EA044762B1 - PHENYLTRIAZOLE INHIBITOR OF PROTEIN-PROOTEIN INTERACTIONS MLL1-WDR5 - Google Patents

Description

Field of technology to which the present invention relates

The present invention relates to the field of medicinal chemistry, more specifically to the class of phenyltriazole inhibitors of the MLL1-WDR5 protein-protein interaction, its preparation and medical applications.

BACKGROUND OF THE INVENTION

Histone methylation plays a key role in many biological processes and is the main focus of research in the field of epigenetic regulation. Translocation and rearrangement of the MLL1 methyltransferase gene for histone H3K4 can lead to mixed lineage leukemia (MLL1, acute myeloid leukemia and acute lymphoid leukemia). Approximately 10% of leukemia patients have an MLL1 gene rearrangement. After the MLL1 gene is rearranged, it fuses with other chaperone proteins to form fusion proteins, and the carcinogenic MLL fusion protein is expressed. The fusion protein can interact with elongation factors associated with RNA polymerase II (Pol II) to form the superelongation complex (SEC). This complex can lead to abnormal expression of the MLL1-regulated Hox gene, which causes a number of serious consequences inducing the onset of MLL leukemia.

Chromosomal translocation of the MLL1 gene occurs in one allele, and wild-type MLL1 is still present. When the wild-type MLL1 allele is knocked out, the MLL fusion protein alone will not lead to leukemia, and the enzymatic activity of wild-type MLL1 is required for the MLL1 fusion protein to cause leukemia. Thus, specific inhibition of wild-type MLL1 enzyme activity leads to the cure of leukemia.

The catalytic activity for H3K4 methylation by MLL1 alone is very weak and can only result in monomethylation; catalytic activity is significantly enhanced upon formation of the MLL1 core catalytic complex, especially catalytic activity towards H3K4me2. The WIN motif at the C terminus of MLL binds to WDR5, RbBP5, Ash2L, and DPY30 to form complexes. MLL1 interacts with WDR5 directly via the C-terminal WIN motif to mediate interactions between the MLL1SET catalytic domain and other protein complexes. When WDR5 is knocked out, H3K4me2/3 levels are reduced and Hox gene expression levels are reduced.

Thus, the use of small molecules to prevent the MLL1-WDR5 protein-protein interaction is an effective way to suppress the enzymatic activity of MLL1 and reduce the expression levels of the Hox and Meis-1 genes, as well as block the progression of leukemia.

Summary of the present invention

The present invention describes a compound having a small molecule that can regulate MLL1-WDR5 protein-protein interactions, which, by interfering with MLL1-WDR5 protein-protein interactions, inhibits MLL1 enzymatic catalysis activity, suppresses H3K4 methylation levels and Hox and Meis gene expression levels. 1, thereby causing apoptosis of leukemia cells. Thus, the compound can be used for the treatment of leukemia. The structure of the compound of the present invention is:

where X represents hydrogen, methyl, methoxy or halogen groups;

Y is -CH2-, -O-, -S-, -CO-, -CH2O-, -NR5-, -CONR6- or -NR7CO-, where _R5 , R6 and R7 are each independently hydrogen, _C1 -C ₄ alkyl, C ₁ -C ₄ haloalkyl, phenyl or substituted phenyl, wherein the substituent is halogen, C 1 -C 4 alkyl, C ₁ -C ₄ alkoxy, amino, hydroxy, mercapto, carboxy, cyano, trifluoromethyl or imidazolyl;

m represents 0-6;

R1 represents hydrogen, amino, hydroxyl, mercapto, carboxyl, cyano, -CONH2, C ₁ -C ₄ alkyl, C1-C4 alkoxy, phenyl, substituted phenyl, substituted or unsubstituted nitrogen-containing or oxygen-containing 3-7 membered heterocyclic ring, - NR ₈ COR9, -CONR10R11 or -NR ₁₀ R ₁₁ , where R ₈ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, phenyl or substituted phenyl, R9 is amino, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl or substituted phenyl, and a substituted or unsubstituted nitrogen-containing or oxygen-containing 3-7 membered heterocyclic ring, R ₁₀ and R ₁₁ independently represent hydrogen, C ₁ -C ₄ alkyl, phenyl or substituted phenyl, and a substituted or unsubstituted nitrogen- or oxygen-containing 3-7-membered heterocyclic ring, or R ₁₀ and R ₁₁ are connected to form a nitrogen- or oxygen-containing 3-7-membered heterocyclic ring

- 1 044762 cyclic ring, wherein the substituent is halogen, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, amino, hydroxyl, mercapto, carboxyl, cyano, trifluoromethyl or imidazolyl;

R2 is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, nitro or cyano, whether disubstituted or trisubstituted;

R3 is amino, methylamino, aminomethyl, hydroxyl, hydroxymethyl, mercapto or CONH2;

R ₄ is N-methylpiperazine, 1,2-dimethylpiperazine or N-methylhomopiperazine.

X is preferably hydrogen, fluorine, chlorine or methyl.

Y is preferably -NR5-, CONR6- or -NR ₇ CO-; and R5, R6 and _R7 are each independently hydrogen, methyl, ethyl, propyl, cyclopropyl or isopropyl.

More preferably, Y is -NR5-, -CONR6- or -NR7CO-; R ₅ , R 6 and R ₇ are each independently substituted phenyl, wherein the substituent is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, methoxy, cyano, halogen, trifluoromethyl or imidazolyl.

Said substituted or unsubstituted nitrogen-containing or oxygen-containing 3-7 membered heterocyclic ring is preferably aziridine, azetidine, tetrahydropyrrole, piperidine, hexamethyleneimine, lactam, tetradyrofuran, tetrahydropyran, morpholine, 1,4-oxazepane, hexahydropyridazine, imidazoline, pyrazolidine , piperazine, and the substituent is halogen, methyl, ethyl, phenyl, hydroxyl, amino, hydroxymethyl or aminomethyl.

R1 is preferably -NR ₈ COR ₉ , -CONR10R11 or -NR10R11, with R ₈ , R ₉ , R ₁₀ and R11 being C1-C4 alkyl.

