WO2006046916A1 - Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases - Google Patents

Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases Download PDF

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Publication number
WO2006046916A1
WO2006046916A1 PCT/SE2005/001610 SE2005001610W WO2006046916A1 WO 2006046916 A1 WO2006046916 A1 WO 2006046916A1 SE 2005001610 W SE2005001610 W SE 2005001610W WO 2006046916 A1 WO2006046916 A1 WO 2006046916A1
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Prior art keywords
alkyl
optionally substituted
phenyl
haloalkyl
methyl
Prior art date
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PCT/SE2005/001610
Other languages
French (fr)
Inventor
Håkan BLADH
Krister Henriksson
Vijaykumar Hulikal
Matti Lepistö
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Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from SE0402636A external-priority patent/SE0402636D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to BRPI0517263-2A priority Critical patent/BRPI0517263A/en
Priority to EP05796607A priority patent/EP1807391A4/en
Priority to AU2005300150A priority patent/AU2005300150A1/en
Priority to MX2007004862A priority patent/MX2007004862A/en
Priority to US11/718,214 priority patent/US20090093485A1/en
Priority to CA002584413A priority patent/CA2584413A1/en
Priority to RSP-2007/0076A priority patent/RS20070076A/en
Publication of WO2006046916A1 publication Critical patent/WO2006046916A1/en
Priority to IL182685A priority patent/IL182685A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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).
  • GR glucocorticoid receptor
  • 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):
  • 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 (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
  • 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]-naphthi
  • 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 cycloal
  • 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.
  • 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 (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
  • 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,
  • 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
  • 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 (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
  • 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
  • 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)).
  • 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;
  • 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 .
  • 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).
  • 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).
  • 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).
  • 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).
  • 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
  • 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).
  • 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 isoquinol
  • 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.
  • 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.
  • 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 .
  • 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
  • L is C 1-4 alkylene (optionally substituted by Ci -4 alkyl) or C 1-4 alkylene-0 (optionally substituted by Ci -4 alkyl).
  • the present invention provides a compound of formula (I) wherein R 1 is hydrogen.
  • 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.
  • 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).
  • 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
  • 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.
  • 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 (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),
  • 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
  • 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 alky
  • 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 (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),
  • 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 (
  • 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
  • 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)
  • 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,
  • 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
  • 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)-benzenesulfonamide; 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-benzenes
  • Naphthalene-2-sulfonic acid [2-(2,6-dimethyl-phenoxy)- 1 -methyl-ethyl]-amide
  • Naphthalene-2-sulfonic acid (3-phenyl-propyl)-amide
  • 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.
  • a compound of the invention can be prepared by coupling a compound of formula (II):
  • Y is a leaving group (for example chlorine), with a compound of formula (III):
  • N-L-W (in) ⁇ in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide
  • a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide
  • 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.
  • 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:
  • collagen diseases of other origins for example systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis
  • Gastrointestinal diseases which coincide with inflammatory, allergic and/or proliferative processes:
  • otitis externa for example caused by contact dermatitis, infection, etc.
  • cerebral edema mainly tumor-induced cerebral edema
  • 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, poly
  • CHF congestive heart failure
  • '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.
  • 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.
  • 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.
  • 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.
  • physiological disorders may present as a “chronic” condition, or an “acute” episode.
  • chronic means a condition of slow progress and long continuance.
  • a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease.
  • acute means an exacerbated event or attack, of short course, followed by a period of remission.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • composition of the invention is one suitable for intravenous, subcutaneous, intraarticular or intramuscular injection.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - 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.
  • a compound of the invention can be combined with a TNF- ⁇ 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 mel
  • the present invention still further relates to the combination of a compound of the invention together with:
  • a leukotriene biosynthesis inhibitor 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 phenothiazin-3-one such as L- 651,392
  • an amidino compound such as CGS-25019c
  • a benzoxalamine such as ontazolast
  • 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.
  • an ⁇ .subl.- and ⁇ .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 ⁇ .subl.- to ⁇ .sub4.-adrenoceptor agonist (such as ⁇ 2 adrenoceptor agonist) such as metaproterenol, isoproterenol, isoprenaline, albuterol, sal
  • MMP- 13 collagenase-3
  • MMP-3 stromelysin- 1
  • MMP-10 stromelysin-2
  • MMP-I l stromelysin-3
  • 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
  • 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
  • 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.
  • a -receptor antagonist comprising: (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 (TGF ⁇ ); (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.
  • an anti-gout agent e.g., colchicine
  • NKP-608C sub 1. and NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418;
  • an elastase inhibitors selected from the group consisting of UT- 77 and ZD-0892;
  • TACE TNF ⁇ converting enzyme inhibitor
  • iNOS induced nitric oxide synthase inhibitor
  • a chemoattractant receptor-homologous molecule expressed on TH2 cells a CRTH2 antagonist.
  • NMP l-Methyl-2-pyrrolidinone app approximately sat saturated aq aqueous
  • Method A Instrument Agilent 1100; Column C 18 Waters Symmetry 2.1 x 30 mm 3.5 ⁇ m; 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 5 ⁇ m; 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.
  • Examples 18 - 76 were synthesised by a method analogous to that described in Example 17 using the corresponding starting materials.
  • Step 1 (2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate
  • 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. ⁇ mmole) was added to a slurry containing Cs 2 CO 3 (487mg, 1.5mmole) and 5- Hydroxyisoquinoline (145mg, lmmole) in 2.5mL DMF.
  • 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 .
  • 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.
  • Examples 85-95 were synthesised by a method analogous to that described in Example 84 using the corresponding starting materials.
  • Phthalic anhydride (50mmole, 7.4g) was dissolved in 10OmL toluene together with L- alaninol (50mmole, 3.9mL) and DIEA (5mmole, 900 ⁇ L). 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+].
  • Examples 97 - 122 were synthesised by a method analogous to that described in Example 96 using the corresponding starting materials.
  • Examples 124 — 129 were synthesised by a method analogous to that described in Example 123 using the corresponding starting materials.
  • 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.
  • TBAT (Llmmole, 594mg) was dissolved in dry THF (12mL) and cooled to 0 0 C under iert conditions.
  • 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).
  • Examples 147 to 153 were synthesised by a method analogous to that described in ⁇ xample 146 using the corresponding starting materials.
  • Examples 154 to 158 were synthesised by a method analogous to that described in ⁇ xample 96, "Sulfonamide coupling", using the corresponding starting materials. cample 154 -(2-AnilmoethylV2,4,6-trimetliylbenzenesulfonamide
  • Example 160 was synthesised using a method analogous to Example 159.
  • 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.
  • Examples 164 - 184 were synthesised by a method analogous to that described in ⁇ xample 17 using the corresponding starting materials.
  • Examples 186- 194 were synthesised by a method analogous to that described in Example 185 using the corresponding starting materials.

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Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt thereof; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating the glucocorticoid receptor in a warm blooded animal).

