Compounds for use as therapeutic agents affecting P53 expression and/or activity

Abstract

The present disclosure relates to compound (I) ##STR00001##
wherein R1 and R2 independently represent a hydrogen atom, a (C.sub.1-C.sub.4)alkoxy group, a fluoro(C.sub.1-C.sub.4)alkoxy group, a hydroxyl group, a benzyloxy group, a di(C.sub.1-C.sub.4)alkylamino group, a pyridyl-vinyl group, a pyrimidinyl-vinyl group, a styryl group, or a NHCOphenyl group; R3, R4 and R5 independently represent a hydrogen atom, a (C.sub.1-C.sub.4)alkyl group, a CONHR6 group, a CONR7R8 group, a SO.sub.2NHR6 group, or a heteroaryl group optionally substituted by a halogen atom, a (CH.sub.2).sub.nNR7R8 group or a hydroxy(C.sub.1-C.sub.4)alkyl group; R6 represents a hydrogen atom, a (CHR9).sub.m(CH.sub.2).sub.nNR7R8 group or a (C.sub.1-C.sub.6)alkyl group optionally substituted by a hydroxyl group; or anyone of its pharmaceutically acceptable salt, for use in a method for preventing, inhibiting or treating a disease in a patient suffering thereof, said disease involving a deregulated p53. Some of said compounds are new and also form part of the disclosure.

Claims

1. A compound selected from the group consisting of: ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 selected from the group consisting of the compounds (9), (16), (17), (18), (19), (21), (24), (25), (50), and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 selected from the group consisting of the compounds (9), (16), (17), (18), (19), (21), (24), (25), and pharmaceutically acceptable salts thereof.

4. The compound according to claim 1 selected from the group consisting of the compound (50), and pharmaceutically acceptable salts thereof.

5. The compound according to claim 1 selected from the group consisting of the compounds (9), (16), (17), (18), (19), (20), (21), (23), (24), (25), (127), and pharmaceutically acceptable salts thereof.

6. The compound according to claim 1 selected from the group consisting of the compounds (130), (132), (133), (134), (135), and pharmaceutically acceptable salts thereof.

7. The compound according to claim 1 selected from the group consisting of the compounds (37), (38), (39), and pharmaceutically acceptable salts thereof.

8. The compound according to claim 1 selected from the group consisting of the compounds (48), (50), (52), and pharmaceutically acceptable salts thereof.

9. The compound according to claim 1 selected from the group consisting of the compounds (83), (84), (86), (87), (89), (90), (91), and pharmaceutically acceptable salts thereof.

10. The compound according to claim 1 selected from the group consisting of the compounds (123), (124), (125) (126), (138), (139), (140), and pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising at least one compound according to claim 1, or any pharmaceutically acceptable salt thereof.

Description

LEGENDS OF FIGURES

(1) FIG. 1. Effect of drugs (40), (1) and (45) on p53 pathway in MCF7 cell lines. (A) Analysis of p53 (total iso forms, blue panel) and its target gene, 133p53 (133 forms, purple panel), at mRNA level by RT-qPCR (B) Analysis of p53 expression at protein level using 4 different antibodies. (C) Quantification of western blot (B) by densitometry using ImageJ software. (D) Analysis of p53-target genes expression by western blot. (E) Quantification of western blot (D) by densitometry using ImageJ software.

(2) FIG. 2. Effect of drugs (40), (1) and (45) on p53 pathway in MDA-MB-231-Luc-D3H2N cell lines maintained in normal medium. (A) Analysis of p53 (TA forms, blue panel) and its target gene, 133p53 (133 forms, purple panel), at mRNA level by RT-qPCR (B) Analysis of p53 expression at protein level using 4 different antibodies. (C) Quantification of western blot (B) by densitometry using ImageJ software. (D) Analysis of p53-target genes expression by western blot. (E) Quantification of western blot (D) by densitometry using ImageJ software.

(3) FIG. 3. Effect of drugs (40), (1) and (45) on p53 pathway in MDA-MB-231-Luc-D3H2N cell lines maintained in FCS-free medium. (A) Analysis of p53 (TA forms, blue panel) and its target gene, 133p53 (133 forms, purple panel), at mRNA level by RT-qPCR (B) Analysis of p53 expression at protein level using 4 different antibodies. (C) Quantification of western blot (B) by densitometry using ImageJ software. (D) Analysis of p53-target genes expression by western blot. (E) Quantification of western blot (D) by densitometry using ImageJ software.

(4) FIG. 4. Effect of drugs (40), (1) and (45) on p53 isoforms expression in MCF7 (A), MDA-MB-231-Luc-D3H2N cell lines maintained in normal medium (B) or in FCS-free medium (D). Analysis of C-terminal p53 isofroms produced by alternative splicing (a, b and g forms) at mRNA level by RT-qPCR (left panel). An example of restoration of p53g-forms expression is shown by nested RT-PCR (right panel).

(5) The following example illustrates in detail the preparation of compounds (2), (1), (18), (9), (21), (127), (26), (40), (39), (45), (48), (49), (50), (52), (65) and (116)) according to the invention and the pharmacological data.

EXAMPLES

Example 1: Compound (2) in Table I

(6) According to route (B), 4-vinylpyridine (5.9 mL, 55 mmoles, 1.1 eq.) was placed in dimethylformamide (50 mL) with 1-bromo-3-nitrobenzene (10.1 g, 50 mmoles, 1 eq.), NaOAc (8.2 g, 100 mmoles, 2 eq.), Pd(OAc).sub.2 (561 mg, 2.5 mmoles, 5 mol %), PPh.sub.3 (1.5 g, 6.0 mmoles, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (6.0 g, 53%).

(7) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.63 (d, J=6.1 Hz, 2H), 8.41 (s, 1H), 8.17 (dd, J=8.2, 2.1 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.40 (d, J=6.1 Hz, 2H), 7.34 (d, J=16.4 Hz, 1H), 7.16 (d, J=16.4 Hz, 1H).

(8) According to route (C), (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (3.0 g, 13.3 mmoles, 1 eq.) and tin (II) chloride dihydrate (15.0 g, 66.5 mmoles, 5 eq.) were placed in EtOH (130 mL). The reaction mixture was heated at 60 C. and stirred for 16 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-4-ylvinyl)phenylamine (1.9 g, 73%).

(9) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.57 (d, J=6.3 Hz, 2H), 7.35 (d, J=6.3 Hz, 2H), 7.26-7.15 (m, 2H), 7.01-6.93 (m, 2H), 6.87 (s, 1H), 6.67 (dd, J=7.9, 2.3 Hz, 1H), 3.74 (br s, 2H).

(10) N,N-diethylpropylenediamine (7 mL, 44 mmoles, 1.1 eq.) was placed in a 3N NaOH aqueous solution (56 mL) and dichloromethane (24 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of 3-bromobenzoyl chloride (5.3 mL, 40 mmoles, 1 eq.) in dichloromethane (40 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-bromo-N-(3-diethylamino-propyl)benzamide (12.5 g, 99%).

(11) .sup.1H NMR (300 MHz, CDCl.sub.3) 9.11 (br s, 1H), 7.90 (t, J=1.9 Hz, 1H), 7.72 (dt, J=7.9, 1.2 Hz, 1H), 7.56 (ddd, J=7.9, 1.9, 1.0 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 3.53 (dt, J=5.7, 4.6 Hz, 2H), 2.64-2.51 (m, 6H), 1.73 (quint, J=5.7 Hz, 2H), 1.02 (t, J=7.2 Hz, 6H).

(12) According to route (A1), a reaction mixture of 3-bromo-N-(3-diethylamino-propyl)benzamide (1.4 g, 4.6 mmoles, 1 eq.), (E)-3-(2-pyridin-4-ylvinyl)phenylamine (1 g, 5.1 mmoles, 1.1 eq.), Pd.sub.2(dba).sub.3 (211 mg, 0.23 mmole, 5 mol %), XPhos (219 mg, 0.46 mmole, 10 mol %) and K.sub.2CO.sub.3 (2.6 g, 18.4 mmoles, 4 eq.) in t-BuOH (6.3 mL) was heated at 80 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on alumina to give (E)-N-(3-diethylamino-propyl)-3-[3-(2-pyridin-4-ylvinyl)phenylamino]benzamide (2) (1.15 g, 58%).

(13) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.70 (s, 1H), 8.51 (d, J=4.9 Hz, 2H), 7.61 (s, 1H), 7.30-7.14 (m, 8H), 7.08-7.00 (m, 2H), 6.89 (d, J=16.4 Hz, 1H), 6.58 (s, 1H), 3.52-3.48 (m, 2H), 2.59-2.40 (m, 6H), 1.69-1.65 (m, 2H), 0.95 (t, J=7.1 Hz, 6H).

(14) .sup.13C NMR (75 MHz, CDCl.sub.3) 167.1, 150.3, 144.7, 143.6, 143.5, 137.6, 136.5, 133.3, 130.0, 129.4, 126.3, 121.1, 120.3, 120.2, 119.1, 118.8, 117.1, 116.9, 53.4, 46.9, 41.4, 25.0, 11.6.

(15) [M+H].sup.+=429.2

Example 2: Compound (1) in Table I

(16) According to route (B), 4-vinylpyridine (2.35 mL, 22 mmoles, 1.1 eq.) was placed in dimethylformamide (20 mL) with 1-bromo-3-nitrobenzene (4 g, 20 mmoles, 1 eq.), NaOAc (3.3 g, 40 mmoles, 2 eq.), Pd(OAc).sub.2 (225 mg, 1 mmole, 5 mol %), PPh.sub.3 (629 mg, 2.4 mmoles, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the organic phase was further washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (2.9 g, 65%).

(17) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.64 (d, J=4.8 Hz, 2H), 8.41 (s, 1H), 8.17 (dd, J=8.2, 1.1 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.40 (d, J=5.7 Hz, 2H), 7.34 (d, J=16.4 Hz, 1H), 7.16 (d, J=16.4 Hz, 1H).

