Benzenesulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (RORγ(T))

Abstract

Benzenesulfonamide derivatives of formula (I), the pharmaceutically acceptable addition salts thereof, the hydrates and/or solvates thereof, and the use of same as inverse agonist of retinoid-related orphan receptor gamma (RORt) are described. A pharmaceutical composition including such compounds, as well as the use thereof for the topical and/or oral treatment of RORt receptor-medicated inflammatory diseases, in particular acne, psoriasis and/or atopic dermatitis are also described.

Claims

1. A compound of formula (II), or a pharmaceutically acceptable addition salt thereof: ##STR00326## in which: q denotes zero or a natural integer ranging from 1 to 3, R.sup.1 represents a linear or branched C.sub.3-C.sub.5 alkyl radical, a C.sub.3-C.sub.5 cycloalkyl radical, a linear or branched C.sub.2-C.sub.5 alkenyl radical, R.sub.2 represents a hydrogen atom or a halogen atom, a linear or branched C.sub.1-C.sub.5 alkyl radical, a linear or branched C.sub.2-C.sub.4 alkenyl radical, a C.sub.1-C.sub.4 alkoxy radical, a cyano group CN; the alkyl, alkenyl and alkoxy radicals optionally being substituted with one or more halogen atoms, R.sup.3 represents a C.sub.1-C.sub.3 alkyl radical, R.sup.4 represents a hydrogen atom or a (CHR.sup.5).sub.n(Z).sub.0(CHR.sup.5).sub.pR.sup.6 group, n, o and p, which are identical or different, denote zero or a natural integer ranging from 1 to 3, Z represents a divalent group chosen from CH.sub.2, NH and O, R.sup.5 and R.sup.5, which are identical or different, represent a hydrogen atom, a methyl radical CH.sub.3, a hydroxyl radical OH, a C.sub.1 hydroxyalkyl radical, a carboxylic radical COOH, R.sup.6 represents: a hydrogen or halogen atom, a heterocyclic radical optionally substituted with one or more halogen atoms, one or more linear or branched C.sub.1-C.sub.3 alkyl groups, one or more OH groups, one or more carbonyl functions O, one or more linear or branched C.sub.1-C.sub.4 hydroxyalkyl groups, a pyrrolidine ring, one or more amino groups, one or more C(O)R7 groups, one or more S(O).sub.2R.sup.7 groups; wherein the heterocyclic radical is a monocyclic heterocyclic ring having 2-6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of a sulfur atom, a nitrogen atom, and an oxygen atom; R.sup.7 representing a linear or branched C.sub.1-C.sub.3 alkyl radical, a hydroxyl radical OH, a linear or branched C.sub.1-C.sub.4 alkoxy radical, or an amino radical N(R.sup.7a)(R.sup.7b); with R.sup.7a and R.sup.7b, which are identical or different, denoting a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical, a C.sub.3-C.sub.6 cycloalkyl radical optionally substituted with one or more OH groups; an aromatic or heteroaromatic radical optionally substituted with one or more halogen atoms, one or more linear or branched C.sub.1-C.sub.3 alkyl groups optionally substituted with one or more halogen atoms, one or more C.sub.1-C.sub.3 alkoxy groups, one or more amino groups NR.sup.11R.sup.12, one or more COR.sup.11 groups, one or more OR.sup.11 groups, one or more C.sub.1-C.sub.4 hydroxyalkyl groups, one or more COOR.sup.11 groups, one or more amido CONR.sup.11R.sup.12 groups, one or more SOR.sup.11 groups, one or more SO.sub.2R.sup.11 groups, one or more NHCOR.sup.11 groups, one or more NHCOOR.sup.11 groups, one or more SO.sub.2NR.sup.11R.sup.12 groups or one or more CN groups; wherein the heteroaromatic radical is a 5- or 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, a nitrogen atom, and an oxygen atom; R.sup.11 and R.sup.12, which are identical or different, representing a hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more halogen atoms; A.sub.1 represents a divalent group selected from the group consisting of NR.sup.a, O, S, SO, SO.sub.2, SO(NH), CH.sub.2, CC, and CH(R.sup.a); given that: R.sup.a represents a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical or an acetyl radical C(O)CH.sub.3, R.sup.b represents a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl group, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4 and Q.sub.5 each represent a CR.sub.2 group, R.sub.2 represents a hydrogen atom or a linear or branched C.sub.1-C.sub.5 alkyl radical, R.sup.a and R.sup.3 can form, together with the carbon atoms to which they are attached, a C.sub.3-C.sub.4 heterocycloalkyl group comprising one sulfur atom and 0 to 1 nitrogen atom, which are optionally substituted with one or more carbonyl functions, one or more C.sub.1-C.sub.3 alkyl radicals, when A.sub.1 represents NR.sup.a, then R.sup.a and R.sup.4 can form, together with the nitrogen atom to which they are attached, a C.sub.2-C.sub.10 heterocycloalkyl group optionally comprising 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, a nitrogen atom and an oxygen atom; said heterocycloalkyl group being optionally substituted with at least one radical R.sup.14, and R.sup.14 represents a linear or branched C.sub.1-C.sub.3 alkyl radical, a linear or branched C.sub.1-C.sub.3 alkoxy radical, a halogen atom, a hydroxyl group OH, a cyano group CN, a CONR.sup.15R.sup.16 group, a SO.sub.2R.sup.16 group, a COR.sup.15 group or an amino group CONR.sup.15R.sup.16 group, a SO.sub.2R.sup.16 group, a COR.sup.15 group or an amino group NR.sup.15R.sup.16; R.sup.15 and R.sup.16, which are identical or different, representing a hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl radical.

2. The compound of formula (II) as defined by claim 1, or the pharmaceutically acceptable addition salt thereof, wherein R.sup.6 represents a heterocyclic radical selected from the group consisting of: ##STR00327## in which: R.sub.7 represents a linear or branched C.sub.1-C.sub.3 alkyl radical, a hydroxyl radical OH, a C.sub.1-C.sub.3 alkoxy radical or an amino radical N(R.sup.7a)(R.sup.7b), R.sup.7a and R.sup.7b, which are identical or different, denote a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical, R.sup.8 and R.sup.9, which are identical or different, represent a hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical, a hydroxyl group OH, a carbonyl group, a (C.sub.1)hydroxyalkyl radical (CH.sub.2OH), an amino group NH.sub.2, R.sup.8 and R.sup.9 can form, together with the carbon atoms to which they are attached, a 5- to 7-membered carbocyclic ring.

3. The compound of formula (II) as defined by claim 1, or the pharmaceutically acceptable addition salt thereof, wherein R.sup.6 represents an aromatic or heteroaromatic radical selected from the group consisting of ##STR00328## in which: R.sub.10 represents a hydrogen atom or a halogen atom; a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more halogen atoms; a carbonyl function (O), a group OR.sup.11, a C.sub.1-C.sub.4 hydroxyalkyl group, an amino group NR.sup.11R.sup.12, a COR.sup.11 group, a COOR.sup.11 group, an amido group CONR.sup.11R.sup.12, a SOR.sup.11 group, a SO.sub.2R.sup.11 group, a NHCOR.sup.11 group, a NHCOOR.sup.11 group, a SO.sub.2NR.sup.11R.sup.12 group or a cyano group CN, R.sup.11 and R.sup.12, which are identical or different, represent a hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl radical optionally substituted with one or more halogen atoms, m denotes zero or a natural integer ranging from 1 to 3.

4. The compound as defined by claim 1, wherein the compound is selected from the group consisting of the following compounds: TABLE-US-00010 imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4- tetrahydro-1.sup.6-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide Compound 1 N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4- (tetrahydropyran-4-ylmethoxy)benzene-N- methylsulfoximine Compound 2 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide Compound 26 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide compound 7 (enantiomer A) N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- ((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide compound 8 (enantiomer B) N-(4-ethylphenyl)-N-isobutyl-3-ethanesulfoximino-4- (tetrahydropyran-4-ylmethoxy)benzenesulfonamide Compound 18 N-(4-ethylphenyI)-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)- N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 30 4-(3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-N-(4-ethylphenyl)- N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 31 N-(4-ethylphenyl)-4-(3-fluorooxetan-3-yl)methoxy)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 32 tert-butyl 4-(4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2- (S-methylsulfonimidoyl)phenoxy)piperidine-1-carboxylate Compound 33 N-(4-ethylphenyl)-N-isobutyl-4-((3-methyloxetan-3- yl)methoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 34 4-(((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)- N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 35 tert-butyl 4-((4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)- 2-(S-methylsulfonimidoyl)phenoxy)methyl)piperidine-1- carboxylate Compound 36 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(pyridin-4-ylmethoxy)benzenesulfonamide Compound 37 N-(4-ethylphenyl)-N-isobutyl-4-(2-(isoxazol-5-yl)ethoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 38 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(pyridin-4-ylmethoxy)benzenesulfonamide Compound 39 4-(2,3-dihydroxypropoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 40 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((tetrahydro-2H-pyran-4- yl)oxy)benzenesulfonamide Compound 42 4-((2,6-dimethylpyridin-4-yl)methoxy)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 43 4-((2,4-difluorobenzyl)oxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 45 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(piperidin-4-ylmethoxy) benzenesulfonamide Compound 46 4-((1-acetylpiperidin-4-yl)oxy)-N-(4-ethylphenyl)-N- isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 47 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((1- (methylsulfonyl)piperidin-4- yl)oxy)benzenesulfonamide Compound 48 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(piperidin-4-ylmethoxy) benzenesulfonamide Compound 49 4-((1-acetylpiperidin-4-yl)methoxy)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 50 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((1- (methylsulfonylpiperidin-4-yl)methoxy) benzenesulfonamide Compound 51 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- [(tetrahydropyran-4-ylmethyl)amino]benzenesulfonamide Compound 52 N-(4-ethylphenyl)-N-isobutyl-4-(methyl((tetrahydro- 2H-pyran-4-yl)methyl)amino)-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 53 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((oxetan-3-ylmethyl)amino)benzenesulfonamide Compound 54 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(((4-methyltetrahydro-2H- pyran-4-yl)methyl)amino)benzenesulfonamide Compound 55 4-(((1,1-dioxidotetrahydrothiophen-3- yl)methyl)amino)-N-(4-ethylphenyl)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide Compound 56 4-(((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)methyl)amino)-N-(4-ethylphenyl)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide Compound 57 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(((6-oxopiperidin-3-yl)methyl)amino)benzenesulfonamide Compound 58 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(((5-oxopyrrolidin-3-yl)methyl)amino)benzenesulfonamide Compound 59 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)amino) benzenesulfonamide Compound 60 N-(4-ethylphenyl)-4-(((3- hydroxycyclobutyl)methyl)amino)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide Compound 61 N-(4-ethylphenyl)-4-(((4-fluorotetrahydro-2H-pyran-4- yl)methyl)amino)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 62 4-(4-acetylpiperazin-1-yl)-N-(4-ethylphenyl)-N- isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 63 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((pyridin-4-ylmethyl)amino)benzenesulfonamide Compound 64 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(2-morpholinoethyl)benzenesulfonamide Compound 65 1-imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4- tetrahydro-1.sup.6-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 69 1-imino-1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3- dihydro-1H-1.sup.6-benzothiazole-6-sulfonic acid (4- ethylphenyl)isobutylamide Compound 76 N-(4-ethylphenyl)-N-isobutyl-4-((2-methoxypyridin- 4-yl)methoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 77 N-(4-ethylphenyl)-N-isobutyl-4-((2-methoxypyridin- 4-yl)methoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 78 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(((R)-2-oxooxazolidin-5- yl)methoxy)benzenesulfonamide Compound 79 4-(4-cyanophenoxy)-N-(4-ethylphenyl)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide Compound 80 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)amino) benzenesulfonamide Compound 81 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyI)-4-(((2-oxooxazolidin-5-yl)methyl) amino)benzenesulfonamide Compound 82 4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-N- (4-ethylphenyl)-N-isobutyl-3-(5-methylsulfonimidoyl) benzenesulfonamide Compound 83 4-(((1-acetylpiperidin-4-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 84 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyI)- 4-((6-oxopiperidin-3- yl)amino)benzenesulfonamide Compound 85 4-((1,1-dioxidotetrahydrothiophen-3-yl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 86 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-thiomorpholinobenzenesulfonamide Compound 87 N-(4-ethylphenyl)-N-isobutyl-4-(((4-methyl-1,2,5-oxadiazol- 3-yl(methyl)amino)-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 88 methyl 3-(((4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2- (S-methylsulfonimidoyl)phenyl)amino)methyl)azetidine- 1-carboxylate Compound 89 N-(4-ethylphenyl)-N-isobutyl-4-(((2-methylpyridin-4-yl) methyl)amino)-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 90 4-((((1R,5S,6S)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)- N-(4-ethylphenyI)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 91 N-(4-ethylphenyl)-4-(((4-hydroxytetrahydro-2H-pyran-4-yl) methyl)amino)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 92 methyl 4-(((4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2- (S-methylsulfonimidoyl)phenyl)amino)methyl) piperidine-1-carboxylate Compound 93 methyl 3-(((4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenyl)amino)methyl) pyrrolidine-1-carboxylate Compound 94 4-(((2-oxaspiro[3.3]heptan-6-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 95 4-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- (((2-oxopiperidin-4-yl)methyl)amino)benzenesulfonamide Compound 96 4-(((3,5-dimethylisoxazol-4-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 97 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((thietan-3-ylmethyl)amino)benzenesulfonamide Compound 99 4-(((1-acetylpyrrolidin-3-yl)methyl)amino)-N-(4-ethylphenyl)- N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 100 N-(4-ethylphenyl)-N-isobutyl-4-((R)-3-methylmorpholino)- 3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 103 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- ((((R)-2-oxooxazolidin-5-yl)methyl)amino)benzenesulfonamide Compound 105 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- ((((S)-2-oxooxazolidin-5-yl)methyl)amino)benzenesulfonamide Compound 106 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- ((2-oxopiperidin-4-yl)amino)benzenesulfonamide Compound 107 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(2-oxa-6-azaspiro[3.5]nonan-6-yl)benzenesulfonamide Compound 109 tert-butyl 6-(4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2- (S-diazaspiro[3.3]heptane-2-carboxylate Compound 110 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- (2-oxa-6-azaspiro[3.3]heptan-6-yl)benzenesulfonamide Compound 111 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(2-oxa-6-azaspiro[3.4]octan-6-1)benzenesulfonamide Compound 112 4-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6-yl)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 113 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)benzenesulfonamide Compound 114 4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 115 4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 117 4-(((2H-tetrazol-5-yl)methyl)amino)-N-(4-ethylphenyl)-N- isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 118 -(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- (2,6-diazaspiro[3.3]heptan-2-yl)benzenesulfonamide Compound 121 4-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(4-ethylphenyl)- N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 122 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- morpholinobenzenesulfonamide Compound 123 N-(4-ethylphenyl)-4-(((4-ethyltetrahydro-2H-pyran-4-yl)methyl) amino)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide Compound 124 N-(4-ethylphenyl)-N-isobutyl-4-(((4-methoxytetrahydro- 2H-pyran-4-yl)methyl)amino)-3- (S-methylsulfonimidoyl)benzenesulfonamide Compound 125 4-(((3-ethyloxetan-3-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl) benzenesulfonamide Compound 126 N-(4-ethylphenyl)-N-isobutyl-4-(((2- methoxypyridin-4-yl)methyl)amino)-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 127 N-(4-ethylphenyl)-4-(4-hydroxypiperidin-1-yl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 128 N-(4-ethylphenyl)-4-((S)-3-hydroxypyrrolidin-1-yl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 129 N-(4-ethylphenyl)-4-((R)-3-hydroxypyrrolidin-1-yl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 130 N-(4-ethylphenyl)-4-(3-hydroxyazetidin-1-yl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 131 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4- (((3-(pyrrolidin-1-yl)oxetan-3-yl)methyl)amino)benzenesulfonamide Compound 132 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((pyrimidin-4- ylmethyl)amino)benzenesulfonamide Compound 133 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(1,4-oxazepan-4-yl)benzenesulfonamide Compound 137 N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-(piperazin-1-yl)benzenesulfonamide Compound 140 N-(4-ethylphenyl)-4-(((3- hydroxycyclobutyl)methyl)amino)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 141 N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)- 4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide Compound 142 and N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)- 4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide Compound 143 or the pharmaceutically acceptable addition salt thereof.

5. The compound as defined by claim 1, wherein the compound is selected from the group consisting of: TABLE-US-00011 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide Compound 26 enantiomer A of Compound 7 N-(4-ethylphenyl)-N-isobutyl-3- ethanesulfoximino-4-(tetrahydropyran-4- ylmethoxy)benzenesulfonamide Compound 18 N-(4-ethylphenyl)-4((4-fluorotetrahydro-2H- pyran-4-yl)methoxy)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 30 4-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-N- (4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 31 4-(((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6- yl)methoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 35 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(pyridin-4- ylmethoxy)benzenesulfonamide Compound 37 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-[(tetrahydropyran-4- ylmethyl)amino]benzenesulfonamide Compound 52 N-(4-ethylphenyl)-N-isobutyl-4- (methyl((tetrahydro-2H-pyran-4- yl)methyl)amino)-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 53 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((4-methyltetrahydro- 2H-pyran-4-yl)methyl)amino)benzenesulfonamide Compound 55 N-(4-ethylphenyl)-4-(((3- hydroxycyclobutyl)methyl)amino)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide Compound 61 N-(4-ethylphenyI)-4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 62 4-(4-acetylpiperazin-1-yl)-N-(4-ethylphenyl)-N- isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide Compound 63 and N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((pyridin-4- ylmethyl)amino)benzenesulfonamide Compound 64 or the pharmaceutically acceptable addition salt thereof.

6. The compound as defined by claim 1, wherein the compound is selected from the group consisting of: TABLE-US-00012 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide Compound 26 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide compound 7 (enantiomer A) N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide compound 8 (enantiomer B) and N-(2,4-dimethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzenesulfonamide Compound 142 or the pharmaceutically acceptable addition salt thereof.

7. A method of treating an inflammatory disorder and/or autoimmune disease, the method comprising administering an effective amount of the compound as defined by claim 1, or the pharmaceutically acceptable addition salt thereof, to an individual subject in need thereof, wherein the inflammatory disorder and/or autoimmune disease is acne, atopic dermatitis and/or psoriasis.

8. A method of treating acne, the method comprising administering an effective amount of the compound as defined by claim 1, or the pharmaceutically acceptable addition salt thereof, to an individual subject in need thereof.

9. A method of treating psoriasis, the method comprising administering an effective amount of the compound as defined by claim 1, or a pharmaceutically acceptable addition salt thereof, to an individual subject in need thereof.

10. A pharmaceutical composition comprising one or more compounds as defined by claim 1 or a pharmaceutically acceptable addition salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition as defined by claim 10, wherein the composition is formulated for treating is acne, atopic dermatitis and/or psoriasis.

12. The pharmaceutical composition as defined by claim 11, wherein the composition is formulated for treating acne.

13. The pharmaceutical composition as defined by claim 11, wherein the composition is formulated for treating atopic dermatitis.

14. The pharmaceutical composition as defined by claim 11, wherein the composition is formulated for treating psoriasis.

15. A method of treating atopic dermatitis, the method comprising administering an effective amount of the compound as defined by claim 1, or the pharmaceutically acceptable addition salt thereof, to an individual subject in need thereof.

Description

EXAMPLES

(1) The standard LCMS method for analyzing the products is as follows: BEH C.sub.18 standard column (1502.1 mm, 1.8 m) solvent: water/acetonitrile 0.1% formic acid.

(2) The preparative HPLC purifications were performed on a C.sub.18 column using, as eluent: 85% acetonitrile in water/0.1% formic acid.

(3) The apparatus used for the chromatography is a 10-20 peak-solution machine, Chiraltechnologie Ic 255 micron column, (eluent phase: supercritical CO.sub.2/methanol, flow rate 4 ml/minute).

(4) The standard LCMS method for analyzing the products is as follows: BEH C18 1502.1 mm, 1 m column, solvent: water/acetonitrile 0.1% formic acid.

(5) The preparative HPLC purifications were performed on a C18 column using, as eluent: 85% acetonitrile in water/0.1% formic acid.

Part I: Synthesis of the Sulfur-Based Sulfonamides Via Reaction Scheme 1

(6) ##STR00149## ##STR00150##

Example 1: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-methanesulfanyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(7) ##STR00151##

1. Synthesis of Intermediate 1.1

(8) ##STR00152##

(4-ethylphenyl)isobutylamine

(9) Isobutyraldehyde (6.33 ml; 0.07 mol) in tetrahydrofuran (100 ml) is added to 4-ethylaniline (9.48 ml; 0.08 mol). The mixture is stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (22.04 g; 0.10 mol) is then added. The mixture is stirred overnight at room temperature, water (100 ml) is added and the resulting mixture is extracted with ethyl acetate (2100 ml).

(10) The organic phases are combined, washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/dichloromethane from 0 to 50% of dichloromethane). The (4-ethylphenyl)isobutylamine is obtained in the form of an orange oil with a compliant .sup.1H NMR.

(11) MS: [M+H]=179

2. Synthesis of Intermediate 1.2

(12) ##STR00153##

N-(4-ethylphenyl)-N-isobutyl-4-methoxybenzenesulfonamide

(13) 3-Bromo-4-methoxybenzenesulfonyl chloride (3.22 g; 11.28 mmol) is added to the (4-ethylphenyl)isobutylamine (2.00 g; 11.28 mmol) and pyridine (5.5 ml; 67.69 mmol) dissolved in tetrahydrofuran (40 ml). The reaction medium is stirred for 4 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated NH.sub.4Cl solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 20% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-4-methoxybenzenesulfonamide (1.63 g; 34%) is obtained in the form of a pale yellow oil with a compliant .sup.1H NMR.

(14) MS: [M+H]=426

3. Synthesis of Intermediate 1.3

(15) ##STR00154##

3-Bromo-N-(4-ethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide

(16) 1M boron tribromide in dichloromethane (5.6 ml; 5.63 mmol) is added slowly at a temperature of 0 C. to the 3-bromo-N-(4-ethylphenyl)-N-isobutyl-4-methoxybenzenesulfonamide (1.60 g; 3.75 mmol) dissolved in dichloromethane (32 ml). The reaction medium is allowed to return slowly to room temperature, stirred for 16 hours and hydrolyzed at a temperature of 0 C. and then extracted with dichloromethane. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(17) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 30% of ethyl acetate). The 3-bromo-N-(4-ethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (1.41 g; 91%) is obtained in the form of a beige-colored solid with a compliant .sup.1H NMR.

