Compounds for use in the treatment of mycobacterial infections

Abstract

The present invention concerns compounds of general formula (I): ##STR00001##
in which Y and Z are chosen from CH and N; T is chosen from CO or SO.sub.2; n is 1 to 3; R1 represents a group chosen, for example, from C1-C3 alkyl chains unsubstituted or substituted by fluorine, the unsubstituted or substituted cyclic, cyano, azido, alkoxy and phenyl groups; and R is chosen from the azido, cyano, alkinyl and 2-benzothiazolyl groups and an optionally substituted aromatic heterocycle with five vertices; and the use thereof in the treatment of bacterial and mycobacterial infections such as, for example, tuberculosis, leprosy and atypical mycobacterial infections. The present invention also concerns pharmaceutical compositions comprising, as the active ingredient, at least one of the abovementioned compounds and optionally an antibiotic activatable via the EthA pathway.

Claims

1. A compound of formula (II): ##STR00158## in which Y and Z are CH; T is chosen from CO or SO.sub.2; n is an integer greater than or equal to 1 and lower than or equal to 3; R is R-7: ##STR00159## in which: R2 is chosen from H, F, Cl, Br, I; R3 is a group chosen from H, linear or branched C1-C6 alkyl chains, linear or branched C1-C6 alkyl chains substituted by at least one fluorine atom, C3-C6 cyclic groups, the cyanomethyl group, the azidomethyl group, linear or branched C1-C4 alkoxy chains, C-C4 hydroxyalkyl groups, C1-C4 alkyl methyl ester groups, C1-C4 methylcarbonylamino alkyl groups, C1-C4 methylsulfone alkyl groups, the unsubstituted phenyl group, a phenyl group substituted by one, two or three substituents chosen, independently from one another, from C1-C3 alkyl chains, trifluoromethyl, C1-3 alkoxy chains, or by a group chosen among the following groups (II-a and II-b): ##STR00160## in which R4 is a group chosen from H, linear or branched C1-C4 alkyl chains, the phenyl group, a phenyl group substituted by at least one halogen atom, a phenyl group substituted by a linear or branched C1-C4 alkyl chain, a phenyl group substituted by a linear or branched C1-C4 alkoxy chain and a phenyl group substituted by a trifluoromethyl group.

2. The compound according to claim 1, wherein T is CO and R3 is CH.sub.2SO.sub.2R wherein the radical R is tert-butyl, methyl, isobutyl, isopentyl, or isohexyl.

3. The compound according to claim 1, wherein said compound corresponds to formula (IV): ##STR00161## in which n, T and R3 are as defined in claim 1.

4. The compound according to claim 3, wherein T is CO and R3 is CH.sub.2SO.sub.2R wherein the radical R is tert-butyl, methyl, isobutyl, isopentyl, or isohexyl.

5. The compound according to claim 1 chosen from the following compounds: Compound 24: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoropropyl)benzene sulfonamide Compound 26: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoroethyl)benzene sulfonamide Compound 27: 4-(2-methylthiazol-4-yl)-N-(4,4,4-trifluorobutyl)benzene sulfonamide Compound 32: 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide Compound 33: 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)methyl acetate Compound 34: 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)ethyl acetate Compound 35: 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)isopropyl acetate Compound 36: N-isopropyl-2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)acetamide Compound 38: 4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide Compound 39: 4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide Compound 43: 4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 47: 4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 49: 4-(2-isobutylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 50: 4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 51: 4 -(2-(cyanomethyl)thiazol -4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 52: 2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)ethyl acetate Compound 53: 2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)isopropyl acetate Compound 54: 4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-ethyl carboxylate Compound 55: 4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-isopropyl carboxylate Compound 56: 4-(thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 62: 4-(5-fluoro-2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 64: 4-(5-chloro-2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide Compound 103: 4-(2-(propylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide; and Compound 104: 4-(2-(phenylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)-benzamide.

6. A method of treatment of bacterial and mycobacterial infection comprising administering, to a patient in need thereof, an effective amount of a compound according to claim 1.

7. A method of treatment of tuberculosis, leprosy or atypical mycobacterial infection comprising administering, to a patient in need thereof, an effective amount of a compound of claim 1.

8. A method of treatment of bacterial and mycobacterial infection comprising administering, to a patient in need thereof, an effective amount of a compound according to claim 3.

9. A method of treatment of tuberculosis, leprosy or atypical mycobacterial infection comprising administering, to a patient in need thereof, an effective amount of a compound of claim 3.

Description

EXPERIMENTAL SECTION

(1) Microwave Synthesis

(2) Microwave synthesis was performed in a CEM Discover microwave oven.

(3) Analysis by Thin-Layer Chromatography

(4) The thin-layer chomatographies (TLC) were performed on aluminum plates covered with a layer of 0.25 mm thickness of silica gel 60 F.sub.254 Merck.

(5) LC-MS Analyses

(6) The LC-MS analyses were performed on two systems: A triple quadrupole Varian 1200 ws system. UV detection is performed at wave lengths of 215 and 254 nm. A Waters Alliance Micromass ZQ 2000 system. Detection is performed by means of Waters 2996 diode array system.

(7) These apparatus are equipped with a C18 TSK-gel Super ODS 2 m (504.6 mm) column or an XBridge C18 (Waters) 5 m (504.6 mm) column. The injection volumes are 20 L.

(8) Two gradients were used 10 min: 100% H.sub.2O/0.1% HCOOH up to 95% ACN/0.1% HCOOH in 7 minutes at a rate of 1 mL.Math.min.sup.1. 5 min: 100% H.sub.2O/0.1% HCOOH up to 95% ACN/0.1% HCOOH in 3 minutes at a rate of 2 mL.min.sup.1. Method a: Varian, gradient 10 min, column SODS Method b: Waters, gradient 10 min, column SODS Method c: Waters, gradient 5 min, column XBridge Method d: Waters, gradient 10 min, column XBridge
NMR Analyses

(9) Nuclear magnetic resonance spectra (NMR) were performed on a Brcker DRX 300 MHz spectrometer. The chemical shifts are expressed in ppm relative to TMS and the coupling constants J in Hz (Hertz). The peaks are described according to the model: (splitting pattern, number of protons per integration, J).

(10) The following abbreviations have been used for the multiplicity of the: s=singulet, d=doublet, t=triplet, q=quadruplet, qn=quintuplet, sx=sextuplet, sp=septuplet, n=nonuplet, br=broad (large).

(11) Purification by Chromatography on a Pre-Packed Silica Column

(12) The chromatographies on a pre-packed silica column were performed on columns of the brand AIT Chromato with a grain size from 20 to 40 m or Grace Reveleris with a grain size of 40 m, using a Flashmart pump.

(13) Purification by High Pressure Liquid Chromatography (HPLC)

(14) The purifications by preparative HPLC were performed by means of a Varian ProStar apparatus using an Omnisphere 10 C.sub.18 250 mm41.4 mm Dynamax column. The gradient used starts from a mixture (20% acetonitrile/80% water/0.1% formic acid) up to a mixture (100% acetonitrile/0.1% formic acid). Detection is performed at wavelengths of 215 and 254 nm.

(15) Melting Point

(16) The melting points of the recrystallized products were measured using the capillaries method, on Bchi B-540 apparatus.

(17) ##STR00008##

Compound 13: 4-acetyl-N-isopentyl benzene sulfonamide

(18) ##STR00009##

(19) 3 g (1 eq.) 4-acetyl benzene sulfonic acid chloride are added to a solution of 2.39 mL (1.5 eq.) 3-methyl-butylamine and 7.54 mL (5 eq.) N-methylmorpholine in 200 mL DMF on a molecular sieve. The mixture is agitated during 3 h at AT. The DMF is evaporated under reduced pressure. The residue is taken over in the ethyl acetate and then washed by means of an aqueous solution of HCl 1N (2) and in brine (1). The organic phases are dried on magnesium sulfate and then concentrated under reduced pressure to yield 3.34 g (90%) of beige powder.

(20) LC-MS: t.sub.R=5.61 min (method a); m/z: [M+H].sup.+=270

(21) CCM: R.sub.f=0.44 (AcOEt 3:7 petroleum ether)

(22) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.16 (d, 2H, .sup.3J=8.67 Hz, 9+10); 7.95 (d, 2H, .sup.3J=8.67 Hz, 7+8); 2.89 (t, 2H, .sup.3J=7.16 Hz); 2.65 (s, 3H, 13); 1.61 (n, 1H, .sup.3J=6.72 Hz, 3); 1.32 (q, 2H, .sup.3J=7.08 Hz, 4); 0.84 (d, 6H, .sup.3J=6.62 Hz, 1+2)

Compound 14: 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide

(23) ##STR00010##

(24) 4.466 g (1 eq.) trimethylphenyl ammonium tribromide are added to a solution of 3.2 g (1 eq.) of 4-acetyl-N-isopentyl benzene sulfonamide (13) in 150 mL glacial acetic acid. The reaction mixture is agitated during 3 h at AT. The acetic acid is evaporated under reduced pressure, the yellow solid thus obtained is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 4.02 g (quantitative) of a yellow oil.

(25) LC-MS: t.sub.R=6.26 min (method a); m/z: [M+H].sup.+=349

(26) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.18 (d, 2H, .sup.3J=8.70 Hz, 7-8); 7.98 (d, 2H, .sup.3J=8.70 Hz, 9-10); 4.71 (s, 2H, 13); 2.90 (t, 2H, .sup.3J=7.10 Hz, 5); 1.62 (n, 1H, .sup.3J=6.70 Hz, 3); 1.32 (q, 2H, .sup.3J=6.90 Hz, 4); 0.84 (d, 6H, .sup.3J=6.60 Hz, 1+2)

Compound 6: 4-(2-methylthiazol-4-yl)-N-isopentyl benzene sulfonamide

(27) ##STR00011##

(28) LC-MS: t.sub.R=6.4 min (method a); m/z: [M+H].sup.+=325

(29) CCM: R.sub.f=0.34 (AcOEt 3:7 petroleum ether)

(30) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.07 (d, 2H, J=8.5 Hz), 7.9 (d, 2H, J=8.5 Hz), 7.56 (s, 1H), 4.48 (t, 1H, J=5.7 Hz), 2.98 (m, 2H), 2.8 (s, 3H), 1.59 (n, 1H, J=6.7 Hz), 1.13 (sextuplet, 2H, J=7.22 Hz), 0.86 (d, 6H, J=6.78 Hz)

Compound 17: 4-(2-(cyanomethyl)thiazol-4-yl)-N-isopentyl benzene sulfonamide

(31) ##STR00012##

(32) 575 mg (1 eq.) 2-cyanothioacetamide are added to a solution of 2 g (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (14) in 200 mL of THF on a molecular sieve. The reaction mixture is agitated under THF reflux during 28 h. The THF is then evaporated under reduced pressure then the solid thus obtained is taken over in the ethyl acetate, washed using water (2) and then in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The brown solid is recrystallized in 5 mL ethanol to yield 946 mg (47%) of pale yellow powder.

(33) LC-MS: t.sub.R=5.67 min (method a); m/z: [M+H].sup.+=350

(34) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.15 (d, 2H, .sup.3J=8.70 Hz, 9+10); 8.05 (s, 1H, 13); 7.90 (d, 2H, .sup.3J=8.70 Hz, 7+8); 4.43 (s, 1H, 15); 2.90 (t, 2H, .sup.3J=7.20 Hz, 5); 1.52-1.68 (m, 1H, 3): 1.33 (q, 2H, .sup.3J=7.10 Hz, 4); 0.84 (d, 6H, .sup.3J=6.65 Hz, 1+2)

(35) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=159.4 (14); 153.7 (12); 139.9 (11); 137.5 (6); 127.2 (7+8); 126.5 (9+10); 117.0 (13); 115.9 (16); 41.0 (5); 38.1 (4); 25 (3); 21.2 (1+2); 20.9 (15)

(36) ##STR00013##

Compound 21: 2-(4-(4-(N-isopentylsulfamoyl)phenyl)thiazol-2-yl)acetamide

(37) ##STR00014##

(38) 100 mg 4-(2-(cyanomethyl)thiazol-4-yl)-N-isopentyl benzene sulfonamide (17) are solubilized in 100 L sulfuric acid at 96%. The solution is agitated at AT during 12 h. The reaction medium is then poured into 100 L of ammonia solution at 28% at 0 C. Ammonia is then added until a pH of 9 is reached. The solution is then filtered, the filtrate pH is neutralized with HCl 1N and then extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure to yield 64 mg (61%) of white powder.

(39) LC-MS: t.sub.R=5.20 min (method a); m/z: [M+H].sup.+=368

(40) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.12 (d, 2H, .sup.3J=8.61 Hz, 9+10); 7.97 (s, 1H, 13); 7.89 (d, 2H, .sup.3J=8.61 Hz, 7+8); 4.05 (s, 1H, 15); 2.90 (t, 2H, .sup.3J=7.18 Hz, 5); 1.62 (n, 1H, .sup.3J=6.40 Hz, 3); 1.34 (q, 2H, .sup.3J=7.08 Hz, 4); 0.84 (d, 6H, .sup.3J=6.62 Hz, 1+2)

(41) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=173.2 (16); 165.9 (14); 154.4 (12); 141.2 (11); 139.6 (6); 128.7 (7+8); 127.9 (9+10); 118.1 (13); 42.5 (5); 39.7 (4); 26.6 (3); 22.8 (1+2)

Compound 22: 2-(4-(4-(N-isopentylsulfamoyl)phenyl)thiazol-2-yl) acetic acid

(42) ##STR00015##

(43) A solution of 200 mg (1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-isopentyl benzene sulfonamide (17) in 2.5 mL water and 45.8 mg (2 eq.) NaOH is heated under reflux during 15 h. The pH is then adjusted to 4-5 at AT by means of a solution of glacial acetic acid. The produce is extracted using ethyl acetate. The organic phases are collected, washed with an aqueous solution of HCl with a pH=4, dried on magnesium sulfate and then evaporated under reduced pressure to yield 122 mg (58%) of beige powder.

(44) LC-MS: t.sub.R=5.07 min (method a); m/z: [M+H].sup.+=369

(45) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.11 (d, 2H, .sup.3J=8.80 Hz, 9+10); 7.97 (s, 1H, 13); 7.89 (d, 2H, .sup.3J=8.80 Hz, 7+8); 2.90 (t, 2H, .sup.3J=7.30 Hz, 5); 1.61 (n, 1H, .sup.3J=6.70 Hz, 3); 1.34 (q, 2H, .sup.3J=7.20 Hz, 4); 0.84 (d, 6H, .sup.3J=6.60 Hz, 1+2)

(46) ##STR00016##
General Procedure (i)

(47) 99 L (5 eq.) N-methylmorpholine and between 1 and 1.5 eq. of corresponding amine are added to a solution of 50 mg (1 eq.) 4-(2-methylthiazol-4-yl)benzene sulfonic acid chloride in 4 mL anhydrous DMF. The mixture is agitated at AT during 2 h. The DMF is evaporated under reduced pressure. The product is taken over in the ethyl acetate, washed using water (2) and then in brine (1). The organic phases are dried on magnesium sulfate and then evaporated under reduced pressure.

Compound 23: N-(3,3-dimethylbutyl)-4-(2-methylthiazol-4-yl)benzene sulfonamide

(48) ##STR00017##

(49) Procedure (i) with 38.7 L (1.5 eq.) 3,3-dimethylbutylamine.

(50) 26.5 mg (44%) of beige powder.

(51) LC-MS: t.sub.R=6.79 min (method a); m/z: [M+H].sup.+=339

(52) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.09 (d, 2H, .sup.3J=8.70 Hz, 10+11); 7.89 (d, 2H, .sup.3J=8.70 Hz, 8+9); 7.84 (s, 1H, 14); 2.86-2.92 (m, 2H, 6); 2.77 (s, 3H, 16); 1.35-1.40 (m, 2H, 5); 0.85 (s, 9H, 1+2+3)

(53) NMR .sup.13C (DMSO-d.sub.6, 75 MHz): ppm=168.7 (15); 154.4 (13); 140.9 (7); 139.5 (12); 128.6 (8+9); 127.8 (10+11); 116.9 (14); 44.3 (5); 40.8 (6); 30.5 (4); 29.7 (1+2+3); 18.9 (16).

Compound 24: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoropropyl)benzene sulfonamide

(54) ##STR00018##

(55) Procedure (i) with 26.9 mg (1 eq.) 2,2,2-trifluoropropylamine hydrochloride.

(56) 26.6 mg (39%) of beige powder.

(57) LC-MS: t.sub.R=5.80 min (method a); m/z: [M+H].sup.+=351

(58) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.10 (d, 2H, .sup.3J=8.80 Hz, 7+8); 7.90 (d, 2H, .sup.3J=8.80 Hz, 5+6); 7.86 (s, 1H, 11); 3.12 (t, 2H, .sup.3J=7.3) Hz, 3); 2.77 (s, 3H, 13); 0.2.39 (qt, 2H, .sup.3J.sub.2-1=10.80 Hz, .sup.3J.sub.2-3=7.30 Hz, 2)

(59) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=168.7 (12); 154.3 (10); 140.5 (4); 139.8 (9); 128.6 (5+6); 127.9 (7+8); 127.6 (q, .sup.1J.sub.C-F=276.1 Hz, 1); 117.1 (11); 37.39 (d, .sup.3J.sub.C-F=3.10 Hz; 3); 35.21 (q, .sup.2J.sub.C-F=27.9 Hz, 2); 18.9 (13).