(18) According to route (C), (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (910 mg, 4 mmoles, 1 eq.) and tin (II) chloride dihydrate (4.5 g, 20 mmoles, 5 eq.) were placed in EtOH (40 mL). The reaction mixture was heated at 60 C. and stirred for 16 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-4-ylvinyl)phenylamine (763 mg, 97%).

(19) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.57 (d, J=5.9 Hz, 2H), 7.35 (d, J=5.9 Hz, 2H), 7.26-7.14 (m, 2H), 7.01-6.92 (m, 2H), 6.87 (s, 1H), 6.67 (dd, J=7.9, 1.4 Hz, 1H), 3.74 (br s, 2H).

(20) 3-methyl-1-butanamine (2.5 mL, 22 mmoles, 1.1 eq.) was placed in a 3N NaOH aqueous solution (15 mL) and dichloromethane (5 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of 3-bromobenzoyl chloride (2.6 mL, 20 mmoles, 1 eq.) in dichloromethane (5 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-bromo-N-(3-methylbutyl)benzamide (5.4 g, 100%).

(21) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.89 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.24 (br s, 1H), 3.45 (q, J=7.0 Hz, 2H), 1.66 (heptuplet, J=6.6 Hz, 1H), 1.50 (q, J=7.0 Hz, 2H), 0.94 (d, J=6.6 Hz, 6H).

(22) According to route (A1), a reaction mixture of 3-bromo-N-(3-methylbutyl)benzamide (373 mg, 1.38 mmole, 1 eq.), (E)-3-(2-pyridin-4-ylvinyl)phenylamine (300 mg, 1.53 mmole, 1.1 eq.), Pd.sub.2(dba).sub.3 (63 mg, 69 moles, 5 mol %), XPhos (66 mg, 138 moles, 10 mol %) and K.sub.2CO.sub.3 (763 mg, 5.52 mmoles, 4 eq.) in t-BuOH (1.7 mL) was heated at 90 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-N-(3-methylbutyl)-3-[3-(2-pyridin-4-ylvinyl)phenylamino]benzamide (1) (333 mg, 63%).

(23) .sup.1H NMR (300 MHz, DMSO-d6) 8.52 (d, J=5.7 Hz, 2H), 8.39 (s, 1H), 8.35-8.30 (m, 1H), 7.55 (d, J=6.0 Hz, 2H), 7.50 (d, J=16.7 Hz, 1H), 7.32-7.27 (m, 5H), 7.20 (d, J=7.6 Hz, 2H), 7.15 (d, J=11.4 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 3.22 (q, J=6.9 Hz, 2H), 1.58 (heptuplet, J=6.6 Hz, 1H), 1.37 (q, J=6.9 Hz, 2H), 0.87 (d, J=6.6 Hz, 6H).

(24) .sup.13C NMR (75 MHz, DMSO-d6) 166.3, 150.0, 143.6, 143.4, 137.2, 136.1, 133.3, 129.7, 129.1, 125.8, 120.9, 119.0, 118.8, 118.2, 117.5, 115.8, 115.6, 38.1, 37.4, 25.3, 22.5.

(25) [M+H].sup.+=386.2

Example 3: Compound (18) in Table I

(26) According to route (B), 4-vinylpyridine (6.4 mL, 59.9 mmoles, 1.1 eq.) was placed in dimethylformamide (55 mL) with 1-bromo-3-nitrobenzene (11 g, 54.4 mmoles, 1 eq.), NaOAc (9 g, 108.8 mmoles, 2 eq.), Pd(OAc).sub.2 (610 mg, 2.7 mmoles, 5 mol %), PPh.sub.3 (1.4 g, 5.4 mmoles, 10 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the organic phase was further washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (7.9 g, 64%).

(27) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.61 (d, J=5.0 Hz, 2H), 8.38 (s, 1H), 8.15 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.38 (d, J=5.0 Hz, 2H), 7.32 (d, J=16.4 Hz, 1H), 7.14 (d, J=16.4 Hz, 1H).

(28) According to route (C), (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (7.9 g, 35 mmoles, 1 eq.) and tin (II) chloride dihydrate (39 g, 175 mmoles, 5 eq.) were placed in EtOH (350 mL). The reaction mixture was heated at 60 C. and stirred for 48 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-4-ylvinyl)phenylamine (5.2 g, 76%).

(29) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.57 (d, J=6.3 Hz, 2H), 7.35 (d, J=6.3 Hz, 2H), 7.30-7.16 (m, 2H), 7.03-6.91 (m, 2H), 6.86 (s, 1H), 6.72-6.60 (m, 1H), 3.74 (br s, 2H).

(30) 3-bromobenzenesulfonyl chloride (0.56 mL, 3.9 mmoles, 1 eq.) and N,N-diisopropylethylamine (1.02 mL, 5.9 mmoles, 1.5 eq.) were placed in anhydrous dichloromethane (20 mL). The reaction mixture was cooled down to 0 C. with an ice bath and N,N-diethylpropylenediamine (1.23 mL, 7.8 mmoles, 2 eq.) was added dropwise. The reaction mixture was then stirred at 0 C. for 2 hours under an inert atmosphere of argon. The mixture was washed with saturated aqueous solutions of NH.sub.4Cl and then NaCl. The aqueous phases were extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-bromo-N-(3-diethylaminopropyl)benzenesulfonamide (524 mg, 38%).

(31) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.98 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 3.12-2.96 (m, 2H), 2.67-2.43 (m, 6H), 1.77-1.58 (m, 2H), 1.06 (t, J=7.1 Hz, 6H).

(32) According to route (A1), a reaction mixture of 3-bromo-N-(3-diethylaminopropyl)benzenesulfonamide (175 mg, 0.50 mmole, 1 eq.), (E)-3-(2-pyridin-4-ylvinyl)phenylamine (108 mg, 0.55 mmole, 1.1 eq.), Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmole, 5 mol %), XPhos (24 mg, 0.05 mmole, 10 mol %) and K.sub.2CO.sub.3 (276 mg, 2 mmoles, 4 eq.) in t-BuOH (2 mL) was heated at 90 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(3-diethylaminopropyl)-3-[3-(2-pyridin-4-ylvinyl)phenylamino]benzenesulfonamide (18) (100 mg, 43%).

(33) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.55 (d, J=5.8 Hz, 2H), 7.58 (s, 1H), 7.39-7.32 (m, 4H), 7.31-7.19 (m, 4H), 7.15 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.98 (d, J=16.3 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 3.15-3.00 (m, 2H), 2.52-2.35 (m, 6H), 1.68-1.53 (m, 2H), 0.96 (t, J=7.1 Hz, 6H).

(34) [M+H].sup.+=465.2

Example 4: Compound (9) in Table I

(35) According to route (B), 4-vinylpyridine (5.9 mL, 55 mmoles, 1.1 eq.) was placed in dimethylformamide (50 mL) with 1-bromo-3-nitrobenzene (10.1 g, 50 mmoles, 1 eq.), NaOAc (8.2 g, 100 mmoles, 2 eq.), Pd(OAc).sub.2 (561 mg, 2.5 mmoles, 5 mol %), PPh.sub.3 (1.5 g, 6.0 mmoles, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (6.0 g, 53%).

(36) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.63 (d, J=6.1 Hz, 2H), 8.41 (s, 1H), 8.17 (dd, J=8.2, 2.1 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.40 (d, J=6.1 Hz, 2H), 7.34 (d, J=16.4 Hz, 1H), 7.16 (d, J=16.4 Hz, 1H).

(37) According to route (C), (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (3.0 g, 13.3 mmoles, 1 eq.) and tin (II) chloride dihydrate (15.0 g, 66.5 mmoles, 5 eq.) were placed in EtOH (130 mL). The reaction mixture was heated at 60 C. and stirred for 16 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-4-ylvinyl)phenylamine (1.9 g, 73%).

(38) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.57 (d, J=6.3 Hz, 2H), 7.35 (d, J=6.3 Hz, 2H), 7.26-7.15 (m, 2H), 7.01-6.93 (m, 2H), 6.87 (s, 1H), 6.67 (dd, J=7.9, 2.3 Hz, 1H), 3.74 (br s, 2H).

(39) NH4OH solution (5.8 mL) was placed in water (24 mL) at 10 C. 3-bromobenzoyl chloride (10 mmol, 1.3 mL) was placed in tetrahydrofurane (8 mL) and added to the aqueous solution. The mixture was stirred for 1 hour at 10 C. The reaction mixture was filtered and further washed with water to give 3-beomo-benzamide (1.7 g, 85%).

(40) .sup.1H NMR (300 MHz, MeOD) 8.04 (s, 1H), 7.84 (d, J=7.0 Hz, 1H), 7.70 (d, J=6.6 Hz, 1H), 7.40-7.38 (t, J=6.8 Hz, 1H).

(41) According to route (A1), a reaction mixture of 3-bromo-benzamide (99 mg, 0.5 mmoles, 1 eq.), (E)-3-(2-pyridin-4-ylvinyl)phenylamine (108 mg, 0.55 mmoles, 1.1 eq.), Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmole, 5 mol %), XPhos (143 mg, 0.05 mmole, 10 mol %) and K.sub.2CO.sub.3 (276 mg, 2.0 mmoles, 4 eq.) in t-BuOH (2.0 mL) was heated at 90 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-[3-(2-pyridin-4-ylvinyl)phenylamino]benzamide (9) (100 mg, 63%).

(42) .sup.1H NMR (300 MHz, MeOD) 8.46 (d, J=6.2 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=6.1 Hz, 1H), 7.46 (d, J=16.1 Hz, 1H), 7.38-7.30 (m, 2H), 7.28 (d, J=8.1 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.16-7.07 (m, 1H).

(43) [M+H].sup.+=314.0

Example 5: Compound (21) in Table I

(44) According to route (B), 4-vinylpyridine (5.9 mL, 55 mmoles, 1.1 eq.) was placed in dimethylformamide (50 mL) with 1-bromo-3-nitrobenzene (10.1 g, 50 mmoles, 1 eq.), NaOAc (8.2 g, 100 mmoles, 2 eq.), Pd(OAc).sub.2 (561 mg, 2.5 mmoles, 5 mol %), PPh.sub.3 (1.5 g, 6.0 mmoles, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (6.0 g, 53%).

