CHEMICAL COMPOUNDS

The present invention relates to sulphonamide derivatives, to their use as medicaments (for example in the treatment of an inflammatory disease state), to pharmaceutical compositions comprising them and to processes for preparing them.

Sulphonamide derivatives are disclosed as antiinflammatories in WO 2004/019935 and WO 2004/050631. Pharmaceutically active sulphonamides are also disclosed in Arch. Pharm. (1980) 313 166-173, J.Med. Chem. (2003) 46 64-73, J. Med. Chem (1997) 40 996- 1004, EP 0031954, EP 1190710 (WO 200124786), US 5861401, US 4948809, US3992441 and WO 99/33786.

It is known that certain non-steroidal compounds interact with the glucocorticoid receptor (GR) and, as a result of this interaction, produce a suppression of inflammation (see, for example, US6323199). Such compounds can show a clear dissociation between anti¬ inflammatory and metabolic actions making them superior to earlier reported steroidal and non-steroidal glucocorticoids. The present invention provides further non-steroidal compounds as modulators (for example agonists, antagonists, partial agonists or partial antagonists) of the glucocorticoid receptor capable of having a dissociation between their anti-inflammatory and metabolic actions.

The present invention provides a compound of formula (I):

wherein:

A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl), NR ¹⁰ R ¹¹ , phenoxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, Ci _-4 alkylthio, CM fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) OrNR ¹⁴ R ¹⁵ ), phenyl (optionally

substituted by halo, C _1-6 alkyl, Ci _-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹⁶ R ¹⁷ ), pyridinyloxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, Ci _-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _{1- 4} alkyl) OrNR ¹⁸ R ¹⁹ ) or pyrazolyl(optionally substituted by halo, C _1-6 alkyl, Ci _-6 alkoxy, Ci _-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) or NR ²⁰ R ²¹ );

R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl;

R ¹ is hydrogen, Ci _-6 alkyl, phenyl, pyridinylC(O), C _3-6 cycloalkyl, (C _3-6 cycloalkyl)CH ₂ or C _{3- 4} alkenyl;

L is a bond, C _1-4 alkylene (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), C _1-4 alkylene-NH (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), CH ₂ C(O)NH, CH(CH ₃ )C(O)NH, Ci _-4 alkylene-0 (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), C ₁ - ₄ alkylene-S (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), Ci _-4 alkylene-S(O) (optionally substituted by Ci _-4 alkyl or C _1-4 haloalkyl) or C _1-4 alkylene-S(O) ₂ (optionally substituted by C _1-4 alkyl or Ci _-4 haloalkyl);

W is cyclohexyl, phenyl, methylenedioxyphenyl, thienyl, pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl, [l,6]-naphthiridinyl, quinolin- 2(l#)-onyl, isoquinolin-l(2#)-onyl, phthalazin-l(2H)-onyl, lH-indazolyl, l,3-dihydro-2H- indol-2-onyl, isoindolin-1-onyl, 3,4-dihydro-lH-isochromen-l-onyl or lH-isochromen-1- onyl;

W is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C ₁ . 4 fluoroalkoxy, nitro, cyano, OH, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ ,

S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , benzyloxy, imidazolyl, C(O)(Ci _-4 allcyl), C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, Ci _-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

Compounds of of formula (I) can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate, p- toluenesulphonate, succinate, glutarate or malonate.

The compounds of formula (I) may exist as solvates (such as hydrates) and the present invention covers all such solvates.

Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl.

Haloalkyl comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 halogen (such as fluorine or chlorine) atoms. It is, for example, CHF ₂ , CF ₃ , CH ₂ CF ₃ , C ₂ F ₅ or CH ₂ Cl. Haloalkoxy comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 halogen (such as fluorine or chlorine) atoms. It is, for example, OCHF ₂ , OCF ₃ , OCH ₂ CF ₃ , OC ₂ F ₅ or OCH ₂ Cl.

Fluoroalkyl comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 fluorine atoms. It is, for example, CHF ₂ , CF ₃ , CH ₂ CF ₃ or C ₂ F ₅ . Fluoroalkoxy comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 fluorine atoms. It is, for example, OCHF ₂ , OCF ₃ , OCH ₂ CF ₃ or OC ₂ F ₅ .

Cycloalkyl is for example, cyclopropyl, cyclopentyl or cyclohexyl.

In one particular aspect the present invention provides a compound of formula (I), wherein A is phenyl, naphthyl, pyridinyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , pyridinyloxy, benzyloxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(Cj _-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Cj _-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl), NR ¹⁰ R ¹¹ , phenoxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(Ci _-4 allcyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 allcyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(C _1- 4 alkyl) or NR ¹⁴ R ¹⁵ ) or phenyl (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, Cj _-4 alkylthio, CF ₃ , OCF ₃ , nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ ,

S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(Ci _-4 allcyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹⁶ R ¹⁷ ); R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are, independently, hydrogen, Ci _-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen, Ci _-6 alkyl, phenyl, pyridylC(O), C _3-6 cycloalkyl, (C _3-6 cycloalkyl)CH ₂ or C _3-4 alkenyl; L is a bond, Ci _-4 alkylene (optionally substituted by Ci _-4 alkyl), C _1-4 alkylene-NH (optionally substituted by Ci _-4 alkyl), CH ₂ C(O)NH, CH(CH ₃ )C(O)NH, Ci _-4 alkylene-0 (optionally substituted by C _1- 4 alkyl); C _1-4 alkylene-S (optionally substituted by C _1-4 alkyl); C _1-4 alkylene-S(O) (optionally substituted by C _1-4 alkyl); Ci _-4 alkylene-S(O) ₂ (optionally substituted by Ci _-4 alkyl); W is phenyl, methylenedioxyphenyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyL benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl or [l,6]-naphthiridinyl; W is optionally substituted by halo, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , benzyloxy, C(O)(Ci _-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 allcyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, Ci _-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof; for use as a medicament.

In another aspect the present invention provides a compound of formula (I), wherein A is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, Ci _-6 alkyl, Ci _-6 alkoxy, Ci _-4 alkylthio, CF ₃ , OCF ₃ , phenoxy (optionally substituted by halo or Ci _-4 alkyl), phenyl (optionally substituted by halo or Ci _-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O) ₂ NH ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , NHC(O)(C _1-4 alkyl) or NR ¹⁰ R ¹¹ ; R ¹⁰ and R ¹¹ are, independently, hydrogen, Cj _-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen, Ci _-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH ₂ or C _3-4 alkenyl; L is a bond, Ci _-4 alkylene (optionally substituted by Ci _-4 alkyl), C _1-4 alkylene-NH (optionally substituted by C _1-4 alkyl), CH ₂ C(O)NH or C _1-4 alkylene-0 (optionally substituted by C _1-4 alkyl); W is phenyl, benzofuranyl, indolyl, tetrahydroquinolinyl, thiazolyl, pyridyl, isoxazolyl, pyrimidinyl or 1,3,5-triazinyl, and W is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , benzyloxy, nitro, cyano, S(O) ₂ NH ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof; for use as a medicament.

In a further aspect the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo (such as fluoro, chloro or bromo), Cj _-6 alkyl, C _1-6 alkoxy, nitro, phenoxy (optionally substituted by C _1-4 alkyl), phenyl (optionally substituted by halo (such as fluoro)), pyridinyloxy Or N(C _1-4 alkyl) ₂ ; R ¹ is hydrogen, C _1-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH ₂ or C _3-4 alkenyl, L is a bond, C _1-4 alkylene (optionally substituted by C _1-4 alkyl), C _1-4 alkylene-NH (optionally substituted by C _1-4 alkyl), CH ₂ C(O)NH or C _1-4 alkylene- O (optionally substituted by C _1-4 alkyl); W is phenyl, benzofuranyl, indolyl, tetrahydroquinolinyl, thiazolyl, pyridyl, isoxazolyl, pyrimidinyl or 1,3,5-triazinyl, and W is optionally substituted by halo (such as chloro or bromo), C _1-6 alkyl, C _1-6 alkoxy, C(O)(C _1-4 alkyl), S(O) ₂ NH ₂ , NO ₂ , CO ₂ (Ci _-4 alkyl) or N(C _1-4 alkyl) ₂ ; or a pharmaceutically acceptable salt thereof; for use as a medicament.

In another aspect the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, Ci _-4 alkylthio, CF ₃ , OCF ₃ , pyridinyloxy, benzyloxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl), NR ¹⁰ R ¹¹ , phenoxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, Ci _-4 alkylthio, CF ₃ , OCF ₃ , nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) or NR ¹⁴ R ¹⁵ ) or phenyl (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) or NR ¹⁶ R ¹⁷ ); R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen, C _1-6 alkyl, phenyl, pyridylC(O), C _3-6 cycloalkyl, (C _3-6 cycloalkyl)CH ₂ or C _3-4 alkenyl; L is a bond, C _1-4 alkylene (optionally substituted by Ci _-4 alkyl), Ci _-4 alkylene-NH (optionally substituted by Ci _-4 alkyl), CH ₂ C(O)NH, CH(CH ₃ )C(O)NH, Ci _-4 alkylene-0 (optionally substituted by C _1-4 alkyl); C _1-4 alkylene-S (optionally substituted by C _1-4 alkyl); C _1-4 alkylene-S(O) (optionally substituted by Ci _-4 alkyl); C _1-4 alkylene-S(O) ₂ (optionally substituted by C _1-4 alkyl); W is phenyl, methylenedioxyphenyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, benzofuranyl, benzthienyl, indolyl, indolinyl,

dihydroindolinyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl or [l,6]-naphthiridinyl; W is optionally substituted by halo, C _1-6 alkyl, C _1- β alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , benzyloxy, C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, Ci _-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, Ci _-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , phenoxy (optionally substituted by halo or C _1-4 alkyl), phenyl (optionally substituted by halo or C _1-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O) ₂ NH ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , NHC(O)(C _1-4 alkyl) or NR ¹⁰ R ¹¹ ; R ¹⁰ and R ¹¹ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen, Ci _-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH ₂ or C _3-4 alkenyl; L is a bond, Ci _-4 alkylene (optionally substituted by C _1-4 alkyl), Ci _-4 alkylene-NH (optionally substituted by Ci _-4 alkyl), CH ₂ C(O)NH or C _1-4 alkylene-0 (optionally substituted by Cμ ₄ alkyl); W is phenyl, benzofuranyl, indolyl, tetrahydroquinolinyl, thiazolyl, pyridyl, isoxazolyl, pyrimidinyl or 1,3,5-triazinyl, and W is optionally substituted by halo, Ci _-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , benzyloxy, nitro, cyano, S(O) ₂ NH ₂ , C(O)(Ci _-4 alkyl), C(O)NH ₂ , NHC(O)(C _1-4 alkyl) or NR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

In a still further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, Ci _-4 alkyl, C _1-4 haloalkyl, Ci _-4 alkoxy or Ci _-4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci _-4 alkyl, C _1-4 haloalkyl, Ci _-4 alkoxy or C _1-4 haloalkoxy) or pyrazolyl (optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, Ci _-4 alkoxy or C _1-4 haloalkoxy)).

In another aspect the invention provides a compound of formula (I) wherein L is C ₃ alkylene (substituted by Ci _-4 alkyl or Ci _-4 haloalkyl), C _2-4 alkylene-NH (substituted by Ci _-4 alkyl or C _1-4 haloalkyl), CH ₂ C(O)NH, CH(CH ₃ )C(O)NH, C _2-4 alkylene-0 (substituted by C _1-4 alkyl or Ci _-4 haloalkyl), C _2-4 alkylene-S (substituted by Ci _-4 alkyl or Ci _-4 haloalkyl), C _2-4 alkylene-S(O) (optionally substituted by Ci _-4 alkyl or Ci _-4 haloalkyl) or C _2-4 alkylene-S(O) ₂

(optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl); wherein C _1-4 alkyl is, for example, methyl or ethyl; and C _1-4 haloalkyl is, for example, CF ₃ .

In yet another aspect the invention provides a compound of formula (I) wherein L is C ₃ alkylene (substituted by C _1-4 alkyl or Cj _-4 haloalkyl), C _2-4 alkylene-NH (substituted by C _1-4 alkyl or C _1-4 haloalkyl) or C _2-4 alkylene-0 (substituted by C _1-4 alkyl or Ci _-4 haloalkyl); wherein C _1-4 alkyl is, for example, methyl or ethyl; and C _1-4 haloalkyl is, for example, CF ₃ .

In a further aspect the invention provides a compound of formula (I) wherein L is C ₃ alkylene (substituted by Ci _-4 alkyl), C ₂ alkylene-NH (substituted by Ci _-4 alkyl) or C ₂ alkylene- O (substituted by Cj _-4 alkyl); wherein Ci _-4 alkyl is, for example, methyl or ethyl. L is, for example, C ₂ alkylene-NH (substituted by Ci _-4 alkyl). L is, for example, C ₂ alkylene-0 (substituted by Ci _-4 alkyl).

In a still further aspect the invention provides a compound of formula (I) wherein L is CH(CH ₃ )CH ₂ CH ₂ (such as in the S-configuration), CH(CH ₃ )CH ₂ NH (such as in the S- configuration), CH(CH ₃ )CH ₂ O (such as in the S -configuration), CH(C ₂ H ₅ )CH ₂ CH ₂ (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ NH (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ O (such as in the S-configuration) or CH(CF ₃ )CH ₂ CH ₂ (such as in the S-configuration).

In another aspect the present invention provides a compound of formula (I) wherein L is CH(CH ₃ )CH ₂ NH (such as in the S-configuration) or it provides a compound of formula (I) wherein L is CH(CH ₃ )CH ₂ O (such as in the S-configuration).

In yet another aspect the present invention provides a compound of formula (I) wherein W is phenyl, pyridyl, indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol- 7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl).

In a further aspect the present invention provides a compound of formula (I) wherein W is indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl).

In a still further aspect the present invention provides a compound of formula (I) wherein W is indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, indazol-4-yl, indazol-5-yl, indazol- 6-yl, indazol-7-yl, quinolin-5-yl or isoquinolin-5-yl.

In another aspect the present invention provides a compound of formula (I) wherein W is indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl or quinolin-5-yl.

In yet another aspect the present invention provides a compound of formula (I) wherein W is optionally substituted by halogen, C _1-4 alkyl, CF ₃ , Ci _-4 alkoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, Ci _-4 alkyl, CF ₃ , C _1-4 alkoxy or OCF ₃ ) or C(O)NH ₂ .

In a further aspect the present invention provides a compound of formula (I) wherein L is C _1-4 alkylene (optionally substituted by Cu ₄ alkyl) or Ci _-4 alkylene-0 (optionally substituted by C _1-4 alkyl); for example L is CH(CH ₃ )CH ₂ O, CH ₂ CH ₂ O, CH(CH ₃ )(CH ₂ ) ₂ or

(CHa) ₃ .

In another aspect of the invention L is C _1-4 alkylene (optionally substituted by Ci _-4 alkyl) or C _1-4 alkylene-0 (optionally substituted by Ci _-4 alkyl).

In yet another aspect the present invention provides a compound of formula (I) wherein R ¹ is hydrogen.

In a still further aspect the present invention provides a compound of formula (I) wherein W is methylenedioxyphenyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl or [l,6]-naphthiridinyl, optionally substituted as defined above. In another aspect of the invention W is linked to L by a ring-carbon in the benzene ring part of its structure (see for example, Example 77, 78, 79, 80 or 83).

In a still further aspect the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl or thienyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , phenoxy (optionally substituted by halo or C _1-4 alkyl), phenyl (optionally substituted by halo or C _1-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O) ₂ NH ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹⁰ R ¹¹ ; R ¹⁰ and R ¹¹ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen; L is C _1-4 alkylene (optionally substituted by Ci _-4 alkyl) or C _1-4 alkylene-0 (optionally substituted by Ci _-4 alkyl); W is phenyl optionally substituted by halo, Ci _-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, CF ₃ , OCF ₃ , benzyloxy, nitro, cyano, S(O) ₂ NH ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , NHC(O)(C _1-4 alkyl) or NR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

In a still further aspect the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl or thienyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, CF ₃ , OCF ₃ , phenoxy (optionally substituted by halo or Ci _-4 alkyl), phenyl (optionally substituted by halo or Ci _-4 alkyl), pyridinyloxy, nitro or cyano; R ¹ is hydrogen; L

is C _1-4 alkylene (optionally substituted by C _1-4 alkyl) or C _1-4 alkylene-0 (optionally substituted by C _1-4 alkyl); W is phenyl optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, CF ₃ , OCF ₃ , nitro or cyano; or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fiuoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl), NR ¹⁰ R ¹¹ , phenoxy (optionally substituted by halo, Ci _-6 alkyl, Ci _-6 alkoxy, Ci _-4 alkylthio, Ci _-4 fluoroalkyl, C _M fiuoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(Ci _-4 aUcyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹⁴ R ¹⁵ ), phenyl (optionally substituted by halo, Ci _-6 alkyl, Ci _-6 alkoxy, Ci _-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(Ci _-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) or NR ¹⁶ R ¹⁷ ), pyridinyloxy (optionally substituted by halo, Ci _-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , C(O)(Ci _-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _{1- 4} alkyl) OrNR ¹⁸ R ¹⁹ ) or pyrazolyl(optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Cj _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) or NR ²⁰ R ²¹ ); R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen; L is C ₃ alkylene (substituted by Ci _-4 alkyl or C _1-4 haloalkyl), C _2-4 alkylene-NH (substituted by C _1-4 alkyl or C _1-4 haloalkyl) or C _2-4 alkylene-0 (substituted by C _1-4 alkyl or C _1-4 haloalkyl) {for example L is C ₃ alkylene (substituted by C _1-4 alkyl), C ₂ alkylene-NH (substituted by C _1-4 alkyl) or C ₂ alkylene-0 (substituted by C _1-4 alkyl)}; W is cyclohexyl, phenyl, methylenedioxyphenyl, thienyl, pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,

quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl, [l,6]-naphthiridinyl, quinolin-2(lH)-onyl, isoquinolin-l(2H)-onyl, phthalazm-l(2H)-onyl, lH-indazolyl, 1,3- dihydro-2H ^" -indol-2-onyl, isoindolin-1-onyl, 3,4-dihydro-lH-isochromen-l-onyl or IH- isochromen-1-onyl; W is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, OH, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , benzyloxy, imidazolyl, C(O)(C _{1- 4} alkyl), C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(0)(C _1-4 alkyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof {for example the compound is not in the form of a salt}.