(18) MS: [M+H]=414

4. Synthesis of Intermediate 1.4

(19) ##STR00155##

N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(20) 4-(Bromomethyl)tetrahydropyran (261 mg; 1.46 mmol) and cesium carbonate (790 mg; 2.43 mmol) are added to the 3-bromo-N-(4-ethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (500 mg; 1.21 mmol) dissolved in N,N-dimethylformamide (10 ml). The reaction medium is stirred for 2 hours at a temperature of 80 C., hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(21) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 30% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (598 mg; 97%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

(22) MS: [M+H]=512

Example 1: Synthesis of Compound 25 According to the Invention

(23) ##STR00156##

(24) Bis(dibenzylideneacetone)palladium(0) (216 mg; 0.38 mmol) is added to a solution, degassed with argon for 15 minutes, of 3-bromo-N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (480 mg; 0.94 mmol), N,N-diisopropylethylamine (490 l; 2.82 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (45 mg; 0.08 mmol) and sodium methanethiolate (264 mg; 3.76 mmol) in 1,4-dioxane (5 ml). The reaction medium is stirred for 3 hours at a temperature of 110 C., hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(25) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 30% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (335 g; 71%) is obtained in the form of a pale yellow solid.

(26) .sup.1H NMR (400 MHz, Chloroform-d) 7.41 (dd, J=8.4, 2.1 Hz, 1H), 7.19-7.11 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 7.04-6.95 (m, 2H), 6.83 (d, J=8.5 Hz, 1H), 4.07 (dt, J=11.5, 2.8 Hz, 2H), 3.95 (d, J=6.4 Hz, 2H), 3.49 (td, J=11.9, 2.1 Hz, 2H), 3.27 (d, J=7.3 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 2.24-2.10 (m, 1H), 1.87-1.74 (m, 2H), 1.59 (s, 11H), 1.25 (t, J=7.6 Hz, 4H), 0.93 (d, J=6.7 Hz, 7H).

(27) MS: [M+H]=478

Example 2: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(28) ##STR00157##

(29) 3-Chloroperoxybenzoic acid (0.17 g; 0.75 mmol) is added portionwise to a solution of N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (0.40 g; 0.84 mmol) in dichloromethane (8 ml) at 0 C. The reaction medium is stirred for 45 minutes, hydrolyzed with aqueous 10% Na.sub.2S.sub.2O.sub.3 solution and extracted with dichloromethane. The organic phase is washed with 1N sodium hydroxide and then dried (Na.sub.2SO.sub.4), filtered and concentrated.

(30) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 50 to 100% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (0.24 g; 58%) is obtained in the form of a white solid.

(31) .sup.1H NMR (DMSO-d.sub.6) : 0.85 (t, J=6.9 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.28-1.48 (m, 3H), 1.65 (tdd, J=11.5, 4.0, 2.1 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 2.74 (s, 3H), 3.21-3.40 (m, 5H), 3.90 (ddd, J=11.5, 4.9, 2.1 Hz, 2H), 4.00-4.15 (m, 2H), 6.94-7.02 (m, 2H), 7.15-7.23 (m, 2H), 7.33-7.35 (m, 1H) 7.64-7.73 (m, 2H)

(32) MS: [M+H]=494

(33) Compound 27: (550 mg; 1.11 mmol) is chromatographed by chiral SFC to separate the two enantiomers (compound 19 and compound 20) below:

(34) Supercritical conditions 100 bar, 70 C.; Chiralpak IC 2504.6 mm 5 column]

Example 3: N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (Compound 19)Enantiomer A of Compound 27

(35) ##STR00158##

(36) (311 mg; 56%) in the form of a white solid

(37) .sup.1H NMR (Chloroform-d) : 0.86-0.96 (m, 6H), 1.23 (t, J=7.6 Hz, 3H), 1.40-1.65 (m, 7H), 1.65-1.87 (m, 2H), 2.11 (s, 1H), 2.63 (q, J=7.6 Hz, 2H), 2.77 (s, 2H), 3.22-3.34 (m, 1H), 3.36-3.45 (m, 1H), 3.48 (dd, J=11.9, 2.2 Hz, 1H), 3.89-4.09 (m, 4H), 6.88 (d, J=8.6 Hz, 1H), 6.94-7.01 (m, 2H), 7.09-7.16 (m, 2H), 7.57 (dd, J=8.6, 2.4 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H)

(38) Retention time (chiral SFC) of 6.0 minutes

Example 4: N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (Compound 20)Enantiomer B of Compound 27

(39) ##STR00159##

(40) (240 mg; 44%) in the form of a white solid

(41) .sup.1H NMR (Chloroform-d) : 0.91 (dd, J=13.3, 6.7 Hz, 6H), 1.23 (t, J=7.6 Hz, 4H), 1.39-1.64 (m, 7H), 1.66-1.79 (m, 2H), 2.02-2.20 (m, 1H), 2.63 (q, J=7.7 Hz, 2H), 2.77 (s, 3H), 3.27 (dd, J=12.9, 6.8 Hz, 1H), 3.36-3.52 (m, 3H), 3.87-4.10 (m, 4H), 6.88 (d, J=8.6 Hz, 1H), 6.94-7.02 (m, 2H), 7.09-7.16 (m, 2H), 7.57 (dd, J=8.6, 2.3 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H)

(42) Retention time (chiral SFC) of 9.9 minutes

Example 5: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-methanesulfoximino-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(43) ##STR00160##

(44) 2,2,2-Trifluoroacetamide (0.13 g; 1.16 mmol), magnesium oxide (0.09 g; 2.33 mmol), rhodium(II) acetate dimer (31 mg; 0.07 mmol) and iodobenzene diacetate (0.29 g; 0.89 mmol) are added to a solution, degassed beforehand with argon, of N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (0.23 g; 0.47 mmol) in dichloromethane (8 ml). The reaction medium is stirred for 4 hours 30 minutes, filtered through Celite and concentrated.

(45) The residue is diluted in methanol (8 ml) and potassium carbonate (0.32 g; 2.33 mmol) is added. The reaction medium is stirred for 30 minutes, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, dried (Na.sub.2SO.sub.4), filtered and concentrated.

(46) The crude product is purified by preparative HPLC. The N-(4-ethylphenyl)-N-isobutyl-3-methanesulfoximino-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (0.08 g; 34%) is obtained in the form of a white solid.

(47) .sup.1H NMR (DMSO-d.sub.6) : 0.84 (d, J=4.5 Hz, 3H), 0.86 (d, J=4.4 Hz, 3H), 1.18 (t, J=7.6 Hz, 3H), 1.27-1.58 (m, 3H), 1.66-1.83 (m, 2H), 2.02-2.21 (m, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.19 (d, J=1.2 Hz, 3H), 3.24-3.39 (m, 4H), 3.83-3.96 (m, 2H), 4.11 (dd, J=6.2, 2.5 Hz, 2H), 4.41 (d, J=1.5 Hz, 1H), 7.01 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H)

(48) MS: [M+H]=509

(49) A procedure similar to that applied to compound 26 to obtain compounds 19 and 20 is performed so as to obtain compounds 7 and 8 (enantiomers of compound 26).

Example 6: N-(4-ethylphenyl)-N-isobutyl-3-(methanesulfinyl)-4-(tetrahydropyran-4-ylmethoxy)benzenesulfoximine (Compound 7)Enantiomer A of Compound 26

(50) ##STR00161##

(51) Same procedure as for example 3, on example 4 (213 mg; 0.43 mmol). The N-(4-ethylphenyl)-N-isobutyl-3-((S)-methanesulfinyl)-4-(tetrahydropyran-4-ylmethoxy)benzenesulfoximine (20 mg; 9%) is obtained in the form of a beige-colored solid with a compliant .sup.1H NMR.

(52) MS: [M+H]=509

Example 7: N-(4-ethylphenyl)-N-isobutyl-3-(methanesulfinyl)-4-(tetrahydropyran-4-ylmethoxy)benzenesulfoximine (Compound 8)Enantiomer B of Compound 26

(53) ##STR00162##

(54) Same procedure as for example 3, on example 5 (132 mg; 0.27 mmol). The N-(4-ethylphenyl)-N-isobutyl-3-((R)-methanesulfinyl)-4-(tetrahydropyran-4-ylmethoxy)benzenesulfoximine (11 mg; 9%) is obtained in the form of an off-white solid with a compliant .sup.1H NMR.

(55) MS: [M+H]=509

Example 8: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzene-N-methylsulfoximine

(56) ##STR00163##

(57) 60% sodium hydride (9.2 mg; 0.23 mmol) is added portionwise to a solution at 0 C. of N-(4-ethylphenyl)-N-isobutyl-3-(methanesulfinyl)-4-(tetrahydropyran-4-ylmethoxy)benzenesulfoximine (90 mg; 0.18 mmol) in N,N-dimethylformamide (1.8 ml). The reaction medium is stirred for 20 minutes at a temperature of 0 C., and iodomethane (22 l; 0.35 mmol) is then added dropwise. The reaction medium is stirred for 20 hours at room temperature, hydrolyzed and extracted with ethyl acetate.

(58) The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated, and the crude product is chromatographed on silica gel (eluent: dichloromethane/methanol from 0 to 5% of methanol).

(59) The N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4-(tetrahydropyran-4-ylmethoxy)benzene-N-methylsulfoximine (59.3 mg; 64%) is obtained in the form of a white solid.

(60) .sup.1H NMR (DMSO-d6) : 0.85 (t, J=7.1 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.30-1.51 (m, 3H), 1.62-1.71 (m, 1H), 1.80 (ddd, J=13.0, 4.1, 2.0 Hz, 1H), 2.08 (s, 1H), 2.34 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 3.20 (s, 3H), 3.22-3.41 (m, 8H), 3.90 (ddd, J=11.5, 4.6, 1.9 Hz, 2H), 4.04 (dd, J=9.5, 6.7 Hz, 1H), 4.17 (dd, J=9.3, 5.6 Hz, 1H), 6.93-7.00 (m, 2H), 7.14-7.21 (m, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.86 (dd, J=8.8, 2.5 Hz, 1H).

(61) MS: [M+H]=523

Example 9: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-methanesulfonyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(62) ##STR00164##

(63) 3-Chloroperbenzoic acid (188 mg; 0.84 mmol) is added portionwise at 0 C. to N-(4-ethylphenyl)-N-isobutyl-3-methanesulfanyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (200 mg; 0.42 mmol) dissolved in dichloromethane (2 ml). The reaction medium is stirred for 72 hours, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 50% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-3-methanesulfonyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (150 mg; 71%) is obtained in the form of a white solid.

(64) .sup.1H NMR (400 MHz, DMSO-d6) 7.86-7.77 (m, 2H), 7.48 (d, J=8.7 Hz, 1H), 7.24-7.17 (m, 2H), 7.05-6.96 (m, 2H), 4.16 (d, J=6.2 Hz, 2H), 3.95-3.86 (m, 2H), 3.32-3.25 (m, 6H), 2.61 (q, J=7.6 Hz, 2H), 2.16-2.09 (m, 1H), 1.77-1.68 (m, 2H), 1.49-1.34 (m, 3H), 1.18 (t, J=7.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 6H).

(65) MS: [M+H]=510

Example 10: Synthesis of ethanesulfinyl-N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(66) ##STR00165##

1. Synthesis of Intermediate 10.1

(67) ##STR00166##

N-(4-ethylphenyl)-3-ethylsulfanyl-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(68) Bis(dibenzylideneacetone)palladium(0) (225 mg; 0.39 mmol) is added to a solution, degassed with argon for 15 minutes, of 3-bromo-N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (500 mg; 0.98 mmol), N,N-diisopropylethylamine (510 l; 2.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (45 mg; 0.08 mmol) and sodium ethanethiolate (91 mg; 1.08 mmol) dissolved in 1,4-dioxane (5 ml). The reaction medium is stirred for 1 hour at 110 C., hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude product is purified by preparative HPLC (C18 column, eluent: from 56% to 62% of acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-3-ethylsulfanyl-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (271 mg; 42%) is obtained in the form of a white solid after trituration in heptane, with a compliant .sup.1H NMR.

(69) MS: [M+H]=492

2. Synthesis of Compound 22 According to the Invention

(70) ##STR00167##

(71) 3-Chloroperbenzoic acid (59 mg; 0.26 mmol) is added portionwise at a temperature of 0 C. to N-(4-ethylphenyl)-3-ethanesulfanyl-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (260 mg; 0.53 mmol) dissolved in dichloromethane (5 ml). The reaction medium is stirred for 1 hour at room temperature, hydrolyzed with aqueous 10% Na.sub.2S.sub.2O.sub.3 solution and then extracted with dichloromethane. The organic phases are combined, washed with 0.1N sodium hydroxide solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(72) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 3-ethylsulfinyl-N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (125 mg; 47%) is obtained in the form of a white solid.

(73) .sup.1H NMR (Chloroform-d) : 0.84 (dd, J=13.3, 6.7 Hz, 6H), 1.10 (t, J=7.4 Hz, 3H), 1.15 (t, J=7.6 Hz, 3H), 1.33-1.55 (m, 2H), 1.58-1.72 (m, 2H), 1.94-2.12 (m, 1H), 2.56 (q, J=7.6 Hz, 2H), 2.73 (dq, J=13.4, 7.4 Hz, 1H), 2.99 (dq, J=13.5, 7.4 Hz, 1H), 3.21 (dd, J=12.8, 6.8 Hz, 1H), 3.28-3.45 (m, 3H), 3.84 (dd, J=9.0, 6.3 Hz, 1H), 3.91 (dd, J=9.0, 6.4 Hz, 1H), 3.98 (ddd, J=11.6, 4.6, 1.8 Hz, 2H), 6.81 (d, J=8.7 Hz, 1H), 6.86-6.93 (m, 2H), 7.01-7.08 (m, 2H), 7.50 (dd, J=8.6, 2.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H)

(74) MS: [M+H]=508

Example 11: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-ethanesulfoximine-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide

(75) ##STR00168##

(76) 2,2,2-Trifluoroacetamide (61 mg; 0.54 mmol), magnesium oxide (44 mg; 1.08 mmol), rhodium(II) acetate (14 mg; 0.03 mmol) and iodobenzene diacetate (133 mg; 0.41 mmol) are added to a solution, degassed beforehand with argon, of 3-ethylsulfinyl-N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (110 mg; 0.22 mmol) in dichloromethane (8 ml). The reaction medium is stirred for 16 hours at room temperature, filtered through Celite and concentrated. The residue obtained is diluted in methanol (8 ml) and potassium carbonate (150 mg; 1.08 mmol) is added. The reaction medium is stirred for 30 minutes, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(77) The crude product is purified by preparative HPLC (C18 column, eluent: from 56% to 62% of acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-ethanesulfoximino-4-(tetrahydropyran-4-ylmethoxy)benzenesulfonamide (23 mg; 20%) is obtained in the form of an off-white solid.

(78) .sup.1H NMR (Chloroform-d) : 0.93 (dd, J=8.4, 6.6 Hz, 6H), 1.25 (q, J=7.4 Hz, 7H), 1.46-1.69 (m, 6H), 1.86 (ddq, J=11.1, 4.5, 2.2 Hz, 2H), 2.14-2.30 (m, 1H), 2.67 (q, J=7.6 Hz, 2H), 2.75 (s, 1H), 3.28 (dd, J=12.8, 7.0 Hz, 1H), 3.31-3.45 (m, 3H), 3.49 (td, J=11.9, 2.2 Hz, 2H), 4.00-4.12 (m, 4H), 6.96-7.01 (m, 2H), 7.04 (d, J=8.8 Hz, 1H), 7.13-7.20 (m, 2H), 7.73 (dd, J=8.7, 2.4 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H)

(79) MS: [M+H]=523

Part II: Synthesis of the Sulfur-Based Sulfonamides Via Reaction Scheme 2

(80) ##STR00169##

Example 12: Synthesis of N-4-ethylphenyl-4-(((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(81) ##STR00170##

1. Synthesis of Intermediate 12.1

(82) ##STR00171##

4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanylbenzenesulfonamide

(83) 4-Bromo-3-(methylthio)benzene-1-sulfonyl chloride (19.63 g; 61.83 mmol) dissolved in tetrahydrofuran (95 ml) is added to (4-ethylphenyl)isobutylamine (10.96 g; 61.83 mmol) and pyridine (30 ml; 371 mmol) dissolved in tetrahydrofuran (370 ml). The reaction medium is stirred for 16 hours at room temperature and then hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated ammonium chloride solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude product is taken up in heptane and suction-filtered.

(84) The 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanylbenzenesulfonamide (21.31 g; 78%) is obtained in the form of a pale yellow solid with a compliant .sup.1H NMR.

(85) MS: [M+H]=444

2. Synthesis of Intermediate 12.2

(86) ##STR00172##

(E)-N-((2-bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)phenyl)(methyl)-4-sulfanylidene)-2,2,2-trifluoroacetamide

(87) 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanylbenzenesulfonamide (5.00 g; 11.30 mmol) and 2,2,2-trifluoroacetamide (1.92 g; 16.95 mmol) dissolved in tetrahydrofuran (10 ml) are added slowly to 60% sodium hydride (0.41 g; 10.17 mmol) suspended in tetrahydrofuran (10 ml) at 0-5 C., and 1,3-dibromo-5,5-dimethylhydantoin (4.85 g; 16.95 mmol) dissolved in tetrahydrofuran (25 ml) is added at a temperature of 0-5 C. The medium is stirred for 1 hour at room temperature. The reaction medium is hydrolyzed with 10% citric acid solution and then extracted with ethyl acetate.

(88) The organic phases are combined, washed with 25% sodium sulfite solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue is taken up in ether and suction-filtered. The (E)-N-((2-bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)phenyl)(methyl)-.sup.4-sulfanylidene)-2,2,2-trifluoroacetamide (4.76 g; 76%) is obtained in the form of a white powder with a compliant .sup.1H NMR.

(89) MS: [M+H]=554

3. Synthesis of Intermediate 12.3

(90) ##STR00173##

2-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-ethyl sulfonimidoyl)benzenesulfonamide

(91) Potassium carbonate (2.79 g; 20.16 mmol) is added to (E)-N-((2-bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)phenyl)(methyl)-.sup.4-sulfanylidene)-2,2,2-trifluoroacetamide (3.72 g; 6.72 mmol) dissolved in methanol (35 ml), and 3-chloroperoxybenzoic acid (2.26 g; 10.08 mmol) is then added slowly at a temperature of 0 C. The reaction medium is stirred for 16 hours at room temperature.

(92) The reaction medium is hydrolyzed and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(93) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 80% of ethyl acetate). The 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (1.51 g; 47%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

(94) MS: [M+H]=474

4. Synthesis of Compound 30 According to the Invention

(95) ##STR00174##

(96) 60% sodium hydride (9 mg; 0.22 mmol) is added slowly to (4-fluorotetrahydropyran-4-yl)methanol (28.33 mg; 0.21 mmol) dissolved in N,N-dimethylformamide (0.5 ml), followed by 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50 mg; 0.11 mmol).

(97) The reaction medium is stirred for 2 hours at room temperature. The reaction medium is hydrolyzed without heating and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(98) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). N-(4-Ethylphenyl)-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (46 mg; 82%) is obtained in the form of a white solid.

(99) .sup.1H NMR (DMSO-d6) : 0.86 (dd, J=6.7, 4.6 Hz, 6H), 1.19 (t, J=7.6 Hz, 3H), 1.36-1.51 (m, 1H), 1.76-2.05 (m, 4H), 2.61 (q, J=7.6 Hz, 2H), 3.19 (d, J=1.0 Hz, 3H), 3.22-3.32 (m, 2H), 3.63 (td, J=11.2, 3.0 Hz, 2H), 3.80 (dt, J=11.2, 2.8 Hz, 2H), 4.34-4.48 (m, 3H), 6.97-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.7, 2.4 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H).

