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Definitions

• the subject of the present invention is new benzothienyl or indole derivatives, their manufacturing process, the pharmaceutical compositions containing them and their use as a medicament, in particular as prenyl transferase protein inhibitors.
• Ras oncogenes are present in many human cancers such as cancer of the pancreas, colon and certain types of leukemia (Barbacid M. Ann. Rev. Biochem ., 1987, 56: 779-827; Bos J.-L. Cancer Res., 1989, 49: 4682-4689).
• the Ras proteins are involved in the signaling process that links growth factors, from the cell surface, to cell proliferation. In normal cells biochemical studies have shown that proteins
• Ras in the inactive state are linked to GDP.
• the Ras proteins exchange GDP for GTP and undergo a conformation change.
• This activated form of the Ras protein propagates the growth signal until the Ras protein returns to its inactive state by hydrolysis of GTP to GDP.
• the mutated Ras proteins, derived from the ras oncogenes, remain in the activated form and therefore transmit a permanent growth signal (Polakis P. and McCormick F. J Biol. Chem, 1993, 268: 13, 9157-9160; Glomset LA. And Farnsworth CC. Annu. Rev. Cell. Biol, 1994, 10: 181-205).
• Ras proteins must be associated with the cell membrane to be active. This process notably involves the addition of an isoprenoid motif (Cl 5 or C20) on the cysteine of the terminal tetrapeptide of Ras proteins called "CAAX box" (in which C represents a cysteine, A an aliphatic amino acid, X an amino acid any).
• C represents a cysteine, A an aliphatic amino acid, X an amino acid any
• Ras proteins This alkylation is catalyzed, depending on the nature of the sequence, by the protein Famesyl Transferase Protein (PFTase) or by the Protein Geranyl Geranyl Transferase (PGGTase I) enzyme which respectively transfer a farnesyl group (Cl 5) or geranyl geranyl (C20 ).
• PFTase protein Famesyl Transferase Protein
• PGGTase I Protein Geranyl Geranyl Transferase
• Blocking the function of Ras proteins should result in inhibition of the growth of tumor cells which depend on the activation of Ras or which express mutated Ras proteins (Perrin D., Halazy S. and Hill BTJ Enzyme Inhi., 1996;
• PFTase inhibitors such as BZA-5B (James GL, Goldstein J.-L., Brown MS et al Science, 1993, 260: 1937-1942) or L-731,734 (Kohi NE, Mosser SD, De Solms SJ et al. Science, 1993, 260: 1934-1937) at the level of cell proliferation as well as with graft-dependent tumors in mice (Kohi NE, Wilson FR, Mosser SD et al. Proc. Natl. Acad.
• BZA-5B James GL, Goldstein J.-L., Brown MS et al Science, 1993, 260: 1937-1942
• L-731,734 Kohi NE, Mosser SD, De Solms SJ et al. Science, 1993, 260: 1934-1937
• inhibitors may also find utility in controlling the proliferation of smooth muscle cells (Indol i et al. Nature Med, 1995, 1: 541-545) and are therefore potentially useful for the treatment or prevention of atherosclerosis and restenosis (JP H7-112930, Cohen, LH et al. Biochem. Pharm., 2000, 60, 1061-1068).
• the subject of the present invention is a new class of protein prenylation inhibitors and more particularly inhibitors of PFTase and / or of PGGTase I which are distinguished from the prior art by their different chemical structure and their remarkable biological property.
• the subject of the present invention is benzothienyl or indole derivatives having the capacity to inhibit PFTase and / or PGGTase I not only at the enzymatic level but also at the cellular level.
• Imidazole derivatives which may contain a benzothienyl or an indole and described as prenyl transferase inhibitors (W09965898)
• the compounds of the present invention have the general formula (I):
• W represents:
• X represents only S.
• Z represents: Imidazole, benzimidazole, isoxazole, tetrazole, oxadiazole, thiadiazole, pyridme, quinazoline, quinoxaline, quinoline, thiophene. These heterocycles can be unsubstituted or substituted by one or more groups chosen from Cj-
• R 2 represents: a) hydrogen, b) C1-C 10 alkyl, cycloalkyl, C 3 -C 30 alkenyl, C 3 -C 20 alkynyl c) phenyl unsubstituted or substituted by one or more residues chosen from CC 6 alkyl, halogen, phenyl, naphthyl, NO 2 , CN, CF 3 , OR 6 , SR 6 , NR 6 R 7 , COOR 6 , CONR ⁇ Ry, COR 6 .
• R 3 represents:
• f represents: a) Hydrogen, b) Ci -Ce alkyl unsubstituted or substituted by one or more residues chosen from aryl, cyanophenyl, nitrophenyl, aminophenyl, methoxyphenyl, hydroxyphenyl, heterocycle, halogen, CN, NO 2 , OR 2 , SR 2 , NR 2 R 3 COOR 2 ; c) an aryle, d) a heterocycle.
• R5 represents: a) phenyl or naphthyl unsubstituted or substituted by one or more residues chosen from Ci-Ce alkyl, halogen, phenyl, naphthyl, NO 2 , CN, CF 3 , ORe, SRe, NR 6 R 7 , COORe , CONReR ?, COR ⁇ s; b) C1-C 15 alkyl, C 3 -C 3 0 alkenyl or C3-C20 alkynyl unsubstituted or substituted by one or more residues chosen among halogen, COOMe, COOH, OR 2, CF 3, CN, SR 2; a cycloalkyl which is unsubstituted or substituted by a halogen, OR 2 , CF 3 , CN, SR 2 ; an unsubstituted or halogen-substituted alkylcycloalkyl, OR 2 , CF 3 , CN
• R ⁇ and R identical or different, represent, a) Hydrogen; Ci -Ci 5 alkyl, C 3 -C 30 alkenyl or C 3 -C 20 alkynyl unsubstituted or substituted by one or more residues chosen from halogen, COOMe, COOH, OR 2 , CF 3 , CN, SR 2 ; cycloalkyl unsubstituted or substituted by halogen, OR 2 , CF 3 , CN, SR 2 alkylcycloalkyle unsubstituted or substituted by halogen, OMe, OH, CF 3 , CN, SMe b) A heterocycle, an alkylheterocycle c) A aryl, alkylaryl, alkyldiaryl d) R ⁇ and R when they are adjacent, taken together, can form a 4 to 6-membered ring with the nitrogen atom to which they are attached and which can contain one or more chosen heteroatoms from
• alkyl represents saturated, linear or branched aliphatic hydrocarbon chains, substituted or unsubstituted by one or more groups chosen from halogen, NH 2 , OH, phenyl and comprising the number of carbon atoms specified.
• cycloalkyl represents cyclic hydrocarbon chains comprising from 3 to 10 carbon atoms.
• alkenyl represents linear or branched hydrocarbon chains having 1 to 6 double bonds and which may be substituted or unsubstituted by one or more groups chosen from halogen, NH 2 , OH, phenyl and comprising the number of carbon atoms specified .
• aryl represents any monocyclic or bicyclic carbon ring which may contain up to 7 atoms per cycle and in which at least one of the rings is aromatic.
• aromatic rings can be unsubstituted or substituted by one or more groups chosen from C ⁇ -C 15 alkyl, halogen, OMe, CN, NO 2 , OH, CF 3 , OCF 3 , OCH 2 Ph, SMe, COOMe, COOEt, COOH .
• heterocycle represents either a stable unicycle containing from 5 to 7 atoms or a stable bicycle containing from 8 to 11 atoms, which can be either saturated or unsaturated, and consisting of carbon atoms and from one to four heteroatoms chosen from N , O or S. Also included in the definition of bicycle are monocyclic heterocycles fused to a benzene nucleus.
• heterocycles can be unsubstituted or substituted by one or more groups chosen from C1-C15 alkyl, halogen, OMe, CN, NO 2 , OH, CF 3 , OCF 3 , OCH 2 Ph, SMe, COOMe, COOEt, COOH.
• alkylcycloalkyle represents hydrocarbon chains aliphatic, linear or branched, saturated or unsaturated comprising from 1 to 15 carbon atoms and precede the mentioned groups the definition of which has been given previously.
• Salts acceptable for therapeutic use of the compounds of the present invention include conventional non-toxic salts of the compounds of the invention such as those formed from organic or inorganic acids.
• inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acids
• organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic, tartaric acids, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic.
• solvates acceptable for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last stage of preparation of the compounds of the invention due to the presence of solvents.
• solvates due to the presence of water or ethanol.
• a particularly preferred class of compounds corresponds to the compounds of general formula (I) in which R 2 , R 3 and R 4 each represent a hydrogen and Y a methylene ( CH 2 ).
• Another particularly preferred class of compounds forming part of the present invention corresponds to the compounds of general formula (I) in which Z represents an imidazolyl or pyridyl residue.
• a third particularly appreciated class of compounds forming part of the present invention corresponds to the compounds of general formula (I) in which Z represents an imidazolyl residue and R 4 a methyl or benzyl group, unsubstituted or substituted by a nitrile, nitro or methoxy group in position 4.
• a fourth particularly appreciated class of compounds forming part of the present invention corresponds to the compounds of general formula (I) in which X represents a sulfur atom.
• a particularly preferred fifth class of compounds forming part of the present invention corresponds to the compounds of general formula (I) in which X represents an NH and R 2 a phenyl.
• the present invention also relates to the preparation of the compounds of general formula (I) by the general methods described in the following synthetic diagrams supplemented, where appropriate, with all the standard manipulations described in the literature or well known to those skilled in the art or although still exemplified in the experimental part.
• Scheme 1 illustrates the first general process usable for the preparation of the compounds of general formula (la).
• Z, Y, X, W, R 2 , R 3 , R 4 , R 6 and R are defined as in the preceding description of the general formula (I).
• Pj represents either a protective group or the COOPj entity can represent an ester.
• Li can represent a leaving group such as for example Cl, Br, I, OSO 2 CH 3 , OSO 2 CF 3 or O-Tosyle.
• the reaction with the amine of general formula (III) will be carried out in the presence of an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, pyridine, NaH, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, CH 2 C1 2 at a temperature between - 20 ° and 100 ° C.
• an organic or inorganic base such as for example Et 3 N, iPr 2 NEt, pyridine, NaH, Cs 2 CO 3 , K 2 CO 3 in a polar anhydrous solvent such as THF, DMF, DMSO, CH 2 C1 2 at a temperature between - 20 ° and 100 ° C.
• Y represents CO
• (CH 2 ) p CO or CH CHCO
• Li can
• reaction with the amine of general formula (III) amounts to the formation of an amide by condensation between this amine and a derivative of carboxylic acid.
• This reaction can be carried out by methods and techniques well known to those skilled in the art.
• a particularly preferred method consists in condensing a carboxylic acid of general formula (II) with an amine of general formula (III) in the presence of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (EDC), of 3-hydroxy- 1,2,3-benzotriazin-4 (3H) -one, of a tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane, at a temperature between - 15 ° C and 40 ° C.
• EDC 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide
• EDC 3-hydroxy- 1,2,3-benzotriazin-4
• a preparation method consists in carrying out a reductive amination using an aldehyde of formula R ' 4 -Z- (CH 2 ) n - ⁇ -CHO in which R ' 4 and Z are defined as above, of an amine of general formula (III) and of a reducing agent such as NaBH 4 , NaBH 3 CN, NaBH (OAc) 3 in a solvent polar such as 1,2-dichloroethane, THF, DMF, MeOH, at a pH which can be controlled by the addition of an acid, such as acetic acid, at a temperature of between -20 ° C. and 100 ° C.
• a reducing agent such as NaBH 4 , NaBH 3 CN, NaBH (OAc) 3
• a solvent polar such as 1,2-dichloroethane, THF, DMF, MeOH
• the intermediate of general formula (IV) is transformed into an intermediate of general formula (V) by reaction with -L in which L 2 can represent a leaving group such as for example Cl, Br, I, OSO 2 CH3, OSO 2 CF3 or O-Tosyle.
