(4-methylbenzamido)-2-[2-(4-methylpiperazino) acetylamino]-anthraquinone)(CC-43)

Compound take CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml) in, at room temperature, was added successively DIPEA (1ml, 6mmole), N - methyl-piperazine (N -methylpiperazine) (0.88ml, 8mmole The mixture was stirred for 5 to 10 minutes and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-43 . Mol. Wt.: 496.5570 (C ₂₉ H ₂₈ N ₄ O ₄ ); R _f : 0.28 (ethyl acetate: n-hexane = 1:2); Yield: 55%; Mp.: 214-215 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 496.2111 (C ₂₉ H ₂₈ N ₄ O ₄ ⁺ ); found, 496.2115; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 1.76 ( s, 3H, -CH ₃ ), 1.96 (br, 4H, -CH ₂ -), 2.38 (br, 4H, -CH ₂ -), 2.43 (s, 3H, -CH ₃ ), 3.13 (s, 2H, -CH ₂ N-), 7.45 (d, J = 7.8 Hz, 2H, Ar-H), 7.87-7.93 (m, 2H, Ar-H), 8.08-8.16 (m, 4H, Ar-H), 8.27 (d, J = 9.0 Hz, 1H, Ar-H), 8.81 (d, J = 8.7 Hz, 1H, Ar-H), 10.01 (s, 1H, Ar-NH-), 10.50 (s, 1H, Ar -NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 20.89, 26.48, 53.13, 54.62, 61.92, 65.54, 127.72, 126.30, 126.40, 126.92, 127.69, 127.92, 127.98, 129.22, 129.43, 130.53, 132.30, 134.12, 134.41, 134.45, 140.21, 142.61, 166.27 (NCO), 168.89, 169.15 (NCO), 181.42 (CO), 183.84 (CO).

Example 47 1-(4-Methylbenzimidino)-2-[2-(4-(2-hydroxyethyl)pyridazine]Ethylamino]-indole (1-(4-methylbenzamido)-2-[2-(4-(2-hydroxyethyl) piperazino]acetylamino]-anthraquinone)(CC-44)

The compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and DIPEA (1 ml, 6 mmole) and 2-hydroxyethylpyridazine (2-(piperazin-1-yl) were added successively at room temperature. Ethanol) (0.97 ml, 8 mol), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-44 . Mol. Wt.: 526.5830 (C ₃₀ H ₃₀ N ₄ O ₅ ); R _f : 0.41 (ethyl acetate: n-hexane = 1:2); Yield: 48%; Mp.: 210-211 ° C (EtOH); HRMS (EI) m/z : Calcd [M] ⁺ , 526.2216 (C ₃₀ H ₃₀ N ₄ O ₅ ⁺ ); found, 526.2219; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 1.92 ( t, J = 6.0 Hz, 2H, -NCH ₂ -), 2.03 (br, 4H, -CH ₂ -), 2.39 (br, 4H, -CH ₂ -), 2.43 (s, 3H, -CH ₃ ), 3.01 (s, 2H, -CH ₂ N-), 3.26-3.30 (m, 2H, -CH ₂ OH), 4.29 (t, J = 5.4 Hz, 1H, -CH ₂ OH), 7.43 (d, J = 8.1 Hz, 2H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.07-8.19 (m, 4H, Ar-H), 8.27 (d, J = 8.7 Hz, 1H, Ar-H ), 8.79 (d, J = 8.7 Hz, 1H, Ar-H), 10.00 (s, 1H, Ar-NH-), 10.50 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO) -d ₆ ) d (ppm): 20.93, 52.32, 52.93, 58.21, 59.1, 61.69, 125.11, 126.37, 126.72, 126.98, 127.81, 128.04, 128.33, 129.24, 130.53, 130.53, 140.68, 142.70, 166.37 (NCO), 169.28 (NCO), 181.50 (CO), 183.77 (CO).