(100) MS: [M+H]=527

(101) With a procedure similar to that described for example 12, the following are obtained:

(102) TABLE-US-00005 Example 13 4-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-N- (4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.7, 4.3 Hz, 6H), 1.12-1.23 (m, 4H), 1.43 (dt, J = 13.6, 6.9 Hz, 1H), 1.79-1.86 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.23 (s, 3H), 3.25-3.36 (m, 2H), 3.61 (dt, J = 8.3, 1.4 Hz, 2H), 3.78 (d, J = 8.4 Hz, 2H), 4.21 (dd, J = 6.9, 1.9 Hz, 2H), 4.41 (d, J = 1.5 Hz, 1H), 6.96-7.03 (m, 2H), 7.17-7.24 (m, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.7, 2.4 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H). MS: [M + H] = 507 Example 14 N-(4-ethylphenyl)-4-((3-fluorooxetan-3- yl)methoxy)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.86 (dd, J = 6.6, 4.3 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.38-1.50 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.16 (d, J = 1.2 Hz, 3H), 3.22-3.41 (m, 2H), 4.46 (d, J = 1.5 Hz, 1H), 4.63-4.86 (m, 6H), 6.97-7.05 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.74 (dd, J = 8.7, 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H). MS: [M + H] = 499 Example 15 tert-butyl 4-(4-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenoxy)piperidine-1- carboxylate .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 3.5 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.42 (s, 11H), 1.70-1.80 (m, 2H), 1.90 (t, J = 10.4 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 3.19 (s, 3H), 3.24-3.31 (m, 2H), 3.38-3.48 (m, 2H), 3.48-3.61 (m, 2H), 4.42 (d, J = 1.4 Hz, 1H), 4.97-5.05 (m, 1H), 6.98-7.05 (m, 2H), 7.17-7.25 (m, 2H), 7.45 (d, J = 9.0 Hz, 1H), 7.64 (dd, J = 8.7, 2.4 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H). MS: [M + H] = 594 Example 16 N-(4-ethylphenyl)-N-isobutyl-4-((3- methyloxetan-3-yl)methoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.86 (dd, J = 6.6, 4.1 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.42 (s, 4H), 2.56-2.67 (m, 2H), 3.21 (d, J = 1.2 Hz, 3H), 3.24-3.32 (m, 2H), 4.30 (d, J = 3.3 Hz, 2H), 4.36 (d, J = 6.0 Hz, 2H), 4.42 (d, J = 1.4 Hz, 1H), 4.62 (dd, J = 5.9, 3.0 Hz, 2H), 6.98-7.05 (m, 2H), 7.18-7.25 (m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.7, 2.5 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H). MS: [M + H] = 495 Example 17 4-(((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6- yl)methoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.7, 4.3 Hz, 6H), 1.18 (t, J = 7.6 Hz, 4H), 1.35-1.51 (m, 1H), 1.79-1.86 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.23 (d, J = 1.2 Hz, 3H), 3.25-3.31 (m, 2H), 3.61 (dt, J = 8.4, 1.3 Hz, 2H), 3.78 (d, J = 8.3 Hz, 2H), 4.21 (dd, J = 7.0, 1.9 Hz, 2H), 4.41 (d, J = 1.4 Hz, 1H), 6.96-7.03 (m, 2H), 7.17-7.24 (m, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.7, 2.4 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H). MS: [M + H] = 507 Example 18 0 tert-butyl 4-04-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenoxy)methyl)piperidine- 1-carboxylate .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 4.4 Hz, 6H), 1.14-1.31 (m, 5H), 1.41 (s, 10H), 1.82 (s, 2H), 2.04 (s, 1H), 2.53-2.66 (m, 3H), 2.77 (s, 2H), 3.17 (d, J = 1.2 Hz, 3H), 3.21-3.31 (m, 2H), 3.99 (d, J = 12.8 Hz, 2H), 4.08-4.15 (m, 2H), 4.41 (d, J = 1.5 Hz, 1H), 6.97-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.37(d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.7, 2.5 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H). MS: [M + H] = 608 Example 19 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(pyridin-4- ylmethoxy)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 4.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.35-1.57 (m, 3H), 1.82-2.01 (m, 1H), 2.11-2.20 (m, 2H), 2.52-2.76 (m, 7H), 3.19 (d, J = 1.2 Hz, 3H), 3.32 (s, 8H), 4.05-4.12 (m, 2H), 4.40 (d, J = 1.5 Hz, 1H), 6.97-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.37 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 8.8, 2.5 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H). MS: [M + H] = 525 Example 20 N-(4-ethylphenyl)-N-isobutyl-4-(2-(isoxazol-5- yl)ethoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 11.0, 6.7 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.43 (t, J = 7.2 Hz, 1H), 2.29-2.38 (m, 2H), 2.60 (d, J = 7.6 Hz, 2H), 3.22-3.39 (m, 4H), 3.54 (d, J = 2.5 Hz, 3H), 4.64 (s, 1H), 6.83 (s, 1H), 6.94-7.04 (m, 2H), 7.22 (d, J = 8.4 Hz, 4H), 7.64 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 8.9, 2.4 Hz, 1H) MS: [M + H] = 506 Example 21 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(pyridin-4- ylmethoxy)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.86 (dd, J = 6.7, 4.3 Hz, 7H), 1.19 (t, J = 7.6 Hz, 3H), 1.36-1.51 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.15 (d, J = 1.2 Hz, 3H), 3.24-3.32 (m, 2H), 4.51 (d, J = 1.5 Hz, 1H), 5.47 (d, J = 2.5 Hz, 2H), 6.97-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.44-7.54 (m, 2H), 7.73 (dd, J = 8.7, 2.5 Hz, 1H), 8.00 (dt, J = 7.9, 2.0 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.79 (d, J = 2.5 Hz, 1H). MS: [M + H] = 502 Example 22 4-(2,3-dihydroxypropoxy)-N-(4-ethylphenyl)-N- isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 3.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.37-1.49 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (t, J = 1.4 Hz, 3H), 3.25-3.31 (m, 2H), 3.53 (t, J = 5.8 Hz, 2H), 3.89 (dd, J = 10.2, 5.1 Hz, 1H), 4.11-4.34 (m, 2H), 4.41 (dd, J = 8.9, 1.4 Hz, 1H), 4.74 (dt, J = 7.7, 5.7 Hz, 1H), 5.08 (d, J = 4.9 Hz, 1H), 6.97-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.39 (dd, J = 8.9, 2.1 Hz, 1H), 7.64-7.73 (m, 1H), 7.95-8.00 (m, 1H). MS: [M + H] = 485 Example 23 3-(4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2- (S-methylsulfonimidoyl)phenoxy)-5-hydroxy-3- methylpentanoic acid .sup.1H NMR (DMSO-d6) : 0.85 (t, J = 5.4 Hz, 7H), 1.17 (t, J = 7.6 Hz, 5H), 1.36-1.48 (m, 1H), 2.60 (q, J = 7.5 Hz, 2H), 3.14 (d, J = 4.9 Hz, 3H), 3.20-3.29 (m, 2H), 4.39-4.71 (m, 5H), 5.26 (s, 1H), 6.99 (d, J = 7.2 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.40 (dt, J = 8.5, 4.3 Hz, 1H), 7.65-7.76 (m, 1H), 7.99 (dd, J = 14.4, 2.4 Hz, 1H). MS: [M + H] = 541 Example 24 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4- yl)oxy)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 3.8 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.36-1.51 (m, 1H), 1.68-1.81 (m, 2H), 1.97-2.07 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.21 (d, J = 1.2 Hz, 3H), 3.32 (m, 2H, 3.50-3.61 (m, 2H), 3.87-3.92 (m, 2H), 4.41 (d, J = 1.5 Hz, 1H), 5.00 (dt, J = 7.3, 3.6 Hz, 1H), 6.98-7.05 (m, 2H), 7.17-7.24 (m, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.8, 2.4 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H) MS: [M + H] = 495 Example 25 4-((2,6-dimethylpyridin-4-yl)methoxy)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 4.0 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.36-1.49 (m, 1H), 2.44 (s, 6H), 2.50-2.66 (m, 3H), 3.21 (d, J = 1.1 Hz, 3H), 3.32 (m, 2H), 4.55 (d, J = 1.4 Hz, 1H), 5.40 (s, 2H), 6.95-7.04 (m, 2H), 7.16-7.24 (m, 4H), 7.40 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.7, 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H) MS: [M + H] = 530 Example 26 ((4S)-4-amino-5-(4-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenoxy)pentanoic acid .sup.1H NMR (DMSO-d6) : 0.84 (d, J = 6.4 Hz, 7H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.7, 6.8 Hz, 1H), 1.74 (dd, J = 14.3, 7.3 Hz, 1H), 1.88 (dt, J = 14.3, 6.9 Hz, 1H), 2.30-2.41 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.01 (d, J = 5.9 Hz, 3H), 3.25 (d, J = 7.3 Hz, 3H), 3.50 (s, 2H), 3.68 (s, 1H), 4.67 (d, J = 23.1 Hz, 1H), 4.95 (d, J = 17.8 Hz, 1H), 7.01 (d, J = 8.1 Hz, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.47 (dd, J = 8.8, 2.9 Hz, 1H), 7.67-7.81 (m, 2H), 12.12 (s, 1H) MS: [M + H] = 526 Example 27 N-(4-ethylphenyl)-N-isobutyl-4-((2- methoxypyridin-4-yl)methoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.89 (ddd, J = 10.8, 6.5, 3.9 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.42-1.54 (m, 1H), 2.66 (q, J = 7.7 Hz, 2H), 3.25 (s, 3H), 3.28-3.35 (m, 2H), 3.92 (s, 3H), 4.61 (s, 1H), 5.50 (s, 2H), 7.05 (d, J = 8.1 Hz, 3H), 7.25 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.57-7.73 (m, 2H), 7.76 (dd, J = 8.9, 2.4 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H). MS: [M + H] = 532 Example 28 0 N-(4-ethylphenyl)-N-isobutyl-4-((2- methoxypyridin-4-yl)methoxy)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 4.7 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.36-1.50 (m, 1H), 1.88 (t, J = 12.8 Hz, 2H), 2.15-2.30 (m, 3H), 2.61 (q, J = 7.6 Hz, 2H), 3.07-3.18 (m, 2H), 3.19 (d, J = 1.2 Hz, 3H), 3.20-3.32 (m, 4H), 4.18 (dt, J = 6.0, 3.6 Hz, 2H), 4.44 (d, J = 1.5 Hz, 1H), 6.97-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.38 (d, J = 8.7 Hz, 1H), 7.68 (dd, J = 8.8, 2.4 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H). MS: [M + H] = 557 Example 29 CD13325 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((R)-2-oxooxazolidin-5- yl)methoxy)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.81-0.89 (m, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.35-1.50 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.18 (dd, J = 4.2, 1.2 Hz, 3H), 3.22-3.32 (m, 2H), 3.59 (dt, J = 32.3, 8.2 Hz, 2H), 4.30-4.45 (m, 2H), 4.46-4.57 (m, 1H), 5.01 (dt, J = 4.8, 2.3 Hz, 1H), 6.96-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.42 (dd, J = 8.8, 2.2 Hz, 1H), 7.65-7.75 (m, 2H), 8.00 (dd, J = 10.9, 2.4 Hz, 1H). MS: [M + H] = 510

Example 30: Synthesis of the Compound 4-((2,4-difluorobenzyl)oxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(103) ##STR00192##

(104) 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.0 mg; 0.11 mmol) is added to a mixture comprising 2,4-difluorobenzyl alcohol (30.5 mg; 0.21 mmol) and cesium carbonate (103.2 mg; 0.32 mmol) dissolved in N,N-dimethylformamide (0.50 ml) after stirring for 20 minutes. The reaction medium is stirred for 20 hours at a temperature of 80 C., hydrolyzed without heating and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated to dryness.

(105) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 4-((2,4-difluorobenzyl)oxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (9.4 g; 16%) is obtained in the form of a white solid.

(106) .sup.1H NMR (DMSO-d6) : 0.86 (dd, J=6.8, 4.4 Hz, 6H), 1.19 (t, J=7.6 Hz, 3H), 1.33-1.53 (m, 1H), 2.62 (t, J=7.6 Hz, 2H), 3.12 (s, 3H), 4.47 (s, 1H), 5.42 (s, 2H), 7.01 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.0 Hz, 3H), 7.38 (t, J=9.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.7, 2.5 Hz, 1H), 7.80 (q, J=8.2 Hz, 1H), 8.03 (d, J=2.5 Hz, 1H).

(107) MS: [M+H]=537

Example 31: Synthesis of the Compound 4-(4-cyanophenoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(108) ##STR00193##

(109) 60% sodium hydride (6.3 mg; 0.16 mmol) is added to (1,1-dioxohexahydro-1.sup.6-thiopyran-4-yl)methanol 4-cyanophenol (13.8 mg; 0.12 mmol) dissolved in N,N-dimethylformamide (1.0 ml). The reaction medium is stirred for 20 minutes, followed by addition of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.0 mg; 0.11 mmol).

(110) The reaction medium is stirred for 1 hour at room temperature and then for 16 hours at a temperature of 80 C. The reaction medium is hydrolyzed by addition of cold water and then extracted with ethyl acetate. The organic phases are combined and then washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(111) The crude product is chromatographed on silica gel, eluting with heptane/ethyl acetate, from 0 to 100% of ethyl acetate. The 4-(4-cyanophenoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (14.5 mg; 24%) is obtained in the form of a white solid.

(112) .sup.1H NMR (DMSO-d6) : 0.87 (dd, J=6.6, 3.9 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.21-1.31 (m, 2H), 1.39-1.51 (m, 1H), 2.57-2.66 (m, 2H), 3.26 (s, 3H), 3.33-3.39 (m, 2H), 4.66 (d, J=1.5 Hz, 1H), 7.00-7.07 (m, 2H), 7.20-7.31 (m, 3H), 7.30-7.38 (m, 2H), 7.72 (dd, J=8.6, 2.4 Hz, 1H), 7.93-8.00 (m, 2H), 8.09 (d, J=2.4 Hz, 1H).

(113) MS: [M+H]=512

Part III: Synthesis of the Sulfur-Based Sulfonamides Via Reaction Scheme 3

(114) ##STR00194##

Example 32: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperidin-4-ylmethoxy)benzenesulfonamide

(115) ##STR00195##

(116) Trifluoroacetic acid (0.2 ml; 2.61 mmol) is added to tert-butyl 4-(4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-(S-methylsulfonimidoyl)phenoxy)piperidine-1-carboxylate (40.0 mg; 0.07 mmol) dissolved in dichloromethane (1.6 ml). The reaction medium is stirred for 1 hour at room temperature, concentrated, diluted with dichloromethane, washed with saturated sodium hydrogen carbonate solution and then with saturated NaCl solution, and dried (Na.sub.2SO.sub.4). The solvents are evaporated off.

(117) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperidin-4-yloxy)benzenesulfonamide (32.1 mg; 97%) is obtained in the form of a white powder.

(118) Mixture of conformers: .sup.1H NMR (DMSO-d6) : 0.86 (dd, J=6.6, 1.5 Hz, 6H), 1.20 (t, J=7.6 Hz, 3H), 1.46-1.61 (m, 1H), 1.77-1.96 (m, 2H), 1.96-2.15 (m, 2H), 2.57-2.68 (m, 2H), 2.77-2.96 (m, 2H), 3.20 (s, 3H), 3.28-3.38 (m, 2H), 3.98-4.21 (m, 1H), 4.75-5.03 (m, 1H), 6.98-7.06 (m, 2H), 7.16-7.23 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.64-7.72 (m, 1H), 8.05 (d, J=2.5 Hz, 1H).

(119) MS: [M+H]=494

Example 33: Synthesis of 4-((1-acetylpiperidin-4-yl)oxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(120) ##STR00196##

(121) 4-Dimethylaminopyridine (1.6 mg; 0.01 mmol) and acetic anhydride (11.2 l; 0.12 mmol) are added to a solution of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperidin-4-yloxy)benzenesulfonamide (65.0 mg; 0.13 mmol) in dichloromethane (2 ml) cooled to a temperature of 10 C.

(122) The reaction medium is stirred for 2 hours at room temperature. The reaction medium is hydrolyzed, followed by addition of saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried (Na.sub.2SO.sub.4) and concentrated to dryness.

(123) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 4-((1-acetylpiperidin-4-yl)oxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (34.8 mg; 49%) is obtained in the form of a white solid.

(124) .sup.1H NMR (DMSO-d6) : 0.86 (dd, J=6.6, 2.3 Hz, 6H), 1.19 (t, 3H), 1.36-1.51 (m, 1H), 1.89-2.07 (m, 5H), 2.61 (q, J=7.6 Hz, 2H), 2.87 (s, 3H), 3.20 (d, J=1.2 Hz, 3H), 3.23-3.31 (m, 5H), 4.47 (d, J=1.5 Hz, 1H), 5.06 (t, J=4.1 Hz, 1H), 6.98-7.05 (m, 2H), 7.18-7.25 (m, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.67 (dd, J=8.7, 2.4 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H).

(125) MS: [M+H]=536

Example 34: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide

(126) ##STR00197##

(127) Triethylamine (18.3 l; 0.13 mmol) and methanesulfonyl chloride (10.2 l; 0.13 mmol) are added to a solution of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperidin-4-ylmethoxy)benzenesulfonamide (65.0 mg; 0.13 mmol) in dichloromethane (1.3 ml).

(128) The reaction medium is stirred for 2 hours at room temperature, hydrolyzed by addition of saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness.

(129) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide (24.8 mg; 32%) is obtained in the form of a white solid.

(130) .sup.1H NMR (DMSO-d6) : 0.86 (dd, J=6.7, 3.4 Hz, 6H), 1.19 (t, J=7.6 Hz, 3H), 1.36-1.51 (m, 1H), 1.81-1.88 (m, 2H), 1.99 (d, J=9.4 Hz, 1H), 2.03 (s, 3H), 2.61 (q, J=7.6 Hz, 2H), 3.19 (d, J=1.2 Hz, 3H), 3.22-3.31 (m, 2H), 3.43-3.52 (m, 1H), 3.53-3.74 (m, 3H), 4.42 (dd, J=3.3, 1.5 Hz, 1H), 5.02-5.09 (m, 1H), 6.98-7.06 (m, 2H), 7.17-7.25 (m, 2H), 7.47 (d, J=8.9 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H)).

(131) MS: [M+H]=572

Example 35: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperidin-4-ylmethoxy)benzenesulfonamide

(132) ##STR00198##

(133) With a procedure similar to that described for example 31, N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperidin-4-ylmethoxy)benzenesulfonamide (68.2 mg; 100%) is obtained in the form of a white powder.

(134) .sup.1H NMR (DMSO-d6) : 0.77 (dd, J=6.6, 4.4 Hz, 6H), 1.11 (t, J=7.6 Hz, 3H), 1.14-1.24 (m, 2H), 1.24-1.43 (m, 1H), 1.70 (d, J=13.3 Hz, 2H), 1.82-1.89 (m, 1H), 2.45-2.51 (m, 2H), 2.51-2.58 (m, 2H), 2.93 (dt, J=12.1, 3.3 Hz, 2H), 3.11 (s, 3H), 3.18 (dd, J=13.0, 7.1 Hz, 3H), 3.99 (dd, J=6.3, 2.3 Hz, 2H), 4.32 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.8, 2.5 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H).

(135) MS: [M+H]=508

Example 36: Synthesis of 4-((1-acetylpiperidin-4-yl)methoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(136) ##STR00199##

(137) With a procedure similar to that described for example 32, 4-((1-acetylpiperidin-4-yl)methoxy)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (6.5 mg; 10%) is obtained in the form of a white solid.

(138) .sup.1H NMR (DMSO-d6) : 0.85 (dd, J=6.7, 4.2 Hz, 6H), 1.08-1.23 (m, 5H), 1.22-1.35 (m, 2H), 1.43 (dt, J=13.4, 6.8 Hz, 1H), 1.88 (d, J=26.7 Hz, 2H), 2.01 (s, 3H), 2.09-2.14 (m, 1H), 2.61 (q, J=7.6 Hz, 3H), 3.08 (t, J=12.8 Hz, 1H), 3.18 (s, 3H), 3.22-3.30 (m, 2H), 3.87 (d, J=13.6 Hz, 1H), 4.11 (q, J=4.4 Hz, 2H), 4.42 (d, J=11.5 Hz, 2H), 7.01 (d, J=7.9 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H).

(139) MS: [M+H]=550

Example 37: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((1-(methylsulfonylpiperidin-4-yl)methoxy)benzenesulfonamide

(140) ##STR00200##

(141) With a procedure similar to that described for example 33, N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((1-(methylsulfonylpiperidin-4-yl)methoxy)benzenesulfonamide (17.2 mg; 25%) is obtained in the form of a white solid.

(142) .sup.1H NMR (DMSO-d6) : 0.85 (dd, J=6.7, 4.3 Hz, 6H), 1.19 (t, J=7.6 Hz, 3H), 1.37-1.51 (m, 3H), 1.89-2.04 (m, 3H), 2.61 (q, J=7.7 Hz, 2H), 2.72-2.83 (m, 2H), 2.88 (s, 3H), 3.18 (s, 3H), 3.28 (d, J=7.8 Hz, 2H), 3.62 (d, J=11.5 Hz, 2H), 4.09-4.20 (m, 2H), 4.42 (s, 1H), 7.01 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.68 (dd, J=8.7, 2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H).

(143) MS: [M+H]=586

Example 38: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-[(tetrahydropyran-4-ylmethyl)amino]benzenesulfonamide

(144) ##STR00201##

(145) A mixture of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (15.0 mg; 0.03 mmol) and 4-aminomethyltetrahydropyran (7.5 l; 0.06 mmol) is stirred overnight at room temperature.

(146) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-[(tetrahydropyran-4-ylmethyl)amino]benzenesulfonamide (9.0 mg; 56%) is obtained in the form of a white solid.

(147) .sup.1H NMR (DMSO-d6, 400 MHz): (ppm) 0.84 (dd, J=6.7, 2.6 Hz, 6H), 1.18 (t, J=7.7 Hz, 3H), 1.28 (dd, J=14.5, 10.3 Hz, 2H), 1.37-1.46 (m, 1H), 1.66 (d, J=13.3 Hz, 2H), 1.87 (s, 1H), 2.61 (q, J=7.4 Hz, 2H), 3.01 (s, 3H), 3.17 (q, J=6.8, 6.4 Hz, 2H), 3.24 (dd, J=7.4, 3.3 Hz, 2H), 3.89 (dd, J=11.6, 4.0 Hz, 2H), 4.74 (s, 1H), 6.95 (d, J=8.9 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 7.50 (d, J=9.0 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.84 (t, J=5.5 Hz, 1H).

(148) MS: [M+H]=508

Example 39: Synthesis of N-(4-ethylphenyl)-N-isobutyl-4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-(S-methylsulfonimidoyl)benzenesulfonamide

(149) ##STR00202##

(150) A solution of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (15.0 mg; 0.03 mmol) in N,N-dimethylformamide (0.20 ml) is stirred overnight at a temperature of 50 C.

(151) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-(S-methylsulfonimidoyl)benzenesulfonamide (9.0 mg; 49%) is obtained in the form of a colorless dry film.

(152) .sup.1H NMR (DMSO-d6) : 0.85 (dd, J=6.6, 3.2 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.44 (dt, J=13.7, 6.8 Hz, 1H), 1.58 (d, J=13.4 Hz, 2H), 1.93 (s, 1H), 2.61 (q, J=7.6 Hz, 2H), 2.82 (s, 3H), 2.93-3.10 (m, 2H), 3.26 (d, J=1.3 Hz, 3H), 3.28-3.30 (m, 2H), 3.80-3.87 (m, 2H), 4.50 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.61 (dd, J=8.6, 2.2 Hz, 1H), 8.13 (d, J=2.3 Hz, 1H).

(153) MS: [M+H]=522

Example 40: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((oxetan-3-ylmethyl)aminobenzenesulfonamide

(154) ##STR00203##

(155) 3-Aminomethyloxetane hydrochloride (33 mg; 0.26 mmol) and triethylamine (51 l; 0.37 mmol) are added to 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.00 mg; 0.11 mmol) dissolved in N,N-dimethylformamide (250 l). The reaction medium is stirred overnight at 50 C.

(156) The crude product is purified directly by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((oxetan-3-ylmethyl)aminobenzenesulfonamide (14.0 mg; 26%) is obtained in the form of a white solid.

