CN103787907B - Aniline compounds as farnesyltransferase inhibitors and uses thereof - Google Patents

Abstract

The present invention provides an aniline compound as shown in formula I or a pharmaceutically acceptable salt thereof: wherein, X is independently selected from: COOH, SO ₂ NH ₂ ; R ₁ and R ₂ are independently selected from H, C ₁ -C ₃ alkyl or alkoxy, CF ₃ , F, Cl, Br, I, NH ₂ , NO ₂ ; m, n are integers from 0 to 5; y is 0 or 1. The compound of the present invention and the pharmaceutically acceptable salt thereof can be used as farnesyl transferase inhibitors or used for preparing drugs for preventing or treating farnesyl transferase-related diseases, and have good pharmaceutical prospect.

Description

Aniline compounds as farnesyltransferase inhibitors and uses thereof

technical field

The invention relates to an aniline compound as a farnesyl transferase inhibitor and its application.

Background technique

Post-translational modification (PTM) is of great significance to protein maturation, and these post-translational modifications include acetylation, alkylation, methylation, and prenylation. Prenylation is catalyzed by farnesyltransferase.

Farnesyl transferase (farnesyltransferase, FTase) is a zinc ion metalloenzyme capable of post-translational modification, which can catalyze the conversion of farnesyl (fifteen carbons) in farnesyl pyrophosphate (FPP) isoprenoid) to a tetrapeptide structure at the carbon-terminus of the Ras protein, this tetrapeptide structure is CAAX (C: cysteine, A: aliphatic amino acid, X: methionine, glutamic acid or alanine), and the farnesyl group is attached to the sulfur atom of cysteic acid. When the Ras protein is farnesylated, the fifteen-carbon isoprenoid connected to the carbon end increases the hydrophobicity of the Ras protein, making it easier for the Ras protein to be fixed on the cell membrane, and the signaling pathways in the cell can be normal Cells can grow, proliferate, and differentiate normally.

The mutation of Ras protein keeps Ras protein in a state of continuous activation, and cell proliferation is out of control, leading to the formation of tumors. Overexpression of mutated Ras protein has been found in 90% of pancreatic cancer, 50% of colon cancer and 30% of lung cancer (Song Yan, Zhou Xiang, Li Huifang, Lu Tao, Anti-tumor inhibitors targeting Ras signal transduction pathway Research Progress, Zhongnan Pharmacy, 2009, 7(4), 293-296). Therefore, the study of farnesyltransferase inhibitors has become one of the focuses of drug development.

Contents of the invention

The present invention comprehensively utilizes computer drug design, medicinal chemistry, and molecular biology methods and technologies to design and synthesize a series of aniline compounds, some of which have significant farnesyltransferase inhibitory activity and have good drug prospects.

The object of the present invention is to provide an aniline compound as shown in formula I or a pharmaceutically acceptable salt thereof:

Wherein, X is independently selected from: COOH, SO ₂ NH ₂ ; R ₁ and R ₂ are independently selected from H, C ₁ to C ₃ alkyl or alkoxy, CF ₃ , F, Cl, Br, I, NH _2. NO ₂ ; m and n are integers from 0 to 5 respectively; y is 0 or 1.

In a preferred embodiment of the present invention, X is COOH, or SO ₂ NH ₂ ; R ₁ and R ₂ are independently selected from H, C ₁ -C2 alkyl, CF ₃ , F, Cl, Br; m,n 0, 1 or 2, respectively.

In a preferred embodiment of the present invention, the aniline compounds are the following compounds (1) to (23):

Another aspect of the present invention is a pharmaceutical composition, which comprises the aniline compound of the present invention or a pharmaceutically acceptable salt thereof.

Preferably, the pharmaceutical composition may also include: suitable diluents or fillers: for example, sugars such as lactose or sucrose, mannitol or sorbitol; suitable cellulose preparations or calcium phosphates (such as tricalcium phosphate or Calcium hydrogen phosphate); suitable binders: such as starch paste, corn starch, wheat starch, rice starch, potato starch, etc.

If necessary, a disintegrating agent and/or a suitable coating agent to resist gastric juice, etc. may also be added. The pharmaceutical composition provided by the invention can be made into various dosage forms and administered orally or by injection.

Another aspect of the present invention is a farnesyl transferase inhibitor comprising the aniline compound of the present invention or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is the use of the aniline compound of the present invention or a pharmaceutically acceptable salt thereof as a farnesyl transferase inhibitor.

Another aspect of the present invention is the use of the aniline compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of farnesyltransferase inhibitors.

Another aspect of the present invention is the use of the aniline compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diseases related to farnesyltransferase.

Description of drawings

Figure 1 IC ₅₀ of the positive compound Tipifarnib as a control.

Detailed ways

The synthetic method of the aniline compound of the present invention is described in detail below.

When X is a carboxyl group COOH, its main preparation steps are shown in the synthetic route: starting from benzaldehyde derivatives (compounds shown in formula II), they are first prepared into corresponding diacids (compounds shown in formula II) by ethyl acetoacetate Compound shown in III), and then the diacid is converted into an anhydride (compound shown in formula IV), and finally the target compound (compound shown in formula I) is obtained.

When X is a sulfonamide group SO ₂ NH ₂ , its main steps are shown in the following route: starting from benzaldehyde derivatives (compound shown in formula II), through N-protected methanesulfonamide (shown in formula VI Compound) to form the corresponding N-protected ethylene sulfonamide derivative (compound shown in formula VII), through Michael addition of dimethyl malonate to obtain a diester compound (compound shown in formula VIII), through Krapcho decarboxylate reaction The monoester compound (compound shown in formula IX) is obtained, the corresponding acid (compound shown in formula X) is obtained through hydrolysis, and the corresponding amide (compound shown in formula XI) is formed with the corresponding aniline compound (compound shown in formula V) , and then remove the protecting group on the sulfonamide N to obtain the target compound (compound shown in formula I).

The present invention will be further described below through the examples, these examples are only used to illustrate the present invention and better understand the content of the present invention, and it does not limit the protection scope of the present invention in any way.