(45) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.63 (d, J=6.1 Hz, 2H), 8.41 (s, 1H), 8.17 (dd, J=8.2, 2.1 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.40 (d, J=6.1 Hz, 2H), 7.34 (d, J=16.4 Hz, 1H), 7.16 (d, J=16.4 Hz, 1H).

(46) According to route (C), (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (3.0 g, 13.3 mmoles, 1 eq.) and tin (II) chloride dihydrate (15.0 g, 66.5 mmoles, 5 eq.) were placed in EtOH (130 mL). The reaction mixture was heated at 60 C. and stirred for 16 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-4-ylvinyl)phenylamine (1.9 g, 73%).

(47) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.57 (d, J=6.3 Hz, 2H), 7.35 (d, J=6.3 Hz, 2H), 7.26-7.15 (m, 2H), 7.01-6.93 (m, 2H), 6.87 (s, 1H), 6.67 (dd, J=7.9, 2.3 Hz, 1H), 3.74 (br s, 2H).

(48) 3-(4-methyl-piperazinyl)-propylamine (1.9 mL, 11 mmoles, 1.1 eq.) was placed in a 3N NaOH aqueous solution (14 mL) and dichloromethane (2 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of 3-bromobenzoyl chloride (1.9 mL, 10 mmoles, 1 eq.) in dichloromethane (14 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-bromo-N-[3-(4-methyl-piperazinyl)]-propylamine (2.8 g, 85%).

(49) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.59 (s, 1H), 7.90 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.28 (t, J=8.2 Hz, 1H), 3.54 (d, J=4.7 Hz, 2H), 2.63-2.50 (m, 4H), 2.46 (broad s, 4H), 2.30 (s, 5H), 1.89-1.54 (m, 2H).

(50) According to route (A1), a reaction mixture of 3-bromo-N-[3-(4-methyl-piperazinyl)]-propylamine (169 mg, 0.50 mmoles, 1 eq.), (E)-3-(2-pyridin-4-ylvinyl)phenylamine (108 mg, 0.55 mmoles, 1.1 eq.), Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmole, 5 mol %), XPhos (24 mg, 0.05 mmole, 10 mol %) and K.sub.2CO.sub.3 (276 mg, 2.0 mmoles, 4 eq.) in t-BuOH (2 mL) was heated at 80 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on alumina to give (E)-[3-(4-methyl-piperazinyl)-propyl]-3-[3-(2-pyridin-4-ylvinyl)-phenylamino]-benzamide (21) (115 mg, 51%).

(51) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.49 (d, J=3.6 Hz, 2H), 8.23 (s, 1H), 7.56 (s, 1H), 7.39-7.11 (m, 7H), 7.14-6.98 (m, 3H), 6.90 (d, J=15.8 Hz, 1H), 6.53 (s, 1H), 3.49 (s, 2H), 3.23 (s, 2H), 2.2.5-2.30 (m, 8H), 2.20 (s, 3H), 1.75-1.70 (m, 2H).

(52) .sup.13C NMR (75 MHz, CDCl3) 167.47, 150.25, 144.65, 143.65, 143.38, 137.49, 136.43, 133.24, 129.95, 129.35, 126.26, 121.02, 120.13, 119.99, 119.17, 118.56, 117.07, 116.68, 58.36, 55.12, 53.37, 46.13, 40.93, 24.40.

(53) [M+1-1].sup.+=456.2

Example 6: Compound (127) in Table I

(54) According to route (B), 4-vinylpyridine (5.9 mL, 55 mmoles, 1.1 eq.) was placed in dimethylformamide (50 mL) with 1-bromo-3-nitrobenzene (10.1 g, 50 mmoles, 1 eq.), NaOAc (8.2 g, 100 mmoles, 2 eq.), Pd(OAc).sub.2 (561 mg, 2.5 mmoles, 5 mol %), PPh.sub.3 (1.5 g, 6.0 mmoles, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (6.0 g, 53%).

(55) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.63 (d, J=6.1 Hz, 2H), 8.41 (s, 1H), 8.17 (dd, J=8.2, 2.1 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.40 (d, J=6.1 Hz, 2H), 7.34 (d, J=16.4 Hz, 1H), 7.16 (d, J=16.4 Hz, 1H).

(56) According to route (C), (E)-4-[2-(3-nitrophenyl)vinyl]pyridine (3.0 g, 13.3 mmoles, 1 eq.) and tin (II) chloride dihydrate (15.0 g, 66.5 mmoles, 5 eq.) were placed in EtOH (130 mL). The reaction mixture was heated at 60 C. and stirred for 16 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-4-ylvinyl)phenylamine (1.9 g, 73%).

(57) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.57 (d, J=6.3 Hz, 2H), 7.35 (d, J=6.3 Hz, 2H), 7.26-7.15 (m, 2H), 7.01-6.93 (m, 2H), 6.87 (s, 1H), 6.67 (dd, J=7.9, 2.3 Hz, 1H), 3.74 (br s, 2H).

(58) According to route (A1), a reaction mixture of 3-bromo-benzenesulfonamide (118 mg, 0.50 mmoles, 1 eq.), (E)-3-(2-pyridin-4-ylvinyl)phenylamine (108 mg, 0.55 mmoles, 1.1 eq.), Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmole, 5 mol %), XPhos (24 mg, 0.05 mmole, 10 mol %) and K.sub.2CO.sub.3 (276 mg, 2.0 mmoles, 4 eq.) in t-BuOH (2 mL) was heated at 80 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on alumina to give (E)-3-[3-(2-pyridin-4-ylvinyl)phenylamino]-benzenesulfonamide (127) (89 mg, 51%).

(59) .sup.1H NMR (300 MHz, MeOD) 8.43 (s, 2H), 7.67 (s, 1H), 7.53 (d, J=5.2 Hz, 2H), 7.42 (d, J=16.5 Hz, 1H), 7.38-7.13 (m, 8H), 7.13-7.07 (m, 1H), 7.09 (d, J=16.5 Hz, 1H).

(60) [M+H].sup.+=352.1

Example 7: Compound (26) in Table I

(61) According to route (B), 2-vinylpyridine (1.18 mL, 11 mmoles, 1.1 eq.) was placed in dimethylformamide (10 mL) with 1-bromo-3-nitrobenzene (2.02 g, 10 mmoles, 1 eq.), NaOAc (1.64 g, 20 mmoles, 2 eq.), Pd(OAc).sub.2 (112 mg, 0.5 mmole, 5 mol %), PPh.sub.3 (315 mg, 1.2 mmole, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the organic phase was further washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-2-[2-(3-nitrophenyl)vinyl]pyridine (1.0 g, 44%).

(62) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.64 (d, J=4.6 Hz, 1H), 8.44 (s, 1H), 8.14 (ddd, J=8.2, 2.1, 0.9 Hz, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.77-7.65 (m, 2H), 7.55 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.28 (d, J=16.0 Hz, 1H), 7.22 (ddd, J=7.5, 4.8, 1.0 Hz, 1H).

(63) According to route (C), (E)-2-[2-(3-nitrophenyl)vinyl]pyridine (1.0 g, 4.4 mmoles, 1 eq.) and tin (II) chloride dihydrate (5.0 g, 22.1 mmoles, 5 eq.) were placed in EtOH (44 mL). The reaction mixture was heated at 60 C. and stirred for 16 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution then with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(2-pyridin-2-ylvinyl)phenylamine (816 mg, 94%).

(64) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.58 (dd, J=4.8, 0.7 Hz, 1H), 7.60 (td, J=7.7, 1.8 Hz, 1H), 7.53 (d, J=16.1 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.18-7.05 (m, 3H), 6.97 (d, J=7.7 Hz, 1H), 6.86 (s, 1H), 6.61 (dd, J=7.9, 1.4 Hz, 1H), 3.76 (br s, 1H).

(65) Pent-4-yn-1-ol (5 g, 59 mmoles, 1.0 eq.) was placed in a dimethylsulfoxide (65 mL) and water (5 mL) solution, together with 1-bromo-4-iodobenzene (16.81 g, 59 mmoles, 1 eq.), NaN.sub.3 (4.64 g, 71.3 mmoles, 1.2 eq.), L-Proline (1.53 g, 11.8 mmoles, 0.2 eq.), Na.sub.2CO.sub.3 (1.26 g, 11.8 mmoles, 0.2 eq.), sodium ascorbate (3.57 g, 23.7 mmoles, 0.4 eq.). CuSO.sub.4.5H.sub.2O (4.7 g, 11.8 mmoles, 0.2 eq.) was added and the reaction mixture was heated at 65 C. and stirred for 16 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was further stirred for 24 hours and then partitioned between a NH.sub.4OH aqueous solution and ethyl acetate. Upon decantation, the aqueous phase was further extracted with ethyl acetate. The organic phases were gathered, washed with a NaCl aqueous solution, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-[1-(4-bromophenyl)-1H-[1,2,3]triazol-4-yl]propan-1-ol (10.36 g, 53%).

(66) .sup.1H NMR (300 MHz, DMSO-d6) 8.61 (s, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 4.52 (t, J=5.2 Hz, 1H), 3.48 (q, J=5.2 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 1.88-1.74 (quint, J=7.5 Hz, 2H).

(67) According to route (A1), a reaction mixture of 3-[1-(4-bromophenyl)-1H-[1,2,3]triazol-4-yl]propan-1-ol (846 mg, 3.0 mmoles, 1 eq.), (E)-3-(2-pyridin-2-ylvinyl)phenylamine (816 mg, 4.2 mmoles, 1.4 eq.), Pd.sub.2(dba).sub.3 (137 mg, 0.15 mmole, 5 mol %), XPhos (143 mg, 0.30 mmole, 10 mol %) and K.sub.2CO.sub.3 (1.66 g, 12.0 mmoles, 4 eq.) in t-BuOH (3.7 mL) was heated at 90 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-(1-{4-[3-(2-pyridin-2-ylvinyl)phenylamino]phenyl}-1H-[1,2,3]triazol-4-yl)propan-1-ol (26) (836 mg, 70%).