Compound 25: 4-(2-methylthiazol-4-yl)-N-(2,2,3,3,3-pentafluoropropyl)benzene sulfonamide

(60) ##STR00019##

(61) Procedure (i) with 38.9 L (1 eq.) 2,2,3,3,3-pentafluoropropylamine, 100 mg sulfonic acid chloride, 8 mL anhydrous DMF and 198 L N-methylmorpholine.

(62) 40.1 mg (29%) of beige powder.

(63) LC-MS: t.sub.R=6.22 min (method a); m/z: [M+H].sup.+=387

(64) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.10 (d, 2H, .sup.3J=8.80 Hz, 7+8); 7.91 (d, 2H, .sup.3J=8.80 Hz, 5+6); 7.86 (s, 1H, 11); 3.70 (td, 2H, .sup.3J.sub.3-2=15.80 Hz, .sup.4J.sub.3-1=0.8 Hz, 3); 2.77 (s, 3H, 13).

Compound 26: 4-(2-methylthiazol-4-yl)-N-(2,2,2-trifluoroethyl)benzene sulfonamide

(65) ##STR00020##

(66) Procedure (i) with 24.4 mg (1 eq.) 2,2,2-trifluoroethylamine hydrochloride.

(67) 19.8 mg (31%) of beige powder.

(68) LC-MS: t.sub.R=5.53 min (method a); m/z: [M+H].sup.+=337

(69) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.09 (d, 2H, .sup.3J=8.80 Hz, 6+7); 7.91 (d, 2H, .sup.3J=8.80 Hz, 4+5); 7.85 (s, 1H, 10); 3.68 (q, 2H, .sup.3J=9.00 Hz, 2); 2.80 (s, 3H, 12)

(70) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=168.7 (11); 154.3 (9); 141.2 (8); 139.8/8); 125.0 (q. .sup.1J.sub.C-F=277 Hz, 1); 117.1 (10); 45.06 (q, .sup.2J.sub.C-F=35.0 Hz, 2); 12.9 (12).

Compound 27: 4-(2-methylthiazol-4-yl)-N-(4,4,4-trifluorobutyl)benzene sulfonamide

(71) ##STR00021##

(72) Procedure (i) with 55.7 mg (1.2 eq.) 4,4,4-trifluorobutylamine, 100 mg sulfonic acid chloride, 5 mL anhydrous DMF and 198 L N-methylmorpholine.

(73) 75.1 mg (54%) of beige powder.

(74) LC-MS: t.sub.R=6.13 min (method b); m/z: [M+H].sup.+=365

(75) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.02 (d, 2H, .sup.3J=8.74 Hz, 8+9); 7.89 (d, 2H, .sup.3J=8.74 Hz, 6+7); 7.46 (s, 1H, 12); 5.10 (t, 1H, .sup.3J=6.39 Hz, NH); 3.03 (q, 2H, .sup.3J=6.64 Hz, 4); 2.22-2.06 (m, 2H, 2); 1.76 (qn, 2H, .sup.3J=7.33 Hz, 3)

(76) NMR .sup.13C (CDCl.sub.3, 75 MHz): ppm=166.8 (13); 153.2 (11); 138.8 (10); 138.5 (5); 127.6 (6+7); 127.0 (8+9); 126.9 (q, .sup.1J.sub.C-F=276 Hz, 1); 115.2 (12); 42.0 (4); 30.9 (q, .sup.2J.sub.C-F=29.0 Hz, 2); 22.6 (3); 19.4 (14).

Compound 28: N-(2,2,3,3,4,4,4-heptafluorobutyl)-4-(2-methylthiazol-4-yl)benzene sulfonamide

(77) ##STR00022##

(78) Procedure (i) with 29.2 L (1.2 eq.) 2,2,3,3,4,4,4-heptafluorobutylamine.

(79) 34 mg (44%) of beige powder.

(80) LC-MS: t.sub.R=6.65 min (method b); m/z: [M+H].sup.+=437

(81) NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=8.02 (d, 2H, .sup.3J=8.70 Hz, 8+9); 7.88 (d, 2H, .sup.3J=8.70 Hz, 6+7); 7.49 (s, 1H, 12); 5.50 (br s, 1H, NH); 3.75 (td, 2H, .sup.3J.sub.4-3=15.30 Hz, .sup.4J.sub.4-2=5.10 Hz, 4); 2.80 (s, 3H, 14)

(82) NMR .sup.19F uncoupled .sup.1H (CDCl.sub.3, 282 MHz): ppm=127.36/127.51 (m, 2F, 3); 118.74 (qt, 2F, .sup.3J.sub.2-1=9.30 Hz, .sup.3J.sub.2-3=5.60 Hz, 2); 80.71, (t, 3F, .sup.3J=9.30 Hz, 1).

(83) ##STR00023##

Compound 30: 4-acetyl-N-(3,3,3-trifluoropropyl)benzene sulfonamide

(84) ##STR00024##

(85) 754 L (5 eq.) N-methylmorpholine and 300 mg (1 eq.) 4-acetylbenzene sulfonic acid chloride are successively added to a solution of 186 mg (1.2 eq.) 3,3,3-trifluoropropylamine hydrochloride in 10 mL anhydrous DMF. The mixture is agitated during 2 h at AT. The DMF is evaporated under reduced pressure. The product is taken over in the ethyl acetate and then washed by means of an aqueous solution of HCl 1N (2) and then in brine (1). The organic phases are dried on magnesium sulfate and then concentrated under reduced pressure to yield 303 mg (75%) of pale yellow powder.

(86) LC-MS: t.sub.R=5.33 min (method a); m/z: [M+H].sup.+=296

(87) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.15 (d, 2H, .sup.3J=8.60 Hz, 7+8); 8.09 (br s, 1H, NH); 7.93 (d, 2H, .sup.3J=8.60 Hz, 5+6); 2.99 (t, 2H, .sup.3J=6.90 Hz, 3); 2.43 (qt, 2H, .sup.3J.sub.2-1=11.22 Hz, .sup.3J.sub.2-3=6.96 Hz, 2)

Compound 31: 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide

(88) ##STR00025##

(89) A solution of 303 mg (1 eq.) 4-acetyl-N-(3,3,3-trifluoropropyl)benzene sulfonamide (30) in 35 mL of glacial acetic acid is added drop by drop to a solution of 386 mg (1 eq.) trimethylphenylammonium tribromide in 30 mL of glacial acetic acid. The reaction mixture is agitated during 4 h at AT. 0.1 eq. brominating reagent are added to consume completely the residual non-brominated ketone. The acetic acid is evaporated under reduced pressure, the yellow solid thus obtained is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 358 mg (93%) of beige solid.

(90) LC-MS: t.sub.R=5.85 min (method a); m/z: [M+H].sup.+=372

Compound 32: 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide

(91) ##STR00026##

(92) 105.4 mg (1.1 eq.) 2-cyanothioacetamide are added to a solution of 358 mg (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (31) in 25 mL THF on a molecular sieve. The reaction mixture is left under THF reflux during 24 h. An additional 0.1 eq 2-cyanothioacetamide are added, the medium is agitated for a further 1 h at 70 C. The THF is then evaporated under reduced pressure and then the solid thus obtained is taken over in the ethyl acetate and washed in brine (2). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The olive-green oil thus obtained is agitated for 1 h at AT in methanol in the presence of MgSO.sub.4 and activated charcoal. The medium is, filtrated to yield a cloudy yellow filtrate. The methanol is evaporated under reduced pressure. The yellow solid is taken over in the ethanol and then filtrated again to yield 270 mg (75%) of yellow solid used as is in the following steps.

(93) LC-MS: t.sub.R=5.35 min (method a); m/z: [M+H].sup.+=376

Compound 33: 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)methyl acetate

(94) ##STR00027##

(95) 1.05 mL (36 eq.) anhydrous methanol, 1.60 mL (18 eq.) TMSCl and 270 mg (1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide (32) are successively added at AT in a dry flask and under argon. The mixture is then agitated at 50 C. during 15 h and then left to return to AT. 1 mL water is then added and the pH is neutralized by means of an aqueous solution saturated with NaHCO.sub.3. The mixture is agitated 10 min at AT and then extracted using ethyl acetate. The organic phases are washed in brine (2), dried on magnesium sulfate and evaporated. The orange solid thus obtained is purified on a pre-packed silica column (EtOAc 1:9 petroleum ether.fwdarw.EtOAc 3:7 petroleum ether) to yield 137 mg (47%) of pale beige powder.

(96) LC-MS: t.sub.R=6.22 min (method b); m/z: [M+H].sup.+=409

(97) NMR .sup.1H (CDCl.sub.3, 300 MHz): ppm=8.06 (d, 2H, .sup.3J=8.40 Hz, 7+8); 7.91 (d, 2H, .sup.3J=8.40 Hz, 5+6); 7.64 (s, 11); 4.81 (t, 1H, .sup.3J=6.50 Hz, NH); 4.17 (s, 2H, 13); 3.81 (s, 3H, 15); 3.25 (q, 2H, .sup.3J=6.70 Hz, 3); 2.37 (qt, 2H, .sup.3J.sub.2-1=10.50 Hz, .sup.3J.sub.2-3=6.80 Hz, 2)

(98) NMR .sup.13C (CDCl.sub.3, 75 MHz): ppm=169.4 (14); 162.3 (12); 153.0 (10); 138.7 (4 or 9); 138.5 (4 or 9); 127.6 (5+6); 127.0 (7+8); 125.9 (q, .sup.1J.sub.C-F=276.7 Hz, 1); 116.6 (11); 52.7 (15); 38.6 (13); 36.7 (3); 34.5 (q, .sup.2J.sub.C-F=29.0 Hz, 2).

Compound 34: 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl)ethyl acetate

(99) ##STR00028##

(100) 186 L (12 eq.) absolute ethanol, 195 L TMSCl (6 eq.) and 100 mg (1 eq.) 4-(2-(cyanonnethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide (32) are successively added at AT in a dry flask and under argon. The mixture is then agitated at 30 C. during 48 h. The nitrile is then converted to 67% in the desired ester and to 33% in carboxylic acid (HPLC analysis, 215 nm). 99 L (3 eq.) SOCl.sub.2 are then added in 466 L (30 eq.) absolute ethanol. The reaction medium is agitated at 40 C. during 48 h and then left to return to AT 1 mL water is then added and the pH is neutralized by means of an aqueous solution saturated with NaHCO.sub.3. The mixture is agitated 10 min at AT and then extracted using ethyl acetate. The organic phases are washed in brine, dried on magnesium sulfate and evaporated. The orange solid thus obtained is purified on a pre-packed silica column (AcOEt 1:9 petroleum ether.fwdarw.AcOEt 3:7 petroleum ether) to yield 66 mg (59%) of pale beige powder.

(101) LC-MS: t.sub.R=6.22 min (method b); m/z: [M+H].sup.+=423

(102) NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=8.04 (d, 2H, .sup.3J=8.70 Hz, 7+8); 7.90 (d, 2H, .sup.3J=8.70 Hz, 5+6); 7.63 (s, 1H, 11); 5.11 (t, 1H, .sup.3J=6.50 Hz, NH); 4.27 (q, 2H, .sup.3J=7.20 Hz, 3); 4.14 (s, 2H, 13); 3.24 (q, 2H, .sup.3J=6.80 Hz, 15); 2.36 (qt, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.90 Hz, 2); 1.33 (t, 3H, .sup.3J=7.10 Hz, 16)

(103) NMR .sup.13C (CDCl.sub.3, 75 MHz): ppm=169.0 (14); 162.6 (12); 153.0 (10); 138.8 (4); 128.6 (9); 127.7 (5+6); 127.1 (7+8); 126 (q, .sup.1J.sub.C-F=276 Hz, 1); 116.7 (11); 61.9 (15); 39.0 (13); 36.7 (3); 34.6 (q, .sup.2J.sub.C-F=28.3 Hz, 2); 14.2 (16)

Compound 35: 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl) isopropyl acetate

(104) ##STR00029##

(105) 244 L (12 eq.) anhydrous isopropanol, 195 L (6 eq.) TMSCl and 100 mg (1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide (32) are successively added at AT in a dry flask and under argon. The mixture is then agitated at 30 C. during 48 h. 197 L (6 eq.) SOCl.sub.2 are then added in 466 L (30 eq.) anhydrous isopropanol. The reaction medium is agitated at 40 C. during 48 h and then left to return to AT. 1 mL water is then added and the pH is neutralized by means of an aqueous solution saturated with NaHCO.sub.3. The mixture is agitated for 10 min at AT and then extracted using ethyl acetate. The organic phases are washed in brine (2), dried on magnesium sulfate and evaporated. The orange solid thus obtained is purified on a pre-packed silica column (AcOEt 1:9 petroleum ether.fwdarw.AcOEt 3:7 petroleum ether). The product is purified a second time on HPLC to yield 29 mg (25%) of pale beige powder.

(106) LC-MS: t.sub.R=6.50 min (method b); m/z: [M+H].sup.+=437

(107) NMR .sup.1H(CDCl.sub.3, 300 MHz): ppm=8.04 (d, 2H, .sup.3J=8.70 Hz, 7+8); 7.90 (d, 2H, .sup.3J=8.70 Hz, 5+6); 7.63 (s, 1H, 11); 5.06-5.18 (m, 15+NH); 4.11 (s, 2H, 13); 3.23 (q, 2H, .sup.3J=6.8 Hz, 3); 2.36 (tq, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.90 Hz, 2); 1.30 (d, 6H, .sup.3J=6.30 Hz, 16+17)

(108) NMR .sup.13C (CDCl.sub.3, 75 MHz): ppm=168.6 (14); 162.8 (12); 152.9 (10); 138.8 (4 or 9); 138.5 (4 or 9); 127.7 (5+6); 127.1 (7+8); 125.9 (q, .sup.1J.sub.C-F=277.5 Hz, 1); 116.7 (11); 69.7 (15); 39.4 (13); 36.7 (3); 34.5 (q, .sup.2J.sub.C-F=28.3 Hz, 2); 21.8 (16+17)

(109) ##STR00030##

Compound 36: N-isopropyl-2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl) thiazol-2-yl)acetamide

(110) ##STR00031##

(111) 54 mg 2-(4-(4-(N-(3,3,3-trifluoropropyl)sulfamoyl)phenyl)thiazol-2-yl) methyl acetate (33) and 1 mL isopropylamine are introduced in a 5 mL dry flask. The mixture is heated under isopropylamine reflux during 5 h. An additional 0.5 mL isopropylamine are added and the mixture is heated under reflux for a further 4 h. The isopropylamine is then evaporated under reduced pressure. The product is taken over in ethyl acetate and washed in brine (2). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The orange solid thus obtained is purified on a pre-packed silica column (DCM 98:2 MeOH) to yield 32 mg (56%) of beige powder.

(112) LC-MS: t.sub.R=5.57 min (method b); m/z: [M+H].sup.+=436

(113) NMR .sup.1H DMSO-d.sub.6 300 MHz): ppm=8.22 (s, 1H, 11); 8.14 (d, 2H, .sup.3J=8.51 Hz, 7+8); 7.89 (d, 2H, .sup.3J=8.51 Hz, 5+6); 4.07 (s, 2H, 13); 3.92-3.79 (m, 1H, 15); 2.99 (t, 2H, .sup.3J=6.91 Hz, 3); 2.43 (qt, 2H, .sup.3J.sub.2-1=11.21 Hz, .sup.3J.sub.2-3=6.96 Hz, 2); 1.08 (d, 6H, .sup.3J=6.58 Hz)

(114) ##STR00032##

Compound 37: 5-methylhexanethioamide

(115) ##STR00033##

(116) 2 mL 5-methylhexanoic acid and 5 mL thionyl chloride are introduced in a 25 mL flask. The mixture is heated at 50 C. during 1 h and then the thionyl chloride is evaporated under reduced pressure. A mixture CH.sub.3CN (5 mL) (10 mL) NH.sub.4OH (28%) is then added at 0 C. The solution is then agitated during 15 min at 0 C. The product is extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure to yield a white powder.

(117) 2.9 g (0.5 eq.) Lawesson reagent and 50 mL anhydrous THF are then added to the product. The solution is agitated at AT during 4 h. The THF is evaporated under reduced pressure and the product is purified on a pre-packed silica column (Cyclohexane 85:15 AcOEt.fwdarw.Cyclohexane 80:20 AcOEt) to yield 950 mg (47%) of transparent oil that then crystallizes.