Description

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):
Figure imgf000002_0001
wherein:
A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, Ci-4 alkylthio, CM fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR14R15), phenyl (optionally substituted by halo, C1-6 alkyl, Ci-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR16R17), pyridinyloxy (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, Ci-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1- 4 alkyl) OrNR18R19) or pyrazolyl(optionally substituted by halo, C1-6 alkyl, Ci-6 alkoxy, Ci-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR20R21);
R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl;
R1 is hydrogen, Ci-6 alkyl, phenyl, pyridinylC(O), C3-6 cycloalkyl, (C3-6 cycloalkyl)CH2 or C3- 4 alkenyl;
L is a bond, C1-4 alkylene (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), C1-4 alkylene-NH (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), CH2C(O)NH, CH(CH3)C(O)NH, Ci-4 alkylene-0 (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), C1- 4 alkylene-S (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), Ci-4 alkylene-S(O) (optionally substituted by Ci-4 alkyl or C1-4 haloalkyl) or C1-4 alkylene-S(O)2 (optionally substituted by C1-4 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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1. 4 fluoroalkoxy, nitro, cyano, OH, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, benzyloxy, imidazolyl, C(O)(Ci-4 allcyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR12R13; R12 and R13 are, independently, hydrogen, Ci-4 alkyl or C3-7 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, CHF2, CF3, CH2CF3, C2F5 or CH2Cl. 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, OCHF2, OCF3, OCH2CF3, OC2F5 or OCH2Cl.
Fluoroalkyl comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 fluorine atoms. It is, for example, CHF2, CF3, CH2CF3 or C2F5. Fluoroalkoxy comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 fluorine atoms. It is, for example, OCHF2, OCF3, OCH2CF3 or OC2F5.
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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(Cj-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Cj-4 alkyl)2, NHC(O)(C1-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(Ci-4 allcyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 allcyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1- 4 alkyl) or NR14R15) or phenyl (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, Cj-4 alkylthio, CF3, OCF3, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(Ci-4 allcyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR16R17); R10, R11, R14, R15, R16 and R17 are, independently, hydrogen, Ci-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen, Ci-6 alkyl, phenyl, pyridylC(O), C3-6 cycloalkyl, (C3-6 cycloalkyl)CH2 or C3-4 alkenyl; L is a bond, Ci-4 alkylene (optionally substituted by Ci-4 alkyl), C1-4 alkylene-NH (optionally substituted by Ci-4 alkyl), CH2C(O)NH, CH(CH3)C(O)NH, Ci-4 alkylene-0 (optionally substituted by C1- 4 alkyl); C1-4 alkylene-S (optionally substituted by C1-4 alkyl); C1-4 alkylene-S(O) (optionally substituted by C1-4 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, C1-6 alkyl, C1- 6 alkoxy, C1-4 alkylthio, CF3, OCF3, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, benzyloxy, C(O)(Ci-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 allcyl) OrNR12R13; R12 and R13 are, independently, hydrogen, Ci-4 alkyl or C3-7 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, CF3, OCF3, phenoxy (optionally substituted by halo or Ci-4 alkyl), phenyl (optionally substituted by halo or Ci-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O)2NH2, C(O)(C1-4 alkyl), C(O)NH2, NHC(O)(C1-4 alkyl) or NR10R11; R10 and R11 are, independently, hydrogen, Cj-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen, Ci-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH2 or C3-4 alkenyl; L is a bond, Ci-4 alkylene (optionally substituted by Ci-4 alkyl), C1-4 alkylene-NH (optionally substituted by C1-4 alkyl), CH2C(O)NH or C1-4 alkylene-0 (optionally substituted by C1-4 alkyl); W is phenyl, benzofuranyl, indolyl, tetrahydroquinolinyl, thiazolyl, pyridyl, isoxazolyl, pyrimidinyl or 1,3,5-triazinyl, and W is optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, benzyloxy, nitro, cyano, S(O)2NH2, C(O)(C1-4 alkyl), C(O)NH2, NHC(O)(Ci-4 alkyl) OrNR12R13; R12 and R13 are, independently, hydrogen, C1-4 alkyl or C3-7 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, C1-6 alkoxy, nitro, phenoxy (optionally substituted by C1-4 alkyl), phenyl (optionally substituted by halo (such as fluoro)), pyridinyloxy Or N(C1-4 alkyl)2; R1 is hydrogen, C1-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH2 or C3-4 alkenyl, L is a bond, C1-4 alkylene (optionally substituted by C1-4 alkyl), C1-4 alkylene-NH (optionally substituted by C1-4 alkyl), CH2C(O)NH or C1-4 alkylene- O (optionally substituted by C1-4 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), C1-6 alkyl, C1-6 alkoxy, C(O)(C1-4 alkyl), S(O)2NH2, NO2, CO2(Ci-4 alkyl) or N(C1-4 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, C1-6 alkyl, C1-6 alkoxy, Ci-4 alkylthio, CF3, OCF3, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, Ci-4 alkylthio, CF3, OCF3, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR14R15) or phenyl (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR16R17); R10, R11, R14, R15, R16 and R17 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen, C1-6 alkyl, phenyl, pyridylC(O), C3-6 cycloalkyl, (C3-6 cycloalkyl)CH2 or C3-4 alkenyl; L is a bond, C1-4 alkylene (optionally substituted by Ci-4 alkyl), Ci-4 alkylene-NH (optionally substituted by Ci-4 alkyl), CH2C(O)NH, CH(CH3)C(O)NH, Ci-4 alkylene-0 (optionally substituted by C1-4 alkyl); C1-4 alkylene-S (optionally substituted by C1-4 alkyl); C1-4 alkylene-S(O) (optionally substituted by Ci-4 alkyl); C1-4 alkylene-S(O)2 (optionally substituted by C1-4 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, C1-6 alkyl, C1- β alkoxy, C1-4 alkylthio, CF3, OCF3, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, benzyloxy, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR12R13; R12 and R13 are, independently, hydrogen, Ci-4 alkyl or C3-7 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, C1-6 alkyl, Ci-6 alkoxy, C1-4 alkylthio, CF3, OCF3, phenoxy (optionally substituted by halo or C1-4 alkyl), phenyl (optionally substituted by halo or C1-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O)2NH2, C(O)(C1-4 alkyl), C(O)NH2, NHC(O)(C1-4 alkyl) or NR10R11; R10 and R11 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen, Ci-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH2 or C3-4 alkenyl; L is a bond, Ci-4 alkylene (optionally substituted by C1-4 alkyl), Ci-4 alkylene-NH (optionally substituted by Ci-4 alkyl), CH2C(O)NH or C1-4 alkylene-0 (optionally substituted by Cμ4 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, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, benzyloxy, nitro, cyano, S(O)2NH2, C(O)(Ci-4 alkyl), C(O)NH2, NHC(O)(C1-4 alkyl) or NR12R13; R12 and R13 are, independently, hydrogen, C1-4 alkyl or C3-7 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, C1-4 haloalkyl, Ci-4 alkoxy or Ci-4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci-4 alkyl, C1-4 haloalkyl, Ci-4 alkoxy or C1-4 haloalkoxy) or pyrazolyl (optionally substituted by C1-4 alkyl, C1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, Ci-4 alkoxy or C1-4 haloalkoxy)).