Example 48 1-(4-Methylbenzimidino)-2-[2-(4-phenylpyridazine)ethinyl]-oxime (1-(4-methylbenzamido)-2-[2-(4-phenylpiperazino) acetylamino]-anthraquinone)(CC-45)

Solution of compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml) in, at room temperature, was added successively DIPEA (1ml, 6mmole), N- phenyl-piperazine (N -phenylpiperazine) (1.22ml, 8mmole The mixture was stirred for 5 to 10 minutes and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, and the crude product was chromatographed; finally, the crude product was recrystallized from hot ethanol to give yellow-green compound CC-45 . Mol. Wt.: 558.6264 (C ₃₄ H ₃₀ N ₄ O ₄ ); R _f : 0.36 (ethyl acetate: n-hexane = 1:2); Yield: 53%; Mp.: 270-271 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 558.2267 (C ₃₄ H ₃₀ N ₄ O ₄ ⁺ ); found, 558.2271; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.21. s, 3H, -CH ₃ ), 2.55 (br, 4H, -CH ₂ -), 2.73 (br, 4H, -CH ₂ -), 3.22 (s, 2H, -CH ₂ N-), 6.64 (d, J = 7.5 Hz, 2H, Ar-H), 6.79 (d, J = 7.2 Hz, 1H, Ar-H), 7.12-7.21 (m, 4H, Ar-H), 7.87-7.92 (m, 2H, Ar -H), 7.98 (d, J = 8.1 Hz, 2H, Ar-H), 8.08-8.19 (m, 2H, Ar-H), 8.29 (d, J = 8.7 Hz, 1H, Ar-H), 8.80 (d, J = 8.7 Hz, 1H, Ar-H), 10.07 (s, 1H, Ar-NH-), 10.52 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆₎ d(ppm): 20.76, 47.66, 52.81, 61.52, 115.40, 118.74, 125.16, 126.28, 126.57, 126.88, 127.84, 127.95, 128.58, 129.05, 129.27, 130.28, 134.11, 134.42, 140.51, 142.46, 150.77, 166.21 ( NCO), 169.05 (NCO), 181.42 (CO), 183.65 (CO).

Example 49 1-(4-Methylbenzimidino)-2-[2-[4-(2-fluorophenyl)pyridazine]Ethylamino]-indole ( 1-(4-methylbenzamido)-2-[2-[4-(2-fluorophenyl) piperazino]acetylamino]-anthraquinone)(CC-46)

The compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml), and DIPEA (1ml, 6mmole), 1-(2-fluorophenyl)pyridazine (1-(2) was added successively at room temperature. -fluorophenyl) piperazine) (1.26 ml, 8 mmole), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture is filtered, and the crude product is chromatographed; finally, the crude product is recrystallized from hot ethanol to give an orange-red compound CC-46 . Mol. Wt.: 576.6169 (C ₃₄ H ₂₉ FN ₄ O ₄ ); R _f : 0.32 (ethyl acetate: n-hexane = 1:2); Yield: 62%; Mp.: 228-229 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 576.2173 ( C ₃₄ H ₂₉ FN ₄ O ₄ ⁺ ); found, 576.2181; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.29 ( s, 3H, -CH ₃ ), 2.58 (br, 8H, -CH ₂ -), 3.17 (s, 2H, -CH ₂ N-), 6.42 (t, J = 7.2 Hz, 1H, Ar-H), 6.97-7.10 (m, 3H, Ar-H), 7.30 (d, J = 7.5 Hz, 2H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.04-8.11 (m, 4H, Ar-H), 8.16-8.19 (m, 1H, Ar-H), 8.29 (d, J = 8.4 Hz, 1H, Ar-H), 8.81 (d, J = 8.4 Hz, 1H, Ar-H), 10.06 (s, 1H, Ar-NH-), 10.56 (s, 1H, Ar-NH-); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) d (ppm): 21.54, 50.19, 53.61, 62.30, 114.94 , 116.26, 116.54, 119.71, 122.85, 122.96, 127.04, 127.33, 127.65, 128.61, 128.81, 129.97, 130.04, 131.26, 133.07, 134.86, 135.18, 141.20, 143.28, 153.96, 167.00 (NCO), 169.77 (NCO), 182.17 (CO), 184.48 (CO).