(68) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.51 (d, J=4.5, 1H), 7.61 (s, 1H), 7.56 (d, J=7.6, 1H), 7.48 (d, J=16.1, 1H), 7.41 (d, J=8.7, 2H), 7.30 (d, J=7.8, 1H), 7.21 (s, 1H), 7.17 (d, J=7.7, 1H), 7.12-7.01 (m, 5H), 6.97 (d, J=7.8, 1H), 6.87 (s, 1H), 4.19 (s, 1H), 3.70 (t, J=6.2, 2H), 2.84 (t, J=7.4, 2H), 2.00 (quint, J=6.7, 2H).

(69) .sup.13C NMR (75 MHz, CDCl.sub.3) 155.6, 149.8, 148.2, 144.0, 142.7, 138.1, 136.9, 132.7, 130.3, 130.0, 128.4, 122.4, 122.1, 121.0, 119.5, 118.9, 117.7, 117.3, 61.9, 32.2, 22.3.

(70) [M+H].sup.+=398

Example 8: Compound (40) in Table I

(71) According to route (B), 1-methoxy-4-vinylbenzene (2.9 mL, 22 mmoles, 1.1 eq.) was placed in dimethylformamide (20 mL) with 1-bromo-3-nitrobenzene (4 g, 20 mmoles, 1 eq.), NaOAc (3.3 g, 40 mmoles, 2 eq.), Pd(OAc).sub.2 (225 mg, 1 mmole, 5 mol %), PPh.sub.3 (629 mg, 2.4 mmoles, 12 mol %). The reaction mixture was heated at 135 C. and stirred for 24 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford (E)-1-nitro-3-(4-(methoxy)styryl)benzene (2.3 g, 45%).

(72) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.35 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.56-7.43 (m, 3H), 7.20 (d, J=16.4 Hz, 1H), 7.01 (d, J=16.4 Hz, 1H), 6.94 (d, J=7.9 Hz, 2H), 3.86 (s, 3H).

(73) According to route (C), (E)-1-nitro-3-(4-(methoxy)styryl)benzene (1.5 g, 5.8 mmoles, 1 eq.) and tin (II) chloride dihydrate (6.6 g, 29.4 mmoles, 5 eq.) were placed in EtOH (58 mL). The reaction mixture was heated at 60 C. and stirred for 48 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-1-nitro-3-(4-(methoxy)styryl)aniline (1.3 g, 99%).

(74) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.46 (d, J=8.7 Hz, 2H), 7.17 (t, J=7.8 Hz, 1H), 7.05 (d, J=16.3 Hz, 1H), 6.97-6.88 (m, 4H), 6.84 (s, 1H), 6.60 (dd, J=7.9, 2.1 Hz, 1H), 3.84 (s, 3H), 3.68 (br s, 2H).

(75) N,N-diethylpropylenediamine (7 mL, 44 mmoles, 1.1 eq.) was placed in a 3N NaOH aqueous solution (56 mL) and dichloromethane (24 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of 3-bromobenzoyl chloride (5.3 mL, 40 mmoles, 1 eq.) in dichloromethane (40 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-bromo-N-(3-diethylamino-propyl)benzamide (12.5 g, 99%).

(76) .sup.1H NMR (300 MHz, CDCl.sub.3) 9.11 (br s, 1H), 7.90 (t, J=1.9 Hz, 1H), 7.72 (dt, J=7.9, 1.2 Hz, 1H), 7.56 (ddd, J=7.9, 1.9, 1.0 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 3.53 (dt, J=5.7, 4.6 Hz, 2H), 2.64-2.51 (m, 6H), 1.73 (quint, J=5.7 Hz, 2H), 1.02 (t, J=7.2 Hz, 6H).

(77) According to route (A1), a reaction mixture of 3-bromo-N-(3-diethylamino-propyl)benzamide (1.2 g, 4 mmoles, 1 eq.), (E)-1-nitro-3-(4-(methoxy)styryl)aniline (1 g, 4.4 mmoles, 1.1 eq.), Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmole, 5 mol %), XPhos (190 mg, 0.4 mmole, 10 mol %) and K.sub.2CO.sub.3 (2.2 g, 16 mmoles, 4 eq.) in t-BuOH (5 mL) was heated at 90 C. and stirred for 20 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-N-(3-diethylamino-propyl)-3-((3-(4-(methoxy)styryl)phenylamino)benzamide (40) (1 g, 55%).

(78) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.59 (s, 1H), 7.52 (s, 1H), 7.43 (d, J=8.7 Hz, 2H), 7.27 (d, J=7.0 Hz, 2H), 7.23 (d, J=7.3 Hz, 2H), 7.18 (s, 1H), 7.13-6.92 (m, 4H), 6.89 (d, J=8.7 Hz, 2H), 3.82 (s, 3H), 3.59-3.47 (m, 2H), 2.62-2.46 (m, 6H), 1.72 (quint, J=5.7 Hz, 2H), 0.99 (t, J=7.2 Hz, 6H).

(79) .sup.13C NMR (75 MHz, CDCl.sub.3) 167.2, 159.5, 144.0, 143.2, 139.1, 136.4, 130.2, 129.8, 129.4, 128.6, 127.9, 119.8, 118.9, 117.6, 116.6, 114.3, 55.5, 53.3, 46.9, 41.3, 25.1, 11.6.

(80) [M+H].sup.+=458.3

Example 9: Compound (39) in Table I

(81) According to route (D), methyl-triphenylphosphonium bromide (3.6 g, 10 mmoles, 2 eq.) was placed in dry toluene (17 mL) with potassium tert-butoxide (1.1 g, 10 mmoles, 2 eq.). The reaction mixture was heated at 70 C. and stirred for 30 minutes under an inert atmosphere of argon. 3-Nitrobenzaldehyde (756 mg, 5 mmoles, 1 eq.) was then added. The reaction mixture was heated at 110 C. and stirred for 2 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was diluted with water and the resulting solution was extracted with ethyl acetate. The organic phase was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 1-nitro-3-vinylbenzene (661 mg, 88%).

(82) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (s, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 6.83-6.66 (m, 1H), 5.87 (d, J=17.5 Hz, 1H), 5.41 (d, J=10.7 Hz, 1H).

(83) According to route (B), 1-nitro-3-vinylbenzene (661 mg, 4.4 mmoles, 1.1 eq.) was placed in dimethylformamide (4 mL) with 1-bromo-3 (trifluoromethoxy)benzene (600 L, 4 mmoles, 1 eq.), NaOAc (661 mg, 8 mmoles, 2 eq.), Pd(OAc).sub.2 (45 mg, 0.2 mmole, 5 mol %), PPh.sub.3 (105 mg, 0.4 mmole, 10 mol %). The reaction mixture was heated at 135 C. and stirred for 10 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford (E)-1-nitro-3-(4-(methoxy)styryl)benzene (355 mg, 28%).

(84) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.37 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.49-7.34 (m, 3H), 7.20-7.00 (m, 3H).

(85) According to route (C), (E)-1-nitro-3-(3-(trifluoromethoxy)styryl)benzene (355 mg, 1.15 mmole, 1 eq.) and tin (II) chloride dihydrate (1.3 g, 5.75 mmoles, 5 eq.) were placed in EtOH (11.5 mL). The reaction mixture was heated at 60 C. and stirred for 10 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford (E)-3-(3-(trifluoromethoxy)styryl)aniline (304 mg, 95%).

(86) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.45-7.34 (m, 3H), 7.20 (t, J=7.8 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.05 (s, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.85 (s, 1H), 6.65 (d, J=7.5 Hz, 1H), 3.71 (br s, 2H).

(87) 3-(4-methylpiperazin-1-yl)propan-1-amine (1.9 mL, 11 mmoles, 1.1 eq.) was placed in a 3N NaOH aqueous solution (14 mL) and dichloromethane (6 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of 3-bromobenzoyl chloride (1.3 mL, 10 mmoles, 1 eq.) in dichloromethane (10 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 10 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 3-bromo-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide (2.8 g, 85%).

(88) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.59 (s, 1H), 7.90 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.34-7.24 (m, 1H), 3.60-3.45 (m, 2H), 2.60-2.63 (m, 8H), 2.30 (s, 3H), 1.80-1.65 (m, 2H).

(89) According to route (A1), a reaction mixture of 3-bromo-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide (169 mg, 0.50 mmoles, 1 eq.), (E)-3-(3-(trifluoromethoxy)styryl)aniline (153 mg, 0.55 mmoles, 1.1 eq.), Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmole, 5 mol %), XPhos (24 mg, 0.05 mmole, 10 mol %) and K.sub.2CO.sub.3 (276 mg, 2 mmoles, 4 eq.) in t-BuOH (2 mL) was heated at 90 C. and stirred for 10 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (E)-N-(3-(diethylamino)propyl)-3-((3-(3-(trifluoromethoxy) styryl)phenyl)amino)benzamide (39) (160 mg, 59%).

(90) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (s, 1H), 7.57 (s, 1H), 7.42-7.36 (m, 2H), 7.33-7.21 (m, 5H), 7.16-7.08 (m, 3H), 7.05-7.01 (m, 3H), 5.89 (s, 1H), 3.57 (t, J=5.5 Hz, 2H), 2.66-2.35 (m, 10H), 2.27 (s, 3H), 1.80 (t, J=5.5 Hz, 2H).

(91) .sup.13C NMR (75 MHz, CDCl.sub.3) 167.5, 149.9, 143.7, 143.2, 139.6, 138.2, 136.5, 130.4, 130.2, 130.0, 129.5, 127.6, 125.1, 120.1, 119.3, 118.9, 118.2, 117.1, 116.6, 58.4, 55.1, 53.4, 46.1, 41.0, 24.4.

(92) [M+H].sup.+=539

Example 10: Compound (45) in Table I

(93) 2-iodobenzoic acid (9.92 g, 40 mmoles, 1 eq.) was placed in toluene (40 mL) under an inert atmosphere of argon. Thionyl chloride (6 mL, 80 mmoles, 2 eq.) was slowly added. The reaction mixture was heated at 80 C. and stirred for 4 hours. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. N,N-Diethylethylenediamine (3.12 mL, 22 mmoles, 1.1 eq.) was placed in a 3N NaOH aqueous solution (15 mL) and dichloromethane (10.7 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of the 2-iodobenzoyl chloride residue (20 mmoles, 4 eq.) in dichloromethane (21.4 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 2-iodo-N-(2-diethylamino-ethyl)benzamide (3.73 g, 51%).