R2 is a trisubstituent and is fluorine, chlorine, bromo, methyl, methoxy, nitro, trifluoromethyl or cyano.

The present invention also includes pharmaceutically acceptable salts of compound (I) and solvates thereof, all of which have the same pharmacological effectiveness as compound (I).

The present invention relates to a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carriers, diluents and excipients.

The present invention also discloses the use of compound (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of diseases mediated by MLL1 by inhibiting the MLL1-WDR5 protein-protein interaction, said diseases such as leukemia involving gene fusion MLL can be treated by inhibiting the enzymatic activity of MLL1.

The dose of the compound of the present invention used in clinical practice is 0.01-1000 mg/day, and the dose may vary depending on the severity of the diseases or dosage forms.

In some embodiments, a compound of formula (I) may contain sufficient basic functional groups to form salts. Exemplary salts include pharmaceutical salts of inorganic acids such as hydrochloride, hydrobromide and sulfate; pharmaceutical salts of organic acids such as acetate, trifluoroacetate, lactate, succinate, fumarate, maleate, citrate, benzoate, mesylate, para-benzoate and para-toluosulfonate.

Moreover, the present invention also relates to methods for producing compounds related to compound (I), which includes the following steps:

O

^R 3 (la) (lb) (Ic) (I) where R1, R ₂ , R ₃ , R4, X, Y and n are defined previously;

where intermediate Ia can be prepared by the following synthetic routes

Below are some pharmacodynamic studies of the compound of the present invention and their results.

- 2 044762

The enzymatic activity of MLL1 is determined by protein-protein interactions of MLL1 and WDR5; MLL1 enzymatic activity influences H3K4 methylation levels. H3K4 methylation levels are abnormally increased in MLL fusion leukemia, while subsequent gene expression levels of Hox and Meis-1 are abnormally increased. When MLL1-WDR5 protein-protein interactions are inhibited, MLL1 catalytic activity is reduced, H3K4 methylation levels are reduced, and Hox and Meis-1 expression levels are reduced, which inhibits the proliferation of leukemia cells.

It has already been reported that the biphenyl compound DDO-2084 is a small molecule inhibitor that can inhibit MLL1-WDR5 protein-protein interactions, reduce the catalytic activity of MLL1 and suppress the expression of Hox and Meis-1 genes (Eur. J. Med. Chem. 2016, 124, 480489.) In the present invention, DDO-2084 was used as a positive control.

Table 1. MLL1-WDR5 protein-protein interaction inhibitory activities of the compounds of the present invention and corresponding biological activities

inhibitory activity in Reduced expression of Hox and Meis-1 genes Numbering of connections in application examples ³ protein- protein in interactions MLL 1 WDR5 PPI (nM) Inhibition in relation to the level of methylation of H3K4 1 <80 Yes Yes 2 <50 Yes Yes 3 <10 Yes Yes 4 <10 Yes Yes 5 <10 Yes Yes 6 <10 Yes Yes 7 <10 Yes Yes 8 <10 Yes Yes 9 <50 Yes Yes 10 <10 Yes Yes 12 <80 Yes Yes 13 <80 Yes Yes 14 <10 Yes Yes 15 <10 Yes Yes 16 <10 Yes Yes 17 <50 Yes Yes 18 <50 Yes Yes 19 <50 Yes Yes 21 <80 Yes Yes 22 <10 Yes Yes 23 <50 Yes Yes 24 <50 Yes Yes 25 <50 Yes Yes DDO- ^2084b 88.7 ±4.9 Yes Yes

^a See Examples for specific compound structures;

^b Structure of DDO-2084: ।

As shown in table. 1, the compounds of the present invention have relatively strong inhibitory activity on MLL1-WDR5 protein-protein interactions.

Reverse transcription PCR (RT-PCR) experiments were also carried out at the cellular level using some of the compounds of the present invention, the results of which are shown in Table 1. 1, demonstrating whether some of the compounds inhibit subsequent expression of the Hox and Meis-1 genes. The results showed that all the compounds of the present invention having MLL1-WDR5 protein-protein interaction inhibitory activity could inhibit the subsequent expression of Hox and Meis-1 genes. The results of inhibition at the cellular level of some of the compounds on subsequent expression of the Hox and Meis-1 genes are presented in FIG. 1. As shown in FIG. 1, the level of inhibition of the compound in example 7 at a concentration of 2.5 μM reached the same level as the level of the positive control DDO-2084 at a concentration of 5 μM on the expression of the Hoxa9 and Meis-1 genes, while example 7 at a concentration of 5 μM showed more significant level than DDO-2084 at a concentration of 5 µM.

In addition, Western blot experiments at the cellular level were carried out using some of the compounds of the present invention, the results of which are shown in Table. 1, demonstrating whether some of the compounds of the present invention inhibit H3K4 methylation levels. The results showed that all compounds of the present invention with MLL1-WDR5 protein-protein interaction inhibitory activity reduced H3K4 methylation levels. Inhibition of MLL1 catalytic activity at the cellular level by certain compounds is depicted in FIG. 2. As shown in FIG. 2, Example 7 could inhibit the catalytic activity of MLL1 in a dose-dependent manner to reduce H3K4me1/2/3 expression levels, and demonstrated that the results from Example 7 were better than DDO-2084 at the same concentration of 10 μM.

Additionally, a published paper (Eur. J. Med. Chem. 2016, 124, 480-489, referred to as document 1 below) has reported a series of biphenyl protein-protein interaction inhibitors MLL1WDR5, and these compounds have the structure:

The compounds of the present invention differ from these compounds by changing the structures in how the two benzene rings are linked, and instead the 5 position is linked by triazole groups. Compounds of the present invention having such modifications have significantly increased aqueous solubility, reduced toxicity while retaining the original MLL1-WDR5 inhibitory activity. Some of the biphenyl compounds from Document 1 and some of the unknown biphenyl compounds were selected for solubility and toxicity studies using the same test methods as in the invention simultaneously, and the results are shown below:

Table 2. Comparison of target activity and solubility of some compounds of the present invention and some compounds from document 1

Inhibitory activity against protein Structures Inhibitory activity against protein Number protein Solution- some protein connections and interaction rity connections from interaction Solution- structure by viii MLL1- (pH = publications (Eur. J. viii MLL1- rity present WDR5 7.4) Med. Chem. 2016, WDR5 PP1 (pH = 7.4) invention (nM) µg/ml 124, 480-489.) (nM) µg/ml

- 4 044762

From a comparison of data for compounds in table. 2 shows that, in the presence of the same other groups, the replacement of benzene rings with triazole groups of the present invention maintained the target activity and significantly increased solubility in water.