Example 50 1-(4-Methylbenzimidino)-2-[2-[4-(2-benzonitrile)pyridazine]Ethylamino]-indole (1-(4-methylbenzamido)-2-[2-[4-(2-cyanophenyl) piperazino]acetylamino]-anthraquinone)(CC-47)

The compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml), and DIPEA (1ml, 6mmole), 1-(2-benzonitrile)pyridazine (1-(2) was added successively at room temperature. -cyanophenyl) piperazine) (1.35 ml, 8 mmole), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, and the crude product was chromatographed. The crude product was recrystallized from hot ethanol to give yellow compound CC-47 . Mol. Wt.: 583.6359 (C ₃₅ H ₂₉ N ₅ O ₄ ); R _f : 0.37 (ethyl acetate: n-hexane = 1:2); Yield: 55%; Mp.: 238-239 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 583.2220 (C ₃₅ H ₂₉ N ₅ O ₄ ⁺ ); found, 583.6359; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.30 ( s, 3H, -CH ₃ ), 2.62 (br, 4H, -CH ₂ -), 2.71 (br, 4H, -CH ₂ -), 3.22 (s, 2H, -CH ₂ N-), 6.50 (d, J = 8.4 Hz, 1H, Ar-H), 7.11 (t, J = 7.5 Hz, 1H, Ar-H), 7.34 (d, J = 8.1 Hz, 2H, Ar-H), 7.58 (t, J = 8.4 Hz, 1H, Ar-H), 7.66 (dd, J = 9.0 Hz, J = 1.5 Hz, 2H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.06-8.19 (m, 4H, Ar-H), 8.29 (d, J = 9.0 Hz, 1H, Ar-H), 8.82 (d, J = 8.7 Hz, 1H, Ar-H), 10.06 (s, 1H, Ar-NH-) , 10.58 (s, 1H, Ar-NH-); ¹³ C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 21.54, 50.19, 53.61, 62.30, 114.94, 116.26, 116.54, 119.71, 122.85, 122.96, 127.04, 127.33, 127.65, 128.61, 128.81, 129.97, 130.04, 131.26, 133.07, 134.86, 135.18, 141.20, 143.28, 153.96, 167.00 (NCO), 169.77 (NCO), 182.17 (CO), 184.48 (CO).

Example 51 1-(4-Methylbenzimidino)-2-[2-[4-(2-methoxyphenyl)pyridazine]Ethylamino]-indole (1-(4-methylbenzamido)-2-[2-[4-(2-methoxyphenyl) piperazino]acetylamino]-anthraquinone)(CC-48)

The compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml), and DIPEA (1ml, 6mmole), 1-(2-methoxyphenyl)pyridazine (1- (2-methoxyphenyl) piperazine) (1.38 ml, 8 mmole), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, and the crude product was chromatographed; finally, the crude product was recrystallized from hot ethanol to give orange compound CC-48 . Mol. Wt.: 588.6524 (C ₃₅ H ₃₂ N ₄ O ₅ ); R _f : 0.34 (ethyl acetate: n-hexane = 1:2); Yield: 58%; Mp.: 215-216 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 588.2373 (C ₃₅ H ₃₂ N ₄ O ₅ ⁺ ); found, 588.2378; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.20 ( s, 3H, -CH ₃ ), 2.69 (br, 8H, -CH ₂ -), 3.22 (s, 2H, -CH ₂ N-), 3.72 (s, 3H, -OCH ₃ ), 6.16 (t, J =2.4 Hz, 1H, Ar-H), 6.24 (d, J = 8.1 Hz, 1H, Ar-H), 6.38 (d, J = 9.0 Hz, 1H, Ar-H), 7.05-7.14 (m, 2H) , Ar-H), 7.88-7.93 (m, 2H, Ar-H), 7.97 (d, J = 8.1 Hz, 2H, Ar-H), 8.08-8.19 (m, 2H, Ar-H), 8.29 ( d, J = 8.7 Hz, 1H, Ar-H), 8.80 (d, J = 8.7 Hz, 1H, Ar-H), 10.08 (s, 1H, Ar-NH-), 10.52 (s, 1H, Ar- NH-); ¹³ C-NMR (125MHz, DMSO-d ₆ ) d (ppm): 20.86,47.63,52.86,54.81,61.53,101.53,103.94,108.06,124.95,126.32,126.74,126.90,127.65,127.97,129.04 , 129.25, 130.12, 132.26, 134.06, 134.41, 134.48, 140.55, 142.50, 153.05, 159.97, 163.71, 166.17 (NCO), 169.05 (NCO), 181.35 (CO), 183.44 (CO).