Example

Example 1

3-Phenyl-4-(4-(4-fluorophenoxy)anilinoyl)-butyric acid (1)

Synthesis of 4-(4-fluorophenoxy)aniline (1.4)

p-Fluoronitrobenzene (705 mg, 5.0 mmol), p-fluorophenol (560 mg, 5.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were dissolved in DMF (5 mL). The reaction was warmed to 70°C and stirred overnight. After the reaction was monitored by TLC, the reaction solution was dissolved in ethyl acetate, extracted with water and brine, the organic phase was separated and dried with anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain 990 mg of light yellow product 1.3, with a yield of 85%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.26 (d, 2H, J=8.8 Hz), 7.37-7.11 (m, 4H), 7.12 (d, 2H, J=9.2 Hz).

SnCl ₂ ·H ₂ O (2.25g, 10mmol) was dissolved in concentrated hydrochloric acid (10mL), compound 1.3 was added into the mixture (249mg, 1mmol), and the reaction solution was heated to reflux for 6 hours. After the reaction, the pH of the reaction solution was adjusted to 10 with aqueous sodium hydroxide solution. Finally, it was extracted with ethyl acetate and water, and the organic phase was separated and washed with water and brine respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the brown target product 1.4, which was directly used in the next reaction without purification.

Synthesis of 4-phenyl-dihydropyran-2,6-dione (1.6)

Benzaldehyde (50 mmol) and ethyl acetoacetate (100 mmol) were thoroughly mixed under cooling in an ice bath, and piperidine (1.0 mL) was added dropwise. The reaction solution was reacted at room temperature for 3 days, and the resulting solid was recrystallized from ethanol to obtain a white solid. Dissolve the resulting white solid in 50% potassium hydroxide aqueous solution (60mL), heat up to 80°C for 2 hours, add ice water and extract with ethyl acetate after the reaction, separate the water phase, and wash the water phase with concentrated hydrochloric acid Adjust pH to 1. Then extracted with ethyl acetate, separated the organic phase, dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain 4.89 g of white solid 1.5, yield 47 %.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.05(s, 2H), 7.30-7.25(m, 4H), 7.21-7.16(m, 1H), 3.45-3.39(m, 1H), 2.64( dd, 2H, J ₁ =6.4 Hz, J ₂ =16.0 Hz), 2.55-2.49 (m, 2H).

Compound 1.5 (1.0g) was dissolved in acetyl chloride (2mL), and heated to reflux, and reacted for 2 hours. After the reaction, petroleum ether was added to the reaction solution to produce a white solid, which was filtered by suction to obtain white solid 1.6. Purified directly for the next reaction.

Synthesis of 3-phenyl-4-(4-(4-fluorophenoxy)anilinoyl)-butyric acid (1)

Compound 1.6 (190 mg, 1.0 mmol) and compound 1.4 (203 mg, 1.0 mmol) were dissolved in dioxane (2 mL), and triethylamine (0.1 mL) was added. The mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was added to water and extracted with ethyl acetate, the organic phase was separated and dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (ethyl acetate:petroleum ether=2:3) to obtain a white The solid compound 1 was 195 mg, and the yield was 50%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.07(s, 1H), 9.88(s, 1H), 7.52(d, 2H, J=8.8Hz), 7.29-7.28(m, 4H), 7.21 -7.17(m, 3H), 7.01-6.98(m, 2H), 6.98(d, 2H, J=8.8Hz), 3.63-3.56(m, 1H), 2.72-2.55(m, 4H).

¹³ C NMR (100MHz, DMSO-d ₆ ): δ173.4, 169.7, 159.6, 157.2, 153.8, 152.6, 144.1, 135.4, 128.7, 127.9, 126.9, 121.3, 120.3, 120.2, 119.3, 117.0, 112.8, 43. 40.6, 38.7.

HRMS (ESI) calcd for _C23H20FNO4Na [M+Na] ⁺ 416.1274 _{, found} 416.1248.

Example 2

3-Phenyl-4-(4-(4-methoxyphenoxy)anicarboyl)-butyric acid (2)

For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced with p-methoxyphenol, and the product was a white solid with a yield of 61%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.05(s, 1H), 9.82(s, 1H), 7.47(d, 2H, J=8.8Hz), 7.29-7.27(m, 4H), 7.21 -7.15 (m, 1H), 6.93 (s, 4H), 6.85 (d, 2H, 9.2Hz), 3.72-3.53 (m, 1H), 2.71-2.54 (m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.3, 169.6, 155.8, 153.6, 150.7, 144.1, 134.7, 128.7, 127.9, 126.8, 121.3, 120.4, 118.4, 115.5, 55.9, 43.2, 40.6, 38.7.

HRMS (ESI) calcd for C ₂₄ H ₂₂ NO ₅ [MH] ⁺ 404.1498, found 404.1502.

Example 3

3-Phenyl-4-(4-(3,4-dichlorophenoxy)phenylcarbamoyl)-butanoic acid (3)

For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced with 3,4-dichlorophenol, and the product was a white solid with a yield of 45%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.07(s, 1H), 9.95(s, 1H), 7.60-7.56(m, 3H), 7.30-7.29(m, 4H), 7.21-7.19( m, 2H), 7.03(d, 2H, J=8.8Hz), 6.94(d, 1H, J=8.4Hz), 3.65-3.55(m, 1H), 2.73-2.55(m, 4H).

¹³ C NMR (100MHz, DMSO-d ₆ ): δ173.3, 169.8, 157.7, 150.8, 144.0, 136.4, 132.4, 131.9, 128.7, 127.9, 126.9, 125.2, 121.3, 120.5, 119.8, 118.3, 43.2, 38.7.

HRMS (ESI) calcd for _C23H20ClNO4 [M+H] ⁺ _444.0769 , found 444.0778 _.