• L 2 can represent a leaving group such as for example Cl, Br, I, OSO 2 CH3, OSO 2 CF3 or O-Tosyle.
• the reaction with the amine of general formula (IV) will be carried out in the presence of a base organic or inorganic such as for example Ei 3 N, iPr 2 NEt, NaH, pyridine, CS2CO3,
• L 2 can also represent a hydroxyl.
• the reaction with the amine of general formula (IV) amounts to the formation of an amide by condensation between this amine and a derivative of carboxylic acid. This reaction can be carried out by methods and techniques well known to those skilled in the art.
• a particularly preferred method consists in condensing a carboxylic acid of general formula WL 2 with an amine of general formula (IV) in the presence of l- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (EDC), of 3-hydroxy-l , 2,3-benzotriazin-4 (3H) -one, of a tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane, at a temperature between - 15 ° C and 40 ° C.
• EDC 3-dimethylaminopropyl) -3-ethyl-carbodiimide
• a method of preparation consists in carrying out a condensation between an isocyanate or an isothiocyanate of formula RgNCO or RgNCS respectively and in which R 6 is defined as above and R 7 represents a hydrogen, with an amine of general formula (IV).
• the reaction with the amine of general formula (IV) will be carried out in an apolar solvent such as toluene or benzene at a temperature between 40 ° and 100 ° C.
• a preparation method consists in carrying out a reductive amination using an aldehyde of formula R 6 - (CH 2 ) n- ⁇ -CHO in which R ⁇ is defined as above, of an amine of general formula (IV) and of a reducing agent such as NaBH 4 , NaBHsCN, NaBH (OAc) in a polar solvent such as 1 , 2-dichloroethane, THF, DMF, MeOH, at a pH that can be controlled by the addition of an acid, such as acetic acid, at a temperature between - 20 ° C and 100 ° C.
• a reducing agent such as NaBH 4 , NaBHsCN, NaBH (OAc)
• a polar solvent such as 1 , 2-dichloroethane, THF, DMF, MeOH
• the carboxylic acid obtained can react with the amine of general formula HNReR. This reaction can be carried out by methods and techniques well known to those skilled in the art.
• a particularly appreciated method consists in condensing these 2 entities in the presence of 1,3-diisopropyIcarbodiimide (DIC), of 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one, of a tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane, at a temperature between - 15 ° C and 40 ° C.
• DIC 1,3-diisopropyIcarbodiimide
• 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one of a tertiary amine such as diisopropylethylamine
• a polar aprotic solvent such as dichloromethane
• R ' represents a protective group
• the methods and techniques well known to those skilled in the art will be used ("Protective Groups in Organic Synthesis", TW Greene, John Wiley & Sons, 1981 and "Protecting Groups” , PJ Kocienski, Thieme Verlag, 1994).
• R ′ represents a solid support, such as for example a trityl resin
• a cleavage of this solid support can be carried out in order to recover the final product.
• a particularly preferred method of cleavage consists in treating the intermediate (VI) with trifluoroacetic acid (TFA) in a polar solvent such as dichloromethane in the presence of triethylsilane at a temperature between 0 ° and 40 ° C.
• TFA trifluoroacetic acid
• Scheme 2 illustrates the second general process which can be used for the preparation of the compounds of general formula (la).
• R ′ 6 corresponds either to R ⁇ or to a precursor of RQ or to a resin in the case of synthesis on a solid support.
• the reaction between the intermediate of general formula (VII) and the amine R 'R 7 NH can be carried out according to the same procedures as those described in the first process above.
• the transformation of the intermediate of formula (VIII) into intermediates of formula (IX) and (X) can be carried out according to the procedures described in the first method above.
• a second method of cleavage consists in treating the intermediate (X) with a base such as LiOH or NaOH in polar solvents such as methanol,
• a particularly preferred method of cleavage consists in treating the resin with a THF / MeOH / LiOH mixture.
• a third method of cleavage allowing this time to obtain a terminal methyl ester consists in carrying out a transesterification by treatment of intermediate (X) with an organic base such as triethylamine (Et 3 N) in a polar solvent such as methanol or THF, at a temperature between 20 ° and
• a particularly preferred method of cleavage consists in treating the resin with a THF / MeOH / Et 3 N mixture in a 1/2/2 proportion at 55 ° C.
• R ′ 6 represents a protective group
• the methods and techniques well known to those skilled in the art will be used (“Protective Groups in Organic Synthesis”, TW Greene, John Wiley
• Scheme 3 illustrates the first general process usable for the preparation of the compounds of general formula (Ib).
• R 2 , R 3 and R ′ are defined as in the preceding descriptions except that these will be judiciously chosen to be compatible with the reduction step and ⁇ ⁇ will preferably be methyl or ethyl.
• R ' 6 corresponds either to R ⁇ (defined above) or to a precursor of R ⁇ .
• the intermediate of general formula (V) is transformed into the intermediate of general formula (XI) by reduction using a reducing agent such as the complex BH3.THF or AIH3 or else LiAlH in the case where the other functions present allow on the molecule, in an anhydrous polar solvent such as THF or ethyl ether at a temperature between -20 and 40 ° C.
• the intermediate (XI) obtained can then be processed by the entity R ' 6 L 3 in which L 3 can represent a leaving group such as for example Cl, Br, I, OSO 2 CH 3 , OSO 2 CF 3 or O -Tosyle.
• reaction with the alcohol of general formula (XI) will be carried out in the presence of an organic base or inorganic such as for example E1 3 N, iPr 2 NEt, pyridine, NaH, Cs 2 C ⁇ 3 , K 2 C ⁇ 3 or a base supported on a solid support such as for example the resin PS-
• an organic base or inorganic such as for example E1 3 N, iPr 2 NEt, pyridine, NaH, Cs 2 C ⁇ 3 , K 2 C ⁇ 3 or a base supported on a solid support such as for example the resin PS-
• L 3 can also represent a hydroxyl.
• the reaction with the alcohol of general formula (XI) returns to the Mitsunobu reaction and can be carried out in the presence of diethylazodicarboxylate
• Scheme 4 illustrates the second general process which can be used for the preparation of the compounds of general formula (Ib).
• R " 6 corresponds either to R ' 6 or to a precursor of R' 6 or to a resin in the case of synthesis on a solid support.
• the reduction reaction of the intermediate of general formula (XIII) can be carried out according to the same procedures as those described in the first method above.
• the transformation of the intermediate of formula (XIV) into intermediates of formula (XV) can be carried out according to the procedures described in the first method above.
• the intermediate of general formula (XV) to the intermediate of general formula (XVI) will be carried out in 3 stages: the first consists in reducing the nitro group by methods and techniques well known to those skilled in the art. preferred is to treat the nitro compound with hydrogen gas in a polar solvent such as methanol, ethanol or THF, at room temperature, in the presence of a catalyst such as Pd / C or Pd (OH) 2 / C.
• a particularly preferred method consists in treating the nitrated compound with tin chloride dihydrate in a polar solvent such as ethanol at a temperature of between 25 and 90 ° C.
• the second and third steps can be carried out according to the procedures described in the above methods.
• Scheme 5 illustrates the general process usable for the preparation of the compounds of general formulas (Ic) and (Id).
• Z, Y, X, W, R 2 , R3, R ' 4 and Rô are defined as in the previous descriptions.
• the intermediate of general formula (XI) is transformed into an intermediate of general formula (XVII) by oxidation of the alcohol to aldehyde by methods and techniques well known to those skilled in the art.
• a particularly appreciated method consists in treating the intermediate (XI) with oxalyl chloride and DMSO in a polar aprotic solvent such as dichloromethane at a temperature between -
• the transformation of the intermediate of general formula (XVII) into an intermediate of general formula (XVIII) can be done by reaction of a phosphonium salt of general formula Ph 3 P + CH 2 R ⁇ V " in which R ⁇ is defined as previously and V represents a halogen, in an anhydrous solvent such as THF in the presence of a base such as butyllithium or potassium tert-butoxide at a temperature between -78 and 25 ° C.
• the next step consists in reduce the double bond of the intermediate of general formula (XVIII) by methods and techniques well known to those skilled in the art.
• a particularly preferred method consists in hydrogenating the compound in the presence of an insoluble catalyst such as palladium on carbon in a polar solvent such as methanol or ethyl acetate.
• Diagram 5 Also to be considered as part of the present invention are all the methods of preparing a compound of general formula (I) from another derivative of general formula (I) in which at least one of the substituents is different.
• a compound of general formula (I) in which Z represents an imidazole and R 4 represents H can be transformed into a compound of general formula (I) in which Z represents an imidazole and R 4 represents a benzyl, by selective protection of the imidazole by reaction with trityl chloride followed by a reaction with a benzyl halide according to a method well known to those skilled in the art.
• the new compounds of general formula (I) When the new compounds of general formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, either by enantioselective synthesis or by resolution.
• Example 1A 2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -6-fluorobenzaldehyde. 2,6-difluorobenzaldehyde (79.7 g; 350 mmol) and potassium phthalimide
• Example ID - 4-Ammobenzo [ô] thiophene-2-carboxyIic acid Compound 1 ⁇ (5 g; 22 mmol) is dissolved in THF (77 ml) and water (26 ml). Soda (30% in water; 3.4 ml; 34 mmol) is added, and the reaction is heated at 80 ° C for 3.5 hours. The reaction mixture is concentrated. The resulting aqueous solution is neutralized with IN HCl, to pH 5.3. The desired product precipitates. It is filtered, rinsed with acetonitrile, and dried (3.5 g, 88%).
• Trityl chloride resin (2.1 mmol / g) (30 g; 63 mmol) is swollen with CH 2 CI 2 (2 x 80 ml) then a solution of 4 (5) -imidazolecarboxaldehyde (18.2 g; 189 mmol) in DMF (134 ml) is added followed by DIE A (134 ml). The mixture is stirred for 36 hours at room temperature then the resin is filtered and washed successively with DMF (2 x), CH 2 C1 2 (2 x), H 2 O (2 x), MeOH (1 x), CH 2 C1 2 (2 x), MeOH (2 x).
• Resin 1E (4 g; 5.6 mmol) is swollen with CH2Cl 2 (2 x 80 ml) then a solution of aniline ID (2.18 g; 11 mmol) in 1,2-dichloroethane (DCE) (30 ml) and methanol (5 ml) is added as well as acetic acid (1.3 ml). The mixture is stirred for 1 minute at room temperature, then the sodium triacetoxyborohydride (4.78 g; 22 mmol) is added. The reaction is stirred for 24 hours. The resin is then filtered, washed successively with MeOH (2 x), H 2 O (2 x), MeOH (2x), CH 2 C1 2 (2 x), and finally dried (4.5 g; 90%).
• DCE 1,2-dichloroethane
• Compound 2 is prepared from IF resin (100 mg; 0.112 mmol) and thiophen-2-ylmethylamine according to the conditions used for the preparation of l_ and respecting the proportions of the various reagents. Quantity obtained: 22 mg (43%). HPLC (Cl 8, ⁇ 220 nM, 100% H2O to 100% CH 2 CN (+ 0.1% TFA) in 8 min): purity 77%.
• the IF resin (100 mg; 1.12 mmol / g; 0.112 mmol) is swollen with CH 2 CI 2 (2 x). Then, 1.1 ml of a solution of DIC (0.4M) and HOOBT (0.4M) in dichloromethane, and 1.1 ml of an amine solution (0.4M) in dichloromethane are added. In the case of amino acid type amines, the tert-butyl ester of the amino acid is used. The mixture is stirred for 18 hours at room temperature under a nitrogen atmosphere.