In addition, subacute toxicity experiments were conducted to evaluate the safety of certain compounds of the present invention in mice. Some of the triazole compounds of the present invention (Examples 4, 6, 7, 16 and 22) and compounds DDO-2113 and DDO-2117 from Document 1 were administered by intraperitoneal injection at a dose of 80 mg/kg to female balb/c mice, 6 mice per group for 10 consecutive days to monitor mouse survival and changes in mean body weight. As shown in FIG. 3, no death was observed after administration for 10 days for some compounds of the present invention (Examples 4, 6, 7, 16 and 22), and there was a slight increase in body weight, while after administration of compounds DDO-2113 and DDO2117 from the document (Eur. J. Med. Chem. 2016, 124, 480-489.) all mice died after administration for 5 days using DDO-2113 at a concentration of 80 mg/kg, and mice receiving DDO-2117 , were characterized by a noticeable decrease in body weight. To compare post-dose survival and changes in mean body weight, there were no deaths and a slight increase in body weight after 10 days of administration of the phenyl-triazole compounds of the present invention, in contrast to deaths and a decrease in body weight after administration of the diphenyl compounds DDO -2113 and DDO-2117, indicating good administration safety of the phenyltriazole compounds of the present invention.

- 5 044762

In this case, DDO-2113 and DDO-2117 are connections from document 1 with structures:

DDO-2113 DDO-2117

Additionally, pntiproliferative activity experiments were carried out on leukemia cells using some of the compounds of the present invention. In table 3 shows the results of evaluating the antiproliferative activity of certain compounds of the present invention against acute leukemia cells, wherein MV4-11 represents a human acute monocytic leukemia cell, Molm-13 represents a human acute myeloid leukemia cell and K562 represents a human chronic myeloid leukemia cell. In table 3 indicates that the compounds of the present invention are effective in inhibiting the proliferation of various types of leukemia cells.

Table 3. Antiproliferative activity of some compounds of the present _____________invention against leukemia cells_____________

Connection numbers in examples GIso/mkM (MV-411) GIso/mkM (Molm-13) GIso/mkM (K562) 1 8.9 ±0.3. 11.8 ±0.9. But. 3 44.6 ± 1.3. 22.8 ±5.5. >100 4 10.5 ±2.0. But. ^b 34.4 ±0.9. 5 15.1 ± 1.2. 13.0 ±0.6. 27.5 ±2.8. 6 10.9 ±0.2. 8.2 ± 0.6. 10.4 ±0.7. 7 8.0 ± 1.2. 9.9 ± 1.9. 12.9 ±0.4. 8 17.8 ±3.6. 11.9 ± 1.5. 34.1 ± 1.2. 9 27.4 ±2.1. But. ^b 35.8 ±2.7. 10 13.5 ± 1.2. 13.5 ± 1.2. 13.5 ± 1.2. AND 13.5 ± 1.5. 13.5 ± 1.5. 13.5 ± 1.5. 12 23.2 ±3.2. But. ^b But. ^b 13 10.1 ± 1.3. 9.2 ± 1.4. 10.5 ±2.0. 14 9.5 ± 1.0. 11.0 ±2.0. 14.1 ± 1.3. 15 14.3 ± 1.7. 18.5 ± 1.9. 12.9 ±0.2. 16 15.1 ±0.9. But. ^b 15.0 ±0.8. 17 10.4 ± 1.1. 7.3 ± 0.8. 21.3 ±2.4. 18 11.2 ± 1.3. 15.4 ±2.2. But. ^b 19 13.7 ± 1.4. 16.8 ±2.0. 13.5 ± 1.2. 20 8.6 ±0.6. 10.1 ± 1.3. 10.5 ±2.0. 21 12.7 ±0.8. 7.7 ± 0.9. 10.5 ±0.8. 22 9.5 ± 0.4. 11.2 ±0.8. 10.9 ±0.7. 23 But. ^b 17.9 ± 1.6. 27.7 ±0.3. 24 11.3 ±0.7. 12.9 ±0.9. 13.5 ±2.2. 25 10.9 ±0.9. 8.5 ± 0.7. 11.3 ±0.7. DDO-2084 17.7 ±2.3. But. ^b 50.5 ±5.5.

^a See specific examples of chemical structures;

^b n.o. means not detected;

The phenyltriazole compounds of the present invention have potent inhibitory activity on MLL1-WDR5 protein-protein interactions, can reduce the catalytic activity of MLL1 on MLL1 at the cellular level, reduce the expression levels of Hox and Meis-1 genes, and induce apoptosis of leukemia cells. Also, the phenyltriazole compounds of the present invention demonstrated good water solubility and pharmaceutical safety and

- 6 044762 can be used to treat leukemia.

Brief description of the figures

In fig. Figure 1 shows the inhibition of the expression of the Hoxa9 and Meis-1 genes in cells of example 7, which was studied using RT-PCR;

In fig. Figure 2 shows example 7 on the enzymatic activity of MLL1 in cells, which was studied using Western blotting;

In fig. 3 provides a comparison of the toxicity of the compounds of the present invention with some of the compounds in Document 1.

Example 1.

Methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H1,2,3-triazole-4-carboxylate ( 1)

Preparation of 4-(4-methylpiperazin-1-yl)-3-nitroaniline (IIb):

Dissolve 4-fluoro-3-nitroaniline (II) (6 g, 38.4 mmol) in 50 ml of acetonitrile, add Nmethylpiperazine (5.8 g, 6.3 ml, 57.6 mmol) and N,N-diisopropylethylamine ( 9.5 ml, 57.6 mmol) and the reaction mixture was refluxed for 12 hours. The crude material was obtained after spin drying and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give red- brown solid (8.9 g, 97.8%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.06 (d, J=8.6 Hz, 1H), 6.76 (s, 1H), 6.69 (d, J=8.5 Hz , 1H), 5.34 (s, 2H), 2.70 (t, J=4.4 Hz, 4H), 2.27 (br s, 4H), 2.09 (s, 3H). m/z (EI-MS): 259.1 [M+Na]+.