Example 4

3-Phenyl-4-(4-(4-chlorophenoxy)anicarboyl)-butyric acid (4)

For the synthesis method, see Example 1, the difference is that the compound 1.2 used in the synthesis of compound 1.4 was replaced with p-chlorophenol, and the product was a white solid with a yield of 54%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.07(s, 1H), 9.91(s, 1H), 7.54(d, 2H, J=8.8Hz), 7.39(d, 2H, J=8.4Hz ), 7.29-7.28 (m, 4H), 7.19-7.18 (m, 1H), 6.99-6.95 (m, 4H), 3.62-3.55 (m, 1H), 2.72-2.55 (m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.3, 169.7, 159.9, 151.6, 144.0, 135.9, 130.2, 128.7, 127.9, 127.0, 126.8, 121.3, 120.1, 119.9, 43.1, 38.7.

HRMS (ESI) calcd for _{C23H20ClNO4Na} [M+Na] ⁺ 432.0979 _, found _432.0949 .

Example 5

3-Phenyl-4-(4-(3-chlorophenoxy)anilinoyl)-butyric acid (5)

For the synthesis method, see Example 1, the difference is that the compound 1.2 used in the synthesis of compound 1.4 was replaced with m-chlorophenol, and the product was a white solid with a yield of 51%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.08(s, 1H), 9.94(s, 1H), 7.56(d, 2H, J=8.4Hz), 7.37(t, 1H, J=8.4Hz ), 7.30-7.27(m, 5H), 7.20-7.14(m, 2H), 7.01(d, 2H, J=8.4Hz), 6.97(s, 1H), 6.90(d, 1H, J=8.0Hz) , 3.60-3.57 (m, 1H), 2.71-2.55 (m, 4H).

¹³ C NMR (100MHz, DMSO-d ₆ ): δ173.3, 169.7, 159.1, 151.0, 144.0, 136.2, 134.4, 131.8, 128.7, 127.9, 126.9, 123.2, 121.3, 120.5, 117.8, 116.6, 43.2, 38.7.

HRMS (ESI) calcd for _{C23H20ClNO4Na} [M+Na] ⁺ 432.0979 _, found _432.0938 .

Example 6

3-Phenyl-4-(4-(3-bromophenoxy)anilinoyl)-butyric acid (6)

For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced with m-bromophenol, and the product was a white solid with a yield of 29%.

¹ H NMR (400MHz, DMSO-d6): δ12.07(s, 1H), 9.94(s, 1H), 7.56(d, 2H, J=8.8Hz), 7.33-7.29(m, 6H), 7.20- 7.19(m, 1H), 7.10(s, 1H), 7.01(d, 2H, 8.4Hz), 7.95(d, 1H, 7.2Hz), 3.62-3.55(m, 1H), 2.73-2.55(m, 4H ).

¹³ C NMR (100MHz, DMSO-d6): δ173.3, 169.7, 159.2, 151.0, 144.1, 136.2, 132.1, 128.7, 127.9, 126.9, 126.1, 122.6, 121.3, 120.6, 120.5, 117.0, 116.6, 43.2, .

HRMS (ESI) calcd for _{C23H20BrNO4Na} [M+Na] ⁺ 476.0473 _, found _476.0490 .

Example 7

3-Phenyl-4-(4-(4-bromophenoxy)anilinoyl)-butyric acid (7)

For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced with p-bromophenol, and the product was a white solid with a yield of 37%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.06(s, 1H), 9.91(s, 1H), 7.55-7.50(m, 4H), 7.29-7.28(m, 4H), 7.19-7.18( m, 1H), 6.98(d, 2H, J=8.4Hz), 6.90(d, 2H, J=8.0Hz), 3.63-3.55(m, 1H), 2.72-2.55(m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.3, 169.7, 157.4, 151.4, 144.0, 135.9, 133.1, 128.7, 127.9, 126.9, 121.3, 120.23, 120.20, 114.9, 43.2, 38.7.

HRMS (ESI) calcd for _{C23H20BrNO4Na} [M+Na] ⁺ 476.0473 _, found _476.0443 .

Example 8

3-Phenyl-4-(4-(4-trifluoromethylphenoxy)anilinoyl)-butyric acid (8)

For the synthesis method, refer to Example 1, except that the compound 1.2 used in the synthesis of compound 1.4 was replaced by p-trifluoromethylphenol, and the product was a white solid with a yield of 36%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.09(s, 1H), 9.97(s, 1H), 7.70(d, 2H, J=8.4Hz), 7.60(d, 2H, J=8.4Hz ), 7.30-7.27 (m, 4H), 7.20-7.19 (m, 1H), 7.09-7.06 (m, 4H), 3.63-3.56 (m, 1H), 2.73-2.56 (m, 4H).

¹³ C NMR (100MHz, DMSO-d ₆ ): δ173.4, 169.8, 161.5, 150.3, 144.0, 136.6, 128.8, 128.7, 127.9, 127.84, 127.80, 127.76, 126.9, 126.1, 123.8, 123.5, 123.2, 122.9, 121.3, 121.1, 120.7, 117.7, 43.2, 40.6, 38.7.

HRMS ( _{ESI) calcd for C24H20F3NO4Na [ M} +Na] ⁺ _466.1242 , found 466.1214.

Example 9

3-Phenyl-4-(4-(4-nitrophenoxy)anilinoyl)-butyric acid (9)

For the synthesis method, see Example 1, the difference is that the compound 1.2 used in the synthesis of compound 1.4 was replaced with p-nitrophenol, and the product was a yellow solid with a yield of 59%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.09(s, 1H), 10.00(s, 1H), 8.22(d, 2H, J=9.2Hz), 7.63(d, 2H, J=8.8Hz ), 7.30-7.29(m, 4H), 7.21-7.17(m, 1H), 7.11(d, 2H, 8.8Hz), 7.08(d, 2H, J=9.2Hz), 3.63-3.56(m, 1H) , 2.73-2.55 (m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.3, 169.9, 163.8, 149.7, 144.0, 142.5, 137.1, 128.7, 127.9, 126.9, 126.6, 121.4, 117.3, 43.2, 40.7, 38.7.