• the resin is then filtered, and rinsed successively with DMF (2 x), CH 2 CI 2 (2 x), MeOH (2x), H 2 O (2x), MeOH (2x) and CH 2 C1 2 (2 x) .
• a solution of acid chloride (0.36M in pyridme; 2.5 ml) or sulfonyl chloride (0.36M in CH 2 C1 2 -Pyridine 50-50; 2.5 ml) is added. The mixture is stirred 5.5 hours at room temperature and under a nitrogen atmosphere.
• the resin is filtered and then washed successively with DMF (2 x), CH 2 C1 2 (2 x), MeOH (2x), H 2 O (2x), MeOH (2x) and CH 2 CI2 (2 x).
• the resin is then cleaved by treatment with a TFA / CH2Cl2 ⁇ t 3 SiH 5/5/1 mixture (3 ml) for 2.5 hours to lead, after evaporation of the filtrate, to the expected product in the form of trifluoroacetate salt.
• the IQA compound is prepared from 2-fluoro-5-nitrobenzaldehyde (15 g; 89 mmol) according to the conditions used for the preparation of IB and respecting the proportions of the various reagents.
• the reaction crude is then purified by flash chromatography
• Example 0B - Ethyl 5-aminobenzo [Z>] thiophene-2-carboxylare Compound IQA (18.9 g; 75 mmol) is dissolved in ethanol (600 ml) under a nitrogen atmosphere. Tin chloride dihydrate (84.9 g; 376 mmol) is added and the reaction mixture is heated at 90 ° C for 18 hours. The reaction is brought to room temperature, then poured onto ice (800 g), and brought back to pH 7-8 by adding a saturated solution of sodium bicarbonate. The solution is extracted with ethyl acetate (2 x 21). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is then purified by flash chromatography (petroleum ether-CHîC 20/80; then 100% CH 2 C1 2 ), to give the desired product (13.6 g, 82%).
• Compound 10C is prepared from compound 10B (6.8 g; 31 mmol) according to the conditions used for the preparation of ID and respecting the proportions of the various reagents. Quantity obtained: 4.99 g (83%).
• Example 10 The trifluoroacetate of '(2S) 2 - ⁇ [5- (2-3H-imidazol-4-ylacetylamino) benzo [b] thiophene-2-carbonyl] amino ⁇ -4-methylpentanoic acid.
• the fmoc-Leu-Wang resin (2.3 g; 0.6 mmol / g; 1.3 mmol) is suspended in piperidine (20% in DMF; 35 ml), and stirred at room temperature for 1.5 hours. It is then filtered, and rinsed successively with DMF (2x), CH 2 CI 2 (2x),
• the resin is then filtered, rinsed successively with DMF (2x), C ⁇ 2 C1 2 (2x), MeOH (2x), CH 2 C1 2 (2x), MeOH (2x), and CH 2 C1 2 (2x). It is then cleaved by treatment with a TFA / CH Cl 2 ⁇ t 3 SiH 5/5/1 mixture (3 ml) for 2.5 hours.
• the oily residue obtained after evaporation is purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C-18 column (Waters; 25x100mm; 6 ⁇ m) using a total gradient of 100% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes, to give the expected product (30 mg; 45%).
• Compounds 11 to 26 are prepared from fmoc-Leu-Wang or Fmoc-Met-Wang resins, and derivatives ID or 10 ⁇ , according to the conditions used for the preparation of 10 and respecting the proportions of the various reagents.
• the desired products are obtained in the form of trifluoroacetate salts.
• the carboxylic acids involved in these syntheses are known: RCOOH Reference
• the organic phase is dried over sodium sulfate, filtered and then evaporated to dryness.
• the syrup obtained is purified by chromatography on a column of silica eluted with a CH 2 Cl 2 / Acetone 9/1 then 1/1 mixture to yield the pure product in the form of a yellow solid (4.8 g; 27%).
• the fmoc-Leu-Wang resin (700 mg; 0.6 mmol / g; 0.42 mmol) is suspended in piperidine (20% in DMF; 15 ml), and stirred at room temperature for 1.5 hours. It is then filtered, and rinsed successively with DMF (2x), CH 2 C1 2 (2x), MeOH (2x) and CH 2 C1 2 (2x). BOP (0.54 g; 1.7 mmol), NMP (10 ml), DIEA (0.29 ml; 1.7 mmol) and the derivative ID (121 mg; 0.63 mmol) are added. The whole is stirred at room temperature for 18 hours.
• the resin is then filtered, rinsed successively with DMF (2x), CH 2 C1 (2x), MeOH (2x), and CH 2 C1 2 (2x).
• This resin is then treated at room temperature with the derivative 27A (250 mg; 1.19 mmol) in DCE (10 ml) and acetic acid (91 ⁇ l; 1.6 mmol) for a few minutes, then sodium triacetoxyborohydride (340 mg; 1.6 mmol) is added and the mixture is stirred for 18 hours.
• the resin is then filtered, rinsed successively with MeOH (2x), H 2 O (2x), MeOH (2x), and CH 2 C1 2 (2x).
• This resin is again treated at room temperature with the derivative 27A (250 mg; 1.19 mmol) in DCE (10 ml) and acetic acid (91 ⁇ l; 1.6 mmol) for a few minutes, then sodium triacetoxyborohydride ( 340 mg; 1.6 mmol) is added and the mixture is stirred for 18 hours.
• the resin is then filtered, rinsed successively with MeOH (2x), H 2 O (2x), MeOH (2x), and CH 2 C1 2 (2x). A portion of this resin (100 mg) is then cleaved by treatment with a LiOH (1M / H 2 O) -MeOH-THF 1-2-5 mixture (3 ml) for 15 minutes at 50 ° C.
• the oily residue obtained after evaporation is purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C-18 column (Waters; 25x100mm; 6 ⁇ m) using a total gradient of 100% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes, to give the expected product (9 mg; 33%).
• Compounds 28 and 29 are prepared from the resins fmoc-Leu-Wang or Fmoc-Met -Wang, and the derivative 10 ⁇ according to the conditions described for the preparation of 27, respecting the proportions of the various reagents.
• the desired products are obtained in the form of trifluoroacetate salts.
• Compounds 30 to 33 are prepared from fmoc-Leu-Wang or Fmoc-Met-Wang resins, ID or 10C derivatives, and benzenesulfonyl chloride or 2-chlorobenzenesulfonyl chloride, according to the conditions described for the preparation of 30, respecting the proportions of the various reagents.
• the fmoc-Leu-Wang resin (700 mg; 0.6 mmol / g; 0.42 mmol) is suspended in piperidine (20% in DMF; 15 ml), and stirred at room temperature for 1.5 hours. It is then filtered, and rinsed successively with DMF (2x),
• This resin is then treated at room temperature with the derivative 27A (250 mg; 1.19 mmol) in DCE (10 ml) and acetic acid (91 ⁇ l; 1.6 mmol) for a few minutes, then sodium triacetoxyborohydride (340 mg; 1.6 mmol) is added and the mixture is stirred for 18 hours.
• the resin is then filtered, rinsed successively with MeOH (2x), H 2 O (2x), MeOH (2x), and CH 2 C1 2 (2x).
• This resin is again treated at room temperature with the derivative 27A (250 mg; 1.19 mmol) in DCE (10 ml) and acetic acid (91 ⁇ l; 1.6 mmol) for a few minutes, then sodium triacetoxyborohydride ( 340 mg; 1.6 mmol) is added and the mixture is stirred for 18 hours.
• the resin is then filtered, rinsed successively with MeOH (2x), H 2 O (2x), MeOH (2x), and CH 2 C1 2 (2x).
• a portion of this resin (150 mg) is then treated with benzenesulfonyl chloride (99 ⁇ l; 0.78 mmol) in dichloromethane (1.25 ml) and pyridine (1.25 ml), at room temperature for 18 hours.
• the resin is then filtered, rinsed successively with DMF (2x), CH 2 CI 2 (2x), H 2 O (2x), MeOH (2x), and CH 2 CI 2 (2x), then cleaved by treatment with a mixture LiOH (1 M / H 2 O) -MeOH-THF 1 -2-5 (3 ml) for 15 minutes at 55 ° C.
• Compound 35 is prepared from the derivative I ⁇ , under the conditions described for the preparation of 34, respecting the proportions of the various reagents.
• HPLC (Cl 8, ⁇ 220 nM, 100% H2O to 100% CH 2 CN (+ 0.1% TFA) in 8 n): purity
• Compound 37 is prepared from derivative 35, under the conditions described for the preparation of 36, respecting the proportions of the various reagents.
• HPLC Cl 8, ⁇ 220 nM, 100% H2O to 100% CH 2 CN (+ 0.1% TFA) in 25 min
• mass spectrum ESI: mz 557 (MH +).
• Compound 39 is prepared from derivative 37, under the conditions described for the preparation of 38, while respecting the proportions of the various reagents.
• Compounds 40 to 86 are prepared from derivatives 38 or 39, and commercial amines, according to the conditions described for the preparation of 40, respecting the proportions of the various reagents.
• Compound 38 120 mg; 0.23 mmol
• Compound 38 is dissolved in a mixture of DMF and CH 2 C1 2 (3 ml; 50/50 v / v) in the presence of H-Met-OMe (25 mg; 0.15 mmol), HOBT (34 mg; 0.26 mmol) and PS-Carbodiimide (Argonaut Technologies; 288 mg; 0.31 mmol).
• H-Met-OMe 25 mg; 0.15 mmol
• HOBT 34 mg; 0.26 mmol
• PS-Carbodiimide Argonaut Technologies; 288 mg; 0.31 mmol
• the whole is stirred at room temperature for 24 hours, then MP-Carbonate (Argonaut Technologies; 276 mg; 0.76 mmol) is added and the reaction is stirred again for 18 hours.
• Compound 10C (2.0 g; 10 mmol) is dissolved in dichloromethane (40 ml) and DMF (80 ml) under a nitrogen atmosphere.
• DIEA 3.3 ml; 29 mmol
• 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.89 g; 10 mmol)
• HOOBT 1-69 g; 10 mmol
• thiomorpholine (0.89 ml; 9 mmol
• Compound 89 is prepared from derivative 89B (1.57 g) according to the conditions used for the preparation of 34 and respecting the proportions of the various reactants.
• the crude reaction product is then purified by flash chromatography (Acetone-CH 2 Cl 2 : 20/80, then MeOH-CH 2 Cl 2 : 5/95), to give the desired product (1.92 g, 72%).
• HPLC (Cl 8, ⁇ 220 nM, 100% H2O to 100% CH 2 CN (+ 0.1% TFA) in 8 min): purity 93%.
• Example 90A La (4-aminobenzo [b] thiophen-2-yl) thiomorpholin-4-ylmethanone.
• Compound 90A is prepared from the derivative ID (2.27 g) according to the conditions used for the preparation of 89A and while respecting the proportions of the various reagents.
• the residual oil is purified by flash chromatography (CH2CI2 then CH 2 CI 2 - Acetone 80-20), to give the desired product (3.3 g).
• Example 90 4- (5 - ⁇ [2- (thiomorpholine-4-carbonyl) benzo [b] thiophen-4-ylamino] methyl ⁇ imidazol-1-ylmethyl) benzonitrile.
• Compound 90 is prepared from the derivative 90A (2.32 g) according to the conditions used for the preparation of 89 and respecting the proportions of the various reagents. The crude reaction is then purified by flash chromatography (CH2CI2, then gradient
• Compounds 91 to 107 are prepared from derivatives 89 or 90, and commercial acid chlorides, according to the conditions described for the preparation of 91, respecting the proportions of the various reagents.
• Compounds 108 and 109 are prepared from derivatives 89 or 90, according to the conditions described for the preparation of 108, while respecting the proportions of the various reagents.
• the residue is purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C-18 column (Waters; 25x100mm; 6 ⁇ m) using a total gradient of 100% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes, to give the desired product.