Preparation of 1-(4-azido-2-nitrophenyl)-4-methylpiperazine (Ia):

Dissolved 4-(4-methylpiperazin-1-yl)-3-nitroaniline (IIb) (4.0 g, 17.0 mmol) in 100 ml of 2M/HC1, lowered the temperature to 0°C, added dropwise 10 ml of aqueous sodium nitrite solution (1.76 g, 25.5 mmol) with stirring for 30 minutes at 0°C dropwise. An aqueous solution of 10 mL of sodium azide (2.2 g, 34.0 mmol) was then added dropwise to the resulting mixture, and the mixture was stirred for 30 min at 0° C. and then stirred for 2 h at room temperature. The product was precipitated with 2M/NaOH pH=9-10, vacuum filtered and heat dried to give a red-brown solid (4.0 g, 91.3%).

1H NMR (300 MHz, DMSO-d6) δ 7.48 (d, J=2.2 Hz, 1H), 7.34-7.20 (m, 2H), 2.85 (t, J=4, 7 Hz, 4H), 2.31 (t, J=4.8 Hz, 4H), 2.11 (s, 3H). m/z (EI-MS): 261.1 [M+H] ^- .

Preparation of methyl 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-triazol-4-methylcarboxylate (Ib):

1-(4-azidonitrophenyl)-4-methylpiperazine (Ia) (1.0 g, 3.8 mmol) was dissolved in 50 ml of methanol, methyl propiolate (0.96 g, 11.4 mmol), copper iodide (0. 07 g, 0.38 mmol), N,Ndiisopropylethylamine (0.12 ml, 0.76 mmol), reflux for 48 h, filter, concentrate and shake with ethyl acetate to give a red-brown solid (0. 8 g, 61.5%).

1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.11-8.01 (m, 1H), 7 .42 (d, J=9.1 Hz, 1H), 3.80 (s, 3H), 2.99 (t, J-5.4 Hz, 4H), 2.35 (t, J=5, 2 Hz, 4H), 2.13 (s, 3H). m/z (EI-MS): 369.2 [M+Na] ⁺ .

Preparation of methyl 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl-1H-1,2,3-methyltriazol-4methylcarboxylate (Ic):

Dissolved methyl 1-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-1H-1,2,3-methyltriazol-4methylcarboxylate (Ib) (3.8 g, 12.0 mmol) in 50 ml methanol, a catalytic amount of Pd/C was added, and hydrogen was pumped through. The reaction mixture was stirred at room temperature for 7 hours and concentrated under vacuum filtration to give a pink solid (3.0 g, 78.9%).

^1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.07 (d, J=1.9 Hz, 2H), 5.15 (s, 2H), 3.90 (s, 3H), 2.87 (t, J=4.5 Hz, 4H), 2.53 (br s, 4H), 2.26 (s, 3H). m/z (ESI-MS): 317.1763 [M+H] ⁺ .

Preparation of methyl 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1yl)phenyl)-1H-1-methyl 2,3-triazol-4- carboxylate (1):

Dissolve methyl 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl-1H-1,2,3-triazol-4methylcarboxylate (Ic) (1.7 g, 5.3 mmol) in 100 ml anhydrous dichloromethane, added pyridine (0.43 ml, 5.3 mmol), added dropwise 20 ml of a solution of 2-chloro-3-methyl-4-fluoro-5-nitrobenzoyl chloride (1.6 g, 6.4 mmol) in dichloromethane in an ice water bath.The reaction mixture was stirred for 2 hours at room temperature, filtered under vacuum and heated by thermal drying to obtain

- 7 044762 light yellow solid. Dissolve the light yellow substance (2.6 g, 4.9 mmol) in ethyl acetate and add tin dichloride (5.5 g, 24.4 mmol). The resulting mixture was refluxed for 3 hours before cooling to room temperature, diluted with 100 ml ethyl acetate, and then neutralized with saturated sodium bicarbonate until a white gel-like precipitate ceased to precipitate. The mixture was filtered under vacuum, and the filter cake was washed with ethyl acetate until ultraviolet absorption ceased. The filtrate was extracted with ethyl acetate until ultraviolet absorption ceased. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate to give the crude product, which is shaken with ethyl acetate, filtered in vacuo to give a gray-white solid 1 (2.3 g, 93.9%).

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.52-9.45 (m, 2H), 8.69 (s, 1H), 7.73 (dd, J=8.7, 2.7 Hz , 1H), 7.46 (d, J=8.6 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 5.53 (s, 2H), 3.92 (s , 3H), 3.00-2.90 (m, 4H), 2.51 (br s, 4H), 2.28 (d, J=2.6 Hz, 3H), 2.24 (s, 3H ). (EI-MS): 502.9 [M+H] ⁺ .

Example 2.

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)1H-1,2,3-triazole-4-carboxylic acid acids (2):

Methyl 1-(3-(5-amino-2-chloro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)1H-1,2,3-triazole-4-carboxylate (1) was dissolved (2.3 g, 4.6 mmol) in THF, lithium hydroxide solution (1 M, 15 ml) was added. The reaction mixture was stirred for 8 hours at room temperature, rotating to remove THF and then acidifying with 2M perchloric acid to give a white solid (1.7 g, 80.4%).

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.52-9.45 (m, 2H), 8.69 (s, 1H), 7.73 (dd, J=8.7, 2.7 Hz , 1H), 7.46 (d, J=8.6 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 5.53 (s, 2H), 3.92 (s , 3H), 3.00-2.90 (m, 4H), 2.50 (br s, 4H), 2.28 (d, J=2.6 Hz, 3H), 2.24 (s, 3H ). (EI-MS): 488.9 [M+H] ⁺ .

Example 3.