HRMS (ESI) calcd for C ₂₃ H ₂₁ N ₂ O ₆ [M+H] ⁺ 421.1400, found 421.1402.

Example 10

3-Phenyl-4-(4-(4-aminophenoxy)anilinoyl)-butyric acid (10)

Compound 9 (500 mg) was dissolved in methanol, and Pd/C (50 mg) was added, plus a hydrogen balloon, and reacted overnight. The product was a yellow solid, and the yield was 64%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.76(s, 1H), 7.41(d, 2H, J=9.2Hz), 7.28-7.27(m, 4H), 7.20-7.16(m, 4H) , 6.77(d, 2H, 9.2Hz), 6.70(d, 2H, J=8.8Hz), 6.70(d, 2H, J=8.8Hz), 3.60-3.52(m, 1H), 2.70-2.53(m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.4, 169.5, 154.8, 146.9, 145.6, 144.1, 134.0, 128.7, 127.9, 126.9, 121.3, 120.9, 117.5, 115.4, 43.2, 40.6, 38.8.

HRMS (ESI) calcd for C ₂₃ H ₂₁ N ₂ O ₄ [MH] ⁺ 389.1501, found 389.1505.

Example 11

3-Phenyl-4-(4-(4-isopropylphenoxy)anicarboyl)-butanoic acid (11)

For the synthesis method, see Example 1, the difference is that the compound 1.2 used in the synthesis of compound 1.4 was replaced with p-isopropylphenol, and the product was a white solid with a yield of 45%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.08(s, 1H), 9.88(s, 1H), 7.51(d, 2H, J=8.4Hz), 7.29-7.28(m, 4H), 7.23 -7.18(m, 3H), 6.92(d, 2H, J=8.4Hz), 6.87(d, 2H, J=8.0Hz), 3.62-3.55(m, 1H), 2.90-2.81(m, 1H), 2.72-2.55 (m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.3, 169.6, 155.7, 152.5, 144.1, 143.5, 135.2, 128.7, 128.1, 127.9, 126.8, 121.2, 119.5, 118.3, 43.1, 38.7, 20.7.

Example 12

3-Phenyl-4-(4-(4-chlorobenzyloxy)anilinoyl)-butyric acid (12)

Synthesis of 4-(4-Chlorobenzyloxy)aniline (12.4)

Compound 12.1 (300mg, 2.0mmol) and compound 12.2 (411mg, 2.0mmol) were added to DMSO (2mL), and potassium carbonate (6mmol, 830mg) was added to react overnight at room temperature. After the reaction, extract with water and ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate to obtain the product 12.3 as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.26 (d, 2H, J=8.8 Hz), 7.37-7.11 (m, 4H), 7.12 (d, 2H, J=9.2 Hz).

Compound 12.3 (300 mg, 1.03 mmol) was dissolved in methanol (5 mL), and 2N aqueous potassium hydroxide solution was added to this solution, and the reaction was heated to reflux overnight. After the reaction, the reaction solution was extracted with water and ethyl acetate, the organic phase was separated, dried and concentrated to obtain compound 12.4, which was directly used in the next reaction without purification.

Synthesis of Compound 12

For the synthesis method, refer to the process of synthesizing compound 1 through compounds 1.4 and 1.6 in Example 1 (a specific step in Example 1 can be specified). The product is a white solid with a yield of 62%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.02(s, 1H), 9.69(s, 1H), 7.47-7.45(m, 4H), 7.41(d, 2H, 8.8Hz), 7.28(d , 4H, J=4.4Hz), 7.20-7.17(m, 1H), 6.91(d, 2H, J=8.8Hz), 3.61-3.31(m, 1H), 2.72-2.56(m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.3, 169.3, 154.4, 144.1, 136.7, 133.0, 132.8, 129.9, 128.9, 128.7, 127.9, 126.8, 121.1, 115.3, 68.9, 43.1, 38.7.

Example 13

3-Phenyl-4-(4-(2-fluorobenzyloxy)anilinoyl)-butyric acid (13)

For the synthesis method, refer to Example 12, except that the compound 12.2 used in the synthesis of compound 12.4 was replaced with o-fluorobenzyl bromide, and the product was a white solid with a yield of 54%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.02(s, 1H), 9.69(s, 1H), 7.51-7.47(m, 1H), 7.38-7.34(m, 3H), 7.24-7.11( m, 7H), 6.89 (d, 2H, J=8.8Hz), 5.03 (s, 2H), 3.56-3.48 (m, 1H), 2.67-2.49 (m, 4H).

¹³ C NMR (100MHz, DMSO-d ₆ ): δ173.4, 169.4, 162.0, 159.6, 154.4, 144.1, 133.1, 131.1, 131.8, 130.7, 128.7, 127.9, 126.8, 125.0, 124.9, 124.5, 124.1, 12 115.9, 115.7, 115.2, 64.14, 64.10, 43.2, 38.7.

HRMS (ESI) calcd for C ₂₃ H ₂₀ BrNO ₄ [MH] ⁺ 406.1455, found 406.1454.

Example 14

3-(4-Methoxyphenyl)-4-(4-(4-chlorophenoxy)anilinoyl)-butyric acid (14)

For the synthesis method, see Example 1, the difference is that the benzaldehyde used in the synthesis of compound 1.6 was replaced by p-methoxybenzaldehyde, and the product was a white solid with a yield of 61%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.03(1H), 9.90(1H), 7.55(d, 2H, J=8.8Hz), 7.39(d, 2H, J=8.8Hz), 7.20( d, 2H, J=8.4Hz), 6.99-6.95(m, 4H), 6.84(d, 2H, J=8.4Hz), 3.71(s, 3H), 3.57-3.50(m, 1H), 2.68-2.53 (m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.4, 168.8, 158.2, 156.9, 151.5, 135.94, 135.87, 130.2, 128.8, 127.0, 121.3, 119.8, 114.1, 55.4, 43.4, 40.9, 37.9.