In another aspect the invention provides a compound of formula (I) wherein L is C3 alkylene (substituted by Ci-4 alkyl or Ci-4 haloalkyl), C2-4 alkylene-NH (substituted by Ci-4 alkyl or C1-4 haloalkyl), CH2C(O)NH, CH(CH3)C(O)NH, C2-4 alkylene-0 (substituted by C1-4 alkyl or Ci-4 haloalkyl), C2-4 alkylene-S (substituted by Ci-4 alkyl or Ci-4 haloalkyl), C2-4 alkylene-S(O) (optionally substituted by Ci-4 alkyl or Ci-4 haloalkyl) or C2-4 alkylene-S(O)2 (optionally substituted by C1-4 alkyl or C1-4 haloalkyl); wherein C1-4 alkyl is, for example, methyl or ethyl; and C1-4 haloalkyl is, for example, CF3.
In yet another aspect the invention provides a compound of formula (I) wherein L is C3 alkylene (substituted by C1-4 alkyl or Cj-4 haloalkyl), C2-4 alkylene-NH (substituted by C1-4 alkyl or C1-4 haloalkyl) or C2-4 alkylene-0 (substituted by C1-4 alkyl or Ci-4 haloalkyl); wherein C1-4 alkyl is, for example, methyl or ethyl; and C1-4 haloalkyl is, for example, CF3.
In a further aspect the invention provides a compound of formula (I) wherein L is C3 alkylene (substituted by Ci-4 alkyl), C2 alkylene-NH (substituted by Ci-4 alkyl) or C2 alkylene- O (substituted by Cj-4 alkyl); wherein Ci-4 alkyl is, for example, methyl or ethyl. L is, for example, C2 alkylene-NH (substituted by Ci-4 alkyl). L is, for example, C2 alkylene-0 (substituted by Ci-4 alkyl).
In a still further aspect the invention provides a compound of formula (I) wherein L is CH(CH3)CH2CH2 (such as in the S-configuration), CH(CH3)CH2NH (such as in the S- configuration), CH(CH3)CH2O (such as in the S -configuration), CH(C2H5)CH2CH2 (such as in the S-configuration), CH(C2H5)CH2NH (such as in the S-configuration), CH(C2H5)CH2O (such as in the S-configuration) or CH(CF3)CH2CH2 (such as in the S-configuration).
In another aspect the present invention provides a compound of formula (I) wherein L is CH(CH3)CH2NH (such as in the S-configuration) or it provides a compound of formula (I) wherein L is CH(CH3)CH2O (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, C1-4 alkyl, CF3, Ci-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, Ci-4 alkyl, CF3, C1-4 alkoxy or OCF3) or C(O)NH2.
In a further aspect the present invention provides a compound of formula (I) wherein L is C1-4 alkylene (optionally substituted by Cu4 alkyl) or Ci-4 alkylene-0 (optionally substituted by C1-4 alkyl); for example L is CH(CH3)CH2O, CH2CH2O, CH(CH3)(CH2)2 or
(CHa)3.
In another aspect of the invention L is C1-4 alkylene (optionally substituted by Ci-4 alkyl) or C1-4 alkylene-0 (optionally substituted by Ci-4 alkyl).
In yet another aspect the present invention provides a compound of formula (I) wherein R1 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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, phenoxy (optionally substituted by halo or C1-4 alkyl), phenyl (optionally substituted by halo or C1-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O)2NH2, C(O)(C1-4 alkyl), C(O)NH2, NHC(O)(Ci-4 alkyl) OrNR10R11; R10 and R11 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen; L is C1-4 alkylene (optionally substituted by Ci-4 alkyl) or C1-4 alkylene-0 (optionally substituted by Ci-4 alkyl); W is phenyl optionally substituted by halo, Ci-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, CF3, OCF3, benzyloxy, nitro, cyano, S(O)2NH2, C(O)(C1-4 alkyl), C(O)NH2, NHC(O)(C1-4 alkyl) or NR12R13; R12 and R13 are, independently, hydrogen, C1-4 alkyl or C3-7 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, C1-6 alkyl, C1-6 alkoxy, CF3, OCF3, phenoxy (optionally substituted by halo or Ci-4 alkyl), phenyl (optionally substituted by halo or Ci-4 alkyl), pyridinyloxy, nitro or cyano; R1 is hydrogen; L is C1-4 alkylene (optionally substituted by C1-4 alkyl) or C1-4 alkylene-0 (optionally substituted by C1-4 alkyl); W is phenyl optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, CF3, OCF3, 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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fiuoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 alkylthio, Ci-4 fluoroalkyl, CM fiuoroalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 aUcyl)2, NHC(O)(Ci-4 alkyl) OrNR14R15), phenyl (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(Ci-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR16R17), pyridinyloxy (optionally substituted by halo, Ci-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, C(O)(Ci-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1- 4 alkyl) OrNR18R19) or pyrazolyl(optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Cj-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) or NR20R21); R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen; L is C3 alkylene (substituted by Ci-4 alkyl or C1-4 haloalkyl), C2-4 alkylene-NH (substituted by C1-4 alkyl or C1-4 haloalkyl) or C2-4 alkylene-0 (substituted by C1-4 alkyl or C1-4 haloalkyl) {for example L is C3 alkylene (substituted by C1-4 alkyl), C2 alkylene-NH (substituted by C1-4 alkyl) or C2 alkylene-0 (substituted by C1-4 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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, OH, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, benzyloxy, imidazolyl, C(O)(C1- 4 alkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(0)(C1-4 alkyl) OrNR12R13; R12 and R13 are, independently, hydrogen, C1-4 alkyl or C3-7 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, C1-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy or Ci-4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy or Ci-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci-4 alkyl, Ci-4 haloalkyl or phenyl (itself optionally substituted by halogen, C1-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy or C1-4 haloalkoxy)); R1 is hydrogen; L is C3 alkylene (substituted by C1-4 alkyl or Ci-4 haloalkyl), C2- 4 alkylene-NH (substituted by Ci-4 alkyl or Ci-4 haloalkyl) or C2-4 alkylene-0 (substituted by Ci-4 alkyl or Ci-4 haloalkyl) {for example L is C3 alkylene (substituted by C1-4 alkyl), C2 alkylene-NH (substituted by Ci-4 alkyl) or C2 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, CF3, Ci-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, Cj-4 alkoxy or OCF3) or C(O)NH2.