(118) LC-MS: t.sub.R=3.03 min (method c); m/z: [M+H].sup.+=146

(119) NMR 1H (CDCl.sub.3 300 MHz): ppm=8.35+7.46 (NH.sub.2); 2.58 (t, 2H, .sup.3J=7.60 Hz, 2); 1.64-1.74 (m, 2H, 3 or 4); 1.50 (sp, 1H, .sup.3J=6.70 Hz, 5); 1.12-1.21 (m, 2H, 3 or 4); 0.82 (d, 6H, .sup.3J=6.60 Hz, 6+7)

Compound 38: 4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide

(120) ##STR00034##

(121) 232 mg (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (31) are added to a solution of 90 mg (1 eq.) 5-methylhexanethioamide (37) in 20 mL anhydrous THF. The reaction medium is heated under reflux during 3 h. The THF is then evaporated under reduced pressure. The product is taken over in the ethyl acetate, washed in water (2) and then in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The yellow oil thus obtained is purified on a pre-packed silica column (Cyclohexane 9:1 AcOEt 4 Cyclohexane 8:2 AcOEt) to yield 60 mg (24%) of beige powder.

(122) LC-MS: t.sub.R=7.60 min (method d); m/z: [M+H].sup.+=421

(123) NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=8.07 (d, 2H, .sup.3J=8.60 Hz, 5+6); 7.91 (d, 2H, .sup.3J=8.60 Hz, 7+8); 7.51 (s, 1H, 11); 4.89 (t, 1H, .sup.3J=6.50 Hz, NH); 3.26 (q, 2H, .sup.3J=6.70 Hz, 3); 3.06 (t, 2H, .sup.3J=7.70 Hz, 13); 2.37 (qt, 2H, .sup.3J.sub.2-1=10.70 Hz .sup.3J.sub.2-3=6.70 Hz, 2); 1.85 (q, 2H, .sup.3J=7.80 Hz, 14); 1.63 (n, 1H, .sup.3J=6.70 Hz, 16); 1.30-1.38 (m, 4H, 15+fat); 0.92 (d, 6H, .sup.3J=6.6 Hz, 17+18)

(124) NMR .sup.13C (CDCl.sub.3 75 MHz): ppm=172.6 (12); 153.0 (10); 139.2 (9); 138.3 (4); 127.7 (7+8); 127.2 (5+6); 120.5-131.5 (q, .sup.1J.sub.C-F=277.2 Hz, 1); 114.9 (11); 38.5 (15); 36.8 (3); 34.6 (q, .sup.2J.sub.C-F=28.4 Hz, 2); 34.0 (13); 28.1 (14); 28.0 (16); 22.7 (17+18)

Compound 39: 4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)-benzene sulfonamide

(125) ##STR00035##

(126) 150 mg (1 eq.) 4-(2-bromoacetyl)-N-isopentyl benzene sulfonamide (31) are added to a solution of 78.3 mg (1 eq.) 2-(tert-butylsulfonyl)ethanethioamide in 7 mL anhydrous THF. The reaction medium is heated under reflux during 72 h. The THF is then evaporated under reduced pressure. The product is taken over in the ethyl acetate, washed in water and then in brine. The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The product thus obtained is purified by HPLC to yield 119 mg (63%) of beige powder.

(127) LC-MS: t.sub.R=5.67 min (method d); m/z: [M+H].sup.+=471

(128) NMR .sup.1H DMSO-d.sub.6 300 MHz): ppm=8.44 (s, 1H, 11); 8.19 (d, 2H, .sup.3J=8.70 Hz, 7+8); 7.94 (t, 1H, .sup.3J=6.0 Hz, NH); 7.90 (d, 2H, .sup.3J=8.70 Hz, 5+6); 5.09 (s, 2H, 13); 3.00 (q, 2H, .sup.3J=6.60 Hz, 3); 2.44 (qt, 2H, .sup.3J.sub.2-1=11.2 Hz, .sup.3J.sub.2-3=7.0 Hz, 2); 1.38 (s, 9H, 15+16+17)

(129) NMR .sup.13C DMSO-d.sub.6 75 Hz: ppm=157.1 (12); 152.5 (10); 139.0 (4); 137.4 (9); 127.2 (5+6); 126.6 (7+8); 126.4 (q, .sup.1J.sub.C-F=277.0 Hz, 1); 120.0 (11); 60.2 (14); 50.3 (13); 36.03 (q, .sup.3J.sub.C-F=3.70 Hz, 3); 66.3 (q, .sup.2J.sub.C-F=27.2 Hz, 2); 22.9 (15+16+17)

(130) ##STR00036##

Compound 40: 4-iodo-N-(3,3,3-trifluoropropyl)benzene sulfonamide

(131) ##STR00037##

(132) 1.82 mL (5 eq.) N-methylmorpholine are added to a solution of 593.2 mg (1.2 eq.) 3,3,3-trifluoropropylamine hydrochloride in 50 mL DMF. The mixture is agitated for 5 min at AT and then 1 g (1 eq.) 4-iodobenzene sulfonic acid chloride is added. The reaction medium is agitated at AT during 2 h. The DMF is evaporated under reduced pressure and then the product is taken over in the ethyl acetate, washed in water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 1.17 g (94%) of pale yellow solid.

(133) LC-MS: t.sub.R=6.22 min (method b); m/z: [MH].sup.=378

(134) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=7.96 (d, 2H, .sup.3J=8.70 Hz, 5+6 or 7+8); 7.60 (d, 2H, .sup.3J=8.70 Hz, 5+6 or 7+8); 4.81 (m, 1H, NH); 3.25 (q, 2H, .sup.3J=6.70 Hz, 3); 2.43 (qt, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.80 Hz, 2)

Compound 41: 4-(4-methylthiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide

(135) ##STR00038##

(136) 40.0 L (1 eq.) 4-methylthiazole, 4.9 mg (0.05 eq.) palladium acetate, 83.7 mg (1 eq.) copper iodide and 150 mg (0.9 eq.) 4-iodo-N-(3,3,3-trifluoropropyl)-benzene sulfonamide (40) are placed successively in a schlenk under an argon flow. 1.5 mL anhydrous DMF are added via a cannula under argon at ambient temperature. The schlenk is drawn three times under vacuum and filled successively with argon. The reaction mixture is agitated at 140 C. under argon during 48 h. The reaction medium is diluted at AT with 2 mL of a mixture of ethyl acetate and of an aqueous solution saturated with NH.sub.4Cl (1:1 by volume). The medium is then filtrated and the solid washed using ethyl acetate. The organic phase is washed in brine (2), dried on magnesium sulfate, filtrated on celite and then evaporated under reduced pressure. The product is then purified on a pre-packed silica column (AcOEt 1:9 Petroleum ether.fwdarw.AcOEt 2:8 petroleum ether) to yield 73 mg (53%) of white powder.

(137) LC-MS: t.sub.R=6.07 min (method b); m/z: [M+H].sup.+=351

(138) NMR .sup.1H (CD.sub.2Cl 300 MHz): ppm=8.11 (d, 2H, .sup.3J=8.70 Hz, 7+8); 7.91 (d, 2H, .sup.3J=8.70 Hz, 5+6); 7.04 (s, 1H, 11); 4.83 (m, 1H, NH); 3.26 (q, .sup.3J=6.70 Hz, 3); 2.51 (s, 3H, 13); 2.39 (tq, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.80 Hz, 2)

(139) NMR .sup.13C (CD.sub.2Cl.sub.2 75 MHz): ppm=164.8 (10); 154.4 (12); 141.0 (4); 137.0 (9); 128.0 (5+6); 127.2 (7+8); 126.85 (q, .sup.1J.sub.C-F=277.1 Hz, 1); 116.9 (11); 36.4 (q, .sup.3J.sub.C-F=3.8 Hz, 3); 33.6 (q, .sup.2J.sub.C-F=27.4 Hz, 2); 17.3 (13)

Compound 42: 4-(benzo[d]thiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzene sulfonamide

(140) ##STR00039##

(141) 48.0 L (1 eq.) 4-methylthiazole, 4.9 mg (0.05 eq.) palladium acetate, 83.7 mg (1 eq.) copper iodide and 150 mg (0.9 eq.) 4-iodo-N-(3,3,3-trifluoropropyl)-benzene sulfonamide (40) are successively placed in a schlenk under an argon flow. 1.5 mL anhydrous DMF are added via a cannula under argon at ambient temperature. The schlenk is drawn three times under vacuum and filled successively with argon. The reaction mixture is agitated at 140 C. under argon during 48 h. The reaction medium is diluted at AT with 2 mL of a mixture of ethyl acetate and of an aqueous solution saturated with NH.sub.4Cl (1:1 by volume). The medium is then filtrated and the solid washed using ethyl acetate. The organic phase is washed in brine (2), dried on magnesium sulfate, filtrated on celite and then evaporated under reduced pressure The product is then purified on a pre-packed silica column (AcOEt 1:9 petroleum ether.fwdarw.AcOEt 2:8 petroleum ether). The product is then recrystallized in 2 mL ethanol to yield 31 mg (20%) of transparent crystals.

(142) LC-MS: t.sub.R=6.73 min (method b); m/z: [M+H].sup.+=387

(143) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.34 (d, 2H, .sup.3J=8.50 Hz, 7+8); 8.21-8.23 (m; 1H, 12 or 15); 8.09-8.14 (m, 2H, NH+12 or 15); 8.00 (d, 2H, .sup.3J=8.50 Hz, 5+6); 7.60 (td, 1H, .sup.3J=7.40 Hz, .sup.4J=1.20 Hz, 13 or 14); 7.53 (td, 1H, .sup.3J=7.40 Hz, .sup.4J=1.20 Hz, 13 or 14); 3.04 (t, 2H, .sup.3J=6.90 Hz, 3); 2.39 (qt, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.80 Hz, 2)

(144) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=166.0 (10); 154.0 (16); 142.4 (9); 136.7 (16); 135.3 (11); 128.5 (5+6); 128.1 (7+8); 127.5 (13 or 14); 126.6 (13 or 14); 126.9 (q, .sup.1J.sub.C-F=273.4 Hz, 1); 123.8 (15 or 12); 123.1 (15 or 12); 36.5 (3); 33.7 (q, .sup.2J.sub.C-F=27.5 Hz, 2)

(145) ##STR00040##

Compound 43: 4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(146) ##STR00041##

(147) 50 mg (1 eq.) 4-(2-methylthiazol-4-yl)benzoic acid, 37 mg (1.1 eq.) 3,3,3-trifluoropropylamine hydrochloride (1.1 eq), 103 mg (1.2 eq.) HBTU, 52 mg (1.5 eq.) HOBt, 118 L (3 eq.) DIEA and 2.5 mL DMF are introduced in this particular order in a 10 mL flask. The solution is agitated during 2 h at AT. The DMF is evaporated under reduced pressure. The product is taken over in the ethyl acetate and then washed successively by means of an aqueous solution saturated with K.sub.2CO.sub.3 (2), an aqueous solution of HCl 1N (2), of water (1) and of brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 67 mg (93%) of beige powder.

(148) LC-MS: t.sub.R=3.10 min (method c); m/z; [M+H].sup.+=315

(149) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=7.99 (d, 2H, .sup.3J=8.50 Hz, 8+9); 7.87 (d, 2H, .sup.3J=8.50 Hz, 6+7); 7.76 (s, 1H, 12); 3.64 (t, 2H, .sup.3J=7.00 Hz, 3); 2.76 (s, 3H, 14); 2.54 (qt, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.80 Hz, 2)

(150) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=168.4 (4); 167.1 (13); 153.6 (11); 137.4 (10); 133.1 (5); 127.4 (6+7); 126.7 (q, .sup.1J.sub.C-F=277.8 Hz, 1); 125.9 (8+9); 114.7 (12); 33.1 (3); 32.7 (q, .sup.2J.sub.C-F=27.5 Hz, 2); 17.5 (14)

(151) ##STR00042##

Compound 45: 4-acetyl-N-(3,3,3-trifluoropropyl)benzamide

(152) ##STR00043##

(153) 546.6 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to a solution of 600 mg (1 eq.) 4-acetylbenzoic acid, 1.66 g (1.2 eq.) HBTU, 98 mg (0.2 eq.) HOBt, and 2.53 mL (4 eq.) DIEA in 15 mL DMF. The reaction medium is then agitated during 2 h at AT. The DMF is then evaporated under reduced pressure. The orange oil thus obtained is taken over in the ethyl acetate and then washed by means of an aqueous solution of HCl 1N (2), an aqueous solution saturated with Na.sub.2CO.sub.3 (2) and then in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The product thus obtained is purified on a pre-packed silica column (Cyclohexane 85:15 AcOEt.fwdarw.80:20.fwdarw.70:30) to yield 837 mg (88%) of white powder.

(154) LC-MS: t.sub.R=2.70 min (method c); m/z: [M+H].sup.+=260

Compound 46: 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide

(155) ##STR00044##

(156) 436.1 mg (1 eq.) trimethylphenylammonium tribromide are added to a solution of 300 mg (1 eq.) 4-acetyl-N-(3,3,3-trifluoropropyl)benzamide (45) in a mixture of 15 mL DCE and 6 mL methanol. The solution is agitated at 50 C. 43.6 mg (0.1 eq) brominating reagent are added after 1 h and 3 h of reaction. The DCE and the methanol are evaporated under reduced pressure. The product is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 387 mg (99%) of beige powder.

(157) LC-MS: t.sub.R=2.93 min (method c); m/z: [M+H].sup.+=340

Compound 47: 4-(2-(4-methylpentyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(158) ##STR00045##

(159) 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) are added to a solution of 43 mg (1 eq.) 5-methylhexanethioamide (37) in 10 mL anhydrous THF. The reaction medium is heated under reflux during 3 h. The THF is then evaporated under reduced pressure. The product is taken over in the ethyl acetate, washed in water (2) and then in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The beige solid thus obtained is purified on a pre-packed silica column (Cyclohexane 9:1 AcOEt) to yield 25 mg (22%) of powder beige.

(160) LC-MS: t.sub.R=3.77 min (method c); m/z: [M+H].sup.+=385

(161) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=7.99 (d, 2H, .sup.3J=8.66 Hz, 8+9); 7.84 (d, 2H, .sup.3J=8.66 Hz, 6+7); 7.51 (s, 1H, 12); 6.83 (t, 1H, .sup.3J=5.70 Hz, NH); 3.73 (q, 2H, .sup.3J=6.50 Hz, 3); 3.06 (t, 2H, .sup.3J=7.77 Hz, 14); 2.53 (qt, 2H, .sup.3J.sub.2-1=10.92 Hz .sup.3J.sub.2-3=6.78 Hz, 2); 1.87 (qn, 2H, .sup.3J=7.85 Hz, 15); 1.66 (n, 1H, .sup.3J=6.65 Hz, 17); 1.36 (q, 2H, .sup.3J=7.51 Hz, 16); 0.95; (d, 6H, .sup.3J=6.63 Hz, 18+19)

Compound 48: 3-methylbutanethioamide

(162) ##STR00046##

(163) 1.01 g (0.5 eq.) Lawesson reagent and 16 mL anhydrous THF are added to 505.8 mg (1 eq.) isovaleramide. The solution is agitated at AT during 4 h and then THF is evaporated under reduced pressure. The product is taken over in the diisopropylic ether and then filtrated. The filtrate is then purified on a pre-packed silica column (DCM 100%) to yield 396 mg (70%) of transparent oil that then crystallizes.

(164) LC-MS: t.sub.R=1.92 min (method c); m/z: [M+H].sup.+=118

(165) NMR .sup.1H (CDCl.sub.3, 300 MHz): ppm=7.65 (br s, 1H, NH); 6.85 (br s, 1H, NH); 2.52 (d, 2H, .sup.3J=7.28 Hz, 2); 2.25 (n, 1H, .sup.3J=6.95 Hz, 3); 1.00 (d, 6H, .sup.3J=6.59 Hz, 4+5)

Compound 49: 4-(2-isobutylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(166) ##STR00047##

(167) 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) are added to a solution of 34.7 mg (1 eq.) 3-methylbutanethioamide (48) in 6 mL anhydrous THF. The reaction medium is heated under reflux during one night. 3.5 mg (0.1 eq) thioamide are added and the solution is agitated for a further 1 h under reflux. The THF is then evaporated under reduced pressure. The product is taken over in the ethyl acetate, washed in water (2) and then in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The residue is purified using preparative HPLC to yield 78 mg (74%) of beige powder.

