WO2008079073A1 - Indazolyl sulphonamide derivatives for the treatment of glucocorticoid receptor mediated disorders - Google Patents

Indazolyl sulphonamide derivatives for the treatment of glucocorticoid receptor mediated disorders Download PDF

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WO2008079073A1
WO2008079073A1 PCT/SE2007/001135 SE2007001135W WO2008079073A1 WO 2008079073 A1 WO2008079073 A1 WO 2008079073A1 SE 2007001135 W SE2007001135 W SE 2007001135W WO 2008079073 A1 WO2008079073 A1 WO 2008079073A1
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alkyl
indazol
oxypropan
fluorophenyl
benzenesulfonamide
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PCT/SE2007/001135
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French (fr)
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Håkan BLADH
Matti Lepistö
Stinabritt Nilsson
Camilla Taflin
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Astrazeneca Ab
Bayer Schering Pharma Aktiengesellschaft
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • A is phenyl, naphthyl, pyridinyl, furyl, thiazolyl, thienyl, thiophene, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl, dihydrobenzofuranyl, quinolinyl or isoquinolinyl, optionally substituted by one or more substituents independently selected from halo, Ci -6 alkyl, Ci -6 alkoxy, Ci -4 thioalkyl, Ci -4 haloalkyl, Ci -4 haloalkoxy, C 3-6 cycloalkyl, pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (Ci -4 al
  • A is phenyl, thiazolyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl, dihydrobenzofuranyl, optionally substituted by one or more substituents independently selected from halo, C 1-6 alkyl, Ci -6 alkoxy, Ci -4 thioalkyl, Ci -4 haloalkyl, Ci -4 haloalkoxy, C 3-6 cycloalkyl, pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (Ci -4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Ci -4 alkyl), S(O) 2 N(Cj
  • A is phenyl substituted with one or more benzyloxy or phenyl
  • A is thiazolyl optionally substituted with one or more methyl.
  • R 3 is hydrogen or Ci -4 alkyl (for example methyl). In another embodiment R 3 is hydrogen.
  • a further aspect the invention provides a compound of formula (I) for treating an inflammatory condition, asthma and/or COPD.
  • the 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) 3 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.
  • adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, forrnoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
  • a steroid such as budesonide
  • a modulator of chemokine receptor function such as a CCRl receptor antagonist

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Abstract

Compounds of formula (I): [Chemical formula should be inserted here. Please see paper copy] 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

Indazolyl sulphonamide derivatives for the treatment of glucocorticoid receptor mediated disorders
The present invention relates to novel indazolyl sulphonamide derivatives, to pharmaceutical compositions comprising such derivatives, to processes for preparing such novel derivatives and to the use of such derivatives as medicaments (for example in the treatment of an inflammatory disease state).
Sulphonamide derivatives are disclosed as anti-inflammatories in WO 2004/019935 and WO 2004/050631. Pharmaceutically active sulphonamides are also disclosed in Arch. Pharm. (1980) 3Jl 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.
The present invention provides a compound of formula (I):
Figure imgf000002_0001
wherein:
A is phenyl, naphthyl, pyridinyl, furyl, thiazolyl, thienyl, thiophene, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl, dihydrobenzofuranyl, quinolinyl or isoquinolinyl, optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, C1-6 alkoxy, C1-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, S(O)2(N-lrnked heterocyclyl), C(O)(C1-4 alkyl), C(O)(C1-4 haloalkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), NR10R11, isoxazolyl, oxazolyl, phenoxy (optionally substituted by halo, C1-6 alkyl, Ci-e alkoxy, Cj-4 thioalkylthioalkyl, C1- 4 haloalkyl, Ci-4 haloalkoxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Cj-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) OrNR14R15), phenyl (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, C1-4 haloalkyl, CM haloalkoxy, nitro, cyano, C(O)2H5 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(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR16R17), pyridinyloxy (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Cw alkyl), S(O)2N(C1-4 alkyl)2, C(O)(Ci-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) or NR18R19), pyrazolyl (optionally substituted by halo, Ci-6 alkyl, Ci-S alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(0)2NH(CM 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) OrNR20R21) or tetrahydrofuranyl (optionally substituted by Ci-6 alkyl); and when A is phenyl adjacent ring carbons may be joined through a group: OCH2O, OCH2CH2O or OCH2CH2; R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen; R2 is hydrogen, Ci-4 alkyl, CM haloalkyl, C3-7 cycloalkyl or C3-7 cyclohaloalkyl; R3 is hydrogen, Ci-4 alkyl or Ci-4 haloalkyl; R3a is hydrogen or C1-4 alkyl; R4 is hydrogen, halogen, Ci-4 alkyl or C1-4 haloalkyl; W is hydrogen or phenyl, C3-7 cycloalkyl, thienyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl optionally substituted by one or more substituents independently selected from halo, Ci-6 alkyl (optionally substituted by Ci-6 alkoxy), Cj-6 alkoxy, CM thioalkyl, CM haloalkyl, Ci-4 haloalkoxy, nitro, cyano, OH, C(O)2H5 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, benzyloxy, imidazolyl, C(O)(Ci-4 alkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) or NR12R13; X is CH2, CH(Ci-4 alkyl), O3 S, S(O), S(O)2 or NH; Y is hydrogen, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, nitro, cyano, OH, C(O)2H, C(O)2(C14 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, benzyloxy, imidazolyl, C(O)(Ci-4 alkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR22R23; and
R 5 R 5 R and R are independently selected from hydrogen, Ci-4 alkyl or C3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.
One embodiment relates to compounds of formula (I) wherein:
A is phenyl, naphthyl, pyridinyl, furyl, thiazolyl, thienyl, thiophene, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl, dihydrobenzofuranyl, quinolinyl or isoquinolinyl, optionally substituted by one or more substituents independently selected from halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, C3-6 cycloalkyl, 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(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, S(O)2(N-linked heterocyclyl), C(O)(C1-4 alkyl), C(O)(Ci-4 haloalkyl), C(O)NH2, C(O)NH(C^ alkyl), C(O)N(Cj-4 alkyl)2, NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), NR10R11, isoxazolyl, oxazolyl, phenoxy (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkylthioalkyl, C1- 4 haloalkyl, C1-4 haloalkoxy, 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)(CM alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-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 alkoxy, C1-4 thioalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, 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)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Cx-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR16R17), pyridinyloxy (optionally substituted by halo, C1-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, 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)(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), pyrazolyl (optionally substituted by halo, Ci-6 alkyl, C1-6 alkoxy, C1-4 thioalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, nitro, cyano, C(O)2H, C(O)2(Cj-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 NR20R21) or tetrahydrofuranyl (optionally substituted by Ci_6 alkyl); and when A is phenyl adjacent ring carbons may be joined through a group: OCH2O, OCH2CH2O or OCH2CH2; R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from hydrogen, C1-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen;
R2 is hydrogen, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl or C3-7 cyclohaloalkyl; R3 is hydrogen, Ci-4 alkyl or C1-4 haloalkyl; R3a is hydrogen or C1-4 alkyl; R4 is hydrogen, halogen, C1-4 alkyl or C1-4 haloalkyl;
W is phenyl, C3-7 cycloalkyl, thienyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl (optionally substituted by Ci-6 alkoxy), Ci-6 alkoxy, C1-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy, nitro, cyano, OH, 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, benzyloxy, imidazolyl, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR12R13; X is CH2, CH(C1-4 alkyl), O, S, S(O), S(O)2 or NH;
Y is hydrogen, halo, C1-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy, 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(C1-4 alkyl)2, NHC(O)(C1-4 alkyl) or NR22R23; and
R 5 R , R and R are independently selected from hydrogen, C1-4 alkyl or C3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof.
Another embodiment relates to compounds of formula (I) wherein: A is phenyl, thiazolyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl or dihydrobenzofuranyl optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, ben2yloxy, cyano, S(O)2(C1-4 alkyl), S(O)2(N-linkedheterocyclyl), C(O)(Ci-4 haloalkyl), NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), oxazolyl, phenyl, pyrazolyl
(optionally substituted by halo, C1-6 alkyl or C1-4 haloalkyl);
R1 is hydrogen;
R2 is hydrogen or C1-4 alkyl; R3 is hydrogen;
R3a is hydrogen;
R4 is hydrogen;
W is phenyl or pyrimidinyl optionally substituted by one or more halo;
X is CH2, O or NH; Y is hydrogen or halo; or a pharmaceutically acceptable salt thereof.
A further embodiment relates to compounds of formula (I) wherein:
A is thiazolyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl or dihydrobenzofuranyl optionally substituted by one or more substituents independently selected from halo, Ci-6 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, benzyloxy, cyano, S(O)2(C1-4 alkyl), S(O)2(N-linked heterocyclyl), C(O)(C1-4 haloalkyl), NHC(O)(Ci-4 alkyl), NHC(O)(C3-6 cycloalkyl), oxazolyl, phenyl, pyrazolyl (optionally substituted by halo, C1-6 alkyl or Ci-4 haloalkyl); R1 is hydrogen; R2 is hydrogen or C1-4 alkyl; R3 is hydrogen; R3a is hydrogen; R4 is hydrogen;
W is phenyl or pyrimidinyl optionally substituted by one or more halo; X is CH2, O or NH; Y is hydrogen or halo; or a pharmaceutically acceptable salt thereof.