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)^^dimethyl-1H-1,2,3-triazole -4-carboxamide (3):

1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)1H-1,2,3-triazole-4-carboxylic acid was dissolved acid (2) (0.18 g, 0.36 mmol) in 10 ml DMF, add BOP (0.32 g, 0.72 mmol), trimethylamine (0.10 ml, 0.72 mmol) and dimethylaminohydrochloride (58 .7 mg, 0.72 mmol), stirred for 4 hours at room temperature. The reaction mixture was then diluted with 50 ml ethyl acetate and DMF was removed by washing with saturated sodium chloride. The organic phase was dried with anhydrous sodium sulfate, the organic solvent was evaporated by rotation to obtain the crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain a gray-white solid. The yield was 78.4%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 9.18 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.71 ( dd, J=8.6, 2.6 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 6.83 (d, J=9.2 Hz, 1H), 5, 50 (s, 2H), 3.11 (br s, 10H), 3.02 (s, 3H), 2.70-2.69 (m, 4H), 2.24 (d, J=2.5 Hz, 3H). (EI-MS): 515.9 [M+H]+.

Example 4.

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Preparation of 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-((morpholine-4-carbonyl)-1H-1, 2,3-triazol-1-yl)phenyl)benzamide (4):

The example was carried out using the methods of Example 3, where dimethylaminohydrochloride was replaced by morpholine to obtain a grey-white solid. The yield was 67.5%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.61(s, 1H), 9.24 (s, 1H), 8.64 (d, J=2.5 Hz, 1H), 7.73 ( dd, J=8.6, 2.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 5, 52 (s, 2H), 4.06 (s, 2H), 3.68 (s, 6H), 3.12 (br s, 8H), 2.69 (s, 3H), 2.26 (d, J=2.6 Hz, 3H). (EI-MS): 558.9 [M+H]+.

Example 5.

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)N-(tetrahydro-2H-pyran-4-yl) -1H-1,2,3-triazole-4-carboxamide (5):

The example was carried out using the methods of Example 3, where dimethylaminohydrochloride was replaced by 4-aminotetrahydropyran to obtain a grey-white solid. The yield was 82.9%.

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.52 (s, 1H), 9.26-9.24 (m, 1H), 8.65 (s, 2H), 7.71 (d, J=8.7 Hz, 1H), 7.42 (d, J=9.4 Hz, 1H), 6.89 (s, 1H), 5.53 (s, 2H), 4.06 (s, 1H), 3.9-3.86 (m, 2H), 2.99 (s, 6H), 2.71 (s, 4H), 2.38 (s, 3H), 2.25 (s, 3H ), 1.71 (s, 4H). (EI-MS): 572.0 [M+H] ⁺ .

Example 6.

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)N-(1-methylpiperidin-4-yl)-1H -1,2,3-triazole-4-carboxamide (6):

The example was carried out using the methods of Example 3, where dimethylaminohydrochloride was replaced by 4-amino-1,1-methylpiperidine to obtain a gray-white solid. The yield was 49.9%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 9.22 (s, 1H), 8.65 (d, J=2.6 Hz, 1H), 8.52 ( d, J=8.2 Hz, 1H), 7.70 (dd, J=8.5, 2.7 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 6, 89 (d, J=9.2 Hz, 1H), 5.54 (s, 2H, 3.78 (s, 1H), 2.92 (t, J=4.6 Hz, 4H), 2.82 -2.78 (m, 2H), 2.26 (d, J=2.7 Hz, 3H), 2.22 (s, 3H), 2.19 (s, 3H), 2.07-1, 86 (m, 4H), 1.751.66 (m, 4H) (EI-MS): 585.0 [M+H] ⁺ .

Example 7.

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)N-(3-morpholinopropyl)-1H-1,2 ,3-triazole-4-carboxamide (7):

The example was carried out using the methods of example 3, where dimethylaminohydrochloride was replaced by N-(3-aminopropyl)morpholine and a gray-white solid was obtained. The yield was 94.2%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 9.22 (s, 1H), 8.85 (t, J=5.8 Hz, 1H), 8.66 ( s, 1H), 7.71 (dd, J=8.6, 2.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 6.89 (d, J=9 ,2 Hz, 1H), 5.53 (s, 2H), 3.62 (t, J=4.6 Hz, 4H), 2.98-2.97 (m, 4H), 2.63 (s , 4H), 2.54 (s, 2H), 2.46-2.36 (m, 6H), 2.33 (s, 3H), 2.26 (d, J=2.6 Hz, 3H) , 1.74-1.70 (m, 2H). (ESI-MS): 615.1 [M+H] ⁺ .

- 9 044762

Example 8.

Preparation of 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-(methylpiperazin-1carbonyl)-1H-1,2,3 -triazol-1-yl)phenyl)benzamide (8):

The example was carried out using the methods of example 3, where dimethylaminohydrochloride was replaced by N-methylpiperazine to obtain a gray-white solid. The yield was 94.2%.

1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.22 (s, 1H), 8.85 (t, J=5.8 Hz, 1H), 8.66 (s , 1H), 7.71 (dd, J=8.6, 2.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 6.89 (d, J=9, 2 Hz, 1H), 5.53 (s, 2H), 3.62 (t, J=4.6 Hz, 4H), 2.98-2.97 (m, 4H), 2.63 (s, 4H), 2.54 (s, 2H), 2.46-2.36 (m, 6H), 2.33 (s, 3H), 2.26 (d, J=2.6 Hz, 3H), 1.74-1.70 (m, 2H). (ESI-MS): 571.0 [M+H] ⁺ .

Example 9.

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)N-(2-morpholinethyl)-1H-1,2 ,3-triazole-4-carboxamide (9):

Using the methods of Example 3, dimethylaminohydrochloride was replaced with N-aminoethylmorpholine to obtain a grey-white solid. The yield was 72.5%.

¹ H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.56 (t, J=5.8 Hz, 1H), 7.71 (dd, J=8.7, 2.6 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 5.54 (s, 2H), 3.58 (t, J=4.6 Hz, 4H), 3.44 (s, 2H), 2.96 (t, J=4.8 Hz, 4H), 2.59 (s, 4H), 2.54 (s, 2H), 2.44 (s, 4H), 2.30 (s, 3H), 2.26 (d, J=2 ,6 Hz, 3H). (ESIMS): 601.0 [M+H] ⁺ .