(168) LC-MS: t.sub.R=3.17 min (method c); m/z: [M+H].sup.+=357

(169) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.01 (d, 2H, .sup.3J=8.60 Hz, 8+9); 7.82 (d, 2H, .sup.3J=8.60 Hz, 6+7); 7.53 (s, 1H, 12); 6.47 (br s, 1H, NH); 3.74 (t, 2H, .sup.3J=6.50 Hz, 3); 2.95 (d, 2H, .sup.3J=6.70 Hz, 14); 2.53 (qt, 2H, .sup.3J.sub.2-1=10.80 Hz, .sup.3J.sub.2-3=6.50 Hz, 2); 2.19 (n, 1H, .sup.3J=6.70 Hz, 15); 1.05 (d, 6H, .sup.3J=6.60 Hz, 16+17)

(170) NMR .sup.13C(CD.sub.2Cl.sub.2, 75 MHz): ppm=171.0 (13); 167.4 (4); 154.0 (11); 138.2 (10); 133.6 (5); 127.8 (6+7); 127.1 (q, .sup.1J.sub.C-F=277.8 Hz, 1); 126.7 (8+9); 114.2 (12); 42.8 (14); 34.0 (q, .sup.2J.sub.C-F=27.5 Hz, 2); 33.8 (3); 30.2 (15); 22.4 (16+17)

Compound 50: 4-(2-(tert-butylsulfonylmethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)-benzamide

(171) ##STR00048##

(172) 10 mg (1 eq,) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) are added to a solution of 57.8 mg (1 eq.) 2-(tert-butylsulfonyl)ethanethioamide in 6 mL anhydrous THF. The reaction medium is agitated and heated under reflux during one night. An additional 11.7 mg (0.2 eq.) thioamide are added and the mixture is agitated for 2 h under reflux. The THF is then evaporated under reduced pressure. The product is taken over in the ethyl acetate, washed in water (2) and then in brine (1). The organic phase is dried and then evaporated under reduced pressure. The residue is purified on the pre-packed silica column (Cyclohexane 85:15 Isopropanol.fwdarw.Cyclohexane 1:1 Isopropanol) to yield 98 mg (76%) of white powder.

(173) LC-MS: t.sub.R=5.23 min (method c); m/z: [M+H].sup.+=435

(174) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.76 (t, 1H, .sup.3J=5.60 Hz, NH); 8.37 (s, 1H, 12); 8.08 (d, 2H, .sup.3J=8.40 Hz, 8+9); 7.93 (d, 2H, .sup.3J=8.40 Hz, 6+7); 5.09 (s, 2H, 14); 3.52 (q, 2H, .sup.3J=6.50 Hz, 3); 2.57 (qt, 2H, .sup.3J.sub.2-1=10.94 Hz, =6.62 Hz, 2); 1.39 (s, 9H, 16+17+18)

(175) NMR .sup.13C (DMSO-d.sub.6, 75 MHz): ppm=166.3 (4); 157.2 (13); 153.7 (11); 136.8 (5); 133.9 (10); 128.3 (6+7); 127.5 (q, .sup.1J.sub.C-F=267 Hz, 1); 126.3 (8+9); 119.3 (12); 60.6 (15); 50.8 (14); 33.3 (q, .sup.3J.sub.C-F=3.5 Hz, 3); 32.9 (q, .sup.2J.sub.C-F=27.0 Hz, 2); 23.4 (16+17+18)

Compound 51: 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(176) ##STR00049##

(177) 107 mg (1.2 eq.) 2-cyanothioacetamide are added to a solution of 300 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 25 mL THF. The medium is agitated during 24 h under reflux. The THF is then evaporated under reduced pressure. The residue is taken over in the ethyl acetate and then washed in brine (2). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 302 mg of orange solid. The raw product brut is thus used in the following reaction.$

(178) LC-MS: t.sub.R=2.96 min (method c); m/z: [MH].sup.=296

Compound 52: 2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl)ethyl acetate

(179) ##STR00050##

(180) 150 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) are added to a solution of 44.4 mg (1 eq.) 2-cyanoethanethioamide in 10 mL THF. The mixture is agitated during 15 h under reflux. The THF is evaporated under reduced pressure and the residue thus obtained is used as is. Under argon, 515 L (20 eq.) absolute ethanol and 545 L (10 eq.) TMSCl are successively added at AT in a dry flask. The mixture is then agitated at 40 C. during 2 h. 200 L SOCl.sub.2 are then added in 1 mL absolute ethanol. The reaction medium is agitated at 40 C. during 2 h and then left to return to AT. 1 mL water is then added and the pH is neutralized by means of an aqueous solution saturated with NaHCO.sub.3. The mixture is agitated for 15 min at AT and then extracted using ethyl acetate. The organic phases are washed in brine (2), dried on magnesium sulfate and evaporated. The orange solid thus obtained is recrystallized in 2 mL absolute ethanol to yield 58 mg (34%) of light brown crystals.

(181) LC-MS: t.sub.R=2.77 min (method c); m/z: [M+H].sup.+=387

(182) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.01 (d, 2H, .sup.3J=8.50 Hz, 8+9); 7.83 (d, 2H, .sup.3J=8.50 Hz, 6+7); 7.65 (s, 1H, 12); 6.47 (br s, 1H, NH); 4.26 (q, .sup.3J=7.10 Hz, 16); 4.14 (s, 2H, 14); 3.73 (q, 2H, .sup.3J=6.40 Hz, 3); 2.53 (qt, 2H, .sup.3J.sub.2-1=10.9 Hz, .sup.3J.sub.2-3=6.60 Hz, 2); 1.32 (t, 3H, .sup.3J=7.10 Hz, 17)

Compound 53: 2-(4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl(isopropyl acetate

(183) ##STR00051##

(184) Under argon, 3.23 mL (48 eq.) isopropanol, 2.66 mL (24 eq.) TMSCl and 300 mg (1 eq.) 4-(2-(cyanomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide (51) are successively added at AT in a dry flask. The solution is agitated during 10 min at AT and then 16 L (1 eq.) water are added. The mixture is then agitated at 40 C. during one night. The pH is neutralized by means of an aqueous solution saturated with NaHCO.sub.3. The mixture is agitated 15 min at AT and then extracted using ethyl acetate. The organic phases are washed in brine (2), dried on magnesium sulfate and evaporated. The residue thus obtained is then purified on a pre-packed silica column (AcOEt 3:7 Cyclohexane) to yield 51 mg (15%) of white solid.

(185) LC-MS: t.sub.R=5.87 min (method d); m/z: [M+H].sup.+=387

(186) NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=7.99 (d, 2H, .sup.3J=8.60 Hz, 8+9); 7.83 (d, 2H, .sup.3J=8.60 Hz, 6+7); 7.58 (s, 1H, 12); 6.44 (m, 1H, NH); 5.14 (sp, 1H, .sup.3J=6.30 Hz, 16); 4.13 (s, 2H, 14); 3.77 (q, 2H, .sup.3J=6.30 Hz, 3); 2.52 (tq, 2H, .sup.3J.sub.2-1=10.8 Hz, .sup.3J.sub.2-3=6.30 Hz, 2); 1.32 (d, 6H, .sup.3J=6.20 Hz, 17+18)

(187) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=168.9 (4); 167.4 (13); 163.0 (15); 154.0 (11); 137.9 (6); 133.9 (5); 127.9 (6+7); 127.3 (q, .sup.1J.sub.C-F=277.0 Hz, 1); 126.8 (8+9); 116.1 (12); 69.8 (16); 39.8 (14); 34.1 (q, .sup.2J.sub.C-F=27.5 Hz, 2); 33.9 (3); 22.0 (17+18)

(188) NMR .sup.19F (CDCl.sub.3, 282.4 MHz): ppm=64.95 (t, .sup.3J=10.8 Hz)

Compound 57: 4-(2-(pyridin-4-yl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(189) ##STR00052##

(190) 32.7 mg (1 eq.) thioisonicotinamide are added to a solution of 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 6 mL THF. The mixture is agitated during one night under reflux. The formed precipitate is filtrated and then washed using di-ethylic ether. The orange solid thus obtained is then taken over using ethyl acetate in a separating funnel, washed with a solution saturated with K.sub.2CO.sub.3 and then with water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The residue is purified on a pre-packed silica column (Cyclohexane 8:2 Isopropanol) to yield 59 mg (66%) of yellow solid.

(191) LC-MS: t.sub.R=2.32 min (method c); m/z: [M+H].sup.+=378

(192) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.70 (m, 2H, 16+17); 8.20 (s, 1H, 12); 8.18 (d, 2H, .sup.3J=8.80 Hz, 8+9); 8.08 (m, 2H, 15+18); 7.94 (d, 2H, .sup.3J=8.80 Hz, 6+7); 3.67 (t, 2H, .sup.3J=7.00 Hz, 3); 2.57 (qt, 2H, .sup.3J.sub.2-1=11.0 Hz, .sup.3J.sub.2-3=7.00 Hz, 2)

(193) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=168.5 (4); 164.7 (13); 155.9 (11); 149.9 (16+17); 141.2 (14); 137.1 (5); 133.7 (10); 127.5 (6+7); 126.6 (q, .sup.1J.sub.C-F=278.1 Hz, 1); 126.2 (8+9); 120.6 (15+48); 117.2 (12); 33.1 (q, .sup.3J.sub.C-F=3.3 Hz, 3); 32.7 (q, .sup.2J.sub.C-F=27.8 Hz)

Compound 58: 4-(2-(2-ethylpyridin-4-yl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(194) ##STR00053##

(195) 45 mg (1.1 eq.) ethionamide are added to a solution of 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 10 mL THF. The mixture is agitated under reflux during 24 h. The formed precipitate is filtrated and then washed using a solution of diethyl ether. The yellow solid thus obtained is then taken over in the ethyl acetate in a separating funnel, washed with a solution saturated with K.sub.2CO.sub.3 and then using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 75 mg (63%) of yellow solid.

(196) LCMS: t.sub.R=3.12 min (method c); (m/z); [M+H].sup.+=406

(197) NMR .sup.1H (CDCl.sub.3, 300 MHz): ppm=8.66 (d, 1H, .sup.3J=5.30 Hz, 16); 8.09 (d, 2H, .sup.3J=8.50 Hz, 8+9); 7.86 (d, 2H, .sup.3J=8.5 Hz, 6+7); 7.78 (s, 1H, 12); 7.69 (m, 2H, 15+17); 6.45 (m, 1H, NH); 3.77 (q, 2H, .sup.3J=6.30 Hz, 3); 2.94 (q, 2H, .sup.3J=7.60 Hz, 19); 2.52 (qt, 2H, .sup.3J.sub.2-1=10.80 Hz, .sup.3J.sub.2-3=6.40 Hz, 2); 1.40 (t, 3H, .sup.3J=7.60 Hz, 20)

(198) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=167.5 (4); 166.5 (13); 165.4 (18); 156.1 (16); 150.6 (16); 140.9 (14); 137.6 (10); 134.4 (5); 128.1 (q, .sup.1J.sub.C,F=276.9 Hz, 1); 128.0 (6+7); 127.0 (8+9); 119.1 (17); 118.2 (15); 116.4 (12); 34.26 (q, .sup.2J.sub.C,F=27.7 Hz, 2); 34.1 (3); 32.0 (19); 14.2 (20)

(199) ##STR00054##

Compound 54: 4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-ethyl carboxylate

(200) ##STR00055##

(201) 150 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46), 71 mg (1.2 eq.) ethyl thiooxamate and 15 mL THF are introduced in a 50 mL flask. The mixture is heated under reflux during 24 h. 11.5 mg (0.2 eq) thioamide are added and the solution is again agitated during 24 h under reflux. 350 mg (3 eq.) PS-Tos-NHNH.sub.2 resin are added and the reaction medium is agitated at AT during one night. The solution is then filtrated and the THF is then evaporated under reduced pressure. The residue is taken over in the ethyl acetate and then washed by means of an aqueous solution saturated with K.sub.2CO.sub.3 (2) and in brine (1). The organic phase is dried on magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained is purified on a pre-packed silica column (Cyclohexane 8:2 AcOEt.fwdarw.Cyclohexane 7:3 AcOEt) to yield 100.1 mg (61%) of powder beige.

(202) LC-MS: t.sub.R=3.22 min (method c); m/z: [M+H].sup.+=373

(203) NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=8.05 (d, 2H, .sup.3J=8.60 Hz); 7.81-7.85 (m, 3H, 6+7+12); 6.44 (m, 1H, .sup.3J=5.90 Hz, NH); 4.53 (q, 2H, .sup.3J=7.10 Hz, 15); 3.75 (q, .sup.3J=6.30 Hz, 3); 2.50 (qt, 2H, .sup.3J.sub.2-1=10.80 Hz, .sup.3J.sub.2-3=6.60 Hz, 2); 1.47 (t, 3H, .sup.3J=7.10 Hz, 16)

Compounds 55: 4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazole-2-isopropyl carboxylate and 56: 4-(thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(204) ##STR00056##

(205) 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46), 40 mg (1.1 eq.) ethyl thiooxamate and 10 mL THF are introduced in a 25 mL flask. The mixture is agitated during 24 h under reflux. The THF is evaporated under reduced pressure. The product is then solubilized in 2.5 mL isopropanol.

(206) In a flask cooled at 0 C., 20.4 mg (3 eq.) sodium are dissolved under argon in 2.5 mL isopropanol. The mixture is heated at 30 C. until complete dissolution of the sodium. The solution in the isopropanol previously obtained is added drop by drop to this solution. The mixture is then agitated during one night under reflux. 500 L SOCl.sub.2 are then added. The solution is agitated during one night at 50 C. The reaction medium is evaporated under reduced pressure and both compounds 55 and 56 formed in identical proportions are separated by preparative HPLC to yield 24 mg of 55 and 21.7 mg of 56.

Compound 55

(207) LC-MS: t.sub.R=4.90 min (method d); m/z: [M+H].sup.+=387

(208) NMR .sup.1H (CDCl.sub.3, 300 MHz): ppm=8.07 (d, 2H, .sup.3J=8.50 Hz); 7.84 (s, 1H, 12); 7.85 (d, 2H, .sup.3J=8.50 Hz, 6+7); 6.42 (m, 1H, NH); 5.37 (sp, 1H, .sup.3J=6.30 Hz, 15); 3.77 (q, 2H, .sup.3J=6.30 Hz, 3); 2.52 (qt, 2H, .sup.3J.sub.2-1=10.70 Hz, .sup.3J.sub.2-3=6.40 Hz, 2); 1.46 (d, 6H, .sup.3J=6.30 Hz, 16+17)

(209) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=166.7 (4); 159.2 (13 or 14); 159.0 (13 or 14); 156.0 (11); 136.6 (10); 134.1 (5); 127.5 (6+7); 126.7 (q, .sup.1J.sub.C-F=276.8 Hz, 1); 126.6 (8+9); 120.2 (12); 70.8 (15); 33.6 (q, .sup.2J.sub.C-F=27.5 Hz, 2); 33.5 (q, .sup.3J.sub.C-F=3.6 Hz, 3); 21.5 (16+17)

Compound 56

(210) LC-MS: t.sub.R=5.82 min (method d); m/z: [M+H].sup.+=301

(211) NMR .sup.1H(CDCl.sub.3, 300 MHz): ppm=8.92 (d, 1H, .sup.4J=1.80 Hz, 13); 8.03 (d, 2H, .sup.3J=8.40 Hz, 8+9); 7.85 (d, 2H, .sup.3J=8.40 Hz, 6+7); 7.64 (d, 1H, .sup.4J=1.80 Hz, 12); 3.77 (q, 2H, .sup.3J=6.30 Hz, 3); 2.51 (qt, 2H, .sup.3J.sub.2-1=10.80 Hz, .sup.3J.sub.2-3=6.40 Hz, 2)

(212) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=166.8 (4); 155.0 (11); 153.3 (13); 137.3 (10); 133.5 (5); 127.4 (6+7); 126.5 (8+9); 114.4 (12); 33.6 (q, .sup.2J.sub.C-F=27.3 Hz, 2); 33.4 (3)

(213) ##STR00057##

Compound 62: 4-(5-fluoro-2-mthylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(214) ##STR00058##

(215) 101 mg (1 eq.) Selectfluor are added to a solution of 90 mg 4-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide (43) in 1.1 mL anhydrous DMF. The solution is agitated during 15 h at 5 C. The LCMS analysis of the reaction medium shows a very weak conversion of the initial product. 0.5 eq Selectfluor are then added at 0 C. and the solution is agitated during one night at 15 C. An additional 1 eq. Selectfluor is then added at 0 C. and the solution is then agitated during 24 h at AT. A conversion >70% is thus obtained. 1 mL of an ammonia solution 2M in the ethanol as well as 0.5 mL of water are added at 0 C. and the solution is agitated at AT during one night. The solvent is then evaporated under reduced pressure. The yellow oil thus obtained is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then concentrated under reduced pressure. The yellow solid thus obtained is purified by preparative HPLC to yield 15 mg (16%) of white powder.