In one embodiment of the invention A is phenyl, thiazolyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl, dihydrobenzofuranyl, optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H, C(O)2(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Cj-4 alkyl)2, S(O)2(N- linked heterocyclyl), C(O)(C1-4 alkyl), C(O)(C1-4 haloalkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl), NHC(O)(C3-6 cycloalkyl), NR10R11, isoxazolyl, oxazolyl, phenoxy (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy, 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(Cj-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR14R15), phenyl (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, 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)(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 NR16R17), pyridinyloxy (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, 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)(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 NR18R19), pyrazolyl (optionally substituted by halo, Ci-6 alkyl, Ci-6 alkoxy, Q-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy, 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(Ci-4 alJcyl), C(O)N(Ci-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR20R21) or tetrahydrofuranyl (optionally substituted by Ci-6 alkyl); and when A is phenyl adjacent ring carbons may be joined through a group: OCH2O, OCH2CH2O or OCH2CH2;
R10, R11, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from hydrogen, Ci-4 alkyl or C3-7 cycloalkyl. In another embodiment A is phenyl. In a further embodiment A is phenyl substituted with one or more substituents independently selected from halo, Cj-6 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, benzyloxy, cyano, S(O)2(Ci-4 alkyl), S(O)2(N- linked heterocyclyl), C(O)(C1-4 haloalkyl), NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), oxazolyl, phenyl, pyrazolyl (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 thioalkyl or C1-4 haloalkyl.
In a further embodiment A is phenyl substituted with one or more methyl.
In another embodiment A is phenyl substituted with one or more methyl and cyclopentyl.
In one embodiment A is phenyl substituted with one or more fluoro or chloro. In yet a further embodiment A is phenyl substituted with one or more trifluoromethyl, difluoromethyl, fluoromethyl or trifluoroacetyl.
In yet another embodiment A is phenyl substituted with one or more methoxy.
In a further embodiment A is phenyl substituted with one or more pyrazolyl or
SO2pyrrolidinyl. In one embodiment A is phenyl substituted with one or more benzyloxy or phenyl
In another embodiment A is phenyl substituted with one or more cyclopropanec or acetamide.
In a further embodiment A is phenyl substituted with one or more cyano or mthylsulfonyl.
In one embodiment A is thiazolyl optionally substituted with one or more substituents independently selected from phenyl, C1-6 alkyl or oxazolyl.
In yet a further embodiment A is thiazolyl optionally substituted with one or more methyl.
In one embodiment A is dihydrobenzofuranyL
In another embodiment A is pyrazolyl optionally substituted with one or more C1-6 alkyl,
C3-6 cycloalkyl or C1-4 haloalkyl. In one embodiment A is pyrazolyl optionally substituted with one or more methyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroacetyl or cyclopentyl.
In another embodiment A is indolyl optionally substituted with one or more methyl.
In yet another embodiment A is benzothiophenyl optionally substituted with one or more methyl or chloro. In one embodiment A is benzothiadiazolyl as in example 21.
In one embodiment A is thiophenyl optionally substituted with one or more pyrazolyl, trifluoromethyl, methyl or oxazolyl. Another embodiment of the present invention relates to compounds of formula (I) wherein R2 is methyl, ethyl or C1-2 fluoroalkyl (such as CF3). In a further embodiment R2 is methyl. Still a further embodiment of the present invention relates to compounds of formula
(I) wherein R3 is hydrogen or Ci-4 alkyl (for example methyl). In another embodiment R3 is hydrogen.
One embodiment of the present invention relates to compounds of formula (I) wherein R3a is hydrogen. Another embodiment of the present invention relates to compounds of formula (I) wherein R4 is hydrogen.
A further embodiment of the present invention relates to compounds of formula (I) wherein Y is hydrogen, halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy or Ci-4 haloalkoxy. In another embodiment Y is hydrogen. In yet another embodiment Y is chloro.
Another embodiment of the present invention relates to compounds of formula (I) wherein X is NH. In one embodiment X is CH2. In yet another embodiment X is O.
One embodiment of the present invention relates to compounds of formula (I) wherein W is phenyl optionally substituted by halo, C1^ alkyl (optionally substituted by Ci-6 alkoxy), C1-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4 haloalkoxy, nitro, cyano, OH, 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, benzyloxy, imidazolyl, C(O)(C1-4 alkyl), C(O)NH2, C(O)NH(Cj-4 alkyl), C(O)N(Ci-4 alkylfa, NHC(O)(C1-4 alkyl) or NR12R13; and R12 and R13 are independently selected from hydrogen, Ci-4 alkyl or C3-7 cycloalkyl.
In another embodiment W is phenyl. In a further embodiment W is phenyl substituted with halo. In yet a further embodiment W is phenyl substituted with fluoro. In one embodiment W is phenyl para-substituted with fluoro. In yet another mbodiment W is pyrimidinyl
Another embodiment relates to compounds of formula (IA)
Figure imgf000010_0001
where A5 X, Y and W are as defined above, or a pharmaceutically acceptable salt thereof.
For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.
For the avoidance of doubt it is to be understood that in this specification 'C1-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term Ci-4alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or fert-butyl.
The term "alkoxy", unless stated otherwise, refers to radicals of the general formula— O-R, wherein R is selected from a hydrocarbon radical. The term "alkoxy" may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system. The term "C^gcycloalkyl" may be, but is not limited to cyclopropyL cyclobutyl, cyclopentyl or cyclohexyl.
In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine, iodine, chlorine or bromine. In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with halogen as defined above. The term "Q- 6haloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, ftuoroethyl, difluoroethyl or bromopropyl. The term "Ci^haloalkoxy" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
When phenyl is substituted by OCH2O, OCH2CH2O or OCH2CH2 these groups link to adjacent carbons on the phenyl ring.
N-Linked heterocyclyl is a nitrogen-linked, non-aromatic, 3- to 7-membered ring containing 1 or 2 nitrogen atoms, said ring being optionally substituted by Ci-4 alkyl. N- Linked heterocyclyl is, for example, pyrrolidinyl or piperidinyl.
For the avoidance of doubt a group A e.g. phenyl, substituted with a group NHC(O)(C3-6 cycloalkyl) means a phenyl substituted with cyclopropanecarboxamide as in example 33. And a phenyl substituted with a group NHC(O)Ci-4 alkyl means a phenyl substituted with acetamide as in example 40.
It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.
Compounds of the present invention have been named with the aid of computer software (ACDLabs 8.0/Name(IUPAC)).
In a further aspect the present invention provides each individual compound: N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,4,6-trimethyl- benzenesulfonamide;
N-[(2S)~ 1 -[6-Chloro- 1 -(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,4,6-trimethyl- benzenesulfonamide;
N-[(2iS}-l-[[l-(4-Fluorophenyl)indazol-5-yl]ammo]propan-2-yl]-2,4,6-trimethyl- benzenesulfonamide; JV-[(2,?)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,3-dihy(irobenzofuran-
5 -sulfonamide;
N-[(2Syi -[I -(4-Fluorophenyl)indazol-5-yI]oxyproρan-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide; iV-[(25)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3,4-dimethyl- benzenesulfonamide;
N-[(2S)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-meth.yl-2-phenyl-
1 ,3-tniazole-5-sulfonamide; iV-[(26)-l-[6-Chloro-l-(4-fluoroph.enyl)indazol-5-yl]oxypropan-2-yl]-4- (trifluoromethoxy)benzenesulfonamide; iV-[(25)-l-[6-Chloro-l-(4-fluorophenyi)indazol-5-yl]oxypropan-2-yl]-l-methyl-indole-5- sulfonamide;
3-Chloro-N-[(2iS)-l-[6-chloro-l-(4-fluoroplienyl)indazol-5-yl]oxypropan-2- yl]benzenesulfonamide; N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3-
(trifluoromethyl)benzenesulfonamide;
JV-[(2,S)-l-[6-chloro-l-(4-fiuorophenyl)indazol-5-yl]oxypropan-2-yl]-5-l,2-oxazol-5-yl- thiophene-2-sulfonamide; l-Cyclopentyl-iV-[(2>S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-ylJ-3,5-dimethyl- pyrazole-4-sulfonamide;
N-[(2<S)-l-[6-chloro-l-(4-fiuoroρlienyl)indazol-5-yl]oxypropan-2-yl]-3-methoxy- benzenesulfonamide; l-(Difluoromethyl)-iV"-[(2lS)-l-[l-(4-fluoroplienyl)indazol-5-yl]oxypropan-2-yl]-5-metb.yl- pyrazole-4-sulfonamide; iV-[(25)-l-[6-chloro-l-(4-fluoroplienyl)indazol-5-yl]oxypropan-2-yl]-2,5-dimethoxy- benzenesulfonamide; ;
N-[(2<S)- 1 -[ 1 -(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3 ,4-dimethyl- benzenesulfonamide;
7V-[(2lS)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l,5-dimetb.yl-pyrazole-4- sulfonamide; iV-[(25)-l-[6-chloro-l-(4-fluoroplienyl)indazol-5-yl]oxypropan-2-yl]-4-pyrazol-l-yl- benzenesulfonamide; iV-[(25)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yljoxyproρan-2-yl]-3,5-dimethyl- benzenesulfonamide; iV-[(2,S)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-8-thia-7,9- diazabicyclo[4.3.0]nona-2,4,6,9-tetraene-5-sulfonamide; 3-Chloro-JV-[(25)-l-[l-(4-fluorophenyl)indazoI-5-yl]oxypropan-2-yl]benzenesulfonamide;
5-Chloro-N-[(2>S)-r-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methyl- benzothiophene-2-sulfonamide;
JV-[(25)-l-[l-(4-fl-uorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methoxy- benzenesulfonamide; JV-[(2)S)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-phenoxy- benzenesulfonamide;