Example 52 1-(4-Methylbenzimidino)-2-[2-[4-(2-pyridyl)pyridazine]Ethylamino]-indole (1-(4-methylbenzamido)-2-[2-[4-(2-pyridyl) piperazino]acetylamino]-anthraquinone)(CC-49)

The compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml), and DIPEA (1ml, 6mmole), 1-(2-pyridyl)pyridazine (1-(2-) was added successively at room temperature. Pyridyl) piperazine) (1.21 ml, 8 mmole), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product is recrystallized from hot ethanol to obtain the earth orange compound CC-49 . Mol. Wt.: 559.6145 (C ₃₃ H ₂₉ N ₅ O ₄ ); R _f : 0.28 (ethyl acetate: n-hexane = 1:2); Yield: 63%; Mp.: 258-259 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 559.2220 (C ₃₃ H ₂₉ N ₅ O ₄ ⁺ ); found, 559.2224; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.16 ( s, 3H, -CH ₃ ), 3.05 (br, 8H, -CH ₂ -), 3.22 (s, 2H, -CH ₂ N-), 6.54 (d, J = 8.4 Hz, 1H, Ar-H), 6.66 (t, J = 6.3 Hz, 1H, Ar-H), 7.08 (d, J = 7.8 Hz, 2H, Ar-H), 7.52 (td, J = 7.7 Hz, J = 2.1 Hz, 1H, Ar- H), 7.87-7.91 (m, 2H, Ar-H), 7.97 (d, J = 8.1 Hz, 2H, Ar-H), 8.07-8.19 (m, 2H, Ar-H), 8.29 (d, J) = 8.7Hz, 1H, Ar-H ), 8.82 (d, J = 9.0Hz, 1H, Ar-H), 10.16 (s, 1H, Ar-NH -), 10.51 (s, 1H, ArNH-); 13 C-NMR (75MHz, DMSO-d ₆ ) d (ppm): 20.88, 44.21, 52.56, 61.54, 107.00, 113.11, 124.91, 126.42, 126.89, 126.99, 127.63, 128.03, 128.21, 129.01, 129.29, 132.26, 133.39, 134.19, 134.52, 134.58, 137.30, 140.73, 142.51, 147.49, 159.15, 166.26, 166.31 (NCO), 169.23 (NCO), 181.54 (CO), 183.63 (CO).

Example 53 1-(4-Methylbenzimidino)-2-[2-[4-(2-pyrimidinyl)pyridazine]Ethylamino]-indole (1-(4-methylbenzamido)-2-[2-[4-(2-pyrimidinyl) piperazino]acetylamino]-anthraquinone)(CC-50)