(94) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.87 (d, J=7.9 Hz, 1H), 7.42-7.34 (m, 2H), 7.13-7.06 (m, 1H), 6.48 (s, 1H), 3.51 (q, J=5.7 Hz, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.57 (q, J=7.2 Hz, 4H), 1.02 (t, J=7.2 Hz, 6H).

(95) According to route (A2), a reaction mixture of 2-iodo-N-(2-diethylamino-ethyl)benzamide (3.3 g, 9.6 mmoles, 1 eq.), 4-(trifluoromethoxy)aniline (1.9 mL, 14.5 mmoles, 1.5 eq.), CuI (183 mg, 0.96 mmol, 10 mol %), L-Proline (221 mg, 1.92 mmol, 20 mol %) and K.sub.2CO.sub.3 (2.6 g, 19.2 mmoles, 2.0 eq.) in DMSO (10 mL) was heated at 80 C. and stirred for 48 hours under an inert atmosphere of argon. The reaction mixture was then partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-(2-diethylamino-ethyl)-2-(4-trifluoromethoxy-phenylamino)-benzamide (45) (1.4 g, 37%).

(96) .sup.1H NMR (300 MHz, CDCl.sub.3) 9.55 (s, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.30-7.21 (m, 3H), 7.15 (d, J=9.1 Hz, 2H), 7.10 (d, J=9.1 Hz, 2H), 6.78 (t, J=7.3 Hz, 1H), 3.44 (t, J=5.9 Hz, 2H), 2.62 (t, J=5.9 Hz, 2H), 2.54 (q, J=7.1 Hz, 4H), 1.02 (t, J=7.1 Hz, 6H).

(97) .sup.13C NMR (75 MHz, CDCl.sub.3) 169.5, 145.2, 143.9, 140.8, 132.2, 127.8, 122.3, 121.4, 119.1, 118.7, 115.6, 51.3, 46.9, 37.2, 12.1.

(98) [M+H].sup.+=396

(99) In a similar manner, compounds (48), (49), (50) and (52) can be prepared.

Example 11: Compound (65) in Table I

(100) 4-bromo-3-methylbenzoic acid (9.92 g, 40 mmoles, 1 eq.) was placed in toluene (40 mL) under an inert atmosphere of argon. Thionyl chloride (6 mL, 80 mmoles, 2 eq.) was slowly added. The reaction mixture was heated at 80 C. and stirred for 4 hours. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. 3-Methyl-1-butanamine (1.393 mL, 12 mmoles, 2 eq.) was placed in a 3N NaOH aqueous solution (8 mL) and dichloromethane (4 mL) was added to the solution. The reaction mixture was cooled down to 0 C. with an ice bath and a solution of the 4-bromo-3-methyl benzoyl chloride residue (6 mmoles, 1 eq.) in dichloromethane (26 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford 4-bromo-3-methyl-N-(3-methylbutyl)benzamide (1.44 g, 84%).

(101) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.64 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 6.02 (s, 1H), 3.47 (q, J=7.0 Hz, 2H), 2.45 (s, 3H), 1.69 (heptuplet, J=6.6 Hz, 1H), 1.51 (q, J=7.0 Hz, 2H), 0.96 (d, J=6.6 Hz, 6H).

(102) According to route (A1), a reaction mixture of 4-bromo-3-methyl-N-(3-methylbutyl)benzamide (284 mg, 1 mmole, 1 eq.), 3-methoxyaniline (185 mg, 1.5 mmole, 1.5 eq.), Pd.sub.2(dba).sub.3 (46 mg, 0.05 mmole, 5 mol %), XPhos (48 mg, 0.10 mmole, 10 mol %) and K.sub.2CO.sub.3 (276 mg, 2 mmoles, 2 eq.) in t-BuOH (1 mL) was heated at 100 C. and stirred for 22 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-(3-methoxyphenylamino)-3-methyl-N-(3-methylbutyl)benzamide (65) (259 mg, 79%).

(103) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.62 (s, 1H), 7.50 (dd, J=1.9, 8.5 Hz, 1H), 7.23-7.14 (m, 2H), 6.69-6.59 (m, 2H), 6.54 (dd, J=2.2, 8.1 Hz, 1H), 6.30 (d, J=5.4 Hz, 1H), 5.73 (s, 1H), 3.75 (s, 3H), 3.40 (q, J=7.0 Hz, 2H), 2.23 (s, 3H), 1.69 (heptuplet, J=6.6 Hz, 1H), 1.50 (q, J=7.0 Hz, 2H), 0.93 (d, J=6.6 Hz, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3) 167.4, 160.9, 144.7, 143.6, 130.4, 130.1, 126.7, 125.8, 125.7, 115.5, 112.2, 107.7, 105.4, 55.4, 38.8, 38.5, 26.2, 22.7, 18.0.

(104) [M+H].sup.+=327

Example 12: Compound (116) in Table I

(105) N,N-diethyl-N-(2-propynyl)amine (5 g, 45 mmoles, 1.0 eq.) was placed in a dimethylsulfoxide (40.5 mL) and water (4.5 mL) solution, together with 1-bromo-3-iodobenzene (12.73 g, 45 mmoles, 1 eq.), NaN.sub.3 (3.51 g, 54 mmoles, 1.2 eq.), L-Proline (1.16 g, 9 mmoles, 0.2 eq.), Na.sub.2CO.sub.3 (0.95 g, 9 mmoles, 0.2 eq.), sodium ascorbate (3.57 g, 18 mmoles, 0.4 eq.). CuSO.sub.4.5H.sub.2O (2.25 g, 9 mmoles, 0.2 eq.) was added and the reaction mixture was heated at 65 C. and stirred for 16 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was further stirred for 24 hours and then partitioned between a NH.sub.4OH aqueous solution and ethyl acetate. Upon decantation, the aqueous phase was further extracted with ethyl acetate. The organic phases were gathered, washed with a NaCl aqueous solution, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford [1-(3-bromophenyl)-1H-[1,2,3]triazol-4-ylmethyl]diethylamine (9.79 g, 70%).

(106) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.99-7.90 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 3.88 (s, 1H), 2.62 (q, J=7.1 Hz, 1H), 1.13 (t, J=7.1 Hz, 1H).

(107) According to route (E), 4-methoxybenzamide (4.53 g, 30 mmoles, 1 eq.), 1-bromo-4-nitrobenzene (6.67 g, 33 mmoles, 1.1 eq.), Pd(OAc).sub.2 (67.3 mg, 0.3 mmoles, 1 mol %), XantPhos (260.4 mg, 0.45 mmoles, 1.5 mol %) and Cs.sub.2CO.sub.3 (15.9 g, 45 mmoles, 1.5 eq.) were placed in dioxane (30 mL). The reaction mixture was heated at 90 C. and stirred for 18 hours under an inert atmosphere of argon. The reaction mixture was then filtered on Celite, washed with CH.sub.2Cl.sub.2 and acetone and the filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from ethanol and filtered to afford 4-methoxy-N-(4-nitrophenyl)benzamide (4.82 g, 60%).

(108) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.27 (d, J=9.3 Hz, 2H), 8.01 (s, 1H), 7.85 (t, J=9.3 Hz, 4H), 7.02 (d, J=9.3 Hz, 2H), 3.90 (s, 3H).

(109) According to route (F), 4-methoxy-N-(4-nitrophenyl)benzamide (4.08 g, 15 mmoles, 1 eq.) and 10% Pd/C (750 mg) were placed in EtOH (75 mL). The reaction mixture was stirred for 6 hours under an atmosphere of H.sub.2. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to afford N-(4-aminophenyl)-4-methoxybenzamide (2.99 g, 82%).

(110) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.87 (d, J=7.9 Hz, 1H), 7.42-7.34 (m, 2H), 7.13-7.06 (m, 1H), 6.48 (s, 1H), 3.51 (q, J=5.7 Hz, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.57 (q, J=7.2 Hz, 4H), 1.02 (t, J=7.2 Hz, 6H).

(111) According to route (A1), a reaction mixture of [1-(3-bromophenyl)-1H-[1,2,3]triazol-4-ylmethyl]diethylamine (247 mg, 0.8 mmole, 1 eq.), N-(4-aminophenyl)-4-methoxybenzamide (213 mg, 0.88 mmole, 1.1 eq.), Pd.sub.2(dba).sub.3 (37 mg, 0.04 mmole, 5 mol %), XPhos (38 mg, 0.08 mmole, 10 mol %) and K.sub.2CO.sub.3 (442 mg, 3.2 mmoles, 4 eq.) in t-BuOH (1 mL) was heated at 100 C. and stirred for 22 hours under an inert atmosphere of argon. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N-{4-[3-(4-diethylaminomethyl)-[1,2,3]triazol-1-yl)phenylamino]phenyl}-4-methoxybenzamide (116) (196 mg, 52%).

(112) .sup.1H NMR (300 MHz, DMSO-d6) 10.03 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.52 (s, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 3H), 3.84 (s, 3H), 3.76 (s, 2H), 2.50-2.41 (m, 4H), 1.03 (t, J=7.1 Hz, 6H). .sup.13C NMR (75 MHz, DMSO-d6) 164.5, 161.8, 145.8, 137.8, 137.7, 133.3, 130.5, 129.5, 127.1, 121.7, 119.1, 114.9, 113.6, 109.8, 106.0, 99.5, 55.4, 46.5, 46.1, 11.9.

(113) [M+H].sup.+=471

Example 13: Pharmacological Data

(114) 13.1. Effects of Compounds on p53 Expression and its Transcriptional Activity

(115) The compounds of the invention have been tested according to the following pharmacological test and the three compounds have been more particularly tested: (40), (1) and (45), all diluted in DMSO. Their effects were thus compared to cells treated with DMSO. A positive control was used, TG003, a benzothiazole compound known to alter splicing through the inhibition of Clk/Sty family activity (Sigma, ref: T5575).