(157) .sup.1H NMR (DMSO-d6) : 0.84 (dd, J=6.7, 2.2 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.35-1.50 (m, 1H), 2.61 (q, J=7.7 Hz, 2H), 3.00 (s, 3H), 3.25 (d, J=6.9 Hz, 2H), 3.58 (dt, J=14.5, 7.1 Hz, 2H), 4.35 (td, J=6.0, 2.8 Hz, 2H), 4.70 (td, J=6.4, 3.3 Hz, 3H), 6.99 (dd, J=8.5, 5.0 Hz, 3H), 7.20 (d, J=7.8 Hz, 2H), 7.51 (dd, J=8.8, 2.5 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.82 (t, J=5.5 Hz, 1H).

(158) MS: [M+H]=480

(159) With a procedure similar to that described for example 40, the following are obtained:

(160) TABLE-US-00006 Example 41 04 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((4-methyltetrahydro-2H- pyran-4-yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 3.3 Hz, 6H), 1.09 (s, 3H), 1.18 (t, J = 7.6 Hz, 3H), 1.31-1.38 (m, 2H), 1.38-1.47 (m, 1H), 1.54 (ddt, J = 14.2, 9.8, 5.0 Hz, 2H), 2.61 (q, J = 7.7 Hz, 2H), 3.01 (s, 3H), 3.07-3.21 (m, 2H), 3.24 (p, J = 5.6 Hz, 2H), 3.51-3.60 (m, 2H), 3.68 (dt, J = 11.8, 4.4 Hz, 2H), 4.84 (s, 1H), 7.00 (d, J = 8.1 Hz, 3H), 7.20 (d, J = 7.9 Hz, 2H), 7.49 (dd, J = 8.9, 2.4 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.98 (t, J = 5.1 Hz, 1H). MS: [M + H] = 522 Example 42 05 4-(((1,1-dioxidotetrahydrothiophen-3- yl)methyl)amino)-N-(4-ethylphenyl)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.7 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.38-1.50 (m, 1H), 1.89 (d, J = 22.1 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.90 (t, J = 12.1 Hz, 1H), 3.03 (d, J = 1.5 Hz, 3H), 3.25 (dd, J = 7.5, 3.9 Hz, 2H), 3.44 (t, J = 6.3 Hz, 2H), 4.73 (d, J = 6.3 Hz, 1H), 7.01 (dd, J = 8.6, 5.9 Hz, 3H), 7.20 (d, J = 8.3 Hz, 2H), 7.49 (dd, J = 8.9, 2.4 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H). MS: [M + H] = 542 Example 43 06 4-(((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)methyl)amino)-N-(4-ethylphenyl)-N-isobutyl-3- (S-methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.2 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.5, 6.8 Hz, 1H), 1.71 (q, J = 12.2 Hz, 2H), 1.91-1.98 (m, 1H), 2.06-2.14 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.02 (s, 3H), 3.10 (dd, J = 28.9, 13.4 Hz, 2H), 3.23-3.28 (m, 4H), 4.74 (d, J = 1.1 Hz, 1H), 6.97-7.02 (m, 3H), 7.20 (d, J = 8.3 Hz, 2H), 7.50 (dd, J = 8.9, 2.4 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.84 (t, J = 5.8 Hz, 1H). MS: [M + H] = 556 Example 44 07 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((6-oxopiperidin-3- yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.8 Hz, 1H), 1.47-1.59 (m, 1H), 1.83-1.93 (m, 1H), 2.02-2.11 (m, 1H), 2.16-2.25 (m, 2H), 2.60 (q, J = 7.7 Hz, 2H), 2.90-2.98 (m, 1H), 3.02 (s, 3H), 3.23-3.29 (m, 3H), 4.75 (s, 1H), 6.97-7.04 (m, 3H), 7.17-7.23 (m, 2H), 7.44-7.53 (m, 2H), 7.71 (dd, J = 2.3, 1.1 Hz, 1H), 7.83 (s, 1H). MS: [M + H] = 521 Example 45 08 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((5-oxopyrrolidin-3- yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.7 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.5, 6.8 Hz, 1H), 2.00 (ddd, J = 16.6, 6.8, 3.6 Hz, 1H), 2.29 (d, J = 8.8 Hz, 1H), 2.60 (q, J = 7.7 Hz, 2H), 2.68-2.78 (m, 1H), 3.02 (s, 3H), 3.24 (dd, J = 7.3, 3.6 Hz, 2H), 3.33-3.44 (m, 2H), 4.74 (s, 1H), 6.97 (s, 1H), 7.00 (d, J = 8.1 Hz, 2H), 7.16-7.23 (m, 2H), 7.50 (dd, J = 8.9, 2.4 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 5.0 Hz, 1H). MS: [M + H] = 507 Example 46 09 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((R)-1-(tetrahydro-2H- pyran-4-yl)ethyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 3.0 Hz, 6H), 1.10-1.23 (m, 6H), 1.26-1.40 (m, 1H), 1.42 (p, J = 7.0 Hz, 2H), 1.57 (d, J = 13.1 Hz, 2H), 1.62-1.79 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.99 (dd, J = 4.0, 1.0 Hz, 3H), 3.19-3.30 (m, 4H), 3.56-3.69 (m, 1H), 3.84-3.95 (m, 2H), 4.78 (d, J = 4.6 Hz, 1H), 6.94-7.02 (m, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.16-7.25 (m, 2H), 7.43-7.53 (m, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.80-7.90 (m, 1H). MS: [M + H] = 522 Example 47 0 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((S)-1-(tetrahydro-2H- pyran-4-yl)ethyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 3.0 Hz, 6H), 1.10-1.23 (m, 6H), 1.24-1.48 (m, 2H), 1.57 (d, J = 13.0 Hz, 1H), 1.62-1.77 (m, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.99 (dd, J = 4.0, 1.0 Hz, 3H), 3.21-3.30 (m, 4H), 3.60 (d, J = 20.4 Hz, 1H), 3.84-3.97 (m, 2H), 4.75-4.82 (m, 1H), 6.94-7.01 (m, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.16-7.24 (m, 2H), 7.43-7.52 (m, 1H), 7.67-7.73 (m, 1H), 7.80-7.88 (m, 1H). MS: [M + H] = 522 Example 48 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((2-oxooxazolidin-5- yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.81-0.87 (m, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (p, J = 6.6 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.02 (t, J = 1.1 Hz, 3H), 3.22-3.28 (m, 3H), 3.60 (ddt, J = 11.1, 6.9, 3.9 Hz, 2H), 4.55 (s, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.82 (s, 1H), 6.94-7.04 (m, 2H), 7.06 (d, J = 8.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.51 (dt, J = 8.9, 2.1 Hz, 1H), 7.60 (s, 1H), 7.72 (dd, J = 3.4, 2.3 Hz, 1H), 7.86-8.01 (m, 1H). MS: [M + H] = 509 Example 49 4-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (Chloroform-d) : 0.90 (dd, J = 9.1, 6.6 Hz, 6H), 1.25 (d, J = 8.2 Hz, 4H), 2.31 (s, 2H), 2.44 (s, 2H), 2.58-2.66 (m, 2H), 3.04 (s, 3H), 3.07-3.23 (m, 4H), 3.24-3.37 (m, 2H), 3.75 (s, 1H), 6.67 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.58 (dd, J = 8.8, 2.2 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H). MS: [M + H] = 542 Example 50 4-(((1-acetylpiperidin-4-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (Chloroform-d) : 0.92 (dd, J = 8.9, 6.7 Hz, 6H), 1.22-1.28 (m, 4H), 1.59 (hept, J = 6.8 Hz, 1H), 1.90 (dddd, J = 26.2, 18.2, 8.2, 4.9 Hz, 4H), 2.12 (s, 3H), 2.65 (q, J = 7.8 Hz, 2H), 3.04 (s, 3H), 3.09-3.17 (m, 4H), 3.24 (dd, J = 12.8, 6.9 Hz, 1H), 3.34 (dd, J = 12.7, 7.7 Hz, 1H), 3.89 (dd, J = 13.2, 3.5 Hz, 1H), 4.66-4.76 (m, 1H), 6.68 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.65 (q, J = 4.4, 3.9 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H). MS: [M + H] = 549 Example 51 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((6-oxopiperidin-3- yl)amino)benzenesulfonamide .sup.1H NMR (Chloroform-d) : 0.90 (dd, J = 9.2, 6.6 Hz, 6H), 1.19-1.27 (m, 5H), 1.58 (hept, J = 7.0 Hz, 1H), 2.55 (s, 2H), 2.64 (d, J = 7.9 Hz, 2H), 3.03 (s, 3H), 3.29 (ddd, J = 39.3, 12.4, 6.9 Hz, 3H), 3.67 (s, 1H), 3.87-3.99 (m, 1H), 6.02 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 8.02 (d, J = 5.8 Hz, 1H). MS: [M + H] = 507 Example 52 4-((1,1-dioxidotetrahydrothiophen-3-yl)amino)-N- (4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (ddd, J = 6.6, 2.3, 1.0 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.7 Hz, 1H), 2.12-2.24 (m, 1H), 2.61 (q, J = 7.5 Hz, 2H), 3.04 (d, J = 2.6 Hz, 3H), 3.07-3.21 (m, 1H), 3.23-3.27 (m, 2H), 3.65 (ddd, J = 20.2, 13.3, 7.0 Hz, 1H), 4.44-4.56 (m, 1H), 4.74 (s, 1H), 4.80 (s, 1H), 7.00 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.54 (dt, J = 8.3, 1.4 Hz, 1H), 7.73 (dd, J = 4.0, 2.3 Hz, 1H), 7.98 (d, J = 7.1 Hz, 1H), 8.12 (d, J = 6.6 Hz, 1H). MS: [M + H] = 528 Example 53 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4- thiomorpholinobenzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (ddd, J = 6.6, 2.3, 1.0 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.7 Hz, 1H), 2.12-2.24 (m, 1H), 2.61 (q, J = 7.5 Hz, 2H), 3.04 (d, J = 2.6 Hz, 3H), 3.07-3.21 (m, 1H), 3.23-3.27 (m, 2H), 3.65 (ddd, J = 20.2, 13.3, 7.0 Hz, 1H), 4.44-4.56 (m, 1H), 4.74 (s, 1H), 4.80 (s, 1H), 7.00 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.54 (dt, J = 8.3, 1.4 Hz, 1H), 7.73 (dd, J = 4.0, 2.3 Hz, 1H), 7.98 (d, J = 7.1 Hz, 1H), 8.12 (d, J = 6.6 Hz, 1H). MS: [M + H] = 528 Example 54 N-(4-ethylphenyl)-N-isobutyl-4-(((4-methyl-1,2,5- oxadiazol-3-yl)methyl)amino)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 3.5 Hz, 6H), 1.13-1.23 (m, 3H), 1.43 (dt, J = 13.6, 6.8 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.80 (dt, J = 6.8, 3.6 Hz, 4H), 3.25 (q, J = 5.9, 5.3 Hz, 4H), 3.31 (s, 3H), 4.53-4.57 (m, 1H), 6.97-7.05 (m, 2H), 7.17-7.26 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4, 2.3 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H). MS: [M + H] = 496

Example 55: Synthesis of N-(4-ethylphenyl)-4-(((3-hydroxycyclobutyl)methyl)amino)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(161) ##STR00218##

(162) 3-Aminomethylcyclobutanol hydrochloride (36.33 mg; 0.26 mmol) and cesium carbonate (120.43 mg; 0.37 mmol) are added to 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.00 mg; 0.11 mmol) dissolved in N,N-dimethylformamide (150 l).

(163) The reaction medium is stirred over the weekend at a temperature of 50 C.

(164) The crude product is purified directly by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-4-(((3-hydroxycyclobutyl)methyl)amino)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (20.0 mg; 38%) is obtained in the form of a white solid.

(165) .sup.1H NMR (DMSO-d6) : 0.84 (dd, J=6.7, 2.4 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.42 (dt, J=13.5, 6.7 Hz, 1H), 1.56 (q, J=8.7 Hz, 1H), 1.94-2.07 (m, 2H), 2.27-2.36 (m, 2H), 2.60 (q, J=7.6 Hz, 2H), 2.99 (s, 3H), 3.24 (dd, J=7.3, 3.5 Hz, 2H), 3.98 (dt, J=14.2, 7.4 Hz, 1H), 4.70 (d, J=1.3 Hz, 1H), 5.03 (t, J=3.1 Hz, 1H), 6.91 (t, J=8.6 Hz, 1H), 6.99 (dd, J=8.4, 1.6 Hz, 2H), 7.17-7.23 (m, 2H), 7.50 (dt, J=8.8, 2.9 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H).

(166) MS: [M+H]=494

(167) With a procedure similar to that described for example 55, the following are obtained:

(168) TABLE-US-00007 Example 56 N-(4-ethylphenyl)-4-(((4-fluorotetrahydro-2H-pyran-4- yl)methyl)amino)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.4 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.8 Hz, 1H), 1.81 (tq, J = 19.3, 9.1 Hz, 4H), 2.09 (s, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.02 (d, J = 0.9 Hz, 3H), 3.25 (dd, J = 7.3, 3.1 Hz, 2H), 3.51-3.63 (m, 4H), 3.74-3.82 (m, 2H), 4.76-4.83 (m, 1H), 7.00 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.9 Hz, 1H), 7.17-7.22 (m, 2H), 7.50 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 8.01 (t, J = 5.8 Hz, 1H) MS: [M + H] = 526 Example 57 0 methyl 3-(((4-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenyl)amino)methyl)azetidine-1- carboxylate .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.3 Hz, 6H), 1.11-1.23 (m, 3H), 1.42 (dt, J = 13.6, 6.7 Hz, 1H), 2.55-2.66 (m, 2H), 2.99 (s, 3H), 3.25 (ddd, J = 17.8, 9.7, 4.2 Hz, 4H), 3.51 (q, J = 6.5 Hz, 1H), 3.56 (s, 3H), 3.67 (dt, J = 12.1, 6.8 Hz, 2H), 4.00 (p, J = 8.0 Hz, 2H), 4.69 (s, 1H), 6.95-7.05 (m, 3H), 7.16-7.24 (m, 2H), 7.50 (dd, J = 8.9, 2.3 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 5.5 Hz, 1H). MS: [M + H] = 537 Example 58 N-(4-ethylphenyl)-N-isobutyl-4-(((2-methylpyridin-4- yl)methyl)amino)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.83 (dd, J = 6.6, 2.0 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.41 (dt, J = 13.6, 6.9 Hz, 1H), 2.45 (s, 3H), 2.59 (q, J = 7.7 Hz, 2H), 3.10 (d, J = 1.0 Hz, 3H), 3.24 (dd, J = 7.4, 2.7 Hz, 2H), 4.58 (d, J = 6.1 Hz, 2H), 4.79 (s, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.95-7.00 (m, 2H), 7.13-7.23 (m, 4H), 7.45 (dd, J = 8.8, 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 8.19 (t, J = 6.0 Hz, 1H), 8.40 (d, J = 5.3 Hz, 1H). MS: [M + H] = 515 Example 59 4-((((1R,5S,6S)-3-oxabicyclo[3.1.0]hexan-6- yl)methyl)amino)-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.1 Hz, 6H), 1.00 (dt, J = 7.0, 3.6 Hz, 1H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.8 Hz, 1H), 1.69 (hept, J = 3.5 Hz, 2H), 2.56-2.66 (m, 2H), 3.02 (d, J = 0.9 Hz, 3H), 3.25 (dd, J = 7.4, 2.5 Hz, 2H), 3.58 (dd, J = 8.2, 2.5 Hz, 2H), 3.74 (dd, J = 8.3, 1.7 Hz, 2H), 4.71 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.95-7.01 (m, 2H), 7.15-7.25 (m, 2H), 7.50 (dd, J = 8.8, 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.77 (t, J = 5.1 Hz, 1H). MS: [M + H] = 506 Example 60 N-(4-ethylphenyl)-4-(((4-hydroxytetrahydro-2H-pyran- 4-yl)methyl)amino)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 1.9 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.8 Hz, 1H), 1.51 (d, J = 13.3 Hz, 2H), 1.62 (dt, J = 15.5, 8.6 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.02 (d, J = 0.8 Hz, 3H), 3.20-3.30 (m, 2H), 3.59-3.70 (m, 2H), 4.69 (d, J = 1.1 Hz, 1H), 4.80 (s, 1H), 6.93-7.03 (m, 3H), 7.16-7.23 (m, 2H), 7.48 (dd, J = 8.9, 2.4 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.88 (t, J = 5.1 Hz, 1H). MS: [M + H] = 524 Example 61 methyl 4-(((4-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenyl)amino)methyl)piperidine- 1-carboxylate .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.41 (dq, J = 13.8, 6.9 Hz, 1H), 1.73 (d, J = 13.3 Hz, 4H), 1.76-1.88 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.01 (d, J = 1.0 Hz, 3H), 3.13-3.20 (m, 2H), 3.24 (dd, J = 7.2, 3.3 Hz, 2H), 3.59 (s, 3H), 3.93-4.10 (m, 4H), 4.74 (d, J = 1.3 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.97-7.02 (m, 2H), 7.17-7.23 (m, 2H), 7.50 (dd, J = 8.9, 2.4 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.83 (t, J = 5.4 Hz, 1H). MS: [M + H] = 565 Example 62 methyl 3-(((4-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S- methylsulfonimidoyl)phenyl)amino)methyl)pyrrolidine- 1-carboxylate .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.41 (dt, J = 13.5, 6.8 Hz, 1H), 1.58-1.76 (m, 1H), 1.93-2.08 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 3.02 (s, 3H), 3.07 (td, J = 8.5, 7.9, 3.9 Hz, 1H), 3.24 (dd, J = 7.3, 3.2 Hz, 4H), 3.43 (td, J = 9.6, 8.2, 4.3 Hz, 1H), 3.50 (ddd, J = 10.2, 7.3, 2.3 Hz, 1H), 3.58 (s, 3H), 4.75 (s, 1H), 6.96-7.03 (m, 3H), 7.17-7.23 (m, 2H), 7.50 (ddd, J = 8.9, 2.3, 1.2 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H). MS: [M + H] = 551 Example 63 4-(((2-oxaspiro[3.3]heptan-6-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.4 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.40 (dq, J = 13.7, 6.9 Hz, 1H), 1.96 (ddd, J = 10.0, 5.7, 2.0 Hz, 2H), 2.28-2.46 (m, 3H), 2.60 (q, J = 7.6 Hz, 2H), 2.99 (d, J = 0.9 Hz, 3H), 3.22 (dtd, J = 14.0, 7.6, 7.0, 5.1 Hz, 4H), 4.49 (s, 2H), 4.59 (s, 2H), 4.71 (d, J = 1.1 Hz, 1H), 6.89 (d, J = 9.0Hz, 1H), 6.97-7.02 (m, 2H), 7.17-7.21 (m, 2H), 7.49 (dd, J = 8.9, 2.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H). MS: [M + H] = 520 Example 64 4-N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((2-oxopiperidin-4- yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.7 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dq, J = 13.9, 7.0 Hz, 2H), 1.86 (d, J = 13.6 Hz, 1H), 1.96 (ddd, J = 16.8, 10.8, 3.4 Hz, 1H), 2.10-2.32 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 3.02 (s, 3H), 3.13 (td, J = 12.4, 11.2, 6.5 Hz, 2H), 3.14-3.30 (m, 4H), 4.77 (s, 1H), 6.96-7.03 (m, 2H), 7.16-7.24 (m, 2H), 7.47-7.55 (m, 1H), 7.54-7.66 (m, 1H), 7.70 (dd, J = 2.4, 1.4 Hz, 1H), 7.86 (d, J = 5.9 Hz, 1H). MS: [M + H] = 521 Example 65 4-(((3,5-dimethylisoxazol-4-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.2 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.41 (dq, J = 13.7, 6.9 Hz, 1H), 2.23 (s, 3H), 2.42 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 3.00 (s, 3H), 3.26 (dd, J = 7.3, 2.9 Hz, 2H), 4.28 (t, J = 5.3 Hz, 2H), 4.75 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 8.7, 2.4 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.80 (t, J = 5.1 Hz, 1H). MS: [M + H] = 519 Example 66 N-(4-ethylphenyl)-4-(((4- hydroxycyclohexyl)methyl)amino)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 2.8 Hz, 6H), 1.01-1.10 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.7, 6.8 Hz, 1H), 1.53 (td, J = 18.2, 15.7, 6.5 Hz, 2H), 1.73-1.90 (m, 4H), 2.60 (q, J = 7.5 Hz, 2H), 3.00 (s, 3H), 3.08 (d, J = 6.8 Hz, 2H), 3.24 (dd, J = 7.5, 3.6 Hz, 2H), 4.53 (d, J = 4.5 Hz, 1H), 4.74 (s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.8, 2.5 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.81 (t, J = 5.4 Hz, 1H). MS: [M + H] = 522 Example 67 0 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((thietan-3- ylmethyl)amino)benzenesulfonamide .sup.1H NMR (Chloroform-d) : 0.93 (dd, J = 9.2, 6.8 Hz, 6H), 1.26 (t, J = 7.6 Hz, 3H), 1.62 (dq, J = 13.6, 7.0 Hz, 1H), 2.67 (q, J = 7.6 Hz, 2H), 3.04 (dd, J = 9.4, 6.0 Hz, 2H), 3.11 (s, 3H), 3.26 (dd, J = 12.9, 7.0 Hz, 1H), 3.32-3.44 (m, 2H), 3.49 (d, J = 7.0 Hz, 2H), 3.57 (h, J = 6.8, 6.4 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H). MS: [M + H] = 496 Example 68 4-(((1-acetylpyrrolidin-3-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H 1H NMR (Chloroform-d) : 0.89 (dd, J = 8.8, 6.6 Hz, 6H), 1.23 (t, J = 7.9 Hz, 3H), 1.57 (hept, J = 6.8 Hz, 1H), 1.65-1.90 (m, 1H), 2.06 (d, J = 2.9 Hz, 3H), 2.21-2.24 (m, 2H), 2.63 (q, J = 7.7 Hz, 2H), 3.03 (d, J = 4.6 Hz, 3H), 3.27 (dtd, J = 20.1, 12.9, 7.5 Hz, 5H), 3.47 (dt, J = 19.3, 9.3 Hz, 1H), 3.55-3.83 (m, 2H), 6.60-6.72 (m, 1H), 6.98 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.98 (dd, J = 4.5, 2.1 Hz, 1H). MS: [M + H] = 535 Example 71 N-(4-ethylphenyl)-N-isobutyl-4-((R)-3- methylmorpholino)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.77 (dd, J = 6.3, 2.6 Hz, 3H), 0.82-0.88 (m, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.44 (dt, J = 13.7, 6.8 Hz, 1H), 2.61 (ddt, J = 8.7, 6.3, 3.4 Hz, 2H), 3.40 (dd, J = 17.2, 1.2 Hz, 3H), 3.44-3.50 (m, 1H), 3.68 (ddd, J = 11.1, 8.0, 3.0 Hz, 1H), 3.78 (ddt, J = 7.9, 5.2, 2.8 Hz, 1H), 3.87 (dd, J = 10.9, 2.4 Hz, 1H), 4.47 (d, J = 1.5 Hz, 1H), 4.62 (d, J = 1.5 Hz, 1H), 6.92-7.05 (m, 2H), 7.19 (dd, J = 8.4, 2.2 Hz, 2H), 7.68 (d, J = 1.3 Hz, 1H), 7.70-7.72 (m, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.25 (t, J = 1.3 Hz, 1H). MS: [M + H] = 494 Example 73 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((((R)-2-oxooxazolidin-5- yl)methyl)amino)benzenesulfonamide .sup.1H NMR (Chloroform-d) : 0.90 (dd, J = 9.3, 6.7 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.59 (dq, J = 13.8, 6.8 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 3.06 (d, J = 2.6 Hz, 3H), 3.24 (ddd, J = 12.8, 7.0, 2.1 Hz, 1H), 3.34 (ddd, J = 12.9, 7.8, 3.3 Hz, 1H), 3.44 (ddd, J = 8.6, 5.9, 2.4 Hz, 1H), 3.53-3.68 (m, 1H), 3.82 (t, J = 8.7 Hz, 1H), 4.93 (qd, J = 6.0, 3.9 Hz, 1H), 5.07 (s, 1H), 6.75 (dd, J = 8.8, 3.0 Hz, 1H), 6.94-7.03 (m, 2H), 7.13-7.19 (m, 2H), 7.57 (dt, J = 8.8, 2.4 Hz, 1H), 8.01 (dd, J = 5.5, 2.2 Hz, 1H). MS: [M + H] = 509 Example 74 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((((S)-2-oxooxazolidin-5- yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 1.9 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dd, J = 13.7, 7.0 Hz, 1H), 1.52 (td, J = 17.8, 15.2, 7.1 Hz, 2H), 1.94-2.09 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 3.01 (s, 3H), 3.24 (d, J = 7.4 Hz, 2H), 3.37-3.46 (m, 2H), 3.78 (d, J = 11.5 Hz, 2H), 4.69 (s, 1H), 6.99 (d, J = 8.2 Hz, 3H), 7.20 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 8.9, 2.4 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H). MS: [M + H] = 509 Example 75 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-((2-oxopiperidin-4- yl)amino)benzenesulfonamide .sup.1H NMR (Chloroform-d) : 0.90 (d, J = 7.3 Hz, 6H), 1.17-1.27 (m, 3H), 1.45-1.68 (m, 2H), 2.57-2.68 (m, 2H), 3.01-3.4 (m, 2H), 3.19-3.40 (m, 2H), 3.48-3.52 (m, 1H), 3.99 (s, 1H), 6.03 (d, J = 40.9 Hz, 1H), 6.72 (s, 1H), 7.00 (d, J = 7.3 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 7.57 (s, 1H), 8.00 (s, 1H). MS: [M + H] = 508 Example 77 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(2-oxa-6-azaspiro[3.5]nonan- 6-yl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.86 (dd, J = 6.7, 4.1 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.44 (dt, J = 13.6, 6.8 Hz, 1H), 1.63 (q, J = 5.6 Hz, 2H), 1.83 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.92 (d, J = 17.9 Hz, 2H), 3.17 (s, 2H), 3.27 (d, J = 1.2 Hz, 3H), 3.33 (s, 2H), 4.29 (d, J = 5.6 Hz, 2H), 4.42-4.62 (m, 3H), 6.97-7.05 (m, 2H), 7.18-7.25 (m, 2H), 7.64-7.75 (m, 2H), 8.15 (d, J = 2.0 Hz, 1H). MS: [M + H] = 520 Example 78 tert-butyl 6-(4-(N-(4-ethylphenyl)-N- isobutylsulfamoyl)-2-(S-methylsulfonimidoyl)phenyl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate .sup.1H NMR (DMSO-d6) : 0.83 (dd, J = 6.6, 3.4 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.39 (s, 9H), 2.60 (q, J = 7.6 Hz, 2H), 3.12 (d, J = 1.5 Hz, 3H), 3.23 (dd, J = 7.3, 5.1 Hz, 2H), 4.05 (s, 4H), 4.20 (d, J = 1.7 Hz, 1H), 4.43 (s, 4H), 6.59 (d, J = 8.9 Hz, 1H), 6.94-7.01 (m, 2H), 7.15-7.23 (m, 2H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H). MS: [M + H] = 591 Example 79 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.83 (dd, J = 6.4, 3.3 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.33-1.47 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.12 (s, 3H), 3.24 (h, J = 6.7, 5.8 Hz, 3H), 4.20 (s, 1H), 4.48 (s, 4H), 4.73 (s, 4H), 6.61 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 8.8, 2.3 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H). MS: [M + H] = 493 Example 80 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(2-oxa-6-azaspiro[3.4]octan-6- yl)benzenesulfonamide .sup.1H 1H NMR (DMSO-d6) : 0.90 (dd, J = 6.8, 3.4 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.41-1.55 (m, 1H), 2.00 (d, J = 5.7 Hz, 4H), 2.66 (q, J = 7.6 Hz, 2H), 2.89-3.09 (m, 4H), 3.36 (s, 3H), 4.43 (s, 4H), 4.57 (s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.3, 2.3 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H). MS: [M + H] = 407 Example 81 0 4-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6-371)-N- (4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.8, 3.4 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.34-1.49 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.13 (s, 3H), 3.25 (dd, J = 7.4, 5.1 Hz, 2H), 4.28 (s, 1H), 4.52 (d, J = 4.5 Hz, 8H), 6.66 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 8.8, 2.3 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H). MS: [M + H] = 540 Example 82 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(2-oxa-7-azaspiro[3.5]nonan- 7-yl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (d, J = 6.7 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.35-1.50 (m, 1H), 2.16-2.30 (m, 2H), 2.61 (q, J = 7.5 Hz, 2H), 3.21 (s, 3H), 3.28 (d, J = 7.3 Hz, 2H), 3.42-3.62 (m, 2H), 3.68-3.83 (m, 2H), 4.21 (s, 1H), 4.54 (dd, J = 6.0, 3.6 Hz, 2H), 4.60 (dd, J = 14.2, 5.9 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 7.19 (dd, J = 8.5, 4.5 Hz, 3H), 7.49 (dd, J = 8.8, 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H). MS: [M + H] = 520 Example 83 4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N- (4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H 1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 1.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.36-1.48 (m, 1H), 1.82-1.97 (m, 2H), 2.53-2.66 (m, 3H), 3.18 (dd, J = 7.4, 1.3 Hz, 3H), 3.28 (dd, J = 7.3, 1.7 Hz, 2H), 3.35-3.48 (m, 1H), 3.77 (td, J = 7.6, 1.7 Hz, 1H), 3.81-3.97 (m, 2H), 4.11 (d, J = 1.7 Hz, 0.5H), 4.46 (d, J = 1.5 Hz, 0.5H), 4.60-4.84 (m, 2H), 6.97-7.05 (m, 2H), 7.14-7.27 (m, 3H), 7.44 (ddd, J = 8.4, 5.7, 2.4 Hz, 1H), 8.07 (dd, J = 14.5, 2.4 Hz, 1H). MS: [M + H] = 493 Example 85 4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N- (4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.83 (dt, J = 5.7, 2.8 Hz, 6H), 1.16 (td, J = 7.6, 2.7 Hz, 3H), 1.20-1.31 (m, 1H), 1.34-1.49 (m, 1H), 1.87-1.99 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 3.17-3.26 (m, 4H), 3.34 (s, 3H), 3.67-3.88 (m, 3H), 4.49 (s, 1H), 6.95-7.01 (m, 2H), 7.15-7.22 (m, 2H), 7.58-7.68 (m, 2H), 8.10 (d, J = 2.2 Hz, 1H). MS: [M + H] = 493 Example 86 4-(((2H-tetrazol-5-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.7, 1.4 Hz, 7H), 1.18 (t, J = 7.6 Hz, 3H), 1.34-1.47 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.08 (s, 3H), 3.25 (d, J = 7.4 Hz, 4H), 4.86 (d, J = 5.7 Hz, 2H), 6.92-7.03 (m, 3H), 7.15-7.23 (m, 2H), 7.53 (dd, J = 8.8, 2.3 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 8.20 (t, J = 5.7 Hz, 1H). MS: [M + H] = 494

