COMPOSITIONS AND METHODS FOR INHIBITING PHENYL TRIAZOLE MLL1-WDR5 PROTEIN-PROTEIN INTERACTION

Abstract

The present disclosure relates to the field of medicinal chemistry, in particular to a phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor (I) and a preparation method thereof, and pharmacodynamics experiments prove that the compound of the present disclosure has relatively strong MLL1-WDR5 protein-protein interaction inhibition activity.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. A method of treating acute leukemia in a subject, the method comprising administering to said subject a compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR00048## wherein X is hydrogen, methyl, methoxy or halogen; Y is —CH2-, —O—, —S—, —CO—, —CH2O—, —NR5-, —CONR6- or —NR7CO—, wherein R5, R6, or R7 each independently is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or substituted phenyl, the substituent is halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxyl, thiol, carboxyl, cyano, trifluoromethyl or imidazolyl; M is 0-6; R1 is hydrogen, amino, hydroxyl, thiol, carboxyl, cyano, —CONH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl, substituted or unsubstituted nitrogen- or oxygen-containing 3 to 7 membered heterocyclic ring, —NR8COR9, —CONR10R11 or —NR10R11, wherein R8 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or substituted phenyl, R9 is amino, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl or substituted phenyl, substituted or unsubstituted nitrogen- or oxygen-containing 3 to 7 membered heterocyclic ring, R10, R11 independently is hydrogen, C1-C4 alkyl, phenyl or substituted phenyl, substituted or unsubstituted nitrogen- or oxygen-containing 3 to 7 membered heterocyclic ring, or R10 and R11 are bonded to form nitrogen- or oxygen-containing 3 to 7 membered heterocyclic ring, wherein the substituent is halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxyl, thiol, carboxyl, cyano, trifluoromethyl or imidazolyl; R2 is disubstituted or trisubstituted halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro or cyano; R3 is amino, methylamino, aminomethyl, hydroxyl, hydroxymethyl, thiol or —CONH2; R4 is N-methylpiperazine, 1,2-dimethyl piperazine or N-methylhomopiperazine; and a pharmaceutically acceptable carrier.

10. The method of claim 9, wherein the acute leukemia is an acute leukemia having an MLL1 gene rearrangement type.

11. The method of claim 9, the compound of the formula (I) or a pharmaceutically is selected from any of the compounds below: ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##

Description

BRIEF DESCRIPTION OF DRAWINGS

[0041] FIG. 1 is the RT-PCR experiment for application Example 7 to show the lowered Hoxa9 and Meis-1 gene expressions in cells

[0042] FIG. 2 is the Western Blot experiment for application Example 7 to show the effects on MLL1 enzymatic activity in cells.

[0043] FIG. 3 is the toxicity comparison of the compounds in this present disclosure to some of the compounds on Article 1

EXAMPLE 1

[0044] ##STR00023##

1-(3-(5-amino-2-chloro-4-fluoro-3-methyl benzoylamino)-4-(4-methyl piperazine-1-group)phenyl)-1H-1,2,3-methyl triazole-4-carboxylate

Preparation of 4-(4-methylpiperazin-1-group)-3-nitroaniline (IIb)

[0045] Dissolve 4-fluoro-3-nitroaniline (II) (6 g, 38.4 mmol) in 50 mL acetonitrile, add N-methylpiperazin (5.8 g, 6.3 mL, 57.6 mmol) and N, N-diisopropylethylamine (9.5 mL, 57.6 mmol), and heat and reflux for 12 h. The crude is obtained after spin dry and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain red-brown solid (8.9 g, 97.8%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ7.06 (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].sup.+.

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

[0046] Dissolve 4-(4-methylpiperazin-1-group)-3-nitroaniline (IIb)(4.0 g, 17.0 mmol) in 100 mL 2M/HCl, reduce the temperature to 0° C., add 10 mL of sodium nitrite (1.76 g, 25.5 mmol) water solution dropwise, stir for 30 min at 0° C., add 10 mL sodium azide (2.2 g, 34.0 mmol) water solution dropwise, stir 30 min at 0° C. and then stir 2 h at room temperature. The product is precipitated with 2M/NaOH at pH=9-10, vacuum filter and heat dry to obtain red-brown solid (4.0 g, 91.3%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ7.48 (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].sup.−.