• Compounds 110 to 118 are prepared from derivatives 89 or 90, and corresponding aldehydes, according to the conditions described for the preparation of 110, respecting the proportions of the various reagents.
• Prep 4000 on a Prep Nova-Pak HR C-18 column (Waters; 25x100mm; 6 ⁇ m) using a total gradient of 100% water (0.1% TFA) to 100% acetonitrile ( 0.1% TFA) in
• the 2-fluorobenzaldehyde (10 g; 80 mmol) is dissolved in THF (400 ml). The solution is cooled to -78 ° C, then nBuLi (1.6M / THF; 50 ml; 80 mmol) is added.
• pyridinium chlorochromate (19.25 g; 59.5 mmol) is introduced into a suspension of celite (22 g) in dichloromethane (300 ml).
• the derivative 119A (11.2 g; 59.5 mmol) previously dissolved in dichloromethane (30 ml) is introduced, then the reaction medium is stirred for 17 hours at room temperature. It is then filtered through a mixture of 2/3 of silica and 1/3 of celite. The filtrate is concentrated under reduced pressure to give the desired product (10.6 g; 98%).
• EXAMPLE 119C The ethyl 3- (butan-1-yI) benzo [b] thiophene-2-carboxylate
• the derivative 119B (10 g; 35.5 mmol) is dissolved under nitrogen atmosphere in acetonitrile (400 ml ), in the presence of potassium carbonate (19.2 g; 138 mmol) and ethyl 2-mercaptoacetate (11.7 ml; 111 mmol).
• the reaction is stirred for 16 hours at 85 ° C.
• the acetonitrile is then evaporated and the residual solid obtained is recovered in 300 ml of water.
• This aqueous phase is extracted twice with 300 mL of acetate ethyl.
• the organic phases are combined and then washed with 300 ml of water.
• the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure.
• the residual oil is purified by flash chromatography (EDP-CH 2 C1 2 gradient
• Example 119E Ethyl 7-amino-3- (butan-1-yI) benzo [b] thiophene-2-carboxylate
• Compound 119E is prepared from compound 119F (1.56 g; 5 mmol) according to the conditions used for the preparation of 10B and while respecting the proportions of the various reagents.
• the derivative 119E (1.26 g; 4.5 mmol) and the compound 27A (1.15 g; 4.5 mmol) are dissolved under nitrogen atmosphere in DCE (32 ml) in the presence of acetic acid (1.2 ml; 23 mmol).
• the mixture is stirred for 48 hours at room temperature, then neutralized with a saturated aqueous solution of sodium bicarbonate.
• the two phases are separated, and the aqueous phase is washed twice with dichloromethane.
• the organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
• the residual oil is purified by flash chromatography (acetone-CH 2 ⁇ 2 0-100 to 50-50 gradient), to give the intermediate imine (1.19 g; 55%).
• Compound 120 is prepared from compound 119 (750 mg; 1.6 mmol) according to the conditions used for the preparation of ID and respecting the proportions of the various reagents.
• Compounds 121 to 126 are prepared from compound 120 (50 mg; 0.11 mmol) and commercial amines, according to the conditions used for the preparation of 40 and respecting the proportions of the various reagents.
• Compound 127A is prepared from the derivative 10C (1.5 g) and thiophene-2-ethylamine (1.36 ml; 11 mmol) according to the conditions used for the preparation of 89A and respecting the proportions of the various reagents.
• the residual oil is purified by flash chromatography (CH 2 C1 2 then CH 2 C1 2 - Acetone 80-20, then CH 2 Cl 2 -EtOAc 70-
• Compound 127 is prepared from the derivative 127A (908 mg) according to the conditions used for the preparation of 89 and respecting the proportions of the various reagents. The crude reaction product is then purified by flash chromatography (CH 2 CI2, then Acetone-
• Compounds 128 to 136 are prepared from compound 10C and commercial amines, according to the conditions used for the preparation of 127 and respecting the proportions of the various reagents. Some aldehydes used are not commercial and have been prepared as follows: 1-Methyl-7H-imidazole-5-carboxaldehyde.
• the trifluoromethanesulfonic anhydride (0.99 ml; 5.9 mmol) is diluted in dichloromethane (22 ml) then the whole is cooled to -78 ° C and treated with a solution of benzyl alcohol (0.61 ml; 5.9 mmol) and 2,6-diisopropylpyridine (1.34 ml; 6.0 mmol) in dichloromethane (9 ml).
• the benzyl trifluoromethanesulfonate thus formed is cannulated in the first solution and the reaction is allowed to return to room temperature slowly (for 2 hours).
• a phosphate buffer solution (p ⁇ 7; 20 ml) is added, and the two-phase mixture is stirred vigorously for 15 minutes.
• the two phases are then separated, and the aqueous phase is extracted three times with dichloromethane.
• the organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
• the residual oil is purified by flash chromatography (CH 2 C1 2 , then Acetone-CH 2 Cl 2 5/95, then MeOH-CH 2 Cl 2 5/95), to give the desired product (615 mg, 56%) .
• the compound was purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C-18 column (Waters; 25 100mm; 6 ⁇ m) using a total gradient of 100% d water (0.1% TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes.
• Compounds 138 to 155 are prepared from derivatives 127, 135 or 136, and commercial acid chlorides, according to the conditions described for the preparation of 91, while respecting the proportions of the various reagents.
• Compounds 156 and 157 are prepared from derivatives 38 or 39, according to the conditions described for the preparation of 40, while respecting the proportions of the various reagents.
• the products were purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C-18 column (Waters; 25x100mm; 6 ⁇ m) using a total gradient of 100% water (0.1 % TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes.
• Example 158B methyl (2S) 4-methylsulfanyl-2 - [(5-amino-3-phenyl-li ⁇ -indole-2-carbonyI) -amino] -butyrate.
• Example 158C (2S) 4-Methylsulfanyl-2 - ( ⁇ 3-phenyl-5 - [(l-trityl-1H-imidazol-4-ylmethyl) -amino] -l / - r -indole-2-carbonyl ⁇ - amino) -methyl butyrate.
• Example 159A 4-methylsulfanyl-2 - [(5 - ⁇ [3- (4-cyano-benzyl) -3H-imidazol-4-ylmethyl] -amino ⁇ -3-phenyl-1-ji-indole-2-carbonyl) - amino] -methyl butyrate.
• a mixture comprising compound 158B (300 mg; 0.75 mmol) and compound 27A (159 mg; 0.75 mmol) in solution in 1,2-dichloroethane (DCE) (3.5 ml) in the presence of acetic acid (1.3 ml) is stirred for 1 minute at room temperature, then sodium triacetoxyborohydride (175 mg; 0.82 mmol) is added. The mixture is stirred overnight at room temperature then it is diluted with ethyl acetate and washed successively with a saturated solution of NaHCO 3 , water and a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated.
• DCE 1,2-dichloroethane
• Example 160A (2S) 2 - ( ⁇ 5- [Benzenesulfonyl- (l-trityl-l # -imidazol-4-ylméthyI) - amino] -3-phenyl-1H-indole-2-carbonyl ⁇ -amino) -4 - (methylsulfanyl) -methyl butyrate
• Compound 158C (150 mg; 0.21 mmol) in solution in pyridine (2.5 ml) is treated, at room temperature, with benzene sulfonyl chloride (53 ⁇ l; 0.42 mmol). After stirring overnight at room temperature, the medium is evaporated to dryness.
• Example 160B (2S) 2 - ( ⁇ 5- [Benzenesulfonyl- (l-trityl-li ⁇ -imidazol-4-ylmethyl) -amino] -amino] -3-phenyl-1 J H r -indole-2-carbonyl ⁇ -amino acid ) -4-methylsulfanyl- butyric
• Compound 161 is prepared from compound 159 A (200 mg; 0.34 mmol) according to the procedure described for the preparation of Example 160B from 158C. The pure compound is isolated in the form of a white foam (88 mg, 44%). Mass spectrum (ESI): m / z 719 (M + H +).
• Acid 162B (50 mg; 0.11 mmol) in DMF (0.5 ml) is treated with PS-carbodiimide resin (94 mg; 1.05 mmol / g; 0.11 mmol) and with a solution of HOBT (1 1.5 mg; 0.085 mmol) in DMF (3 ml) for 30 min then thiophen-2-yl-methylamine (8.4 mg; 0.0744 mmol) in solution in DMF (1 ml) is added and the mixture is stirred at room temperature for 24 h. The medium is diluted with CH 2 C1 2 (3 ml) then treated with MP-carbonate resin (77.5 mg; 3.2 mmol / g; 0.24 mmol).
• Example 163 A - 5 - [[3- (4-Cyano-benzyl) -3H-imidazol-4-ylmethyl] - (4-nitro-benzoyl) -amino] -3-phenyl-11-indole-2-indole-2-carboxylic acid
• Compound 163 is obtained from acid 163 A (50 mg; 0.083 mmol) and thiophen-2-yl-methylamine according to the procedure described for the transformation of Example 162B in 162 (30 mg; 45%).
• the derivatives of the present invention are inhibitors of prenylation of proteins and more particularly of farnesylation of ras proteins as shown by studies of inhibition of the famesyl transferase protein and of the geranylgeranyl transferase protein.
• Examples 170 to 186 Compounds 170 to 180 are prepared in the form of TFA salts from the derivatives 127, 135 or 136, and the corresponding aldehydes, according to the conditions described for the preparation of 170, while respecting the proportions of the various reagents.
• Compound 127 50 mg; 0.11 mmol
• methanol 1.5 ml
• acetic acid 0.68M / EtOH; 0.5 ml; 0.45 mmol
• the supported cyanoborohydride (Fluka; 2 mmol / g; 169 mg; 0.33 mmol) is added and the whole is stirred at room temperature until disappearance of the product 127.
• the reaction mixture is filtered, and the polymer is rinsed twice with methanol. The solution is concentrated.
• the residue is purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C ⁇ 8 column (Waters; 25 x 100 mm; 6 ⁇ m) using a total gradient of 100% water ( 0.1% TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes, then lyophilized to give the product 170 in the form of TFA salt.
• the compounds 181 to 185 are prepared in the form of HCl salts from the derivative 127, and the corresponding aldehydes, according to the conditions described for the preparation of 159A, in the presence of a large excess of aldehyde. They are then purified by HPLC preparation (Waters Prep 4000), on xth column Prep Nova-Pak HR C 18 (Waters; 25 x
• Example 177 9.30 (t, 1H); 9.16 (s, 1H); 7.90-7.86 (m, 3H); 7.73 (d, 1H); 7.50-7.40 (m, 4H); 7.10-7.0 (m, 2H); 6.97 (dd, 1H); 6.84 (dd, 1H); 5.60 (s, 2H); 4.63 (d, 2H); 4.45 (s, 2H); 3.19 (t, 2H); 1.38 (se, 2H); 1.3-1.2 (m, 8H); 0.84 (t, 3H).
• Example 179 9.30 (t, 1H); 9.14 (s, 1H); 7.9-7.86 (m, 3H); 7.73 (d, 1H); 7.5-7.4 (m, 4H); 7.1-7.0 (m, 2H); 6.98 (dd, 1H); 6.83 (dd, 1H); 5.59 (s, 2H); 4.63 (d, 2H); 4.46 (s, 2H); 3.20 (t, 2H); 1.38 (quin, 2H); 1.21 (sex, 2H); 0.83 (t, 3H).
• Example 181 9.33 (s, 1H); 8.93 (t, 1H); 8.80 (d, 1H); 8.76 (s, 1H); 8.33 (d, 1H); 7.96 (t, 1H); 7.89 (d, 2H); 7.83 (s, 1H); 7.75 (d, 1H); 7.60 (s, 1H); 7.45 (d, 2H); 7.33 (d, 1H), 7.15-7.10 (m, 2H); 7.00-6.90 (m, 2H); 5.66 (s, 2H); 4.79 (s, 2H); 4.71 (s, 2H); 3.48 (q, 2H); 3.07 (t, 2H).