JV-[(2ιS)-l-[6-chloro-l-(4-fl.uorophenyl)indazol-5-yl]oxypropan-2-yl]benzothiazole-6- sulfonamide; iV-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxyproρan-2-yl]-4-phenyl-benzenesulfonamide; 7V-[(2^)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2-(2,2,2- trifluoroacetyl)-3,4-dihydro-lH-isoquinoline-7-sulfonamide; iV-[(2tS)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l-methyl-indole-5- sulfonamide;
N-[(2S)- 1 - [6-chloro- 1 -(4-fluorophenyl)indazol-5-yl] oxypropan-2-yl]- 1 ,3 -dimethyl- pyrazole-4-sulfonamide;
N-[(2S)- 1 -[I -(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-5- 1 ,2-oxazol-5-yl-thiophene-2- sulfonamide;
N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,3-dihydrobenzofuran-5- sulfonamide; iV-[5-[[(25)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]sulfamoyl]-2- methyl-phenyl]cyclopropanecarboxamide;
N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3,5-dimethyl- benzenesulfonamide;
N-[(2(S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-pyrazol-l-yl- benzenesulfonamide;
N- [(25)- 1 - [6-chloro- 1 -(4-fluorophenyl)indazol-5-yl] oxypropan-2-yl]-4-pyrrolidin- 1 - ylsulfonyl-benzenesulfonamide; JV-[(2<S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,5-dimethoxy- benzenesulfonamide;
N-[(26)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3,5-dimethyl-l,2-oxazole-4- sulfonamide; N-[(2)S)-l-[l-(4-fluorophenyl)indazol-5-yI]oxypropan-2-yl]-l,5-dimethyl-pyrazole-4- sulfonamide;
N-[4-[[(2S)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2- yl]sulfamoyl]phenyl]acetamide;
N- [(2S)- 1 -[ 1 -(4-Fluorophenyl)indazol-5 -yl] oxypropan-2-yl]benzothiazole-6-sulfonamide; 4-Cyano-N-[(2)S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]benzenesulfonamide;
N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-phenoxy- benzenesulfonamide;
JV"-[(25)-l-[l-(4-fl-uorophenyl)indazol-5-yl]oxypropan-2-yl]-2-(2)2,2-trifluoroacetyl)-3,4- dihydro-lH4soquinoline-7-sal£onamids; N-[(2,S)-l-[l-(4-fliιorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methylsulfonyl- benzenesulfonamide;
JV-[(2ιS)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l,2-dimethyl- imidazole~4-sulfonamide;
N- [(2S)- 1 - [ 1 -(4-fluorophenyl)indazol-5 -yl]oxypropan-2-yl] -5 - [ 1 -methyl-5- (trifiuoromethyl)pyrazol-3-yl]thiophene-2-sulfonamide;
N-[5-[[(21S)-l-[l-(4-fluorophenyl)mdazol-5-yl]oxyρropan-2-yl]sulfamoyl]-2-methyl- phenyljcyclopropanecarboxamide;
N-[(2S)-l -[I -(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]- 1 ,3 -dimethyl-pyrazole-4- sulfonamide; N-[(25)-4-[l-(4-fluoroph.enyl)indazol-5-yl]butan-2-yl]-2;4,6-trimethyl- benzenesulfonamide;
2,4,6-Trimethyl-Ν-[(2S)-4-(l-pyrimidin-5-ylindazol-5-yl)butan-2-yl]benzenesulfonamide; or, JV~[(2S)- 1 -[6-chloro- 1 -(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-propyl- benzenesulfonamide, or a pharmaceutically acceptable salt thereof. The compounds of formula (I) and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated or unsolvated forms, as well as cocrystalline forms and the present invention encompasses all such forms.
Compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, fumarate, hemiiumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate,p-toluenesulphonate, benzenesulphonate, ethanesulphonate, 2-naρhthalenesulfonate, mesytilenesulfonate, nitric acid, 1,5-naphthalene-disulρhonate, p-xylenesulphonate, aspartate or glutamate.
They may also include basic addition salts such as an alkali metal salt for example sodium or potassium salts, an alkaline earth metal salt for example calcium or magnesium salts, a transition metal salt such as a zinc salt, an organic amine salt for example a salt of triethylamine, diethylamine, morpholine, N-methyipiperidine, N-ethylpiperidine, piperazine, procaine, dibenzylamine, JVjV-dibenzylethylamine, choline or 2-aminoethanol or amino acids for example lysine or arginine.
Compounds of formula (I) may include an asymmetric centre and be chiral in nature. Where the compound is chiral, it may be in the form of a single stereoisomer, such as a enantiomer, or it may be in the form of mixtures of these stereoisomers in any proportions, including racemic mixtures. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC. Alternatively the optical isomers may be obtained by asymmetric synthesis, or by synthesis from optically active starting materials.
Process The compounds of formula (I) can be prepared using or adapting methods disclosed in the art, or by using or adapting the methods disclosed in the Examples below. Starting materials for the preparative methods are either commercially available or can be prepared by using or adapting literature methods.
One embodiment the present invention relates to processes for the preparation of compounds of formula (I);
(a) by coupling a compound of formula (II):
Figure imgf000016_0001
with a compound of formula (III):
Figure imgf000016_0002
wherein L1 is a leaving group (such as halogen (for example chloro) or mesylate or tosylate), in a suitable solvent (such as THF or DMF), in the presence of a suitable base (such as a In(Ci-6 alkyl)amine, for example diisopropylethylamine) and at a suitable temperature (such as —10 to 5O0C), or (b) by coupling a compound of formula (IV):
Figure imgf000016_0003
wherein L2 is a leaving group (such as halogen, mesylate or tosylate) with a compound of formula (V):
Figure imgf000016_0004
in a suitable solvent (such as an aromatic solvent, for example toluene), in the presence of a suitable base (such as a alkali metal alkoxide (for example sodium fert-butoxide) or, sodium hydride (for example when X is CH2)) at a suitable termperature (for example in the range 80 to 12O0C), or (c) by coupling a compound of formula (Vl):
Figure imgf000017_0001
with a compound of formula (VII):
Figure imgf000017_0002
wherein L is a leaving group (such as halogen, mesylate or tosylate), in a suitable solvent (such as DMF or acetonitrile), in the presence of a suitable base (such as an alkali metal carbonate, for example cesium carbonate or potassium carbonate) at a suitable temperature (for example in the range 50 to 15O0C).
The invention relates to processes for the preparation of the compounds of formula (I) as well as the intermediates.
Medical use
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 anti-proliferative 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, chronic obstructive pulmonary disease bronchitis of different origins Adult respiratory distress syndrome (ARDS), acute respiratory distress syndrome
Bronchiectases 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, Behcet's disease 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, discoid lupus erythematosus, sclerodermia, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis
Sjogren's syndrome, Still syndrome, Felty's syndrome Vitiligo
Soft-tissue rheumatism
(iii) Allergies, which coincide with inflammatory, allergic and/or proliferative processes:
All forms of allergic reactions, for example Quincke's edema, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, contact dermatitis (e.g. allergic and irritative), allergic vascular diseases
Allergic vasculitis inflammatory vasculitis
(iv) Vascular inflammations (vasculitides)
Panarteritis nodosa, temporal arteritis, erythema nodosum Polyarteris nodosa
Wegner's granulomatosis
Giant-cell arteritis
(v) Dermatological diseases, which coincide with inflammatory, allergic and/or proliferative processes: atopic dermatitis (mainly in children) exfoliative dermatitis, psoriasis IS
erythematous diseases, triggered by different noxae, for example radiation, chemicals, burns, etc. acid burns bullous dermatoses, such as, for example, autoimmune pemphigus vulgaris, bullous pemphigoid diseases of the lichenoid group itching (for example of allergic origins) all forms of eczema, such as, for example, atopic eczema or seborrheal eczema rosacea pemphigus vulgaris erythema exudativum multiforme erythema nodosum balanitis
Pruritis, such as, for example, allergic origin) Manifestation of vascular diseases vulvitis inflammatory hair loss, such as alopecia areata cutaneous T-cell lymphoma
Rashes of any origin or dermatoses Psoriasis and parapsoriasis groups
Pityriasis rubra pilaris
(vi) Nephropathies, which coincide with inflammatory, allergic and/or proliferative processes: nephrotic syndrome all nephritides, such as, for example, glomerulonephritis
(vii)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 (viii) Gastrointestinal diseases, which coincide with inflammatory, allergic and/or proliferative processes: regional enteritis (Crohn's disease)
Gastritis Reflux esophagitis ulcerative colitis gastroenteritis of other origins, for example native sprue
(ix) Proctological diseases, which coincide with inflammatory, allergic and/or proliferative processes: anal eczema fissures haemorrhoids idiopathic proctitis
(x) Eye diseases, which coincide with inflammatory, allergic and/or proliferative processes: allergic keratitis, uvenitis iritis conjunctivitis blepharitis optic neuritis chorioiditis sympathetic ophthalmia
(xi) 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
(xii) 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 Meningitis spinal cord injury
Stroke
(xiii) Blood diseases, which coincide with inflammatory, allergic and/or proliferative processes: acquired haemolytic anemia thrombocytopenia such as for example idiopathic thrombocytopenia
M. Hodgkins or Non-Hodgkins lymphomas, thrombocythemias, erythrocytoses
(xiv) 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
(xv) Endocrine diseases, which coincide with iiiflammatory, allergic and/or proliferative processes: endocrine orbitopathy thyrotoxic crisis de Quervain's thyroiditis
Hashimoto's thyroiditis
Hyperthyroidism Basedow's disease
Granulomatous thyroiditis
Lymphadenoid goiter
(xvi) . Transplants, which coincide with inflammatory, allergic and/or proliferative processes; (xvii) Severe shock conditions, which coincide with inflammatory, allergic and/or proliferative processes, for example anaphylactic shock (xviii) 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.