The compound CC-12 (0.86g, 2mmole) was dissolved in anhydrous tetrahydrofuran (30ml), and DIPEA (1ml, 6mmole), 1-(2-pyrimidinyl)pyridazine (1-(2-) was added successively at room temperature. Pyrimidyl) piperazine) (1.13 ml, 8 mmole), stirred for 5 to 10 minutes, and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered, the filtrate was taken, concentrated under reduced pressure, and extracted with ethyl acetate several times, then water was removed by magnessium sulfate, concentrated under reduced pressure, and then the crude product was washed with ethyl acetate/hexane; The product was recrystallized from hot ethanol to give the yellow-green compound CC-50 . Mol. Wt.: 560.6025 (C ₃₂ H ₂₈ N ₆ O ₄ ); R _f : 0.32 (ethyl acetate: n-hexane = 1:2); Yield: 41%; Mp.: 267-268 ° C (EtOH); HRMS (EI) m/z : calcd [M] ⁺ , 560.2172 (C ₃₂ H ₂₈ N ₆ O ₄ ⁺ ); found, 560.2170; ¹ H-NMR (300 MHz, DMSO-d ₆ ) d (ppm): 2.20 ( s, 3H, -CH ₃ ), 3.05 (br, 8H, -CH ₂ -), 3.11 (s, 2H, -CH ₂ N-), 3.22 (br, 8H, -CH ₂ -), 6.66 (d, J = 4.8 Hz, 1H, Ar-H), 7.16 (d, J = 7.8 Hz, 1H, Ar-H), 7.87-7.91 (m, 2H, Ar-H), 8.01 (d, J = 6.0 Hz, 2H, Ar-H), 8.08-8.19 (m, 2H, Ar-H), 8.32 (d, J = 7.2 Hz, 1H, Ar-H), 8.82 (d, J = 8.7 Hz, 1H, Ar-H ), 10.19 (s, 1H, Ar-NH-), 10.54 (s, 1H, Ar-NH-); ¹³ C-NMR (125MHz, DMSO-d ₆ ) d (ppm): 20.98, 42.53, 43.01, 52.46 , 61.44, 110.28, 111.11, 124.77, 126.32, 126.89, 127.44, 127.92, 128.14, 128.90, 129.18, 130.18, 132.26, 134.06, 134.48, 142.39, 157.65, 158.07, 161.24, 166.12, (NCO), 169.08 (NCO), 181.35 (CO), 183.39 (CO).

Example 54 Telomerase Sequence Reproduction (TRAP) Screening for Telomerase Inhibitor Results

In the telomere sequence replication method, it is expected that a commercially available TS primer can be used to mimic the telomere sequence, and a G-quadruplex can be formed by itself under normal physiological conditions. When the compound stabilizes the structure, the telomerase cannot extend the telomere length. Further, the effect of inhibiting telomerase is achieved, and thus the synthesized CC-01 ^to CC-50 is used to find a compound having an inhibitory effect on telomerase by using a telomere sequence replication method.

In the results of colloidal electrophoresis (Fig. 5A to Fig. 5C), the positive control group (P) replaced the compound with three times of sterilization; the negative control group (N) was 5 μl of 0.1 mg/ml RNase A (CLONTECH). In place of the compound, a number of telomere fragments were produced in the positive control group (P), but not in the negative control group (N). 10 μM was selected as the concentration of the screening compound, and all the compounds were first screened first, and then the more effective compounds were selected for screening at different concentrations. The results are shown in Figure 5A to Figure 5C. There is no significant telomerase inhibition effect from 01 to CC-50; therefore, it is speculated that both the symmetric disubstituted or asymmetric 1,2-disubstituted guanamine anthraquinone derivatives have inhibitory effects on telomerase. Relatively poor.

Example 55 Screening Results of Secreted Alkaline Phosphatase Assay (SEAP System) and MTT Assay

The results of SEAP and MTT analysis can be found in Tables 1 to 5. The results show that the structure of the compound has a symmetrical (CC-01 to CC-03) and asymmetrical (CC-06 to CC-08) branched structure at 1 μM. The poisoning ability in 10μM and 100μM is much better than 1,2-diaminoanthraquinone. In addition, the compound structures CC-01 and CC-06 are more toxic, and their poisoning ability is even better than that of mitoxantrone and doxorubicin. Most of the compound structures of compounds CC-09 to CC-22 have strong poisoning ability under the action of high concentration (100 μM, 10 μM). In addition, the compound structures CC-14 and CC-15 with more potential for toxic killing can be found. The structure of these two compounds still has a strong poisoning effect under the action of low concentration (1 μM), and its inhibition ability is even better than that of mitoxantrone and doxorubicin. The structure is good. In addition, in compounds CC-23 to CC-32, the compound structure of CC-28 was found to be more promising, and its ability to inhibit the activity of cancer cells was no less than that of mitoxantrone and doxorubicin. The structure of CC-33 to CC-50 compounds in the high concentration (100μM, 10μM) environment, the ability of cell cytotoxicity decreased, especially under the 10μM poisoning effect, the most obvious difference (poison reduction), only Compounds CC-43 and CC-44, at this concentration, are the more inhibitory structures in this series of compounds (CC-35 to CC-50).