• Examples 186 to 222 Compounds 186 to 222 are prepared from derivatives 127, 135 or 136, and corresponding acid chlorides, according to the conditions described for the preparation of 91, while respecting the proportions of the various reagents. The products are then purified by filtration on silica using CombiFlash Optix 10 (Isco), and using a gradient of methanol in dichloromethane (0 to 10%). Compounds 186 to 198 and 205 to 222 were taken up in a mixture of water, acetonitrile and TFA, then lyophilized to be characterized in the form of TFA salts.
• Example 201 9.45 (t, 1H); 8.04 (s, 1H); 8.01 (d, 1H); 7.80 (d, 2H); 7.75 (s, 1H); 7.60 (s, 1H); 7.41 (d, 1H); 7.21 (d, 2H); 7.09 (d, 1H); 7.05 (s, 1H); 6.98 (dd, 1H); 6.52 (s, 1H); 5.32 (s, 2H); 4.82 (s, 2H); 4.65 (d, 2H); 1.88 (t, 2H); 1.34 (quin, 2H); 1.07 (sex, 2H); 0.71 (t, 3H).
• Example 202 9.45 (t, 1H); 8.04 (s, 1H); 8.01 (d, 1H); 7.80 (d, 2H); 7.75 (s, 1H); 7.59 (s, 1H); 7.42 (d, 1H); 7.21 (d, 2H); 7.09 (d, 1H); 7.05 (d, 1H); 6.98 (dd, 1H); 6.53 (s, 1H); 5.32 (s, 2H); 4.82 (s, 2H); 4.65 (d, 2H); 1.87 (t, 2H); 1.35-1.00 (m, 8H); 0.76 (t, 3H).
• Example 214 9.48 (t, 1H); 9.18 (s, 1H); 8.1-8.0 (m, 2H); 7.86 (d, 2H); 7.79 (d, 1H); 7.50 (s, 1H); 7.45-7.40 (m, 3H); 7.23 (dd, 1H); 7.06 (d, 1H); 6.99 (dd, 1H); 5.56 (s, 2H); 4.93 (s, 2H); 4.66 (d, 2H); 1.97 (sep, 1H); 1.86 (d, 2H); 0.74 (d, 6H).
• Example 223 Compound 223 is prepared from the derivative 10B (1.5 g, 6.7 mmol) and aldehyde 223 A, according to the conditions described for the preparation of 34, respecting the proportions of the various reactants. Quantity obtained: 2.19 g (86%). A fraction of this product is taken up in a mixture of water, acetonitrile and TFA, then lyophilized to be characterized.
• Compound 224 is prepared from derivative 223 (2.65 g, 6.7 mmol) and n-butyraldehyde, according to the conditions described for the preparation of 34, respecting the proportions of the various reactants. Quantity obtained: 1.23 g (41%). A fraction of this product is taken up in a mixture of water, acetonitrile and TFA, then lyophilized to be characterized.
• the residual oil is purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C 18 column (Waters; 25 x 100 mm; 6 ⁇ m) using a total gradient of 100% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) in 15 minutes, to give the desired product in the form of TFA salt (111 mg, 82%).
• HPLC (Cis, ⁇ 220 nm, 100% H 2 O to 100% CH 3 CN (+ 0.1% TFA) in 8 min): purity 99%.
• Example 227A - ⁇ 5 - [(3-Benzyl-5H-imidazol-4-ymethyl) butylamino] benzo [b] thiophen-2-yl ⁇ methanal.
• Compound 225 (799 mg; 1.97 mmol) is dissolved in DMSO (10 ml) at room temperature and under a nitrogen atmosphere.
• Triethylamine (1.1 ml; 7.88 mmol) and the sulfur trioxide-pyridine complex (783 mg; 4.92 mmol) are added, then the reaction mixture is stirred for 5 hours.
• Ethyl acetate (50 ml) is added, and the reaction is washed with 80 ml of water. The aqueous phase is extracted twice with ethyl acetate.
• Example 227 - Compound 227 is prepared from the derivative 227A (120 mg, 0.3 mmol) and n-propylamine, according to the conditions described for the preparation of 34, respecting the proportions of the various reagents.
• the residual oil is purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR C ⁇ 8 column (Waters; 25 x 100 mm; 6 ⁇ m) using a total gradient of 100% water (0.1% TFA) at 100% acetonitrile (0.1% TFA) in 15 minutes, to give the desired product in the form of TFA salt (47 mg; 46%).
• Example 228A Buryltriphenylphosphonium iodide.
• the triphenylphosphine (4.35 g; 17 mmol) is dissolved in toluene (75 ml) under a nitrogen atmosphere and in the presence of 1-iodobutane (1.8 ml; 16 mmol).
• the reaction mixture is heated overnight to 90 ° C, then cooled to 0 ° C.
• the desired product precipitates. It is filtered and dried (2.55 g; 36%).
• Example 228 - Compound 228A (1.1 g; 0.49 mmol) is dissolved under a nitrogen atmosphere in 1,4-dioxane (4 ml), then potassium tert-butoxide (IM / THF; 2.5 ml; 2.5 mmol) is added. A bright orange color immediately appears.
• Compound 227A (200 mg; 0.19 mmol), pre-diluted in dioxane (4 ml), is then added. The reaction mixture is stirred for 20 minutes at room temperature, then neutralized by adding water. The aqueous phase is extracted three times with DCM. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated. Residual oil is purified by preparative HPLC using a gradient total of 100% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) in 50 minutes, to give the desired product in the form of TFA salt (279 mg, 100%).
• Example 230B Ethyl 4-benzylamino-3-propylbenzo [b] thiophene-2-carboxylate.
• Compound 230B is prepared from compound 230A (11.4 g, 42 mmol) according to the conditions used for the preparation of 1B_ while respecting the proportion of the various reactants. Quantity obtained: 11.1 g (74%).
• Example 230 - Compound 230C (754 mg; 3.2 mmol) is dissolved in 1,2-DCE (28 ml) in the presence of the derivative 27A (809 mg; 3.8 mmol) and acetic acid (820 ⁇ l; 14 mmol) , at room temperature and under a nitrogen atmosphere, for a few minutes, then sodium triacetoxyborohydride (1.03 g; 4.9 mmol) is added. After 18 hours of stirring, ethyl acetate (50 ml) and a saturated aqueous sodium bicarbonate solution (100 ml) are added.
• the aqueous phase is extracted twice with ethyl acetate.
• the organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
• the crude reaction product is then purified by flash chromatography to give the intermediate imine (688 mg). This is dissolved in methanol (5 ml) and THF (18 ml) under a nitrogen atmosphere and at room temperature, then sodium borohydride (170 mg) is added. After 18 hours of stirring, the reaction mixture is concentrated, then taken up in DCM and filtered through celite. The filtrate is concentrated, and the residue is purified by flash chromatography (Acetone / DCM 20/80, then DCM MeOH 90/10), to give the desired product (790 mg, 66%). A fraction of this product is taken up in a mixture of water, acetonitrile and TFA, then lyophilized to be characterized.
• the compounds 231 and 232 are prepared in the form of TFA salts from the derivative 230 and the corresponding acid chlorides, according to the conditions described for the preparation of 231, while respecting the proportions of the various reagents.
• Example 231 7.92 (d, 1H); 7.81 (s, 1H); 7.69 (d, 2H); 7.46 (t, 1H); 7.35-7.25 (m, 1H); 7.20-7.00 (m, 6H); 6.83 (s, 1H); 6.77 (d, 1H); 5.54 (d, 1H); 5.42 (d, 1H); 5.22 (d, 1H); 4.34 (q, 2H); 4.20 (d, 1H); 3.30-3.10 (m, 2H); 1.55-1.35 (m, 2H); 1.33 (t, 3H); 0.89 (t, 3H).
• Compound 234 is prepared from derivative 233 (870 mg, 1.73 mmol), according to the conditions described for the preparation of ID, respecting the proportions of the various reagents, but only heating at 40 ° C for 2 hours. Quantity obtained: 668 mg (82
• Compounds 235 to 247 are prepared in the form of TFA salts from the derivative 234 and the corresponding amines, according to the conditions described for the preparation of 40, respecting the proportions of the various reagents.
• the products are then purified by filtration on silica using CombiFlash Optix 10 (Isco), and using a gradient of methanol in dichloromethane (0 to 10%). They are then taken up in water, acetonitrile and TFA, then lyophilized to be characterized.
• Example 244 9.17 (s, 1H); 8.79 (t, 1H); 8.05-8.00 (m, 2H); 7.85 (d, 2H); 7.77 (d, 1H); 7.49 (s, 1H); 7.41 (d, 2H); 7.21 (dd, 1H); 5.56 (s, 2H); 4.93 (s, 2H); 3.24 (q, 2H); 1.96 (sep, 1H); 1.86 (d, 2H); 1.55 (sex, 2H); 0.91 (t, 3H); 0.74 (d, 6H).
• Example 248 9.17 (s, 1H); 8.79 (t, 1H); 8.05-8.00 (m, 2H); 7.85 (d, 2H); 7.77 (d, 1H); 7.49 (s, 1H); 7.41 (d, 2H); 7.21 (dd, 1H); 5.56 (s, 2H); 4.93 (s, 2H); 3.24 (q, 2H); 1.96 (sep, 1H); 1.86 (d, 2H); 1.55 (
• Compound 248 is prepared from derivative 34 (5.48 g, 13 mmol) and n-pentanoyl chloride, according to the conditions described for the preparation of 233, respecting the proportions of the various reactants. Quantity obtained: 5.41g (83%). HPLC (C 18 , ⁇ 220 nm, 100% H 2 O to 100% CH 3 CN (+ 0.1% TFA) in 8 min): purity 98%.
• Compound 249 is prepared from derivative 248 (5.41 g, 11 mmol), according to the conditions described for the preparation of 234, respecting the proportions of the various reagents. Quantity obtained: 5.1 g (98%).
• the compounds 250 to 256 are prepared in the form of HCl salts from the derivative 249 and the corresponding amines, according to the conditions described for the preparation of 40, respecting the proportions of the various reagents.
• the products are then purified by preparative HPLC (Waters Prep 4000), on a Prep Nova-Pak HR Ci s column (Waters; 25 x 100 mm; 6 ⁇ m) using a total gradient of 100% water (0.1% HCl) to 100% acetonitrile (0.1% HCl) in 15 minutes, then lyophilized to give the desired products in the form of HCl salts.
• Example 252 9.27 (s, 1H); 9.09 (t, 1H); 8.84 (s, 1H); 8.74 (d, 1H); 8.39 (d, 1H); 8.07-8.00 (m, 2H); 7.90 (t, 1H); 7.85 (d, 2H); 7.78 (s, 1H); 7.53 (s, 1H); 7.42 (d, 2H); 7.23 (d, 1H); 5.58 (s, 2H); 4.91 (s, 2H); 3.63 (t, 2H); 3.08 (t, 2H); 1.95 (t, 2H); 1.38 (quin, 2H); 1.09 (sex, 2H); 0.72 (t, 3H).
• Compound 257A is prepared from the derivative 10 A (6.48 g, 29 mmol), according to the conditions used for the preparation of ID and respecting the proportions of the various reagents. Quantity obtained (13.1 g, 99%).
• Example 257B N- (pyridin-3-ylmethyl) -5-nitrobenzo [£] thiophene-2-carboxamide.
• Compound 257B is prepared from the derivative 257A (6.48 g, 29 mmol) and 3-aminomethylpyridine according to the conditions used for the preparation of 89A and respecting the proportions of the various reagents. At the end of the reaction, the medium is concentrated, then taken up in DCM and water. The desired product precipitates. It is filtered and dried. Quantity obtained: 7.7 g
• Example 257C N- (pyridin-3-ylmethyl) -5-aminobenzo [b] thiophene-2-carboxamide.