(216) LC-MS: t.sub.R=2.93 min (method c), 5.32 min (method d); m/z: [M+H].sup.+=333

(217) NMR .sup.1H (CD.sub.2Cl.sub.2 300 MHz): ppm=7.97 (d, 2H, .sup.3J=8.30 Hz, 8+9); 7.81 (d, 2H, .sup.3J=8.30 Hz, 6+7); 6.52 (br s, 1H, NH); 3.70 (q, 2H, .sup.3J=6.50 Hz, 3); 3.63 (d, 3H, .sup.5J=2.30 Hz, 14); 2.50 (qt, .sup.3J.sub.2-1=10.90 Hz, .sup.3J.sub.2-3=6.70 Hz, 2)

(218) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=167.4 (4); 158.2 (d, .sup.1J.sub.C-F=302.1 Hz, 12); 154.5 (d, .sup.3J.sub.C-F=10.X Hz, 13); 135.7 (d, .sup.3J.sub.C-F=5.8 Hz, 10); 133.6 (5); 133.5 (d, .sup.2J.sub.C-F=12.7 Hz, 11); 127.8 (6+7); 127.3 (d, .sup.4J.sub.C-F=6.1 Hz, 8+9); 127.2 (q, .sup.1J.sub.C-F=275.4 Hz 1); 34.2 (q, .sup.2J.sub.C-F=27.0 Hz, 2), 34.0 (3); 20.7 (14)

Compound 64: 4-(5-chloro-2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(219) ##STR00059##

(220) 50 mg (1 eq.) 4-(2-methylthiazol-4-yl)benzoic acid are added to a solution of 5 mL thionyle chloride. The mixture is agitated at 50 C. during 2 h. 2 mL thionyle chloride are then added and the solution is agitated for a further 2 h at 50 C. A third adjunction of 2 mL SOCl.sub.2 is then performed and the solution is agitated for a further 2 h at 50 C. The reaction medium is then evaporated under reduced pressure and the residue thus obtained (compound 63) is taken over in the dichloromethane. 34 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride and 158 L (4 eq.) DIEA are added to the reaction medium and the solution is agitated during one night at AT. The dichloromethane is then evaporated under reduced pressure and the residue is then taken over in the ethyl acetate. The organic phase is washed in brine (2), dried on magnesium sulfate and then evaporated under reduced pressure. The beige oil thus obtained is then purified a first time on a pre-packed silica column (Cyclohexane 85:15 iPrOH). The recovered white powder is not pure. The product is then purified on preparative HPLC to yield 23.5 mg (29%) of white powder.

(221) LCMS: t.sub.R=3.37 min (method c); m/z: [M+H].sup.+=349, [MH].sup.=347

(222) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.08 (d, 2H, .sup.3J=8.40 Hz, 8+9); 7.84 (d, 2H, .sup.3J=8.40 Hz, 6+7); 6.50 (m, 1H, NH); 3.74 (q, 2H, .sup.3J=6.40 Hz, 3); 2.70 (s, 3H, 14); 2.53 (qt, 2H, .sup.3J.sub.2-1=10.90 Hz, .sup.3J.sub.2-3=6.40 Hz, 2)

(223) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=167.4 (4); 163.6 (13); 148.2 (11); 136.7 (10); 134.1 (5); 128.8 (6+7); 127.4 (8+9); 127.3 (q, .sup.1J.sub.C,F=277 Hz, 1); 121.1 (12); 34.1 (q, .sup.2J.sub.C,F=27.6 Hz, 2); 34.0 (q, .sup.3J.sub.C-F=3.1 Hz, 3); 20.1 (14)

(224) ##STR00060##

Compound 65: 5-bromo-N-(3,3,3-trifluoropropyl)picolinamide

(225) ##STR00061##

(226) 296 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to a solution of 400 mg (1 eq.) 5-bromopicolinic acid, 1.40 mL (1.2 eq.) of T3P solution at 50% in lAcOEt and 1.03 mL (3 eq.) DIEA in 10 mL dAcOEt. The mixture is agitated during 3 h at AT. Water and ethyl acetate are then added. The organic phase is washed using water (2) and then in brine (1), dried on magnesium sulfate and evaporated under reduced pressure to yield 433 mg (74%) of white solid.

(227) LC-MS: t.sub.R=2.58 min (method c); m/z: [M+H].sup.+=297

(228) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.73 (dd, 1H, .sup.4J.sub.7-8=2.25 Hz, .sup.5J.sub.8-6=0.52 Hz, 8); 8.16 (dd, 1H, .sup.3J.sub.7-6=8.39 Hz, .sup.4J.sub.7-8.sup.=2.27 Hz, 7); 8.01 (dd, 1H, .sup.3J.sub.6-7=8.33 Hz, .sup.5J.sub.6-8=0.59 Hz, 6); 3.67 (q, 2H, .sup.3J=6.79 Hz, 3); 2.53 (qt, 2H, .sup.3J.sub.2-1=10.99 Hz, .sup.3J.sub.2-3=7.11 Hz, 2)

Compound 66: 5-acetyl-N-(3,3,3-trifluoropropyl)picolinamide

(229) ##STR00062##

(230) 400 mg (1 eq.) 5-bromo-N-(3,3,3-trifluoropropyl)picolinamide (65) are added to a solution of 95 mg (0.1 eq.) PdCl.sub.2(PPh.sub.3).sub.2 in 3.5 mL toluene in a tube of Schlenk type under argon. The mixture is agitated during 5 min at AT and then 545 L (1.2 eq.) tributyl(1-ethoxyvinyl)stannane are added, still under argon. The reaction medium is then agitated during one night at 90 C. The solution is cooled at AT and then 1 mL of an aqueous solution of hydrochloric acid 1N are added. The mixture is then agitated during 1 h at AT. The reaction medium is neutralized by means of an aqueous solution saturated with NaHCO.sub.3 and then extracted using ethyl acetate. The organic phases are collected, washed in brine (2), dried on magnesium sulfate and filtrated on celite. The yellow residue thus obtained is purified on a pre-packed silica column (Cyclohexane 95:5 AcOEt.fwdarw.9:1.fwdarw.85:15.fwdarw.75:25.fwdarw.7:3) to yield 250 mg (71%) of white solid.

(231) LC-MS: t.sub.R=1.57 min (method c); m/z: [M+H].sup.+=261

Compound 67: 5-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)picolinamide

(232) ##STR00063##

(233) 332 mg (1 eq.) trimethylphenylammonium tribromure are added to a solution of 230 mg (1 eq.) 5-acetyl-N-(3,3,3-trifluoropropyl)picolinamide (66) in a mixture of DCE (12.5 mL)/MeOH (5 mL). The mixture is agitated during 24 h at 70 C. The mixture of solvent is then evaporated under reduced pressure. The residue is taken over in the ethyl acetate and washed in water and then in brine. The organic phase is dried on magnesium sulfate and evaporated under reduced pressure to yield a yellow solid that is then solubilized in 2 mL absolute EtOH. 101 mg (1.5 eq.) thioacetamide are then added and the reaction medium is agitated during 4 h under reflux. The EtOH is evaporated under reduced pressure and the residue is taken over in the ethyl acetate. The organic phase is washed using water (2) and in brine (1), dried on magnesium sulfate and then evaporated under reduced pressure. The residue is purified by preparative HPLC to yield 125 mg (45%) of white powder.

(234) LC-MS: t.sub.R=2.53 min (method c); m/z: [M+H].sup.+=316

(235) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=9.15 (dd, 1H, .sup.4J.sub.8-7=2.20 Hz, .sup.5J.sub.8-6=0.75 Hz, 8); 8.40 (dd, 1H, .sup.3J.sub.7-6=8.18 Hz, .sup.4J.sub.7-8=2.23 Hz, 7); 8.12 (dd, 1H, .sup.3J.sub.6-7=8.18 Hz, .sup.5J.sub.6-8=0.74 Hz, 6); 7.94 (s, 1H, 11); 3.69 (t, 2H, .sup.3J=7.11 Hz, 3); 2.78 (s, 3H, 13); 2.55 (qt, .sup.3J.sub.2-1=10.97 Hz, .sup.3J.sub.2-3=7.22 Hz, 2)

(236) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=167.7 (12); 165.2 (4); 150.7 (10); 148.2 (5); 146.2 (8); 134.3 (7); 132.7 (9); 126.5 (q, .sup.1J.sub.C-F=275.9 Hz, 1); 121.7 (6); 116.2 (11); 32.8 (q, .sup.2J.sub.C-F=27.8 Hz, 2); 32.6 (q, .sup.3J.sub.C-F=3.7 HZ, 3); 17.5 (13)

(237) ##STR00064##

Compound 68: 6-chloro-N-(3,3,3-trifluoropropyl)nicotinamide

(238) ##STR00065##

(239) 700 mg (1 eq.) 6-chloro-nicotinic acid chloride are added to a solution of 595 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride and 1.75 mL (4 eq.) N-methylmorpholine in 40 mL anhydrous DCM. The reaction medium is agitated during 1 h at AT. An additional equivalent (700 mg) of acid chloride is added and the solution is agitated during one night at AT. The DCM is evaporated under reduced pressure. The solid thus obtained is taken over in a mixture of Cylohexane 1:1 Ethyl acetate and then filtrated on silica. The product is then purified on a pre-packed silica column (Cyclohexane 7:3 AcOEt) to yield 918 mg (92%) of white powder.

(240) LC-MS: t.sub.R=2.32 min (method c); m/z: [M+H].sup.+=253, [MH].sup.=251

Compound 69: 6-iodo-N-(3,3,3-trifluoropropyl)nicotinamide

(241) ##STR00066##

(242) 28 L (0.2 eq.) acetic acid chloride are added under argon to a solution of 500 mg (1 eq.) 6-chloro-N-(3,3,3-trifluoropropyl)nicotinamide (68), 1.48 g (5 eq.) NaI in 15 mL acetonitrile in a carrousel tube. The solution is agitated at 105 C. during one night. The acetonitrile is evaporated under reduced pressure, the product is then taken over in the ethyl acetate, filtrated, washed with an aqueous solution of Na.sub.2SO.sub.3 at 10% and then with an aqueous solution of Na.sub.2CO.sub.3 at 5% and then in brine. The organic phase is then dried on magnesium sulfate and then evaporated under reduced pressure to yield 619 mg (91%) of white powder.

(243) LC-MS: t.sub.R=2.33 min (method c); m/z: [M+H].sup.+=345, [MH].sup.=343

Compound 70: 6-acetyl-N-(3,3,3-trifluoropropyl)nicotinamide

(244) ##STR00067##

(245) 300 mg (1 eq.) 6-iodo-N-(3,3,3-trifluoropropyl)nicotinamide (69) are added to a solution of 61 mg (0.1 eq.) PdCl.sub.2(PPh.sub.3).sub.2 in 2.6 mL toluene. The reaction medium is agitated for 5 min at AT and then 353 L (1.2 eq.) tributyl(1-ethoxyvinyl)stannane are added under argon. The reaction medium is then agitated under argon during one night at 110 C. The reaction medium is cooled at AT, and then 8 mL of an aqueous solution of HCl 1N are added and the solution is agitated during 2 h at AT. The reaction medium is neutralized by means of an aqueous solution saturated with NaHCO.sub.3. The medium is extracted using ethyl acetate. The organic phases are collected, washed in brine (2), dried on magnesium sulfate and filtrated on celite. The brown residue thus obtained is solubilized in 5 mL acetonitrile and then filtrated. The filtrate is then purified by preparative HPLC to yield 89 mg (35%) of white powder.

(246) LC-MS: t.sub.R=4.10 min (method d); m/z: [M+H].sup.+=261, [MH].sup.=259

Compound 71: 6-(2-methylthiazol-4-yl)-N-(3,3,3-trifluoropropyl)nicotinamide

(247) ##STR00068##

(248) 129 mg (1 eq.) trimethylphenylammonium tribromide are added to a solution of 89 mg (1 eq.) 6-acetyl-N-(3,3,3-trifluoropropyl)nicotinamide (70) in 5.9 mL of a mixture DCE 5:2 MeOH. The reaction medium is agitated at 50 C. during 2 h. The LCMS analysis of the milieu shows a conversion rate close to zero, the reaction is then heated at 70 C. during 72 h. The LCMS analysis of the milieu shows an incomplete conversion of the reaction medium and the formation of two majority products: mono-brominated ketone and mono-chlorinated ketone, as well as a little di-chlorinated ketone. The reaction is however stopped, and the solvent mixture is evaporated under reduced pressure. The residue is taken over in 1 mL absolute ethanol. 26 mg (1 eq.) thioacetamide are then added and the solution is agitated during 1 h under reflux. An additional 13 mg (0.5 eq.) are added and the reaction medium is agitated during 3 h under reflux and then cooled at AT. 6 mL diethyl ether are added and the solution is cooled in a refrigerator during one night. The formed precipitate is filtrated and then washed using diethyl ether. The precipitate is taken over in the ethyl acetate and then washed with an aqueous solution saturated with NaHCO.sub.3 (2) and then in brine (1). The organic phase is then dried on magnesium sulfate and then evaporated under reduced pressure in order to yield 39 mg (34%) of white powder.

(249) LC-MS: t.sub.R=2.28 min (method c); m/z: [M+H].sup.+=316, [MH].sup.=314

(250) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.97 (dd, 1H, .sup.4J.sub.6-7=2.29 Hz, .sup.5J.sub.6-8=0.84 Hz, 6); 8.24 (dd, 1H, .sup.3J.sub.7-8=8.27 Hz, .sup.4J.sub.7-6=2.30 Hz, 7); 8.13 (dd, 1H, .sup.3J.sub.8-7, =8.30 Hz, .sup.5J.sub.8-6=0.81 Hz, 8); 8.11 (s, 1H, 11); 3.65 (t, 2H, .sup.3J=7.00 Hz, 3); 2.76 (s, 3H, 13); 2.55 (qt, 2H, .sup.3J.sub.2-1=10.84 Hz, .sup.3J.sub.2-3=7.13 Hz, 2)

(251) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=167.3 (12); 166.4 (4); 154.4 (9); 153.4 (10); 148.1 (6); 136.1 (7); 128.5 (5); 126.6 (q, .sup.1J.sub.C-F=276.3 Hz, 1); 120.3 (8); 118.8 (11); 33.1 (q, =9.74 Hz, 3); 32.6 (q, .sup.2J.sub.C-F=27.7 Hz, 2); 17.6 (13)

(252) ##STR00069## ##STR00070## ##STR00071## ##STR00072##

Compound 72: 4-(2-methyloxazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(253) ##STR00073##

(254) 100 mg (1 eq.) 4-acetyl-N-(3,3,3-trifluoropropyl)benzamide (45) are added to a solution of 21 mg (1.2 eq.) acetamide in 300 L toluene. The reaction medium is agitated in a microwave reactor during 10 min at 110 C. (P.sub.max=300W). 240 mg (3 eq.) Tos-NHNH.sub.2 resin are added. The solution is agitated one night at AT and then filtrated. The solution is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure in order to yield 68 mg (77%) of beige powder.

(255) LC-MS: t.sub.R=2.30 min (method c); m/z: [M+H].sup.+=299, [MH].sup.=297

(256) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=7.97 (s, 12); 7.84-7.77 (m, 4H, 6+7+8+9); 3.70 (q, 2H, .sup.3J=6.50 Hz, 3); 2.60-2.44 (m, 3H, 14+2)

(257) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=167.6 (4); 162.8 (13); 140.0 (11); 134.9 (5 or 10); 134.8 (5 or 10); 133.6 (12); 127.8 (6+7 or 8+9); 127.1 (q, .sup.1J.sub.C-F=277.0 Hz, 1); 125.7 (6+7 or 8+9); 33.8 (q, .sup.2J.sub.C-F=27.1 Hz, 2); 33.8 (q, .sup.3J.sub.C-F=3.7 Hz, 3); 14.0 (3)

Compound 73: 4-cyano-N-(3,3,3-trifluoropropyl)benzamide

(258) ##STR00074##

(259) 305 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to a solution of 300 mg (1 eq.) 4-cyanobenzoic acid, 1.46 mL (1.2 eq.) of T3P solution at 50% in the ethyl acetate and 1.4 mL (4 eq.) DIEA in 3 mL ethyl acetate. The reaction medium is agitated one night at AT. The solution is then washed using water (2) and then in brine (1). The organic phase is dried on magnesium sulfate, evaporated under reduced pressure to yield 424 mg (86%) of white solid.

(260) LC-MS: t.sub.R=2.31 min (method c); m/z: [MH].sup.=241

(261) NMR .sup.1H (CDCl.sub.3, 300 MHz): ppm=7.86 (d, 2H, .sup.3J=8.47 Hz, 6+7); 7.75 (d, 2H, .sup.3J=8.47 Hz, 8+9); 6.50 (br, s, 0.5H, NH); 3.74 (q, 2H, .sup.3J=6.30 Hz; 3); 2.49 (qt, 2H, .sup.3J.sub.2-1=10.69 Hz, .sup.3J.sub.2-3=6.38 Hz; 2)

Compound 74: 4-(N-hydroxycarbamimidoyl)-N-(3,3,3-trifluoropropyl)benzamide

(262) ##STR00075##

(263) 300 mg (1 eq.) 4-cyano-N-(3,3,3-trifluoro-propyl)-benzamide (73) are added to a solution of 129 mg (1.5 eq.) hydroxylamine hydrochloride and 343 L (1.6 eq.) DIEA in 2.5 mL ethanol. The solution is agitated under reflux during 2 h. The solvent is then evaporated under reduced pressure. The residue is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and evaporated under reduced pressure to yield 330 mg (97%) of white powder.