Example 89: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzenesulfonamide

(169) ##STR00245##

(170) Trifluoroacetic acid (0.28 ml; 3.59 mmol) is added to tert-butyl 6-(4-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-(S-methylsulfonimidoyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (55.0 mg; 0.09 mmol) dissolved in dichloromethane (2.75 ml). The reaction medium is stirred for 4 hours at room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried (Na.sub.2SO.sub.4) and concentrated. The residue is taken up in ether and suction-filtered.

(171) The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzenesulfonamide (44.9 mg; 880%) is obtained in the form of a white solid.

(172) .sup.1H NMR (DMSO-d6) : 0.83 (dd, J=6.6, 3.3 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.25 (s, 1H), 1.34-1.47 (m, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.12 (d, J=1.8 Hz, 3H), 3.23 (dd, J=7.2, 4.7 Hz, 2H), 3.79 (s, 2H), 4.21 (d, J=7.3 Hz, 1H), 4.37 (s, 1H), 4.40 (s, 2H), 6.61 (dd, J=9.1, 3.7 Hz, 1H), 6.94-7.01 (m, 2H), 7.15-7.23 (m, 2H), 7.41 (dd, J=8.8, 2.3 Hz, 1H), 7.93 (dd, J=4.7, 2.3 Hz, 1H).

(173) MS: [M+H]=492

Example 90: Synthesis of 4-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(174) ##STR00246##

(175) 4-Dimethylaminopyridine (0.72 mg; 0.01 mmol) and acetic anhydride (5.6 l; 0.06 mmol) are added to a solution of 4-oxo-1-piperidin-4-yl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (4-ethylphenyl)isobutylamide (29.0 mg; 0.06 mmol) in dichloromethane (1.45 ml) cooled to 10 C. The reaction medium is stirred for 30 minutes at room temperature. The reaction medium is hydrolyzed with saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(176) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 4-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (23.10 mg; 73%) is obtained in the form of a white solid.

(177) .sup.1H NMR (DMSO-d6) : 0.84 (dd, J=6.8, 3.4 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.34-1.47 (m, 1H), 1.76 (s, 3H), 2.60 (q, J=7.6 Hz, 2H), 3.12 (s, 3H), 3.16-3.28 (m, 2H), 4.03 (s, 2H), 4.21 (s, 1H), 4.31 (s, 2H), 4.45 (s, 4H), 6.61 (d, J=8.9 Hz, 1H), 6.98 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.43 (dd, J=8.8, 2.3 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H).

(178) MS: [M+H]=533

Example 91: Synthesis of 4-(4-acetylpiperazin-1-yl)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(179) ##STR00247##

(180) A mixture of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.0 mg; 0.11 mmol) and 1-piperazin-1-ylethanone (67.68 mg; 0.53 mmol) is stirred over the weekend at 50 C.

(181) The crude product is purified directly by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 4-(4-acetylpiperazin-1-yl)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (20.0 mg; 36%) is obtained in the form of a white solid.

(182) .sup.1H NMR (DMSO-d6) : 0.85 (dd, J=6.7, 3.5 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.44 (dt, J=13.7, 6.9 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.04 (dq, J=23.9, 5.3 Hz, 4H), 3.34 (d, J=1.2 Hz, 3H), 3.61 (d, J=5.4 Hz, 4H), 4.57 (d, J=1.4 Hz, 1H), 6.97-7.05 (m, 2H), 7.17-7.25 (m, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.4, 2.3 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H).

(183) MS: [M+H]=521

Example 92: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((pyridin-4-ylmethyl)amino)benzenesulfonamide

(184) ##STR00248##

(185) A mixture of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.0 mg; 0.11 mmol) and 4-picolylamine (53.62 l; 0.53 mmol) is stirred over the weekend at 50 C.

(186) The crude product is purified directly by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((pyridin-4-ylmethyl)amino)benzenesulfonamide (26.0 mg; 49%) is obtained in the form of a white solid.

(187) .sup.1H NMR (DMSO-d6) : 0.83 (d, J=6.7 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.41 (hept, J=6.7 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 3.11 (s, 3H), 3.23 (dd, J=7.3, 2.5 Hz, 2H), 4.64 (d, J=5.9 Hz, 2H), 4.79 (s, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.97 (d, J=7.9 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.36 (d, J=5.1 Hz, 2H), 7.44 (dd, J=9.1, 2.4 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 8.21 (t, J=6.0 Hz, 1H), 8.54 (d, J=5.2 Hz, 2H).

(188) MS: [M+H]=501

(189) With a procedure similar to that described for example 92, the following are obtained:

(190) TABLE-US-00008 Example 94 N-(4-ethylphenyl)-4-(((4-ethyltetrahydro-2H- pyran-4-yl)methyl)amino)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.81 (t, J = 7.6 Hz, 3H), 0.84 (dd, J = 6.7, 3.4 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.38-1.57 (m, 7H), 2.61 (q, J = 7.6 Hz, 2H), 3.00 (d, J = 0.8 Hz, 3H), 3.10-3.21 (m, 2H), 3.21-3.28 (m, 2H), 3.61 (q, J = 6.2 Hz, 4H), 4.85 (s, 1H), 6.99-7.04 (m, 3H), 7.16-7.24 (m, 2H), 7.51 (dd, J = 8.9, 2.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.92 (t, J = 4.9 Hz, 1H). MS: [M + H] = 536 Example 95 0 N-(4-ethylphenyl)-N-isobutyl-4-(((4- methoxytetrahydro-2H-pyran-4-yl)methyl)amino)- 3-(S-methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.6 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.7, 6.9 Hz, 1H), 1.61 (ddd, J = 14.2, 9.0, 4.2 Hz, 2H), 1.75 (t, J = 10.6 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.00 (d, J = 0.9 Hz, 3H), 3.13 (s, 3H), 3.19-3.32 (m, 4H), 3.57 (ddd, J = 11.1, 8.5, 2.5 Hz, 2H), 3.62-3.70 (m, 2H), 4.74 (d, J = 1.1 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.99-7.04 (m, 2H), 7.16-7.22 (m, 2H), 7.51 (dd, J = 8.8, 2.3 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.81 (t, J = 4.7 Hz, 1H). Example 96 4-(((3-ethyloxetan-3-yl)methyl)amino)-N-(4- ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.6, 3.0 Hz, 6H), 0.91 (t, J = 7.4 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.7, 6.8 Hz, 1H), 1.70-1.81 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.01 (d, J = 0.9 Hz, 3H), 3.21-3.30 (m, 2H), 3.37-3.56 (m, 2H), 4.36 (d, J = 1.3 Hz, 2H), 4.38 (d, J = 5.0 Hz, 2H), 4.80 (s, 1H), 6.97-7.04 (m, 2H), 7.05 (d, J = 9.0 Hz, 1H), 7.16-7.25 (m, 2H), 7.53 (dd, J = 8.8, 2.3 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.98 (t, J = 5.1 Hz, 1H). MS: [M + H] = 508 Example 97 N-(4-ethylphenyl)-N-isobutyl-4-(((2- methoxypyridin-4-yl)methyl)amino)-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.83 (dd, J = 6.6, 1.9 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.42 (dq, J = 13.6, 6.7 Hz, 1H), 2.54-2.64 (m, 2H), 3.09 (d, J = 0.9 Hz, 3H), 3.24 (dd, J = 7.3, 2.6 Hz, 2H), 3.84 (s, 3H), 4.58 (d, J = 6.0 Hz, 2H), 4.79 (s, 1H), 6.73-6.77 (m, 2H), 6.95-6.99 (m, 3H), 7.15-7.20 (m, 2H), 7.44 (dd, J = 8.8, 2.4 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 8.13 (dd, J = 5.3, 0.7 Hz, 1H), 8.17 (t, J = 6.1 Hz, 1H). MS: [M + H] = 531 Example 98 N-(4-ethylphenyl)-4-(4-hydroxypiperidin-1-yl)-N- isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.85 (dd, J = 6.7, 3.3 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.43 (dt, J = 13.4, 6.6 Hz, 1H), 1.60 (t, J = 9.5 Hz, 2H), 1.82-1.91 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.84 (q, J = 9.2 Hz, 2H), 3.18-3.30 (m, 4H), 3.66 (s, 1H), 4.52 (d, J = 1.5 Hz, 1H), 4.71 (d, J = 4.3 Hz, 1H), 6.95-7.04 (m, 2H), 7.17-7.24 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 2.3 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H). MS: [M + H] = 494 Example 99 N-(4-ethylphenyl)-4-((S)-3-hydroxypyrrolidin-1- yl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 1.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.8 Hz, 1H), 1.86 (d, J = 9.6 Hz, 1H), 2.01 (ddd, J = 14.4, 10.7, 4.8 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.21 (dd, J = 12.9, 1.3 Hz, 3H), 3.27-3.29 (m, 2H), 3.67 (q, J = 8.2 Hz, 1H), 3.73-3.85 (m, 1H), 3.91 (dd, J = 10.8, 4.5 Hz, 1H), 4.01 (d, J = 1.8 Hz, 1H), 4.28 (d, J = 1.5 Hz, 1H), 4.39 (s, 1H), 5.01 (dd, J = 19.6, 3.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 12.6, 8.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 8.9, 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H). MS: [M + H] = 480 Example 100 N-(4-ethylphenyl)-4-((R)-3-hydroxypyrrolidin-1- yl)-N-isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 1.5 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (dt, J = 13.6, 6.8 Hz, 1H), 1.86 (d, J = 9.6 Hz, 1H), 2.01 (ddd, J = 14.4, 10.7, 4.8 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.21 (dd, J = 12.9, 1.3 Hz, 3H), 3.27-3.29 (m, 2H), 3.67 (q, J = 8.2 Hz, 1H), 3.73-3.85 (m, 1H), 3.91 (dd, J = 10.8, 4.5 Hz, 1H), 4.01 (d, J = 1.8 Hz, 1H), 4.28 (d, J = 1.5 Hz, 1H), 4.39 (s, 1H), 5.01 (dd, J = 19.6, 3.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 12.6, 8.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 8.9, 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H). MS: [M + H] = 480 Example 101 N-(4-ethylphenyl)-4-(3-hydroxyazetidin-1-yl)-N- isobutyl-3-(S- methylsulfonimidoyl)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 3.1 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.41 (dt, J = 14.1, 7.0 Hz, 1H), 2.60 (q, J = 7.7 Hz, 2H), 3.11 (d, J = 1.3 Hz, 3H), 3.24 (dd, J = 7.3, 4.5 Hz, 2H), 4.02 (dd, J = 10.5, 5.7 Hz, 2H), 4.20 (d, J = 1.5 Hz, 1H), 4.50 (s, 2H), 5.71 (s, 1H), 6.63 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 7.16-7.25 (m, 2H), 7.40 (dd, J = 8.8, 2.3 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H). MS: [M + H] = 466 Example 102 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(((3-(pyrrolidin-1- yl)oxetan-3-yl)methyl)amino)benzenesulfonamide .sup.1H NMR (DMSO-d6) : 0.84 (dd, J = 6.6, 2.0 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H), 1.42 (p, J = 6.9 Hz, 1H), 1.76 (d, J = 6.2 Hz, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2.73 (q, J = 5.9 Hz, 4H), 2.96 (d, J = 0.9 Hz, 3H), 3.25 (dd, J = 7.4, 1.6 Hz, 2H), 3.55-3.72 (m, 2H), 4.29 (dd, J = 8.5, 6.6 Hz, 2H), 4.59 (s, 1H), 4.78 (d, J = 6.7 Hz, 2H), 6.97-7.02 (m, 3H), 7.17-7.23 (m, 2H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.85 (t, J = 4.2 Hz, 1H). MS: [M + H] = 549

Example 103: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((pyrimidin-4-ylmethyl)amino)benzenesulfonamide

(191) ##STR00258##

(192) 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.0 mg; 0.11 mmol) and 4-(aminomethyl)pyrimidine (34.6 mg; 0.32 mmol) are introduced into a microwave tube. The reaction medium is stirred for 30 minutes at 100 C. under microwave irradiation.

(193) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((pyrimidin-4-ylmethyl)amino)benzenesulfonamide (15.0 mg; 28%) is obtained in the form of a beige-colored solid.

(194) .sup.1H NMR (DMSO-d6) : 0.83 (dd, J=6.6, 1.5 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.41 (dt, J=13.7, 6.8 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.11 (d, J=1.0 Hz, 3H), 3.24 (dd, J=7.4, 1.4 Hz, 2H), 4.72 (dd, J=5.7, 1.9 Hz, 2H), 4.75-4.79 (m, 1H), 6.81 (d, J=8.9 Hz, 1H), 6.93-7.01 (m, 2H), 7.15-7.23 (m, 2H), 7.47 (dd, J=8.8, 2.3 Hz, 1H), 7.50 (dd, J=5.2, 1.4 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 8.35 (t, J=5.9 Hz, 1H), 8.77 (d, J=5.2 Hz, 1H), 9.17 (d, J=1.4 Hz, 1H).

(195) MS: [M+H]=502

Example 107: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(1,4-oxazepan-4-yl)benzenesulfonamide

(196) 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.0 mg; 0.11 mmol) is added to 1,4-oxazepane (16.0 mg; 0.16 mmol) and N,N-diisopropylethylamine (0.11 ml; 0.63 mmol) dissolved in dimethyl sulfoxide (2 ml).

(197) The reaction medium is heated at a temperature of 150 C. for 20 minutes with microwave irradiation. The reaction medium is hydrolyzed with 1N hydrochloric acid solution and diluted, and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated under vacuum.

(198) The crude product is purified directly by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(1,4-oxazepan-4-yl)benzenesulfonamide (23.8 mg; 46%) is obtained in the form of a white solid.