Preparation of 1-(4-(4-methylpiperazin-1-group)-3-nitrophenyl)-1H-1,2,3-triazole methyl carboxylate (Ib)

[0047] Dissolve 1-(4-azido-nitrophenyl)-4-methylpiperazine (Ia) (1.0 g, 3.8 mmol) in 50 mL methanol, add methyl propiolate (0.96 g, 11.4 mmol), cuprous iodide (0.07 g, 0.38 mmol), N,N-diisopropylethylamine (0.12 mL, 0.76 mmol), heat reflux for 48 h, filter, concentrate, and beat up with ethyl acetate to obtain red-brown solid (0.8 g, 61.5%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.45 (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].sup.+.

Preparation of 1-(3-amino-4-(4-methylpiperazin-1-group)phenyl-1H-1,2,3-methyl triazole-4-methyl carboxylate (Ic)

[0048] Dissolve 1-(4-(4-methylpiperazin-1-group)-3-nitrophenyl)-1H-1,2,3-methyl triazole-4-methyl carboxylate (Ib) (3.8 g, 12.0 mmol) in 50 mL methanol, add Pd/C of catalytic amount, pump in hydrogen, stir at room temperature for 7 h, concentrate by vacuum filtering to obtain pink solid (3.0 g, 78.9%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.28 (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].SUP.+..

Preparation of 1-(3-(5-Amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-1H-1, Methyl 2,3-triazole-4-carboxylate (1)

[0049] Dissolve 1-(3-amino-4-(4-methylpiperazin-1-group)phenyl-1H-1,2,3-triazole-4-methyl carboxylate (Ic) (1.7 g, 5.3 mmol) in 100 mL anhydrous dichloromethane, add pyridine (0.43 mL, 5.3 mmol), add 20 mL dichloromethane solution of 2-chloro-3-methyl-4-fluoro-5-nitrobenzoyl chloride (1.6 g, 6.4 mmol) drop wise in ice-water bath, stir 2 h at room temperature, filter under vacuum and heat dry to obtain light yellow solid; dissolve the light yellow (2.6 g, 4.9 mmol) in ethyl acetate, add stannous chloride (5.5 g, 24.4 mmol), heat and reflux for 3 h before cooling down to room temperature, dilute with 100 mL ethyl acetate, neutralize with saturated sodium bicarbonate till no additional white gel-like precipitating out, filter under vacuum, wash the filter cake with ethyl acetate till no ultraviolet absorption, extract the filtrate with ethyl acetate till no ultraviolet absorption, combine the organic phases, dry with anhydrous sodium sulfate, concentrate to obtain the crude product, beat up with ethyl acetate, filter under vacuum to obtain gray-white solid 1 (2.3 g, 93.9%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.52-9.45 (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].sup.+.

EXAMPLE 2

[0050] ##STR00024##

Preparation of 1-(3-(5-Amino-2-chloro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-1H-1,2,3-Triazole-4-carboxylic acid (2)

[0051] Dissolve 1-(3-(5-Amino-2-chloro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-Methyl formate (1) (2.3 g, 4.6 mmol) in THF, add lithium hydroxide solution (1M, 15 mL), stir for 8 h at room temperature, rotate dry to remove THF followed by acidification using 2M chloric acid to obtain white solid (1.7 g, 80.4%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.52-9.45 (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].sup.+.

EXAMPLE 3

[0052] ##STR00025##

Preparation of 1-(3-(5-Amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-N, N-dimethyl-1H-1,2,3 triazole-4-carboxamide (3)

[0053] Dissolve 1-(3-(5-Amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-1H-1,2,3-Triazole-4-carboxylic 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 dimethylamino hydrochloride (58.7 mg, 0.72 mmol), stir for 4 h at room temperature. Dilute the reaction mixture with 50 mL ethyl acetate, remove DMF with saturated sodium chloride, dry the organic phase with anhydrous sodium sulphate, dry out the organic solvent with rotations to obtain raw product, isolate and purify with silica gel column chromatography (Dichloromethane:methanol=50:1) to obtain gray white solid. The yield is 78.4%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.59 (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].sup.+.