In yet another aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C _1-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy or Ci _-4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci _-4 alkyl, Ci _-4 haloalkyl, C _1-4 alkoxy or Ci _-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci _-4 alkyl, Ci _-4 haloalkyl or phenyl (itself optionally substituted by halogen, C _1-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy or C _1-4 haloalkoxy)); R ¹ is hydrogen; L is C ₃ alkylene (substituted by C _1-4 alkyl or Ci _-4 haloalkyl), C _{2- 4} alkylene-NH (substituted by Ci _-4 alkyl or Ci _-4 haloalkyl) or C _2-4 alkylene-0 (substituted by Ci _-4 alkyl or Ci _-4 haloalkyl) {for example L is C ₃ alkylene (substituted by C _1-4 alkyl), C ₂ alkylene-NH (substituted by Ci _-4 alkyl) or C ₂ alkylene-0 (substituted by Ci _-4 alkyl)}; W is phenyl, pyridyl, indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl) {for example W is indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5- yl) or isoquinolinyl (for example isoquinolin-5-yl)}; wherein W is optionally substituted by halogen, Ci _-4 alkyl, CF ₃ , Ci _-4 alkoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, C _1-4 alkyl, CF ₃ , Cj _-4 alkoxy or OCF ₃ ) or C(O)NH ₂ .

In a further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or Ci _-4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci _-4 alkyl, Ci _-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci _-4 alkyl, Ci _-4 haloalkyl or phenyl (itself optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy)); R ¹ is hydrogen; L is C ₃ alkylene (substituted by C _1-4 alkyl or C _1-4 haloalkyl), C _{2- 4} alkylene-NH (substituted by C _1-4 alkyl or C _1-4 haloalkyl) or C _2-4 alkylene-0 (substituted by

C _1-4 alkyl or C _1-4 haloalkyl) {for example L is C ₃ alkylene (substituted by C _1-4 alkyl), C ₂ alkylene-NH (substituted by C _1-4 alkyl) or C ₂ alkylene-0 (substituted by C _1-4 alkyl)}; W is indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl or quinolin-5-yl; wherein W is optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 aikoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 aikoxy or OCF ₃ ).

In another aspect the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, C _1-6 aikoxy, C _1-4 alkylthio, C _M fluoroalkyl, C _1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl), NR ¹⁰ R ¹¹ , phenoxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 aikoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) OrNR ¹⁴ R ¹⁵ ), phenyl (optionally substituted by halo, C _1-6 alkyl, C _1-6 aikoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) OrNR ¹⁶ R ¹⁷ ), pyridinyloxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 aikoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _{1- 4} alkyl) or NR ¹⁸ R ¹⁹ ) or pyrazolyl(optionally substituted by halo, C _1-6 alkyl, C _1-6 aikoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, Ci _-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) or NR ²⁰ R ²¹ ); R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen; L is CH(CH ₃ )CH ₂ CH ₂ (such as in the S- configuration), CH(CH ₃ )CH ₂ NH (such as in the S-configuration), CH(CH ₃ )CH ₂ O (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ CH ₂ (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ NH (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ O (such as in the S-configuration) or CH(CF ₃ )CH ₂ CH ₂ (such as in the S-configuration); W is cyclohexyl, phenyl, methylenedioxyphenyl, thienyl, pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl,

pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl, [l,6]-naphthiridinyl, quinolin-2(lH)-onyl, isoquinolin-l(2H)-onyl, phthalazin-l(2H)-onyl, lH-indazolyl, l,3-dihydro-2H ^~ -indol-2-onyl, isoindolin-1-onyl, 3,4-dihydro-l.H-isochromen-l-onyl or lH-isochromen-1-onyl; W is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, OH, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , benzyloxy, imidazolyl, C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, Ci _-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof {for example the compound is not in the form of a salt} .

In yet another aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, Ci _-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C _1-4 alkyl, Ci _-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci _-4 alkyl, Ci _-4 haloalkyl or phenyl (itself optionally substituted by halogen, Ci _-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy)); R ¹ is hydrogen; L is CH(CH ₃ )CH ₂ CH ₂ (such as in the S-configuration), CH(CH ₃ )CH ₂ NH (such as in the S-configuration), CH(CH ₃ )CH ₂ O (such as in the S- configuration), CH(C ₂ H ₅ )CH ₂ CH ₂ (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ NH (such as in the S-configuration), CH(C ₂ Hs)CH ₂ O (such as in the S -configuration) or CH(CF ₃ )CH ₂ CH ₂ (such as in the S-configuration); W is phenyl, pyridyl, indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol- 5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl) {for example W is indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl)}; wherein W is optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy or OCF ₃ ) or C(O)NH ₂ .

In a further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C _1-4 alkyl, Ci _-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, Ci _-4 alkoxy

or C _1-4 haloalkoxy) or pyrazolyl (optionally substituted by C _1-4 alkyl, C _1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or Ci _-4 haloalkoxy)); R ¹ is hydrogen; L is CH(CH ₃ )CH ₂ CH ₂ (such as in the S-configuration), CH(CH ₃ )CH ₂ NH (such as in the S-configuration), CH(CH ₃ )CH ₂ O (such as in the S- configuration), CH(C ₂ H ₅ )CH ₂ CH ₂ (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ NH (such as in the S-configuration), CH(C ₂ H ₅ )CH ₂ O (such as in the S-configuration) or CH(CF ₃ )CH ₂ CH ₂ (such as in the S-configuration); W is indazol-4-yl, indazol-5-yl, indazol-6- yl, indazol-7-yl or quinolin-5-yl; wherein W is optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy or OCF ₃ ).

In another aspect the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C _1-6 alkyl, Ci _-6 alkoxy, C _1-4 alkylthio, Ci _-4 fluoroalkyl, Ci _-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl), NR ¹⁰ R ¹¹ , phenoxy (optionally substituted by halo, Ci _-6 alkyl, Ci _-6 alkoxy, Ci _-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) Or NR ¹⁴ R ¹⁵ ), phenyl (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, Ci _-4 fluoroalkyl, Ci _-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , C(O)(Ci _-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(Ci _-4 alkyl) OrNR ¹⁶ R ¹⁷ ), pyridinyloxy (optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (Ci _-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _{1- 4} alkyl) or NR ¹⁸ R ¹⁹ ) or pyrazolyl(optionally substituted by halo, Ci _-6 alkyl, Ci _-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, Ci _-4 fluoroalkoxy, nitro, cyano, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , C(O)(C _1-4 alkyl), benzyloxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) or NR ²⁰ R ²¹ ); R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; R ¹ is hydrogen; L is CH(CH ₃ )CH ₂ NH (such as in the S-

configuration) or L is CH(CH ₃ )CH ₂ O (such as in the S-configuration); W is cyclohexyl, phenyl, methylenedioxyphenyl, thienyl, pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl, [l,6]-naphthiridinyl, quinolin- 2(lH)-onyl, isoquinolin-l(2H)-onyl, phthalazin-l(2H)-onyl, 1/f-indazolyl, l,3-dihydro-2H- indol-2-onyl, isoindolin-1-onyl, 3,4-dihydro-lH-isochromen-l-onyl or lH-isochromen-1- onyl; W is optionally substituted by halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkylthio, C _1-4 fluoroalkyl, C _1-4 fluoroalkoxy, nitro, cyano, OH, C(O) ₂ H, C(O) ₂ (C _1-4 alkyl), S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(Cj _-4 alkyl) ₂ , benzyloxy, imidazolyl, C(O)(C _1-4 alkyl), C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , NHC(O)(C _1-4 alkyl) OrNR ¹² R ¹³ ; R ¹² and R ¹³ are, independently, hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof {for example the compound is not in the form of a salt} .

In yet another aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, Ci _-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy) or pyrazolyl (optionally substituted by C _1-4 alkyl, Ci _-4 haloalkyl or phenyl (itself optionally substituted by halogen, Ci _-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy)); R ¹ is hydrogen; L is CH(CH ₃ )CH ₂ NH (such as in the S-configuration) or L is CH(CH ₃ )CH ₂ O (such as in the S-configuration); W is phenyl, pyridyl, indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol- 5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl) {for example W is indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl)}; wherein W is optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy or OCF ₃ ) or C(O)NH ₂ .

In a further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C _1-4 alkyl, Q _-4 haloalkyl, Ci _-4 alkoxy or Ci _-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci _-4 alkyl, C _1-4 haloalkyl or phenyl

(itself optionally substituted by halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy)); R ¹ is hydrogen; L is CH(CH ₃ )CH ₂ NH (such as in the S -configuration) or L is CH(CH ₃ )CH ₂ O (such as in the S-configuration); W is indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl or quinolin-5-yl; wherein W is optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy, OCF ₃ , phenyl (itself optionally substituted by halogen, C _1-4 alkyl, CF ₃ , C _1-4 alkoxy or OCF ₃ ).

In a still further aspect the present invention provides a compound: 4-Bromo-N-( 1 -methyl-3-phenyl-propyl)-benzenesulfonamide; 4-Chloro-N-( 1 -methyl-3-phenyl-propyl)-benzenesulfonamide; 4-Bromo-2-methyl-N-(l-methyl-3-phenyl-propyl)-benzenesulfona mide; N-(I -Methyl-3 -phenyl-propyl)-4-trifluoromethoxy-benzenesulfonamide; 4-Methoxy-2,3 ,6-trimethyl-N-( 1 -methyl-3 -phenyl-propyl)-benzenesulfonamide; 4-tert-Butyl-N-(l-methyl-3-phenyl-propyl)-benzenesulfonamide ; N-(l-Methyl-3-phenyl-propyl)-4-phenoxy-benzenesulfonamide; 4'-Fluoro-biphenyl-4-sulfonic acid ( 1 -methyl-3 -phenyl-propyl)-amide; N-(l-Methyl-3-phenyl-ρropyl)-4-proρyl-benzenesulfonamide; N-(l-Methyl-3-phenyl-propyl)-4-trifluoromethyl-benzenesulfon amide; 4-(l,l-Dimethyl-propyl)-N-(l-methyl-3-phenyl-propyl)-benzene sulfonamide; N-(l-Methyl-3-phenyl-propyl)-3-trifluoromethyl-benzenesulfon amide; Biphenyl-4-sulfonic acid (l-methyl-3-phenyl-propyl)-amide; 5 -Bromo-thiophene-2-sulfonic acid ( 1 -methyl-3 -pheny l-propyl)-amide ; 4-fl-Butoxy-N-(l-methyl-3-ρhenyl-propyl)-benzenesulfonamide ; 2,4,6-Trimethyl-N-(l-methyl-3-phenyl-propyl)-benzenesulfonam ide; N-(l-Methyl-3-phenyl-propyl)-3-p-tolyloxy-benzenesulfonamide ; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-3-nitro-benzenes ulfonamide; 4-Bromo-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benzenes ulfonamide; N-{4-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethylsulfamoyl]-phen yl}-acetamide; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-nitro-benzenes ulfonamide; 4-Bromo-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-2-methyl -benzenesulfonamide; N-[2-(2,6-Dimethyl-ρhenoxy)-l-methyl-ethyl]-4-methoxy-benze nesulfonamide; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-trifluorometho xy-benzenesulfonamide; 4-tert-Butyl-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-ben zenesulfonamide; 4-Cyano-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benzenes ulfonamide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-phenoxy-benzen esulfonamide;

4'-Fluoro-biphenyl-4-sulfonic acid [2-(2,6-dimethyl-phenoxy)-l-metliyl-ethyl]-amide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-propyl-benz enesulfonamide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-(4-fluoro-p henoxy)-benzenesulfonamide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-(l,l-dimeth yl-propyl)-benzenesulfonaniide;

Naphthalene-2-sulfonic acid [2-(2,6-dimethyl-phenoxy)- 1 -methyl-ethyl]-amide;

Biphenyl-4-sulfonic acid [2-(2,6-dimethyl-phenoxy)- 1 -methyl-ethyl]-amide;

5-Bromo-thiophene-2-sulfonic acid [2-(2,6-dimethyl-phenoxy)- 1 -methyl-ethyl]-amide;

2-Bromo-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benze nesulfonamide;

N-[2-(2,6-Dimethyl-plienoxy)-l-methyl-ethyl]-3-methoxy-be nzenesulfonamide;

4-«-Butoxy-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-b enzenesulfonamide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-(pyridin-2- yloxy)-benzenesulfonamide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-2,4,6-trimeth yl-benzenesulfonamide;

N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-3-p-tolyloxy- benzenesulfonamide;

4-Bromo-2-methyl-N-(2-phenoxy-ethyl)-benzenesulfonamide;

N-(2-Phenoxy-ethyl)-4-trifluorometlioxy-benzenesulfonamid e;

4-(l,l-Dimethyl-propyl)-N-(2-phenoxy-ethyl)-benzenesulfon amide;

Biphenyl-4-sulfonic acid (2-phenoxy-ethyl)-amide;

2,4,6-Trimethyl-N-(2-phenoxy-ethyl)-benzenesulfonamide;

4-Bromo-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Bromo-2-methyl-N-(3-phenyl-propyl)-benzenesulfonamide;

N-(3-Phenyl-propyl)-4-trifluoromethoxy-benzenesulfonamide ;

4-Methoxy-2,3,6-trimethyl-N-(3-phenyl-propyl)-benzenesulf onamide;

4-tert-Butyl-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Phenoxy-N-(3-phenyl-propyl)-benzenesulfonamide;

4'-Fluoro-biphenyl-4-sulfonic acid (3-phenyl-propyl)-amide;

N-(3-Phenyl-propyl)-4-propyl-benzenesulfonamide;

4-(4-Fluoro-phenoxy)-N-(3-phenyl-propyl)-benzenesulfonami de;

4-(l , 1 -Dimethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

Naphthalene-2-sulfonic acid (3-phenyl-propyl)-amide;

Biphenyl-4-sulfonic acid (3-phenyl-propyl)-amide;

5-Bromo-thiophene-2-sulfonic acid (3-phenyl-propyl)-amide;

2,4,6-Trimethyl-N-(3-phenyl-propyl)-benzenesulfonamide;

N-(3 -Phenyl-propyl)-3 -p-tolyloxy-benzenesulfonamide;

N-[(lS)-2-(5-Isoquinolinyloxy)-l-methylethyl]-2,4,6-trime thylbenzenesulfonamide;

N-[(lS)-2-(lH-Indol-4-yloxy)-l-metliylethyl]-2,4,6-trimet hylbenzenesulfonamide;

2,4,6-Trimethyl-N-[(lS)-l-methyl-2-(5-quinolmyloxy)ethyl] benzenesulfonamide;

N-[(lS)-2-(l,3-Benzodioxol-5-yloxy)-l-methylethyl]-2 ₅ 4,6-trimethylbenzenesulfonamide;

2,4,6-Trimethyl-N-[(l S)- 1 -methyl-2-(4-quinolinyloxy)ethyl]benzenesulfonamide;

2,4,6-Trimethyl-N-[(lS)-l-metb.yl-2-(4-quinazolinyloxy)et hyl]benzenesulfonamide;

2,4,6-Trimethyl-N-[(lS)-l-methyl-2-(8-quinolinyloxy)ethyl ]benzenesulfonamide;

5-Fluoro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)be nzamide;

2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-5-methylbe nzamide;

2-Hydroxy-6-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)b enzamide;

5-Chloro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)be nzamide;

2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-4-methylbe nzamide;

2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)benzamide;

4-Fluoro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)be nzamide;

4-Chloro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)be nzamide;

5-Cyano-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)ben zamide;

2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-5-methoxyb enzamide;

3-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-4-methylbe nzamide;

2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-4-methoxyb enzamide;

2,5-Dichloro-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methyletli yl]tliiophene-3-sulfonamide;

N-[(l S)-2-(Isoquinolin~5-yloxy)- 1 -methylethyl]-5-methyl- 1 -phenyl- lH-pyrazole-4- sulfonamide; l-(Difluoromethyl)-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methyle thyl]-3,5-dimethyl-lH- pyrazole-4-sulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-2,5-dimeth ylfuran-3-sulfonamide;

2,5-Dichloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]t hiopherie-3-sulfonamide;

3-Bromo-5-chloro-N-[(l S)- 1 -methyl-2-(qumolin-5-yloxy)ethyl]thiophene-2-sulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-5-[l-methy l-5-(trifluoromethyl)-lH-pyrazol-

3 -yl]thiophene-2-sulfonamide; l-(Difluoromethyl)-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methyle thyl]-5-methyl-lH-pyrazole-4- sulfonamide;

5-Methyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]-l-ph enyl-lH-pyrazole-4-sulfonamide;