(264) LC-MS: t.sub.R=3.74 min (method d); m/z: [MH].sup.=274

(265) NMR .sup.1H DMSO-d.sub.6 300 MHz): ppm=9.79 (s, 1H, OH); 8.70 (t, 1H, .sup.3J=5.52 Hz, NH-amide); 7.83 (d, 2H, .sup.3J=8.55 Hz, 6+7 or 8+9); 7.77 (d, 2H, .sup.3J=8.48 Hz, 7+6 or 8+9); 5.89 (s, 2H, NH.sub.2); 3.50 (q, 2H, .sup.3J=6.49 Hz, 3); 2.55 (qt, 2H, .sup.3J.sub.2-1=11.42 Hz, .sup.3J.sub.2-3=6.94 Hz, 2).

Compound 75: 4-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(3,3,3-trifluoropropyl)benzamide

(266) ##STR00076##

(267) 330 mg (1 eq.) 4-(N-hydroxycarbamimidoyl)-N-(3,3,3-trifluoropropyl)benzamide (74) are added to a solution of 78 L (1.1 eq.) acetic acid, 1.84 mL (2.5 eq.) of T3P solution at 50% in the ethyl acetate and 643 L (3 eq.) DIEA in 9 mL ethyl acetate. The solution is agitated during one night under reflux. The conversion is incomplete. The reaction medium is then evaporated under reduced pressure. 1 mL ethyl acetate, 368 L (0.5 eq) T3P and 107 L (0.5 eq.) DIEA are added. The solution is agitated during 48 h under reflux. 2 mL of water are then added and the reaction is agitated during 15 min at AT The organic phase is then washed using water (2) and then in brine (1), dried on magnesium sulfate and evaporated under reduced pressure. The residue thus obtained is purified on a pre-packed silica column (Cyclohexane 9:1 Isopropanol) to yield 215 mg (66%) of white solid.

(268) LC-MS: t.sub.R=2.37 min (method c); m/z: [M+H].sup.+=300, [MH].sup.=298

(269) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.86 (t, 1H, .sup.3J=5.54 Hz, NH); 8.09 (d, 2H, .sup.3J=8.46 Hz, 8+9); 7.99 (d, 2H, .sup.3J=8.55 Hz, 6+7); 3.52 (q, 2H, .sup.3J=6.42 Hz, 3); 2.68-2.50 (m, 5H, 13+2)

(270) NMR .sup.13C (DMSO-d.sub.6 75 MHz): ppm=177.8 (12); 167.1 (11); 165.6 (4); 136.6 (5); 128.8 (10); 128.1 (6+7); 127.0 (8+9); 126.9 (q, =277.12 Hz, 1); 32.9 (3); 32.4 (q, 2J.sub.C-F=27.1 Hz, 2)

Compound 76: 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzoate

(271) ##STR00077##

(272) 1.66 g (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to a solution of 2 g (1 eq.) mono-methylterephtalate, 5.04 g (1.2 eq.) HBTU, 0.3 g (0.2 eq.) HOBt and 7.7 mL (4 eq.) DIEA in 45.5 mL DMF on a molecular sieve. The reaction medium is agitated at AT during 1 h. The DMF is then evaporated under reduced pressure. The residue is taken over in the ethyl acetate and then washed with a solution saturated with NaHCO.sub.3 (2), a solution of hydrochloric acid 1N (2) using water (1) and in brine (1). The organic phase is then dried on magnesium sulfate and then evaporated under reduced pressure. The residue thus obtained is purified on a pre-packed silica column (Cyclohexane 9:1 AcOEt.fwdarw.Cyclohexane 85:15 AcOEt) to yield 1.25 g (41%) of white powder. The impure fractions are again purified on a pre-packed silica column (Cyclohexane 9:1 AcOEt) to yield 1.27 g (41%) of white powder. This results in a yield of 82%.

(273) LCMS: t.sub.R=2.44 min (method c); m/z: [MH].sup.=274

(274) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm: 8.10 (d, 2H, .sup.3J=8.63 Hz, 8+9 or 6+7); 7.83 (d, 2H, .sup.3J=8.55 Hz, 7+6 or 8+9); 6.60 (br s, 1H, NH); 3.95 (s, 3H, 12); 3.74 (q, 2H, .sup.3J=6.45 Hz, 3); 2.53 (qt, 2H, .sup.3J.sub.2-1=10.93 Hz, .sup.3J.sub.2-3=6.63 Hz, 2)

Compound 77: 4-(3,3,3-trifluoropropylcarbamoyl)benzoic acid

(275) ##STR00078##

(276) 300 mg (1 eq.) 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzoate (76) are added to a solution of 244.6 mg (4 eq.) potassium hydroxide in 2.66 mL MeOH. The mixture is agitated under reflux during 2 h. The reaction medium is then evaporated under reduced pressure. The white solid thus obtained is taken over in a mixture water: AcOEt. The aqueous phase is washed using ethyl acetate and then acidified by means of an aqueous solution of hydrochloric acid 1N up to pH=2. The formed white precipitate is then solubilized in the ethyl acetate. The organic phase is washed using water (2) and then in brine (1), dried on magnesium sulfate and then concentrated under reduced pressure to yield 254 mg (89%) of white powder.

(277) LC-MS: t.sub.R=4.28 min (method d); m/z: [MH].sup.=260

(278) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=13.21 (br s, 1H, COOH); 8.84 (t, 1H, .sup.3J=5.56 Hz, NH); 8.02 (d, 2H, .sup.3J=8.25 Hz, 6+7 or 8+9); 7.91 (d, 2H, .sup.3J=8.25 Hz, 6+7 or 8+9); 3.50 (q, 2H, .sup.3J=6.30 Hz, 3); 2.55 (qt, 2H, .sup.3J.sub.2-1=11.44 Hz, .sup.3J.sub.2-3=6.96 Hz, 2)

Compound 78: 4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(3,3,3-trifluoropropyl)benzamide

(279) ##STR00079##

(280) 100 mg (1 eq.) 4-(3,3,3-trifluoropropylcarbamoyl)benzoic acid (77) are added to a solution of 28.4 mg (1 eq.) acetamidoxime, 570 L (2.5 eq.) of T3P solution at 50% in the ethyl acetate, 199 L (3 eq.) DIEA in 191 L ethyl acetate. The mixture is agitated under reflux during 12 h. The CCM analysis of the medium shows an incomplete conversion. 228 L (1 eq.) of T3P solution and 66 L (1 eq.) DIEA are then added. The reaction is agitated for a further 24 h under reflux. 200 L of water are added to the reaction medium at AT and the solution is agitated during 10 min at AT. The product is purified by preparative HPLC to yield 88 mg (77%) of white powder.

(281) LC-MS: t.sub.R=3.00 min (method c); m/z: [MH].sup.=298

(282) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.21 (d, 2H, .sup.3J=8.42 Hz, 8+9); 7.91 (d, 2H, .sup.3J=8.42 Hz, 6+7); 6.54 (br s, H, NH); 3.75 (q, 2H, .sup.3J=6.41 Hz, 3); 2.61-2.46 (m, 5H, 13+2)

(283) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=174.8 (4); 168.5 (12); 166.6 (4); 138.1 (5); 128.6 (8+9); 128.0 (6+7); 127.4 (10); 127.0 (q, .sup.1J.sub.C-F=276.8 Hz, 1); 34.0 (3); 33.9 (q, .sup.2J.sub.C-F=27.6 Hz, 2); 11.9 (13)

Compound 80: 4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzamide

(284) ##STR00080##

(285) 100 mg (1 eq.) 4-(3,3,3-trifluoropropylcarbamoyl)benzoic acid (77) are added to a solution of 31.2 mg (1.1 eq.) acetylhydrazine, 570 L (2.5 eq.) of T3P solution at 50% in the ethyl acetate and 199 L (3 eq.) DIEA in 196 L ethyl acetate. The solution is agitated during 24 h under reflux. The LCMS analysis of the reaction medium shows the formation of 50% of the desired product and of 50% of the non-cyclized intermediate product. 66 L (1 eq.) DIEA and 228 L of T3P solution at 50% in the ethyl acetate are then added and the solution is agitated during 48 h under reflux. The solution is left to return at AT and then 1 mL of water is added and the mixture is agitated during 15 min at AT. The organic phase is then washed using water (2) and in brine (1), dried on magnesium sulfate and evaporated under reduced pressure to yield 102 mg (90%) of white powder.

(286) LC-MS: t.sub.R=4.68 min (method d); m/z: [MH].sup.=298

(287) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.07 (d, 2H, .sup.3J=8.44 Hz, 8+9); 7.88 (d, 2H, .sup.3J=8.44 Hz, 6+7); 6.73 (br s, 1H, NH); 3.72 (q, 2H, .sup.3J=6.46 Hz, 3); 2.60 (s, 3H, 13); 2.50 (qt, 2H, .sup.3J.sub.2-1=10.85 Hz, .sup.3J.sub.2-3=6.64 Hz, 2)

(288) NMR .sup.13C (CD.sub.2Cl.sub.2, 75 MHz): ppm=166.8 (4); 164.7 (12); 164.5 (11); 137.2 (5); 128.1 (6+7); 127.2 (10); 127.2 (8+9); 127.0 (q, .sup.1J.sub.C-F=275.9 Hz, 1); 34.1 (q, .sup.3J.sub.C-F=2.8 Hz, 3); 33.9 (q, .sup.2J.sub.C-F=27.7 Hz, 2); 11.3 (13)

Compound 81: 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzonitrile

(289) ##STR00081##

(290) 482 mg (1.5 eq.) Lawesson reagent are added at AT to a solution of 100 mg (1 eq.) 4-cyanobenzoic acid, 51 mg (1 eq.) acetylhydrazine, 606 L (1.5 eq.) of T3P solution at 50% in the ethyl acetate and 295 L (2.5 eq.) DIEA in 1.5 mL ethyl acetate. The solution is then heated during one night under reflux. The reaction medium is cooled at AT and then 5 mL of water are added. The solution is agitated during 15 min at AT. The organic phase is washed with an aqueous solution saturated with NaHCO.sub.3 (2) and then in brine (1), dried on magnesium sulfate and evaporated under reduced pressure. The yellow oil thus obtained is used as is in the following reaction.

(291) LC-MS: t.sub.R=2.10 min (method c); m/z: [M+H].sup.+=202

Compound 82: 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzoic acid

(292) ##STR00082##

(293) 137 mg (1 eq.) 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzonitrile (81) are added to 5 mL of an aqueous soda solution at 10%. The mixture is agitated during 1 h under reflux and then cooled at AT and finally washed using ethyl acetate. The aqueous phase is then acidified by means of a solution of HCl 1N up to pH=2 and then extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under, reduced pressure. The product is used as is in the following step.

(294) LC-MS: t.sub.R=1.65 min (method c); m/z: [MH].sup.=219

Compound 83: 4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3,3,3-trifluoropropyl)benzamide

(295) ##STR00083##

(296) 101 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to a solution of 150 mg (1 eq.) 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzoic acid (82), 485 L (1.2 eq.) of T3P solution at 50% in the ethyl acetate and 353 L (3 eq.) DIEA in 3 mL ethyl acetate. The solution is agitated during one night at AT. 81 L (0.2 eq.) of T3P solution are added and the mixture is agitated during 4 h at AT. 2 mL of water are added and the reaction medium is agitated during 15 min at AT. The organic phase is washed using water (2) and then in brine (1), dried on magnesium sulfate and then evaporated under reduced pressure. The residue thus obtained is purified on a pre-packed silica column (DCM.fwdarw.DCM 99:1 MeOH.fwdarw.DCM 98:2 MeOH) to yield 22 mg (10%) of white powder.

(297) LC-MS: t.sub.R=2.17 min (method c); m/z: [M+H].sup.+=316, [MH].sup.=314

(298) NMR .sup.1H (CD.sub.2Cl.sub.2, 300 MHz): ppm=8.04 (d, 2H, .sup.3J=8.71 Hz, 8+9); 7.95 (d, 2H, .sup.3J=8.71 Hz, 6+7); 3.65 (t, 2H, .sup.3J=6.99 Hz, 3); 2.83 (s, 3H, 13); 2.55 (qt, .sup.3J.sub.2-1=10.88 Hz, .sup.3J.sub.2-3=7.10 Hz, 2)

(299) NMR .sup.13C (CD.sub.2Cl.sub.2, 300 MHz): ppm=169.7 (11); 169.1 (4); 168.4 (12); 137.7 (5 or 10); 134.0 (5 or 10); 129.3 (6+7); 128.9 (8+9); 128.0 (q, .sup.1J.sub.C-F=276.3 Hz, 1); 34.5 (3); 34.0 (q, .sup.2J.sub.C-F=27.8 Hz, 2)

Compound 84: N1-(3,3,3-trifluoropropyl)terephthalamide

(300) ##STR00084##

(301) 2 mL ammonia solution 7N in the methanol are added to a solution of 200 mg 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzoate (76) in 2 mL methanol. The solution is agitated during 36 h under reflux. The LCMS and CCM analyses of the reaction medium show nearly no conversion of the starting ester. 500 L of water and 163 mg (4 eq.) KOH are then added and the reaction medium is agitated during one night under reflux. The solution is acidified up, to pH=4 by means of a solution of hydrochloric acid 1N. The formed white precipitate is filtrated and dried one night in a desiccator (148 mg).

(302) The product is then solubilized in 10 mL of a mixture DCE:SOCl.sub.2 (1:1). The, solution is agitated during 4 h at 50 C. The solution is concentrated under reduced pressure and then taken over at 0 C. in 15 mL of a mixture CH.sub.3CN:NH.sub.4OH 28% (2:1). The solution is, agitated at AT for one night. The reaction medium is extracted using ethyl acetate. The organic phases are regrouped and then washed using water (2) and in brine (1), dried on magnesium sulfate and evaporated under reduced pressure to yield 115 mg (61%) of white solid.

(303) LC-MS: t.sub.R=1.77 min (method c); m/z: [MH].sup.=259

Compound 85: 4-(2-oxo-1,3,4-oxathiazol-5-yl)-N-(3,3,3-trifluoropropyl)benzamide

(304) ##STR00085##

(305) 75 L (2 eq.) (chlorothio)formyle chloride are added to a solution of 115 mg (1 eq.) N1-(3,3,3-trifluoropropyl)terephthalamide (84) in 1.1 mL toluene. The reaction medium is agitated during 24 h at 90 C. 38 L (1 eq.) (chlorothio)formyle chloride are then added and the reaction is agitated at 90 C. during a further 24 h. The toluene is evaporated under reduced pressure. The residue is taken over in some dichloromethane and then filtrated to yield 95 mg (68%) of white solid.

(306) LC-MS: t.sub.R=2.57 min (method c); m/z: [MH].sup.=317

(307) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.90 (t, 1H, .sup.3J=5.67 Hz, NH); 8.05-8.00 (m, 4H, 6+7+8+9); 3.52 (q, 2H, .sup.3J=6.44 Hz, 3); 2.57 (qt, 2H, .sup.3J.sub.2-1=11.34 Hz, .sup.3J.sub.2-3=6.70 Hz, 2)

Compound 89: 3-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)-1,2,4-thiadiazole-5-ethyl carboxylate

(308) ##STR00086##

(309) 383 mL (10 eq.) ethyl cyanoformiate are added to a solution of 100 mg (1 eq.) 4-(2-oxo-1,3,4-oxathiazol-5-yl)-N-(3,3,3-trifluoropropyl)benzamide (85) in 400 L 1,2-dichloro-benzene. The mixture is agitated during 30 min at 160 C. in a microwave reactor. The solution is cooled at AT and then 6 mL acetonitrile are then added. The formed precipitate is filtrated to yield 302 mg (85%) of white powder.

(310) LC-MS: t.sub.R=2.77 min (method c); m/z: [M+H].sup.+=374

(311) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.44 (d, 2H, .sup.3J=8.56 Hz, 8+9); 7.97 (d, 2H, .sup.3J=8.56 Hz, 6+7); 4.54 (q, 2H, .sup.3J=7.16 Hz, 14); 3.66 (t, 2H, .sup.3J=7.04 Hz, 3); 2.55 (qt, 2H, .sup.3J.sub.2-1=10.83 Hz, .sup.3J.sub.2-3=7.04 Hz, 2); 1.47 (t, 3H, .sup.3J=7.13 Hz, 15)

Compound 90: 4-(5-(hydroxymethyl)-1,2,4-thiadiazol-3-yl)-N-(3,3,3-trifluoropropyl)-benzamide

(312) ##STR00087##

(313) 550 L of a solution 2M of LiBH.sub.4 in the THF are added at 0 C. and under argon to a solution of 140 mg 3-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)-1,2,4-thiadiazole-5-ethyl carboxylate (89) in 3.5 mL anhydrous THF. The solution is agitated during 30 min at 0 C. 0.5 mL of an aqueous solution saturated with NH.sub.4Cl are then added to neutralize the excess of hydride. The medium is concentrated under reduced pressure. The residue thus obtained is then purified on a pre-packed silica column (Toluene 97:3 MeOH Toluene 95:5 MeOH) to yield 108 mg (44%) of white powder.