EXAMPLE 4

[0054] ##STR00026##

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

[0055] Using the methods in application Example 3, replace dimethylamino hydrochloride by morpholine to obtain gray white solid. The yield is 67.5%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.61 (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].sup.+.

EXAMPLE 5

[0056] ##STR00027##

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

[0057] Using the methods in application Example 3, replace dimethylamino hydrochloride with 4-aminotetrahydropyran to obtain gray white solid. The yield is 82.9%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.52 (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].sup.+.

EXAMPLE 6

[0058] ##STR00028##

Preparation of 1-(3-(5-Amino-2-chloro-4-fluoro-3-methylbenzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-N-(1-methylpiperidin-4-group)-1H-1,2,3-triazole-4-carboxamide

[0059] Using the methods in application Example 3, replace dimethylamino hydrochloride with 4-amino-1-1methylpiperidin to obtain gray white solid. The yield is 49.9%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.48 (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), 1.75-1.66 (m, 4H). (EI-MS): 585.0[M+H].sup.+.

EXAMPLE 7

[0060] ##STR00029##

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-ethyl benzoylamino) 4-(4-methylpiperazin-1-group)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (7)

[0061] Using the methods in application Example 3, replace dimethylamino hydrochloride with N-(3-aminopropyl)morpholine, and obtain gray-white solid. The yield is 94.2%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.51 (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].SUP.+..

EXAMPLE 8

[0062] ##STR00030##

Preparation of 5-amino-2-chloro-4-fluoro-3-ethyl-N-(2-(4-methylpiperazin-1-group)-5-(4-(methylpiperazin-1-Carbonyl)-1H-1,-1H-1,2,3-triazole-1-group) Phenyl)-carboxamide (8)

[0063] Using the methods in application Example 3, replace dimethylamino hydrochloride with N-methylpiperazin to obtain gray-white solid. The yield is 94.2%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.51 (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].sup.+.

EXAMPLE 9

[0064] ##STR00031##

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-ethyl benzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-N-(2-Morpholine ethyl)-1H-1,2,3-triazole-4-carboxamide (9)

[0065] Using the methods in application Example 3, replace dimethylamino hydrochloride with N-Aminoethylmorpholine to obtain gray-white solid. The yield is 72.5%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.51 (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). (ESI-MS): 601.0[M+H].sup.+.

EXAMPLE 10

[0066] ##STR00032##

Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-ethyl benzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-N-(3-aminopropyl)-1H-1,2,3-triazole-4-carboxamide (10)

[0067] Using the methods in application Example 3, replace dimethylamino hydrochloride with 1,3-propylene diamine to obtain gray-white solid. The yield is 64.5%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.85 (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].sup.+.

EXAMPLE 11

[0068] ##STR00033##

Preparation of 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-group)-5-(1H-1,2,3-triazole-1-group) phenyl) benzamide (11)

[0069] Using the methods in application Example 1, replace ethyl propiolate with Trimethyl ethynyl silicon to obtain gray-white solid after three reaction steps. The yield of the three steps is 23.8%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.76-8.68 (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].sup.+.

EXAMPLE 12

[0070] ##STR00034##

Tert-butyl(1-(3-(5-amino-2-chloro-4-fluoro-3-ethyl benzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-1H-1,2,3-triazole-4-group) aminomethyl ester (12)

[0071] Using the methods in application Example 1, replace Methyl propiolate with tert-butyl ethynyl carbamateto obtain gray-white solid after three reaction steps. The yield of the three steps is 20.1%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 13

[0072] ##STR00035##

5-amino-N-(5-(4-amino-1H-1,2,3-triazole-1-group)-2-(4-methylpiperazin-1-group)phenyl)-2-chloro-4-fluoro-3-Methylbenzamide (13)