5-Chloro-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylethyl]thiop liene-2-sulfonamide;

5-Chloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]thiop hene-2-sulfonamide;

Methyl 4-({[(lS)-2-(isoquinolm-5-yloxy)-l-methylethyl]amino}sulfony l)-2,5-dimetliyl-3- furoate;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]thiophene-3 -sulfonamide; l-Ethyl-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylethyl]-lH-py razole-4-sulfonamide;

2-[((2S)-2-{[(2,5-Dichloro-3-thienyl)sulfonyl]ammo}propyl )oxy]benzamide; l-(Difluoromethyl)-3,5-dimethyl-N-[(lS)-l-methyl-2-(quinolin -5-yloxy)ethyl]-lH-pyrazole-

4-sulfonamide;

N-[(lS)-l-Methyl-2-(quinolm-5-yloxy)ethyl]-5-[l-methyl-5- (trifluoromethyl)-lH-pyrazol-3- yl]thiophene-2-sulfonamide; l-Ethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]-lH-pyraz ole-4-sulfonamide;

2-({(2S)-2-[({5-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol- 3-yl]-2-thienyl}sulfonyl)- aminojpropyl} oxy)benzamide;

2-[((2S)-2-{[(2,5-Dimethyl-3-thienyl)sulfonyl]amino}propy l)oxy]benzamide;

2,5-Dimetb.yl-N-[(lS)-l-methyl-2-(qumolin-5-yloxy)ethyl]f uran-3-sulfonamide;

2-[((2S)-2-{[(2,5-Dimethyl-3-furyl)sulfonyl]amino}propyl) oxy]benzamide;

2-{[(2S)-2-({[l-(Difluoromethyl)-3,5-dimethyl-lH-pyrazol- 4-yl]sulfonyl}amino)ρroρyl]- oxy}benzamide; l-Ethyl-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylethyl]-3-met hyl-lH-pyrazole-4- sulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-l,3,5-trim ethyl-lH-pyrazole-4-sulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-3,5-dimeth ylisoxazole-4-sulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methyletliyl]-2,5-dimet hylthiophene-3-sulfonamide;

2 ₃ 4,6-Trimethyl-N-{(lS)-l-inethyl-2-[(8-methylqumolin-5- yl)amino]ethyl}- benzenesulfonamide;

2,4,6-Trimethyl-N- {(1 S)- 1 -methyl-2-[(6-methylquinolin-5-yl)amino]etliyl} - benzenesulfonamide;

N- [( 1 S)-2-( 1 H-Indazol-4-ylamino)- 1 -methylethyl]-2,4,6-trimethylbenzenesulfonamide;

2 ₅ 4,6-Trimethyl-N-[(l S)- 1 -methyl-2-(quinolm-5-ylamino)ethyl]benzenesulfonamide;

N-[(lS)-2-(lH-Indazol-6-ylamino)-l-methylethyl]-2,4,6-tri methylbenzenesulfonamide;

2,4,6-Trimethyl-N- {(1 S)- 1 -methyl-2-[(2-methylquinolin-5-yl)amino]ethyl} - benzenesulfonamide;

N-[(lS)-2-(lH-Indazol-5-ylamino)-l-methylethyl]-2,4,6-trimet hylbenzenesulfonamide;

N-((lS)-2-{[2-Chloro-4-(methylsulfonyl)phenyl]amino}-l-me thylethyl)-2,4,6- trimethylbenzenesulfonamide;

N-[(lS)-2-(4-Cyano-2,6-dimethylρhenoxy)-l-methylethyl]-2 ,4,6- trimethylbenzenesulfonamide;

N-[(lS)-2-(3-Cyanophenoxy)-l-methylethyl]-2,4,6-trimethyl benzenesulfonamide;

N-[(l S)-2-(3-Methoxyphenoxy)- 1 -methylethyl]-2,4,6-trimethylbenzenesulfonamide;

N-[2-(3,5-Dimethoxyphenoxy)-l-methylethyl]-2,4,6-trimethy lbenzenesulfonamide;

N-[2-(4-Cyano-2-methoxyphenoxy)-l-methylethyl]-2,4,6-trim ethylbenzenesulfonamide;

N- {2-[(2-Bromopyridin-3 -yl)oxy] - 1 -methylethyl} -2,4,6-trimethylbenzenesulfonamide;

2,4,6-Trimetliyl-N-{l-methyl-2-[(2-methylpyridin-3-yl)oxy ]ethyl}benzenesulfonamide;

2- {2-[(Mesitylsulfonyl)amino]propoxy} -N-methylbenzamide;

4-{2-[(Mesitylsulfonyl)amino]propoxy}benzamide;

N-{2-[4-(lH-Imidazol-l-yl)phenoxy]-l-methylethyl}-2,4,6-t rimethylbenzenesulfonamide;

N-[(lS)-2-(3,4-Dimethoxyphenoxy)-l-methylethyl]-2,4,6-tri methylbenzenesulfonamide;

N-(2-{2-[(Mesitylsulfonyl)amino]propoxy}phenyl)acetamide;

N-{2-[(6-Chloropyridin-3-yl)oxy]-l-methylethyl}-2,4,6-tri methylbenzenesulfonamide;

N-[(lS)-2-(2H-Indazol-3-yloxy)-l-methylethyl]-2,4,6-trime thylbenzenesulfonamide;

4-Methyl-N-[3-phenyl-l-(trifluoromethyl)propyl]benzenesul fonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-2,4-dimeth ylbenzenesulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-3 ₅ 4-dimethylbenzenesulfonamide;

N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-2,5-dimeth ylbenzenesulfonamide;

2,4-Dimethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]b enzenesulfonamide;

3,4-Dimethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]b enzenesulfonamide;

2-[((2S)-2-{[(2,4-Dimethylphenyl)sulfonyl]amino}propyl)ox y]benzamide;

2,5-Dimethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]b enzenesulfonamide;

2- [((2 S)-2-{[(3 ,4-Dimethylρhenyl) sulfonyl] amino } ρropyl)oxy]benzamide;

N-(2-Anilinoethyl)-2,4,6-trimethylbenzenesulfonamide;

N-[2-(2,6-Dimethylphenoxy)-l-methylethyl]-4-(trifluoromet hyl)benzenesulfonamide;

N-(2-Anilinoethyl)-4'-fluorobiphenyl-4-sulfonamide;

N-(2-Anilinoethyl)-4-methoxy-2,3,6-trimethylbenzenesulfon amid;

N-(2-Anilinoethyl)-4-bromo-2-methylbenzenesulfonamid;

l-(4-Fluorophenyl)-7V-[(l ₁ S)-2-(isoquinolin-5-yloxy)-l-methylethyl]-3,5-dimethyl -lH ^' - pyrazole-4-sulfonamide;

N- [( 1 £)-2-(Isoqumolin-5 -y loxy) - 1 -methylethyl] -3,5 -dimethyl- 1 -phenyl- lH ^~ -pyrazole-4- sulfonamide;

N,2,4,6-Tetramethyl-N-[(1 S)- 1 -methyl-3-phenylpropyl]benzenesulfonamide;

2,4,6-Trimethyl-N- { 1 -[(quinolin-5-yloxy)methyl]propyl}benzenesulfonamide;

5-Chloro-2-{2-[(mesitylsulfonyl)amino]butoxy}benzamide;

2,4-Dichloro-6-metliyl-N-[(lS)-l-methyl-2-(quinolin-5-ylo xy)ethyl]benzenesulfonamide;

5-Chloro-2-{[(2S)-2-({[4-(4-fluorophenoxy)phenyl]sulfonyl }amino)ρroρyl]oxy}benzamide;

5 -Chloro-2- { [(2S)-2-( { [4-(4-methoxyphenoxy)phenyl] sulfonyl} amino)propyl] oxy } - benzamide;

5-Chloro-2-{[(2S)-2-({[3-(4-chlorophenoxy)phenyl]sulfonyl }amino)propyl]oxy}benzamide;

2,4,5-Trichloro-N-[(l S)- 1 -methyl-2-(quinolin-5-yloxy)ethyl]benzenesulfonamide;

5-Chloro-2- { [(2S)-2-( { [3 -(3 ,4-dichlorophenoxy)phenyl] sulfonyl} amino)propyl]oxy } - benzamide;

3-(4-Chlorophenoxy)-N-[(lS)-l-methyl-2-(quinolin-5-yloxy) ethyl]benzenesulfonamide;

5-Chloro-2-[((2S)-2-{[(2,4-dichloro-5-fluorophenyl)sulfon yl]amino}propyl)oxy]benzamide;

5-Chloro-2- { [(2S)-2-( { [3 -(4- methoxyphenoxy)phenyl]sulfonyl}amino)propyl]oxy}benzamide;

5-Chloro-2-[((2S)-2-{[(2-methoxy-4-methylphenyl)sulfonyl] amino}propyl)oxy]benzamide;

4-(4-Fluorophenoxy)-N-[(lS)-l-methyl-2-(quinolin-5-yloxy) ethyl]benzenesulfonamide;

5-Chloro-2-[((2S)-2-{[(5-chloro-2-methoxyphenyl)sulfonyl] amino}propyl)oxy]benzamide;

3-Cyano-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]benzen esulfonamide;

2,4-Dichloro-5-fl.uoro-N-[(lS)-l-methyl-2-(quinolin-5-ylo xy)ethyl]benzenesulfonamide;

2-[((2S)-2-{[(5-Bromo-2-methoxyphenyl)sulfonyl]amino}prop yl)oxy]-5-chlorobenzamide;

5-Chloro-2-[((2S)-2-{[(2-methoxy-5-methylphenyl)sulfonyl] amino}propyl)oxy]benzamide;

5-Chloro-2-{[(2S)-2-({[4'-(trifluoromethyl)biρhenyl-4-yl ]sulfonyl}ammo)proρyl]oxy}- benzamide;

4-(4-Methoxyphenoxy)-N-[(lS)-l-methyl-2-(quinolin-5-yloxy )ethyl]benzenesulfonamide;

5-Chloro-2-[((2S)-2-{[(6-phenoxypyridin-3-yl)sulfonyl]ami no}propyl)oxy]benzamide;

5-Bromo-6-chloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)eth yl]pyridine-3-sulfonamide;

5-Bromo-2-methoxy-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)et hyl]benzenesulfonamide;

N-[(lS)-l-Methyl-2-(quinolin-5-yloxy)ethyl]-l-benzothioph ene-2-sulfonamide;

5-Chloro-2-[((2S)-2-{[(2,4-dimethoxyphenyl)sulfonyl]amino}pr opyl)oxy]benzamide;

2-({(2S)-2-[(l-Benzothien-2-ylsulfonyl)amino]propyl}oxy)- 5-clilorobenzamide;

5-Chloro-2-[((2S)-2-{[(4-methoxy-2,3,6-trimethylphenyl)su lfonyl]amino}propyl)oxy]- benzamide;

5-Chloro-2-[((2S)-2-{[(5-fluoro-3-methyl-l-benzothien-2-y l)sulfonyl]amino}propyl)oxy]- benzamide;

5-Chloro-2-[((2S)-2-{[(5-chloro-3-methyl-l-benzothien-2-y l)sulfonyl]amino}propyl)oxy]- benzamide;

2-{[(2S)-2-({[4-Bromo-2-(trifluoromethoxy)phenyl]sulfonyl }amino)propyl]oxy}-5- chlorobenzamide;

2,4,6-Trichloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethy l]benzenesulfonamide;

4-Methoxy-2,3,6-trimethyl-N-[(lS)-l-methyl-2-(quinolin-5- yloxy)ethyl]- benzenesulfonamide; or,

4-Bromo-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]-2-(tr ifluoromethoxy)- benzenesulfonamide; or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can be prepared using or adapting methods disclosed in the art, or by using or adapting the method disclosed in the Examples below. Starting materials for the preparative methods are either commercially available or can be prepared by literature methods, adapting literature methods.

For example, a compound of the invention can be prepared by coupling a compound of formula (II):

wherein Y is a leaving group (for example chlorine), with a compound of formula (III):

R ¹

N-L-W (in) π in a suitable solvent (such as tetrahydrofuran or N,N-dimethylformamide) at a temperature in the range -1O ⁰ C to 5O ⁰ C.

The invention further provides processes for the preparation of the compounds of formula (I).

Because of their ability to bind to the glucocorticoid receptor the compounds of formula (I) are useful as anti-inflammatory agents, and can also display antiallergic, immunosuppressive and antiproliferative actions. Thus, a compound of formula (I), or a pharmaceutically acceptable salt thereof can be used as a medicament for the treatment or prophylaxis of one or more of the following pathologic conditions (disease states) in a mammal (such as a human): (i) Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• chronically obstructive lung diseases of any origin, mainly bronchial asthma

• bronchitis of different origins

• all forms of restructive lung diseases, mainly allergic alveolitis

• all forms of pulmonary edema, mainly toxic pulmonary edema

• sarcoidoses and granulomatoses, such as Boeck's disease

(ii) Rheumatic diseases/auto-immune diseases/degenerative joint diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, collagenoses

• reactive arthritis

• inflammatory soft-tissue diseases of other origins

• arthritic symptoms in degenerative joint diseases (arthroses)

• traumatic arthritides

• collagen diseases of other origins, for example systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis

• Sjogren's syndrome, Still syndrome, Felty's syndrome

(iii) Allergies, which coincide with inflammatory, allergic and/or proliferative processes:

• All forms of allergic reactions, for example Quincke's edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, contact dermatitis

(iv) Dermatological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• atopic dermatitis (mainly in children)

• psoriasis

• erythematous diseases, triggered by different noxae, for example radiation, chemicals, burns, etc.

• acid burns

• bullous dermatoses

• diseases of the lichenoid group

• itching (for example of allergic origins)

• seborrheal eczema

• rosacea

• pemphigus vulgaris

• erythema exudativum multiforme

• erythema nodosum

• balanitis

• vulvitis

• inflammatory hair loss, such as alopecia areata

• cutaneous T-cell lymphoma

(v) Nephropathies, which coincide with inflammatory, allergic and/or proliferative processes:

• nephrotic syndrome

• all nephritides

(vi) Liver diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• acute liver cell decomposition

• acute hepatitis of different origins, for example virally-, toxically- or pharmaceutical agent-induced

• chronically aggressive and/or chronically intermittent hepatitis

(vii) Gastrointestinal diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• regional enteritis (Crohn's disease)

• ulcerative colitis

• gastroenteritis of other origins, for example native sprue

(viii) Proctological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• anal eczema

• fissures

• haemorrhoids

• idiopathic proctitis

(ix) Eve diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• allergic keratitis, uvenitis iritis

• conjunctivitis

• blepharitis

• optic neuritis

• chorioiditis

• sympathetic ophthalmia

(x) Diseases of the ear-nose-throat area, which coincide with inflammatory, allergic and/or proliferative processes:

• allergic rhinitis, hay fever

• otitis externa, for example caused by contact dermatitis, infection, etc.

• otitis media

(xi) Neurological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• cerebral edema, mainly tumor-induced cerebral edema

• multiple sclerosis

• acute encephalomyelitis

• different forms of convulsions, for example infantile nodding spasms

(xii) Blood diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• acquired haemolytic anemia

• idiopathic thrombocytopenia

(xiii) Tumor diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• acute lymphatic leukaemia

• malignant lymphoma

• lymphogranulomatoses

• lymphosarcoma

• extensive metastases, mainly in breast and prostate cancers

(xiv) Endocrine diseases, which coincide with inflammatory, allergic and/or proliferative processes:

• endocrine orbitopathy

• thyrotoxic crisis

• de Quervain's thyroiditis

• Hashimoto's thyroiditis

• hyperthyroidism

(xv) Transplants, which coincide with inflammatory, allergic and/or proliferative processes;

(xvi) Severe shock conditions, which coincide with inflammatory, allergic and/or proliferative processes, for example anaphylactic shock (xvii) Substitution therapy, which coincides with inflammatory, allergic and/or proliferative processes, with:

• innate primary suprarenal insufficiency, for example congenital adrenogenital syndrome

• acquired primary suprarenal insufficiency, for example Addison's disease, autoimmune adrenalitis, meta-infective, tumors, metastases, etc.

• innate secondary suprarenal insufficiency, for example congenital hypopituitarism

• acquired secondary suprarenal insufficiency, for example meta-infective, tumors, etc.

(xviii) Emesis, which coincides with inflammatory, allergic and/or proliferative processes:

• for example in combination with a 5-HT3-antagonist in cytostatic-agent-induced vomiting.

Without prejudice to the foregoing, the compounds of formula (I) can also be used to treat disorders such as: Conies Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's Syndrome, disorders

associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, oesophageal varicies, Addison's Disease, muscle weakness, increased melanin pigmentation of the skin, weight loss, hypotension, hypoglycemia, Cushing's Syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, tissue rejection associated with organ transplant, malignancies such as leukemias and lymphomas, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Thl/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, and Little's syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cinhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, dermatomyositis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, lichen planus, erythema nodosum acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma, psychoses, cognitive disorders (such as memory disturbances) mood disorders (such as depression and bipolar disorder), anxiety disorders and personality disorders.