(116) Two breast cancer cell lines have been treated with 5 M of drugs for 48 hours: wild-type p53 MCF7 cells and mutant p53 (R280K) MDA-MB-231-Luc-D3H2N provided by Caliper Life Science (parental Line source: American Type Culture collection). The MDA-MB-231-Luc-D3H2N cells were maintained in two different media during treatment: a DMEM supplemented with 10% foetal calf serum (FCS) and a FCS-free medium for 24 hours followed by 24 hours in a complete medium. The MC7 cells were maintained in a DMEM/FCS 10% medium.

(117) Cells were harvested after 48 hours of treatment. Total RNAs (RNeasy Mini-Kit, Qiagen) and proteins (NuPage LDS 1, Invitrogen) were extracted to analyse mRNA expression by nested RT-PCR or RT-qPCR and protein expression by Western Blot.

(118) 1. Protocols:

(119) Analysis of p53 expression was assessed both at mRNA (full-length and truncated, 133p53 isoforms) and protein (full-length) levels by RT-qPCR and Western Blot, respectively.

(120) The p53 isoform cDNA being too long to be specifically quantified by RT-qPCR, a semi-quantitative RT-PCR method was therefore used, requiring high quality total RNA 28S/18S ratio (>1.5). After reverse-transcription of 500 ng of total RNA using random primers, actin cDNA was amplified by PCR to confirm reverse-transcription efficiency. 0.5 g of total RNA from each tumour sample was reverse-transcribed (AMV RT, 45 C, random primer) and cDNA quality confirmed by amplification of actin by PCR in 30 cycles. p53 isoform cDNA was amplified by 2 nested PCR of 30 cycles using primers specific of each isoforms as described in Bourdon et al. (Genes Dev., 2005, 19: 2122). Tumours were considered to express each p53 isoform after sequencing of the corresponding PCR fragment.

(121) p53 protein expression was determined using a panel of 4 different antibodies, namely DO1, SAPLI, CMI and DO12 as described in Bourdon et al. (Genes Dev., 2005, 19: 2122), to avoid problem of detection due to post-translational modification.

(122) The rabbit anti-p53 antibodies were diluted at 1/1000, and revealed with Horse-Radish Peroxydase (HRP)-conjugated anti-IgG antibodies purchased from GE-Healthcare and diluted at 1/5000 (Ref.: NA9340).

(123) The Western Lightning Chemiluminescence (ECL) reagents were purchased from PerkinElmer (Ref.: NEL103C001EA).

(124) The amount of total proteins in each extract was quantified using BCA kit (promega). 8% SDS-PAGE gels were used. Equal amount (30 g) of proteins was loaded on each lane. Proteins were then transferred electrophoretically on nitrocellulose membrane. Membranes were blocked in TBS/0.1% Tween 20 containing 3% milk for one hour and then incubated overnight with the primary antibodies diluted in TBS/0.1% Tween 20 containing 3% milk. After several washes in TBS/Tween, membranes were incubated with anti-rabbit Ig antibodies linked to HRP. Membranes were developed with ECL according to the manufacturer's instructions.

(125) Scanned autoradiographs were quantified using AIDA/2D densitometry software.

(126) Analysis of p53 transcriptional activity was assessed through analysis of p53-target gene expression by Western-blot. Four p53-target genes were studied: Hdm2, Bcl-2, p21 and Bax. Hdm2 is known to bind p53 and to negatively regulate p53 activity and stability. p21 is known to mediate p53 dependent cycle arrest. Bcl 2 is known to have an anti-proliferative effect and an apoptotic protective effect, while Bax is known to have a pro-apoptic effect. Bax was not detected in both MCF7 and MDA-MB-231-Luc-D3H2N cells, while p21 was not detected in MDA-MB-231-Luc-D3H2N cells maintained in FCS-free medium. The Western-blot was performed as above described using the antibodies described in Bourdon et al., Genes Dev., 2005, 19: 2122.

(127) 2. Results

(128) In the wild-type p53 MCF7 cells, the three compounds (40), (1) and (45) did not change total p53 expression (total isoforms, TA) at mRNA levels (FIG. 1A), while compounds (40) and (45) decreased p53 protein levels (full-length) (FIG. 1B, C). This decrease was associated with a decreased expression of Bcl-2 and Hdm2 but not of p21 (FIGS. 1D, E). The same pattern of p53-target gene expression was observed with compound (1). Compounds (40) and (1) increased 133p53 mRNA level (FIG. 1A).

(129) In mutant p53 MDA-MB-231-Luc-D3H2N cells maintained in normal medium, the three compounds (40), (1) and (45) decreased p53 expression at mRNA levels (total isoforms, TA) (significant decrease for drug (1), p-value <0.01) (FIG. 2A), while compounds did not change p53 protein levels (full-length) (FIG. 2B, C). Compounds (40) and (1) did not affect p53-target genes expression, while a slight decrease of p53-target gene expression was observed with compound (45) (FIG. 2D, E).

(130) In the mutant p53 MDA-MB-231-Luc-D3H2N cells maintained in FCS-free medium, compounds (1) and (45), but not compound (40), decreased p53 expression at mRNA levels (total isoforms, TA) (FIG. 3A, blue panel), while compounds did not change p53 protein levels (full-length) (FIG. 3B, C). Compound (40) did not affect p53-target genes expression, while a slight decrease of Hdm2 and of Bcl-2 was observed with compound (1) and (45), respectively (FIG. 3D, E).

(131) 3. Conclusion:

(132) Compounds (40) and (45) decreased the expression of both p53 protein (full-length) and its target gene in wild-type p53 MCF7 cells.

(133) Compounds (1) and (45) decreased the p53 mRNA level (total isoforms) in mutant p53 MDA-MB-231-Luc-D3H2N cells maintained in normal medium and in FCS-free medium.

(134) These compounds affect expression of both p53 and its target genes, in a p53 mutation dependent manner.

(135) 13.2. Effect of Compounds on p53 Isoforms Expression

(136) 1. Protocol:

(137) Expression of p53 isoforms produced by alternative splicing (, and ) was analysed at mRNA levels by RT-qPCR using primers/probe specific of each C-terminal variants. The -forms are the most abundant forms. In the low abundant forms, -forms are more expressed than -forms.

(138) A semi-quantitative RT-PCR method requiring high quality total RNA 28S/18S ratio (>1.5). After reverse-transcription of 500 ng of total RNA using random primers, actin cDNA was amplified by PCR to confirm reverse-transcription efficiency. 0.5 g of total RNA from each tumour sample was reverse-transcribed (AMV RT, 45C, random primer) and cDNA quality confirmed by amplification of actin by PCR in 30 cycles. p53 isoform cDNA was amplified by 2 nested PCR of 30 cycles using primers specific of each isoforms as described by Bourdon et al. (Genes Dev., 2005, 19: 2122). Tumours were considered to express each p53 isoform after sequencing of the corresponding PCR fragment.

(139) 2. Results:

(140) In the wild-type p53 MCF7 cells, the three compounds (40), (1) and (45) did not change -form expression at mRNA levels (FIG. 4A), while they tend to increase the expression of - and -forms (FIG. 4A).

(141) In the mutant p53 MDA-MB-231-Luc-D3H2N cells maintained in normal medium, the three compounds (40), (1) and (45) did not change -form expression at mRNA levels (FIG. 4B), while they tend to increase the expression of - and -forms (FIG. 4B). Significant increased of -forms (by 3-fold) and of -forms (by 2-fold) was observed for compound (45). The restoration of -forms by compound (1) was confirmed by nested RT-PCR (FIG. 4B, right panel).

(142) In the mutant p53 MDA-MB-231-Luc-D3H2N cells maintained in FCS-free medium, the three compounds (40), (1) and (45) did not change -form expression at mRNA levels (FIG. 4C), while compound (45) tend to increase the expression of - and -forms (FIG. 4C). While no significant increase of -forms was observed by RT-qPCR, restoration of -forms by compound (1) was shown by nested RT-PCR (FIG. 4C, right panel).

(143) 3. Conclusion:

(144) The tested compounds affect p53 splicing independently of p53 mutation status (i.e. increase expression of - and -forms).

(145) 13.3. General Conclusion

(146) The compounds of the invention present an effect on p53 isoforms expression and activity.

(147) As an illustration of said effect, the three here above identified tested compounds have different effect on p53 isoforms expression and activity. They increase the expression of p53/-forms at mRNA levels. A decrease in p53 protein and its target gene was observed for the compound (45) (independently of p53 mutation status), for compound (40) (in wild-type p53 cells) and for compound (1) (in mutant p53 cells).

(148) The tested compounds affect p53 family isoforms expression and activity, and consequently the p53 pathway. Surprisingly, the main effect of drugs (40), (1) and (45) is a reduction of p53 expression and its pathway, while, to the knowledge of the inventors, all existing drugs activate p53 pathway. Up to now, to the knowledge of the inventors no drug, which can repress p53 expression, has been described.

(149) It follows that the compounds according to the present invention demonstrate an effect over the p53 gene isoforms family expression and activity.

(150) The table below summarizes the effect of the compounds of the invention on p53 and the therapeutic indications for which they may be proposed.

(151) TABLE-US-00003 Therapeutic Effects p53 status (40) (1) (45) indication Decrease of Wild-type X X cancer p53 protein p53 and target Mutant p53 X X Others than genes cancer Modification Wild-type X X X cancer of p53 p53 isoforms ratio Mutant p53 X X X Others than cancer

(152) 13.4 Effect of Drug Compounds on Invasion of MDA-MB231-D3H2LN Cells into Collagen

(153) Further, some compounds of formula (I) have been tested on invasion in order to study their activity against cancer as shown below.