[0073] Dissolve Tert-butyl(1-(3-(5-amino-2-chloro-4-fluoro-3-ethyl benzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-1H-1,2,3-triazole-4-group) aminomethyl ester (1.0 g, 2.2 mmol) in 20 mL dichloromethane, add 10 mL trifluoroacetate, stir for 1 h at room temperature, adjust pH=8-9 using saturated sodium bicarbonate, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate and dry with rotation to obtain grey solie. The yield is 87.3%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 14

[0074] ##STR00036##

N-(1-(3-(5-amino-2-chloro-4-fluoro-3-ethyl benzoylamino)-4-(4-methylpiperazin-1-group)phenyl)-1H-1,2,3-triazole-4-group)-1-methylpiperidine-4-formamide (14)

[0075] Dissolve 5-amino-N-(5-(4-amino-1H-1,2,3-triazole-1-group)-2-(4-methylpiperazin-1-group)phenyl)-2-chloro-4-fluoro-3-Methylbenzamide (13) (0.2 g, 0.34 mmol) in 5 mL DMF, add BOP (0.30 g, 0.68 mmol), trimethylamine (0.09 mL, 0.68 mmol) and 1-Methylpiperidine-4-formic acid (97.3 mg, 0.68 mmol), stir for 4 h at room temperature. Dilute the reaction with 50 mL ethyl acetate, remove DMF by washing with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, dry out the organic solvent with rotation to obtain raw product, isolate and purify with chromatography on silica gel column (dichloromethane:methanol=20:1) to obtain grey white solid. The yield is 73.9%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.72-8.64 (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). (EI-MS): 485.1 [M+Na].sup.+.

EXAMPLE 15

[0076] ##STR00037##

N-(1-(3-(5-amino-2-chloro-4-fluoro-3-Methyl benzoylamino)-4-(4-methylpiperazin group)phenyl)-1H-1,2,3-Triazopyridine-4-group) Piperidine-4-formamide (15)

[0077] Using the methods in application Example 14, replace 1-Methylpiperidine-4-formic acid with 4-piperidinic acid, grey while solid is obtained. The yield is 88.7%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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), 2.82-2.65 (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].sup.+.

EXAMPLE 16

[0078] ##STR00038##

5-amino-N-(5-(4-(4-Aminobutyrylamino)-1H-1,2,3-triazol-1-group)-2-(4-methylpiperazin-1-group)phenyl)-2-chloro-4-fluoro-3-methyl benzoylamino (16)

[0079] Using the methods in application Example 14, replace 1-Methylpiperidine-4-formic acid with γ-aminobutyric acid to obtain grey white solid. The yield is 88.7%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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): 571.1[M+Na].sup.+.

EXAMPLE 17

[0080] ##STR00039##

5-amino-2-chloro-4-fluoro-N-(5-(4-(3-Hydroxypropionylamino)-1H-1,2,3-triazol-1-group)-2-(4-methylpiperazin-1-group)phenyl)-3-methyl benzoylamino

[0081] Using the methods in application Example 14, replace 1-Methylpiperidine-4-formic acid with 3-Hydroxypropionic acid to obtain grey white solid. The yield is 84.9%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 18

[0082] ##STR00040##

5-amino-2-chloro-N-(5-(4-(4-(dimethylaminomethyl)benzyl)-1H-1,2,3-triazol-1-group)-2-(4-methylpiperazin-1-group group)phenyl)-4-fluoro-3-Methyl benzoyl (18)

[0083] Using the methods in application Example 1, replace methyl propiolate with N,N,-Dimethyl-4-(prop-2-yne-1-group) to obtain grey white solid in three steps. The yield of the three steps is 34.4%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 19

[0084] ##STR00041##

5-amino-2-chloro-N-(5-(4-(2-(Dimethylamino)ethyl)-1H-1,2,3-triazol-1-group)-2-(4-methylpiperazin-1-group group)phenyl)-4-fluoro-3-Methyl benzoyl (19)

[0085] Using the methods in application Example 1, replace methyl propiolate with N,N,-dimethyl-but-3-alkyne-1-amine to obtain grey white solid in three steps. The yield of the three steps is 31.6%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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): 606.1[M+Na].sup.+.