(199) .sup.1H NMR (Methanol-d4) : 0.93 (d, J=6.7 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.49-1.64 (m, 1H), 2.09 (p, J=6.0 Hz, 2H), 2.67 (q, J=7.6 Hz, 2H), 3.39 (d, J=7.3 Hz, 2H), 3.48 (s, 3H), 3.90 (dd, J=6.2, 3.5 Hz, 2H), 3.95 (t, J=6.1 Hz, 2H), 6.98-7.05 (m, 2H), 7.17-7.24 (m, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.74 (dd, J=8.4, 2.3 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H).

(200) MS: [M+H]=494

(201) TABLE-US-00009 Example 107 N-(4-ethylphenyl)-N-isobutyl-3-(S- methylsulfonimidoyl)-4-(1,4-oxazepan- 4-yl)benzenesulfonamide .sup.1H NMR (Methanol-d4) : 0.93 (d, J = 6.7 Hz, 6H), 1.25 (t, J = 7.6 Hz, 3H), 1.49-1.64 (m, 1H), 2.09 (p, J = 6.0 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 3.39 (d, J = 7.3 Hz, 2H), 3.48 (s, 3H), 3.90 (dd, J = 6.2, 3.5 Hz, 2H), 3.95 (t, J = 6.1 Hz, 2H), 6.98-7.05 (m, 2H), 7.17-7.24 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.4, 2.3 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H). MS: [M + H] = 494

Example 110: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperazin-1-yl)benzenesulfonamide

(202) ##STR00260##

(203) Piperazine (18.2 mg; 0.21 mmol) is added to a solution of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (50.00 mg; 0.11 mmol) in N,N-dimethylformamide (0.20 l). The reaction medium is stirred overnight at 60 C. The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.2% of ammonium carbonate). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(piperazin-1-yl)benzenesulfonamide (30.0 mg; 53%) is obtained in the form of a white solid.

(204) .sup.1H NMR (DMSO-d6) : 0.85 (dd, J=6.6, 3.5 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.43 (dt, J=13.8, 6.9 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 2.87 (t, J=4.7 Hz, 4H), 2.99 (d, J=5.0 Hz, 4H), 3.35 (s, 3H), 4.53 (s, 1H), 6.97-7.04 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.4, 2.3 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H).

(205) MS: [M+H] 479

Example 111: Synthesis of N-(4-ethylphenyl)-4-(((3-hydroxycyclobutyl)methyl)amino)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(206) ##STR00261##

(207) 3-Chloroperbenzoic acid (24.4 mg; 0.11 mmol) is added at 0 C. to N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-thiomorpholinobenzenesulfonamide (27.0 mg; 0.05 mmol) dissolved in dichloromethane (250 l). The reaction medium is stirred for 5 hours at room temperature, hydrolyzed with 1N sodium hydroxide solution and extracted with dichloromethane. The organic phases are combined, washed with water, dried (MgSO.sub.4) and concentrated under vacuum.

(208) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 4-(1,1-dioxidothiomorpholino)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (8.0 mg; 28%) is obtained in the form of an off-white solid.

(209) .sup.1H NMR (DMSO-d6) : 0.86 (d, J=6.6 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.43 (dt, J=13.5, 6.8 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.31 (d, J=7.8 Hz, 2H), 3.35-3.40 (m, 7H), 3.49 (dd, J=6.8, 3.4 Hz, 4H), 6.94-7.05 (m, 2H), 7.17-7.25 (m, 2H), 7.83-7.91 (m, 3H).

(210) MS: [M+H] 529

Part III: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 3

(211) ##STR00262##

Example 112: Synthesis of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(2-morpholinoethyl)benzenesulfonamide

(212) ##STR00263##

1. Synthesis of Intermediate 112.1

(213) ##STR00264##

N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-vinylbenzenesulfonamide

(214) Cesium carbonate (206.45 mg; 0.63 mmol), tert-butyl N-(2-oxiranylmethyl)carbamate (101.66 mg; 0.42 mmol) and water (0.40 ml) are added to a solution of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (100.0 mg; 0.21 mmol) in 1,4-dioxane (1.2 ml). The reaction medium is degassed under argon for 10 minutes, followed by addition of bis(tri-tert-butylphosphine)palladium(0) (10.79 mg; 0.02 mmol; 0.10 eq.). The reaction medium is stirred for 2 hours at 90 C., filtered through Celite and rinsed with ethyl acetate. The organic phase is washed with saturated sodium hydrogen carbonate solution and then with water, dried (MgSO.sub.4), filtered and concentrated to dryness. The crude product is purified by chromatography on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-vinylbenzenesulfonamide (70.0 mg; 79%) is obtained in the form of a colorless oil with a compliant .sup.1H NMR.

(215) MS: [M+H]=422

2. Synthesis of the Compound N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(2-morpholinoethyl)benzenesulfonamide

(216) A mixture of N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-vinylbenzenesulfonamide (70.0 mg; 0.17 mmol; 1.00 eq.) and morpholine (1.0 ml; 11.59 mmol) is stirred for 30 minutes at room temperature.

(217) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(4-ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-(2-morpholinoethyl)benzenesulfonamide (25.00 mg; 29.59%) is obtained in the form of an ocher-colored powder.

(218) .sup.1H NMR (DMSO-d6) : 1.10 (d, J=6.5 Hz, 6H), 1.43 (t, J=7.6 Hz, 3H), 1.69 (dt, J=13.4, 6.8 Hz, 1H), 2.71 (d, J=5.4 Hz, 2H), 2.83-2.90 (m, 2H), 3.36 (s, 8H), 3.84 (t, J=4.5 Hz, 3H), 4.79 (s, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.95 (s, 2H), 8.32 (s, 1H).

(219) MS: [M+H]=508

Part IV: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 4

(220) ##STR00265##

Example 113: Synthesis of N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

(221) ##STR00266##

1. Synthesis of Intermediate 113.1

(222) ##STR00267##

(2,4-dimethylphenyl)isobutylamine

(223) A solution of 2,4-dimethylaniline (30 ml; 0.24 mol) and of isobutyraldehyde (20 ml; 0.22 mol) in tetrahydrofuran (320 ml) is stirred for 30 minutes at room temperature, and sodium triacetoxyborohydride (70 g; 0.33 mol) is then added portionwise. The reaction medium is stirred for 3 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried (MgSO.sub.4).

(224) The solvents are evaporated off. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 10% of ethyl acetate).

(225) The (2,4-dimethylphenyl)isobutylamine (29.9 g; 77%) is obtained in the form of a yellow oil with a compliant NMR.

(226) MS: [M+H]=177

2. Synthesis of Intermediate 113.2

(227) ##STR00268##

4-bromobenzene-1,3-disulfonyl dichloride

(228) A mixture of 4-bromobenzenesulfonyl chloride (50 g; 0.20 mol) and of chlorosulfonic acid (260 ml; 3.91 mol) is stirred for 6 hours at 150 C. The reaction medium is poured slowly and cautiously onto a mixture of water and ice and is extracted with dichloromethane. The organic phases are combined, dried (MgSO.sub.4), filtered and concentrated. The 4-bromobenzene-1,3-disulfonyl dichloride (54 g; 78%) is obtained in the form of a grayish powder with a compliant NMR.

(229) MS: [M+H]=177

3. Synthesis of Intermediate 113.3

(230) ##STR00269##

2-bromo-5-[(2,4-dimethylphenyl)isobutylsulfamoyl]benzenesulfonyl chloride

(231) 4-Bromobenzene-1,3-disulfonyl dichloride (1.0 g; 2.82 mmol) dissolved in tetrahydrofuran (5 ml) is added to (2,4-dimethylphenyl)isobutylamine (0.50 g; 2.82 mmol) and pyridine (1.4 ml; 17.0 mmol) dissolved in tetrahydrofuran (20 ml). The reaction medium is stirred for 16 hours at room temperature. The reaction medium is hydrolyzed and then extracted with ethyl acetate. The organic phases are combined, washed with aqueous 1M hydrochloric acid solution and then with saturated NaCl solution, dried (Na.sub.2SO.sub.4) and concentrated.

(232) The 2-bromo-5-[(2,4-dimethylphenyl)isobutylsulfamoyl]benzenesulfonyl chloride (1.23 g; 88%) is obtained in the form of a yellow oil with a compliant NMR.

4. Synthesis of Intermediate 113.4

(233) ##STR00270##

4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanylbenzenesulfonamide

(234) 2-Bromo-5-[(2,4-dimethylphenyl)isobutylsulfamoyl]benzenesulfonyl chloride (1.67 g; 3.37 mmol) dissolved in toluene (8 ml) is added slowly to triphenylphosphine (2.66 g; 10.12 mmol) suspended in toluene (17 ml). The reaction medium is stirred for 4 hours at 90 C. The reaction medium is concentrated under vacuum and dissolved in N,N-dimethylformamide (14.5 ml) without purification, and potassium carbonate (0.51 g; 3.72 mmol) and iodomethane (0.32 ml; 5.08 mmol) are then added. The reaction medium is stirred for 20 minutes at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried (Na.sub.2SO.sub.4).

(235) The solvents are evaporated off. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 10% of ethyl acetate).

(236) The 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-methylsulfanylbenzenesulfonamide (775.30 mg; 52%) is obtained in the form of a white solid with a compliant NMR.

(237) MS: [MH]=441

5. Synthesis of Intermediate 113.5

(238) ##STR00271##

(E)-N-((2-bromo-5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)(methyl)-4-sulfanylidene)-2,2,2-trifluoroacetamide

(239) 4-Bromo-N-(2,4-dimethylphenyl)-N-isobutyl-3-methylsulfanylbenzenesulfonamide (755.0 mg; 1.71 mmol) and 2,2,2-trifluoroacetamide (289.34 mg; 2.56 mmol) dissolved in tetrahydrofuran (1.51 ml) are added slowly to 60% sodium hydride (61.43 mg; 1.54 mmol) suspended in tetrahydrofuran (3.78 ml) at 0-5 C. 1,3-Dibromo-5,5-dimethylhydantoin (732 mg; 2.56 mmol) dissolved in tetrahydrofuran (1.5 ml) is then added.

(240) The medium is stirred for 1 hour at room temperature, hydrolyzed by addition of saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic phases are combined and then washed with 25% sodium sulfite solution and then twice with saturated sodium chloride solution and dried (Na.sub.2SO.sub.4). The solvents are evaporated off.

(241) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 50% of ethyl acetate). The (E)-N-((2-bromo-5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)(methyl)-4-sulfanylidene)-2,2,2-trifluoroacetamide (233.0 mg; 25%) is obtained in the form of a white powder with a compliant 1H NMR.

(242) MS: [MH]=552

6. Synthesis of Intermediate 113.6

(243) ##STR00272##

4-bromo-N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide

(244) Potassium carbonate (172.30 mg; 1.25 mmol) is added to (E)-N-((2-bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)phenyl)(methyl)-4-sulfanylidene)-2,2,2-trifluoroacetamide (230.0 mg; 0.42 mmol) dissolved in methanol (2.3 ml), and 3-chloroperoxybenzoic acid (139.7 mg; 0.62 mmol) is then added slowly at 0 C. The reaction medium is stirred for 3 days at room temperature. The reaction medium is hydrolyzed and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried (Na.sub.2SO.sub.4). The solvents are evaporated off.

(245) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 80% of ethyl acetate). The 4-bromo-N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (70.8 mg; 36%) is obtained in the form of a white solid with a compliant NMR.

(246) MS: [M+H]=475

7. Synthesis of N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

(247) ##STR00273##

(248) 60% sodium hydride (8.74 mg; 0.22 mmol) is added slowly at a temperature of 0 C. to (tetrahydropyran-4-yl)methanol (18.62 mg; 0.16 mmol) dissolved in N,N-dimethylformamide (1.38 ml), followed by 4-bromo-N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzenesulfonamide (69.0 mg; 0.15 mmol). The reaction medium is stirred for 2 hours at room temperature and then for 1 hour at 80 C. The reaction medium is hydrolyzed without heating and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried (Na.sub.2SO.sub.4). The solvents are evaporated off.

(249) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The N-(2,4-dimethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (44.81 mg; 59.54%) is obtained in the form of a white solid.

(250) .sup.1H NMR (DMSO-d6) : 0.76 (dd, J=6.8, 3.2 Hz, 3H), 0.82-0.91 (m, 1H), 0.95 (t, J=6.7 Hz, 3H), 1.25 (q, J=3.6, 2.6 Hz, 1H), 1.40 (p, J=4.2 Hz, 2H), 1.43 (s, 1H), 1.75 (d, J=7.5 Hz, 1H), 2.23-2.32 (m, 6H), 3.06 (ddd, J=21.2, 13.1, 4.6 Hz, 1H), 3.20 (dd, J=2.7, 1.2 Hz, 3H), 3.35-3.44 (m, 2H), 3.87-3.95 (m, 2H), 4.12 (dd, J=6.3, 3.6 Hz, 2H), 4.45 (dd, J=50.6, 1.5 Hz, 1H), 6.58 (dd, J=16.3, 8.1 Hz, 1H), 6.94 (dd, J=8.1, 2.0 Hz, 1H), 7.13 (s, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.74 (td, J=8.6, 2.5 Hz, 1H), 8.05 (dd, J=4.9, 2.4 Hz, 1H)

(251) MS: [M+H]=509

Part V: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 5

(252) ##STR00274##

Example 114: Synthesis of N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

(253) ##STR00275##

1. Synthesis of Intermediate 114.1

(254) ##STR00276##

Isopropyl(4-methoxy-2-methylphenyl)amine

(255) Sodium triacetoxyborohydride (4.63 g; 21.9 mmol) is added to a solution of 4-methoxy-2-methylaniline (2.0 g; 14.6 mmol) in acetone (20 ml). The reaction medium is heated for 10 minutes at a temperature of 70 C. under microwave irradiation. The reaction medium is poured onto ice and extracted with dichloromethane. The organic phases are combined, washed with saturated sodium chloride solution, dried (MgSO.sub.4), filtered and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 15% of ethyl acetate). The isopropyl(4-methoxy-2-methylphenyl)amine (1.43 g; 55%) is obtained in the form of a yellow oil with a compliant NMR.

(256) MS: [M+H]=180

2. Synthesis of Intermediate 114.2

(257) ##STR00277##

4-bromo-N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-methylsulfanylbenzenesulfonamide

(258) 4-Bromo-3-(methylthio)benzene-1-sulfonyl chloride (500 mg; 1.57 mmol) is added to isopropyl(4-methoxy-2-methylphenyl)amine (290 mg; 1.62 mmol) and pyridine (2.4 ml). The reaction medium is heated for 20 minutes at a temperature of 100 C. under microwave irradiation, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with 1N hydrochloric acid solution and then with saturated sodium chloride solution and dried (MgSO.sub.4). The solvents are evaporated off.

(259) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 4-bromo-N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-methylsulfanylbenzenesulfonamide (570 mg; 81%) is obtained in the form of a yellow oil with a compliant NMR.

(260) MS: [M+H]=444

3. Synthesis of Intermediate 114.3

(261) ##STR00278##

(E)-N-((2-bromo-5-(N-isopropyl-N-(4-methoxy-2-methylphenyl)sulfamoyl)phenyl)(methyl)-4-sulfanylidene)-2,2,2-trifluoroacetamide

(262) 4-Bromo-N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-methylsulfanylbenzenesulfonamide (565 mg; 1.27 mmol) and 2,2,2-trifluoroacetamide (215.6 mg; 1.91 mmol) dissolved in tetrahydrofuran (1.1 ml) are added slowly to 60% sodium hydride (45.8 mg; 1.14 mmol) suspended in tetrahydrofuran (2.8 ml) at 0-5 C., followed by addition of the solution of 1,3-dibromo-5,5-dimethylhydantoin (545.3 mg; 1.91 mmol) in tetrahydrofuran (1.13 ml). The medium is stirred for 2 hours at room temperature, hydrolyzed by addition of 10% citric acid solution and then extracted with ethyl acetate. The organic phases are combined, then washed with 25% sodium sulfite solution and then twice with saturated sodium chloride solution and dried (Na.sub.2SO.sub.4). The solvents are evaporated off.

(263) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The (E)-N-((2-bromo-5-(N-isopropyl-N-(4-methoxy-2-methylphenyl)sulfamoyl)phenyl)(methyl)-.sup.4-sulfanylidene)-2,2,2-trifluoroacetamide (706 mg; 100%) is obtained in the form of a colorless oil with a compliant NMR.

(264) MS: [MH]=557

4. Synthesis of Intermediate 114.4

(265) ##STR00279##

4-bromo-N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)benzenesulfonamide

(266) Potassium carbonate (549 mg; 3.97 mmol) is added to (E)-N-((2-bromo-5-(N-isopropyl-N-(4-methoxy-2-methylphenyl)sulfamoyl)phenyl)(methyl)-.sup.4-sulfanylidene)-2,2,2-trifluoroacetamide (735 mg; 1.32 mmol) dissolved in methanol (7.4 ml), and 3-chloroperoxybenzoic acid (445 mg; 1.98 mmol) is then added slowly at 0 C. The reaction medium is stirred for 2 hours at room temperature, hydrolyzed and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried (MgSO.sub.4). The solvents are evaporated off.

(267) The crude product is chromatographed on silica gel (heptane/ethyl acetate, from 40 to 80% of ethyl acetate). The 4-bromo-N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)benzenesulfonamide (211.6 mg; 34%) is obtained in the form of a white solid with a compliant NMR.

(268) MS: [M+H]=477

5. Synthesis of N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

(269) 60% sodium hydride (12.6 mg; 0.32 mmol) is added slowly at 0 C. to (tetrahydropyran-4-yl)methanol (26.8 mg; 0.23 mmol) dissolved in N,N-dimethylformamide (2 ml), followed by 4-bromo-N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)benzenesulfonamide (100 mg; 0.21 mmol). The reaction medium is stirred for 1 hour at room temperature and for 90 minutes at a temperature of 60 C., and then hydrolyzed and extracted with ethyl acetate. The organic phases are combined and then washed with saturated sodium chloride solution and dried (Na.sub.2SO.sub.4). The solvents are evaporated off.

(270) The product is chromatographed on silica gel (eluent: dichloromethane/methanol from 0 to 10% of methanol).

(271) The N-isopropyl-N-(4-methoxy-2-methylphenyl)-3-(S-methylsulfonimidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (76.2 mg; 71%) is obtained in the form of a white solid.

(272) .sup.1H NMR (DMSO-d6) : 0.79-0.93 (m, 4H), 0.98 (dd, J=6.8, 2.1 Hz, 3H), 1.26 (dd, J=10.8, 4.6 Hz, 2H), 1.41 (tdd, J=12.3, 7.6, 4.4 Hz, 2H), 1.75 (t, J=11.7 Hz, 2H), 2.10 (d, J=8.7 Hz, 1H), 2.25 (d, J=8.3 Hz, 3H), 3.19 (d, J=1.2 Hz, 3H), 3.33-3.43 (m, 2H), 3.82-3.99 (m, 2H), 4.02-4.19 (m, 2H), 4.34-4.55 (m, 2H), 6.57-6.76 (m, 2H), 6.92 (t, J=2.2 Hz, 1H), 7.41 (dd, J=8.8, 2.9 Hz, 1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 8.14 (t, J=2.7 Hz, 1H)

(273) MS: [M+H]=511

Part VI: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 6

(274) ##STR00280##

Example 116: Synthesis of N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide

(275) ##STR00281##

1. Synthesis of Intermediate 116.1

(276) ##STR00282##

N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide

(277) 4-Fluorobenzenesulfonyl chloride (2.78 g; 14.27 mmol) is added to the (4-ethylphenyl)isobutylamine (2.3 g; 12.28 mmol) and diisopropylamine (5.5 ml; 67.69 mmol) dissolved in tetrahydrofuran (25 ml). The reaction medium is stirred for 16 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated ammonium chloride solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(278) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 10% of ethyl acetate). The N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (2.09 g; 48%) is obtained in the form of an orange-yellow solid with a compliant .sup.1H NMR.

(279) MS: [M+H]=336

2. Synthesis of Intermediate 116.2

(280) ##STR00283##

Bis[4-[(4-ethylphenyl)isobutylsulfamoyl]thiobenzene] disulfide

(281) A mixture of N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (1.0 g; 2.98 mmol) and sodium hydrogen sulfide (2.1 g; 37.26 mmol) in 1-methyl-2-pyrrolidinone (4 ml) is stirred for 2 hours at 80 C. and then for 16 hours at room temperature. The reaction medium is diluted with ethyl acetate and acidified by addition of concentrated HCl and then extracted. The organic phases are combined, washed with water, dried (MgSO.sub.4), filtered and concentrated to dryness. The bis[4-[(4-ethylphenyl)isobutylsulfamoyl]thiobenzene] disulfide (1.04 g; 50%) obtained is used directly in the next reaction.

(282) MS: [M+H]=698

3. Synthesis of N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide

(283) Potassium carbonate (0.41 g; 2.96 mmol) is added to a solution of bis[4-[(4-ethylphenyl)isobutylsulfamoyl]thiobenzene] disulfide (1.03 g; 1.48 mmol) in N,N-dimethylformamide (15 ml). The reaction medium is stirred for 5 minutes, followed by addition of 4-(bromomethyl)tetrahydropyran (0.53 g; 2.96 mmol) and then sodium formaldehyde sulfoxylate (0.60 g; 4.44 mmol) and water (20 l; 1.10 mmol). The reaction medium is stirred for 1 hour at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (MgSO.sub.4), filtered and concentrated. The crude product is chromatographed on silica gel, eluting with heptane/ethyl acetate, from 5 to 30% of ethyl acetate. The N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide (1.10 g; 83%) is obtained in the form of a solid.

(284) .sup.1H NMR (400 MHz, DMSO-d6) 7.55-7.34 (m, 4H), 7.23-7.15 (m, 2H), 7.02-6.93 (m, 2H), 3.90-3.81 (m, 2H), 3.30-3.21 (m, 3H), 3.02 (d, J=6.6 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 1.79-1.68 (m, 2H), 1.48-1.36 (m, 1H), 1.36-1.22 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.84 (d, J=6.7 Hz, 6H).

(285) MS: [M+H]=448

Example 117: Synthesis of N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfinyl)benzenesulfonamide

(286) ##STR00284##

(287) 3-Chloroperbenzoic acid (414 mg; 1.85 mmol) is added portionwise to a solution of N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide (787 mg; 1.76 mmol) in dichloromethane (20 ml) at 0 C.