Example 10.

Preparation of 1 -(3 -(5 -amino-2-chloro-4-fluoro-3 -methylbenzoylamino)-4-(4-methylpiperazin-1 -yl)phenyl)N-(3-aminopropyl)-1H-1,2 ,3-triazole-4-carboxamide (10):

The example was carried out using the methods of Example 3, where dimethylaminohydrochloride was replaced with 1,3-propylenediamine to obtain a grey-white solid. The yield was 64.5%.

1H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.70 (s, 1H), 8.45 (d, J=2.1 Hz, 1H), 7.36 (dd , J=7.5, 2.0 Hz, 1H), 7.25 (s, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.78 (d, J=5, 7 Hz, 1H), 4.13 (s, 2H), 3.25-3.19 (m, 6H), 2.98 (t, J=4.9 Hz, 4H), 2.67-2, 58 (m, 5H), 2.39 (s, 3H), 2.19-2.13 (m, 2H), 1.14 (s, 2H). (ESI-MS): 545.0 [M+H]+.

Example 11.

5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(1H-1,2,3-triazol-1-yl)phen- 10 044762 nyl)benzamide (11):

The example was carried out using the methods of Example 1, where methyl propiolate was replaced with trimethylsilylacetylene to obtain a gray-white solid after three reaction steps. The yield after three stages was 23.8%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.76-8.68 (m, 2H), 8.49 (d, J=2.1 Hz, 1H), 8.18 (d, J=7 .5 Hz, 1H), 7.27 (dd, J=7.5, 2.0 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.75 (d, J =5.7 Hz, 1H), 4.15 (s, 2H), 3.20 (t, J=5.1 Hz, 4H), 2.98 (t, J=5.0 Hz, 4H), 2.60(s, 3H), 2.39(s, 3H). (EI-MS): 444.9 [M+Na]+.

Example 12.

tert-Butyl(1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)1H-1,2,3-triazol- 4-yl)carbamate (12):

The example was carried out using the methods of Example 1, where methyl propiolate was replaced by tert-butylethynyl carbamate to obtain a grey-white solid after three reaction steps. The yield after three reaction steps was 20.1%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.25 ( dd, J=7.5, 2.0 Hz, 1H), 7.18 (s, 1H), 6.80 (dd, J=19.7, 6.6 Hz, 2H), 4.17 (s , 2H), 3.20 (t, J=5.1 Hz, 4H), 2.98 (t, J=5.1 Hz, 4H), 2.60 (s, 3H), 2.39 (s , 3H), 1.50 (s, 9H). (EI-MS): 560.0 [M+Na] ⁺ .

Example 13.

5-Amino-N-(5-(4-amino-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro -3methylbenzamide (13)

Tert-butyl(1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1yl)phenyl)-1H-1,2,3-triazol- 4-yl)carbamate (1.0 g, 2.2 mmol) in 20 ml dichloromethane, 10 ml trifluoroacetate was added. The reaction mixture was stirred for 1 hour at room temperature, the pH was adjusted to 8-9 using a saturated sodium bicarbonate solution, and extracted with dichloromethane. Dry the organic phase with anhydrous sodium sulfate and spin dry to obtain a gray solid. The yield was 87.3%.

1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.25 (dd , J=7.5, 2.0 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.70 (d, J=5.7 Hz, 1H), 5.80 (s, 2H), 4.15 (s, 2H), 3.20 (t, J=5.3 Hz, 4H), 2.98 (t, J=5.2 Hz, 4H), 2.60 (s, 3H), 2.39 (s, 3H). (EI-MS): 459.9 [M+Na] ⁺ .

Example 14.

N-(1-(3-(5-Amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H1,2,3-triazolopyridine-4- yl)-1-methylpiperidine-4-carboxamide (14):

5-αmino-N-(5-(4-amino-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2chloro-4-fluoro- 3-methylbenzamide (13) (0.2 g, 0.34 mmol) in 5 ml DMF, added BOP (0.30 g, 0.68 mmol), triethylamine (0.09 ml, 0.68 mmol) and 1 -methylpiperidine-4-carboxylic acid (97.3 mg, 0.68 mmol). The reaction mixture was stirred for 4 hours at room temperature, then diluted with 50 ml of ethyl acetate, and DMF was removed by washing with saturated sodium chloride solution. The organic phase was dried using anhydrous sodium sulfate, the organic solvent was evaporated by rotation with

- 11 044762 obtaining the crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a gray-white solid. The output was

73.9%.

1H NMR (300 MHz, DMSO-d6) δ 8.72-8.64 (m, 2H), 8.08 (s, 1H), 7.71 (s, 1H), 7.25 (dd, J= 7.5, 20 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H), 6.69 (d, J=5.7 Hz, 1H), 4.16 (s, 2H, 3.20 (t, J=5.3 Hz, 4H), 3.05-2.95 (m, 6H), 2.60 (s, 3H), 2.50-2.45 (m, 1H) , 2.39-2.37 (m, 6H), 2.14-2.09 (m, 2H), 2.05-1.98 (m, 2H), 1.81-1.70 (m, 2H).(EIMS): 485.1 [M+Na]+.

Example 15.

N-(1 -(3 -(5-Amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1 -yl)phenyl)-1H1,2,3-triazopyridine-4- yl)piperidine-4-carboxamide (15):

The example was carried out using the methods of Example 14, where 1-methylpiperidine-4-carboxylic acid was replaced by 4-piperidine carboxylic acid, a gray-white solid was obtained. The yield was 88.7%.

1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.71 (s , 1H), 7.26 (dd, J=7.5, 2.0 Hz, 1H), 6.80 (dd, J=23.8, 6.6 Hz, 2H), 4.15 (s, 2H), 3.27-3.17 (m, 6H), 2.98 (t, J=5.0 Hz, 4H), 2.822.65 (m, 3H), 2.60 (s, 3H), 2.39 (s, 3H), 2.03-1.96 (m, 2H), 1.74-1.69 (m, 2H), 1.22 (s, 1H). (EI-MS): 571.1 [M+Na]+.