In a further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or Ci-4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci-4 alkyl, Ci-4 haloalkyl or phenyl (itself optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy)); R1 is hydrogen; L is C3 alkylene (substituted by C1-4 alkyl or C1-4 haloalkyl), C2- 4 alkylene-NH (substituted by C1-4 alkyl or C1-4 haloalkyl) or C2-4 alkylene-0 (substituted by C1-4 alkyl or C1-4 haloalkyl) {for example L is C3 alkylene (substituted by C1-4 alkyl), C2 alkylene-NH (substituted by C1-4 alkyl) or C2 alkylene-0 (substituted by C1-4 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, C1-4 alkyl, CF3, C1-4 aikoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 aikoxy or OCF3).
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, C1-6 alkyl, C1-6 aikoxy, C1-4 alkylthio, CM fluoroalkyl, C1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, C1-6 alkyl, C1-6 aikoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR14R15), phenyl (optionally substituted by halo, C1-6 alkyl, C1-6 aikoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR16R17), pyridinyloxy (optionally substituted by halo, C1-6 alkyl, C1-6 aikoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1- 4 alkyl) or NR18R19) or pyrazolyl(optionally substituted by halo, C1-6 alkyl, C1-6 aikoxy, C1-4 alkylthio, C1-4 fluoroalkyl, Ci-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) or NR20R21); R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen; L is CH(CH3)CH2CH2 (such as in the S- configuration), CH(CH3)CH2NH (such as in the S-configuration), CH(CH3)CH2O (such as in the S-configuration), CH(C2H5)CH2CH2 (such as in the S-configuration), CH(C2H5)CH2NH (such as in the S-configuration), CH(C2H5)CH2O (such as in the S-configuration) or CH(CF3)CH2CH2 (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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, OH, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, benzyloxy, imidazolyl, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR12R13; R12 and R13 are, independently, hydrogen, Ci-4 alkyl or C3-7 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, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci-4 alkyl, Ci-4 haloalkyl or phenyl (itself optionally substituted by halogen, Ci-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy)); R1 is hydrogen; L is CH(CH3)CH2CH2 (such as in the S-configuration), CH(CH3)CH2NH (such as in the S-configuration), CH(CH3)CH2O (such as in the S- configuration), CH(C2H5)CH2CH2 (such as in the S-configuration), CH(C2H5)CH2NH (such as in the S-configuration), CH(C2Hs)CH2O (such as in the S -configuration) or CH(CF3)CH2CH2 (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, C1-4 alkyl, CF3, C1-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 alkoxy or OCF3) or C(O)NH2.
In a further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, Ci-4 alkoxy or C1-4 haloalkoxy) or pyrazolyl (optionally substituted by C1-4 alkyl, C1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or Ci-4 haloalkoxy)); R1 is hydrogen; L is CH(CH3)CH2CH2 (such as in the S-configuration), CH(CH3)CH2NH (such as in the S-configuration), CH(CH3)CH2O (such as in the S- configuration), CH(C2H5)CH2CH2 (such as in the S-configuration), CH(C2H5)CH2NH (such as in the S-configuration), CH(C2H5)CH2O (such as in the S-configuration) or CH(CF3)CH2CH2 (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, C1-4 alkyl, CF3, C1-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 alkoxy or OCF3).
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, C1-6 alkyl, Ci-6 alkoxy, C1-4 alkylthio, Ci-4 fluoroalkyl, Ci-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) Or NR14R15), phenyl (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, Ci-4 fluoroalkyl, Ci-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, C(O)(Ci-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR16R17), pyridinyloxy (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1- 4 alkyl) or NR18R19) or pyrazolyl(optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, Ci-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR20R21); R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen; L is CH(CH3)CH2NH (such as in the S- configuration) or L is CH(CH3)CH2O (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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, OH, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Cj-4 alkyl)2, benzyloxy, imidazolyl, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR12R13; R12 and R13 are, independently, hydrogen, C1-4 alkyl or C3-7 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, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy) or pyrazolyl (optionally substituted by C1-4 alkyl, Ci-4 haloalkyl or phenyl (itself optionally substituted by halogen, Ci-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy)); R1 is hydrogen; L is CH(CH3)CH2NH (such as in the S-configuration) or L is CH(CH3)CH2O (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, C1-4 alkyl, CF3, C1-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 alkoxy or OCF3) or C(O)NH2.
In a further aspect the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C1-4 alkyl, Q-4 haloalkyl, Ci-4 alkoxy or Ci-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci-4 alkyl, C1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy)); R1 is hydrogen; L is CH(CH3)CH2NH (such as in the S -configuration) or L is CH(CH3)CH2O (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, C1-4 alkyl, CF3, C1-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 alkoxy or OCF3).
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)-benzenesulfonamide; 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-benzenesulfonamide; 4-(l,l-Dimethyl-propyl)-N-(l-methyl-3-phenyl-propyl)-benzenesulfonamide; N-(l-Methyl-3-phenyl-propyl)-3-trifluoromethyl-benzenesulfonamide; 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)-benzenesulfonamide; N-(l-Methyl-3-phenyl-propyl)-3-p-tolyloxy-benzenesulfonamide; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-3-nitro-benzenesulfonamide; 4-Bromo-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benzenesulfonamide; N-{4-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethylsulfamoyl]-phenyl}-acetamide; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-nitro-benzenesulfonamide; 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-benzenesulfonamide; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-trifluoromethoxy-benzenesulfonamide; 4-tert-Butyl-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benzenesulfonamide; 4-Cyano-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benzenesulfonamide; N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-phenoxy-benzenesulfonamide;
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-benzenesulfonamide;
N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-(4-fluoro-phenoxy)-benzenesulfonamide;
N-[2-(2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-(l,l-dimethyl-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]-benzenesulfonamide;
N-[2-(2,6-Dimethyl-plienoxy)-l-methyl-ethyl]-3-methoxy-benzenesulfonamide;
4-«-Butoxy-N-[2-(2,6-dimethyl-phenoxy)-l-methyl-ethyl]-benzenesulfonamide;
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-trimethyl-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-benzenesulfonamide;
4-(l,l-Dimethyl-propyl)-N-(2-phenoxy-ethyl)-benzenesulfonamide;
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)-benzenesulfonamide;
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)-benzenesulfonamide;
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-trimethylbenzenesulfonamide;
N-[(lS)-2-(lH-Indol-4-yloxy)-l-metliylethyl]-2,4,6-trimethylbenzenesulfonamide;
2,4,6-Trimethyl-N-[(lS)-l-methyl-2-(5-quinolmyloxy)ethyl]benzenesulfonamide;
N-[(lS)-2-(l,3-Benzodioxol-5-yloxy)-l-methylethyl]-254,6-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)ethyl]benzenesulfonamide;
2,4,6-Trimethyl-N-[(lS)-l-methyl-2-(8-quinolinyloxy)ethyl]benzenesulfonamide;
5-Fluoro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)benzamide;
2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-5-methylbenzamide;
2-Hydroxy-6-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)benzamide;
5-Chloro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)benzamide;
2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-4-methylbenzamide;