As used herein the term "congestive heart failure" (CHF) or 'congestive heart disease" refers to a disease state of the cardiovascular system whereby the heart is unable to efficiently pump an adequate volume of blood to meet the requirements of the body's tissues and organ systems. Typically, CHF is characterized by left ventricular failure (systolic dysfunction) and fluid accumulation in the lungs, with the underlying cause being attributed to one or more heart or cardiovascular disease states including coronary artery disease, myocardial infarction, hypertension, diabetes, valvular heart disease, and cardiomyopathy. The term "diastolic

congestive heart failure" refers to a state of CHF characterized by impairment in the ability of the heart to properly relax and fill with blood. Conversely, the term "systolic congestive heart failure" refers to a state of CHF characterized by impairment in the ability of the heart to properly contract and eject blood.

As will be appreciated by one of skill in the art, physiological disorders may present as a "chronic" condition, or an "acute" episode. The term "chronic", as used herein, means a condition of slow progress and long continuance. As such, a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease. Conversely, the term "acute"means an exacerbated event or attack, of short course, followed by a period of remission. Thus, the treatment of physiological disorders contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear.

In another aspect the present invention provides the use of a compound or formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy (such as a therapy described above).

In yet another aspect the present invention provides the use of a compound or formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a glucocorticoid receptor mediated disease state (such as a disease state described above).

In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an inflammatory (such as an arthritic) condition.

In a still further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an asthmatic or dermatological condition.

In another aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of COPD.

The present invention further provides a method of treating a glucocorticoid receptor mediated disease state in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In order to use a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a mammal, said active ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, (active ingredient) and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition comprising mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition can comprise from 0.05 to 99 %w (per cent by weight), for example from 0.05 to 80 %w, such as from 0.10 to 70 %w (for example from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition.

A pharmaceutical composition of the present invention can be administered in a standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. Thus, a the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be formulated into the form of, for example, an aerosol, a powder (for example dry or dispersible), a tablet, a capsule, a syrup, a granule, an aqueous or oily solution or suspension, an (lipid) emulsion, a suppository, an ointment, a cream, drops, or a sterile injectable aqueous or oily solution or suspension.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule containing between O.lmg and Ig of active ingredient.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous, intraarticular or intramuscular injection.

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β- cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. Tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

The invention further relates to combination therapies or compositions wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states.

In particular, for the treatment of the inflammatory diseases (for example rheumatoid arthritis, COPD, asthma or allergic rhinitis) a compound of the invention can be combined with a TNF-α inhibitor (such as an anti-TNF monoclonal antibody (such as Remicade, CDP- 870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-I / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin), a COX-2 inhibitor (such as meloxicam, celecoxib, rofecoxib, valdecoxib or etoricoxib) low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine or auranofin, or parenteral or oral gold.

The present invention still further relates to the combination of a compound of the invention together with:

• a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5- lipoxygenase activating protein (FLAP) antagonist, such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, an N-(5-substituted)-thiophene-2- alkylsulfonamide, a 2,6-di-tert-butylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591, MK-886 or BAY x 1005;

• a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTD.sub4. or LTE.sub4. selected from the group consisting of a phenothiazin-3-one such as L- 651,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIIL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro- 245913, iralukast (CGP 45715A) or BAY x 7195;

• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;

• an antihistaminic H.subl . receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine;

a gastroprotective H.sub2. receptor antagonist; an α.subl.- and α.sub2.- adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride; an anticholinergic agent such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; a β.subl.- to β.sub4.-adrenoceptor agonist (such as β2 adrenoceptor agonist) such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoteroL salmeterol, terbutaline, orciprenaline, bitolterol mesylate or pirbuterol, or a methylxanthanine including theophylline and aminophylline; sodium cromoglycate; or a muscarinic receptor (Ml, M2, and M3) antagonist; an insulin-like growth factor type I (IGF-I) mimetic; an inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate or mometasone furoate; an inhibitor of a matrix metalloprotease (MMP), such as a stromelysin, a collagenase, or a gelatinase or aggrecanase; such as collagenase- 1 (MMP-I), collagenase-2 (MMP-

8), collagenase-3 (MMP- 13), stromelysin- 1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-I l) or MMP-12; a modulator of chemokine receptor function such as CCRl, CCR2, CCR2A, CCR2B,

CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and

CX ₃ CRl for the C-X ₃ -C family; an osteoporosis agent such as raloxifene, droloxifene, lasofoxifene or fosomax; an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate; a compound useful in the treatment of AIDS and/or HIV infection for example: an agent which prevents or inhibits the viral protein gpl20 from engaging host cell CD4

{such as soluble CD4 (recombinant); an anti-CD4 antibody (or modified / recombinant antibody) for example PRO542; an anti-groupl20 antibody (or modified / recombinant antibody); or another agent which interferes with the binding of

group 120 to CD4 for example BMS 806}; an agent which prevents binding to a chemokine receptor, other than CCR5, used by the HIV virus {such as a CXCR4 agonist or antagonist or an anti-CXCR4 antibody} ; a compound which interferes in the fusion between the HIV viral envelope and a cell membrane {such as an anti- group 41 antibody; enfuvirtide (T-20) or T- 1249}; an inhibitor of DC-SIGN (also known as CD209) {such as an anti-DC-SIGN antibody or an inhibitor of DC-SIGN binding} ; a nucleoside/nucleotide analogue reverse transciptase inhibitor {for example zidovudine (AZT) ₃ nevirapine, didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir, adefovir or tenofovir (for example as free base or as disoproxil fumarate)}; a non-nucleoside reverse transciptase inhibitor {for example nevirapine, delavirdine or efavirenz}; a protease inhibitor {for example ritonavir, indinavir, saquinavir (for example as free base or as mesylate salt), nelfmavir (for example as free base or as mesylate salt), amprenavir, lopinavir or atazanavir (for example as free base or as sulphate salt)}; a ribonucleotide reductase inhinbitor {for example hydroxyurea}; or an antiretroviral {for example emtricitabine}; or, • an existing therapeutic agent for the treatment of osteoarthritis, for example a non¬ steroidal anti-inflammatory agent (hereinafter NSAID's) such as piroxicam or diclofenac, a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen, a fenamate such as mefenamic acid, indomethacin, sulindac or apazone, a pyrazolone such as phenylbutazone, a salicylate such as aspirin, a COX-2 inhibitor such as celecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intra-articular therapy such as a corticosteroid or a hyaluronic acid such as hyalgan or synvisc, or a P2X7 receptor antagonist.

The present invention still further relates to the combination of a compound of the invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin- B.subl. - and B.sub2. -receptor antagonist; (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGFβ); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony

stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK. sub 1. and NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; (xx) an elastase inhibitors selected from the group consisting of UT- 77 and ZD-0892; (xxi) a TNFα converting enzyme inhibitor (TACE); (xxii) an induced nitric oxide synthase inhibitor (iNOS); or (xxiii) a chemoattractant receptor-homologous molecule expressed on TH2 cells (a CRTH2 antagonist).

The following compounds illustrate compounds of formula (I)

Example 3

Example 1 Example 2

Example 4

Example 5

Example 7

Example 10

Example 9

Example 12 Example 13

-Example 16

Example 15

The following abbreviations are used in the following preparative Examples:

THF tetrahydrofuran

TFA trifluoroacetic acid

DMSO dimethylsulfoxide

DMF N,N-dimethylformamide

TBAT ΛζΛζN-tributylbutan-l-ammium difluoro(triphenyl)silicate

DIEA diisopropylethyl amine

NMP l-Methyl-2-pyrrolidinone app approximately sat saturated aq aqueous

General Methods

¹ H NMR spectra were recorded on a Varian Mercury-VX 300 MHz instrument or aVarian Unity 400MHz instument. The central peaks of chloroform-d (δ _H 7.27 ppm), acetnitrile-d3 (δ _H 1-95 ppm), or ΩMSO-d6 (δ _H 2.50 ppm) were used as internal references.

Low resolution mass spectra and accurate mass determination were recorded on a Hewlett- Packard 1100 LC-MS system equipped with APCI ionisation chamber. Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

The following methods were used for LC/MS analysis

Method A: Instrument Agilent 1100; Column C ₁₈ Waters Symmetry 2.1 x 30 mm 3.5μm; Flow rate 0.7 ml/min; Mass APCI; UV-absorption was measured at 254nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 5-95%/B 8 min, 95% B 2 min. Method B: Instrument Agilent 1100; Column Kromasil C ₁₈ 3 x 100 mm 5μm; Flow rate 1.0 ml/min; UV-absorption was measured at 254nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 10-100%B 20 min, 100% B 1 min.

Example 17

4-Bromo-N-d-methyl-3-phenyl-propyl)-benzenesulfonamide

4-Bromo-benzenesulfonyl chloride (120μL 0.3M /THF) was mixed with l-methyl-3- phenyl-propylamine (lOOμL 0.3M/pyridine) and stirred overnight in ambient temperature before it was evaporated to dryness under reduced pressure. The residue was purified on HPLC-C ₁₈ yielding 2.1mg (25%).

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.68 (ddt, J= 23.9, 8.8, 2.1 Hz, 3H), 7.30 - 7.15 (m, 3H), 7.06 (dd, J= 6.7, 1.6 Hz, 2H), 4.48 (d, J= 5.9 Hz, IH), 3.35 (q, J= 6.2 Hz, IH), 2.57 (ddd, J= 29.9, 14.0, 7.9 Hz, 3H), 1.71 (td, J= 7.8, 6.6 Hz, 2H), 1.10 (d, J= 6.6 Hz, 3H) LC (method A) rt = 6.1 min. UV 254 nm

Examples 18 - 76 were synthesised by a method analogous to that described in Example 17 using the corresponding starting materials.

Example 18 4-Chloro-N-Cl-methyl-3-phenyl-propylVbenzenesulfonamide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.79 (dt, J= 9.0, 2.2 Hz, 2H), 7.47 (dt, J= 8.9, 2.2 Hz, 2H), 7.30 - 7.17 (m, 3H), 7.06 (d, J= 6.8 Hz, 2H) ₃ 4.46 (d, J= 7.7 Hz, IH), 3.37 (quintet, J= 6.7 Hz, IH), 2.57 (ddd, J= 29.9, 14.0, 7.8 Hz, 2H), 1.71 (td, J= 7.8, 6.6 Hz, 2H), 1.10 (d, J- 6.6 Hz, 3H) LC (method A) rt = 6.0 min. UV 254 nm.

Example 19 4-Bromo-2-methyl-N-(l-methyl-3-phenyl-propyiybenzenesulfonam ide

¹ HNMR (299.944 MHz, CDCl ₃ ) δ 7.82 (d, J= 8.3 Hz, IH), 7.50 - 7.42 (m, 2H), 7.28 - 7.16 (m, 3H), 7.03 - 7.00 (m, 2H), 4.48 (s, IH), 3.31 (d, J= 5.5 Hz, IH), 2.63 (s, 3H), 2.61 - 2.45 (m, 2H), 1.76 - 1.64 (m, 2H), 1.11 (d, J= 6.4 Hz, 3H) LC (method A) rt = 6.5 min. UV 254 nm.

Example 20 N-(l-Methyl-3-phenyl-propyl)-4-trifluoromethoχy-benzenesulf onamide

LC (method A) rt = 6.3 min. UV 254 nm.

Example 21

4-Methoxy-2,3.6-trimethyl-N-f 1 -methyl-3 -phenyl-propylVbenzenesulfonamide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.26 - 7.12 (m, 3H), 7.02 - 6.97 (m, 2H), 6.58 (s, IH),

3.87 (s, 3H), 3.30 (q, J= 6.5 Hz ₃ IH), 2.65 (s, 3H) ₅ 2.59 (s, 4H), 2.57 - 2.43 (m, 6H), 2.16 (s,

3H), 1.73 - 1.63 (m, 2H) ₃ 1.10 (d, J= 6.6 Hz ₃ 3H)

APCI-MS m/z: 362.2 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 22

4-fert-Butyl-N-( 1 -metlτyl-3 -phenyl-propylVbenzenesulfonamide

¹ H NMR (299.944 MHz ₃ CDCl ₃ ) δ 7.83 (dd, J= 6.8, 1.8 Hz ₃ 2H) ₃ 7.54 (dd, J= 6.8, 1.8 Hz ₃

2H) ₃ 7.30 - 7.17 (m, 3H) ₃ 7.06 (d, J= 6.6 Hz ₃ 2H) ₃ 4.49 (d ₃ J= 8.1 Hz ₃ IH), 3.42 (quintet, J=

6.8 Hz ₃ IH) ₃ 2.58 (dtd, J= 21.9, 14.1, 7.9 Hz, 2H), 1.75 - 1.67 (m, 2H) ₃ 1.38 (s ₃ 9H), 1.12 (d,

J= 6.6 Hz ₃ 3H)

APCI-MS m/z: 346.3 [MH+].

LC (method A) rt = 6.6 min. UV 254 nm.

Example 23 N-(l-Methyl-3-phenvl-propvlV4-phenoxv-benzenesulfbnamide

APCI-MS m/z: 382.1 [MH+].

LC (method A) rt = 6.6 min. UV 254 nm.

Example 24 4'-Fluoro-biphenyl-4-sulfonic acid (l-methyl-3-phenyl-propyl ^' )-amide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 8.01 (dd, J= 6.7, 1.9 Hz, 2H), 7.75 (dd, J= 6.7, 1.7 Hz, 2H), 7.70 - 7.64 (m, 2H), 7.35 - 7.23 (m, 5H), 7.15 - 7.13 (m, 2H), 4.52 (s, OH) ₅ 3.52 (q, J= 6.4 Hz, IH), 2.67 (ddd, J= 32.7, 14.0, 7.9 Hz, 3H), 1.81 (dd, J= 14.5, 7.9 Hz, 2H), 1.21 (d, J = 6.6 Hz, 3H) LC (method A) rt = 6.6 min. UV 254 nm.

Example 25 N-(l-Methyl-3-phenyl-proρylV4-propyl-benzenesulfonamide

APCI-MS m/z: 332.2 [MH+].

LC (method A) rt = 6.5 min. UV 254 nm.

Example 26 N-d-Methyl-3-phenyl-propylV4-trifluoromethyl-benzenesulfonam ide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.99 (d, J= 8.1 Hz, 2H), 7.78 (d, J= 8.3 Hz, 2H), 7.30 ^■ 7.18 (m, 3H), 7.06 - 7.04 (m, 2H), 4.57 (d, J= 8.4 Hz, IH), 3.42 (dt, J= 14.9, 6.6 Hz, IH), 2.59 (ddd, J= 29.1, 13.9, 7.6 Hz, 2H), 1.77 - 1.70 (m, 2H), 1.13 (d, J= 6.4 Hz, 3H) LC (method A) rt = 6.2 min. UV 254 nm.

Example 27

4-(U -Dimethyl-propylVN-f 1 -methyl-3-phenyl-propyD-benzenesulfonamide

APCI-MS m/z: 360.2 [MH+].

LC (method A) rt = 7.2 min. UV 254 nm.

Example 28 N-(l-Methyl-3-phenyl-propylV3-trifluoromethyl-benzenesulfona mide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 8.16 (s, IH), 8.05 (d, J= 7.9 Hz, IH), 7.84 (d, J= 7.9 Hz, IH), 7.66 (t, J= 7.9 Hz, IH), 7.29 - 7.16 (m, 3H), 7.07 - 7.04 (m, 2H), 4.50 (d, J= 8.6 Hz, IH), 3.42 (dq, J= 8.3, 6.6 Hz, IH), 2.57 (ddd, J= 30.5, 14.1, 8.0 Hz, 2H), 1.73 (td, J= 7.8, 6.7 Hz, 2H), 1.11 (d, J= 6.6 Hz, 3H) LC (method A) rt = 6.2 min. UV 254 nm.

Example 29

Biphenyl-4-sulfonic acid fl-methyl-3-phenyl-propyr)-amide

APCI-MS m/z: 366.2 [MH+]. LC (method A) rt = 6.5 min. UV 254 nm.

Example 30 5-Bromo-thiophene-2-sulfonic acid ri-methyl-3-phenyl-propyl)-amide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.29 - 7.20 (m, 3H), 7.19 - 7.12 (m, IH), 7.09 - 7.04 (m, 2H), 7.00 (d, J= 4.0 Hz, IH), 4.50 (d, J= 8.1 Hz, IH), 3.40 (quintet, J= 6.8 Hz, IH), 2.58 (td, J= 7.9, 5.3 Hz, 2H), 1.72 (dd, J= 20.2, 2.2 Hz, 2H), 1.13 (d, J= 6.6 Hz, 3H) LC (method A) rt = 6.1 min. UV 254 nm.

Example 31

4-w-Butoxy-N-f 1 -methyl-3 -phenyl-propyD-benzenesulfOnamide

APCI-MS m/z: 362.2 [MH+].

LC (method A) rt = 6.7 min. UV 254 nm.

Example 32 2A6-Trimemyl-N-(l-memyl-3-phenyl-propylVbenzenesulfonamide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.31 - 7.16 (m, 3H), 7.05 - 7.00 (m, 4H), 4.43 (s, IH),

3.33 (t, J= 6.5 Hz, IH), 2.67 (s, 6H), 2.64 - 2.47 (m, 2H), 2.36 (s, 3H), 1.75 - 1.67 (m, 2H),

1.14 (d, J= 6.6 Hz, 3H)

APCI-MS m/z: 332.2 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 33 N-d-Methyl-3-phenyl-propyl)-3-p-tolyloxy-benzenesulfonamide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 7.57 - 7.53 (m, IH), 7.29 - 7.14 (m, 6H) ₃ 7.08 - 7.04 (m, 2H), 6.91 (dt, J= 8.9, 2.4 Hz, 2H) ₅ 7.46 - 7.41 (m, 2H), 4.57 (s, IH), 3.38 (q, J= 6.5 Hz, IH), 2.65 - 2.46 (m, 2H), 2.36 (s, 3H), 1.69 (td, J= 8.0, 6.6 Hz, 2H), 1.09 (d, J= 6.6 Hz, 3H) APCI-MS m/z: 396.2 [MH+]. LC (method A) it = 6.9 min. UV 254 nm.