Example 15

3-(4-methylphenyl)-4-(4-(4-chlorophenoxy)anilinoyl)-butyric acid (15)

For the synthesis method, see Example 1, the difference is that the benzaldehyde used in the synthesis of compound 1.6 was replaced by p-tolualdehyde, and the product was a white solid with a yield of 55%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.04(s, 1H), 9.91(s, 1H), 7.55(d, 2H, J=9.2Hz), 7.39(d, 2H, J=8.8Hz ), 7.17(d, 2H, J=8.0Hz), 7.08(d, 2H, J=8.0Hz), 6.97-6.95(m, 4H), 3.58-3.51(m, 1H), 2.69-2.53(m, 4H), 2.25(s, 3H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173, 4, 169.7, 156.9, 151.5, 141.0, 135.9, 135.8, 130.2, 129.3, 127.7, 127.0, 121.2, 120.1, 119.8, 43.2, 38.3, 21.1.

HRMS (ESI) calcd for _C24H23ClNO4 [M+H] ⁺ _424.1316 , _found 424.1315.

Example 16

3-(4-Chlorophenyl)-4-(4-(4-chlorophenoxy)anilinoyl)-butyric acid (16)

For the synthesis method, see Example 1, the difference is that the benzaldehyde used in the synthesis of compound 1.6 was replaced by p-chlorobenzaldehyde, and the product was a white solid with a yield of 54%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.12(s, 1H), 9.93(s, 1H), 7.54(d, 2H, J=8.8Hz), 7.39(d, 2H, J=8.4Hz ), 7.34-7.30 (m, 4H), 6.99-6.95 (m, 4H), 3.62-3.54 (m, 1H), 2.73-2.55 (m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.2, 169.5, 156.9, 151.6, 143.0, 135.8, 131.4, 130.2, 129.9, 128.6, 127.0, 121.3, 120.1, 119.8.

HRMS (ESI) _calcd for _C23H20Cl2NO4 [MH] ⁺ _444.0769 , _found 444.0771.

Example 17

3-(4-Hydroxyphenyl)-4-(4-(4-chlorophenoxy)anilinoyl)-butyric acid (17)

Compound 14 (500mg, 1.14mmol) was dissolved in dichloromethane (50mL) under ice-cooling, then a solution of boron tribromide in dichloromethane (6mL, 1.0M in CH ₂ Cl ₂ ) was added dropwise, and the temperature The reaction was carried out for 30 minutes after warming to room temperature. After the reaction, carefully add water to the reaction liquid to extract the reaction, remove dichloromethane, then extract with ethyl acetate, separate the organic phase and concentrate to dryness, column chromatography separation (ethyl acetate:petroleum ether=2:1 ) to obtain a white solid with a yield of 53%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.00(s, 1H), 9.87(s, 1H), 7.54(d, 2H, J=9.2Hz), 7.39(d, 2H, J=9.2Hz ), 7.07(d, 2H, J=8.8Hz), 6.98-6.95(s, 4H), 6.66(d, 2H, J=8.8Hz), 3.51-3.44(m, 1H), 2.65-2.50(m, 4H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ173.5, 169.9, 156.9, 156.2, 151.5, 135.9, 134.1, 130.2, 128.7, 121.3, 120.1, 119.8, 115.4, 43.5, 41.0, 40.0.

HRMS (ESI) calcd for C ₂₃ H ₁₉ ClNO ₅ [MH] ⁺ 424.0952, found 424.0952.

Example 18

2-Phenyl-3-(4-(3-chlorophenoxy)anilinoyl)propanesulfonamide (18)

N,N-bis(4-methoxybenzyl)methanesulfonamide (19.4)

Compound 18.1 (6.80 g, 50 mmol) and compound 18.2 (6.85 g, 50 mmol) were dissolved in ethanol (100 mL), and heated to reflux for 2 hours. After the reaction, the solvent in the reaction system was removed, and the obtained oil was dissolved in ethanol (100 mL), and sodium borohydride (2.8 g, 73.6 mmol) was added in portions under ice bath, and heated to reflux for 2 hours. After the reaction, the solvent was removed, and the obtained oil was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and the solvent was removed to obtain compound 18.3, which was directly used in the next step without purification.

Compound 18.3 (7.32g, 28.5mmol) was dissolved in dichloromethane (60mL), methanesulfonyl chloride (3.25g, 28.5mmol) was added under ice-cooling, and then heated to room temperature for 5 hours. After the reaction, extract with dichloromethane and water, separate the organic phase, dry over anhydrous sodium sulfate, concentrate and separate by column chromatography (ethyl acetate:petroleum ether=1:4) to obtain 6.03g of compound 18.4 as a white solid. The rate is 63%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.19(d, 4H, J=8.4Hz), 6.89(d, 4H, J=8.8Hz), 4.19(s, 4H), 3.74(s, 6H ), 2.89(s, 3H).

MS (EI) m/z: 335 [M] ⁺ .

Synthesis of compound 18.6

Compound 18.4 (2.01g, 15mmol) was placed in a 100mL cryogenic reaction flask and cooled to -20°C, LiHMDS solution in anhydrous tetrahydrofuran was added dropwise into the cryogenic reaction flask, the reaction solution was stirred for half an hour, and dichlorophosphoric acid was added Ethyl ester (2.60g, 15mmol). After one hour, benzaldehyde (1.59g, 15mmol) was added, and then the reaction solution was raised to room temperature and reacted for one hour. After the reaction, the reaction solution was extracted with water and ethyl acetate, and the organic phase was separated. , dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (ethyl acetate:petroleum ether=1:10) to obtain 4.87g of compound 18.6 as a white solid, with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.64-7.50(m, 5H), 7.38(d, 1H, J=15.8Hz), 7.24-7.18(m, 5H), 6.86(d, 4H, J=8.4Hz), 4.21(s, 4H), 3.71(s, 6H).

MS (EI) m/z: 423 [M] ⁺ .