Example 16.

5-Amino-N-(5-(4-(4-aminobutyrylamino)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)2-chloro- 4-fluoro-3-methylbenzamide (16)

The example was carried out using the methods of Example 14, where 1-methylpiperidine-4-carboxylic acid was replaced by γ-aminobutyric acid to obtain a gray-white solid. The yield was 88.7%.

^1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.25 (dd, J=7.5 , 2.0 Hz, 1H), 6.80 (dd, J=21.4, 6.6 Hz, 2H), 4.17 (s, 2H), 4.17 (s, 2H), 3.20 (t, J=5.1 Hz, 4H), 3.08-3.04 (m, 2H), 2.98 (t, J=5.1 Hz, 4H), 2.60 (s, 3H) , 2.50 (t, J=8.2 Hz, 2H), 2.39 (s, 3H), 2.10-2.04 (m, 2H), 1.19 (s, 2H). (EI-MS): 545.0 [M+Na]+.

Example 17.

5-Amino-2-chloro-4-fluoro-N-(5-(4-(3-hydroxypropionylamino)-1H-1,2,3-triazol-1-yl)-2-(4methylpiperazin-1-yl) phenyl)-3-methylbenzamide

The example was carried out using the methods of Example 14, where 1-methylpiperidine-4-carboxylic acid was replaced by 3-hydroxypropionic acid to obtain a gray-white solid. The yield was 84.9%.

1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.71 (s , 1H), 7.25 (dd, J=7.5, 2.0 Hz, 1H), 6.80 (dd, J=21.8, 6.6 Hz, 2H), 4.36 (t, J=5.0 Hz, 1H), 4.17 (s, 2H), 3.83-3.79 (m, 2H), 3.20 (t, J=5.1 Hz, 4H), 2, 98 (t, J=5.0 Hz, 4H), 2.60 (s, 3H), 2.39-2.35 (m, 5H). (EI-MS): 532.1 [M+Na]+.

Example 18.

- 12 044762

5-Amino-2-chloro-N-(5-(4-(4-(dimethylaminomethyl)benzyl)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1 -yl )phenyl)-4-fluoro-3-methylbenzamide (18):

The example was carried out using the methods of Example 1, where methyl propiolate was replaced with N,Ndimethyl-4-(prop-2-yn-1-yl)benzamide to obtain a gray-white solid in three steps. The yield after three reaction steps was 34.4%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.49-8.44 (m, 2H), 7.74-7.68 (m, 2H), 7.56 -7.50 (m, 2H), 7.26 (dd, J=7.4, 1.9 Hz, 1H), 6.75 (d, J=5.9 Hz, 1H), 4.16 ( s, 2H), 3.88 (d, J=1.2 Hz, 2H), 3.20 (t, J=5.1 Hz, 4H), 3.0-2.95 (m, 10H), 2.60(s, 3H), 2.38(s, 3H). (EI-MS): 606.1 [M+Na] ⁺ .

Example 19.

5-Amino-2-chloro-N-(5-(4-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1yl)phenyl )-4-fluoro-3-methylbenzamide (19):

The example was carried out using the methods of Example 1, where methyl propiolate was replaced with N,Ndimethyl-but-3-yn-1-amine to obtain a gray-white solid in three steps. The yield after three reaction steps was 31.6%.

Ή NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.28 (s, 1H), 7.26 (dd , J=7.5, 2.0 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.74 (d, J=5.7 Hz, 1H), 4.15 (s, 2H), 3.20 (t, J=5.1 Hz, 4H), 2.98 (t, J=5.0 Hz, 4H), 2.71-2.61 (m, 4H) , 2.60 (s, 3H), 2.40-2.39 (m, 9H). (EI-MS): 516.0 [M+Na] ⁺ .

Example 20.

5-Amino-2-fluoro-N-(3-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluoro-6-(4-methylpiperazin-1-yl)phenyl) -4fluoro-3-methylbenzamide (20):

The example was carried out using the methods of Example 1, where 4-fluoro-3-nitroaniline was replaced by 2,4difluoro-3-nitroaniline and methyl propiolate by ethylethynyl ether to produce a gray-white solid in five steps. The yield after five stages was 12.8%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 7.98 (s, 1H), 7.30 (dd, J=7.5, 5.7 Hz, 1H), 6.74 (d, J=5.7 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H), 4.76-4.72 (m, 2H), 4.15 (s , 2H), 3.20 (t, J=5.1 Hz, 4H), 2.98 (t, J=5.0 Hz, 4H), 2.60 (s, 3H), 2.39 (s , 3H), 1.56 (t, J=8.0 Hz, 3H). (EI-MS): 507.1 [M+Na] ⁺ .

Example 21.

N-(3-(4-((2-Amino-2-oxoethyl)amino)-1H-1,2,3-triazol-1-yl)-2-fluoro-6-(4-methylpiperazin-1yl)phenyl )-2-chloro-4-fluoro-5-hydroxyl-3-methylbenzamide (21):

The example was carried out using the method of Example 1, where 4-fluoro-3-nitroaniline was replaced by 2,4difluoro-3-nitroaniline, and methyl propiolate by 2-(ethynylamino)acetamide and 2-chloro-3-methyl-4-fluoro-5-13 044762 nitrobenzoyl chloride - 2-chloro-3-methyl-4-fluoro-5-hydroxybenzoyl chloride to produce a white solid in five reaction steps. The yield after five stages was 9.7%.

1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.07 (d, J=10.4 Hz, 2H), 7.34-7.24 (m, 2H), 6 .59 (d, J=7.5

Hz, 1H), 5.98 (s, 2H), 5.93 (s, 1H), 4.03 (s, 2H), 3.20 (t, J=5.1 Hz, 4H), 2, 98 (t, J=5.0 Hz, 4H), 2.60 (s, 3H), 2.38 (s, 3H). (EI-MS): 536.2 [M+Na]+.

Example 22.