In summary, in the pharmacological test of SEAP and MTT, there is a strong poisoning effect at low concentration (1μM) (cell survival rate is less than 50%), which is CC-01, CC-06, CC-14. , CC-15 and CC-28 compounds, meaning that these compounds have the ability to kill H1299 non-small cell lung cancer cell lines, and their effects are even more potential than the structure of mitoxantrone and doxorubicin. The CC-33 compound had no obvious poisoning effect at low and high concentrations (1 μM, 10 μM, 100 μM). The others were poisonous at high concentrations (100 μM, 10 μM).

Representative structural formulae of the compounds of the invention, as shown in Formula I:

Wherein when R _a and R _b are the same substituents, all of which are defined by R ₁ of Table 2, they are compounds CC-01, CC-02, CC-03 and CC-04; wherein when R _a is a table 3 is defined by R ₂ and R _b is In the case of formula II, it is compound CC-05 ^~ CC-32; where R _a is Formula III, R _b Formula IV, and when R ₃ is hydrogen (H) or fluorine (F), that is, the structural formula of compounds CC-33, CC-34, respectively; wherein when R _a is Formula V, R _b is Formula VI, and R ₄ is as defined in Table 5, which is the compound CC-35 ^~ CC-50.

Example 56 Screening results of cancer cell lines by the American Cancer Research Center (NCI)

The US Cancer Center NCI screening system consists of 60 different human tumor cells, and each compound is tested for its ability to grow or cytotoxic to various cancers and tumors at a certain concentration.

NCI uses CC-04, CC-12, CC-23, CC-38, and CC-43 as test compounds (as shown in Table 6) to test the results (as shown in Table 7 and Annexes 1 to 5). Among them, for cancer cells such as Leukemia, Non-Small Cell Lung Cancer, Colon Cancer, CNS Cancer, Melanoma, Ovarian Cancer, Renal Cancer, Prostate Cancer, Breast Cancer, etc., the compound CC-12 can inhibit the growth effect thereof. Compound CC-23 inhibits the growth of Leukemia, Melanoma cancer cells. Compound CC-43 inhibits the growth of Leukemia, Melanoma, Ovarian Cancer cells. In addition, in the test of human multi-drug resistant breast cancer cell NCI/ADR-RES (derived from ovarian cancer), compounds CC-12, CC-23, and CC-43 were found to have resistance to adriamycin (ADR). Comparing the compounds CC-12 and CC-43 structures with the compounds mitoxantrone and doxorubicin in the NCI database values, it was even found that CC-43 (0.13 μM) compound structure inhibits the growth ability of 50% of cancer cell lines. (GI ₅₀ ) is equivalent to the structure of the compound of doxorubicin (0.11 μM) (Fig. 6).

The detailed description of the preferred embodiments of the present invention is intended to be limited to the scope of the invention, and is not intended to limit the scope of the invention. The patent scope of this case.

In summary, this case is not only innovative in the 1,2-disubstituted guanamine oxime derivatives, but also in its preparation and treatment of cancer. It should be fully in line with the novelty and progressiveness of the law. Invent the patent requirements, 提出 apply in accordance with the law, and ask your bureau to approve the application for the invention patent, in order to invent invention, to the sense of virtue.

The following is a detailed description of a preferred embodiment of the present invention and its accompanying drawings, and the technical contents of the present invention and its functions will be further understood; the drawings relating to the embodiment are:

Figure 1 is a flow chart for the preparation of compounds CC-01 ^~ CC-03, CC-05 ^~ CC-08.

Figure 2 is a flow chart for the preparation of compounds CC-04, CC-09 ^~ CC-22, CC-23 ^~ CC-32.