(314) LC-MS: t.sub.R=2.18 min (method c); m/z: [M+H].sup.+=332, [MH].sup.=330

Compound 92: 4-azido-N-(3,3,3-trifluoropropyl)benzamide

(315) ##STR00088##

(316) 1.05 g (1 eq.) 3,3,3-trifluoropropylamine hydrochloride are added to a solution of 1.14 g (1 eq.) 4-azidobenzoic acid, 536 mg (0.5 eq) HOBt 3.19 g (1.2 eq) HBTU and 4.85 mL (4 eq.) DIEA in 5 mL DMF. The solution is agitated one night at AT and then evaporated under reduced pressure. The residue is dissolved in the ethyl acetate and washed with an aqueous solution saturated with NaHCO.sub.3 (2), an aqueous solution of HCl 1N (1) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 1.77 g (98%) of a light brown solid.

(317) LC-MS: t.sub.R=2.65 min (method c); m/z: [MH].sup.=257

(318) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=7.86 (d, 2H, .sup.3J=8.91 Hz, 6+7 or 8+9); 7.15 (d, 2H, .sup.3J=8.92 Hz, 6+7 or 8+9); 3.61 (t, 2H, .sup.3J=6.97 Hz, 3); 2.51 (qt, =10.99 Hz, .sup.3J.sub.2-3=7.05 Hz, 2)

(319) Procedure (ii): General Procedure for Forming Triazole by Click Chemistry

(320) ##STR00089##

(321) 1 eq. alkyne is added to a solution of 115 mg (1 eq.) 4-azido-N-(3,3,3-trifluoropropyl)benzamide (92), 8 mg (0.1 eq.) CuSO.sub.4, 99.1 mg (1 eq.) sodium ascorbate in 6 mL of a mixture t-BuOH/H.sub.2O (1/1). The solution is agitated one night at AT.

Compound 93: 4-(4-isopentyl-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)benzamide

(322) ##STR00090##

(323) Procedure (ii) with 65.7 L 5-methylhexyne. The medium is filtrated after reaction. The product still present in the aqueous phase is extracted using ethyl acetate. The product is then dried in a desiccator to yield 93 mg (53%) of beige solid.

(324) LC-MS: t.sub.R=2.93 min (method c); m/z: [M+H].sup.+=355

(325) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.84 (br s, 1H, NH); 8.69 (s, 1H, 11); 8.03 (br m, 4H, 6+7+8+9); 3.53 (q, 2H, .sup.3J=6.34 Hz, 3); 2.73 (t, 2H, .sup.3J=7.42 Hz, 13); 2.58 (qt, .sup.3J.sub.2-1=11.40 Hz, .sup.3J.sub.2-3=7.11 Hz, 2); 1.67-1.54 (m, 3H, 14+15); 0.94 (d, 6H, .sup.3J=6.13 Hz, 16+17)

Compound 94: 4-(4-isobutyl-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)benzamide

(326) ##STR00091##

(327) Procedure (ii) with 58.9 L 4-methylpentyne. After one night, the conversion is not total. 1 eq. alkyne, 0.5 eq. sodium ascorbate and 0.05 eq. CuSO.sub.4 are added to the reaction medium. The solution is agitated during 4 h at AT. The product is extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure to yield 128 mg (75%) of a light brown powder.

(328) LC-MS: t.sub.R=2.77 min (method c); m/z: [M+H].sup.+=341

(329) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.42 (s, 1H, 11); 8.05-7.97 (m, 4H, 6+7+8+9); 3.65 (t, 2H, .sup.3J=6.98 Hz, 3); 2.67 (d, 2H, .sup.3J=6.85 Hz, 13); 2.55 (qt, .sup.3J.sub.2-1=10.93 Hz, .sup.3J.sub.2-3=6.93 Hz, 2); 2.03 (n, 1H, .sup.3J=6.75 Hz, 14); 0.99 (d, 6H, .sup.3J=6.63 Hz, 15+16)

Compound 95: 4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)-benzamide

(330) ##STR00092##

(331) Procedure (ii) with 42.4 L ethynylcyclopropane. Part of the product is recovered by filtration of the formed precipitate. The remaining product in the filtrate is extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure to yield 73 mg (45%) of a white powder.

(332) LC-MS: t.sub.R=2.52 min (method c); m/z: [M+H].sup.+=325

(333) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=8.84 (br s, 1H, NH); 8.64 (s, 1H, 11); 8.05-7.97 (m, 4H, 6+7+8+9); 3.53 (q, 2H, .sup.3J=6.44 Hz, 3); 2.58 (qt, 2H, .sup.3J.sub.2-1=11.51 Hz, .sup.3J.sub.2-3=6.95 Hz, 2); 2.09-2.00 (m, 1H, 13); 1.02-0.96+0.84-0.79 (m, 4H, 14+15)

Compound 96: 4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)-benzamide

(334) ##STR00093##

(335) Procedure (ii) with 29.2 L propargyl alcohol. The product is extracted using ethyl acetate. The organic phases are regrouped, dried on magnesium sulfate and then evaporated under reduced pressure to yield 52 mg (33%) of a beige powder.

(336) LC-MS: t.sub.R=2.03 min (method c); m/z: [M+H].sup.+=315

(337) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.57 (s, 1H, 11); 8.07-7.99 (m, 4H, 6+7+8+9); 4.79 (s, 2H, 13); 3.67 (t, 2H, .sup.3J=6.97 Hz, 3); 2.57 (qt, 2H, .sup.3J.sub.2-1=10.91 Hz, .sup.3J.sub.2-3=6.98 Hz, 2)

(338) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=168.9 (4); 150.3 (12); 140.6 (5 or 10); 135.5 (5 or 10); 130.1 (6+7); 128.0 (q, .sup.1J.sub.C-F=276.1 Hz, 1); 122.3 (11); 121.2 (8+9); 56.4 (13); 34.6 (3); 34.0 (q, .sup.2J.sub.C-F=27.7 Hz, 2)

Compound 97: 4-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoropropyl)-benzamide

(339) ##STR00094##

(340) Procedure (ii) with 37.9 L 3-butyn-1-ol. No precipitate is observed. The product is extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure to yield 135 mg (82%) of beige solid.

(341) LC-MS: t.sub.R=2.07 min (method c); m/z: [M+H].sup.+=329

(342) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=8.44 (s, 1H, 11); 8.04-7.96 (m, 4H, 6+7+8+9); 3.89 (t, 2H, .sup.3J=6.62 Hz, 14); 3.65 (t, 2H, .sup.3J=6.98 Hz, 3); 3.00 (t, 2H, .sup.3J=6.51 Hz, 13); 2.44 (qt, 2H, .sup.3J.sub.2-1=10.85 Hz, .sup.3J.sub.2-3=7.09 Hz, 2)

(343) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=168.9 (4); 147.3 (12); 140.7 (5 or 10); 135.4 (5 or 10); 130.1 (6+7); 128.0 (q, .sup.1J.sub.C-F=275.8 Hz, 1); 122.2 (11); 121.1 (8+9); 61.9 (14); 34.6 (3); 34.0 (q, .sup.2J.sub.C-F=28.1 Hz, 2); 29.9 (13)

Compound 98: 4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(3,3,3-trifluoro-propyl)benzamide

(344) ##STR00095##

(345) Procedure (ii) with 48.9 L 2-methyl-3-butyn-2ol. Part of the product is recovered by filtration of the formed precipitate. The remaining product in the filtrate is extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure. The product is dried in a desiccator to yield 80 mg (53%) of white powder.

(346) LC-MS: t.sub.R=2.18 min (method c); m/z: [MH].sup.=341

(347) NMR .sup.1H DMSO-d.sub.6 300 MHz): ppm=8.84 (t, 1H, .sup.3J=5.18 Hz, NH); 8.71 (s, 1H, 11); 8.08-8.01 (m, 4H, 6+7+8+9); 5.29 (s, 1H, OH); 3.53 (q, 2H, .sup.3J=6.40 Hz, 3); 2.58 (qt, 2H, .sup.3J.sub.2-1=11.53 Hz, .sup.3J.sub.2-3=6.72 Hz, 2)

Compound 99: 1-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)-1H-1,2,3-triazole-4-methyl carboxylate

(348) ##STR00096##

(349) Procedure (ii) with 41.4 L methyl propiolate. After one night, the conversion is not total. 0.5 eq. alkyne, 0.5 eq. sodium ascorbate and 0.05 eq. CuSO.sub.4 are added to the reaction medium. The solution is agitated during 4 h at AT. The product is extracted using ethyl acetate. The organic phases are collected, dried on magnesium sulfate and then evaporated under reduced pressure to yield 156 mg (91%) of a beige powder.

(350) LC-MS: t.sub.R=2.37 min (method c); m/z: [M+H].sup.+=343

(351) NMR .sup.1H (DMSO-d.sub.6, 300 MHz): ppm=9.62 (s, 1H, 11); 8.89 (t, 1H, .sup.3J=5.56 Hz, NH); 8.14 (d, 2H, .sup.3J=8.88 Hz, 8+9); 8.06 (d, 2H, .sup.3J=8.88 Hz, 6+7); 3.91 (s, 3H, 14); 3.54 (q, .sup.3J=6.46 Hz, 3); 2.59 (qt, 2H, .sup.3J.sub.2-1=11.44 Hz, .sup.3J.sub.2-3=7.06 Hz, 2)

(352) NMR .sup.13C (DMSO-d.sub.6, 75 MHz): ppm=165.1 (13); 160.5 (4); 139.7 (12); 138.0 (5 or 10); 134.5 (5 or 10); 128.9 (6+7); 127.5 (11); 126.9 (q, .sup.1J.sub.C-F=277.1 Hz, 1); 120.2 (8+9); 52.1 (14); 32.9 (3); 32.4 (q, .sup.2J.sub.C-F=26.6 Hz, 2)

Compound 100: 4-(3,3,3-trifluoropropylcarbamoyl)methyl benzimidate hydrochloride

(353) ##STR00097##

(354) 15 mL of a solution of hydrochloric acid 4N in dioxane are added under argon at 0 C. to a solution of 300 mg 4-cyano-N-(3,3,3-trifluoropropyl)benzamide (73) in 1 mL MeOH. The mixture is agitated during one night at AT. 20 mL diethyl ether are added and the solution is cooled in a refrigerator during one hour. The precipitate is then filtrated, washed using diethyl ether and dried in a desiccator to yield 359 mg (93%) of white powder.

(355) LC-MS: t.sub.R=1.85 min (method c); m/z: [M+H].sup.+=275, [MH].sup.=273

Compound 101: 4-(5-methyl-4H-1,2,4-triazol-3-yl)-N-(3,3,3-trifluoropropyl)benzamide

(356) ##STR00098##

(357) 169 L (1.5 eq.) DIEA are added to a solution of 200 mg 4-(3,3,3-trifluoropropylcarbamoyl) methyl benzimidate hydrochloride (100) in 5 mL absolute ethanol. The reaction medium is agitated during 15 min at AT. The acetylhydrazine is then added and the solution is agitated during 60 h under reflux. The ethanol is evaporated under reduced pressure. The solid rose thus obtained is purified by preparative HPLC and then lyophilized to yield 123 mg (64%) of white powder.

(358) LC-MS: t.sub.R=1.92 min (method c); m/z: [M+H].sup.+=299, [MH].sup.=297

(359) NMR .sup.1H (CD.sub.3OD, 300 MHz 8.08 (d, 2H, .sup.3J=8.59 Hz, 8+9); 7.90 (d, 2H, .sup.3J=8.68 Hz, 6+7); 3.64 (t, 2H, .sup.3J=7.02 Hz, 3); 2.62-2.46 (m, 5H, 13+2)

(360) ##STR00099##

Compound 102: (4-(4-(3,3,3-trifluoropropylcarbamoyl)phenyl)thiazol-2-yl) methanaminium di-bromhydrate

(361) ##STR00100##

(362) 73 mg (1.1 eq.) N-benzyloxycarbonylglycine thioamide are added to a solution of 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 5 mL anhydrous THF. The solution is agitated during 3 h at 70 C. The THF is then evaporated under reduced pressure and the solid thus obtained is used as is 1 mL of a HBr solution at 25% in the acetic acid is added and the reaction medium is agitated during 1 h at AT 8 mL diethyl ether are then added at AT to form a precipitate that is cooled in an ice-water bath. The precipitate is then filtrated, washed using cold diethyl ether and then dried in a desiccator to yield 157 mg of pale brown solid. The product is separated in two for the synthesis of the compounds 103 and 104.

(363) LC-MS: t.sub.R=1.85 min (method c); m/z: [M+H].sup.+=330

Compound 103: 4-(2-(propylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide

(364) ##STR00101##

(365) 20 L (1.2 eq.) propane sulfonic acid chloride are added to a solution of 75 mg (1 eq.) of compound 102 and 82 L N-methylmorpholine in 1.5 mL anhydrous DCM. The reaction medium is agitated during 2 h at AT. The DCM is evaporated under reduced pressure and then the residue is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 54 mg (76%) of beige powder.

(366) LC-MS: t.sub.R=2.60 min (method c); m/z: [MH].sup.=434

(367) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm: 8.05 (d, 2H, .sup.3J=8.43 Hz, 8+9); 7.96 (s, 1H, 12); 7.89 (d, 2H, .sup.3J=8.49 Hz, 6+7); 4.63 (s, 2H, 14); 3.66, (t, 2H, .sup.3J=6.99 Hz, 3); 3.15-3.09 (m, 2H, 15); 2.56 (qt, 2H, .sup.3J.sub.2-1=10.89 Hz, .sup.3J.sub.2-3=7.11 Hz, 2); 1.84 (sx, 2H, .sup.3J=7.60 Hz, 16); 1.04 (t, 3H, .sup.3J=7.46 Hz, 17).

Compound 104: 4-(2-(phenylsulfonamidomethyl)thiazol-4-yl)-N-(3,3,3-trifluoro-propyl)benzamide

(368) ##STR00102##

(369) 23 L (1.2 eq.) benzene sulfonic acid chloride are added to a solution of 75 mg (1 eq.) of compound 102 and 82 L N-methylmorpholine in 1.5 mL anhydrous DCM. The reaction medium is agitated during 2 h at AT. The DCM is evaporated under reduced pressure and then the residue is taken over in the ethyl acetate and then washed using water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure to yield 51 mg (67%) of beige powder.

(370) LC-MS: t.sub.R=2.73 min (method c); m/z: [MH].sup.=468

(371) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=7.96 (d, .sup.3J=8.50 Hz, 8+9); 7.87 (m, 5H, 6+7+12+16+20); 5.57 (m, 3H, 17+18+19); 4.47 (s, 2H, 14); 3.65 (t, 2H, .sup.3J=7.00 Hz, 3); 2.55 (qt, 2H, .sup.3J.sub.2-1=11.0 Hz, .sup.3J.sub.2-3=7.10 Hz, 2)

(372) ##STR00103## ##STR00104##

Compound 105: N-(prop-2-ynyl)benzene sulfonamide

(373) ##STR00105##

(374) 200 L (1 eq.) benzene sulfonic acid chloride, 129 L (1.2 eq.) propargylamine, 8 mL DCM and 1.08 mL (4 eq.) DIEA are agitated at AT during 2 h. The DCM is evaporated under reduced pressure and then the residue is taken over in the ethyl acetate, washed in water (2) and in brine (1). The organic phase is dried on magnesium sulfate and then evaporated under reduced pressure. The residue is purified by preparative HPLC to yield 238 mg (78%) of a transparent oil.

(375) LC-MS: t.sub.R=2.42 min (method c); m/z: [MH].sup.=194

(376) CCM: R.sub.f=0.14 (AcOEt 2:8 Cyclohexane)

Compound 106: 4-(3-(phenylsulfonamido)prop-1-ynyl)-N-(3,3,3-trifluoropropyl)-benzene sulfonamide

(377) ##STR00106##

(378) 50 mg (1 eq.) N-(prop-2-ynyl)benzene sulfonamide (105), 87 mg (0.9 eq.) 4-iodo-N-(3,3,3-trifluoropropyl)benzene sulfonamide (42), 8.3 mg (0.05 eq.) bis(triphenylphosphine) palladium(II) chloride, 40.2 mg (0.9 eq.) copper iodide, and 120 L (0.5 mL/mmol) triethylamine are placed successively in a schlenk under an argon flow. The anhydrous DMF is added via a cannula under argon at ambient temperature. The reaction mixture is agitated at 70 C. under argon during 48 h.

(379) The reaction medium is then diluted at AT by adjunction of a mixture of AcOEt:NH.sub.4Cl.sub.sat (1:1). The formed precipitate is filtrated and washed using ethyl acetate. The organic phase is washed with an aqueous solution saturated with NH.sub.4Cl (2) and then in brine (1), dried on magnesium sulfate, filtrated on celite and then evaporated under reduced pressure. The solid orange thus obtained is solubilized in the minimum of acetonitrile and then the product is precipitated by adjunction of diisoprpylic ether and filtrated to yield 38 mg (33%) of beige powder.