Synthesis of compound 18.7

Compound 18.6 was dissolved in acetonitrile (20mL), then a solution of sodium methoxide (1.08g, 20mmol) in methanol (20mL) was added, and then dimethyl malonate (2.65g, 20mmol) was added, and the reaction solution was heated to reflux for two days. After the reaction, it was concentrated and extracted with water and ethyl acetate, separated in the organic phase, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (ethyl acetate:petroleum ether=1:5) to obtain 3.14g of compound 18.7 as white crystals. The rate is 57%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.31-7.23(m, 5H), 7.06(d, 4H, J=8.0Hz), 6.83(d, 4H, J=8.4Hz), 4.09(d , 2H, J=15.2Hz), 3.94(d, 1H, J=9.2Hz), 3.91(d, 2H, J=15.2Hz), 3.85-3.80(m, 1H), 3.72(s, 6H), 3.70 -3.63 (m, 4H), 3.46-3.42 (dd, 1H, J ₁ =2.8Hz, J ₂ =14.4Hz), 3.36 (s, 3H).

MS (ESI) m/z: 555 [M+H] ⁺ .

Compound 18.9 Synthesis

Compound 18.7 (360 mg, 0.65 mmol) was dissolved in DMF (2 mL), and two drops of water were added dropwise, then lithium chloride (196 mg, 3.25 mmol) was added, and the reaction was refluxed for 5 hours. After the reaction was completed, it was extracted with water and ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain an oily crude product (18.8). Compound 18.8 was dissolved in methanol (5 mL), then added with water (2 mL) of monowater and lithium hydroxide (137 mg, 3.25 mmol), and the reaction was stirred overnight at room temperature. After the reaction, extract with water and ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, concentrate and separate by column chromatography (ethyl acetate:petroleum ether=1:2) to obtain 255mg of white crystal compound 18.9, yield 81 %.

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.15(s, 1H), 7.32-7.20(m, 5H), 7.13(d, 4H, 8.8Hz), 6.85(d, 4H, 8.8Hz), 4.18(d, 2H, J=15.2Hz), 4.08(d, 2H, J=14.8), 3.73(s, 6H), 3.54-3.48(m, 2H), 3.28-3.23(dd, 1H, _J 4.8Hz, J ₂ =12.8Hz), 2.96-2.90 (dd, 1H, J ₁ =4.4Hz, J ₂ =16.0Hz), 2.64-2.58 (dd, 1H, J ₁ =9.2Hz, J ₂ =16.0Hz ).

Synthesis of Compound 18.10

Compound 18.9 (97mg, 0.20mmol) and the corresponding amine compound, namely 4-(4-chlorophenoxy)aniline were dissolved in DMF, and HBTU (92mg, 0.24mmol) and DIPEA (32mg, 0.24mmol) were added, React overnight at room temperature. After the reaction, extract with water and ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, concentrate and separate by column chromatography (ethyl acetate:petroleum ether=1:3) to obtain 107mg of white solid compound 18, yield 78 %.

¹ H NMR (400MHz, CDCl ₃ ): δ9.89(s, 1H), 7.51(d, 2H, J=8.8Hz), 7.38(d, 2H, J=8.8Hz), 7.31-7.21(m, 5H ), 7.13(d, 4H, J=8.8Hz), 6.96(d, 2H, J=9.2Hz), 6.95(d, 2H, J=8.8Hz), 6.84(d, 2H, J=8.8Hz), 4.19(d, 2H, J=15.2Hz), 4.07(d, 2H, J=15.2), 3.74-3.69(m, 7H), 3.55(dd, 1H, J ₁ =6.8Hz, J ₂ =14.4Hz) , 3.53-3.35 (m, 1H), 2.93 (dd, 1H, J ₁ =5.6Hz, J ₂ =15.2Hz), 2.71 (dd, 1H, J ₁ =9.2Hz, J ₂ =14.8Hz).

¹³ C NMR (100MHz, DMSO-d ₆ ): δ169.1, 159.1, 156.9, 151.6, 142.6, 135.7, 130.3, 130.2, 128.7, 128.5, 128.2, 127.2, 127.1, 121.3, 120.1, 119.8, 114.2, 57. 55.5, 49.8, 42.6, 37.7.

Synthesis of Compound 18

Compound 18.10 (50 mg, 0.073 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 3 hours. After the reaction, the solvent was removed, extracted with water and ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (dichloromethane:methanol=50:1) to obtain 21 mg of compound 18 as a white solid. The rate is 65%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.89(s, 1H), 7.50(d, 2H, J=8.8Hz), 7.38(d, 2H, J=8.8Hz), 7.33-7.27(m , 3H), 7.21-7.18(m, 2H), 6.96(d, 2H, J=9.2Hz), 6.95(d, 2H, J=9.2Hz), 6.86(s, 2H), 3.78-3.71(m, 1H), 3.54-3.49(dd, 1H, J ₁ =7.2Hz, J ₂ =14.4Hz), 3.31-3.26(dd, 1H, J ₁ =6.0Hz, J ₂ =14.4Hz), 3.02-2.97(dd , 1H, J ₁ =5.6Hz, J ₂ =14.8Hz), 2.76-2.70 (dd, 1H, J ₁ =7.2Hz, J ₂ =14.8Hz).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ169.3, 156.9, 151.6, 143.3, 135.8, 130.2, 128.7, 127.1, 121.3, 120.1, 119.8, 60.1, 42.5, 37.9.

HRMS (ESI) calcd _{for C22H21ClN2O4S} [M+Na] ⁺ _467.0808 , _found 467.0806.

Example 19

2-Phenyl-3-(4-(3,4-dichlorophenoxy)anicarboyl)propanesulfonamide (19)

For the synthesis method, see Example 18, the difference is that the 4-(4-chlorophenoxy)aniline used in the synthesis of compound 18.10 is replaced by 4-(3,4-dichlorophenoxy)aniline to obtain the product As a white solid, the yield is 29%.