(288) The medium is stirred for 3 hours 30 minutes. At 0 C., 13 ml of 1N sodium hydroxide solution are added dropwise, followed by addition of 13 ml of water. The reaction medium is extracted with dichloromethane. The organic phases are washed with aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered and concentrated. The oil obtained is precipitated from dichloromethane and heptane. The solid is filtered off, rinsed with heptane and dried. The N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfinyl)benzenesulfonamide (755 mg; 88%) is obtained in the form of a white solid.

(289) 1H NMR (400 MHz, DMSO-d6) 0.86 (d, J=6.6 Hz, 7H), 1.18 (t, J=7.6 Hz, 3H), 1.51-1.24 (m, 3H), 1.55 (d, J=13.3 Hz, 1H), 1.83 (d, J=13.0 Hz, 1H), 2.16-1.98 (m, 1H), 2.60 (q, J=7.6 Hz, 2H), 2.81 (dd, J=13.1, 5.0 Hz, 1H), 2.93 (dd, J=13.2, 8.6 Hz, 1H), 3.38-3.28 (m, 4H), 3.95-3.70 (m, 2H), 7.08-6.85 (m, 2H), 7.27-7.14 (m, 2H), 7.80-7.66 (m, 2H), 7.95-7.81 (m, 2H),

(290) MS: [M+H]=464

(291) The compound N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfinyl)benzenesulfonamide (450 mg; 1.11 mmol) is chromatographed by chiral SFC to separate the two enantiomers (compound 13 and compound 14) below:

(292) [Supercritical conditions: 100 bar, 70 C.; Chiralpak IC 2504.6 mm 5 column, eluent: CO.sub.2/ethanol: 30 g of ethanol]

Example 118: N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfoximine (Compound 13)Enantiomer A of Compound 29

(293) (150 mg; 22%) in the form of a white crystalline solid

(294) .sup.1H NMR (400 MHz, DMSO-d6) 7.91-7.84 (m, 2H), 7.76-7.69 (m, 2H), 7.20 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.3 Hz, 2H), 3.84 (dd, J=22.1, 12.3 Hz, 2H), 3.45-3.17 (m, 4H), 2.93 (dd, J=13.2, 8.6 Hz, 1H), 2.81 (dd, J=13.1, 5.0 Hz, 1H), 2.66-2.48 (m, 2H), 2.08 (dddd, J=19.9, 12.3, 8.7, 4.1 Hz, 1H), 1.89-1.79 (m, 1H), 1.60-1.25 (m, 4H), 1.18 (t, J=7.6 Hz, 3H), 0.86 (d, J=6.7 Hz, 6H).

(295) Retention time (chiral SFC) of 6.92 minutes

Example 119: N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfonamide (Compound 14)Enantiomer B of Compound 29

(296) (120 mg; 18%) in the form of a white solid

(297) .sup.1H NMR (400 MHz, DMSO-d6) 7.92-7.80 (m, 2H), 7.80-7.64 (m, 2H), 7.28-7.11 (m, 2H), 7.04-6.92 (m, 2H), 3.85 (ddd, J=21.3, 10.9, 4.2 Hz, 2H), 3.47-3.18 (m, 4H), 2.93 (dd, J=13.2, 8.6 Hz, 1H), 2.81 (dd, J=13.1, 5.0 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 2.08 (dtt, J=19.8, 8.2, 4.1 Hz, 1H), 1.94-1.72 (m, 1H), 1.64-1.24 (m, 4H), 1.18 (t, J=7.6 Hz, 3H), 0.86 (d, J=6.7 Hz, 6H).

(298) Retention time (chiral SFC) of 9.31 minutes

Example 120: Synthesis of N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfoximinyl)benzenesulfonamide

(299) ##STR00285##

(300) 2,2,2-Trifluoroacetamide (121 mg; 1.07 mmol), magnesium oxide (87 mg; 2.15 mmol), rhodium(II) acetate dimer (28 mg; 0.06 mmol) and iodobenzene diacetate (263 mg; 0.82 mmol) are added to a solution, degassed beforehand with argon, of N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfonamide (199 mg; 0.43 mmol) in dichloromethane (7 ml). The reaction medium is stirred at room temperature for 20 hours, filtered through Celite and concentrated. The residue obtained is diluted in methanol (7 ml), and potassium carbonate (297 mg; 2.15 mmol) is added.

(301) The medium is stirred for 30 minutes at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(302) The crude product is chromatographed on silica gel (eluent: 10/90 heptane/ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfoximinyl)benzenesulfonamide (87 mg; 41%) is obtained in the form of a cream-colored solid.

(303) .sup.1H NMR (400 MHz, DMSO-d6) 0.86 (dd, J=6.8, 1.9 Hz, 6H), 1.35-1.06 (m, 5H), 1.44 (dt, J=13.5, 6.9 Hz, 1H), 1.77-1.50 (m, 2H), 2.06 (t, J=9.2 Hz, 1H), 2.61 (d, J=7.6 Hz, 2H), 3.29-3.16 (m, 3H), 3.37 (d, J=7.2 Hz, 2H), 3.76 (dt, J=11.7, 3.1 Hz, 2H), 4.55 (s, 1H), 7.07-6.84 (m, 2H), 7.19 (dd, J=8.6, 2.0 Hz, 2H), 7.89-7.62 (m, 2H), 8.09 (dd, J=8.4, 2.0 Hz, 2H).

(304) MS: [M+H]=479

Part VII: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 7

(305) ##STR00286## ##STR00287##

Example 121: Synthesis of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoate

(306) ##STR00288##

1. Synthesis of Intermediate 121.1

(307) ##STR00289##

methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoate

(308) Methyl 5-chlorosulfonyl-2-fluorobenzoate (720 mg; 2.85 mmol) is added to (4-ethylphenyl)isobutylamine (0.95 g; 4.27 mmol) and pyridine (1.38 ml; 0.02 mol; 6.00 eq.) dissolved in tetrahydrofuran (16 ml). The reaction medium is stirred at room temperature for 16 hours, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(309) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 5 to 20% of ethyl acetate). The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoate (800 mg; 71%) is obtained in the form of a beige-colored solid with a compliant .sup.1H NMR.

(310) MS: [M+H]=394

2. Synthesis of Intermediate 121.2

(311) ##STR00290##

Bis[(tetrahydropyran-4-yl)methane bisulfide

(312) A mixture of 4-(bromomethyl)tetrahydropyran (1.0 g; 5.58 mmol) and sodium hydrogen sulfide (0.44 g; 7.82 mmol) in dimethylformamide (4 ml) is stirred at room temperature for 2 hours. The reaction medium is diluted with ether and acidified by addition of concentrated HCl and then extracted. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness. The bis[(tetrahydropyran-4-yl)methane bisulfide (565.00 mg; 77%) obtained in the form of a clear oil is used directly in the next reaction.

(313) MS: [M+H]=263

3. Synthesis of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoate

(314) ##STR00291##

(315) Potassium carbonate (81 mg; 0.59 mmol) is added to methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoate (200 mg; 0.51 mmol) and bis(tetrahydropyran-4-yl)methane bisulfide (133.39 mg; 0.51 mmol; 1.00 eq.) in acetonitrile (2 ml). The reaction medium is stirred at room temperature for 16 hours, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried and concentrated.

(316) The crude product is chromatographed on silica gel, eluting with heptane/ethyl acetate: 5 to 20% of ethyl acetate. The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoate (214 mg; 83%) is obtained in the form of a white solid.

(317) 1H NMR (400 MHz, DMSO-d6) 0.85 (d, J=6.6 Hz, 7H), 1.18 (t, J=7.6 Hz, 3H), 1.37 (dtd, J=36.3, 12.9, 12.1, 7.3 Hz, 3H), 1.91-1.70 (m, 4H), 2.61 (q, J=7.6 Hz, 2H), 2.98 (d, J=6.7 Hz, 2H), 3.35-3.24 (m, 4H), 3.91-3.80 (m, 5H), 7.05-6.98 (m, 2H), 7.23-7.17 (m, 2H), 7.66-7.59 (m, 2H), 7.89 (d, J=1.9 Hz, 1H).

(318) MS: [M+H]=506

Example 122: Synthesis of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethanesulfinyl)benzoate

(319) ##STR00292##

(320) 3-Chloroperbenzoic acid (70 mg; 0.31 mmol) is added to a solution of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoate (150 mg; 0.30 mmol) in dichloromethane (5 ml) at a temperature of 0 C. The reaction medium is stirred for 2 hours. At 0 C., 1N sodium hydroxide is added dropwise, followed by addition of water, and the reaction medium is then extracted with dichloromethane.

(321) The organic phases are washed with aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered and evaporated.

(322) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 10 to 30% of ethyl). The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethanesulfinyl)benzoate (140 mg; 90%) is obtained in the form of a white solid.

(323) 1H NMR (400 MHz, DMSO-d6) 0.86 (dd, J=6.7, 4.0 Hz, 6H), 1.19 (t, J=7.6 Hz, 3H), 1.67-1.23 (m, 3H), 1.97 (dd, J=16.3, 5.1 Hz, 1H), 2.66-2.55 (m, 3H), 2.22 (s, 1H), 3.09 (dd, J=12.8, 9.7 Hz, 1H), 3.44-3.31 (m, 4H), 3.89 (s, 5H), 7.07-6.97 (m, 2H), 7.22 (d, J=8.3 Hz, 2H), 8.02 (d, J=1.9 Hz, 1H), 8.08 (dd, J=8.3, 2.0 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H).

(324) MS: [M+H]=522

Example 123: Synthesis of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoic Acid

(325) ##STR00293##

(326) A mixture of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethanesulfanyl)tetrahydropyran-4-ylbenzoate (277 mg; 0.47 mmol) and lithium hydroxide (0.70 ml; 1.00 M; 0.70 mmol) in tetrahydrofuran (6.93 ml) is stirred at a temperature of 60 C. for 24 hours. The reaction medium is hydrolyzed with 1N sodium hydroxide and extracted with ethyl acetate. The organic phases are combined and washed with 1N sodium hydroxide.

(327) The aqueous phases are combined, acidified with HCl and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over magnesium sulfate, filtered and concentrated.

(328) The crude product is chromatographed on silica gel, eluting with heptane/ethyl acetate+1% AcOH, 10 to 50% of ethyl acetate. The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoic acid (87.00 mg; 36%) is obtained in the form of a solid after crystallization from a mixture of methanol and dichloromethane.

(329) 1H NMR (400 MHz, DMSO-d6) 0.85 (d, J=6.6 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.50-1.24 (m, 3H), 1.89-1.67 (m, 3H), 2.66-2.55 (m, 2H), 2.94 (d, J=6.6 Hz, 2H), 3.30 (d, J=7.1 Hz, 3H), 4.03-3.71 (m, 2H), 7.04-6.97 (m, 2H), 7.25-7.16 (m, 2H), 7.59 (s, 2H), 8.10-7.74 (m, 1H), 13.46 (s, 1H).

(330) MS: [M+H]=492

Example 124: Synthesis of N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide

(331) ##STR00294##

(332) Lithium borohydride (9 mg; 0.40 mmol) is added to methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-(tetrahydropyran-4-ylmethylsulfanyl)benzoate (113 mg; 0.22 mmol) in tetrahydrofuran (3 ml). The reaction medium is stirred at room temperature for 16 hours, hydrolyzed with 5% citric acid for 1 hour and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated.

(333) The crude product is chromatographed on silica gel (eluent: 80/20 heptane/ethyl acetate). The N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide (106 mg; 96%) is obtained in the form of a white solid.

(334) .sup.1H NMR (Chloroform-d) : 0.84 (d, J=6.7 Hz, 6H), 1.16 (t, J=7.6 Hz, 3H), 1.35 (qd, J=13.1, 12.4, 3.6 Hz, 2H), 1.50 (hept, J=6.7 Hz, 1H), 1.73 (d, J=12.3 Hz, 1H), 2.51-2.62 (m, 2H), 2.64 (d, J=1.7 Hz, 2H), 2.87 (d, J=6.5 Hz, 2H), 3.22 (d, J=7.4 Hz, 2H), 3.31 (td, J=11.8, 1.9 Hz, 2H), 3.92 (ddd, J=12.5, 4.6, 1.5 Hz, 2H), 4.65 (s, 2H), 6.87-6.94 (m, 2H), 7.06 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.2 Hz, 1H), 7.33 (dd, J=8.3, 2.2 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H)

(335) MS: [M+H]=478

Example 125: Synthesis of N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfonamide

(336) ##STR00295##

(337) 3-Chloroperoxybenzoic acid (302.47 mg; 1.35 mmol) is added to a solution of N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethylsulfanyl)benzenesulfonamide (614.00 mg; 1.29 mmol) in dichloromethane (20.00 ml). The medium is stirred at room temperature for 4 hours. At a temperature of 0 C., the reaction medium is added to water and extracted with ethyl acetate. The organic phases are washed with brine, dried over magnesium sulfate, filtered and evaporated.

(338) The crude product is chromatographed on silica gel, eluting with heptane/ethyl acetate, from 50 to 100% of ethyl acetate). The N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfonamide (455 mg; 71%) is obtained in the form of a white solid.

(339) .sup.1H NMR (DMSO-d.sub.6) 0.84 (d, J=6.7 Hz, 6H), 1.16 (t, J=7.6 Hz, 3H), 1.19-1.50 (m, 3H), 1.47-1.63 (m, 1H), 1.86 (ddd, J=13.1, 3.9, 2.1 Hz, 1H), 2.12 (dq, J=15.5, 5.7, 4.0 Hz, 2H), 2.55-2.69 (m, 3H), 2.94 (dd, J=13.2, 9.4 Hz, 1H), 3.33 (d, J=3.1 Hz, 3H), 3.74-3.95 (m, 2H), 4.60 (dd, J=5.3, 3.3 Hz, 2H), 5.65 (dd, J=5.9, 4.8 Hz, 1H), 6.86-7.07 (m, 2H), 7.10-7.30 (m, 2H), 7.57-7.76 (m, 2H), 8.01 (d, J=8.1 Hz, 1H).

(340) MS: [M+H]=494

(341) Compound 15 (377 mg; 0.76 mmol) is chromatographed by chiral SFC to separate the two enantiomers below

(342) [Supercritical conditions: 100 bar, 70 C.; Chiralpak IC 2504.6 mm 5 column, eluent: CO.sub.2/methanol: 45% of methanol]

Example 126: N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfonamide (Compound 11)Enantiomer A of Compound 15

(343) (146 mg; 39%) in the form of a white solid

(344) .sup.1H NMR (400 MHz, DMSO-d6) 8.01 (d, J=8.1 Hz, 1H), 7.76-7.57 (m, 2H), 7.30-7.10 (m, 2H), 7.07-6.86 (m, 2H), 5.65 (dd, J=5.9, 4.8 Hz, 1H), 4.60 (dd, J=5.3, 3.3 Hz, 2H), 3.95-3.74 (m, 1H), 3.33 (d, J=3.1 Hz, 2H), 2.94 (dd, J=13.2, 9.4 Hz, 1H), 2.69-2.55 (m, 2H), 2.12 (dq, J=15.5, 5.7, 4.0 Hz, 1H), 1.86 (ddd, J=13.1, 3.9, 2.1 Hz, 1H), 1.63-1.47 (m, 1H), 1.50-1.19 (m, 2H), 1.16 (t, J=7.6 Hz, 3H), 0.84 (d, J=6.7 Hz, 6H).

(345) Retention time (chiral SFC) of 2.49 minutes

Example 127: N-(4-ethylphenyl)-3-hydroxymethyl-N-isobutyl-4-(tetrahydropyran-4-ylmethanesulfinyl)benzenesulfonamide (Compound 12)Enantiomer B of Compound 15 (134 mg; 36%) in the Form of a White Solid

(346) .sup.1H NMR (400 MHz, DMSO-d6) 8.01 (d, J=8.1 Hz, 1H), 7.76-7.57 (m, 2H), 7.30-7.10 (m, 2H), 7.07-6.86 (m, 2H), 5.65 (dd, J=5.9, 4.8 Hz, 1H), 4.60 (dd, J=5.3, 3.3 Hz, 2H), 3.95-3.74 (m, 1H), 3.33 (d, J=3.1 Hz, 2H), 2.94 (dd, J=13.2, 9.4 Hz, 1H), 2.69-2.55 (m, 2H), 2.12 (dq, J=15.5, 5.7, 4.0 Hz, 1H), 1.86 (ddd, J=13.1, 3.9, 2.1 Hz, 1H), 1.63-1.47 (m, 1H), 1.50-1.19 (m, 2H), 1.16 (t, J=7.6 Hz, 3H), 0.84 (d, J=6.7 Hz, 6H).

(347) Retention time (chiral SFC) of 2.92 minutes

Part VIII: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 8

(348) ##STR00296##

Example 128: Synthesis of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(349) ##STR00297##

1. Synthesis of Intermediate 128.1

(350) ##STR00298##

3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride

(351) 4H-Benzo[1,4]thiazin-3-one (4.0 g; 24.21 mmol) is added slowly to chlorosulfonic acid (6.5 ml; 96.84 mmol) cooled to 10 C. The temperature is maintained below 20 C. The reaction medium is stirred at room temperature for 1 hour and then heated to a temperature of 65 C., poured slowly onto ice and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over sodium sulfate and concentrated. The residue is taken up in ether and suction-filtered.

(352) The 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride (4.88 g; 76%) is obtained in the form of an ocher-colored powder.

(353) MS: [M+H]=262

2. Synthesis of Compound 10 According to the Invention

(354) ##STR00299##

(355) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride (3.27 g; 12.41 mmol) is added to (4-ethylphenyl)isobutylamine (2 g; 11.28 mmol) and pyridine (40 ml; 495.56 mmol) dissolved in tetrahydrofuran (5.4 ml). The reaction medium is stirred at room temperature for 2 hours, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with 1N hydrochloric acid solution, with brine, dried over sodium sulfate and concentrated.

(356) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 50% of ethyl acetate). The 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (2.53 g; 55%) is obtained in the form of a yellow solid.

(357) .sup.1H NMR (Chloroform-d) : 0.93 (d, J=6.7 Hz, 7H), 1.25 (td, J=7.6, 4.3 Hz, 4H), 1.53-1.67 (m, 2H), 2.67 (q, J=7.6 Hz, 2H), 3.32 (d, J=7.4 Hz, 2H), 3.50 (s, 2H), 6.94-7.04 (m, 2H), 7.07 (d, J=1.9 Hz, 1H), 7.12-7.20 (m, 2H), 7.22 (dd, J=8.2, 1.8 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 8.28 (s, 1H).

(358) MS: [M+H]=405

Example 129: Synthesis of 3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(359) ##STR00300##

(360) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 1.28 mmol) is dissolved in the 1M borane-tetrahydrofuran complex with 5 mmol NaBH.sub.4 (35 ml). The reaction medium is refluxed for 30 minutes and then cooled to a temperature of 0 C. and poured slowly into methanol (35 ml).

(361) The solvents are concentrated and the residue is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate).

(362) The 3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (437 mg; 86%) is obtained in the form of a white crystalline solid after recrystallization from an ethyl acetate/heptane mixture.

(363) .sup.1H NMR (DMSO-d6) : 0.82 (d, J=6.7 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.31-1.47 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 2.97-3.05 (m, 2H), 3.25 (d, J=7.3 Hz, 2H), 3.48 (dt, J=7.0, 3.0 Hz, 2H), 6.48-6.56 (m, 2H), 6.75 (d, J=2.0 Hz, 1H), 6.95-7.04 (m, 3H), 7.14-7.21 (m, 2H).

(364) MS: [M+H]=391

Example 130: Synthesis of 4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(365) ##STR00301##

(366) Sodium triacetoxyborohydride (33 mg; 0.15 mmol) is added at a temperature of 0 C. to 3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (20 mg; 0.05 mmol), 4-formyltetrahydropyran (29 mg; 0.26 mmol) and acetic acid (0.15 l) dissolved in 1,2-dichloroethane. The reaction medium is stirred at room temperature for a period of 24 hours, water is added and the resulting mixture is extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over sodium sulfate and concentrated.

(367) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 50% of ethyl acetate). The 4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (15 mg; 59%) is obtained in the form of a beige-colored solid.

(368) 1H NMR (DMSO-d6) : 0.84 (d, J=6.6 Hz, 7H), 1.06-1.27 (m, 6H), 1.40-1.48 (m, 3H), 1.68-1.79 (m, 1H), 2.55-2.66 (m, 2H), 3.01 (d, J=6.9 Hz, 2H), 3.08 (t, J=4.8 Hz, 2H), 3.19 (t, J=11.5 Hz, 2H), 3.26 (d, J=7.3 Hz, 2H), 3.62 (t, J=4.8 Hz, 2H), 3.82 (dd, J=11.0, 4.2 Hz, 2H), 6.54 (s, 1H), 6.71 (d, J=7.9 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.21 (d, J=7.9 Hz, 2H).

(369) MS: [M+H]=489

Example 131: Synthesis of 1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-14-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(370) ##STR00302##

(371) 3-Chloroperbenzoic acid (124 mg; 0.55 mmol) is added, at a temperature of 0 C., to 4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (300 mg; 0.61 mmol) dissolved in dichloromethane (6 ml). The reaction medium is stirred at room temperature for 30 minutes, hydrolyzed with aqueous 10% Na.sub.2S.sub.2O.sub.3 solution and extracted with dichloromethane. The organic phases are combined, washed with 0.1N sodium hydroxide solution, with brine, dried over sodium sulfate and concentrated.

(372) The crude product is chromatographed on silica gel (eluent: dichloromethane/methanol, from 0 to 10% of methanol). The 1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.4-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (274 mg; 88%) is obtained in the form of a white solid by crystallization from a water/acetone mixture.

(373) 1H NMR (DMSO-d6) : 0.85 (dd, J=6.6, 1.3 Hz, 6H), 1.12-1.28 (m, 5H), 1.44 (dt, J=12.8, 9.6 Hz, 3H), 1.71-1.88 (m, 1H), 2.61 (q, J=7.6 Hz, 2H), 2.85 (td, J=13.6, 3.4 Hz, 1H), 3.09-3.36 (m, 12H), 3.64 (dt, J=14.0, 3.8 Hz, 1H), 3.78-3.90 (m, 3H), 6.81 (d, J=7.3 Hz, 2H), 7.01-7.08 (m, 2H), 7.19-7.26 (m, 2H), 7.70 (d, J=8.2 Hz, 1H).