Example 34 N-[2-( ^' 2,6-Dimethyl-phenoxy ^' )-l-methyl-ethyll-3-nitro-benzenesulfonamide

LC (method A) rt = 5.9 min. UV 254 nm.

Example 35 4-Bromo-N-r2-(2,6-dimethyl-phenoxy ^v )-l-methyl-ethyll-benzenesulfonamide

LC (method A) rt = 6.4 min. UV 254 nm.

Example 36 N-{4-r2-(2.6-Dimethvl-phenoxvVl-methvl-ethvlsulfamoyl]-phenv U-acetamide

APCI-MS m/z: 377.2 [MH+].

LC (method A) rt = 5.0 min. UV 254 nm.

Example 37 N-[2-(2,6-Dimethyl-phenoxy ^' )-l-methyl-ethyll-4-nitro-benzenesulfonamide

LC (method A) rt = 6.0 min. UV 254 nm.

Example 38 4-Bromo-N-r2-(2,6-dimethyl-phenoxyVl-methyl-ethyll-2-methyl- benzenesulfonamide

APCI-MS m/z: 412.1, 414.1 [MH+]. LC (method A) rt = 6.7 min. UV 254 nm.

Example 39 N-r2-(2,6-Dimethyl-phenoxy)-l-methyl-ethvn-4-methoxy-benzene sulfonamide

APCI-MS m/z: 350.2 [MH+].

LC (method A) rt = 5.8 min. UV 254 nm.

Example 40 N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyll-4-trifluorometho xy-benzenesulfonamide

LC (method A) rt = 6.6 min. UV 254 nm.

Example 41 4-tert-Butyl-N-r2-(2,6-dimetliyl-phenoxy)-l-methyl-ethyll-be nzenesulfonamide

APCI-MS m/z: 376.3 [MH+].

LC (method A) rt = 6.9 min. UV 254 nm.

Example 42 4-Cyano-N-[2-(2,6-dimethyl-phenoxyVl-methyl-ethyl]-benzenesu lfonamide

LC (method A) rt = 5.7 min. UV 254 nm.

Example 43 N-r2-( ^" 2,6-Dimethyl-phenoxyVl-methyl-ethyll-4-phenoxy-benzene sulfonamide

APCI-MS m/z: 412.3 [MH+].

LC (method A) rt = 6.8 min. UV 254 nm.

Example 44 4'-Fluoro-biphenyl-4-sulfonic acid r2-( ^' 2,6-dimethyl-phenoxyVl-methyl-ethyl]-amide

APCI-MS m/z: 414.2 [MH+].

LC (method A) rt = 6.8 min. UV 254 nm.

Example 45 N-[2-(2,6-Dimethyl-phenoxyyi-methγl-ethyl1-4-propyl-benzene sulfonamide

APCI-MS m/z: 362.2 [MH+].

LC (method A) rt = 6.8 min. UV 254 nm.

Example 46 N-[2-( ^" 2,6-Dimethyl-phenoxy ^' )-l-methyl-ethyl1-4-(4-fluoro-phenoxy)-benzenesulfonam ide

APCI-MS m/z: 430.1 [MH+]. LC (method A) rt = 6.8 min. UV 254 nm.

Example 47

N-F2-f 2.6-Dimethyl-phenoxvV 1 -methvl-ethvn-4-f 1.1 -dimethyl-propvlVbenzenesulfonamide

APCI-MS m/z: 390.2 [MH+].

LC (method A) rt = 7.4 min. UV 254 nm.

Example 48

Naphthalene-2-sulfonic acid [2-(2,6-dimethyl-phenoxyVl-methyl-ethyl1-amide

APCI-MS m/z: 370.1 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 49

Biphenyl-4-sulfonic acid r2-(2,6-dimethyl-phenoxy)- 1 -methyl-ethyli-amide

APCI-MS m/z: 396.2 [MH+].

LC (method A) rt = 6.8 min. UV 254 nm.

Example 50

5-Bromo-thiophene-2-sulfonic acid [2-(2,6-dimethyl-phenoxyV 1 -methyl-ethyl] -amide

LC (method A) rt = 6.4 min. UV 254 nm.

Example 51 2-Bromo-N-[2-(2,6-dimethyl-phenoxyVl-methyl-ethyl]-benzenesu lfonamide

APCI-MS m/z: 398.0, 400.0 [MH+]. LC (method A) rt = 6.2 min. UV 254 nm.

Example 52 N-[2-f2,6-Dimethyl-phenoxy)-l-methyl-ethyll-3-methoxy-benzen esulfonamide

APCI-MS m/z: 350.2 [MH+].

LC (method A) rt = 6.0 min. UV 254 nm.

Example 53

4-n-Butoxy-N- r2-(2,6-dimethyl-phenoxyV 1 -methyl-ethyll -benzenesulfonamide

APCI-MS m/z: 392.2 [MH+].

LC (method A) rt = 7.0 min. UV 254 nm.

Example 54 N-r2-( ^f 2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-rpyridin-2-ylo xyVbenzenesulfonamide

APCI-MS m/z: 413.2 [MH+]. LC (method A) rt = 6.0 min. UV 254 nm.

Example 55 N-[2-(2,6-Dimethyl-phenoxyVl-methyl-ethyll-2.4.6-trimethyl-b enzenesulfonamide

APCI-MS m/z: 362.2 [MH+].

LC (method A) rt = 6.8 min. UV 254 nm.

Example 56 N-r2-(2,6-Dimethyl-phenoxy ^* )-l-methyl-ethyl1-3-τ)-tolyloxy-benzenesulfonamide

APCI-MS m/z: 426.2 [MH+].

LC (method A) rt = 7.1 min. UV 254 nm.

Example 57 4-Bromo-2-methyl-N-(2-phenoxy-ethyl>benzenesulfonamide

LC (method A) rt = 5.9 min. UV 254 nm.

Example 58 N-(2-Phenoxy-ethylV4-trifluoromethoxy-benzenesulfonamide

LC (method A) rt = 5.9 min. UV 254 nm.

Example 59

4-d , 1 -Dimethyl-propyl)-N-C2-phenoxy-ethylVbenzenesulfonamide

APCI-MS m/z: 348.2 [MH+].

LC (method A) rt = 6.7 min. UV 254 nm.

Example 60

Biphenγl-4-sulfonic acid (2-phenoxy-ethyD-amide

APCI-MS m/z: 354.1 [MH+].

LC (method A) rt = 6.0 min. UV 254 nm.

Example 61 2A6-Trimethyl-N-(2-phenoxy-ethylVbenzenesulfonamide

APCI-MS m/z: 320.2 [MH+].

LC (method A) rt = 6.0 min. UV 254 nm.

Example 62 4-Bromo-N-(3-phenyl-propylVbenzenesulfonamide

LC (method A) rt = 6.0 min. UV 254 nm.

Example 63 4-Bromo-2-methyl-N-f3-phenyl-ρropviybenzenesulfonamide

LC (method A) rt = 6.3 min. UV 254 nm.

Example 64

N-(3-Phenyl-propylV4-trifluoromethoxy-benzenesulfbnamide

LC (method A) rt = 6.2 min. UV 254 nm.

Example 65 4-Methoxy-2,3,6-trimethyl-N-(3-phenyl-propyl)-benzenesulfona mide

APCI-MS m/z: 348.2 [MH+].

LC (method A) rt = 6.3 min. UV 254 nm.

Example 66 4-tert-Butyl-N-(3-phenyl-propyl)-benzenesulfonamide

APCI-MS m/z: 332.2 [MH+].

LC (method A) rt = 6.5 min. UV 254 nm.

Example 67 4-Phenoxy-N-(3-phenyl-propyl)-benzenesulfonamide

APCI-MS m/z: 368.2 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 68

4'-Fluoro-biphenyl-4-sulfonic acid Q-phenyl-propyD-amide

APCI-MS m/z: 370.1 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 69 N-f3-Phenyl-propylV4-propyl-benzenesulfonamide

APCI-MS m/z: 318.2 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 70 4-( ^" 4-Fluoro-phenoxvVN-(3-phenvl-propylVbenzenesulfonamide

APCI-MS m/z: 386.2 [MH+].

LC (method A) rt = 6.5 min. UV 254 nm.

Example 71

4-f U -Dimethyl-propylVN-f 3-ρhenyl-propyiybenzenesulfbnamide

APCI-MS m/z: 346.3 [MH+].

LC (method A) rt = 7.0 min. UV 254 nm.

Example 72

Naphthalene-2-sulfonic acid (3-phenyl-propyD-amide

APCI-MS m/z: 326.2 [MH+].

LC (method A) rt = 6.0 min. UV 254 nm.

Example 73

Biphenyl-4-sulfonic acid (3-phenyl-propyD-amide

APCI-MS m/z: 352.1 [MH+].

LC (method A) rt = 6.4 min. UV 254 nm.

Example 74

5-Bromo-thiophene-2-sulfonic acid (3-phenyl-propylVamide

LC (method A) rt = 6.0 min. UV 254 nm.

Example 75 2A6-Trimethyl-N-(3-phenyl-propyl)-benzenesulfonamide

APCI-MS m/z: 318.2 [MH+].

LC (method A) rt = 6.0 min. UV 254 nm.

Example 76

N-(3 -Phenyl-propyD-3 -p-tolyloxy-benzenesulfonamide

APCI-MS m/z: 382.1 [MH+].

LC (method A) rt = 6.7 min. UV 254 nm.

Example 77 N-r(lS)-2-r5-Isoquinolinyloxy)-l-methylethyll-2.4.6-trimethy lbenzenesulfonamide

Chiral

Step 1 : (2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate

L-Alaninol (4.8g, 64mmole) and 2-mesitylenesulfonyl chloride (3Og ₃ 137mmole) were dissolved in 20OmL pyridine and stirred at room temperature overnight. The mixture was evaporated, dissolved in ethyl acetate(200ml) and washed with IM HCl/aq, sat. NaHCO ₃ /aq. The organic layer was dried, concentrated and purified on a silica gel column chromatography (heptane-ethylacetate). APCI-MS m/z: 440.1 [MH+].

Step 2: N-[(l S)-2-(5-Isoquinolinyloxy)- 1 -methylethyl]-2,4,6-trimethylbenzenesulfonamide

(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (263mg, O.όmmole) was added to a slurry containing Cs ₂ CO ₃ (487mg, 1.5mmole) and 5- Hydroxyisoquinoline (145mg, lmmole) in 2.5mL DMF. The reaction mixture was stirred overnight in room teperature before it was diluted with ethyl acetate (2OmL) and washed with lMHCl/aq. The organic layer was dried, concentrated and purified on HPLC-C ₁₈ .

¹ H NMR (299.946 MHz, DMSO) δ 9.54 (s, IH), 8.54 (d, J= 6.2 Hz, IH), 8.11 (d, J= 6.2 Hz, IH), 7.84 (dd, J= 15.7, 8.5 Hz, 2H), 7.67 (t, J= 8.1 Hz, IH), 7.23 (d, J= 7.3 Hz, IH), 6.83 (d, J= 0.4 Hz, 2H), 4.04 - 3.92 (m, 2H), 3.65 (dq, J= 13.2, 6.6 Hz, IH), 2.50 (s, 6H), 2.11 (d, J= 11.6 Hz, 3H), 1.16 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 385.1 [MH+].

Examples 78 - 83 were synthesised by a method analogous to that described in Example 77 using (2S)-2-[(mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate and the corresponding starting materials.

Example 78 N-rriSV2-riH-Indol-4-yloxyVl-methylethvn-2,4,6-trimethylbenz enesulfonamide

¹ H NMR (299.946 MHz, DMSO) δ 10.94 (s, IH), 7.66 (d, J= 8.6 Hz, IH), 7.10 (t, J= 2.8 Hz, IH), 6.93 - 6.80 (m, 4H), 6.23 - 6.16 (m, 2H), 3.85 (dd, J= 9.7, 5.7 Hz, IH), 3.69 (dd, J- 9.7, 6.6 Hz, 2H), 3.46 - 3.37 (m, IH), 2.50 (s, 6H), 2.17 (s, 3H), 1.03 (d, J= 6.8 Hz, 2H) APCI-MS m/z: 373.1 [MH+].

Example 79 2,4 _< 6-Trimethyl-N-rClSVl-methyl-2-( ^' 5-quinolinyloxy')ethvnbenzenesulfonamide

¹ H NMR (299.946 MHz, DMSO) δ 9.13 (dd, J= 4.8, 1.7 Hz, IH), 8.79 (dd, J= 8.4, 0.7 Hz, IH), 7.88 (d, J= 8.6 Hz, IH), 7.65 (d, J= 8.6 Hz ₅ IH), 7.83 - 7.75 (m, 2H), 7.04 (d, J= 7.7 Hz, IH), 6.82 (s, 2H), 6.72 (s, IH), 4.06 - 3.94 (m, 2H), 3.70 - 3.62 (m, IH), 2.50 (s, 6H), 2.13 (s, 3H), 1.17 (d, J= 6.8 Hz, 2H) APCI-MS m/z: 385.3 [MH+].

Example 80

N-F(I SV2-d3-Benzodioxol-5-yloxyVl-metliylethvn-2,4,6-trimethylben zenesulfonamide

i HNMR (299.946 MHz, DMSO) δ 7.62 (d, J= 8.6 Hz, IH), 6.95 (s, 2H), 6.68 (d, J= 8.4 Hz, IH), 6.23 (d, J= 2.4 Hz, IH), 6.08 (dd, J- 8.5, 2.5 Hz, IH), 5.89 (s, 2H), 3.67 - 3.53 (m, 2H), 3.39 - 3.30 (m, IH), 2.50 (s, 6H), 2.21 (s, 3H), 1.00 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 378.2 [MH+].

Example 81

2 A6-Trimethyl-N-[( 1 S)- 1 -methyl-2-( ^' 4-quinolinyloxy)ethyl]benzenesulfonamide

Chiral

1 H NMR (299.946 MHz, DMSO) δ 8.10 (dd, J= 8.1, 1.1 Hz, IH), 7.90 (d, J= 7.5 Hz, IH), 7.81 (d, J= 9.5 Hz, IH), 7.74 - 7.64 (m, 2H), 7.42 (ddd, J= 8.0, 6.3, 1.7 Hz, IH), 6.56 (s, 2H), 6.15 (d, J= 7.5 Hz, IH), 4.40 (dd, J= 14.6, 4.1 Hz, IH), 3.91 (dd, J= 14.7, 10.5 Hz, IH), 3.62 (dd, J= 6.2, 3.7 Hz, IH), 2.20 (s, 6H), 2.13 (s, 3H), 1.21 (d, J= 6.6 Hz, 3H) APCI-MS m/z: 385.1 [MH+].

Example 82 2.4.6-Trimethyl-N-rriSVl-metliyl-2-(4-quinazolinyloxy ^> )ethyllbenzenesulfonamide

Chiral

HNMR (299.946 MHz, DMSO) δ 8.08 (s, IH), 7.96 (dd, J= 7.9, 1.1 Hz, IH), 7.82 - 7.76 (m, IH), 7.73 (d, J= 9.4 Hz, IH), 7.57 (dd, J= 8.0, 0.3 Hz, IH), 7.49 (ddd, J= 8.1, 7.1, 1.1 Hz, IH), 6.52 (s, 2H), 3.98 (dd, J= 12.7, 2.8 Hz, IH), 3.70 - 3.53 (m, 2H), 2.36 (s, 6H), 1.91 (s, 3H), 1.13 (d, J= 6.4 Hz, 3H) APCI-MS m/z: 386.2 [MH+].

Example 83 2,4,6-Trimethyl-N-r( ^' lSVl-metliyl-2-(8-qumolinyloxy)ethvnbenzenesulfonaniid e

Chiral

¹ HNMR (299.946 MHz, DMSO) δ 9.14 (dd, J= 5.0, 1.5 Hz, IH), 9.02 (d, J= 8.1 Hz, IH), 8.04 (dd, J= 8.3, 5.0 Hz, IH), 7.82 (d, J= 8.1 Hz, IH), 7.73 (t, J= 8.1 Hz, IH), 7.41 (d, J= 7.3 Hz, IH), 6.76 (dd, J= 0.3, 4.1 Hz, 2H), 4.21 (dd, J= 10.3, 5.3 Hz, 2H), 4.04 (dd, J= 10.3, 5.9 Hz, IH), 3.70 (dd, J= 20.9, 5.7 Hz, IH), 2.11 (d, J- 7.0 Hz, 3H), 1.24 (d, J= 6.8 Hz, 3H), 2.50 (s, 6H) APCI-MS m/z: 385.1 [MH+].

Example 84

5 -Fluoro-2-r ((2S)-2-rf mesitylsulfonypaminolpropyl} oxy)benzamide

(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate

L-Alaninol (4.8g, 64mmole) and 2-mesitylenesulfonyl chloride (3Og, 137mmole) were dissolved in 20OmL pyridine and stirred at room temperature overnight. The mixture was evaporated, dissolved in ethyl acetate (200ml) and washed with IM HCl/aq , sat. NaHCO ₃ /aq.

The organic layer was dried, concentrated and purified on a silica gel column chromatography (heptane-ethyl acetate). APCI-MS m/z: 440.1 [MH+].