(154) Standard operating procedure:

(155) Background:

(156) A key step in the generation of tumor metastasis is the invasion of tumor cells into the extracellular matrix, a major component of which is collagen. Therefore, the invasion of tumor cells into collagen in vitro may be indicative of the generation of metastasis in vivo. E. g., MDA-MB231-luc-D3H2LN mouse breast cancer cells display indeed both higher invasion into collagen in vitro and a higher metastatic potential in vivo as compared to MDA-MB231 cells (from which they were derived). Using these MDA-MB231-luc-D3H2LN cells as a model, the aim of the experiment described here is to identify drug compounds that inhibit the invasion of tumor cells into collagen in vitro, therefore potentially inhibiting also the generation of tumor metastasis in vivo.

(157) Assay Principle:

(158) Step 1: Preparation of cells at the bottom of a collagen gel: Cells are suspended in a liquid collagen solution (4 C.), distributed into BSA-coated wells, and then collected at the bottom of the wells by centrifugation. The collagen is then solidified by incubation at 37 C. The BSA coating improves the adhesion of the collagen gel.

(159) Step 2: Pre-treatment with the compounds to be tested: Concentrated drug solutions are then added on top of the collagen, and cells are pre-incubated for 24 h with the drugs at low serum conditions (0.025% FBS).

(160) Step 3: Stimulation of invasion: Medium with 5% FBS is then added in order to stimulate invasion of the cells into the collagen gel.

(161) Step 4: Fixation and staining: Following another 24 h incubation, cells are fixed and nuclei are stained.

(162) Step 5: Analysis: Finally, plates are analyzed using an automated microscope. Fluorescent beads that have been included into the BSA coating serve to detect the bottom of the wells. Pictures of the stained nuclei are taken at the same level (0 m) as well as 25 m and 50 m above.

(163) Note:

(164) In order to detect possible toxic effects, all compounds are tested in parallel in a viability assay. The viability assay is performed in parallel on serum-starved cells (as in the invasion assay) vs. cells under normal culture conditions (10% FBS).

(165) Materials:

(166) General equipment: Freezer (20 C.), refrigerator (4 C.), ice machine, water bath (37 C.), incubator (37 C./5% CO.sub.2), cell culture hood, vortex, vacuum pump, microscope, Malassez cell, Pipet aid, micropipettes (for pipetting 1-1000 l), multichannel pipettes (for pipetting 20-2000), standard cell culture centrifuge, refrigerated centrifuge for 96 well plates

(167) General consumables: Sterile 96 well cell culture plates (for the viability assay), sterile tubes (1.5/15/50 ml), sterile pipettes (5/10/25 ml), sterile micropipette tips (for pipetting 1-1000 l), sterile Pasteur pipettes, sterile reagent reservoirs

(168) General products: Sterile PBS, sterile Milli-Q water, DMSO, decomplemented FBS (frozen aliquots), 0.1 N NaOH, 1 M Hepes, MEM without serum (not older than 1 month), 2.5MEM without serum (not older than 1 month), MEM with 10% FBS (not older than one month), 0.25% trypsin/1 mM EDTA solution, 37% formaldehyde solution

(169) Specific Equipment:

(170) plate reader: Tecan Infinite F200

(171) automated microscope: Cellomics ArrayScan VTI HCS Reader

(172) Specific Consumables:

(173) sterile black 96 well plates (for the invasion assay): Perkin Elmer ViewPlate-96 F TC, ref. 6005225

(174) sterile 96 deep well polypropylene plates (for drug preparation): Starlab, ref. S1896-5110

(175) Specific Products:

(176) rat tail collagen, type 1: BD Biosciences, ref. 354236 (note: each new lot has to be validated)

(177) red fluorescent beads (1 m diameter): Invitrogen, ref. F13083

(178) Y-27632 (5 mM aqueous solution): Calbiochem, ref. 688001 (in solution) or 688000 (dry powder)

(179) BSA without fatty acids (sterile-filtered 4% aqueous solution): Sigma, ref. A8806 (dry powder)

(180) Hoechst 33342 nuclear stain (10 mg/ml): Invitrogen, ref. H3570

(181) MTS reagent: Promega CellTiter 96 AQueous One Solution Reagent, ref. G3581

(182) drug compounds to be tested: generally 25 or 50 mM in 100% DMSO (aliquots stored at 20 C., then at 4 C. for max. 3 months)

(183) MDA-MB231-luc-D3H2LN cells:

(184) Limits for the cell cultures to be used in the assays:

(185) total passage number: max. 30

(186) last passage: between 2 and 4 days before, between 1:3 and 1:20

(187) cell density: between 50 and 90% (optimally 70%) (between 1 and 2106 cells per 100 mm dish)

Experimental Procedures

(188) General Considerations:

(189) Controls and Plate Maps:

(190) Invasion assay: Negative control: No drug (just DMSO at equivalent concentration). Positive control: 10 M Y-27632. To avoid edge effects, only the 60 central wells B2-G11 are used; lines A and H as well as columns 1 and 12 remain free. Each drug is tested at least in triplicate. The positive and negative controls should be tested in double triplicates at different positions on each plate. Typical plate map (=negative control, +=positive control, 1-16=16 different drug compounds):

(191) TABLE-US-00004 1 2 3 4 5 6 7 8 9 10 11 12 A B 1 2 3 4 5 6 7 8 + C 1 2 3 4 5 6 7 8 + D 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15 16 F + 9 10 11 12 13 14 15 16 G + 9 10 11 12 13 14 15 16 H

(192) Viability Assays:

(193) No additional controls. The MTS viability assay is based on colorimetric detection of a product generated by the mitochondrial activity of the cells. Each drug is tested at least in duplicate. To detect potential direct interactions with the assay substrate, each drug is also tested in absence of cells (background signals). Typical plate map (controls and drug compounds as in the invasion assay, lines A-B and E-F: with cells, lines C-D and G-H: without cells; each 1 plate with 10% vs. 0.025% FBS):

(194) TABLE-US-00005 1 2 3 4 5 6 7 8 9 10 11 12 A 1 2 3 4 5 6 7 8 + B 1 2 3 4 5 6 7 8 + C 1 2 3 4 5 6 7 8 + D 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15 16 F + 9 10 11 12 13 14 15 16 G + 9 10 11 12 13 14 15 16 H + 9 10 11 12 13 14 15 16

(195) The volumes or other quantities indicated in the following are required for testing 16 drug compounds per 96 wells-plate at 5 M each (+ controls) in an invasion assay and each one viability assay on serum-starved cells vs. cells under normal culture conditions according to the plate maps above. According to the number of tested compounds, the volumes and other quantities should be adapted for testing more or less compounds or different concentrations.

(196) Day 1: Preparation and Treatment of the Cells (all Steps are Performed Under a Cell Culture Hood):

(197) Preparation of 100 concentrated drug solutions in 10% DMSO:

(198) prepare 10% DMSO in sterile PBS: 1.8 ml sterile PBS+0.2 ml DMSO

(199) prepare 100 l/well 10% DMSO in PBS in 16 wells of a sterile 96 well polypropylene plate

(200) add each 1 or 2 l of the 50 or 25 mM compound stock solutions, respectively

(201) mix by pipetting up and down

(202) Preparation of 4 concentrated drug and control solutions in 0.4% DMSO in MEM+0.1% FBS:

(203) prepare MEM+0.1% FBS: 12 ml MEM without serum+12 l FBS (freshly thawed aliquot)

(204) prepare 480 l/well MEM+0.1% FBS in 20 wells of a sterile 96 deep well polypropylene plate

(205) negative controls (no drug): add each 20 l 10% DMSO in sterile PBS

(206) positive controls (Y-27632): add each 14 l sterile PBS+2 l DMSO+4 l 5 mM Y-27632 (freshly thawed aliquot)

(207) drug compounds: add each 20 l of the 100 concentrated drug solutions in 10% DMSO

(208) mix by pipetting up and down

(209) store at RT until use

(210) Coating of the Plates for the Invasion Assay:

(211) mix 9.5 ml MEM without serum+0.5 ml 4% BSA without fatty acids+1 l vortexed fluorescent beads (i. e. dilute 1:10000), vortex, distribute 100 l/well into the plate for the invasion assay

(212) centrifuge 30 with 1800g at 4 C. (e. g. 3000 rpm in a Jouan GR412 centrifuge)

(213) remove supernatants by aspiration

(214) Preparation of a 10106 Cells/Ml Cell Suspension (During the Centrifugation of the Plates):

(215) remove medium, wash cells with 10 ml/dish PBS, add 1 ml/dish 0.25% trypsin/1 mM EDTA

(216) incubate 30-60 s at 37 C.

(217) add 5-10 ml/dish pre-warmed MEM+10% FBS

(218) homogenize by pipetting up and down using a 10 ml pipette, pool all

(219) count cells using a Malassez cell

(220) centrifuge 2106 (or more) cells for 5 with 150g at RT (850 rpm in a std. cell culture centrifuge)

(221) remove supernatant, resuspend cell pellet in 0.2 ml (or more, respectively) MEM without serum, yielding 10106 cells/ml

(222) Preparation of the Invasion Assay (on Ice; Start During the Centrifugation of the Cells):

(223) mix on ice in a pre-chilled tube: example for a 3.4 mg/ml collagen stock solution; volumes of collagen and water to be adapted according to the stock concentration of each collagen lot:

(224) 2.8 ml 2.5MEM

(225) 441 l water

(226) 140 l 1 M Hepes

(227) 49 l 1 N NaOH

(228) 3.5 ml 3.4 mg/ml collagen stock solution (yielding 1.7 mg/ml collagen in 7 ml)

(229) homogenize by pipetting gently up and down (keep on ice)

(230) add 70 l of the 10106 cells/ml cell suspension, homogenize by pipetting gently up and down (yields 0.1106 cells/ml in 1.7 mg/ml collagen in 7 ml 1MEM+20 M Hepes) (keep on ice)

(231) distribute 100 l/well (i. e. 10000 cells/well) into the coated wells of the plate for the invasion assay (all on ice)

(232) centrifuge 5 with 200g at 4 C. (e. g. 1000 rpm in a Jouan GR412 centrifuge)

(233) add 200 l/well PBS to all free wells

(234) incubate 30 at 37 C./5% CO.sub.2 (solidification of the collagen)

(235) Preparation of the Viability Assay on Serum-Starved Cells:

(236) add 50 l of the 10106 cells/ml cell suspension to 5 ml MEM without serum (yields 0.1106 cells/ml)

(237) distribute 100 l/well of this suspension (i. e. 10000 cells/well) or MEM without serum without cells, respectively, into a standard 96 well tissue culture plate, according to the plate map above

(238) add 200 l/well PBS to all free wells incubate 30 at 37 C./5% CO.sub.2

(239) Preparation of the Viability Assay on Cells Under Normal Culture Conditions:

(240) add 30 l of the 10106 cells/ml cell suspension to 5 ml MEM+10% FBS (yields 0.06106 cells/ml)

(241) distribute 100 l/well of this suspension (i. e. 6000 cells/well) or MEM+10% FBS without cells, respectively, into a standard 96 well tissue culture plate, according to the plate map above

(242) add 200 l/well PBS to all free wells

(243) incubate 30 at 37 C./5% CO.sub.2

(244) Treatment with the Drugs:

(245) add each 33 l/well of the 4 concentrated drug solutions in MEM+0.1% FBS to the corresponding wells in all three plates, according to the plate maps above

(246) incubate 24 h at 37 C./5% CO.sub.2

(247) Day 2: Addition of FBS to Stimulate the Invasion:

(248) Microscopic Observation After 24 h of Treatment:

(249) examine the cells of the viability assays

(250) Addition of FBS (Under a Cell Culture Hood):

(251) prepare MEM+5% FBS: 7.2 ml MEM without serum+0.8 ml FBS (freshly thawed aliquot or rest of the aliquot thawed the day before if kept at 4 C.)