Figure 3 is a flow chart for the preparation of compounds CC-09, CC-12, CC-33, CC-34, CC-35 ^~ CC-50.

Figure 4 shows the test compounds that were sent to the US Cancer Center (NCI) for drug screening.

Figure 5A shows the results of telomere sequence replication analysis of compounds CC-01 ^~ CC-18; Figure 5B shows the results of telomere sequence replication analysis of compounds CC-19 ^~ CC-42; Figure 5C shows compounds CC-43 ^~ CC -50 telomere sequence replication analysis results; D for treatment of doxrubicin, M for treatment of mitoxantrone, and A for treatment of 1,2-diaminoanthrquione.

Figure 6 shows the results of tests for inhibiting the growth ability (GI ₅₀ ) of ₅₀ % of cancer cell lines of compounds CC-12, CC-43, mitoxantrone and doxorubicin.

Claims (4)

A novel 1,2-disubstituted guanamido fluorene derivative is selected from the group consisting of 1-(2-fluorobenzamide)-2-(chloroacetamido)-oxime, 1-(3) -Fluorobenzoguanamine)-2-(chloroacetamido)-indole, 1-(4-fluorobenzamide)-2-(chloroethylamino)-indole, 1- (2-Chomobenzoguanamine)-2-(chloroacetamido)-indole, 1-(3-chlorobenzamide)-2-(chloroacetamido)-hydrazine, 1-(4-Chlorobenzylidinium)-2-(chloroacetamido)-indole, 1-[2-(trifluoromethyl)benzylideneamino]-2-(chloroacetamidine) Amino)-indole, 1-[3-(trifluoromethyl)benzylammonium]-2-(chloroethylamino)-indole, 1-[4-(trifluoromethyl)benzene Methionamine]-2-(chloroacetamido)-indole, 1-[2,5-bis-(trifluoromethyl)benzamideamino]-2-(chloroacetamido) -蒽醌, 1-[(2-furylmethyl)amino]-2-(chloroacetamido)-indole, 1-[(2-thienylmethyl)amino]-2-( Chloroacetamido)-indole, 1-[(5-isoxazolylmethyl)amino]-2-(chloroacetamido)-indole, N- [2-(2-chloroethyl) Amidino)-9,10-dioxo-9,10-dihydroindol-1-yl]-2,5-dimethylfuran-3-carboxamide, 1-[2-(phenoxy) Acetylamino]-2-(chloroacetamido)-indole, 1-[2-(phenylsulfonate) Ethylamino]-2-(chloroacetamido)-indole, 1-(benzylammonium)-2-[2-[4-(2-fluorophenyl)pyridazine] Amidino]-indole, 1-(4-methylbenzimidino)-2-[2-[(1,3-dioxolan-2-ylmethyl)(methyl)amino Ethylamino]-indole, 4-methyl- N- (2-(2-methyl(2-(pyridyl-2-ethyl)amine)acetamido)-9,10-di Oxo-9,10-dihydroindole-1)phenylamine, 1-(4-methylbenzamide)-2-[2-(1,4-dioxo-8-azaspiro[ 4.5]decane-8-yl)acetamido]-indole, 1-(4-methylbenzimidino)-2-[2-(4-phenylpyridazine)acetamido] -蒽醌, 1-(4-methylbenzamide)-2-[2-[4-(2-fluorophenyl)pyridazine]ethylamino]-indole, 1-(4- Methyl benzalkonium)-2-[2-[4-(2-benzonitrile)pyridazine]acetamido]-indole, 1-(4-methylbenzamide)- 2-[2-[4-(2-methoxyphenyl)pyridazine]acetamido]-indole, 1-(4-methylbenzimidino)-2-[2-[4- (2-pyridyl)pyridazine]acetamido]-indole, and 1-(4-methylbenzamide)-2-[2-[4-(2-pyrimidinyl)pyridazine] A group consisting of acetamido]-oxime. A pharmaceutical composition for treating cancer comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is useful for poisoning cancer cells. The pharmaceutical composition according to claim 3, wherein the cancer cell is a non-small cell lung cancer cell.