Methyl 5-fluoro-2-hydroxybenzoate

5-Fluoro-2-hydroxybenzoic acid (468mg, 3 mmole) was refluxed in methanol (20 mL +6 drops of cone H ₂ SO ₄ ) overnight followed by evaporation to dryness. The product was used in next step without further purification.

5-Fluoro-2-hydroxybenzamide

Methyl 5-fluoro-2-hydroxybenzoate was dissolved in 37% NH ₃ /aq ( 2OmL) and stirred at 50°C for 60 hours. The solution was concentrated, diluted with ethylacetate (2OmL) and washed with brine. The product was used in the next step without any further purification. APCI-MS m/z: 156.0 [MH+].

Aryl ether formation: 5-Fluoro-2-({(2S)-2-[(mesitylsulfonyl)aminoJpropyl}oxy)benza mide

(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (263mg, 0.6mmole) was added to a slurry containing Cs ₂ CO ₃ (487mg, 1.5mmole) and 5-fluoro-2- hydroxybenzamide (app. lmmole) in 2.5mL DMF. The reaction mixture was stirred overnight in room teperature before it was diluted with ethylacetate (2OmL) and washed with IM HCl/aq. The organic layer was dried, concentrated and purified on HPLC-C ₁₈ .

¹ H NMR (299.946 MHz ₅ DMSO) δ 7.79 (d, J= 8.4 Hz, IH), 7.63 (s, 2H), 7.50 (dd, J= 9.5, 3.3 Hz, IH), 7.20 (ddd, J= 9.1, 7.7, 3.4 Hz, IH), 6.99 - 6.88 (m, 3H), 3.87 (d, J= 5.9 Hz, 2H), 3.56 - 3.45 (m, IH), 2.50 (s, 6H), 2.18 (s, 3H), 0.93 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 395.2 [MH+].

Examples 85-95 were synthesised by a method analogous to that described in Example 84 using the corresponding starting materials.

Example 85 2-( ^' {(2SV2-r( ^' Mesitylsulfonyl ^' )amino]propylloxyV5-methylbenzamide

Chiral

¹ H NMR (299.946 MHz, DMSO) δ 7.78 (d, J= 8.6 Hz ₃ IH), 7.59 - 7.51 (m, 2H), 7.40 (s,

IH), 7.14 (mult, IH), 6.92 (s, 2H), 6.78 (d, J= 8.4 Hz, IH), 3.83 (d, J= 5.8 Hz ₅ 2H), 3.50 (dd,

J= 8.3, 6.6 Hz, IH), 2.50 (s, 6H), 2.20 (s, 3H), 2.18 (d, J= 3.1 Hz, 3H), 0.91 (d, J= 6.8 Hz,

3H)

APCI-MS m/z: 391.1 [MH+].

Example 86 2-Hvdroxy-6-({f2SV2-rfmesitylsulfonvDammo]propyl|oxy)benzami de

¹ H NMR (299.946 MHz, DMSO) δ 8.07 (d, J= 22.4 Hz, 2H) ₃ 7.79 (d, J= 8.4 Hz, IH), 7.20 (t, J= 8.3 Hz ₃ IH), 6.92 (s, 2H) ₃ 6.39 (ddd, J= 21.5, 8.3, 0.8 Hz, 2H), 3.96 - 3.79 (m, 2H), 3.66 - 3.52 (m, IH), 2.50 (s, 6H) ₃ 2.19 (s, 3H), 0.88 (d, J= 6.6 Hz, 3H) APCI-MS m/z: 393.2 [MH+].

Example 87 5-Chloro-2-r{( ^" 2S)-2-r(mesitylsulfonyl)aminolρropyl|oxy)benzamide

¹ H NMR (299.946 MHz, DMSO) δ 7.79 (d ₃ J= 8.4 Hz ₃ IH) ₃ 7.71 (t, J= 2.5 Hz ₃ IH) ₃ 7.66 -

7.60 (m, 2H) ₃ 7.39 (dd, J= 8.8, 2.9 Hz, IH) ₃ 6.97 (d, J= 9.0 Hz, IH), 6.90 (s, 2H) ₃ 3.90 (d, J

= 5.9 Hz, 2H), 3.53 (dd, J= 20.7, 5.9 Hz, IH), 2.50 (s, 6H), 2.18 (s, 3H) ₃ 0.94 (d, J= 6.8 Hz ₃

3H)

APCI-MS m/z: 411.1 [MH+].

Example 88

2-({( ^' 2S)-2-r(Mesitylsulfonyl)amino]propyl|oxyV4-methylbenza mide

Chiral

¹ H NMR (299.946 MHz, DMSO) δ 7.80 (d, J= 8.4 Hz, IH), 7.69 (d, J= 7.7 Hz, IH), 7.51 (s, IH), 7.35 (s, IH), 6.91 (s, 2H), 6.77 (d, J= 7.9 Hz, IH), 6.73 (s, IH), 3.87 (d, J= 5.7 Hz, 2H), 3.59 - 3.45 (m, IH), 2.50 (s, 6H), 2.24 (s, 3H), 2.17 (s, 3H), 0.92 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 391.1 [MH+].

Example 89 2-({(2S)-2-r(Mesitylsulfonyl)amino]propyl>oxy)benzamide

¹ H NMR (399.988 MHz, CDC13) δ 8.05 (dd, J= 7.8, 1.7 Hz, IH), 7.92 - 7.82 (m, IH), 7.37 (s, IH), 7.00 (t, J= 7.6 Hz, 2H), 6.94 (s, 2H), 6.80 (d, J= 8.2 Hz, IH), 5.73 - 5.60 (m, IH), 4.05 - 3.94 (m, 2H), 3.89 - 3.78 (m, IH), 2.66 (s, 6H) ₅ 2.29 (s, 3H), 1.13 (d ₅ J= 6.8 Hz ₅ 3H) APCI-MS m/z: 377.2 [MH+].

Example 90

4-Fluoro-2-({(2S)-2-r(mesitvlsulfonvDamino]propvU oxy)benzamide

¹ HNMR (299.946 MHz, DMSO) δ 7.87 - 7.79 (m, 2H), 7.49 (s, 2H) ₅ 6.94 - 6.72 (m, 4H), 3.92 - 3.87 (m, 2H) ₅ 3.54 (dd, J= 8.2, 6.7 Hz ₅ IH) ₅ 2.50 (s, 6H), 2.17 (s, 3H) ₅ 0.93 (d ₅ J= 6.8 Hz, 3H) APCI-MS m/z: 395.2 [MH+].

Example 91 4-Chloro-2-(l(2SV2-[(mesitylsulfonyl)aminolpropγl}oxy)benza mide

¹ H NMR (299.946 MHz, DMSO) δ 7.80 (d, J= 8.4 Hz, 2H) ₅ 7.76 (d, J= 8.4 Hz, 2H), 7.55 (s, 2H), 7.53 (s, 2H), 7.06 - 6.99 (m, 2H), 6.90 (s, 2H), 3.91 (d, J= 5.9 Hz, 2H), 3.57 - 3.48 (m, 10H), 2.50 (s, 10H), 2.18 (s, 3H), 0.94 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 411.1 [MH+].

Example 92

5-Cvano-2-f(f2SV2-[(mesitylsulfonvDammo]propyl}oxy)benzam ide

¹ H NMR (299.944 MHz, CDCl ₃ ) δ 8.27 (d, J= 2.2 Hz, IH), 7.95 (s, IH), 7.69 (dd, J= 8.6, 2.4 Hz, IH), 6.97 - 6.91 (m, 3H), 6.85 (s, IH), 6.04 (d, J= 7.5 Hz, IH), 4.15 (dd, J= 9.2, 3.9 Hz, IH) ₅ 4.06 - 3.86 (m, 2H), 2.67 (s, 6H) ₅ 2.31 (s, 3H) ₅ 1.05 (d, J= 6.6 Hz ₅ 3H) APCI-MS m/z: 402.1 [MH+].

Example 93

2-r{C2S)-2-[(Mesitylsulfonyl)ammo]propyUoxy)-5-methoxyben zamide

Chiral

¹ HNMR (299.946 MHz ₅ DMSO) δ 7.78 (d, J= 8.4 Hz ₅ IH), 7.61 (s, IH) ₅ 7.49 (s, IH) ₅ 7.32 (d, J= 3.1 Hz ₅ IH) ₅ 6.95 - 6.81 (m, 4H) ₅ 3.81 (d ₅ J= 5.7 Hz ₅ 2H) ₅ 3.68 (s ₅ 3H) ₅ 3.53 - 3.42 (m, IH) ₅ 2.50 (s, 6H) ₅ 2.18 (s ₅ 3H), 0.91 (d, J= 6.8 Hz ₅ 3H)

APCI-MS m/z: 407.2 [MH+].

Example 94

3-({(2S)-2-r( ^" Mesitylsulfonyl)aminolpropyl}oxyV4-methylbenzamide

¹ H NMR (299.946 MHz, DMSO) δ 7.84 (s, IH), 7.67 (d, J= 8.4 Hz, IH), 7.31 (dd, J= 1.6, 1.4 Hz, IH), 7.23 - 7.17 (m, 2H), 7.10 (dd, J= 7.7, 0.6 Hz, IH), 6.92 (s, 2H), 3.75 (ddd, J= 34.1, 9.7, 5.8 Hz, 2H), 3.51 - 3.41 (m, IH), 2.50 (s, 6H), 2.16 (d, J= 6.6 Hz, 3H), 2.01 (s, 3H), 1.04 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 391.1 [MH+].

Example 95 2-d(2S)-2-r(Mesitylsulfonyl)ammo1propyl|oxy)-4-methoxybenzam ide

¹ H NMR (299.946 MHz, DMSO) δ 7.84 - 7.76 (m, 2H), 7.44 (s, IH), 7.26 (s, IH), 6.91 (s, 2H), 6.54 (ddd, J= 8.8, 4.0, 2.3 Hz, IH), 6.41 (d, J= 2.4 Hz, IH), 3.91 - 3.86 (m, 2H), 3.74 (s, 3H), 3.54 (dd, J= 8.2, 6.5 Hz, IH), 2.50 (s, 6H), 2.17 (s, 3H), 0.91 (d, J= 6.8 Hz, 3H) APCI-MS m/z: 407.2 [MH+].

Example 96 2,5-Dichloro-N-r(lS)-2-(isoquinolin-5-yloxy)-l-methylethvnth iophene-3-sulfonamide

Chiral

2-[(lS)-2-Hydroxy-l-methylethyl]-lH-isoindole-l,3(2H)-dione

Phthalic anhydride (50mmole, 7.4g) was dissolved in 10OmL toluene together with L- alaninol (50mmole, 3.9mL) and DIEA (5mmole, 900μL). The mixture was refluxed with continues removal of water with a Dean-Stark apparatus for two hours before it was washed with IM HCl/aq , sat. NaHCO ₃ /aq. The organic layer was dried, concentrated and used in the next step without any further purification. APCI-MS m/z: 206.0 [MH+].

(2S)-2-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)propyl 4-methylbenzenesulfonate

4-Methylbenzenesulfonyl chloride (43mmole, 8.2g) and 2-[(lS)-2-hydroxy-l- methylethyl]-lH-isoindole-l,3(2H)-dione (43mmole, 8.8g) were dissolved in pyridine (20OmL) and stirred overnight in room temperature. The mixture was evaporated, dissolved in ethyl acetate (200ml) and washed with IM HCl/aq, sat. NaHCO ₃ /aq. The organic layer was dried, concentrated and purified on a silica gel column chromatography (heptane-ethyl acetate). APCI-MS m/z: 360.0 [MH+].

2-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-lH-isoindo le-l,3(2H)-dione

(2S)-2-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)propyl 4-methylbenzenesulfonate (8 mmole, 2.9g) was added to a slurry containing Cs ₂ CO ₃ (4g, 12mmole) and 5- hydroxyisoquinoline (1.3g, 8.8mmole) in 10OmL DMF. The reaction mixture was stirred for two hours at 100°C before it was diluted with water (20OmL) and extracted with ethylacetate (3x15OmL). The combined organic layers were dried, concentrated and purified on a silica gel column chromatography (heptane-ethyl acetate).

Amine preparation [(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]amine

2-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-lH-isoindo le-l,3(2H)-dione (4.7mmole, 1.56g) was dissolved in ethanol (4OmL) together with hydrazine hydrate (14.1mmole, 684μL) and acetic acid (14.1mmole, 805μL) and refluxed for 3 hours. Solid material was removed by filtration and the solution was concentrated and purified on an ion exchange column (DOWEX 50WX2-400). APCI-MS m/z: 203.1 [MH+].

Sulfonamide coupling: 2,5-Dichloro-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylethyl]t hiophene-3-sulfonamide

2,5-Dichlorothiophene-3-sulfonyl chloride (lOOμL, 0.3M/THF) was mixed with [(I S)- 2-(isoquinolin-5-yloxy)-l-methylethyl]amine (lOOμL, 0.3M/pyridine) and stirred overnight in ambient temperature before it was evaporated to dryness under reduced pressure. The residue was purified on HPLC-C ₁ S. APCI-MS m/z: 349.1 [MH+]. LC (method A) rt = 3.2 min. UV 254 nm.

Examples 97 - 122 were synthesised by a method analogous to that described in Example 96 using the corresponding starting materials.

Example 97

N-[(lSV2-(Isoquinolin-5-yloxyVl-methylethyll-5-methyl-l-p henyl-lH-pyrazole-4- sulfonamide

Chiral

APCI-MS m/z: 423.2 [MH+]. LC (method A) rt = 3.7 min. UV 254 nm.

Example 98 l-( ^" DifluoromethylVN-rriSV2-(isoquinolin-5-yloxyVl-methyle thyl1-3,5-dimethyl-lH- pyrazole-4-sulfonamide

Chiral

APCI-MS m/z: 411.1 [MH+].

LC (method A) rt = 3.4 min. UV 254 nm.

Example 99

N-[dS)-2-dsoquinolm-5-yloxy)-l-methylethyll-2,5-dimethylfura n-3-sulfonamide

Chiral

APCI-MS m/z: 361.1 [MH+].

LC (method A) rt = 3.6 min. UV 254 run.

Example 100 2,5-Dichloro-N-r(lSVl-methyl-2-(quinolin-5-yloxy ^> )ethyllthiophene-3-sulfonamide

Chiral

APCI-MS m/z: 416.9, 419.0 [MH+]. LC (method A) rt = 4.0 min. UV 254 nm.

Example 101 3-Bromo-5-chloro-N-rriS)-l-methyl-2-( ^' quinolin-5-yloxy ^' )ethyl1thiophene-2-sulfonamide

Chiral

APCI-MS m/z: 460.9, 463.0 [MH+]. LC (method A) rt = 4.1 min. UV 254 nm.

Example 102

N-[riSV2-dsoquinolm-5-yloxyVl-methylethyl1-5-ri-methyl-5- rtrifluoromethγlVlH-pyrazol-

3-yi]thiophene-2-sulfonamide

APCI-MS m/z: 497.0 [MH+].

LC (method A) rt = 4.5 min. UV 254 nm.

Example 103 l-(DifluoromethvD-N-r(lS)-2-(isoqumolm-5-yloxy)-l-methylethy l]-5-methyl-lH-pyrazole-4- sulfonamide

APCI-MS m/z: 397.1 [MH+].

LC (method A) rt = 3.3 min. UV 254 nm.

Example 104

5-Methyl-N-[(lS)-l-methyl-2-( ^' quinolm-5-yloxy ^> )ethyll-l-phenyl-lH-pyrazole-4-sulfonamide

Chiral

APCI-MS m/z: 416.1 [MH+].

LC (method A) rt = 3.6 min. UV 254 nm.

Example 105 5-Chloro-N-[(lSV2-( ^' isoquinolin-5-yloxy)-l-methylethyl]thiophene-2-sulfona mide

APCI-MS m/z: 383.0 [MH+].

LC (method A) rt = 3.8 min. UV 254 nm.

Example 106 5-Chloro-N-rdSVl-methyl-2-rqumolin-5-yloxykmyl1thiophene-2-s ulfonamide

APCI-MS m/z: 383.0 [MH+].

LC (method A) rt = 3.8 min. UV 254 nni.

Example 107

Methyl 4-r{[(lSV2-(isoqumolin-5-yloxyVl-methylethyl1amino>sulfon ylV2,5-dimethyl-3- furoate

Chiral

APCI-MS m/z: 419.2 [MH+].

LC (method A) rt = 3.8 min. UV 254 nm.

Example 108

N-[Cl SV2-(Isoqumolin-5-yloxy)- 1 -methylethylithiophene-3-sulfonamide

APCI-MS m/z: 349.1 [MH+].

LC (method A) rt = 3.2 min. UV 254 nm.

Example 109 l-Ethyl-N-[dS)-2-(isoquinolin-5-yloxyVl-methylethvn-lH-pyraz ole-4-sulfonamide

Chiral

APCI-MS m/z: 361.1 [MH+]. LC (method A) rt = 2.9 min. UV 254 nm.

Example 110

2-r(C2S ^' )-2-{r(2,5-Dichloro-3-thienyl)siilfonyl]aminolpropyl ^' )oxylbenzamide

APCI-MS m/z: 409.0, 410.9 [MH+]. LC (method A) rt = 4.7 min. UV 254 nm.

Example 111 l-(DifluoromethylV3,5-dimethyl-N-r(lS ^' )-l-methyl-2-rqumolin-5-yloxy ^' )ethyl]-lH-pyrazole-

4-sulfonamide

APCI-MS m/z: 411.1 [MH+].