(xix) Emesis, which coincides with inflammatory, allergic and/or proliferative processes: for example in combination with a 5-HT3-antagonist in cytostatic-agent-induced vomiting.
Pains of inflammatory origins, e.g., lumbago
Other different stages of disease including diabetes type I (insulin-dependent diabetes), Guillain-Barre syndrome, restenoses after percutaneous transluminal angioplasty, Alzheimer's disease, acute and chronic pain, arteriosclerosis, reperfusion injury, thermal injury, multiple organ injury secondary to trauma, acute purulent meningitis, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, and granulocyte transfusion.
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, muscle weakness, increased melanin pigmentation of the skin, weight loss, hypotension, hypoglycemia, Cushing's Syndrome, obesity, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, tissue rejection associated with organ transplant, malignancies such as leukemias and lymphomas, rheumatic fever, 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, hypercalcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, Little's syndrome, systemic inflammation, inflammatory bowel disease, Wegener's granulomatosis, giant cell arthritis, osteoarthritis, angioneurotic edema, tendonitis, bursitis, autoimmune chronic active hepatitis, hepatitis, cinhosis, panniculitis, inflamed cysts, pyoderma gangrenosum, eosinophilic fasciitis, relapsing polychondritis, sarcoidosis Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, lichen planus, erythema nodosum acne, hirsutism, toxic epidermal necrolysis, erythema multiform, 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 of formula
(I), or a pharmaceutically acceptable salt tihereof, for use in therapy (such as a therapy described above). In yet another aspect the present 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 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)3 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma.
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.
A further aspect the invention provides a compound of formula (I) for treating an inflammatory condition, asthma and/or COPD.
The present invention further provides a method of treating a glucocorticoid receptor mediated disease state, an inflammatory condition, asthma and/or COPD, 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 the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. In this specification, unless stated otherwise, the terms "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist. The term 'agonist' mean a compound that by any means, partly or completely, provokes the transduction pathway leading to the production of a response. The term "disorder", unless stated otherwise, means any condition and disease associated with glucocorticoid receptor activity. Pharmaceutical composition
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)3 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 SO %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 0.1 mg and 1 g 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 GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with one or more agents for the treatment of any of the above disease states.
For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD, asthma or allergic rhinitis a GR agonist of the invention can be combined with one or more agents for the treatment of such a condition. Where such a combination is to be administered by inhalation, then the one or more agents is selected from the list comprising:
• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;
• a selective β.sub2. adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, forrnoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
• a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
• a steroid (such as budesonide); • a modulator of chemokine receptor function (such as a CCRl receptor antagonist); or,
• an inhibitor of p38 kinase function.
In another embodiment of the invention where such a combination is for the treatment of COPD, asthma or allergic rhinitis, the GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, can be administered by inhalation or by the oral route and this is in combination with a xanthine (such as aminophylline or theophylline) . which can be administered by inhalation or by the oral route. The GR agonist of formula (T) and xanthine may be administered together. They may be administered sequencially. Or they may be administered separately. Examples
The following Examples illustrate the invention. The following abbreviations are used in the Examples:
THF tetrahydrofuran TFA trifluoroacetic acid
DMSO dimethylsulfoxide
DMF N,N-dimethylformamide
TBAT N,N,N-tributylbutan-l-aminium difluoro(triphenyl)silicate
DIEA diisopropylethyl amine NMP l-Methyl-2-pyrrolidinone
BINAP (R)-(+)-2,2'-Bis(diρhenylρhosρhino)- 1 , 1 '-binaphthyl
Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
LDA litium diisopropylamide
Pd-18 l,l-bis(di-tery-butylphosphino)ferrocene palladium dichloride
General Methods
NMR spectra were recorded on a Varian Mercury- VX 300 MHz instrument or a Varian
Inova 400MHz instrument. The central peaks of chloroform-d (H 7.27 ppm), acetone (H 2.05 ppm), dichloromethane-d2 (H 5.32 ppm)or
Figure imgf000027_0001
(H 2.50 ppm) were used as internal references.
The following methods were used for LC/MS analysis:
Method A: Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI;
Flow rate 0.7 mL/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ; Gradient 15-95%/B 2.7 min, 95% B 0.3 min.
Method B: Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI;
Flow rate 0.7 mL/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ; Gradient 5-95%/B 7.2 min.
The following method was used for GC-MS analysis: Low resolution mass spectra and accurate mass determination were recorded on a Hewlett- Packard GC. MS system equipped with EI ionisation chamber, 7OeV.
The following method was used for LC analysis: Method A. Instrument Agilent 1100; Column: Kromasil CIS 100 x 3 mm, 5μ particle size, Solvent A: 0.1 %TF A/water, Solvent B: 0.08%TFA/acetonitrile Flow: 1 mL/min, Gradient 10-100%/B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 im.
A Kromasil KR-100-5-C18 column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitrile/water (0.1% TFA) at a flow rate of 10 mL/min was used for preparative HPLC. Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.
Example 1
N-[f2^-l-ri-(4-Fluorophenyl)indazol-5-yl1oxypropan-2-yl1-2.4.6-trimethyl- benzenesulfonamide
Figure imgf000028_0001
(2S)'2-[(Mesitylsulfonyl)amino]propyl 2, 4, 6-trimethylbenzenesulfonate
L-Alaninol (173 mg, 2.3 mmol) and 2-mesitylenesulfonyl chloride (1.0 g, 4.8 mmol) were dissolved in 5 mL pyridine and stirred at room temperature overnight. The mixture was evaporated, dissolved in ethyl acetate (40 mL) and washed with IM HCl, sat. NaHCO3. The organic layer was dried, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate).
1H NMR (400 MHz, CDCl3) δ 6.94 (d, J= 20.0 Hz, 4H), 4.85 (d, J= 8.1 Hz, IH), 3.88 - 3.70 (m, 2H), 3.56 - 3.45 (m, IH), 2.57 (d, J= 34.8 Hz, 12H), 2.30 (d, J= 11.0 Hz, 6H), 1.14 (d, J= 6.7 Hz, 3H).
APCI-MS m/z (method A): 440.1 [MH+].
l-(4'Fluorophenyl)-5-methoxy-lH-indazole
2-Fluoro-methoxy-benzaldehyde (2.1 mmol, 320 mg), 4-fluorophenylhydrazine hydrochloride (2.1 mmol, 340 mg) and cesium carbonate. (3 mmol, 2.0 g) were diluted in 6 mL NMP and heated in a microwave reactor (300 W, 20 min, 150 0C). After cooling to room temperate the reaction mixture was diluted with dichloromethane (20 mL) and washed with IM HCl, sat NaHCO3. The organic phase was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, IH), 7.76 - 7.67 (m, 2H), 7.61 (d, J= 21.3 Hz, IH), 7.33 - 7.22 (m, 2H), 7.21 - 7.12 (m, 2H), 3.93 (s, 3H). APCI-MS m/z (method A): 243.1 [MH+].
l-(4-Fluorophenyl)-lH-indazol-5-ol l-(4-Fluorophenyl)-5-methoxy-lH-indazole (1.0 mmol, 242 mg) was dissolved in dichloromethane (4 mL) and BBr3 (4 mL, 1 M/CH2CI2) was added. The reaction mixture was stirred in room temperature overnight before it was quenched with water (20 mL). The product was extracted with dichloromethane (2 x 20 mL) and washed with sat NaHCO3.
The organic phase was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, IH), 7.73 - 7.65 (m, 2H), 7.57 (d, J= 9.0 Hz,
IH)5 7.30 (t, J= 18.7 Hz5 2H), 7.13 - 7.02 (m, 2H), 3.33 (s, IH). APCI-MS m/z (method A): 229.1 [MH+].
N-((lS)-2-{[l-(4-Fluorophenyl)-lH-indazol-5-yl]oxy}-l-methylethyl)-2,4,6- trimethylbenzenesulfonamide
(25)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (52 mg, 0.12 mmol) was added to a slurry containing CS2CO3 (84 mg, 0.26 mmol) and l-(4- fluorophenyl)-lH-indazol-5-ol (24 mg, 0.11 mmol) in 2 mL DMF. The reaction mixture was stirred overnight in room temperature before it was diluted with ethylacetate (20 mL) and washed with IM HCl. The organic layer was dried, concentrated and purified by HPLC-C18.