1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-N(2-morpholinethyl)-1H- -1,2,3-triazole-4-carboxamide (22):

The example was carried out using the methods of Example 3, where 4-fluoro-3-nitroaniline was replaced by 2fluoro-4-methyl-3-nitroaniline and dimethylaminohydrochloride by -N-(2-aminoethyl)morpholine to obtain a grey-white solid. The yield over six stages was 8.8%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.52 (s, 1H), 7.25 (s, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.78 (d, J=5.7 Hz, 1H) 6.72 (d, J=7.5 Hz, 1H), 4.15 (s, 2H), 3.74 (t , J=4.7 Hz, 4H), 3.55-3.53 (m, 2H), 3.20 (t, J=5.1 Hz, 4H), 2.98 (t, J=5, 1 Hz, 4H), 2.61-2.59 (m, 5H), 2.51 (t, J=4.7 Hz, 4H), 2.40-2.39 (m, 6H). (EI-MS): 615.1 [M+Na]+.

Example 23.

N-(3 -(4-(3-aminopropionylamino))-1H-1,2,3-triazol-1 -yl)-2-methyl-6-(4-methylpiperazin-1 yl)phenyl)-2-chloro -4-fluoro-5-hydroxy-3-methylbenzamide (23):

The example was carried out using the methods of Example 14, where 4-fluoro-3-nitroaniline was replaced by 2-fluoro-4-methyl-3-nitroaniline, 2-chloro-3-methyl-4-fluoro-5-nitrobenzoyl chloride - 2-chloro-3-methyl -4-fluoro5-hydroxybenzoyl chloride, 1-methylpiperidine-4-carboxylic acid - β-alanine, to obtain a white solid in six steps. The yield over six stages was 7.2%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.06 (d, J=5.7 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 5.93 (s, 1H), 3.20 ( t, J=5.1 Hz, 4H), 3.01-2.93 (m, 4H), 2.93-2.91 (m, 1H), 2.60 (s, 3H), 2.45 (s, 3H), 2.44-2.42 (m, 2H), 2.38 (s, 3H), 1.24 (s, 2H). (EI-MS): 615.1 [M+Na]+.

Example 24.

1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-N-(2morpholinethyl)- 1H -1,2,3-triazole-4-carboxamide (24):

The example was carried out using the methods of Example 3, where N-methylpiperazine was replaced by Nmethylhomopiperazine and dimethylaminohydrochloride by N-(2-aminoethyl)morpholine to obtain a grey-white solid. The yield over six stages was 7.3%.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 8.70 (s, 1H), 7.31 (dd, J=7.5, 2.0 Hz, 1H), 7.25 (s, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.70 (d, J=5.7 Hz, 1H), 4.16 (s, 2H), 3.74 (t, J=4.7 Hz, 4H), 3.60 (t, J=4.8 Hz, 2H), 3.55-3.53 (m, 2H), 3.46-3 .44 (m, 2H), 2.91-2.89 (m, 2H), 2.61-2.58 (m, 4H), 2.52-2.50 (m, 4H), 2.39 (s, 3H), 2.31 (s, 3H), 1.64-1.60 (m, 2H). (EI-MS): 615.1 [M+Na]+.

-

Claims (8)

Example 25. 1-3-(5-amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-N-(2morpholinethyl)-1H-1,2, 3-triazole-4-carboxamide (24) The example was carried out using the methods of Example 3, where N-methylpiperazine was replaced by 1,2-dimethylpiperazine and dimethylaminohydrochloride by N-(2-aminoethyl)morpholine to obtain a grey-white solid. The yield of the six stages was 7.3%. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 8.70 (s, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.31 ( dd, J=7.5, 2.0 Hz, 1H), 7.25 (s, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.70 (d, J=5 .7 Hz, 1H), 4.18 4.04 (m, 7H), 3.66 3.53 (m, 2H), 3.35 3.31 (m, 1H), 3.20 3.07 ( m, 4H), 2.93 2.87 (m, 1H), 2.73 2.58 (m, 2H), 2.51 2.37 (m, 7H), 2.34-2.20 (m , 3H), 1.16 (d, J=6.8 Hz, 3H). (EI MS): 615.1 [M+Na]+. CLAIM 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof K _E (O where the phenyl ring is substituted with two or three R2 substituents, X is hydrogen, methyl, methoxy or halogen; Y is -CH2-, -O-, -CO-, -NR5-, -CONR6- or -NR ₇ CO-, wherein R ₅ , R ₆ and R ₇ are each independently hydrogen; m represents 0-3; R1 is hydrogen, amino, hydroxyl, -CONH2, C1-C4 alkoxy, substituted or unsubstituted nitrogen- or oxygen-containing 3-7 membered heterocyclic ring or -NR10R11, where _R10 and R11 are independently hydrogen, C1-C4 alkyl, substituted or unsubstituted nitrogen- or oxygen-containing 3-7-membered heterocyclic ring containing one oxygen atom, one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, or R ₁₀ and R11 are connected to form a nitrogen- or oxygen-containing 3-7- a membered heterocyclic ring containing one oxygen atom, one or two nitrogen atoms or one nitrogen atom and one oxygen atom, where the substituent is C1-C4 alkyl; R2 is independently in each case halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro or cyano; R ₃ represents amino or hydroxyl; R4 is N-methylpiperazinyl, 1,2-dimethylpiperazinyl or N-methylhomopiperazinyl. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents hydrogen, fluorine, chlorine or methyl. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where Y represents -NR ₅ -, -CONR ₆ - or -NR ₇ CO-; R ₅ , R ₆ and R ₇ are each independently hydrogen. 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said substituted or unsubstituted nitrogen- or oxygen-containing 3-7-membered heterocyclic ring containing one oxygen atom, one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, represents is piperidine, tetrahydrofuran, tetrahydropyran, morpholine or piperazine, and the substituent on the nitrogen- or oxygen-containing 3-7-membered heterocyclic ring is independently in each case methyl. 5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -NR10R11, wherein _R10 and R11 is C1-C4 alkyl. 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the phenyl ring is substituted with two or three R2, and independently in each case R2 represents fluorine, chlorine, bromine, methyl, - 15 044762 methoxy, nitro, trifluoromethyl or cyano. 7. Connection selected from or a pharmaceutically acceptable salt thereof. 8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises the following structures: -