LC (method A) rt = 3.4 min. UV 254 nm.

Example 112

N-r(lSVl-Methyl-2-fquinolm-5-yloxy^ethyl]-5-ri-methyl-5-r trifluoromethylVlH-pyrazol-3- yl]thiophene-2-sulfonamide

APCI-MS m/z: 497.0 [MH+].

LC (method A) rt = 4.5 min. UV 254 nm.

Example 113

1 -Ethvl-N-r(lSVl-methvl-2-rquinolin-5-yloxv')ethvl1-lH-pvrazo le-4-sulfonamide

Chiral

APCI-MS m/z: 361.1 [MH+].

LC (method A) rt = 2.9 min. UV 254 nm.

Example 114

2-({(2SV2-r({5-ri-Methyl-5-rtrifluoromethylVlH-pyrazol-3- yll-2-thienvnsulfonylV aminolpropyl} oxy)benzamide

APCI-MS m/z: 489.1 [MH+].

LC (method A) rt = 5.1 min. UV 254 nm.

Example 115 2-[( ^" (2SV2-([(2,5-Dimethyl-3-thienyl ^' )sulfonyl1ammo|propyl)oxy1benzamide

APCI-MS m/z: 369.1 [MH+].

LC (method A) rt = 4.4 min. UV 254 nm.

Example 116 2.5-Dimethvl-N-rdS)-l-methvl-2-( ^/ quinolin-5-vloxv')ethvl1fιιran-3-sulfonamide

Chiral

APCI-MS m/z: 361.1 [MH+].

LC (method A) rt = 3.7 min. UV 254 nm.

Example 117 2-r((2S)-2-{r(2,5-Dimethyl-3-furyl)sulfonyllammo|propyDoxy1b enzamide

APCI-MS m/z: 353.2 [MH+].

LC (method A) rt = 4.2 min. UV 254 nm.

Example 118

2- 11Y2S V2-C ( F 1 -rDifluoromethylV3 ,5-dimethyl- lH-pyrazol-4-yll sulfonyl) amino^propyl]- oxylbenzamide

Chiral

APCI-MS m/z: 403.0 [MH+].

LC (method A) rt = 3.9 min. UV 254 nm.

Example 119 l-Ethyl-N-rriSV2-αsoquinolm-5-yloxyVl-methγlethyll-3-methy l-lH-pyrazole-4- sulfonamide

Chiral

APCI-MS m/z: 375.2 [MH+].

LC (method A) rt = 3.0 min. UV 254 nm.

Example 120

N-[Q SV2-dsoquinolin-5-yloxv)-l-methvlethvll-l,3.,5-trimethvl-lH- pvrazole-4-sulfonamide

Chiral

APCI-MS m/z: 375.1 [MH+].

LC (method A) rt = 2.9 min. UV 254 nm.

Example 121 N-[(lS)-2-(Isoqumolm-5-yloxyVl-methylethyl]-3,5-dimethylisox azole-4-sulfonamide

Chiral

APCI-MS m/z: 362.2 [MH+].

LC (method A) rt = 3.3 min. UV 254 nm.

Example 122 N-[(lS)-2-(Isoqumolm-5-yloxy)-l-methylethyll-2,5-dimethylthi ophene-3-sulfonamide

Chiral

APCI-MS m/z: 377.2 [MH+].

LC (method A) rt = 3.8 min. UV 254 nm.

Example 123

2,4,6-Trimethyl-N-(dSVl-methyl-2-r( ^' 8-methylαumolin-5-vDaminolethyl>- benzenesulfonamide

Chiral

(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate was prepared as described in Example 77.

2,4,6-Trimethyl-N-{(lS)-l-methyl-2-[(8-methylquinolin-5-y l)amino]ethyl}benzene- sulfonamide

(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (132mg, 0.3mmole) and 8-methylquinolin-5-amine (47mg, 0.3mmole) were dissolved in NMP (ImL) and heated to 130°C for 2 hours. The reaction mixture was purified directly on HPLC-C ₁₈ .

¹ H NMR (399.99 MHz, DMSO) δ 8.80 (d, J= 5.2 Hz, IH) ₃ 8.34 (d, J= 9.4 Hz, IH), 7.57 (d, J= 8.4 Hz, IH), 7.36 (dd, J= 8.6, 4.1 Hz, IH), 7.19 (d, J= 7.8 Hz, IH), 6.83 (s, 2H), 6.11 (d, J= 7.8 Hz, IH), 6.06 (t, J= 5.6 Hz, IH), 3.38 (q, J= 7.1 Hz, IH), 3.06 (dd, J= 13.7, 8.1 Hz, 2H), 2.50 (s, 6H), 2.49 (s, 3H), 2.14 (s, 3H), 1.01 (d, J= 6.6 Hz, 3H) APCI-MS m/z: 398.1 [MH+].

Examples 124 — 129 were synthesised by a method analogous to that described in Example 123 using the corresponding starting materials.

xample 124 ^.ό-Trimethyl-N-lflSVl-methyl-Σ-rrό-methylqumolin-S-vDami noiethyll- enzenesulfonamide

Chiral

H NMR (399.99 MHz, DMSO) δ 8.80 (d, J= 3.0 Hz, IH), 8.34 (d, J= 7.6 Hz, IH), 7.57 (s, H), 7.36 (dd, J= 8.4, 4.1 Hz, IH), 7.19 (d, J= 7.8 Hz, IH), 6.83 (s, 2H), 6.11 (d, J= 7.8 Hz, H), 6.07 (t, J= 5.6 Hz, IH) ₃ 3.40 - 3.33 (m, IH), 3.06 (d, J= 5.3 Hz, 2H), 2.50 (s, 6H), 2.50 3, 3H), 2.14 (s, 3H), 1.01 (d, J= 6.5 Hz, 3H) LPCI-MS m/z: 398.1 [MH+].

Example 125

I-[Y 1 S )-2-( 1 H-Indazol-4-ylamino)- 1 -methylethyl] -2 A6-trimethylbenzenesulfonamide

Chiral

HNMR (399.991 MHz, cd3cn) δ 7.92 (s, IH), 7.03 (d, J= 7.7 Hz, IH), 6.87 (t, J= 7.8 Hz, :H), 6.81 (s, 2H) ₅ 6.21 (d, J= 7.4 Hz, IH), 5.68 (d, J= 8.1 Hz, IH), 3.60 - 3.49 (m, IH), 3.21 mult, 2H), 2.51 (s ₅ 6H), 2.18 (s, 3H), 1.14 (d, J= 6.6 Hz, 3H) ^PCI-MS m/z: 373.1 [MH+].

kample 126

L4.6-Trimethyl-N-[dSVl-methyl-2-(quinolin-5-ylammo)ethyl] benzenesulfonamide

Chiral

HNMR (299.946 MHz, cd3cn) δ 8.80 (d, J= 4.0 Hz, IH), 8.10 (d, J= 8.6 Hz, IH), 7.34 mult, 3H), 6.74 (s, 2H), 6.36 (d, J= 7.7 Hz, IH), 5.68 (d, J= 7.9 Hz, IH), 5.23 (s, IH), 3.57 mult, IH), 3.18 (mult, 2H), 2.51 (s, 6H), 2.12 (s, 3H), 1.17 (d, J= 6.6 Hz, 3H)

JPCI-MS m/z: 384.1 [MH+].

xample 127 [-r(lS ^" )-2-(lH-Indazol-6-ylammo)-l-methylethyll-2 ₁ 4,6-trimethylbenzenesulfonamide

HNMR (399.991 MHz, cd3cn) δ 7.83 (s, IH), 7.41 (d, J= 8.7 Hz, IH), 6.90 (s, 2H), 6.38 id, J= 8.8, 1.9 Hz, IH), 6.34 (s, IH), 5.63 (d, J= 8.1 Hz, IH), 3.46 (t, J= 6.5 Hz, IH), 3.07 td, J= 13.4, 7.7 Hz, 2H), 2.56 (s, 6H), 1.10 (d, J= 6.6 Hz, 3H), 2.17 (s, 3H) ϋPCI-MS m/z: 373.1 [MH+].

Example 128

^.e-Trimethyl-N-ldSVl-methyl-Σ-r^-methylquinolin-S-vDami noiethvU- enzenesulfonamide

Chiral

H NMR (399.991 MHz, cd3cn) δ 7.99 (d, J= 8.7 Hz, IH), 7.36 (t, J= 8.0 Hz, IH), 7.23 (d, J = 8.7 Hz, IH), 7.17 (d, J= 8.4 Hz, IH), 6.77 (s, 2H), 6.31 (d, J= 7.7 Hz, IH), 5.69 (d, J= 6.7 Iz, IH), 5.17 (s, IH), 3.56 (d, J= 6.0 Hz, IH), 3.16 (mult, 2H), 2.64 (s, 3H), 2.52 (s, 6H), L 14 (s, 3H), 1.17 (d, J= 6.7 Hz, 3H) ^PCI-MS m/z: 398.1 [MH+].

Example 129 ^< J-rπSV2-dH-Indazol-5-vlaminoVl-methvlethvπ-2,4,6-tri methvlbenzenesulfonamide

H NMR (399.991 MHz, cd3cn) δ 7.85 (s, IH), 7.39 (d, J= 8.6 Hz, IH) ₃ 6.95 (s, 2H), 6.85 (s, H), 6.83 (d, J= 2.1 Hz, IH) ₃ 5.82 (d, J= 8.2 Hz ₃ IH) ₃ 3.50 (t, J= 6.4 Hz ₃ IH) ₃ 3.12 (mult, H), 2.57 (s ₃ 6H), 2.21 (s, 3H), 1.06 (d, J= 6.7 Hz ₃ 3H) PCI-MS m/z: 373.1 [MH+].

xample 130

[-(( 1 SV 2- { r2-Chloro-4-fmethylsulfonyl)phenyll amino} - 1 -methylethylV2,4,6- imethylbenzenesulfonamide

HNMR (399.99 MHz ₃ DMSO) δ 7.63 (d, J= 2.1 Hz, IH) ₃ 7.55 (s, IH) ₃ 7.47 (dd ₃ J= 8.7, 2.0 Iz ₃ IH) ₃ 6.89 (s, 2H), 6.58 (d, J= 8.8 Hz, IH) ₃ 6.16 (t, J= 5.8 Hz, IH) ₃ 3.22 - 3.03 (m, 6H) ₃ .51 (s, 6H) ₃ 2.20 (s, 3H), 1.01 (d, J= 6.5 Hz ₃ 3H) ϋPCI-MS m/z: 445.0 [MH+].

Examples 131-144 were prepared via the aryl ether formation as described in Example 4, using (2S)-2-[(mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate and the orresponding starting materials.

Example 131

J-rflSV2-r4-Cvano-2.6-dimethylphenoxyVl-methylethyl1-2,4, 6- rimethylbenzenesulfonamide

H NMR (299.946 MHz ₃ DMSO) δ 7.76 (d, J= 8.4 Hz ₃ IH) ₃ 7.50 (s, 2H) ₃ 7.01 (s, 2H) ₃ 3.82 - i.71 (m, OH) ₃ 3.57 - 3.37 (m, 3H) ₃ 2.55 (s, 6H) ₃ 2.24 (s, 3H) ₃ 2.10 (s, 6H) ₃ 1.13 (d, J= 6.6 Hz ₃

>H)

^PCI-MS m/z: 387.2[MH+].

H NMR (399.988 MHz, CDC13) δ 8.14 (dd, J= 7.8, 1.7 Hz, IH), 7.84 (s, IH), 7.38 (dd, J= 5.6, 1.8 Hz, IH), 7.09 (t, J= 7.5 Hz, IH), 6.94 (s, 2H), 6.82 (d, J= 8.4 Hz, IH), 4.94 - 4.82 n, IH), 3.99 - 3.96 (m, 2H), 3.88 - 3.78 (m, IH), 3.06 (d, J= 4.9 Hz, 3H), 2.65 (s, 6H), 2.29 !, 3H), 1.12 (d, J= 6.8 Hz, 3H) PCI-MS m/z: 391.2 [MH+].

xample 139 -|2-f( ^' MesitylsulfonvDammo1propoxy>benzaniide

H NMR (299.944 MHz, CDCl ₃ ) δ 7.73 (dd, J= 6.9, 1.9 Hz, 2H), 6.91 (s, 2H), 6.77 (d, J= .2 Hz, 2H), 5.03 (d, J= 7.9 Hz, IH), 3.89 - 3.74 (m, 2H), 3.75 - 3.63 (m, IH), 6.16 - 5.63 (m, H), 2.65 (s, 6H), 2.27 (s, 3H), 1.26 (d, J= 6.8 Hz, 3H) LPCI-MS m/z: 377.3 [MH+].

Example 140

J- (2-F4-C 1H-Imidazol- 1 -vDphenoxy]- 1 -methylethyl} -2,4,6-trimethylbenzenesulfonamide

H NMR (299.944 MHz, CDCl ₃ ) 59.02 (s, IH), 7.58 (s, IH), 7.46 - 7.39 (m, 3H), 6.96 (d, J= 1.3 Hz, 4H), 5.10 (d, J= 8.1 Hz, IH), 3.92 (t, J= 4.2 Hz, 2H), 3.77 - 3.62 (m, IH), 2.67 (s, iH), 2.29 (s, 3H), 1.26 (d, J= 6.8 Hz, 3H) UPCI-MS m/z: 400.2 [MH+].

Nf-[(lS)-2-f2H-Indazol-3-yloxy)-l-methylethyll-2,4,6-trimeth ylbenzenesulfonamide

Chiral

HNMR (399.99 MHz ₃ DMSO) δ 11.79 (s, IH), 7.72 (d, J= 8.6 Hz, IH), 7.36 (d, J= 8.0 Hz, H), 7.30 (d, J= 3.5 Hz, 2H), 6.98 (dt, J= 8.0, 3.9 Hz, IH), 6.88 (s, 2H), 4.14 - 4.00 (m, 2H), 1.63 (quintet, J= 6.9 Hz, IH), 2.54 (s, 6H), 2.16 (s, 3H), 1.11 (d, J= 6.7 Hz, 3H) ^PCI-MS m/z: 374.1 [MH+].

Example 145 kMethyl-N-rS-phenyl-l-CtrifluoromethvDpropynbenzenesulfonami de

-Methyl-N- [( 1 Z)-3 -phenylpropylidene]benzenesulfonamide

A mixture of 4-methylbenzenesulfonamide (10 mmole, 1.7Ig), 3-phenylpropanal lOmmole, 1.34g) and sodium p-toluenesulfinate (llmmole, 1.78g) in formic acid (15mL) nd water (15mL) was stirred over night. The resulting white precipitate was filtered off, cashed with water (2x1 OmL), pentane (1OmL) and dissolved in dichloromethane (10OmL). laturated NaHCO ₃ /aq (7OmL) was added and the mixture was stirred vigorously for 2 hours, 'he organic phase was decanted and the aqueous phase was extracted with CH ₂ Cl ₂ . The ombined phases was dried and evaporated to dryness and used in the next step without any urther purification.

-Methyl-N-[3-phenyl-l-(trifluoromethyl)propyl]benzenesulf onamide

TBAT (Llmmole, 594mg) was dissolved in dry THF (12mL) and cooled to 0 ⁰ C under iert conditions. In a separate flask 4-methyl-N-[(lZ)-3-phenylpropylidene]- enzenesulfonamide (1 mmole, 287mg) and trimethyl(trifluoromethyl)silane (1.2mmole, 70mg) were dissolved in dry THF (1OmL) and slowly added to the TBAT-solution. The lixture was stirred for 45 min at 0°C before it was quenched with sat. NH ₄ Cl/aq (6mL) . At

Dom temperature the mixture was extracted with ethylacetate. The organic phase was dried, oncentrated and purified on a silica gel column chromatography (heptane-ethyl acetate).

H NMR (299.946 MHz, DMSO) δ 8.71 (d, J= 8.6 Hz, IH), 7.88 (dt, J= 6.5, 1.9 Hz, 2H), .54 (d, J= 7.9 Hz, 2H) ₃ 7.42 - 7.26 (m, 3H), 7.16 - 7.12 (m, 2H), 4.18 - 4.00 (m, IH), 2.55 - .34 (m, 5H), 2.06 - 1.91 (m, IH), 1.88 - 1.70 (m, IH) ³ F NMR (470.314 MHz ₃ DMSO) δ -74.42 (d)

Example 146

J-[(lS)-2-fIsoquinolin-5-yloxy ^' )-l-methylethyll-2,4-dimethylbenzenesulfonamide

:,4-Dimethylbenzenesulfonyl chloride

2,4-Dimethylbenzenesulfonic acid (lOmmole, 1.86g), DIEA (10 mmole, 1.7mL) and yanuric chloride (lOmmole, 1.84g) were dissolved in acetone (4OmL) and the reaction nixture was refluxed overnight. After cooling to room temperature the mixture was filtered hrough a Celite pad. Solvent was removed by evaporation under reduced pressure. The iroduct was used in the next step without any further purification.

¹ J- [( 1 S)-2-(Isoquinolin-5 -yloxy)- 1 -methylethyl] -2,4-dimethylbenzenesulfonamide

The sulfonamide coupling was performed as described in Example 96 using the iorresponding starting materials. ^PCI-MS m/z: 371.2 [MH+]. .C (method A) rt = 3.8 min. UV 254 nm.

Examples 147 to 153 were synthesised by a method analogous to that described in ϊxample 146 using the corresponding starting materials.