1HNMR (500 MHz, DMSO-^6) δ 8.20 (s, IH), 7.79 - 7.75 (m, 2H), 7.72 (d, J= 8.4 Hz, IH), 7.66 (d, J= 9.0 Hz, IH), 7.42 (t, J= 15.4 Hz, 2H), 7.08 (d, J= 2.3 Hz, IH), 6.97 (s, 2H), 6.86 (dd, J= 9.2, 2.3 Hz, IH), 3.88 - 3.73 (m, 2H), 3.54 - 3.45 (m, IH), 2.56 (s, 6H), 2.19 (s, 3H), 1.11 (d, J = 6.7 Hz5 3H);
APCI-MS m/z (method A): 468.1 [MH+]. Example 2
JV-rf25r)-l-[6-Chloro-l-f4-fluorophenyl)indazol-5-yl1oxypropan-2-yll-2,4,6-trimethyl- benzenesulfonamide
Figure imgf000030_0001
was prepared analogous to Example 1 but with the corresponding starting material.
1HNMR (400 MHz, DMSO-^) δ 8.19 (s, IH), 7.78 (s, IH), 7.77 - 7.71 (m, 2H)5 7.69 (d, J= 8.1 Hz, IH), 7.36 (t, J= 8.8 Hz, 2H), 7.26 (s, IH), 6.85 (s, 2H), 3.97 - 3.73 (m, 2H), 3.56 - 3.43 (m, IH), 2.50 (s, 6H), 2.06 (s, 3H), 1.09 (d, J= 6.7 Hz, 3H). APCI-MS m/z (method A): 502.0 [MH+].
Example 3
N-[(2^)-l-rri-(4-Fluorophenyl)indazol-5-yl1aminolpropa]i-2-yl"|-2,4,6-trimethyl- benzenesulfonamide
Figure imgf000030_0002
(2S)-2-[(Mesitylsulfonyl)amino] propyl 2, 4, 6-trimethylbenzenesulfonate was prepared as described in Example 1.
N-[(2S)-l-Aminopropan-2-yl]-2,4,6-trimethyl-benzenesulfonamide
(2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (1 mmol, 349 mg) was dissolved in acetonitrile (3 mL) and NH3 (32 % in H20, 10 mL) was added. The reaction mixture was stirred in room temperature for 2 hours before it was evaporated to dryness and purified on an ion exchange column (DOWEX 50WX2-400). APCI-MS m/z: 257.1 [MH+].
5-Bromo-l-(4-fluorophenyl)-indazole p-Fluorophenylboronic acid (7.11 g, 50.8 mmol), anhydrous cupric acetate (6.92 g, 38.1 mmol) and pyridine (4.1 mL, 50.8 mmol) was added to 5-bromo-lH-indazole (5.00 g, 25.4 mmol) in dichloromethane (150 mL). After stirring overnight the reaction mixture was filtered through celite, washed with dichloromethane and evaporated. The residue was suspended in toluene and purified by chromatography (SiO2, toluene) to give the title compound (2.2 g).
1HNMR (400 MHz5 CDCl3) δ 8.14 (s, IH), 7.96 (s, IH), 7.66 (m, 2H), 7.58-7.49 (m, 2H), 7.29-7.21 (m, 2H).
N-[(2S)-l-[[l-(4-Fluorophenyl)indazol~5-yl]amino]propan-2-yl]-2, 4, 6-trimethyl- benzenesulfonamide
Copper (I) iodide (0.01 mmol, 2.5 mg) and ethylene glycol (0.51 mmol, 32 mg) were dissolved iso-propanol (3 mL) followed by N-[(2S)-l-aminopropan-2-yl]-2,4,6-trimethyl- benzenesulfonamide (0.33 mmol, 86 mg) and 5-bromo-l-(4-fluorophenyl)indazole (0.26 mmol, 75 mg) and finally K3PO4 (0.51 mmol, 109 mg). The reaction mixture was degassed and the reaction tube was filled with argon before it was refluxed in 48 h. The product was purified by HPLC-Ci8.
1HlSlMR (500 MHz5 DMSO-J6) δ 8.20 (s, IH), 7.80 - 7.74 (m, 2H), 7.73 (d, J= 8.4 Hz,
IH), 7.66 (d, J = 9.1 Hz, IH), 7.42 (t, J = 17.2 Hz, 2H), 7.08 (d, J = 2.3 Hz, IH), 6.97 (s, 2H), 6.86 (dd, J = 9.1, 2.3 Hz, IH), 3.87 - 3.73 (m, 2H), 3.54 - 3.46 (m, IH), 2.56 (s, 6H),
2.19 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H).
APCI-MS m/z (method A): 467.1 [MH+].
Example 4 iV"-[(2^-l-[6-CMoro-l-(4-fluorophenynmdazol-5-yl]oxypropan-2-yll-23-dihy&obenzofuran- 5-sulfonamide
Figure imgf000031_0001
2-[(lS)-2-hydroxy-l-methylethyl]~lH'isoindole~l,3(2H)-dione:
Phthalic anhydride (0.11 mol, 16.6 g) was dissolved in 200 mL toluene together with L- alaninol (0.11 mol, 8.4 g). The mixture was refluxed with continues removal of water with a Dean-Stark apparatus for three hours before it was washed with IM HCl, sat. NaHCO3. The organic layer was dried, concentrated and used in the next step without any further purification.
1HNMR (400 MHz5 DMSO-Gf6) δ 7.88 - 7.77 (m, 4H), 4.91 (t, J= 6.0 Hz, IH), 4.33 - 4.19 (m, IH), 3.89 - 3.78 (m, IH), 3.60 - 3.48 (m, IH), 1.32 (d, J= 7.1 Hz3 3H). APCI-MS m/z (method A): 206.0 [MH.
(2S)-2-(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)propyl 4-methylhenzenesulfonate: 4-Methylbenzenesulfonyl chloride (43 mmol, 8.2 g) and 2-[(lS)-2-hydroxy-l- methylethyl]-lH-isoindole-l,3(2H)-dione (43 mmol, 8.8 g) were dissolved in pyridine (200 mL) and stirred over night in room temperature. The mixture was evaporated, dissolved in ethyl acetate(200 mL) and washed with IM HCl, sat. NaHCO3. The organic layer was dried, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate). APCI-MS m/z (method A): 360,0 [MH+].
6-Chloro~l-(4-fluorophenyl)-5-methoxy-indazole
Was prepared analogous to Example 1 but with the corresponding starting material. 1H NMR (300 MHz, CDCl3) δ 8.11 (d, 2H), 7.74 (d, IH), 7.68 - 7.61 (m, 2H), 7.28 - 7.19 (m, 3H), 4.00 (s, 3H).
APCI-MS m/z (method A): 360,0 [MH+].
6-Chloro-l-(4-fluorophenyl)indazol-5-ol
Was prepared analogous to Example 1 but with the corresponding starting material. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J= 0.7 Hz, IH), 7.70 (s, IH), 7.67 - 7.60 (m, 2H), 7.37 (s, IH), 7.28 - 7.23 (m, 2H), 5.43 (s, IH). APCI-MS m/z (method A): 360,0 [MH+].
2-[(2S)-l-[6-chloro-l-(4-fluorophenyl)indazoϊ-5-yl]oxypropan-2~yl]isoindole-l,3~dione: (25)-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)propyl 4-methylbenzenesulfonate (5.0 mmol, 1.8 g) was added to a slurry containing Cs2CO3 (2.4 g, 6.9 mmol) and 6-chloro-l- (4-fluorophenyl)indazol-5-ol (1.2 g, 4.6 mmol) in 20 mL DMF. The reaction mixture was stirred for two hours at 100 0C before it was diluted with water (70 mL) and extracted with ethylacetate (3 x 70 mL). The combined organic layers were dried, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, IH), 7.93 - 7.88 (m, 2H), 7.79 - 7.75 (m, 2H)3 7.68 - 7.62 (m, 3H), 7.34 - 7.22 (m, 3H), 5.05 - 4.93 (m, IH), 4.66 (t, J= 9.3 Hz, IH), 4.38 (dd, J= 9.3, 5.7 Hz, IH), 1.68 (d, J= 7.1 Hz, 3H). APCI-MS m/z (method A): 450.2 [MH+].
(2S)-l-[6-chloro-l-(4~fluorophenyl)indazol-5-yl]oxypropan-2-amine 2-[(lS)-2-(Isoquinolin-5-yloxy)-l-methylethylj-lH-isoindole-l,3(2H)-dione (2.3 mmol, 1.05 g) was dissolved in 33% methylamine in ethanol (20 mL) and stirred in room tempature over night. The solution was concentrated and purified by HPLC-C18. 1H NMR (400 MHz5 CDCl3) δ 8.16 (s, IH), 7.81 (s, IH), 7.74 - 7.67 (m, 2H), 7.36 - 7.28 (m, 3H), 4.13 - 4.06 (m, IH), 3.87 (t, J= 18.3 Hz, IH), 3.62 - 3.50 (m, IH), 2.27 (s, 2H), 1.33 (d, J= 17.1 Hz, 5H).
APCI-MS m/z (method A): 203.1 [MH+].
N-[(2S)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,3- dihydrobenzofuran-5 'sulfonamide 2,3-Dihydro-l-benzofuran-5-sulfonyl chloride (lOOμL, 0.3M/ACN) was mixed with
(2S)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-amine (100 μL, 0.3 M/pyridine) and stirred overnight in ambient temperature before it was evaporated to dryness under reduced pressure. The residue was purified on HPLC-Ci8 APCI-MS m/z (method A): 502.4 [MH+], LC-MS: (method B): rt = 8.24 min.