2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)benzamide;
4-Fluoro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)benzamide;
4-Chloro-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)benzamide;
5-Cyano-2-({(2S)-2-[(mesitylsulfonyl)amino]propyl}oxy)benzamide;
2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-5-methoxybenzamide;
3-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-4-methylbenzamide;
2-({(2S)-2-[(Mesitylsulfonyl)amino]propyl}oxy)-4-methoxybenzamide;
2,5-Dichloro-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methyletliyl]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-methylethyl]-3,5-dimethyl-lH- pyrazole-4-sulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-2,5-dimethylfuran-3-sulfonamide;
2,5-Dichloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]thiopherie-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-methyl-5-(trifluoromethyl)-lH-pyrazol-
3 -yl]thiophene-2-sulfonamide; l-(Difluoromethyl)-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylethyl]-5-methyl-lH-pyrazole-4- sulfonamide;
5-Methyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]-l-phenyl-lH-pyrazole-4-sulfonamide; 5-Chloro-N-[(lS)-2-(isoquinolin-5-yloxy)-l-methylethyl]thiopliene-2-sulfonamide;
5-Chloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]thiophene-2-sulfonamide;
Methyl 4-({[(lS)-2-(isoquinolm-5-yloxy)-l-methylethyl]amino}sulfonyl)-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-pyrazole-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-pyrazole-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}propyl)oxy]benzamide;
2,5-Dimetb.yl-N-[(lS)-l-methyl-2-(qumolin-5-yloxy)ethyl]furan-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-methyl-lH-pyrazole-4- sulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-l,3,5-trimethyl-lH-pyrazole-4-sulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-3,5-dimethylisoxazole-4-sulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methyletliyl]-2,5-dimethylthiophene-3-sulfonamide;
234,6-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;
254,6-Trimethyl-N-[(l S)- 1 -methyl-2-(quinolm-5-ylamino)ethyl]benzenesulfonamide;
N-[(lS)-2-(lH-Indazol-6-ylamino)-l-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
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-trimethylbenzenesulfonamide;
N-((lS)-2-{[2-Chloro-4-(methylsulfonyl)phenyl]amino}-l-methylethyl)-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-trimethylbenzenesulfonamide;
N-[(l S)-2-(3-Methoxyphenoxy)- 1 -methylethyl]-2,4,6-trimethylbenzenesulfonamide;
N-[2-(3,5-Dimethoxyphenoxy)-l-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
N-[2-(4-Cyano-2-methoxyphenoxy)-l-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
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-trimethylbenzenesulfonamide;
N-[(lS)-2-(3,4-Dimethoxyphenoxy)-l-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
N-(2-{2-[(Mesitylsulfonyl)amino]propoxy}phenyl)acetamide;
N-{2-[(6-Chloropyridin-3-yl)oxy]-l-methylethyl}-2,4,6-trimethylbenzenesulfonamide;
N-[(lS)-2-(2H-Indazol-3-yloxy)-l-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
4-Methyl-N-[3-phenyl-l-(trifluoromethyl)propyl]benzenesulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-2,4-dimethylbenzenesulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-354-dimethylbenzenesulfonamide;
N-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethyl]-2,5-dimethylbenzenesulfonamide;
2,4-Dimethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]benzenesulfonamide;
3,4-Dimethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]benzenesulfonamide;
2-[((2S)-2-{[(2,4-Dimethylphenyl)sulfonyl]amino}propyl)oxy]benzamide;
2,5-Dimethyl-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]benzenesulfonamide;
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-(trifluoromethyl)benzenesulfonamide;
N-(2-Anilinoethyl)-4'-fluorobiphenyl-4-sulfonamide;
N-(2-Anilinoethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamid;
N-(2-Anilinoethyl)-4-bromo-2-methylbenzenesulfonamid; l-(4-Fluorophenyl)-7V-[(l1S)-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-yloxy)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)sulfonyl]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]benzenesulfonamide;
2,4-Dichloro-5-fl.uoro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]benzenesulfonamide;
2-[((2S)-2-{[(5-Bromo-2-methoxyphenyl)sulfonyl]amino}propyl)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]amino}propyl)oxy]benzamide;
5-Bromo-6-chloro-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]pyridine-3-sulfonamide;
5-Bromo-2-methoxy-N-[(lS)-l-methyl-2-(quinolin-5-yloxy)ethyl]benzenesulfonamide;
N-[(lS)-l-Methyl-2-(quinolin-5-yloxy)ethyl]-l-benzothiophene-2-sulfonamide; 5-Chloro-2-[((2S)-2-{[(2,4-dimethoxyphenyl)sulfonyl]amino}propyl)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)sulfonyl]amino}propyl)oxy]- benzamide;
5-Chloro-2-[((2S)-2-{[(5-fluoro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}propyl)oxy]- benzamide;
5-Chloro-2-[((2S)-2-{[(5-chloro-3-methyl-l-benzothien-2-yl)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)ethyl]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-(trifluoromethoxy)- 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):
Figure imgf000022_0001
wherein Y is a leaving group (for example chlorine), with a compound of formula (III):
R1
N-L-W (in) π in a suitable solvent (such as tetrahydrofuran or N,N-dimethylformamide) at a temperature in the range -1O0C to 5O0C.
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
CX3CRl for the C-X3-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)
Figure imgf000033_0001
Figure imgf000033_0002
Example 3
Example 1 Example 2
Figure imgf000033_0003
Example 4
Figure imgf000033_0004
Example 5
Figure imgf000033_0006
Figure imgf000033_0005
Example 7
Figure imgf000033_0007
Example 10
Example 9
Figure imgf000034_0001
Example 12 Example 13
Figure imgf000034_0003
-Example 16
Figure imgf000034_0002
Figure imgf000034_0004
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
1H NMR spectra were recorded on a Varian Mercury-VX 300 MHz instrument or aVarian Unity 400MHz instument. The central peaks of chloroform-d (δH 7.27 ppm), acetnitrile-d3 (δH 1-95 ppm), or ΩMSO-d6 (δH 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 C18 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 C18 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
Figure imgf000035_0001
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-C18 yielding 2.1mg (25%).
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000036_0001
1H NMR (299.944 MHz, CDCl3) 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-propyiybenzenesulfonamide
Figure imgf000036_0002
1HNMR (299.944 MHz, CDCl3) 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-benzenesulfonamide
Figure imgf000036_0003
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
Figure imgf000037_0001
1H NMR (299.944 MHz, CDCl3) 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 Hz3 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 Hz3 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
Figure imgf000037_0002
1H NMR (299.944 MHz3 CDCl3) δ 7.83 (dd, J= 6.8, 1.8 Hz3 2H)3 7.54 (dd, J= 6.8, 1.8 Hz3
2H)3 7.30 - 7.17 (m, 3H)3 7.06 (d, J= 6.6 Hz3 2H)3 4.49 (d3 J= 8.1 Hz3 IH), 3.42 (quintet, J=
6.8 Hz3 IH)3 2.58 (dtd, J= 21.9, 14.1, 7.9 Hz, 2H), 1.75 - 1.67 (m, 2H)3 1.38 (s3 9H), 1.12 (d,
J= 6.6 Hz3 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
Figure imgf000037_0003
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
Figure imgf000038_0001
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000038_0002
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-benzenesulfonamide
Figure imgf000038_0003
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000039_0001
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-benzenesulfonamide
Figure imgf000039_0002
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000039_0003
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
Figure imgf000040_0001
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000040_0002
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
Figure imgf000040_0003
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000041_0001
1H NMR (299.944 MHz, CDCl3) 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
Figure imgf000041_0002
LC (method A) rt = 5.9 min. UV 254 nm.