(380) LC-MS: t.sub.R=3.13 min (method c); m/z

(381) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=7.92 (m, 2H, 14+18 or 15+17); 7.74 (d, 2H, .sup.3J=8.40 Hz, 5+6); 7.50-7.57 (m, 3H, 16+(14+18 or 15+17)); 7.30 (d, 2H, .sup.3J=8.40 Hz, 7+8); 4.07 (s, 2H, 12); 3.08 (t, 2H, .sup.3J=7.10 Hz, 3); 2.36 (qt, 2H, .sup.3J.sub.2-1=10.60 Hz, .sup.3J.sub.2-3=6.80 Hz, 2)

(382) NMR .sup.13C (CD.sub.3OD, 75 MHz): ppm=142.3 (4); 141.2 (13); 133.7 (16); 133.2 (7+8); 130.1 (14+18ou15+17); 128.4 (14+18ou15+17); 128.3 (9); 127.9 (5+6); 127.5 (q, .sup.1J=276.7 Hz, 1); 88.7 (11); 83.3 (10); 37.4 (3); 35.2 (q, .sup.2J=28.2 Hz, 2); 33.8 (12)

Compound 107: N-(prop-2-ynyl)methane sulfonamide

(383) ##STR00107##

(384) A solution of 288 L (1 eq.) methane sulfonic acid chloride in 3 mL diethyl ether is added to a solution of 500 L (2 eq.) propargylamine in 6 mL diethyl ether cooled at 0 C. The mixture is agitated during 30 min. The formed precipitate is filtrated and washed twice using ether. The filtrate is evaporated under reduced pressure to yield 178 mg (37%) of a white solid.

(385) LC-MS: t.sub.R=1.92 min (method c); m/z: [M+H].sup.+=134 NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=4.69 (m, 1H, NH); 4.00 (dd, 2H, .sup.3J.sub.3-NH=6.20 Hz, .sup.4J.sub.3-1=2.50 Hz, 2); 3.10 (s, 3H, 4); 2.41 (t, 1H, .sup.3J=2.50 Hz, 1)

Compound 108: 4-(3-(methylsulfonamido)prop-1-ynyl)-N-(3,3,3-trifluoropropyl)-benzene sulfonamide

(386) ##STR00108##

(387) 136 mg (1.2 eq.) tetrabutylammonium acetate, 1 mg (0.002 eq.) Pd EnCat.sup.30, 142 mg (1 eq.) 4-iodo-N-(3,3,3-trifluoropropyl)benzene sulfonamide (42) and 50 mg (1 eq.) N-(prop-2-ynyl)methane sulfonamide (107) are added to 500 L DMF. The solution is agitated during 24 h at 80 C. A mixture of AcOEt:NH.sub.4Cl.sub.sat 1:1 (2 mL) is added to the reaction medium. The mixture is agitated for 10 min and then filtrated to recover the palladium beads. The product is recovered in the organic phase by extraction Water:AcOEt. The organic phase is then washed in brine (1), dried on magnesium sulfate, filtrated on celite and evaporated under reduced pressure. The product is purified on a pre-packed silica column (Cyclohexane 95:5 Isopropanol.fwdarw.Cyclohexane 90:10 Isopropanol). 39 mg (27%) of a beige solid are recovered.

(388) LC-MS: t.sub.R=2.78 min (method c); m/z: [M+H].sup.+=385

(389) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=7.84 (d, 2H, .sup.3J=8.59 Hz, 5+6 or 7+8); 7.64 (d, 2H, .sup.3J=8.59 Hz, 5+6 or 7+8); 4.17 (s, 2H, 12); 3.12-3.08 (m, 5H, 13+3); 2.38 (qt, 2H, .sup.3J.sub.2-1=10.78 Hz, .sup.3J.sub.2-3=7.28 Hz, 2)

Compound 111: 4-iodo-N-(3,3,3-trifluoropropyl)benzamide

(390) ##STR00109##

(391) 300 mg (1 eq.) 4-acetylbenzoic acid, 181 mg (1 eq.) 3,3,3-trifluoropropylamine hydrochloride, 33 mg (0.2 eq.) HOBT, 551 mg (1.1 eq.) HBTU and 10 mL DMF are successively added in a 25 mL flask. 840 L (4 eq.) DIEA are then added and the mixture is agitated 2 h at AT The DMF is evaporated under reduced pressure. The residue is taken over in the ethyl acetate and then washed in brine (2). The organic phase is then evaporated under reduced pressure and the product is then purified on a pre-packed silica column (Cyclohexane 8:2 AcOEt) to yield 327 mg (77%) of white powder.

(392) LC-MS: t.sub.R=3.25 min (method c); m/z: [M+H].sup.+=344

(393) NMR .sup.1H (CDCl.sub.3 300 MHz): ppm=7.80 (d, 2H, .sup.3J=8.50 Hz); 7.47 (d, .sup.3J=8.50 Hz); 6.34 (m, 1H, NH); 3.72 (q, 2H, .sup.3J=6.30 Hz, 3); 2.47 (tq, 2H, .sup.3J.sub.2-1=10.70 Hz, .sup.3J.sub.2-3=6.40 Hz, 2)

(394) NMR .sup.19F CDCl.sub.3 282.4 MHz): ppm=64.92 (t, .sup.3J=10.8 Hz)

Compound 112: 4-(3-(phenylsulfonamido)prop-1-ynyl)-N-(3,3,3-trifluoropropyl)-benzamide

(395) ##STR00110##

(396) 50 mg (1 eq.) N-(prop-2-ynyl)benzene sulfonamide (105), 83.5 mg (0.95 eq.) 4-iodo-N-(3,3,3-trifluoropropyl)benzamide (111), 9 mg (0.05 eq.) bis(triphenylphosphine)palladium(II) chloride, 48 mg (1 eq.) copper iodide, and 128 L (0.5 mL/mmol) triethylamine are placed successively in a schlenk under argon flow. 1 mL anhydrous DMF is added via a cannula under argon at AT. The reaction mixture is agitated at 70 C. under argon during 48 h. The reaction medium is diluted at AT by adjunction of a mixture of 1:1 AcOEt:NH.sub.4Cl.sub.sat. The precipitate thus formed is filtrated and washed using ethyl acetate. An extraction is performed using a mixture AcOEt:NH.sub.4Cl.sub.sat. The organic phase is washed in brine (1), dried on magnesium sulfate, filtrated on celite and then evaporated under reduced pressure. The brown oil thus obtained is purified by pre-packed silica column (DCM 95:5 AcOEt) to yield 30 mg (29%) of a light brown solid.

(397) LC-MS: t.sub.R=5.43 min (method d); m/z: [M+H].sup.+=411

(398) NMR .sup.1H (CD.sub.3OD, 300 MHz): ppm=7.94 (dd, 2H, .sup.3J=7.40 Hz, .sup.4J=1.60 Hz, 15+19); 7.71 (d, 2H, .sup.3J=8.40 Hz, 6+7 or 8+9); 7.55 (m, 3H, 16+17+18); 7.21 (d, 2H, .sup.3J=8.40 Hz, 6+7 or 8+9); 4.07 (s, 2H, 13); 3.62 (t, 2H, .sup.3J=7.00 Hz, 3); 2.52 (qt, 2H, .sup.3J.sub.2-1=10.90 Hz, .sup.3J.sub.2-3=7.00 Hz, 2);

(399) Evaluation of the Compounds' Activity

(400) TSA Test (Thermal Shift Assay)

(401) The heat denaturation of proteins is a phenomenon that has been studied for a long time, by means of many techniques, based notably on calorimetry (DSC: Differential Scanning calorimetry) or fluorescence (DSF: Differential Scanning Fluorimetry or also Fluorescence Thermal Shift Assay).

(402) The Thermal Shift Assay test uses a fluorescent marker, in our case Sypro Orange. The fluorescence intensity of this compound is amplified when it is in a hydrophobic environment. Thus, in normal conditions, in an aqueous solution and in the presence of the native protein, the marker fluoresces little, as the hydrophobic zones of the protein are not accessible. When the protein becomes denatured under the effect of heat, the marker will be able to interact with its hydrophobic regions, causing an increase in fluorescence. It is thus possible to determine the melting temperature of the protein, denoted by T.sub.m, corresponding to a state where the protein is 50% denatured.

(403) This technique enables the stabilizing or destabilizing effect on the protein of a specific ligand to be measured. For this, the experience is carried out with the protein alone and then by incubating the protein with a potential ligand. Two different values for the melting temperature are then obtained that enable a temperature difference T.sub.m expressed in C. to be defined. If T.sub.m>0, the ligand stabilizes the protein, if T.sub.m<0, the ligand destabilizes the protein. The greater |T.sub.m|, the greater the ligand's stabilizing or destabilizing effect. Yet as the stabilizing power is linked to the ligand's affinity for the protein, the higher the T.sub.m is, the greater the ligand's affinity for this protein.

(404) This TSA fluorescence test thus enables the affinity of our ligands for the EthR protein to be quantified and for them to, be classified according to their ascending T.sub.m value.

(405) Surface Plasmon Resonance test (SPR) (described in the article Ethionamide Boosters Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a series of potent 1,2,4-Oxadiazole EthR Inhibitors published in 2012 in the Journal of Medicinal Chemistry)

(406) After having measured the ligands' affinity for the protein, it is necessary to verify that this does indeed result in the inactivation of the transcriptional repressor, thus preventing it from binding to its operon. For this, a functional test based on the principle of surface plasmon resonance is used. Surface Plasmon Resonance (SPR) makes it possible to visualize in real time the phenomena of association or dissociation between a partner immobilized on a biosensor and, a second partner injected in a continuous flow onto this surface. In the present case, the SPR technique enables the interaction between the EthR protein (analyte injected in continuous flow) and the ethA gene promoter (partner immobilized on the surface) to be visualized. Two cells are used for the test: a measuring cell onto which the so-called relevant DNA is affixed, i.e. corresponding to the ethA gene promoter, and a control cell on which is a non-relevant (thus different) DNA strand of same length, enabling the non-specific protein/DNA interactions to be removed. In a first step, the EthR protein is injected alone, until saturation, which enables a signal SI.sub.EthR corresponding to the quantity of EthR protein that has come to bind to the DNA to be measured. In a second step, the experience is reiterated in the presence of a potential ligand at different concentrations. If the compound binds to the EthR, thus preventing it from coming to bind on the DNA, a diminution of the response of the dose-dependent signal (SI.sub.EthR+lig) is observed.

(407) By using the equation hereafter, it is possible to calculate for each concentration a percentage for the inhibition of the ligand under examination:

(408) $\%\mathrm{Inhibition}=100\frac{{\mathrm{SI}}_{\mathrm{EthR}}-{\mathrm{SI}}_{\mathrm{EthR}+\mathrm{Lig}}}{{\mathrm{SI}}_{\mathrm{EthR}}}$

(409) By representing the variation of the inhibition percentage depending on the ligand concentration, a value for IC.sub.50 can be deduced.

(410) Potentiation of Ethionamid cell test (described in the article Ethionamide Boosters Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a series of potent 1,2,4-Oxadiazole EthR Inhibitors published in 2012 in the Journal of Medicinal Chemistry)

(411) The preceding test validates the, compounds' capacity to inhibit the EethR/DNA interaction by binding to the EthR protein. The third test used makes it possible to ascertain that these compounds are capable of potentiating the bactericide activity of ethionamide on M. tuberculosis alone or on macrophages infected by M. tuberculosis. This test is a High Content Screening (HCS) or dense content screening test. HCS tests are performed on cell cultures that enable certain phenotypic features of a microorganism (e.g. a bacterium) in a given environment to be studied. The phenotypic changes observed can range from the increase (or decrease) of the production of certain marked proteins to the modification of the morphology of the microorganism under consideration.

(412) This test aims to determine the ligand concentration necessary to potentiate ten times the activity of ethionamide (ETH).

(413) To measure, the ligand concentration necessary for potentiating ten times the activity of ETH, a constant concentration of ethionamide (0.1 g/mL corresponding to 1/10.sup.th of its CMI.sub.99) is chosen. By varying the ligand concentration, the concentration necessary to inhibit 50% of the bacterial growth, i.e. the concentration necessary to potentiate ten times the activity of ethionamide, can be determined. This concentration will be denoted EC.sub.50.

(414) Measurement of the Solubility

(415) 40 L of a solution at 10 mM in DMSO of the sample are added at 1.96 mL MeOH or PBS at pH 7.4. The samples are then agitated during 24 h at AT, centrifuged during 5 min and then filtrated on filters of 0.45 m size. 20 L of each solution are then added to 180 L MeOH and then analyzed by LC-MS. The solubility is determined as ratio of the surfaces of the mass signals PBS/MeOH.

(416) Measurement of the log D

(417) 40 L of a solution at 10 mM in the DMSO of the sample are added to 1.96 mL of a mixture of 1/1 octanol/PBS at pH 7.4. The solution is agitated during 2 h at AT. 20 L of each phase are added to 180 L MeOH and analyzed by LC-MS. Each compound is evaluated in triplicate. The log D is determined as being the logarithm of the ratio of the product concentrations in the octanol and PBS phases, determined par the mass signals.

(418) Measured Biological Activities

(419) Each of the following tables consolidates the formulas of the tested compounds or the definitions of the different variable radicals mentioned in the Markush formula preceding the respective table and corresponding to the tested compounds as well as the values of T.sub.m, EC.sub.50 experimentally measured according to the aforementioned protocols and which corresponds to the number of atoms constituting each molecule and different from the hydrogen atom.

(420) ##STR00111##

(421) TABLE-US-00001 TABLE 1 Compound R2 T.sub.m ( C.) EC.sub.50 (M) HA 6 H.sub.3C.fwdarw. 6.1 5.7 21 17 5.3 7.9 23 21 4.6 5.0 24

(422) ##STR00114##

(423) TABLE-US-00002 TABLE 2 Compound R1 n T.sub.m ( C.) EC.sub.50 (M) HA 6 CH(CH.sub.3).sub.2 2 6.1 5.7 21 23 C(CH.sub.3).sub.3 2 2.3 >20 22 24 CF.sub.3 2 8.5 0.29 22 25 CF.sub.2CF.sub.3 1 8.6 >20 24 26 CF.sub.3 1 6.3 7.9 21 27 CF.sub.3 3 6.6 >2.5 23 28 CF.sub.2CF.sub.2CF.sub.3 1 7.3 >2.5 27

(424) ##STR00115##

(425) TABLE-US-00003 TABLE 3 Compound R3 T.sub.m ( C.) EC.sub.50 (M) HA 24 H.sub.3C.fwdarw. 8.5 0.29 22 33 9.5 0.86 26 34 0.15 0.15 27 35 11.6 0.30 28 36 0.21 28 38 0 12.4 0.39 27 39 7.3 0.20 29

(426) TABLE-US-00004 TABLE 4 Compound Structure T.sub.m ( C.) EC.sub.50 (M) HA 41 6.8 0.66 22 42 0.30 25

(427) ##STR00124##

(428) TABLE-US-00005 TABLE 5 Compound R3 T.sub.m ( C.) EC.sub.50 (M) HA 43 H3C 11.4 0.083 21 52 10.1 0.19 26 53 13.2 0.33 27 50 9.6 0.041 28 103 6.6 0.32 28 104 1.2 0.15 31 47 0 13.0 0.030 26 54 9.6 >2.5 25 55 8.2 0.73 26 49 12.6 <0.040 24 56 H 8.1 0.36 20 57 12.6 <0.010 26 58 13.3 <0.010 28

(429) ##STR00136##

(430) TABLE-US-00006 TABLE 6 Compound R2 T.sub.m ( C.) EC.sub.50 (M) HA 62 F 0.055 22 64 Cl 8.7 0.35 22

(431) ##STR00137##

(432) TABLE-US-00007 TABLE 7 Compound Ar EC.sub.50 (M) HA 67 0.120 21 71 1.7 21

(433) TABLE-US-00008 TABLE 8 Com- T.sub.m EC.sub.50 pound Structure ( C.) (M) HA 92 0 6.0 1.1 18

(434) ##STR00141##

(435) TABLE-US-00009 TABLE 9 Compound R3 T.sub.m ( C.) EC.sub.50 (M) HA 93 3.8 >10 25 94 4.1 1.2 24 95 3.5 1.7 23 97 1.2 2.0 23

(436) ##STR00146##

(437) TABLE-US-00010 TABLE 10 Compound R3 Het EC.sub.50 (M) HA 72 H.sub.3C.fwdarw. 0.18 21 75 H.sub.3C.fwdarw. 0.062 21 78 H.sub.3C.fwdarw. 0.21 21 80 H.sub.3C.fwdarw. 0 0.96 21 83 H.sub.3C.fwdarw. 1.4 21 90 0.13 22

(438) ##STR00154##

(439) TABLE-US-00011 TABLE 11 Com- T.sub.m, EC.sub.50 pound R3 T ( C.) (M) HA 106 SO.sub.2 3.3 1.8 29 108 SO.sub.2 1.4 >10 24 112 CO 4.2 0.23 28

(440) TABLE-US-00012 TABLE 12 Compound IC.sub.50 (M) Solubilit (M) LogD 6 4.9 0.1 20 3.55 24 0.55 0.02 41.4 3.12 35 2.8 3.76 38 <1 >4 43 0.48 0.06 46.9 2.82 49 0.44 0.01 4.4 3.91 57 29 3.07 58 3.3 3.95