• Compound 257C is prepared from the derivative 257B (7.9 g, 25 mmol) according to the conditions used for the preparation of 229 and while respecting the proportions of the various reagents. Quantity obtained: 6.41 g (90%) Mass spectrum (ESI): m / z 284 (MH + ).
• Example 257 - Compound 257 is prepared from the derivative 257C (3.5 g, 12.3 mmol) and aldehyde 27A according to the conditions used for the preparation of 230 and respecting the proportions of the various reagents. Quantity obtained: 5.2 g (72%)
• Example 258A N- (2-Pyridin-2-ylethyl) -5-nitrobenzo [b] thiophene-2-carboxamide.
• Compound 258A is prepared from derivative 257A (6.4 g, 29 mmol) and 2- (2-aminoethyl) pyridine according to the conditions used for the preparation of
• Example 258B N- (2-Pyridin-2-ylethyl) -5-aminobenzo [é] raiophene-2-carboxamide.
• Compound 258B is prepared from the derivative 258A (8.7 g, 26 mmol) according to the conditions used for the preparation of 229 and while respecting the proportions of the various reagents. Quantity obtained: 7.52 g (95%)
• Example 258 - Compound 258 is prepared from the derivative 258B (4.0 g, 13.4 mmol) and aldehyde 27A according to the conditions used for the preparation of 230 and respecting the proportions of the various reagents. Quantity obtained: 5.38 g Mass spectrum (ESI): m / z 493 (MH + ).
• Example 259B La (5-aminobenzo [b] thiophen-2-yl) - (4-methylpiperazin-1-yI) methanone.
• Compound 259B is prepared from the derivative 259A (3.69 g, 12 mmol) according to the conditions used for the preparation of 229 and while respecting the proportions of the various reagents. Quantity obtained: 3.17 g (95%)
• Example 259 - Compound 259 is prepared from the derivative 259B (0.9 g, 3.3 mmol) and aldehyde 27A according to the conditions used for the preparation of 230 and respecting the proportions of the various reagents. Quantity obtained: 1.14 g
• Compound 260A is prepared from derivative 257A (3.2 g, 14 mmol) and 2-pyrrolidin-1-ylethylamine according to the conditions used for the preparation of
• Example 260 - Compound 260 is prepared from the derivative 260B (1.5 g; 5.2 mmol) and the aldehyde 27A according to the conditions used for the preparation of 230 and respecting the proportions of the various reactants. Quantity obtained: 1.68 g (57%) HPLC (XTerra MS, ⁇ 220 nm, 100% H 2 O at 100% CH 3 CN (+ 0.1% TFA) in 6 min): purity 86%.
• Example 261A N- (2-morpholino-4-ylethyl) -5-nitrobenzo [b] thiophene-2-carboxamide.
• Compound 261A is prepared from the derivative 257A (2.6 g, 12 mmol) and from 1- (2-aminoethyl) mo ⁇ holine according to the conditions used for the preparation of 89A and respecting the proportions of the various reagents.
• the medium is concentrated, then taken up in DCM and water and 20 ml of IN sodium hydroxide solution.
• the aqueous phase is extracted three times with DCM.
• the organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
• Example 261B N- (2-morpholino-4-ylethyl) -5-aminobenzo [b] thiophene-2-carboxamide.
• Compound 261B is prepared from derivative 261A (4.76 g) according to the conditions used for the preparation of 229 and while respecting the proportions of the various reagents. Quantity obtained: 3.22 g (90%)
• Example 261 - Compound 261 is prepared from the derivative 261B (1.00 g; 3.27 mmol) and aldehyde 27A according to the conditions used for the preparation of 230 and respecting the proportions of the various reagents. Quantity obtained: 568 mg
• the compounds 262 to 264 are prepared in the form of HCl salts from the derivative 127, and the corresponding sulfonyl chlorides, according to the conditions described for the preparation of 36, respecting the proportions of the various reagents.
• Example 262 9.20 (s, 1H); 9.00 (t, 1H); 8.05-7.85 (m, 5H); 7.69 (s, 1H); 7.55 (d, 2H); 7.46 (d, 2H); 7.34 (d, 1H); 7.00-6.90 (m, 3H); 5.68 (s, 2H); 5.02 (s, 2H); 3.80-3.4 (m, H 2 O + 3H); 3.55-3.50 (m, 2H); 3.08 (t, 2H).
• Example 265 9.77 (t, 1H); 9.21 (s, 1H); 8.83 (s, 1H); 8.74 (d, 1H); 8.32 (d, 1H); 8.08 (s, 1H); 7.93 (d, 2H); 7.90 (d, 1H); 7.86 (dd, 1H); 7.51 (d, 1H); 7.50 (s, 1H); 7.47 (d, 2H); 7.41 (AB, 4H); 6.89 (dd, 1H); 5.67 (s, 2H); 4.89 (s, 2H); 4.61 (d, 2H); 2.42 (s, 3H).
• Example 272 9.22 (s, 1H); 9.18 (t, 1H); 8.78 (d, 1H); 8.36 (t, 1H); 7.95 (s, 1H); 7.94 (d, 2H); 7.87 (d, 2H); 7.80 (te, 1H); 7.50- 7.40 (m, 8H); 6.86 (d, 1H); 5.67 (s, 2H); 4.90 (s, 2H); 3.72 (q, 2H); 3.29 (t, 2H); 3.01 (Sept, 1H); 1.23 (d, 6H).
• Example 276 9.83 (t, 1H); 9.24 (s, 1H); 8.86 (s, 1H); 8.78 (d, 1H); 8.39 (d, 1H); 8.13 (d, 2H); 8.10 (s, 1H); 7.95-7.8 (m, 3H); 7.71 (d, 2H); 7.55 (s, 1H); 7.52 (s, 1H); 7.46 (d, 2H); 6.93 (d, 1H); 5.66 (s, 2H); 4.98 (s, 2H); 4.65 (d, 2H).
• Example 284 9.68 (t, 1H); 9.20 (s, 1H); 8.80 (s, 1H); 8.72 (d, 1H); 8.27 (d, 1H); 8.07 (s, 1H); 7.95-7.75 (m, 5H); 7.72 (d, 1H); 7.68 (s, 1H); 7.60-7.2 (m, 5H); 7.10 (d, 1H); 5.63 (s, 2H); 5.17 (s, 2H); 4.61 (d, 2H).
• Example 294 10.68 (sc, 1H); 9.37 (t, 1H); 9.24 (s, 1H); 8.15 (s, 1H); 7.90-7.85 (m, 3H); 7.75-7.65 (m, 4H); 7.58 (s, 1H); 7.45-7.35 (m, 3H); 7.09 (d, 1H); 5.65 (s, 2H); 5.17 (s, 2H); 3.64 (se, 4H); 3.34 (de, 2H); 2.95 (sc, 2H); 2.09 (sc, 2H); 2.05-1.80 (m, 2H).
• Compounds 295 to 332 are prepared in the form of HCl salts from derivatives 257, 258, 259 or 260 and the corresponding acid chlorides, according to the conditions described for the preparation of 91, respecting the proportions of the various reactants .
• the products are then purified by filtration on silica using the CombiFlash Optix 10 (Isco), and using a gradient of methanol in dichloromethane (0 to 20%). Finally, they are taken up in a mixture of water, acetonitrile and hydrochloric acid (IN in water), then lyophilized to be characterized.
• Example 298 9.90 (t, 1H); 9.31 (s, 1H); 8.90 (s, 1H); 8.80 (d, 1H); 8.46 (d, 1H); 8.23 (s, 1H); 8.05 (d, 1H); 7.97 (t, 1H); 7.84 (d, 2H); 7.80 (s, 1H); 7.55 (s, 1H); 7.41 (d, 2H); 7.26 (d, 1H); 5.59 (s, 2H); 4.92 (s, 2H); 4.58 (d, 2H); 1.94 (t, 2H); 1.40 (quin, 2H); 1.20-1.00 (m, 4H); 0.76 (t, 3H).
• Example 304 9.30 (s, 1H); 9.20 (t, 1H); 8.82 (d, 1H); 8.45 (t, 1H); 8.08 (s, 1H); 8.03 (d, 1H); 7.95 (d, 1H); 7.89 (t, 1H); 8.85 (d, 2H); 7.79 (s, 1H); 7.51 (s, 1H); 7.40 (d, 2H); 7.26 (d, 1H); 5.58 (s, 2H); 4.96 (s, 2H); 3.75 (q, 2H); 3.34 (t, 2H); 1.90 (se, 1H); 0.79 (sc, 2H); 0.60 (se, 2H).
• Example 306 9.27 (s, 1H); 9.03 (t, 1H); 8.84 (s, 1H); 8.74 (d, 1H); 8.39 (d, 1H); 8.10-8.00 (m, 2H); 7.90 (t, 1H); 7.85 (d, 2H); 7.78 (s, 1H); 7.53 (s, 1H); 7.42 (d, 2H); 7.23 (d, 1H); 5.58 (s, 2H); 4.91 (s, 2H); 3.8-3.2 (m, H 2 O + 2H); 3.08 (t, 2H); 1.95 (t, 2H); 1.38 (quin, 2H); 1.09 (sex, 2H); 0.72 (t, 3H).
• Example 314 9.88 (t, 1H); 9.31 (s, 1H); 8.88 (s, 1H); 8.79 (d, 1H); 8.43 (d, 1H); 8.23 (s, 1H); 8.06 (d, 1H); 7.94 (dd, 1H); 7.84 (d, 2H); 7.81 (s, 1H); 7.51 (s, 1H); 7.39 (d, 2H); 7.29 (dd, 1H); 5.58 (s, 2H); 4.98 (s, 2H); 4.66 (d, 2H); 1.2 (sc, 1H); 0.80 (sc, 2H); 0.61 (q, 2H).
• Example 322 11.56 (sc, 1H); 9.30 (s, 1H); 7.90-7.80 (m, 3H); 7.68 (s, 1H); 7.62 (s, 1H); 7.60 (s, 1H); 7.42 (d, 2H); 7.35-7.15 (m, 6H); 5.67 (s, 2H); 5.13 (s, 2H); 4.35 (sc, 2H); 3.70 (sc, H 2 O + 2H); 3.43 (se, 2H); 3.10 (sc, 2H); 2.77 (s, 3H).
• Example 327 10.64 (sc, 1H); 9.35 (t, 1H); 9.25 (s, 1H); 8.22 (s, 1H); 8.04 (d, 1H); 7.85 (d, 2H); 7.78 (s, 1H); 7.54 (s, 1H); 7.41 (d, 2H); 7.26 (dd, 1H); 5.57 (s, 2H); 4.92 (s, 2H); 3.63 (te, 4H); 3.35 (de, 2H); 3.04 (sc, 2H); 2.05-1.85 (m, 6H); 1.43 (sex, 2H); 0.73 (t, 3H).
• Example 331 10.62 (sc, 1H); 9.32 (t, 1H); 9.28 (s, 1H); 8.10 (s, 1H); 7.9-7.8 (m, 3H); 7.70 (s, 1H); 7.64 (s, 1H); 7.40 (d, 2H); 7.19 (d, 1H); 7.06 (t, 1H); 6.78 (sc, 3H); 5.66 (s, 2H); 5.13 (s, 2H); 3.65-3.5 (m, 7H); 3.33 (de, 2H); 3.02 (sc, 2H); 2.00 (se, 2H); 1.95-1.85 (m, 2H).
• Compounds 333 to 340 are prepared, in the form of HCl salts, from derivatives 257, 258, 259 or 260 and the corresponding aldehydes, according to the conditions described for the preparation of 170, respecting the proportions of the various reagents.