(374) MS: [M+H]=505

Example 132: Synthesis of 1-imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-16-benzo[1,4]thiazine-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(375) ##STR00303##

(376) 2,2,2-Trifluoroacetamide (109 mg; 0.97 mmol), rhodium(II) acetate (26 mg; 0.06 mmol), magnesium oxide (78 mg; 1.93 mmol) and iodobenzene diacetate (249 mg; 0.77 mmol) are added to a solution, degassed beforehand with argon, of 1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.4-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (195.00 mg; 0.39 mmol) in dichloromethane (10 ml). The reaction medium is stirred at room temperature for 16 hours, filtered through Celite and concentrated. The residue obtained is diluted in methanol (10 ml), and potassium carbonate (267 mg; 1.93 mmol) is added.

(377) The reaction medium is stirred for 30 minutes and then hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvents are evaporated off. The crude product is chromatographed on silica gel (eluent: dichloromethane/methanol, from 0 to 5% of methanol).

(378) The 1-imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.6-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (44.50 mg; 21.97%) is obtained in the form of a white solid.

(379) 1H NMR (DMSO-d6) : 0.86 (t, J=4.9 Hz, 8H), 1.09-1.33 (m, 9H), 1.36-1.49 (m, 3H), 1.75 (qd, J=8.6, 7.9, 4.2 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.17 (dd, J=15.8, 9.0 Hz, 4H), 3.34-3.46 (m, 3H), 3.85 (ddd, J=23.1, 9.5, 4.1 Hz, 4H), 4.74 (s, 1H), 6.68 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 7.05 (d, J=8.2 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 7.84 (d, J=8.1 Hz, 1H).

(380) MS: [M+H]=519

Example 133: Synthesis of 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(381) ##STR00304##

(382) 4-(Bromomethyl)tetrahydropyran (18 mg; 0.10 mmol) is added to 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (20 mg; 0.05 mmol) and cesium carbonate (24 mg; 0.07 mmol) dissolved in 1-methyl-2-pyrrolidone (0.4 ml).

(383) The reaction medium is heated at 80 C. for 24 hours, hydrolyzed and then extracted with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate.

(384) The solvents are evaporated off and the crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 50% of ethyl acetate).

(385) The 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (10.4 mg; 40%) is obtained in the form of a beige-colored solid.

(386) .sup.1H NMR (DMSO-d6) : 0.85 (d, J=6.8 Hz, 7H), 1.17 (t, J=7.6 Hz, 3H), 1.25 (d, J=6.5 Hz, 2H), 1.37-1.67 (m, 10H), 1.68-1.77 (m, 5H), 2.44 (dt, J=11.1, 4.0 Hz, 10H), 2.60 (q, J=7.6 Hz, 2H), 3.17 (s, 1H), 3.33-3.38 (m, 5H), 3.80 (dt, J=11.3, 3.7 Hz, 7H), 3.92 (s, 1H), 7.02 (d, J=7.8 Hz, 2H), 7.18 (dd, J=18.5, 8.4 Hz, 3H), 7.42 (d, J=8.4 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 12.17 (s, 2H)

(387) MS: [M+H]=503

Example 134: Synthesis of 1,3-dioxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-14-benzo[1,4]thiazine-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(388) ##STR00305##

(389) 3-Chloroperbenzoic acid (161 mg; 0.72 mmol) is added, at 0 C., to 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (400 mg; 0.80 mmol) dissolved in dichloromethane (8 ml).

(390) The reaction medium is stirred at room temperature for 1 hour, hydrolyzed with aqueous 10% Na.sub.2S.sub.2O.sub.3 solution and extracted with dichloromethane. The organic phases are combined, washed with 0.1N sodium hydroxide solution and then with brine, and dried over sodium sulfate. The solvents are concentrated and the crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 80% of ethyl acetate). The 1,3-dioxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.4-benzo[1,4]thiazine-6-sulfonic acid (4-ethylphenyl)isobutylamide (358 mg; 87%) is obtained in the form of a white solid.

(391) 1H NMR (DMSO-d6) : 0.87 (d, J=6.6 Hz, 6H), 1.01-1.23 (m, 5H), 1.37-1.53 (m, 3H), 1.62-1.83 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 3.05-3.22 (m, 2H), 3.33-3.49 (m, 2H), 3.72-3.89 (m, 3H), 4.04 (dd, J=14.8, 8.5 Hz, 1H), 4.29-4.39 (m, 2H), 7.01-7.08 (m, 2H), 7.21-7.28 (m, 2H), 7.43 (dd, J=7.8, 1.5 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 8.08 (d, J=7.8 Hz, 1H).

(392) MS: [M+H]=519

Part IX: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 9

(393) ##STR00306##

Example 135: Synthesis of 1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-14-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(394) ##STR00307##

1. Synthesis of Intermediate 135.1

(395) ##STR00308##

3-bromo-N-(4-ethylphenyl)-N-isobutyl-4-methoxybenzenesulfonamide

(396) 3-Fluoro-4-nitrobenzenesulfonyl chloride (5.57 g; 22.56 mmol) is added to a solution of (4-ethylphenyl)isobutylamine (4.0 g; 22.56 mmol) and pyridine (11 ml; 135.37 mmol) in tetrahydrofuran (80 ml). The reaction medium is stirred for 16 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated NH.sub.4Cl solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(397) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 10% of ethyl acetate). The 3-bromo-N-(4-ethylphenyl)-N-isobutyl-4-methoxybenzenesulfonamide (7.02 g; 82%) is obtained in the form of a flaky white solid with a compliant .sup.1H NMR.

(398) MS: [M+H]=381

2. Synthesis of Intermediate 135.2

(399) ##STR00309##

ethyl {5-[(4-ethylphenyl)isobutylsulfamoyl]-2-nitrophenylsulfanyl}acetate

(400) Ethyl thioglycolate (0.86 ml; 7.89 mmol) is added slowly to a solution of N-(4-ethylphenyl)-3-fluoro-N-isobutyl-4-nitrobenzenesulfonamide (3.0 g; 7.89 mmol) and triethylamine (1.31 ml; 9.46 mmol) in tetrahydrofuran (75 ml). The reaction medium is stirred for 16 hours at room temperature.

(401) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 30% of ethyl acetate).

(402) The ethyl {5-[(4-ethylphenyl)isobutylsulfamoyl]-2-nitrophenylsulfanyl}acetate (3.49 g; 92%) is obtained in the form of a bright yellow solid with a compliant .sup.1H NMR.

(403) MS: [M+H]=481.

3. Synthesis of Intermediate 135.3

(404) ##STR00310##

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(405) Iron powder (1.16 g; 20.81 mmol) is added to a solution of ethyl {5-[(4-ethylphenyl)isobutylsulfamoyl]-2-nitrophenylsulfanyl}acetate (2.00 g; 4.16 mmol) in ethanol (20 ml) and acetic acid (5 ml).

(406) The reaction medium is stirred for 2 hours at a temperature of 80 C., returned to room temperature, diluted with ethyl acetate and then filtered through Celite. The filtrate is washed with saturated NaHCO.sub.3 solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(407) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (0.98 g; 58%) is obtained in the form of a white powder with a compliant .sup.1H NMR.

(408) MS: [M+H]=405

4. Synthesis of Intermediate 135.4

(409) ##STR00311##

3-Oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(410) 4-(Bromomethyl)tetrahydropyran (797 mg; 4.45 mmol) is added to a mixture of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (900 mg; 2.22 mmol) and cesium carbonate (1.09 g; 3.34 mmol) in 1-methyl-2-pyrrolidone (20 ml).

(411) The reaction medium is stirred for 4 hours at a temperature of 110 C., hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(412) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (1.11 g; 99%) is obtained in the form of a white solid with a compliant .sup.1H NMR.

(413) MS: [M+H]=503

5. Synthesis of Intermediate 135.5

(414) ##STR00312##

1,3-Dioxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-14-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(415) 3-Chloroperoxybenzoic acid (223 mg; 0.99 mmol) is added, at a temperature of 0 C., to 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 0.99 mmol) dissolved in dichloromethane (10 ml). The reaction medium is stirred for 30 minutes at room temperature, hydrolyzed with aqueous 10% Na.sub.2S.sub.2O.sub.3 solution and extracted with dichloromethane. The organic phases are combined, washed with 0.1N sodium hydroxide solution and with brine, and then dried (Na.sub.2SO.sub.4) and concentrated.

(416) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 80% of ethyl acetate). The 1,3-dioxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.4-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (310 mg; 60%) is obtained in the form of a white crystalline powder after crystallization from an ethanol/heptane mixture.

(417) MS: [M+H]=519

6. Synthesis of Intermediate 135.6

(418) ##STR00313##

4-(Tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(419) 3-Oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 0.99 mmol) is added to a 1M solution of stabilized borane/tetrahydrofuran complex in tetrahydrofuran (35 ml). The reaction medium is stirred at reflux, cooled and poured at 0 C. into methanol (35 ml). The solvents are concentrated.

(420) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 50% of ethyl acetate). The 4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (466 mg; 95%) is obtained in the form of a white crystalline solid after recrystallization from ether, with a compliant .sup.1H NMR.

(421) MS: [M+H]=489

7. Synthesis of Compound 71 According to the Invention

(422) ##STR00314##

(423) 3-Chloroperoxybenzoic acid (175.4 mg; 0.78 mmol) is added, at a temperature of 0 C., to 4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (425.0 mg; 0.87 mmol) dissolved in dichloromethane (8.5 ml). The reaction medium is stirred for 15 minutes at room temperature, hydrolyzed with aqueous 10% Na.sub.2S.sub.2O.sub.3 solution and then extracted with dichloromethane. The organic phases are combined, washed with 0.1N sodium hydroxide solution and then with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(424) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate and then dichloromethane/methanol, from 0 to 10% of methanol). The 1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.4-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (379 mg; 86%) is obtained in the form of a white crystalline powder after crystallization from an ether/heptane mixture.

(425) 1H NMR (DMSO-d6) : 0.84 (d, J=6.7 Hz, 6H), 1.19 (t, J=7.6 Hz, 3H), 1.35 (dddd, J=34.9, 26.9, 14.1, 8.5 Hz, 3H), 1.53-1.61 (m, 2H), 2.02 (ddd, J=11.6, 7.6, 3.7 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 2.87 (td, J=13.7, 3.4 Hz, 1H), 3.14 (ddd, J=13.9, 4.1, 2.3 Hz, 1H), 3.20-3.33 (m, 8H), 3.42-3.50 (m, 2H), 3.69 (dt, J=14.1, 3.7 Hz, 1H), 3.82-3.98 (m, 3H), 6.97-7.04 (m, 2H), 7.09 (d, J=9.1 Hz, 1H), 7.16-7.23 (m, 2H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H)

(426) MS: [M+H]=505

Example 136: Synthesis of 1-imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-16-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(427) ##STR00315##

(428) 2,2,2-Trifluoroacetamide (185 mg; 1.63 mmol), rhodium(II) acetate dimer (44 mg; 0.10 mmol), magnesium oxide (132 mg; 3.27 mmol) and iodobenzene diacetate (421 mg; 1.31 mmol) are added to a solution, degassed beforehand with argon, of 1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.4-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (330 mg; 0.65 mmol) in dichloromethane (16.5 ml).

(429) The reaction medium is stirred for 16 hours at room temperature, filtered through Celite and concentrated. The residue is diluted in methanol (16.50 ml) and potassium carbonate (452 mg; 3.27 mmol) is added. The reaction medium is stirred for 30 minutes, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(430) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid).

(431) The 1-imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4-tetrahydro-1.sup.6-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (44.5 mg; 13%) is obtained in the form of a cream-colored crystalline powder after recrystallization from a heptane/dichloromethane mixture.

(432) 1H NMR (DMSO-d6) : 0.73-0.94 (m, 7H), 1.19 (t, J=7.6 Hz, 3H), 1.22-1.36 (m, 4H), 1.42 (dt, J=13.6, 6.8 Hz, 1H), 1.58 (d, J=13.1 Hz, 2H), 1.85-2.10 (m, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.20-3.32 (m, 4H), 3.34-3.51 (m, 3H), 3.86 (dd, J=11.4, 4.0 Hz, 2H), 3.94 (p, J=3.7 Hz, 2H), 4.68 (s, 1H), 7.00 (dd, J=15.4, 8.7 Hz, 3H), 7.20 (d, J=8.1 Hz, 2H), 7.27 (dd, J=9.2, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H).

(433) MS: [M+H]=520

Part X: Synthesis of Sulfur-Based Sulfonamides Via Reaction Scheme 10

(434) ##STR00316##

Example 137: Synthesis of 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic Acid (4-ethylphenyl)isobutylamide

(435) ##STR00317##

1. Synthesis of Intermediate 137.1

(436) ##STR00318##

2-Oxo-2,3-dihydrobenzothiazole-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(437) 2-Oxo-2,3-dihydrobenzothiazole-6-sulfonyl chloride (2.97 g; 11.28 mmol) is added to (4-ethylphenyl)isobutylamine (2.00 g; 11.28 mmol) and pyridine (5.5 ml; 67.69 mmol) dissolved in tetrahydrofuran (40 ml). The reaction medium is stirred for 16 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with saturated NH.sub.4Cl solution and then with brine, dried (MgSO.sub.4) and concentrated.

(438) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 10% of ethyl acetate). The 2-oxo-2,3-dihydrobenzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (2.67 g; 61%) is obtained in the form of a flaky white solid with a compliant .sup.1H NMR.

(439) MS: [M+H]=391

2. Synthesis of Compound 72 According to the Invention

(440) ##STR00319##

(441) 4-(Bromomethyl)tetrahydropyran (2.25 g; 12.55 mmol) is added to 2-oxo-2,3-dihydrobenzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (2.45 g; 6.27 mmol) and cesium carbonate (3.07 g; 9.41 mmol) dissolved in 1-methyl-2-pyrrolidone (50 ml). The reaction medium is stirred for 4 hours at 90 C., hydrolyzed and extracted with ethyl acetate. The organic phases are combined and then washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.

(442) The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The 3-oxo-4-(tetrahydropyran-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide (2.19 g; 72%) is obtained in the form of a white crystalline solid.

(443) 1H NMR (DMSO-d6) : 0.85 (d, J=6.6 Hz, 7H), 1.13-1.22 (m, 4H), 1.24-1.55 (m, 6H), 2.03 (ddt, J=10.8, 6.9, 3.4 Hz, 1H), 2.50-2.66 (m, 3H), 3.23 (td, J=11.6, 2.1 Hz, 2H), 3.34 (s, 1H), 3.83 (ddd, J=11.3, 4.4, 1.9 Hz, 2H), 3.90 (d, J=7.3 Hz, 2H), 6.96-7.04 (m, 2H), 7.14-7.22 (m, 2H), 7.42 (dd, J=8.6, 1.9 Hz, 1H), 7.57 (s, 1H), 8.05 (d, J=1.9 Hz, 1H)

(444) MS: [M+H]=489

Example 138: Synthesis of 2,2-dimethyl-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydrobenzothiazole-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(445) ##STR00320##

1. Synthesis of Intermediate 138.1

(446) ##STR00321##

3,3-disulfanediylbis(N-(4-ethylphenyl)-N-isobutyl-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

(447) A mixture of 2-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydrobenzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 1.02 mmol) and sodium hydroxide (410 mg; 10.23 mmol), methanol (6 ml) and water (100 l) is stirred for 16 hours at a temperature of 80 C. The reaction medium is diluted with 20 ml of ethyl acetate.

(448) The organic phase is washed with 20 ml of saturated NH.sub.4Cl solution, 20 ml of saturated NaHCO.sub.3 solution and 20 ml of water, dried (MgSO.sub.4), filtered and concentrated to dryness. The 3,3-disulfanediylbis(N-(4-ethylphenyl)-N-isobutyl-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (500 mg; 53%) is obtained in the form of a yellow oil with a compliant .sup.1H NMR.

(449) MS: [M+H]=923

2. Synthesis of Compound 73 According to the Invention

(450) ##STR00322##

2,2-dimethyl-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydrobenzothiazole-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(451) 2,2-Dimethoxypropane (1.0 ml; 8.35 mmol) and pyridinium p-toluenesulfonate (245 mg; 0.97 mmol) are added to 3,3-disulfanediylbis(N-(4-ethylphenyl)-N-isobutyl-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (300 mg; 0.32 mmol). The reaction medium is stirred for 16 hours at a temperature of 80 C. 3 drops of acetic acid are then added and the reaction medium is stirred for 2 hours at 80 C.

(452) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 2,2-dimethyl-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydrobenzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (70 mg; 40%) is obtained in the form of a clear yellow oil.

(453) 1H NMR (DMSO-d6) : 0.83 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.21-1.33 (m, 2H), 1.31-1.47 (m, 1H), 1.63 (s, 8H), 1.80 (s, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.08 (d, J=7.2 Hz, 2H), 3.22-3.30 (m, 4H), 3.87 (dd, J=11.5, 3.8 Hz, 2H), 6.47 (d, J=8.4 Hz, 1H), 6.99-7.03 (m, 2H), 7.07 (dq, J=8.3, 2.1 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.16-7.21 (m, 2H).

(454) MS: [M+H]=503

Example 139: Synthesis of 2,2-dimethyl-1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-14-benzothiazole-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(455) ##STR00323##

(456) 3-Chloroperoxybenzoic acid (30 mg; 0.15 mmol) is added to a solution of 2,2-dimethyl-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydrobenzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (70 mg; 0.14 mmol) in dichloromethane (2 ml). The reaction medium is stirred for 45 minutes at room temperature, diluted with dichloromethane (10 ml) and water (5 ml), and extracted.

(457) The organic phases are combined, dried (MgSO.sub.4), filtered and concentrated.

(458) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 2,2-dimethyl-1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-1.sup.4-benzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (20 mg; 28%) is obtained in the form of a pale yellow solid.

(459) 1H NMR (DMSO-d6) : 0.85 (d, J=6.7 Hz, 6H), 1.19 (dd, J=15.7, 8.1 Hz, 6H), 1.25-1.49 (m, 3H), 1.56 (d, J=12.1 Hz, 2H), 1.64 (s, 3H), 1.90 (s, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.18-3.28 (m, 2H), 3.87 (dt, J=10.6, 4.9 Hz, 2H), 7.00 (t, J=8.9 Hz, 3H), 7.19 (d, J=8.1 Hz, 2H), 7.46 (dd, J=8.5, 2.1 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H).

(460) MS: [M+H]=519

Example 140: Synthesis of the Compound 1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-1)4-benzothiazole-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(461) ##STR00324##

(462) Paraformaldehyde (473 ml; 1.08 mmol), pyridinium p-toluenesulfonate (163 mg; 0.65 mmol) and 1,2-dichloroethane (3 ml) are added to 3,3-disulfanediylbis(N-(4-ethylphenyl)-N-isobutyl-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (200 mg; 0.22 mmol).

(463) The reaction medium is stirred for 16 hours at 80 C., filtered, diluted with dichloromethane, dried (MgSO.sub.4) and filtered. 3-Chloroperoxybenzoic acid (107 mg; 0.48 mmol) is added to the filtrate. The reaction medium is stirred for 30 minutes at room temperature, diluted with dichloromethane (20 ml) and water (10 ml), and extracted. The organic phase is washed with a sodium sulfite solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

(464) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-1.sup.4-benzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (70 mg; 66%) is obtained in the form of a white solid.

(465) 1H NMR (DMSO-d6) : 0.85 (dd, J=6.7, 3.5 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.22-1.34 (m, 2H), 1.42 (dt, J=13.6, 6.9 Hz, 1H), 1.55 (t, J=13.0 Hz, 2H), 1.87-2.09 (m, 1H), 2.61 (q, J=7.5 Hz, 2H), 3.27 (ddt, J=12.1, 9.7, 6.3 Hz, 4H), 3.40 (dd, J=14.5, 7.4 Hz, 1H), 3.54 (dd, J=14.5, 7.2 Hz, 1H), 3.81-3.89 (m, 2H), 4.49 (d, J=13.6 Hz, 1H), 4.76 (d, J=13.6 Hz, 1H), 6.95-7.04 (m, 2H), 7.11 (d, J=9.0 Hz, 1H), 7.19 (d, J=8.3 Hz, 2H), 7.43 (dd, J=8.8, 2.0 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H). MS: [M+H]=491

Example 141: Synthesis of 1-imino-1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-16-benzothiazole-6-sulfonic Acid (4-ethylphenyl)isobutylamide

(466) ##STR00325##

(467) 2,2,2-Trifluoroacetamide (40.3 mg; 0.36 mmol), rhodium(II) acetate dimer (9.5 mg; 0.02 mmol), magnesium oxide (30 mg; 0.71 mmol) and iodobenzene acetate (92 mg; 0.29 mmol) are added to a solution, degassed beforehand with argon, of 1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-1.sup.4-benzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (70 mg; 0.14 mmol) in dichloromethane (2 ml). The reaction medium is stirred for 3 days at room temperature, filtered through Celite and concentrated to dryness. The residue is taken up in methanol (1 ml), to which is added potassium carbonate (100 mg; 0.71 mol). The reaction medium is stirred for 1 hour, diluted with ethyl acetate (20 ml) and extracted.

(468) The organic phase is washed with saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried (MgSO.sub.4), filtered and concentrated.

(469) The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-imino-1-oxo-3-(tetrahydropyran-4-ylmethyl)-2,3-dihydro-1H-1.sup.6-benzothiazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (25 mg; 33.34%) is obtained in the form of a beige-colored solid.

(470) 1H NMR (DMSO-d6) : 0.84 (d, J=6.4 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.29 (ddd, J=18.9, 11.8, 7.0 Hz, 2H), 1.42 (p, J=6.9 Hz, 1H), 1.48-1.65 (m, 2H), 1.93 (d, J=11.7 Hz, 1H), 2.61 (q, J=7.5 Hz, 2H), 3.25 (m, 4H), 3.46 (t, J=7.0 Hz, 2H), 3.86 (d, J=9.7 Hz, 2H), 4.49 (t, J=4.3 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 7.08-7.24 (m, 4H), 7.37 (dd, J=9.4, 2.3 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 8.23 (d, J=4.9 Hz, 1H).

(471) MS: [M+H]=506