¹ H NMR (400MHz, CDCl ₃ ): δ9.92(s, 1H), 7.58(d, 1H, J=9.2Hz), 7.53(d, 2H, J=9.2Hz), 7.33-7.27(m, 4H ), 7.21-7.19(m, 2H), 7.01(d, 2H, J=9.2Hz), 6.94-6.91(dd, 1H, J ₁ =5.2Hz, J ₂ =9.2Hz), 6.85(s, 2H) , 3.78-3.71(m, 1H), 3.54-3.49(dd, 1H, J ₁ =7.6Hz, J ₂ =15.2Hz), 3.31-3.26(dd, 1H, J ₁ =6.0Hz, J ₂ =14.0Hz ), 3.03-2.97 (dd, 1H, J ₁ =5.6 Hz, J ₂ =15.2 Hz).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ169.3, 157.6, 150.9, 143.3, 136.3, 132.4, 131.9, 128.7, 128.0, 127.1, 125.2, 121.3, 120.5, 119.8, 118.3, 60.1, 42.5, 37.9.

HRMS (ESI) calcd for C ₂₂ H ₂₀ Cl ₂ N ₂ O ₄ S [M+Na] ⁺ 501.0419, found 501.0421.

Example 20

2-(4-methoxyphenyl)-3-(4-(3,4-dichlorophenoxy)anicarboyl)propanesulfonamide (20)

For the synthetic method, see Example 18, the difference is that the benzaldehyde used in the process of synthesizing compound 18.6 is replaced by p-methoxybenzaldehyde; the 4-(4-chlorophenoxy)aniline used in the process of synthesizing compound 18.10 Substituting 4-(3,4-dichlorophenoxy)aniline, the product was obtained as a white solid with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ): δ9.91(s, 1H), 7.58(d, 1H, J=8.8Hz), 7.54(d, 2H, J=9.2Hz), 7.23(d, 2H, 8.8 Hz), 7.20(d, 1H, J=2.8Hz), 7.02(d2H, J=8.8Hz), 6.94-6.91(dd, 1H, J ₁ =2.8Hz, J ₂ =8.8Hz), 6.85(d, 2H, J=8.8Hz), 6.82(s, 2H), 3.71-3.66(m, 4H), 3.51-3.46(dd, 1H, J ₁ =3.46Hz, J ₂ =14.4Hz), 3.27-3.22(dd , 1H, J ₁ =5.2Hz, J ₂ =14.8Hz), 2.73-2.66 (dd, 1H, J ₁ =9.2Hz, J ₂ =14.8Hz).

HRMS (ESI) calcd for _C23H20BrNO4 [M+Na] ⁺ 531.0524, _{found 531.0522} .

Effects of compounds provided by the invention on farnesyltransferase inhibitory activity in vitro:

1. Induced expression of FTase

1.1 Pre-cultivation

Take 30 μl of preserved pRSFDuet-FNTαβ-BL21 (this strain comes from Professor Gerrit J.K.Praefcke) bacteria solution and inoculate it into 5 mL of kanamycin-resistant LB medium, the final concentration of kanamycin is 50 μg/mL, 37°C, 230rpm shaker Incubate overnight.

1.2 Expansion of cultivation

Inoculate 3.0 mL of overnight cultured bacterial solution into 500 mL of sterilized LB medium, add kanamycin at a final concentration of 50 μg/mL, and incubate on a shaking table at 37°C and 230 rpm.

1.3 Induced expression

When cultured at a constant temperature until OD600 was 0.6, the inducer IPTG was added to a final concentration of 0.5 mM, and ZnCl ₂ was added to a final concentration of 0.5 mM, and induced for 16 hours at 16° C. and 230 rpm.

1.4 Collect bacteria

Centrifuge the bacterial solution at 4000rpm for 20min at 4°C, discard the supernatant medium, resuspend the bacteria with sterile water, centrifuge again at 10,000rpm for 10min, discard the supernatant, and store the bacterial pellet at -80°C.

2. Purification of FTase

2.1 Ultrasonic crushing

Suspend the cells with 20mL lysis buffer (50mM Tris, 200mM NaCl, 50μM ZnCl ₂ , 5mM MgCl ₂ , 1mM β-mercaptoethanol, 20mM imidazole, pH 7.7), and ultrasonicate five times on an ice bath (300W, working 5 seconds, 10 seconds apart, 30 jobs). The cell homogenate obtained after crushing was centrifuged at 10,000 rpm for 30 min at 4°C, and the supernatant was to be combined with the resin.

2.2 Protein purification

Ni-NTA chromatography column pretreatment: after letting go of ethanol, wash with water 3-4 times, combine with NiSO ₄ for 20min, wash with water 3-4 times, and equilibrate with elution buffer.

Combine the protein supernatant in the previous step with the pretreated Ni column resin for 4h, reload it into the chromatography column, and wash it with 80mL of elution buffer (50mM trishydroxymethylaminomethane Buffer, 200mM NaCl, 50μM ZnCl ₂ , 5mM MgCl ₂ , 1mM β-mercaptoethanol, 20mM imidazole, pH 7.7) flow through the chromatography column four times, try to wash off the impurities, and then add about 10ml of elution buffer solution (50mM Tris buffer, 200mM NaCl, 50μM ZnCl ₂ , 5mM MgCl ₂ , 1mM β-mercaptoethanol, 200mM imidazole, pH 7.7), make it flow out slowly, control the flow rate for about 10 seconds per drop, divide into tubes collect. Put the protein into MD34-14 dialysis bag, and use dialysis buffer (50mM Tris buffer, 200mM NaCl, 50μM ZnCl ₂ , 5mM MgCl ₂ , 1mM β-mercaptoethanol, pH7.7) was dialyzed twice, each time for 4-5 hours, and then concentrated to about 1ml with a microporous concentrator tube. The protein was temporarily stored at 4°C for SDS-PAGE to detect protein molecular weight and purity. After sampling, add 20% glycerol and store at -80°C.