• the products are then purified by filtration on silica using the CombiFlash Optix 10 (Isco), and using a gradient of methanol in dichloromethane (0 to 20%). Finally, they are taken up in a mixture of water, acetonitrile and hydrochloric acid (IN in water), then lyophilized to be characterized.
• Example 335 8.01 (s, 1H); 7.81 (d, 2H); 7.70 (d, 1H); 7.53 (s, 1H); 7.22 (d, 2H); 7.01 (d, 1H); 6.9-6.8 (m, 2H); 5.39 (s, 2H); 4.35 (s, 2H); 3.90 (se, 4H); 3.12 (sc, 6H); 2.69 (s, 3H); 1.41 (sex, 2H); 0.78 (t, 3H).
• Example 336 9.32 (s, 1H); 7.88 (d, 2H); 7.74 (d, 1H); 7.58 (s, 1H); 7.50 (s, 1H); 7.44 (d, 2H); 7.06 (sc, 1H); 6.85 (from, 1H); 5.64 (s, 2H); 4.47 (s, 2H); 4.42 (de, 2H); 3.54 (sc, 2H); 3.45 (from, 2H); 3.22 (te, 2H); 3.11 (qe, 2H); 2.78 (d, 3H); 1.38 (quin, 2H); 1.22 (sex, 2H); 0.83 (t, 3H).
• Example 337 9.30 (s, 1H); 9.03 (se, 1H); 8.82 (d, 1H); 8.47 (t, 1H); 7.95 (d, 1H); 7.93- 7.85 (m, 4H); 7.69 (d, 1H); 7.48 (s, 1H); 7.43 (d, 2H); 7.00 (se, 1H); 6.83 (d, 1H); 5.63 (s, 2H); 4.48 (s, 2H); 3.73 (from, 2H); 3.34 (t, 2H); 3.19 (t, 2H); 1.43 (q, 2H); 0.80 (t, 3H).
• Compound 341 is prepared, in the form of the HCl salt, from the derivative 259B (60 mg;
• Compound 342 is prepared, in the form of the HCl salt, from the derivative 257C (60 mg; 0.21 mmol) and l-methyl-2-formylbenzimidazole, according to the conditions described for the preparation of 170, respecting the proportions various reagents.
• the residue is purified by preparative HPLC (Waters Prep 4000), on xm column Prep Nova-Pak HR C 18
• Compound 343 is prepared from the 259B derivative (64 mg; 0.23 mmol) and 2-pyridin-3-ylacetic acid, according to the conditions described for the preparation of 40, respecting the proportions of the various reagents. Quantity obtained: 35 mg (42%) HPLC (C 18 XTerra, ⁇ 220 nm, 100% H 2 O to 100% CH 3 CN (+ 0.1% TFA) in 8 min): purity 99%.
• Example 344A - iV- (Pyridin-4-yl) -5-nitrobenzo [b] thiophene-2-carboxamide Compound 344A is prepared from the derivative 257A (2.5 g, 11 mmol) and 4-aminopyridine (1.37 g; 14 mmol) according to the conditions used for the preparation of 89 A, respecting the proportions of the various reagents, using DMF as solvent, and heating at 45 ° C for 24 hours. At the end of the reaction, the medium is concentrated, then taken up in DCM and water and 20 ml of IN sodium hydroxide solution. The aqueous phase is extracted three times with DCM. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
• the hydrochloride of compound 344B is prepared from the hydrochloride of derivative 344A (630 mg) according to the conditions used for the preparation of 229, respecting the proportions of the various reagents and using water and methanol as solvents. Quantity obtained: 496 mg (86%)
• Example 344 - Compound 344 is prepared from the derivative 344B (780 mg) and 1-methyl-2-formylbenzimidazole according to the conditions used for the preparation of 230 and respecting the proportions of the various reagents.
• Example 345A (5-Nitrobenzo [b] thiophen-2-yI) - (4-ethyl! Piperazin-1-yl) methanone
• Compound 345A is prepared from the derivative 257A (1.6 g, 7.2 mmol) and 1 - ethylpiperazine according to the conditions used for the preparation of 89A and respecting the proportions of the various reagents.
• the medium is concentrated, then taken up in DCM and water and 20 ml of IN sodium hydroxide solution.
• the aqueous phase is extracted three times with DCM.
• the organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
• Example 345B 5-Aminobenzofblthiophen-2-vl) - (4-ethylIpiperazin-1-vDmethanone
• Compound 345B is prepared from the derivative 345A (2.2 g, 6.8 mmol) according to the conditions used for the preparation of 229 and respecting the proportions of the various reagents Quantity obtained: 1.93 g (97%) 1 H NMR, DMSO-de (ppm): 7.58 (d, 1 H); 7.41 (s, 1 H); 6.98 (d, 1 H); 6.79 (dd, 1 H ); 5.19 (se, 2H); 3.65 (se, 4H); 2.45-2.35 (m, 6H); 1.01 (t, 3H).
• Example 345 - Compound 345 is prepared from the derivative 345B (1.0 g) and 1-methyl-2-formylbenzimidazole, according to the conditions described for the preparation of 170, respecting the proportions of the various reagents. Quantity obtained: 1.25 g (83%) HPLC (C 18 XTerra, ⁇ 220 nm, 100% H 2 O at 100% CH 3 CN (+ 0.1% TFA) in 8 min): purity 99%.
• Compounds 346 to 349 are prepared in the form of HCl salts from derivatives 260B, 258B or 261B and 1-methyl-2-formylbenzimidazole, according to the conditions described for the preparation of 344, respecting the proportions of the various reagents .
• the products are then purified by flash chromatography on silica, then taken up in a mixture of water, acetonitrile and hydrochloric acid (IN in water), and finally lyophilized to be characterized.
• Example 346 8.56 (t, 1H); 7.82 (s, 1H); 7.66 (d, 1H) 7.60 (d, 1H); 7.52 (d, 1H); 7.4-7.15 (m, 3H); 7.01 (dd, 1H); 6.44 (t, 1H); 4.60 (d, 2H) 3.85 (s, 3H); 3.36 (t, 2H); 2.56 (t, 2H); 2.54-5.49 (m, 4H + DMSO); 1.67 (sc, 4H)
• Example 348 8.54 (sc, 1H); 7.81 (s, 1H); 7.66 (d, 1H); 7.60 (d, 1H); 7.51 (d, 1H); 7.3-7.15 (m, 3H); 7.01 (d, 1H); 6.44 (sc, 1H); 4.61 (se, 2H); 3.85 (s, 3H); 3.56 (sc, 4H); 3.36 (sc, 2H); 2.50-5.2 (m, 6H + DMSO).
• Example 351 11.19 (sc, 1H); 8.00 (s, 1H); 7.95 (d, 1H); 7.88 (from, 1H); 7.80 (d, 1H); 7.71 (s, 1H); 7.55-7.45 (m, 3H); 7.44 (d, 2H); 7.30-7.05 (m, 3H); 5.60 (s, 2H); 4.55-4.3 (m, 2H); 4.00 (s, 3H); 3.9-3.3 (m, H 2 O + 4H); 3.15-3.05 (m, 2H); 2.77 (se, 3H).
• Example 356 9.72 (t, 1H); 8.85 (s, 1H); 8.76 (d, 1H); 8.38 (d, 1H); 8.13 (d, 1H); 8.00-7.80 (m, 4H); 7.60-7.53 (m, 3H); 7.12 (t, 1H); 7.07 (s, 1H); 6.97 (d, 1H); 6.82 (dd, 1H); 5.64 (s, 2H); 4.62 (d, 2H); 3.95 (s, 3H); 3.60 (s, 3H).
• Example 358 11.88 (sc, 1H); 10.85 (sc, 1H); 8.50 (d, 2H); 8.35 (s, 1H); 8.09 (d, 1H); 8.05 (s, 1H); 7.75 (d, 2H); 7.53-7.46 (m, 3H); 7.22 (t, 1H); 7.14 (t, 1H); 5.20 (s, 2H); 3.79 (s, 3H); 2.2-2.15 (m, 1H); 1.8-0.8 (m, 10H).
• Example 365 10.70 (sc, 1H); 9.38 (t, 1H); 8.29 (sc, 2H); 8.12 (d, 1H); 7.89 (d, 1H); 7.79 (d, 1H); 7.65-7.50 (m, 3H); 5.41 (s, 2H); 3.95 (s, 3H); 3.65 (sc, H 2 O + 4H); 3.35 (de, 2H); 3.05-3.00 (m, 2H); 2.22 (te, 1H); 1.95-0.70 (m, 14H).
• Example 372 11.04 (s, 1H); 9.39 (t, 1H); 8.29 (s, 1H); 8.25 (s, 1H); 8.13 (d, 1H); 7.93 (d, 1H); 7.83 (d, 1H); 7.65-7.50 (m, 3H); 5.46 (s, 2H); 3.98 (from, 2H); 3.96 (s, 3H); 3.84 (te, 2H); 3.75-3.70 (m, 2H); 3.55 (de, 2H); 3.35-3.30 (m, 2H); 3.13 (qe, 2H); 2.16 (t, 2H); 2.51 (sex, 2H); 0.78 (t, 3H).
• Compounds 377 to 383 are prepared in the form of HCl salts from derivatives 341, 342, 344, 345, 346. 347 or 348 and n-propionaldehyde, according to the conditions described for the preparation of 170, respecting the proportions of the various reagents.
• the products are then purified by filtration on silica using the CombiFlash Optix 10 (Isco), and using a gradient of methanol in dichloromethane (0 to 20%). Finally, they are taken up in water, acetonitrile and hydrochloric acid (IN in water), then lyophilized to be characterized.
• Example 381 10.82 (sc, 1H); 9.22 (t, 1H); 8.04 (s, 1H); 7.99 (d, 1H); 7.83 (d, 1H); 7.72 (d, 1H); 7.61 (t, 1H); 7.55 (t, 1H); 7.29 (d, 1H); 7.16 (dd, 1H); 5.23 (s, 2H); 4.11 (s, 3H); 3.9-3.5 (m, H 2 O + 4H); 3.51 (t, 2H); 3.33 (de, 2H); 3.01 (sc, 2H); 2.00 (se, 2H); 1.90-1.85 (m, 2H); 1.68 (sex, 2H); 0.94 (t, 3H).
• Example 383 9.25 (t, 1H); 8.05 (s, 1H); 8.01 (d, 1H); 7.83 (d, 1H); 7.73 (d, 1H); 7.63 (t, 1H);
• Compounds 384 and 388 are prepared in the form of HCl salts from derivatives 341 or 346 and benzenesulfonyl chloride, according to the conditions described for the preparation of 91, respecting the proportions of the various reagents.
• Compounds 385, 386, 387, 389 and 390 are prepared in the form of HCl salts from derivatives 342, 344, 345, 347 or 348, and benzenesulfonyl chloride, according to the conditions described for the preparation of 36, respecting the proportions of the various reagents.
• the products are then purified by filtration on silica using the CombiFlash Optix 10 (Isco), and using a gradient of methanol in dichloromethane (0 to 20%). Finally, they are taken up in water, acetonitrile and hydrochloric acid (IN in water), then lyophilized to be characterized.
• Example 388 9.15 (t, 1H); 8.80 (d, 1H); 8.43 (t, 1H); 8.03 (s, 1H); 8.00-7.60 (m, 11H); 7.58-7.45 (m, 2H); 7.25 (d, 1H); 5.49 (s, 2H); 4.03 (s, 3H); 3.75-3.70 (m, 2H); 3.31 (t, 2H).
• Example 389 12.03 (se, 1H); 9.38 (t, 1H); 8.21 (s, 1H); 7.99 (d, 1H); 7.88-7.63 (m, 8H); 7.55-7.48 (m, 2H); 7.28 (dd, 1H); 5.50 (s, 2H); 4.03 (s, 3H); 3.97 (from, 2H); 3.83 (te, 2H); 3.75-3.65 (m, 2H); 3.53 (de, 2H); 3.25-3.00 (m, 2H); 3.32 (se, 2H).