Example 5
N-rf2iy)-l-ri-r4-Fluorophenyl)indazol-5-yl1oxyproρan-2-yl]-4- (trifluoromethoxy)benzenesulfonamide Chiral
Figure imgf000034_0001
2-[(lS)-2-hydroxy-l-methylethylJ-lH-isoindole-l,3(2H)-dione was prepared as described in Example 4.
l-(4-Fluorσphenyl)-lH-indazol-5-ol was prepared as described in Example 1.
2-[(2S)-l~[l-(4-fluorophenyl)inda∑ol-5-yl]oxypropan-2-yl]isoindolβ'l,3-dione 2-[(15)-2-Hydroxy-l-methylethyl]-lH-isoindole-13(2H)-dione (3.1 mmol, 637 mg), i-(4- Fluorophenyl)-lH-uidazol-5-ol (3.1 mmol, 708 mg) and triphenylphosphine (3.4 mmol, 895 mg) were dissolved in THF (25 mL). DiώOpropylazodicarboxylate (3.4 mmol, 657 μl) was added dropwise to the reaction mixture before heated to 75 0C for 3 days. The mixture was concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate). 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J= 3.4 Hz, IH)3 7.86 - 7.82 (m, 2H), 7.73 - 7.60 (m, 4H), 7.57 - 7.47 (m, IH), 7.26 - 7.13 (m, 3H), 7.08 - 7.00 (m, IH), 4.93 - 4.79 (m, IH), 4.63 (t, J= 16.5 Hz, IH), 4.29 - 4.20 (m, IH), 1.60 (d, J= 7.2 Hz, 3H). APCI-MS m/z (method A): 416.3 [MH+].
(2S)-l-[6~chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-amine was prepared analogous to Example 4 but with the corresponding starting material. 1HNMR (400 MHz, CDCl3) δ 8.18 (s, IH)57.82 (s, IH), 7.76 - 7.63 (m, 2H), 7.36 - 7.28 (m, 3H), 4.13 - 4.05 (m, IH), 3.88 (t, J= 16.5 Hz, IH), 3.62 - 3.50 (m, IH), 2.27 (s, 2H), 1.32 (d, J= 21.2 Hz, 3H). APCI-MS m/z (method A): 320.2 [MH+],
N-[(2S)-1-[1 -(4-fluorophenyl) indazol-5-yl] oxypropan-2-yl]~4- (trifluoromethoxy)benzenesulfonamide was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 510.3 [MH+], LC-MS (method B): rt = 8.51 min.
Example 6 iV-r(21Sf)-l-r6-Chloro-l-f4-fluorophenyl)indazol-5-vlloxvDropan-2-vn-3.4-dimethyl- benzenesulfonamide
Figure imgf000035_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 488.4 [MH+]; LC-MS (method B) rt = 8.71 min. 0
Example 7
N-[(2ιS^-l-r6-Chloro-l-f4-fluorophenyl)indazol-5-yl"loxypropan-2-vn-4-methyl-2-phenyl- 1 ,3-thiazole-5-sulfonamide Chiral
Figure imgf000035_0002
s was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 557.3 [MH+]; LC-MS (method B) rt = 8.89 min.
Example 8
N-[(2lSf)-l-f6-Chloro-l-(4-fluorophenyl)indazol-5-yl1oxypropan-2-yn-4-o (trifluoromethoxy)benzenesulfonarm'de
Figure imgf000035_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A):: 544.3 [MH+]; LC-MS (method B) rt = 8.84 min. Example 9
Λr-[('2)S^-l-r6-Chloro-l-(4-fluorophenyl)indazol-5-vnoxypropaB-2-yn-l-methyl-mdole-5- sulfonamide
O o CH3 Cl chiral
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 513.3 [MH+]; LC-MS (method B) rt = 8.33 min.
Example 10 3-Chloro-iV-['(2i$r)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2- ylibenzenesulfonamide
Figure imgf000036_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 494.3 [MH+]; LC-MS (method B) rt = 8.65 min.
Example 11
N-rf2»y)-l-ri-(4-Fluorophenyl)indazol-5-ylloxypropan-2-vn-3- (trifluoromethyl)benzenesulfonamide
Figure imgf000036_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z(method A): 494.3 [MH+]; LC-MS (method B) rt = 8.42 min.
Example 12
JV-[(2y)-l-r6-Chloro-l-f4-fluorophenyl)indazol-5-vHoxypropan-2-yl1-5-1.2-oxazol-5-yl- thiophene-2-sulfonamide
Figure imgf000037_0001
was prepared analogous to Example 4 but with the corresponding starting material- APCI-MS m/z(method A): 533.3 [MH+]; LC-MS (method B) rt = 8.22 min.
Example 13 l-Cvclot)entyl-N-r('2^f)-l-ri-(4-fluorophenyl)indazol-5-yl1oxypropan-2-vn-3,S-dimethyl- pyrazole-4-sulfonamide Chiral
Figure imgf000037_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z(method A): 512.5 [MH+]; LC-MS (method B) rt = 8.33 min.
Example 14
N-[(26f)-l-r6-Chloro-l-('4-fluorophenyl)indazol-5-ylloxypropan-2-yll-3-methoxy- benzenesulfonamide
Figure imgf000037_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z(method A): 490.3 [MH+]; LC-MS (method B) rt = 8.37 min.
Example 15 l-(Difl-αoromethyl)-JV-[(21y)-l-ri-f4-iluorophenyl)indazol-5-vnoxypropan-2-yl]-5-methyl- pyrazole-4-sulfonamide π o 2H3 Chiral
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z(method A): 480.4 [MH+]: LC-MS (method B) rt = 7.76 min. Example 16 iy-fΩ^-l-rθ-Chloro-l-f^fluoiOphenvDindazol-S-ylloxypropan^-yll^J-dimethoxy- benzenesulfonamide
Figure imgf000038_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z(method A):: 520.4 [MH+]; LC-MS (method B) rt = 8.44 min.
Example 17
N-Ff 2S)- 1 -H -f 4-Fluorophenyl)indazol-5-yl1oxyρropan-2-yl"|-3 ,4-dimethyl- benzenesulfonamide
Figure imgf000038_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z(method A): 454.4 [MH+]; LC-MS (method B) rt = 8.36 min.
Example 18
N-r(2iSf)-l-r6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl1-l,5-dimethyl-pyrazole- 4-sulfonamide
Figure imgf000038_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z(method A): 478.3 [MH+]; LC (method B) rt = 7.66 min.
Example 19
N-\(2S)- 1 - ["6-Chloro- 1 -(4-fluorophenyl)indazol-5-vi]oxypropan-2-yH -4-pyrazol- 1 -yl- benzenesulfonamide
Figure imgf000039_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z(method A): 526.4 [MH+]; LC-MS (method B) rt = 8.14 min.
Example 20 iV-r("2^)-l-r6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yll-3,5-dimethyl- benzenesulfonamide
Figure imgf000039_0002
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z: 488.4 [MH+], LC-MS (method B) rt = 8.81 min.
Example 21
JV-rr2^-l-r6-Chloro-l-(4-fluorophenyl)indazol-5-yl1oxypropan-2-vn-8-thia-7,9- diazabicyclor4.3.01nona-2,4,6,9-tetraene-5-sulfonamide
Figure imgf000039_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z(method A):: 518.3 [MH+]; LC-MS (method B) rt = 8.24 min.
Example 22 3 -Chloro-N- 1(2S)- 1 - [ 1 -f 4-fluorophenyl)indazol-5-yl] oxypropan-2-yl"lbenzenesulfonamide
Figure imgf000039_0004
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z(method A):: 460.3 [MH+]; LC-MS (method B) rt = 8.33 min. Example 23
S-Chloro-N-rf 2,S")- 1 -f 1 -(4-fluorophenylN)indazol-5-yl]oxypropan-2-yl]-3-methyl- benzothiophene-2-sulfonamide
Figure imgf000040_0001
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 530.2 [MH+]; LC-MS (method B) rt = 8.78 min.
Example 24
N-[(25r)-l-[l-('4-Fluorophenγl)rndazol-5-yl1oxypropan-2-yl"|-3-methoxy- benzenesulfonamide
Figure imgf000040_0002
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 456.4 [MH+]; LC-MS (method B) rt = 8.02 min.
Example 25
7V-[f2iSf)-l-r6-ChIoro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl1-4-phenoxy- benzenesulfonamide
Figure imgf000040_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 552.4 [MH+]; LC-MS (method B) rt = 9.02 min.
Example 26
JV-[(2yi-l-f6-Chloro-l-f4-fluorophenyl)mdazol-5-yl]oxypropan-2-vnbenzothiazole-6- sulfonamide
Figure imgf000041_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 517.3 [MH+]; LC (method B) rt = 7.90 min.
Example 27
N-[C2^-l-fl-r4-Fluorophenyl)indazol-5-yl]oxypropan-2-yl1-4-phenyl-benzenesulfonamide
OH3Q o Chiral
Figure imgf000041_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 502.4 [MH+]; LC-MS (method B) rt = 8.63 min.