EXAMPLE 20

[0086] ##STR00042##

5-amino-2-fluoro-N-(3-(4-Ethoxy-1H-1,2,3-triazol-1-group)-2-fluoro-6-(4-methylpiperazin-1-group)phenyl)-4-fluoro-3-Methyl benzoyl (20)

[0087] Using the methods in application Example 1, replace 4-fluoro-3-Nitroaniline with 2,4-difluoro-3-nitroaniline and methyl propiolate with ethyl ethynyl ether to obtain grey white solid in five steps. The yield of the five steps is 12.8%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 21

[0088] ##STR00043##

N-(3-(4-((2-amino-2-Oxoethyl)amino)-1H-1,2,3-triazol-1-group)-2-fluoro-6-(4-methylpiperazin-1-group)phenyl)-2-chloro-4-fluoro-5-hydroxyl-3-Methyl benzoyl (21)

[0089] Using the method in application Example 1, replace 4-fluoro-3-Nitroaniline with 2,4-difluoro-3-nitroaniline, methyl propiolate with 2-(ethynylamino) Acetamide and 2-chloro-3-methyl-4-fluoro-5-Nitrobenzoyl chloride with 2-chloro-3-methyl-4-fluoro-5-hydroxybenzoyl chloride to obtain white solid in five reactions. The yield of the five reactions is 9.7%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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): 507.1[M+Na].sup.+.

EXAMPLE 22

[0090] ##STR00044##

1-(3-(5-amino-2-chloro-4-fluoro-3-Methyl benzoylamino)-2-methyl-4-(4-methylpiperazin-1-group)phenyl)-N-(2-Morpholine ethyl)-1H-1,2,3-triazol-4-formamide (22)

[0091] Using the methods in application Example 3, replace 4-fluoro-3-Nitroaniline with 2-fluoro-4-methyl-3-Nitroaniline and Dimethylamino hydrochloride with N-(2-Aminoethyl) Morpholine to obtain grey white solid. The yield of the six steps is 8.8%.

[0092] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 23

[0093] ##STR00045##

N-(3-(4-(3-Aminopropionylamino))-1H-1,2,3-triazol-1-group)-2-methyl-6-(4-methylpiperazin-1-group)phenyl)-2-chloro-4-fluoro-5-hydroxyl-3-Methyl benzoyl (23)

[0094] Using the methods in application Example 14, replace 4-fluoro-3-Nitrobenzene with 2-fluoro-4-methyl-3-Nitrobenzene, 2-chloro-3-methyl-4-fluoro-5-Nitrobenzoyl chloride with 2-chloro-3-methyl-4-fluoro-5-Hydroxybenzoyl chloride, 1-methylpiperidine-4-carboxylic acid with ß-Alanine to obtain white solid in six steps. The yield of the six steps is 7.2%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.70 (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].sup.+.

EXAMPLE 24

[0095] ##STR00046##

1-(3-(5-amino-2-chloro-4-fluoro-3-Methyl benzoylamino)-4-(4-methyl-1,4-Diazepane-1-group)phenyl)-N-(2-Morpholine ethyl)-1H-1,2,3-triazol-4-formamide (24)

[0096] Using the methods in application Examples 3, replace N-Methylpiperazine with N-Methyl homopiperazine and Dimethylamino hydrochloride with N-(2-aminoethyl)morpholine to obtain white solid. The yield of the six steps is 7.3%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.79 (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].sup.+.

EXAMPLE 25

[0097] ##STR00047##

1-3-(5-amino-2-chloro-4-fluoro-3-Methyl benzoylamino)-4-(3,4-Dimethylpiperazine-1-group)phenyl)-N-(2-Morpholine ethyl)-1H-1,2,3-triazol-4-formamide (24)

[0098] Using the methods in application Example 3, replace N-Methylpiperazine with 1,2-Dimethylpiperazine and Dimethylamino hydrochloride with N-(2-aminoethyl)morpholine to obtain grey white solid. The yield of the six steps is 7.3%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ8.80 (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].sup.+.