(252) add 33 l/well to all wells of invasion and viability assays

(253) incubate 24 h at 37 C./5% CO.sub.2

(254) Day 3: Stop:

(255) Microscopic Observation After 48 h of Treatment:

(256) examine the cells of the viability assays

(257) Viability Assays: MTS Assay:

(258) add each 33 l/well of the MTS reagent, incubate 2.5 h at 37 C./5% CO.sub.2

(259) shake and read absorbance at 490 nm (proportional to the viability)

(260) calculate the background-corrected signals by subtracting the means of the background signals in absence of cells from the corresponding signals in presence of cells

(261) normalize the background-corrected signals with respect to the mean signal of the negative controls (no drug) (viabilities are thus expressed in % of control)

(262) Invasion Assays: Fixation and Staining (Formaldehyde Must be Manipulated Under a Dume Cupboard):

(263) freshly prepare 1 g/ml Hoechst 33342 in 18.5% formaldehyde: 5 ml PBS (not necessarily sterile)+5 ml 37% formaldehyde+1 l 10 mg/ml Hoechst 33342 (note: for one plate, a smaller volume would be sufficient, but the minimal pipetted volume should not be below 1 l)

(264) add 50 l/well to all wells of the invasion assay (yields 4.3% formaldehyde final)

(265) seal with black film (provided with the plates)

(266) incubate at least 7 h at RT

(267) Day 3: 17 (min. 7 h/max. 2 Weeks After Fixation and Staining): Analysis of the Invasion Assay:

(268) Lecture using the Cellomics ArrayScan VTI HCS Reader:

(269) BioApplication: SpotDetector.V3

(270) Plate type: Perkin Elmer 96 well

(271) Parameters of the Assay Protocol:

(272) objective: 10(NA 0.45)

(273) apotome: yes (resulting optical slice: 11.7 M)

(274) fields per well: 8

(275) autofocus in each field

(276) autofocus channel: 1

(277) channel 1 (autofocus on, and photo of the fluorescent beads at the bottom of the wells): filter: XF93-TRITC; exposure time: usually between 0.002 and 0.01 s

(278) channel 2 (photo of the stained cells at the same level as the fluorescent beads): filter: XF100-Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: 0 M

(279) channel 3 (photo of the stained cells 25 M above the fluorescent beads): filter: XF100-Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: 25 M

(280) channel 4 (photo of the fluorescent cells 50 M above the fluorescent beads): filter: XF100-Hoechst; exposure time: usually between 0.02 and 0.1 s; z offset: 50 M

(281) TABLE-US-00006 object identification: method: fixed threshold: 100-32767 object selection parameters: min. max. SpotArea: 20 1000000000000 SpotShapeBFR: 0.2 1000 SpotShapeBAR: 0 1000 SpotAvgInten: 200 32767 SpotTotalInten: 4000 (thus 1000000000000 not limiting) TargetAvgInten: 0 32767 TargetTotalInten: 0 1000000000000

(282) Analysis of the Results of the Scan Using vHCS Viewer:

(283) export the results: for each well:

(284) number of valid fields

(285) number of objects in each valid field in each of the channels 2, 3 and 4 (field details)

(286) mean numbers of objects per valid field for each well, in each of the channels 2, 3 and 4

(287) exclude wells with less than 6 valid fields per well from further analysis

(288) visually check all photos for any apparent problems, such as bad focusing or obviously inhomogeneous collagen structure (bubbles, . . . ), . . . ; in case of apparent problems: document, then exclude the corresponding wells from further analysis

(289) Further Analysis of the Results of the Invasion Assay (Using e. g. Excel):

(290) for each well, calculate the mean invasion distance of the counted cells: (25 mnumber of cells at 25 m+50 mnumber cells at 50 m)/sum of cells at 0, 25 and 50 m

(291) for all four parameters (number of cells at 0 m, number of cells at 25 m, number of cells at 50 m, mean invasion distance of the counted cells), calculate means, SD and CV of the replicates (n=6 for the controls; n=3 for the samples)

(292) invalidate any replicate with a CV50% (compound to be re-tested, or assay to be repeated if CV50% for the untreated negative control or the compound Y-27632-treated positive control). Y27632 is a selective inhibitor of the Rho-associated protein kinase p160ROCK of the following formula

(293) ##STR00158##

(294) validate the assay only if the mean invasion distance of the cells treated with 10 M Y-27632 (positive control) is decreased by 40% as compared to the untreated negative control

(295) plot graphs of all four parameters (number of cells at 0 m, number of cells at 25 m, number of cells at 50 m, mean invasion distance of the counted cells)

(296) Results

(297) Anti-invasive effect in MDA-MB231 breast cancer cells: 0.5 fold effect compared to 10 M Y-27632 ref. compound.

(298) TABLE-US-00007 0.5 fold effect compared Compound to 10 M Y-27632 (M) 6 0.7 0.1 9 1.1 0.4 16 0.75 0.19 17 0.83 0.09 18 0.55 0.05 19 0.25 0.05 21 0.17 0.04 22 0.3 0.05 24 0.64 0.2 25 0.5 0.21 49 0.13 0.3 50 1 129 0.2

(299) The compounds according to the present invention demonstrate an anti-invasive effect predictive for their activity against cancer.

(300) Therefore, the result of the tests carried out on the compounds disclosed in the present invention show that said compounds and their pharmaceutically acceptable salts, and more particularly compounds (6), (9), (16), (17), (18), (19), (21), (22), (24), (25), (49), (50) and (129) as well as their pharmaceutically acceptable salts, may be used in a method to inhibit, prevent and/or treat cancer.

(301) For this purpose an effective amount of a said compound may be administered to a patient suffering from cancer.

(302) Others indications than cancer may include inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, hepatic disorders, such as cholestasis, autoimmune diseases, and ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction.

(303) Therefore, the result of the tests carried out on the compounds disclosed in the present invention show that said compounds may be useful to inhibit, prevent and/or treat cancer and/or atherosclerosis for patients exhibiting mutated p53, inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, pathogenesis of a number of hepatic disorders, such as cholestasis, autoimmune diseases, and ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction.

(304) The following type of cancer may more particularly be treated by the compounds according to the present invention: namely colorectal cancer, pancreatic cancer, lung cancer including non-small cell lung cancer, breast cancer, bladder cancer, gall bladder cancer, thyroid cancer, melanoma, liver cancer, uterine/cervical cancer, oesophageal cancer, kidney cancer, ovarian cancer, prostate cancer, head and neck cancer, or stomach cancer, etc.

(305) For this purpose an effective amount of a said compound may be administered to a patient suffering from cancer and/or atherosclerosis for patients exhibiting mutated p53, inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, hepatic disorders, such as cholestasis, autoimmune diseases, ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction.

(306) The present invention is also related to the use of at least a compound chosen among a compound of anyone of formula (I), (Iab), (Ia), (Ib), (Ic), (Id), (Ie), (If) as defined above, and compounds (1) to (140) as defined above, or one of its pharmaceutically acceptable salts according to the present invention for the manufacture of a pharmaceutical composition intended for the treatment of cancer and/or atherosclerosis for patients exhibiting mutated p53, inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, hepatic disorders, such as cholestasis, autoimmune diseases, ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction.

(307) The present invention also encompasses pharmaceutical compositions comprising at least a compound chosen among new compounds (9), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (37), (38), (39), (48), (49), (50), (52), (83), (84), (85), (86), (87), (88), (89), (90), (91), (92), (123), (124), (125), (126), (127), (128), (129), (130), (131), (132), (133), (134), (135), (136), (137), (138), (139) and (140) as defined above or any pharmaceutically acceptable salt thereof.

(308) Thus, these pharmaceutical compositions contain an effective amount of said compound, and one or more pharmaceutical excipients.

(309) The aforementioned excipients are selected according to the dosage form and the desired mode of administration.

(310) In this context they can be present in any pharmaceutical form which is suitable for enteral or parenteral administration, in association with appropriate excipients, for example in the form of plain or coated tablets, hard gelatine, soft shell capsules and other capsules, suppositories, or drinkable, such as suspensions, syrups, or injectable solutions or suspensions, in doses which enable the daily administration of from 0.1 to 1000 mg of active substance.

(311) The present invention further relates to a method of treatment of patients suffering from cancer and/or atherosclerosis said patients exhibiting mutated p53, inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, pathogenesis disorders such as cholestasis, autoimmune diseases and ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction for patients exhibiting a deregulated p53, which comprises at least a step of administration to a patient suffering thereof of an effective amount of a compound of anyone of formula (I), (Iab), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above and (1) to (140) or one of its pharmaceutically acceptable salts.