Example 28
N-rf2y>-l-r6-Chloro-l-f4-fluorophenyl)indazol-5-ylloxypropan-2-yl1-2-(2,2,2- trifluoroacetvD-3 ,4-dihydro- 1 H-isoquinoline-7-sulfonamide
Figure imgf000041_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 611.3 [MH+]; LC-MS (method B) rt = 8.42 min.
Example 29
JV-[f2^)-l-["l-(4-Fluorophenyl)indazol-5-yl]oxypropan-2-yll-l-methyl-mdole-5- sulfonamide
Figure imgf000041_0004
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 479.3 [MH+]; LC-MS (method B) rt = 8.00 min. Example 30
JV-ff2>y)-l-r6-Chloro-l-r4-fluorophenyl')indazol-5-yl1oxypropan-2-vll-l,3-dimethvl- pyrazole-4-sulfonamide
Figure imgf000042_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z: 478.3 [MH+]; LC-MS (method B) rt = 7.66 min.
Example 31
_V-lY2iSΗ -Fl -(4-Fluorophenvπindazol-5-vnoxypropan-2-yll-5-L2-oxazol-5-yl-thiophene- 2-sulfonamide
Figure imgf000042_0002
was prepared analogous to Example 5 but with the corresponding starting material.' APCI-MS m/z: 499.3 [MH+]; LC-MS (method B) rt = 7.90 min.
Example 32
N-[(2ιy)-l-ri-r4-Fluorophenyl)indazol-5-vnoxypropan-2-γl]-2,3-dihydrobenzoturan-5- sulfonamide Chiral
Figure imgf000042_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z: 468.4 [MH+]; LC-MS (method B) rt = 7.90 min.
Example 33
JV-[5-rrf26f)-l-r6-Chloro-l-(4-fluorophenyl)indazol-5-vnoxyρropan-2-vπsulfamovπ-2- methyl-phenylicyclopropanecarboxamide
Figure imgf000043_0001
was prepared analogous to Example 4 but with the corresponding starting material. wAPCI-MS m/z (method A): 557.3 [MH+]; LC-MS (method B) rt = 8.11 min.
Example 34 iV-rr2^-l-ri-C4-Fluorophenyl)indazol-5-ylloχγpropan-2-vn-3,5-dimethyl- benzenesulfonamide
Figure imgf000043_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 454.4 [MH+]; LC-MS (method B) rt = 8.43 min.
Example 35 iV-[('21y)-l-[l-(4-Fluorophenyl)indazol-5-yl]oxypropaii-2-yl]-4-pyrazol-l-yl- benzenesulfonamide Chiral
Figure imgf000043_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 492.4 [MH+]; LC-MS (method B) it = 7.81 min.
Example 36 N-[(2iS^-l-[6-Chloro-l-('4-fluorophenyl')indazoI-5-yl]oxypropan-2-vn-4-pyrrolidin-l- ylsulfonyl-benzenesulfonamide
Figure imgf000043_0004
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 593.3 [MH+]; LC-MS (method B) rt = 8.26 min.
Example 37
N-r(2^-l-fl-r4-Fluorophenyl)indazol-S-vnoxypropaα-2-yll-2.5-dimethoxγ- benzenesulfonarnide
Figure imgf000044_0001
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 486.4 [MH+]; LC-MS (method B) rt = 8.03 min.
Example 38
N-[('26r)-l-ri-f4-Fluorophenyl)indazol-5-yl]oxypropan-2-yll-3,5-dimethyl-l,2-oxazole-4- sulfonamide
Figure imgf000044_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 445.4 [MH+]; LC-MS (method B) rt = 7.81 min.
Example 39
N-1Y2SΗ -[I -f4-Fmorophenyl)indazol-5-yl1oxypropan-2-yl]-l ,5-dimethyl-pyrazole-4- sulfonamide
Figure imgf000044_0003
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 444.4 [MH+]; LC-MS (method B) rt = 7.22 min.
Example 40 iV-r4-rrf26f)-l-r6-Chloro-l-(4-fluorophenyl)indazol-5-vnoxyρropan-2- ylisnlfamoyllphenyll acetamide
Figure imgf000045_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 517.3 [MH+]; LC (method B) rt = 7.56 min.
Example 41
N-[(2)S)-l-[l-(4-Fluorophenyl)iBdazol-5-yl]oxypropan-2-yl]benzothiazole-6-sulfonamide
Figure imgf000045_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 483.3 [MH+]; LC-MS (method B) rt = 7.54 min.
Example 42
4-Cyano-N-f(2tSl-l-fl-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yllbenzenesulfonamide
Figure imgf000045_0003
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 451.4 [MH+]; LC-MS (method B) rt = 7.77 min.
Example 43 N-["C2^-l-ri-f4-Fluorophenyl)indazol-5-yl]oxypropan-2-γπ-4-phenoxy- benzenesulfonamide
Figure imgf000045_0004
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 517.9 [MH+]; LC-MS (method B) rt = 8.71 min.
Example 44 JV-r(2^-l-ri-(4-Fluorophenyl)indazol-5-yl1oxypropan-2-yl1-2-("2.2.2-trifluoroacetylV3.4- £ffΛv£/rø-Iff-isoquinoline-7-sulfonamide
Figure imgf000046_0001
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 577.3 [MH+]; LC-MS (method B) rt = 8.13 min.
Example 45 iV-r(2>S^-l-|'l-(4-Fluorophenyl)indazol-S-vnoxypropan-2-yl]-3-methylsulfonyl- benzenesulfonamide
Figure imgf000046_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 504.3 [MH+]; LC-MS (method B) rt = 7.48 min.
Example 46
N-rr2iSr)-l-r6-Chloro-l-f4-fluorophenyl)indazol-5-ylloxyprot)an-2-vn-1.2-dimethyl- imidazole-4-sulfonamide
Figure imgf000046_0003
was prepared analogous to Example 4 but with the corresponding starting material. APCI-MS m/z (method A): 478.3 [MH+]; LC-MS (method B) rt = 7.09 min.
Example 47 iV-[f21Sf)-l-ri-(4-Fluorophenγl)iαdazol-5-yl]oxyρropaα-2-vn-5-|rl-methyl-5- (trifluoromethvDpyrazol-3-vnthiophene-2-sulfonamide
Figure imgf000047_0001
was prepared analogous to Example 5 but with, the corresponding starting material. APCI-MS m/z (method A): 580.3 [MH+]; LC-MS (method B) rt = 8.51 min.
Example 48 iV-r5-rrr26r)-l-ri-(4-Fluorophenyl)indazol-5-vπoxypropan-2-yl1sulfamoyll-2-methyl- phenylicyclopropanecarboxamide
Figure imgf000047_0002
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 523.4 [MH+]; LC-MS (method B) rt = 7.72 min.
Example 49 JV"-[f2iS)-l-fl-("4-Fluorophenyl)indazol-5-yl]oxypropan-2-yll-l,3-dirnethyl-pyrazole-4- sulfonamide
Figure imgf000047_0003
was prepared analogous to Example 5 but with the corresponding starting material. APCI-MS m/z (method A): 444.4 [MH+]; LC-MS (method B) rt = 7.21 min.
Example 50
JV-r(2^-4-ri-(4-Fluorophenyl)rndazol-5-yllbutan-2-yl"l-2,4,6-trimethyl- benzenesulfonamide
Figure imgf000048_0001
tert-ButylN-[(2S)-but-3-en-2-yl]carbamate
72-Butyl lithium (2.5 M in hexans, 19.4 mL, 48.4 mmol) was added dropwise under 15 minutes to a suspension of methyltriphenylfosfonium bromide (20.2 g, 56.6 mmol) in anhydrous THF (200 mL) at 0°C. The mixture was stirred at 0 0C for 30 minutes, then at room temperature for Ih. The mixture was cooled to -20 0C and tert-butyl [( IS)-I -methyl- 2-oxo ethyl] carbamate (7.00 g, 40.0 mmol) dissolved in anhydrous THF (100 mL) was added dropwise during Ih. After stirring overnight at room temperature and 2 h at 50 0C, the mixture was cooled with an ice-bath. Saturated aqueous ammonium chloride and water was added to give a clear solution. The mixture was extracted with diethyl ether (250 mL), and the organic phase was dried over magnesium sulfate. Destination of the solvents at atmospheric pressure, followed by vaccura destination gave the title compound (86 °C, 13 mbar) as a liquid (2.1 g). 1HNMR (400 MHz, CD2Cl2) δ 5.83 (m, IH)5 5.12 (m, IH), 5.04 (m, IH)3 4.51 (broad s, IH), 4.17 (broad s, IH), 1.42 (s, 9H), 1.19 (d, J = 6.9 Hz, 3H).
tert-ButylN-[(E!2S)-4-[l~(4-fluorophenyl)indazol-5-yl]but-3-en-2-yl]carbamate
A mixture of tert-butyl l-methylprop-2-enylcarbamate (255 mg, 1.49 mmol), 5-bromo-l-
(4-fluorophenyl)-indazole (see example 3) (220 mg, 0.75 mmol), tetrabutylammonium iodide (415 mg, 1.12 mmol), N-ethyldiisopropylamine (1.5 mL), Pd-118 (49 mg, 0.075 mmol) and DMF (10 mL) was stirred under an argon atmosphere at 60 0C overnight. The mixture was concentrated and partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. Purification by chromatography (SiO2, light petroleum ether/t-butyl methyl ether) gave the title compound as an oil (217 mg).