Example 35 4-Bromo-N-r2-(2,6-dimethyl-phenoxyv)-l-methyl-ethyll-benzenesulfonamide
Figure imgf000041_0003
LC (method A) rt = 6.4 min. UV 254 nm.
Example 36 N-{4-r2-(2.6-Dimethvl-phenoxvVl-methvl-ethvlsulfamoyl]-phenvU-acetamide
Figure imgf000041_0004
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
Figure imgf000042_0001
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
Figure imgf000042_0002
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-benzenesulfonamide
Figure imgf000042_0003
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-trifluoromethoxy-benzenesulfonamide
Figure imgf000042_0004
LC (method A) rt = 6.6 min. UV 254 nm.
Example 41 4-tert-Butyl-N-r2-(2,6-dimetliyl-phenoxy)-l-methyl-ethyll-benzenesulfonamide
Figure imgf000043_0001
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]-benzenesulfonamide
Figure imgf000043_0002
LC (method A) rt = 5.7 min. UV 254 nm.
Example 43 N-r2-("2,6-Dimethyl-phenoxyVl-methyl-ethyll-4-phenoxy-benzenesulfonamide
Figure imgf000043_0003
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
Figure imgf000044_0001
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-benzenesulfonamide
Figure imgf000044_0002
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)-benzenesulfonamide
Figure imgf000044_0003
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
Figure imgf000044_0004
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
Figure imgf000045_0001
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
Figure imgf000045_0002
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
Figure imgf000045_0003
LC (method A) rt = 6.4 min. UV 254 nm.
Example 51 2-Bromo-N-[2-(2,6-dimethyl-phenoxyVl-methyl-ethyl]-benzenesulfonamide
Figure imgf000045_0004
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-benzenesulfonamide
Figure imgf000046_0001
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
Figure imgf000046_0002
APCI-MS m/z: 392.2 [MH+].
LC (method A) rt = 7.0 min. UV 254 nm.
Example 54 N-r2-(f2,6-Dimethyl-phenoxy)-l-methyl-ethyl]-4-rpyridin-2-yloxyVbenzenesulfonamide
Figure imgf000046_0003
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-benzenesulfonamide
Figure imgf000046_0004
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
Figure imgf000047_0001
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
Figure imgf000047_0002
LC (method A) rt = 5.9 min. UV 254 nm.
Example 58 N-(2-Phenoxy-ethylV4-trifluoromethoxy-benzenesulfonamide
Figure imgf000047_0003
LC (method A) rt = 5.9 min. UV 254 nm.
Example 59
4-d , 1 -Dimethyl-propyl)-N-C2-phenoxy-ethylVbenzenesulfonamide
Figure imgf000047_0004
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
Figure imgf000048_0001
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
Figure imgf000048_0002
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
Figure imgf000048_0003
LC (method A) rt = 6.0 min. UV 254 nm.
Example 63 4-Bromo-2-methyl-N-f3-phenyl-ρropviybenzenesulfonamide
Figure imgf000048_0004
LC (method A) rt = 6.3 min. UV 254 nm. Example 64
N-(3-Phenyl-propylV4-trifluoromethoxy-benzenesulfbnamide
Figure imgf000049_0001
LC (method A) rt = 6.2 min. UV 254 nm.
Example 65 4-Methoxy-2,3,6-trimethyl-N-(3-phenyl-propyl)-benzenesulfonamide
Figure imgf000049_0002
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
Figure imgf000049_0003
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
Figure imgf000050_0001
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
Figure imgf000050_0002
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
Figure imgf000050_0003
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
Figure imgf000050_0004
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
Figure imgf000051_0001
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
Figure imgf000051_0002
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
Figure imgf000051_0003
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
Figure imgf000051_0004
LC (method A) rt = 6.0 min. UV 254 nm. Example 75 2A6-Trimethyl-N-(3-phenyl-propyl)-benzenesulfonamide
Figure imgf000052_0001
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
Figure imgf000052_0002
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-trimethylbenzenesulfonamide
Chiral
Figure imgf000052_0003
Step 1 : (2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate
L-Alaninol (4.8g, 64mmole) and 2-mesitylenesulfonyl chloride (3Og3 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. NaHCO3/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 Cs2CO3 (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-C18.
1H 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-trimethylbenzenesulfonamide
Figure imgf000053_0001
1H 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
Figure imgf000053_0002
1H 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 Hz5 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-trimethylbenzenesulfonamide
Figure imgf000054_0001
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
Figure imgf000054_0002
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
Figure imgf000055_0001
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)ethvnbenzenesulfonaniide
Chiral
Figure imgf000055_0002
1HNMR (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
Figure imgf000055_0003
(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. NaHCO3/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 H2SO4) 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% NH3/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)benzamide
(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (263mg, 0.6mmole) was added to a slurry containing Cs2CO3 (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-C18.
1H NMR (299.946 MHz5 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
Figure imgf000057_0001
1H NMR (299.946 MHz, DMSO) δ 7.78 (d, J= 8.6 Hz3 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 Hz5 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)benzamide
Figure imgf000057_0002
1H 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 Hz3 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
Figure imgf000057_0003
1H NMR (299.946 MHz, DMSO) δ 7.79 (d3 J= 8.4 Hz3 IH)3 7.71 (t, J= 2.5 Hz3 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 Hz3
3H)
APCI-MS m/z: 411.1 [MH+]. Example 88
2-({('2S)-2-r(Mesitylsulfonyl)amino]propyl|oxyV4-methylbenzamide
Chiral
Figure imgf000058_0001
1H 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
Figure imgf000058_0002
1H 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 (d5 J= 6.8 Hz5 3H) APCI-MS m/z: 377.2 [MH+].
Example 90
4-Fluoro-2-({(2S)-2-r(mesitvlsulfonvDamino]propvU oxy)benzamide
Figure imgf000058_0003
1HNMR (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 Hz5 IH)5 2.50 (s, 6H), 2.17 (s, 3H)5 0.93 (d5 J= 6.8 Hz, 3H) APCI-MS m/z: 395.2 [MH+]. Example 91 4-Chloro-2-(l(2SV2-[(mesitylsulfonyl)aminolpropγl}oxy)benzamide
Figure imgf000059_0001
1H 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)benzamide
Figure imgf000059_0002
1H NMR (299.944 MHz, CDCl3) 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 Hz5 3H) APCI-MS m/z: 402.1 [MH+].