Example 147 ^l J-rdSV2-Qsoquinolin-5-yloxyVl-methy1ethyl1-3.4-dimethy lbenzenesulfonamide

Example 151

-r((2S)-2-{r(2,4-Dimethylphenyl)sulfonyllamino|propyl)oxy lbenzamide

.PCI-MS m/z: 363.2 [MH+].

,C (method A) rt = 4.5 min. UV 254 am.

Sample 152

,5-Dimethyl-N-[ ^' ( ^' lSVl-methyl-2-(qumolin-5-yloxy)ethyl]benzenesulfonamid e

Chiral

O ¹ CI-MS m/z: 371.2 [MH+].

,C (method A) rt = 3.8 min. UV 254 nm.

Example 153

:- \((2 S)-2- { \(3 ,4-Dimethylphenyl)sulfbnvπ amino } propyDoxyibenzamide

Chiral

^PCI-MS m/z: 363.2 [MH+].

.C (method A) rt = 4.5 min. UV 254 nm.

Examples 154 to 158 were synthesised by a method analogous to that described in ϊxample 96, "Sulfonamide coupling", using the corresponding starting materials.

cample 154 -(2-AnilmoethylV2,4,6-trimetliylbenzenesulfonamide

PCI-MS m/z: 319.4 [MH+].

C (method A) rt = 4.6 min. UV 254 nm.

xample 155 -r2-r2,6-DimethylphenoxyVl-methylethvn-4-(trifluoromethyl)be nzenesulfonamide

,C (method A) rt = 5.4 min. UV 254 nm.

Example 156 [-(2-Anilinoethyl)-4'-fluorobiphenyl-4-sulfonamide

sJPCI-MS m/z: 371.0 [MH+].

,C (method A) rt = 5.0 min. UV 254 nm.

Example 157 'J-(2-Anilinoethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonam id

PCI-MS m/z: 349.1 [MH+].

C (method A) rt = 4.7 min. UV 254 nm.

xample 158 ^' -(2-AnilinoethylV4-bromo-2-methylbenzenesulfonamid

PCI-MS m/z: 369.1, 371.1 [MH+].

C (method A) rt = 4.8 min. UV 254 nm.

xample 159 -r4-FluorophenylViV-rri5)-2-risoqumolin-5-yloxyVl-methylethy l1-3.5-dimethyl-lH- yrazole-4-sulfonamide

-(4-Fluorophenyl)-3,5-dimethyl-lH-pyrazole

4-Fluorophenylhydrazine hydrochloride (3mmole, 488mg) and acetylacetone 3mmole, 310μL) were refluxed in ethanol (25mL) for 1 hour before the reaction mixture was vaporated to dryness. The residue was used in the next step without any purification.

-(4-Fluorophenyl)-3,5-dimethy 1- lH-pyrazole-4-sulfonyl chloride l-(4-Fluorophenyl)-3,5-dimethyl-lH-pyrazole (app. 3mmole) was dissolved in hloroform (4OmL). Chlorosulfonic acid (30mmole, 2mL) was added dropwise and the saction mixture was refluxed for 2 hours. After cooling the mixture to room temperature ulfuryl chloride (25mmole, 2mL) was added. The reaction mixture was refluxed for 3hours efore it was diluted with chloroform and washed with water. The organic phase was dried, oncentrated and purified on a silica gel column chromatography (heptane-ethyl acetate). LPCI-MS m/z: 288.9 [MH+].

-(4-Fluorophenyl)-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylet hyl]-3,5-dimethyl-lH- ιyrazole-4-sulfonamide

Amine preparation and Sulfonamide coupling were conducted using a method nalogous to that described in Example 96.

H NMR (399.99 MHz, DMSO) δ 9.53 (s, IH), 8.55 (d, J= 6.1 Hz, IH), 8.31 (d, J= 6.1 Hz,

H), 7.99 (d, J= 8.1 Hz, IH), 7.84 (d, J= 8.3 Hz, IH), 7.72 (t, J= 8.0 Hz, IH), 7.36 (mult,

H), 4.12 - 4.01 (m, 2H), 3.75 - 3.69 (m, IH), 2.37 (s, 3H), 2.32 (s, 3H), 1.24 (t, J= 6.8 Hz,

H)

O ¹ CI-MS m/z: 455.1 [MH+].

example 160

/-r( ^' l _l S ^f )-2-( ^' Isoquinolin-5-yloxy)-l-methylethyll-3,5-dimethyl-l-phe nyl-liJ ^r -pyrazole-4- ulfonamide

Example 160 was synthesised using a method analogous to Example 159.

H NMR (399.99 MHz, DMSO) δ δ9.50 (s, IH) ₅ 8.53 (d, J= 6.1 Hz, IH), 8.28 (d, J= 6.1 Hz, H), 7.98 (d, J= 8.2 Hz, IH), 7.82 (d, J= 8.2 Hz, IH), 7.71 (t, J= 8.0 Hz, IH), 7.54 - 7.43 m, 3H), 7.32 (dd, J= 6.4, 1.8 Hz, 3H), 4.06 (quintet, J= 4.7 Hz, 2H), 3.75 (q, J= 6.4 Hz, H), 2.39 (s, 3H), 2.34 (s, 3H), 1.25 (d, J= 6.8 Hz, 3H) UPCI-MS m/z: 437.1 [MH+].

Example 161

J,2,4,6-Tetramethyl-N-| ^' ( ^' lS ^' )-l-methyl-3-phenylpropyllbenzenesulfonamide Chiral

2,4,6-Trimethyl-N-[(lS)-l-metliyl-3-phenylpropyl]benzenes ulfonaniide (109mg, ι.33mmol) and potassium carbonate (272mg, 2.0mmol) was dissolved in DMF (ImI), the olution was cooled to 0°C and iodomethane (41μl, 0.66mmol) was added dropwise. The eaction mixture was stirred for 15h at ambient temperature, dispersed between iichloromethane and water and extracted with dichloromethane. The combined organic ihases were dried over sodium sulphate, filtered and evaporated.

HNMR (299.944 MHz, CDCl ₃ ) δ 7.26 - 7.15 (m, 3H), 7.08 - 7.04 (m, 2H), 6.93 (s, 2H),

1.75 (q,lH), 2.74 (s,3H), 2.58 (s, 6H), 2.56 - 2.40 (m, 2H), 2.31 (s, 3H), 1.86 - 1.64 (m, 2H),

.19 (d, 3H).

,C (method B) rt = 16.2 min. UV 254 nm.

Example 162

'.4,6-Trimethyl-N- { 1 -r(quinolm-5-yloxy)methyl]prorM)benzenesulfonamide

The title compound was obtained from 2-mesitylenesulfonyl chloride, 2-aminobutan- -ol and quinolin-5-ol by a method analogous to that described in Example 77.

HNMR (400MHz, CDCl ₃ ) δ 8.96 (dd, IH), 8.52 (d,lH), 7.74 (d,lH), 7.53 (s,lH), 7.39 m,lH), 6.83 (s,2H), 6.68 (d,lH) ₅ 5.50 (bs, IH), 4.12 (dd, IH), 3.98 (dd, IH), 3,63 (m, IH), ».63 (s, 6H), 2.24 (s, 3H), 1.75 (m, 2H), 0.91 (t, 3H). ^PCI-MS m/z: 399 [MH+].

C (method B) rt = 8.1 min. UV 254 nm.

xample 163 -Chloro-2-{2-r(mesitylsulfonyl)amino1butoxy}benzaniide

The title compound was obtained from 2-mesitylenesulfonyl chloride, 2-aminobutan- -ol and 5-chloro-2-hydroxybenzamide by a method analogous to that described in Example 7.

HNMR (400MHz, dimethylsulfoxide-d ₆ ) δ 7.73 (d, IH), 7.43 (dd, IH), 6.97 (d, IH), 6.93 s, 2H), 3.95 (m,2H), 3.36 (m,lH), 2.53 (s, 6H), 2.21 (s, 3H), 1.54 - 1.35 (m, 2H), 0.68 (t,

H). tfCI-MS m/z: 425/427 (3:1) [MH+].

.C (method B) rt = 11.7 min. UV 254 nm.

Examples 164 - 184 were synthesised by a method analogous to that described in ϊxample 17 using the corresponding starting materials.

Example 164

L4-Dichloro-6-methyl-N-fdS)-l-methyl-2-rquinolin-5-yloxy ^> )ethyllbenzenesulfonamide

^PCI-MS m/z: 425/427 [MH+].

JC (method A) rt = 4.0 min. UV 254 nm.

Example 165

>-Chloro-2- (r(2SV2-({r4-r4-fluorophenoxv ^' )phenvl1sulfonvUammo)propvl]oxvlbenzamide .

: (method A) rt = 4.2 min. UV 254 nm

sample 169

Chloro-2- { [(2S)-2-( { [3-f 3,4-dichlorophenoxy)phenyl1sulfonγl| amino)propylloxy} -

Chiral

PCI-MS m/z: 529/531 [MH+].

C (method A) rt = 6.2 min. UV 254 nm

sample 170

-(4-ChIQrOPhBnOXv ^" ) -N-r(lSVl-methyl-2-(qumolin-5-yloxy)ethyllbenzenesulfonamide

^Chiral

JPCI-MS m/z: 469/471 (3:1) [MH+]. C (method A) rt = 4.9 min. UV 254 nm

,xample 171 -Chloro-2-[((2SV2-{[(2,4-dichloro-5-fluorophenvDsulfonyl1amm o>propyl)oxy1benzamide

Chiral

O ¹ CI-MS m/z: 455/457 [MH+].

,C (method A) rt = 5.1 min. UV 254 nm

Example 172

;-chioro-2-{r(2sy2-αr3-(4- nethoxyphenoxy^phenyl] sulfonyll amino)propyl] oxy } benzamide

VPCI-MS m/z: 491/493 (3:1) [MH+]. X (method A) rt = 5.5 min. UV 254 nm

Example 173 )-Chloro-2-rr(2SV2-{r(2-methoxy-4-methylplienvDsulfonyl1amin o>propyl)oxylbenzamide

Chiral

\PCI-MS m/z: 413/415 (3:1) [MH+]. X (method A) rt = 4.8 min. UV 254 nm

Example 174 l-(4-Fluorophenoxy)-N-[ClSVl-methyl-2-fquinolin-5-yloxy)ethy l]benzenesulfonamide

\PCI-MS m/z: 453 [MH+]. LC (method A) rt = 4.6 min. UV 254 nm

Example 175 5-Chloro-2-[( ^' ( ^' 2S)-2-{r( ^' 5-chloro-2-methoxyphenyl)sulfonyl]amino>propyl)oxy] benzamide

Chiral

\PCI-MS m/z: 433/435 (3:1) [MH+]. LC (method A) rt = 5.0 min. UV 254 nm

Example 176 -Cvano-N-[(1SVl-methvl-2-(quinolin-5-yloxy')ethvllbenzenesul fonamide

tf ^> CI-MS m/z: 368 [MH+].

,C (method A) rt = 3.2 min. UV 254 nm

Example 177 :,4-Dichloro-5-fluoro-N-[(1S)l-metliyl-2-( ^' quinolm-5-yloxy)ethyllbenzenesulfonamide

^PCI-MS m/z: 429/431 [MH+].

.C (method A) rt = 4.0 min. UV 254 nm

Example 178 l-[((2SV2-{[(5-Bromo-2-methoxyphenyl)sulfonyl1amino>propy l)oxy1-5-chlorobenzamide

U ¹ CI-MS m/z: 477/479 (1:1) [MH+]. X (method A) rt = 5.0 min. UV 254 nm

Example 179 )-Chloro-2-[T( ^' 2SV2-{r(2-methoxy-5-methylphenvDsulfonyl1amino>prop yDoxy1benzamide

.PCI-MS m/z: 413/415 (3:1) [MH+]. C (method A) rt = 4.8 min. UV 254 ran

,xample 180

-Chloro-2-{[(2SV2-f{[4'-rtrifluoromethvDbiphenyl-4-yllsul fonyl>amino ^v )propylloxyl- enzamide

kPCI-MS m/z: 513/515 (3:1) [MH+]. ,C (method A) rt = 6.0 min. UV 254 nm

Example 181 -(4-Methoxyphenoxy)-N-[(lSVl-methyl-2-( ^' quinolin-5-yloxy ^' )ethyl]benzenesulfonamide Chiral

tfCI-MS m/z: 465 [MH+].

SZ (method A) rt = 4.5 min. UV 254 nm

Example 182 i-Chloro-2-r(( ^' 2S)-2-{r( ^' 6-phenoxypyridin-3-yl ^' )sulfonvnamino>propyl ^' )oxylbenzamide

^PCI-MS m/z: 462/464 (3:1) [MH+].

X (method A) rt = 5.1 min. UV 254 nm

Example 183 i-Bromo-6-chloro-N-r(lS)-l-methyl-2-( ^' qumolin-5-yloxy)etliyl]pyridine-3-sulfonamide ^Chiral

VPCI-MS m/z: 456/458 [MH+].

X (method A) rt = 3.7 min. UV 254 nm

Example 184 )-Bromo-2-methoxy-N-r(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl lbenzenesulfonamide

Chiral

\PCI-MS m/z: 451/453 (1:1) [MH+]. X (method A) rt = 4.0 min. UV 254 nm

Example 185 v[-[riSVl-Methyl-2-rqumolm-5-yloxy)ethyl]-l-benzothiophene-2 -sulfonamide

Chiral

To a solution of (2S)-l-(quinolin-5-yloxy)propan-2-amine in DMF (lOOμL ).3M/DMF) was added diisopropylethylamine (120μL 0.3M /THF) followed by 1- )enzothiophene-2-sulfonyl chloride (120μL 0.3M /THF). The reaction mixture was stirred wernight at ambient temperature, evaporated to dryness under reduced pressure and purified HI HPLC-C ₁₈ . ^PCI-MS m/z: 399 [MH+].

C (method A) rt = 3.9 min. UV 254 nm

Examples 186- 194 were synthesised by a method analogous to that described in Example 185 using the corresponding starting materials.

Example 186

-Chloro-2-r((2SV2-{[(2,4-dimethoxyphenyl ^' )sulfonyl]ammo|propyl)oxylbenzamide

tf CI-MS m/z: 429/431 (3:1) [MH+]. ,C (method A) rt = 4.6 min. UV 254 nm

example 187

:-({(2SV2-[d-Benzothien-2-ylsulfonyl)amino]propyl>oxy) -5-chlorobenzamide

^PCI-MS m/z: 425/427 (3:1) [MH+]. .C (method A) rt = 5.1 min. UV 254 nm

Example 188

)-Chloro-2-[(( ^' 2S ^' )-2-{[( ^' 4-methoxy-2,3,6-trimethylphenyl)sulfonyl]ammo>propy l ^' )oxy1-

)enzamide

PCI-MS m/z: 531/532 [MH+].

C (method A) rt = 5.5 min. UV 254 nm

sample 192 4,6-Trichloro-N-[(lS)-l-methyl-2-fquinolin-5-yloxy)ethyl]ben zenesulfonamide

Chiral

PCI-MS m/z: 445/447 [MH+].

C (method A) rt = 4.0 min. UV 254 nm

xample 193

-Methoxy-2,3,6-trimethyl-N-[dSVl-methyl-2-( ^' quinolm-5-yloxy)ethyl]-benzenesulfonamide Chiral

J ^» α-MS m/z: 415 [MH+].

£ (method A) rt = 4.0 min. UV 254 nm

Example 194

-Bromo-N-rπSVl-methyl-2-( ^' αuinolin-5-yloxy')ethyl1-2-rtrifluoromethoxyV lenzenesulfonamide

Chiral

LPCI-MS m/z: 505/507 (1:1) [MH+]. ,C (method A) rt = 4.2 min. UV 254 nm

Example 195

Iuman Glucocorticoid Receptor (GK) Assay

The assay is based on a commercial kit from Panvera/Invitrogen (Part number P2893). Tie assay technology is fluorescence polarization. The kit utilises recombinant human GR Panvera, Part number P2812), a Fluoromone™ labelled tracer (GS Red, Panvera, Part number '2894) and a Stabilizing Peptide 1OX (Panvera, Part number P2815). The GR and Stabilizing 'eptide reagents are stored at -70°C while the GS Red is stored at -2O ⁰ C. Also included in tie kit are IM DTT (Panvera, Part number P2325, stored at -20°C) and GR Screening buffer OX (Panvera, Part number P2814, stored at -70°C initially but once thawed stored at room smperature). Avoid repeated freeze/thaws for all reagents. The GR Screening buffer 1OX omprises 10OmM potassium phosphate, 20OmM sodium molybdate, ImM EDTA and 20% )MSO.

Test compounds (lμL) and controls (lμL) in 100% DMSO were added to black iolystyrene 384-well plates (Greiner low volume black flat-bottom, part number 784076). 1% control was 100%DMSO and 100% control was lOμM Dexamethasone. Background olution (8μL; assay buffer 10X, Stabilizing Peptide, DTT and ice cold MQ water) was added o the background wells. GS Red solution (7μL; assay buffer 10X, Stabilizing Peptide, DTT, ϊS Red and ice cold water) was added to all wells except background wells. GR solution 7μL; assay buffer 10X, Stabilizing Peptide, DTT, GR and ice cold water) was added to all veils. The plate was sealed and incubated in a dark at room temperature for 2hours. The )late was read in an Analyst plate reader (LJL Biosystems/Molecular Devices Corporation) or ither similar plate reader capable of recording fluorescence polarization (excitation vavelength 530nm, emission wavelength 59OnM and a dichroic mirror at 561nm). The IC50 values were calculated using XLfit model 205.