• Compound 391 is prepared from derivative 88 according to the method described for the preparation of 344A in the presence of an excess of 4-aminopyridine. Examples 392 to 395
• Example 395 11.06 (se, IH); 9.38 (t, 1H); 9.31 (s, 1H); 8.10 (s, 1H); 7.90-7.80 (m, 3H); 7.72 (s, 1H); 7.65 (s, 1H); 7.41 (d, 2H); 7.19 (d, 1H); 7.06 (t, 1H); 6.79 (sc, 3H); 5.66 (s, 2H); 5.13 (s, 2H); 4.0-3.95 (m, 2H); 3.88-3.81 (m, 2H); 3.71-3.68 (m, 2H); 3.57 (s, 3H); 3.57-3.52 (m, 2H); 3.32 (sc, 2H); 3.20-3.10 (m, 2H).
• Compounds 396 to 400 are prepared in the form of HCl salts from derivative 261 or derivative 391 and the corresponding acid chloride, according to the conditions described for the preparation of 91, while respecting the proportions of the various reagents.
• the products are then purified by filtration on silica using the CombiFlash Optix 10 (Isco), and using a methanol gradient in dichloromethane (0 to 20%). Finally, they are taken up in water, acetonitrile and hydrochloric acid (IN in water), then lyophilized to be characterized.
• Compound 401 is prepared in the form of HCl salts from the derivative 261 and benzene sulfonyl chloride, according to the conditions described for the preparation of 36, respecting the proportions of the various reagents.
• Compound 402 is prepared in the form of HCl salts from the derivative 261 and benzaldehyde, according to the conditions described for the preparation of 159 A, while respecting the proportions of the various reagents.
• Compound 403 is prepared in the form of HCl salts from derivative 261 and propionaldehyde, according to the conditions described for the preparation of 170, respecting the proportions of the various reagents.
• Example 401 11.03 (se, 1H); 9.38 (t, 1H); 9.21 (s, 1H); 8.10 (s, 1H); 7.94 (d, 2H); 7.89 (d, 1H); 7.77 (t, 1H); 7.64-7.59 (m, 2H); 7.54-7.46 (m, 6H); 6.88 (dd, 1H); 5.67 (s, 2H); 4.93 (s, 2H); 4.00-3.96 (m, 2H); 3.88-3.81 (m, 2H); 3.72-3.70 (m, 2H); 3.57-3.53 (m, 2H); 3.33 (sc, 2H); 3.15-3.10 (m, 2H).
• Example 403 11.25 (sc, 1H); 9.44-9.21 (m, 2H); 8.04 (s, 1H); 7.91 (d, 2H); 7.73 (d, 1H); 7.48 (s, 1H); 7.44 (d, 2H); 6.99 (sc, 1H); 6.87 (d, 1H); 5.66 (s, 2H); 4.49 (s, 2H); 3.99-3.96 (m, 2H); 3.91-3.84 (m, 2H); 3.72-3.70 (m, 2H); 3.57-3.53 (m, 2H); 3.34-3.32 (m, 2H); 3.20 (t, 2H); 3.15-3.1 l (m, 2H); 1.44 (sex, 2H); 0.81 (t, 3H).
• Examples 404 to 406 Compound 404 is prepared in the form of HCl salts from the derivative 391 and benzene sulfonyl chloride, according to the conditions described for the preparation of 36, respecting the proportions of the various reagents.
• Compounds 405 and 406 are prepared in the form of HCl salts from derivative 391 or derivative 259B and the corresponding aldehydes, according to the conditions described for the preparation of 170, while respecting the proportions of the various reagents. The products are then purified by filtration on silica using the CombiFlash Optix
• Examples 407 and 408 Compounds 407 and 408 is prepared from derivative 249 according to the method described for the preparation of 344A in the presence of two equivalents of aminopyridine.
• Example 409A 2- (4-Methylpiperazine-1-ylmethyl) benzo [b] thiophen-5-ylamine.
• Compound 259B 300 mg; 1.0 mmol is dissolved in anhydrous THF (3 ml) and lithium aluminum hydride (IM solution in THF; 4.35 ml; 4.3 mmol) is added slowly under an atmosphere of nitrogen.
• the reaction mixture is stirred at 70 ° C until the reaction is complete (5 hours). It is then cooled to room temperature and then neutralized (attention, very violent reaction) by successive additions of water (165 ⁇ l), a soda solution (15% in water, 165 ⁇ l) and water (495 .mu.l).
• the resulting suspension is filtered, and the precipitate is washed with DCM.
• the filtrate is concentrated to give a pale yellow solid (336 mg, 84% purity). It is used in subsequent operations without any other form of purification.
• Example 409 - The compound 409 (336 mg, 84%) is prepared from the derivative 409A and the derivative 27 A, according to the conditions described for the preparation of 170 while respecting the proportions of the various reagents. Quantity obtained: 388 mg (78%) 1 H NMR, DMSO-d 6 (ppm): 7.80 (d, 2H); 7.75 (s, 1H); 7.47 (d, 1H); 7.26 (d, 2H); 6.99 (s, 1H); 6.93 (s, 1H); 6.73 (s, 1H); 6.62 (d, 1H); 5.87 (sc, 1H); 5.38 (s, 2H); 4.07 (s, 2H); 3.67 (s, 2H); 2.55-2.20 (m, 8H); 2.14 (s, 3H).
• Example 410 The compound 409 (336 mg, 84%) is prepared from the derivative 409A and the derivative 27 A, according to the conditions described for the preparation of 170 while respecting the proportions of the various reagents. Quantity obtained
• Compound 410 is prepared from the derivative 409 (388 mg) and pentanoyl chloride, according to the conditions described for the preparation of 91 while respecting the proportions of the various reagents.
• the crude reaction product is purified by flash chromatography (DCM7MeOH / NH 4 OH 90/9/1), to give the desired product (284 mg, 62%).
• HPLC C 18 XTerra, ⁇ 220 nm, 100% H 2 O to 100% CH 3 CN (+ 0.1% TFA) in 8 min: purity 98%.
• the mixture is then co-evaporated twice with toluene and the residual oil is purified by preparative HPLC (Waters Prep 4000), on a LiCliroprep RP-18 column (Merck; 50 x 150 mm; 15-25 ⁇ m) using a total gradient of 100% water (0.1% HCl) to 100% acetonitrile ( 0.1% HCl) in 25 minutes, then lyophilized to give the product 411 in the form of the HCl salt (30 mg).
• the famesylation of the dansylated peptide GCVLS catalyzed by the protein enzyme Famesyl Transferase, causes a change in the emission spectrum of the dansyl group, and in particular an increase in the emission at 505 nm when the molecule is excited at 340 nm. Measured with a specfrofluorimeter, this emission is proportional to the activity of the enzyme (Pompliano et al., J. Am. Chem. Soc. 1992; 114: 7945-7946).
• Dansylated dansyl peptide-GCVLS (Neosystem / France, France) Enzyme: The famesyl transferase protein is partially purified from beef brain by ion exchange chromatography on Q-sepharose (Pharmacia) (Moores et al., J.
• the reaction mixture containing 2 ⁇ M of FPP, 2 ⁇ M of dansyl GCVLS with or without (zero) the quantity of enzyme giving an intensity of 100 to the spectrofluorimeter after incubation for 10 minutes at 37 ° C. is prepared on ice.
• 360 ⁇ L of reaction mixture are mixed with 40 ⁇ l of concentrated test product 10x or solvent, and incubated for 10 minutes at 37 ° C.
• the reaction is stopped on ice and the intensity of the fluorescence is measured (excitation 340 nm, slit 4 nm, emission 505 nm, slit 10 nm).
• the tests are carried out in duplicate. The results are expressed as a percentage of inhibition. Under these conditions, the derivatives of the present invention have been identified as potent inhibitors of the famesyl transferase protein (IC 50 ⁇ 10 ⁇ M).
• GGPT I is partially purified from beef brain by ion exchange chromatography on Q-sepharose (Pharmacia); elution at 0.23 and 0.4 M NaCl resp. (Moores et al., J. Biol. Chem. 1991, 266: 14603-14610; Reiss et al., Cell 1990, 62: 81-88).
• the reaction mixture containing 0.2 ⁇ M of 3 H-GGPP, 1 ⁇ M of RhoA-GST with or without (zero) 5 ⁇ l of GGPT / test, is prepared on ice.
• reaction mixture 45 ⁇ l of reaction mixture are mixed with 5 ⁇ l of test product 10 ⁇ concentrated or of solvent, and incubated for 45 min at 37 ° C. An aliquot of 45 ⁇ l is placed on a P81 phosphocellulose filter (Whatman, Maidstonee, UK) numbered, washed with 50% ethanol, phosphoric acid (0.5%) and counted by scintillation. The tests are performed in duplicate. The results are expressed as a percentage of inhibition.
• the procedure is similar to that above, except that the measurements are carried out in 96-well plates (Nunc, France) then the reactions are passed on a 96-well “Unifilter” (Whatman, Maidstone, UK) containing a buffer. of phosphocellulose P81 using a “Filtermate 196” system (Packard, France). After washing with 50% ethanol, phosphoric acid (0.5%), the filters are counted by scintillation on a “Packard Topcount” instrument. The tests are carried out in triplicate. The results are expressed as a percentage of inhibition.
• PFTase either selectively compared to PGGTase or equivalent:
• compositions containing, as active ingredients, a compound of general formula (I) or a physiologically acceptable salt of a compound of general formula (I) associated with one or more therapeutic agents, such as for example anticancer agents such as for example cytotoxic anticancer agents such as navelbine, vinflunine, taxol, taxotere, 5-fluorouracil, methotrexate, doxorabicin, camptothecin, gemcitabine, etoposide, cis-platinum or BCNU or hormonal anticancer drugs like tamoxifen or medroxyprogesterone.
• anticancer agents such as for example cytotoxic anticancer agents such as navelbine, vinflunine, taxol, taxotere, 5-fluorouracil, methotrexate, doxorabicin, camptothecin, gemcitabine, etoposide, cis-platinum or BCNU or hormonal anticancer drugs like tamoxifen or medroxyproge
• an inhibitor of the biosynthesis of famesyl and geranylgeranyl pyrophosphates such as an inhibitor of HMG-CoA reductase such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin.
• Radiation treatment X-rays or gamma rays
• an inhibitor of the Faresyl Transferase protein belonging to the present invention can also be combined with the administration of an inhibitor of the Faresyl Transferase protein belonging to the present invention.
• These treatments can be used for the treatment or prevention of cancers such as lung cancer, pancreas, skin, head, neck, uterus, ovaries, anal, stomach, colon, breast, esophagus, small intestine, thyroid gland, prostate, kidney, bladder, acute or chronic leukemia, or a combination of 2 or more of these cancers.
• cancers such as lung cancer, pancreas, skin, head, neck, uterus, ovaries, anal, stomach, colon, breast, esophagus, small intestine, thyroid gland, prostate, kidney, bladder, acute or chronic leukemia, or a combination of 2 or more of these cancers.
• These treatments can also be used for the treatment or prevention of restenosis or atherosclerosis, infections linked to PFTase such as hepatitis delta or even benign proliferative disorders.
• the present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula (I) or one of its acceptable salts for pharmaceutical use, mixed or associated with
• compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
• inert diluents such as starch, cellulose, sucrose, lactose or silica
• These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
• compositions for oral administration there can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, oils vegetable or paraffin oil.
• inert diluents such as water, ethanol, glycerol, oils vegetable or paraffin oil.
• These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
• the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents.
• These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating the composition of the sterilizing agents, by irradiation or by heating.
• compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.75 g) per day, preferably orally for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

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