Example 93
2-r{C2S)-2-[(Mesitylsulfonyl)ammo]propyUoxy)-5-methoxybenzamide
Chiral
Figure imgf000059_0003
1HNMR (299.946 MHz5 DMSO) δ 7.78 (d, J= 8.4 Hz5 IH), 7.61 (s, IH)5 7.49 (s, IH)5 7.32 (d, J= 3.1 Hz5 IH)5 6.95 - 6.81 (m, 4H)5 3.81 (d5 J= 5.7 Hz5 2H)5 3.68 (s5 3H)5 3.53 - 3.42 (m, IH)5 2.50 (s, 6H)5 2.18 (s5 3H), 0.91 (d, J= 6.8 Hz5 3H) APCI-MS m/z: 407.2 [MH+].
Example 94
3-({(2S)-2-r("Mesitylsulfonyl)aminolpropyl}oxyV4-methylbenzamide
Figure imgf000060_0001
1H 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-methoxybenzamide
Figure imgf000060_0002
1H 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-methylethvnthiophene-3-sulfonamide
Chiral
Figure imgf000060_0003
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. NaHCO3/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. NaHCO3/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-isoindole-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 Cs2CO3 (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-isoindole-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]thiophene-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-C1S. 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-phenyl-lH-pyrazole-4- sulfonamide
Chiral
Figure imgf000062_0001
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-methylethyl1-3,5-dimethyl-lH- pyrazole-4-sulfonamide
Chiral
Figure imgf000062_0002
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-dimethylfuran-3-sulfonamide
Chiral
Figure imgf000063_0001
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
Figure imgf000063_0002
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
Figure imgf000063_0003
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
Figure imgf000063_0004
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-methylethyl]-5-methyl-lH-pyrazole-4- sulfonamide
Figure imgf000064_0001
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
Figure imgf000064_0002
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-sulfonamide
Figure imgf000064_0003
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-sulfonamide
Figure imgf000065_0001
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>sulfonylV2,5-dimethyl-3- furoate
Chiral
Figure imgf000065_0002
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
Figure imgf000065_0003
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-pyrazole-4-sulfonamide
Chiral
Figure imgf000065_0004
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
Figure imgf000066_0001
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
Figure imgf000066_0002
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-rtrifluoromethylVlH-pyrazol-3- yl]thiophene-2-sulfonamide
Figure imgf000066_0003
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-pvrazole-4-sulfonamide Chiral
Figure imgf000067_0001
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
Figure imgf000067_0002
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
Figure imgf000067_0003
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
Figure imgf000067_0004
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|propyDoxy1benzamide
Figure imgf000068_0001
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
Figure imgf000068_0002
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-methyl-lH-pyrazole-4- sulfonamide
Chiral
Figure imgf000068_0003
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
Figure imgf000069_0001
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-dimethylisoxazole-4-sulfonamide
Chiral
Figure imgf000069_0002
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-dimethylthiophene-3-sulfonamide
Chiral
Figure imgf000069_0003
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
Figure imgf000069_0004
(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-yl)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-C18.
1H 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-vDaminoiethyll- enzenesulfonamide
Chiral
Figure imgf000071_0001
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
Figure imgf000071_0002
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 (s5 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
Figure imgf000071_0003
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-214,6-trimethylbenzenesulfonamide
Figure imgf000072_0001
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-vDaminoiethvU- enzenesulfonamide
Chiral
Figure imgf000072_0002
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-trimethvlbenzenesulfonamide
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 Hz3 IH)3 3.50 (t, J= 6.4 Hz3 IH)3 3.12 (mult, H), 2.57 (s3 6H), 2.21 (s, 3H), 1.06 (d, J= 6.7 Hz3 3H) PCI-MS m/z: 373.1 [MH+].
xample 130
[-(( 1 SV 2- { r2-Chloro-4-fmethylsulfonyl)phenyll amino} - 1 -methylethylV2,4,6- imethylbenzenesulfonamide
Figure imgf000073_0001
HNMR (399.99 MHz3 DMSO) δ 7.63 (d, J= 2.1 Hz, IH)3 7.55 (s, IH)3 7.47 (dd3 J= 8.7, 2.0 Iz3 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 Hz3 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
Figure imgf000073_0002
H NMR (299.946 MHz3 DMSO) δ 7.76 (d, J= 8.4 Hz3 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 Hz3
>H)
^PCI-MS m/z: 387.2[MH+].
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000074_0003
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000076_0001
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
Figure imgf000076_0002
H NMR (299.944 MHz, CDCl3) 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
Figure imgf000076_0003
H NMR (299.944 MHz, CDCl3) 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+].
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0003
Nf-[(lS)-2-f2H-Indazol-3-yloxy)-l-methylethyll-2,4,6-trimethylbenzenesulfonamide
Chiral
Figure imgf000078_0001
HNMR (399.99 MHz3 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-CtrifluoromethvDpropynbenzenesulfonamide
Figure imgf000078_0002
-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 NaHCO3/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 CH2Cl2. 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]benzenesulfonamide
TBAT (Llmmole, 594mg) was dissolved in dry THF (12mL) and cooled to 00C 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. NH4Cl/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) 3F NMR (470.314 MHz3 DMSO) δ -74.42 (d)
Example 146
J-[(lS)-2-fIsoquinolin-5-yloxy')-l-methylethyll-2,4-dimethylbenzenesulfonamide
Figure imgf000079_0001
:,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.
1J- [( 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 lJ-rdSV2-Qsoquinolin-5-yloxyVl-methy1ethyl1-3.4-dimethylbenzenesulfonamide
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000080_0003
Figure imgf000080_0004
Example 151
-r((2S)-2-{r(2,4-Dimethylphenyl)sulfonyllamino|propyl)oxylbenzamide
Figure imgf000081_0001
.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]benzenesulfonamide
Chiral
Figure imgf000081_0002
O1CI-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
Figure imgf000081_0003
^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
Figure imgf000082_0001
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)benzenesulfonamide
Figure imgf000082_0002
,C (method A) rt = 5.4 min. UV 254 nm.
Example 156 [-(2-Anilinoethyl)-4'-fluorobiphenyl-4-sulfonamide
Figure imgf000082_0003
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-trimethylbenzenesulfonamid
Figure imgf000082_0004
PCI-MS m/z: 349.1 [MH+].
C (method A) rt = 4.7 min. UV 254 nm.
xample 158 '-(2-AnilinoethylV4-bromo-2-methylbenzenesulfonamid
Figure imgf000083_0001
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-methylethyl1-3.5-dimethyl-lH- yrazole-4-sulfonamide
Figure imgf000083_0002
-(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-methylethyl]-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)
O1CI-MS m/z: 455.1 [MH+].
example 160
/-r('llSf)-2-('Isoquinolin-5-yloxy)-l-methylethyll-3,5-dimethyl-l-phenyl-liJr-pyrazole-4- ulfonamide
Example 160 was synthesised using a method analogous to Example 159.