2.3 SDS-PAGE electrophoresis to detect protein concentration and purity

Take 10 μl of each collected sample, add an equal amount of loading buffer, cook in a sample cooker at 100°C for ten minutes, and centrifuge at 4000rpm for 2min. Prepare the SDS-PAGE gel according to the gel preparation method in the experimental method, install the electrophoresis system, add the electrophoresis buffer, select the sample volume according to the gel hole, generally 10 μl, connect the electrodes, and perform electrophoresis at 90V, bromine After the phenol blue enters the separation gel, change the voltage to 120V. When the bromophenol blue just runs out of the separation gel, stop the electrophoresis. Remove the rubber plate, put the peeling gel into the staining solution for 2-3 hours, add the decolorization solution, and place it on a decolorization shaker at 80rpm for decolorization. After it was completely removed, the experimental results were recorded with a gel imaging system, and the purity was 75.4%.

2.4 Determination of protein concentration by Bradford method

Using the Bradford method for measuring protein concentration, first draw a standard curve and make two parallel sets.

After shaking and mixing, place it at room temperature for 5-10 minutes, draw the standard curve with the protein content as the abscissa and the absorbance value (A595) as the ordinate.

Dilute the concentrated protein 20 times, take 2 μl, add 198 μl staining solution, and read the absorbance value.

The measured protein concentration was 35mg/ml, 1ml in total.

3. Farnesyltransferase Activity Assay

The determination method of farnesyltransferase activity is mainly carried out according to the method of David L. Pompliano. The substrate N-dansyl-GCVLS (a modified polypeptide, GCVLS represents the amino acid sequence) was dissolved in DMSO to 1 mM, and farnesyl pyrophosphate (FPP) was buffered with detection buffer (50 mM Tris-buffered solution, 20μM ZnCl ₂ , 10mM MgCl ₂ , 5mM dithiothreitol, 0.02% glucopyranoside, pH7.5) diluted to 10μM. Farnesyltransferase was diluted with dialysis buffer into different concentration gradients (25μM, 20μM, 10μM, 5μM, 2.5μM).

According to the reaction system in Table 1, a BioTek-Synergy2 microplate reader was used to perform the enzyme activity test experiment. The total reaction system is 50 μl. First, the detection buffer is added to the wells of a 384-well plate, then N-dansyl-GCVLS (a modified polypeptide, GCVLS represents the amino acid sequence) and enzymes of different concentrations are added, and finally Farnese is added. base pyrophosphate to initiate the reaction. After the reaction started, the change of the fluorescence absorption intensity was detected every 30 seconds at excitation 340nm and emission 505nm, and the whole reaction process was detected for 10 minutes. Obtain the fluorescence curve with time, and then determine the optimal enzyme activity conditions.

Table 1 Farnesyl transferase (Ftase) activity assay system

test buffer N-dansyl-GCVLS (1mM) Farnesyl pyrophosphate (10 μM) farnesyltransferase 44.4μl 0.1μl 5μl 0.5μl

4. Screening of Farnesyltransferase Inhibitors (FTT)

4.1 Positive IC ₅₀ of Tipifarnib

The positive compound was dissolved in DMSO into a 5 mM stock solution, and then diluted into a concentration gradient (50 μM, 25 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.5 μM, 0.1 μM, 0.05 μM). Calculate the required amount of buffer, N-dansyl-GCVLS and farnesyltransferase (final concentration 0.2μM) according to the number of wells to be added, pre-mix, add to the 384-well plate with a row gun, and then add separately 0.1 μl of positive tipirfarnib with concentration gradient was incubated at room temperature for 10 minutes, and the substrate farnesyl pyrophosphate was added for reading. Three parallel experiments were set up for each experiment, and DMSO was used as a blank to obtain the IC ₅₀ map of tipifarnib (Fig. 1).

4.2 Primary Screening

After the enzyme activity test, select the appropriate enzyme concentration (0.2μM) for inhibitor screening. The compound was diluted with DMSO, and the initial screening was performed at 10 μM, and tipifarnib was used as a positive control. The reaction system is shown in Table 2:

Table 2 Compound screening system

test buffer N-dansyl-GCVLS (1mM) Compound (10 μM) FTase FPP (10μM) 44.2μl 0.1μl 0.2μl 0.5μl 5μl

5 Experimental results

As shown in Table 3 below from the experimental results, it can be seen that the enzyme inhibitory activity when the group x is a carboxyl group is the best, followed by sulfonamide, and amide is the weakest; when _R is a small hydrophobic group and y is 0, the enzyme inhibitory activity The inhibitory activity is better, indicating that this part occupies the hydrophobic active pocket of the enzyme, and the space is small; R ₁ should be a small hydrophilic group, such as hydroxyl or amino.

Table 3 IC ₅₀ of compounds 1-20 against FTase

Claims (6)

1. an amino benzenes compounds, it is compound shown in formula I or its acceptable salt on pharmacology:

Wherein, X is COOH or SO ₂nH ₂; R ₁and R ₂independently be selected from: H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂or NO ₂middle one; M and n is respectively the integer of 0 ~ 5; Y is 0 or 1;

But do not comprise following compounds:

2. amino benzenes compounds as claimed in claim 1, it is characterized in that, described aminated compounds is one of following compounds or its acceptable salt on pharmacology:

3. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises the amino benzenes compounds described in claim 1 or 2.

4. the application of amino benzenes compounds in the medicine preparing prevention or treatment and farnesyl transferase relative disease;

Wherein, described for amino benzenes compounds be compound shown in formula I or its acceptable salt on pharmacology:

Wherein, X is COOH or SO ₂nH ₂; R ₁and R ₂independently be selected from: H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂or NO ₂middle one; M and n is respectively the integer of 0 ~ 5; Y is 0 or 1.

5. the application of pharmaceutical composition in the medicine preparing prevention or treatment and farnesyl transferase relative disease;

Wherein, compound shown in described pharmaceutical composition contained I or its acceptable salt on pharmacology:

Wherein, X is COOH or SO ₂nH ₂; R ₁and R ₂independently be selected from: H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂or NO ₂middle one; M and n is respectively the integer of 0 ~ 5; Y is 0 or 1.

6. the application as described in claim 4 or 5, wherein said is prostate cancer, lung cancer, mammary cancer, carcinoma of the pancreas or colorectal carcinoma with farnesyl transferase relative disease.