Figure imgf000084_0001
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
Figure imgf000085_0001
2,4,6-Trimethyl-N-[(lS)-l-metliyl-3-phenylpropyl]benzenesulfonaniide (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, CDCl3) 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).
Figure imgf000085_0002
,C (method B) rt = 16.2 min. UV 254 nm.
Example 162
'.4,6-Trimethyl-N- { 1 -r(quinolm-5-yloxy)methyl]prorM)benzenesulfonamide
Figure imgf000085_0003
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, CDCl3) 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
Figure imgf000086_0001
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-d6) 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
Figure imgf000086_0002
^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 .
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000087_0004
: (method A) rt = 4.2 min. UV 254 nm
sample 169
Chloro-2- { [(2S)-2-( { [3-f 3,4-dichlorophenoxy)phenyl1sulfonγl| amino)propylloxy} -
Chiral
Figure imgf000088_0001
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
Figure imgf000088_0002
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-fluorophenvDsulfonyl1ammo>propyl)oxy1benzamide
Chiral
Figure imgf000088_0003
O1CI-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
Figure imgf000089_0001
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-methylplienvDsulfonyl1amino>propyl)oxylbenzamide
Chiral
Figure imgf000089_0002
\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)ethyl]benzenesulfonamide
Figure imgf000089_0003
\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
Figure imgf000089_0004
\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')ethvllbenzenesulfonamide
Figure imgf000090_0001
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
Figure imgf000090_0002
^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>propyl)oxy1-5-chlorobenzamide
Figure imgf000090_0003
U1CI-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>propyDoxy1benzamide
Figure imgf000090_0004
.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-yllsulfonyl>aminov)propylloxyl- enzamide
Figure imgf000091_0001
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
Figure imgf000091_0002
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
Figure imgf000091_0003
^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
Figure imgf000092_0001
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)ethyllbenzenesulfonamide
Chiral
Figure imgf000092_0002
\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
Figure imgf000092_0003
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-C18. ^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
Figure imgf000093_0001
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
Figure imgf000093_0002
^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>propyl')oxy1-
)enzamide
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000095_0001
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]benzenesulfonamide
Chiral
Figure imgf000095_0002
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
Figure imgf000095_0003
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
Figure imgf000096_0001
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 -2O0C. 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.
Figure imgf000097_0001
Figure imgf000098_0001

Claims

1. A compound of formula (I):
Figure imgf000099_0001
wherein:
A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), NR10R11, phenoxy (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, C(O)(Ci-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) or NR14R15), phenyl (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, C(O)(Ci-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR16R17), pyridinyloxy (optionally substituted by halo, Ci-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, Ci-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR18R19) or pyrazolyl(optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) or NR20R21);
R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are, independently, hydrogen, Ci-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen, C1-6 alkyl, phenyl, pyridinylC(O), C3-6 cycloalkyl, (C3-6 cycloalkyl)CH2 or C3-4 alkenyl;
L is a bond, C1-4 alkylene (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), C1-4 alkylene-NH (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), CH2C(O)NH,
CH(CH3)C(O)NH, C1-4 alkylene-0 (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), C1-4 alkylene-S (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), C1-4 alkylene-S(O) (optionally substituted by C1-4 alkyl or C1-4 haloalkyl) or C1-4 alkylene-
S(O)2 (optionally substituted by C1-4 alkyl or C1-4 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(lH)-onyl, isoquinolin-l(2/i)-onyl, phthalazin-l(2/i)-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, C1-6 alkyl, C1-6 alkoxy, C1-4 alkylthio, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, nitro, cyano, OH, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, benzyloxy, imidazolyl,
C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR12R13;
R12 and R13 are, independently, hydrogen, C1-4 alkyl or C3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I) as claimed in claim 1 wherein A is phenyl (optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, Ci-4 alkoxy or C1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1- 4 haloalkoxy) or pyrazolyl (optionally substituted by C1-4 alkyl, C1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C1-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy or Ci-4 haloalkoxy)).
3. A compound of formula (I) as claimed in claim 1 or 2 wherein W is phenyl, pyridyl, indolyl, indazolyl, quinolinyl or isoquinolinyl.
4. A compound of formula (I) as claimed in claim 1, 2 or 3 wherein W is optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 alkoxy, OCF3, phenyl (itself optionally substituted by halogen, C1-4 alkyl, CF3, C1-4 alkoxy or OCF3) or C(O)NH2.
5. A compound of formula (I) as claimed in claim 1, 2, 3 or 4 wherein L is C3 alkylene (substituted by C1-4 alkyl or C1-4 haloalkyl), C2-4 alkylene-NH (substituted by C1-4 alkyl or C1-4 haloalkyl), CH2C(O)NH, CH(CH3)C(O)NH, C2-4 alkylene-0 (substituted by C1-4 alkyl or C1-4 haloalkyl), C2-4 alkylene-S (substituted by C1-4 alkyl or C1-4 haloalkyl), C2-4 alkylene-S(O) (optionally substituted by C1-4 alkyl or C1-4 haloalkyl) or C2-4 alkylene-S(O)2 (optionally substituted by C1-4 alkyl or C1-4 haloalkyl).
6. A compound of formula (I) as claimed in claim 5 wherein L is CH(CH3)CH2CH2, CH(CH3)CH2NH, CH(CH3)CH2O, CH(C2H5)CH2CH2, CH(C2H5)CH2NH, CH(C2H5)CH2O or CH(CF3)CH2CH2.
7. A process for the preparation of a compound of formula (I) comprising coupling a compound of formula (II):
Figure imgf000101_0001
wherein Y is a leaving group, with a compound of formula (III):
R1
N-L-W (in) π in a suitable solvent at a temperature in the range -1O0C to 5O0C.
8. A pharmaceutical composition comprising a compound or formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A compound or formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 for use in therapy.
10. The use of a compound or formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in the manufacture of a medicament for use in therapy.
11. A method of treating a glucocorticoid receptor mediated disease state in a mammal, 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.
PCT/SE2005/001610 2004-10-29 2005-10-26 Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases WO2006046916A1 (en)

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US9458118B2 (en) 2013-09-10 2016-10-04 Chromocell Corporation Sodium channel modulators for the treatment of pain and diabetes
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use

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CR9022A (en) 2007-10-04
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EP1807391A4 (en) 2010-01-06
AU2005300150A1 (en) 2006-05-04
US20090093485A1 (en) 2009-04-09
EP1807391A1 (en) 2007-07-18
PA8651001A1 (en) 2006-06-02
MX2007004862A (en) 2007-05-09
BRPI0517263A (en) 2008-10-07
UY29182A1 (en) 2006-05-31
CA2584413A1 (en) 2006-05-04
ECSP077349A (en) 2007-04-26
TW200630326A (en) 2006-09-01
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KR20070068432A (en) 2007-06-29
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