1H NMR (400 MHz, CD2Cl2) δ 8.14 (s, IH), 7.76-7.67 (m, 3H), 7.64 (m, IH), 7.55 (m, IH), 7.25 (m, 2H), 6.62 (d, J= 16.1 Hz, IH), 6.20 (dd, J1 = 15.9 Hz3 J2 = 5.7 Hz, IH), 4.64 (broad s, IH), 4.38 (broad s, IH), 1.45 (s, 9H)3 1.32 (d, J = 6.9 Hz3 3H). tert-ButylN-[(2S)-4-[l-(4-fluorophenyl)indazol-5-yl]butan-2-yl] carbamate A solution oftert-bntyl (2jE)-3-[l-(4-fluorophenyl)-lH-indazol-5-yl]-l-methylprop-2- enylcarbamate (99 mg, 0.26 mmol) in ethanol (13 mL) was hydrogenated over Pd on carbon (5%, 33 mg) at atmospheric pressure for 2 1A h. Filtering through celite and evaporation gave the title compound (103 mg). APCI-MS m/z (method A): 384.1[MH+].
(2S)'4-[l~(4-Fluorophβnyl)indazol-5-yl]butan-2-amine Trifluoroacetic acid (0.80 mL) was added to a solution of tert-butyl (lS)-3-[l-(4- fluorophenyl)-lH-indazol-5-yl]-l-methylpropylcarbamate (100 mg, 0.26 mmol) in dichloromethane (4.0 mL). After stirring for 1 h the solution was evaporated and co- evaporated with toluene. Conversion into the base form on a BondElut SCX ion exchanger using methanol/ammonia as eluent gave the title compound (69 mg). APCI-MS m/z (method A): 284.1 [MH+] .
N-[(2S)-4-[l-(4-Fluorophenyl)indazol-5-yl]butan-2-yl]-2,4,6-trimethyl- benzenesulfonamide
A solution of 2-mesitylenesulfonyl chloride (105 mg, 0.48 mmol) in THF (2.0 mL) was added to 3-[l-(4-fiuorophenyl)-lH-indazol-5-yl]-l-methylpropylamine (69 mg, 0.24 mmol) and N-diisopropylethylamine (0.25 mL) in THF (3.0 mL). The mixture was stirred overnight, concentrated and purified by HPLC-C18. Concentration and lyophilisation from tert-butanol gave the title compound (100 mg).
1H NMR (400 MHz, CD2Cl2) δ 8.07 (s, IH), 7.69 (m, 2H), 7.56 (d, J = 8.7 Hz, IH), 7.36 (s, IH), 7.25 (m, 2H), 7.13 (dd, Ji = 8.7 Hz, J2 = 1.4 Hz, IH), 6.97 (s, 2H), 4.43 (d, J = 8.3
Hz, IH), 3.28 (m, IH), 2.67 (m, 2H), 2.58 (s, 6H), 2.30 (s, 3H), 1.71 (m, 2H), 1.08 (d, J =
6.7 Hz, d).
APCI-MS m/z (method A): 466.1 [MH+].
Example 51
2,4,6-Trimethvl-N-r(2S)-4-(l-pvrimidin-5-vluidazol-5-vI)butan-2-vnbenzenesulfonamide
Figure imgf000050_0001
10
5-Bromo-l-(pyrimidin-5-yl)-indazole
The title compound was prepared by the method of H. -J. Christau et al., Eur. J. Org.
Chem., 2004, 695-709. A mixture of 5-bromo-liJ-indazole (296 mg, 1.5 mmol), 5-bromopyrimidine (477 mg, 3.0 mmol), salicylaldoxime (41 mg, 0.3 mmol), copper(I) oxide (11 mg, 0.075 mmol) and cesium carbonate (1.47 g, 4.5 mmol) in acetonitrile (6 mL) was stirred under argon at 82
0C over night. The mixture was diluted with dichlorornethane, filtered through Celite and the filtrate was washed with water. The organic phase was dried over magnesium sulfate, evaporated and purified by chromatography (SiO2, dichloromethane/ethyl acetate 4/1) to give the title compound as a white powder (88 mg).
1HNMR (400 MHz, CD2Cl2) δ 9.21 (s, 2H), 9.19 (s, IH), 8.27 (d, IH), 8.02 (m, IH)3 7.69
(m, IH), 7.63 (m, IH).
tβrt-ButylN-[(E,2S)-4-(l-pyrimidin-5-ylindazol-5-yl)but-3-en-2-yl] carbamate
The title compound (67 mg) was prepared from 5-bromo-l-(pyrimidin-5-yl)-indazole (87 mg, 0.32 mmol) and tert-butyl l-methylprop-2-enylcarbamate (108 mg, 0.632 mmol) by a method analogous to that described in example 50, however the used reaction temperature was 800C. 1H NMR (400 MHz, CD2Cl2) δ 9.21 (s, 2H), 9.15 (s, IH), 8.26 (s, IH), 7.77 (s, IH), 7.73 (d, IH), 7.63 (dd, IH)1 6.63 (d, J = 15.9 Hz, IH)3 6.24 (dd, J1 = 15.9 Hz, J2 = 5.8 Hz, IH), 4.69 (broad s, IH), 4.39 (broad S3 IH), 1.45 (s, 9H), 1.33 (d, J = 6.7 Hz3 3H).
tert'ButylN-[(2S)-4~(l-pyrimidin-5-ylindazol-5-yl)butan-2-yl] carbamate A solution of tert-butyl N-[(E,2S)-4-(l -pyrimidin-5-ylindazol-5-yl)but-3-en-2- yl]carbamate (67 mg, 0.18 mmol) in ethanol (7 mL) was hydrogenated over Pd on carbon (5%, 30 mg) at atmospheric pressure. After 5h more Pd on carbon (5%, 10 mg) and ethanol was added (3 mL). After hydrogenation at atmospheric pressure for another 4 h, the reaction mixture was filtered through celite and evaporated. Purification on HPLC-C1S gave the title compound (50 mg).
1H NMR 400 MHz, CD2Cl2) δ 9.26 (s, 2H), 9.15 (s, IH)3 8.24 (s, IH), 7.74 (d, IH), 7.66 (s, IH), 7.41 (dd, IH), 4.47 (broad s, IH), 3.66 (m, IH), 2.81 (m, 2H), 1.78 (m, 2H), 1.43 (s, 9H), 1.16 (d, J = 6.6 Hz, 3H).
(2S)-4-(l-Pyrimidin-5-ylindazol-5-yl)butan-2-amine
The title compound (36 mg) was obtained from tert-butyl N-[(2S)-4-(l-pyrimidin-5- ylindazol-5-yl)butan-2-yl]carbamate (50 mg, 0.14 mmol) by a method analogous to that described in example 50.
APCI-MS m/z (method A): 268.1[MH+].
2,4,6-Trimethyl-N-[(2S)-4-(l-pyrimidin-5-ylindazol-5-yl)butan-2-yl]benzenesulfonamide
(2S)-4-(l-Pyrimidin-5-ylindazol-5-yl)butan-2-amine (35 mg, 0.13 mmol) was reacted with 2-mesitylenesulfonyl chloride (72 mg, 0.33 mmol) by a method analogous to that described in example 50. Purification on HPLC-Qg followed by lyophilisation from dioxane gave the title compound (49 mg).
1R NMR (400 MHz, CD2Cl2) δ 9.23 (s, 2H), 9.15 (s, IH), 8.20 (s, IH), 7.68 (d, J = 8.7 Hz,
IH), 7.68 (s, IH), 7.44 (s, IH)3 7.24 (dd, IH), 6.98 (s, 2H), 4.45 (broad d, IH), 3.29 (m, IH), 2.70 (m, 2H), 2.59 (s, 6H), 2.30 (s, 3H), 1.73 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H); APCI-
MS m/z (method A): 450.1 [MH+J.
Example 52 iV-ff2S)-l-r6-chloro-l-f4-fluorophenyl)indazol-5-ylloxypropan-2-yn-4-propyl- benzenesulfonamide
Figure imgf000051_0001
was prepared analogous to Example 1 but with the corresponding starting material. 1HNMR (400 MHz, DMSO-d6) δ 8.29 (s, IH), 7.91 (s, 2H)3 7.83 - 7.72 (m, 4H)5 7.46 - 7.37 (m, 3H), 7.33 (d, J= 8.2 Hz, 2H), 4.01 - 3.94 (m, IH), 3.90 - 3.83 (m, IH), 3.58 - 3.52 (m, IH)3 2.54 (t, J= 7.4 Hz3 2H), 1.52 (m, 2H)3 1.11 (d, J= 6.9 Hz, 3H)5 0.82 (t, J= 7.4 Hz3 3H). APCI-MS m/z (method A): 502.1 [MH+].
Example 53
Human Glucocorticoid Receptor (GR) Assay
The assay is based on a commercial kit from Panvera/Invitrogen (Part number P2893). The assay technology is fluorescence polarization. The kit utilises recombinant human GR (Panvera, Part number P2812), a Fluoromone™ labelled tracer (GS Red, Panvera, Part number P2894) and a Stabilizing Peptide 1OX (Panvera, Part number P2815). The GR and Stabilizing Peptide reagents are stored at -70°C while the GS Red is stored at - 200C. Also included in the kit are IM DTT (Panvera, Part number P2325, stored at -2O0C) and GR Screening buffer 1 OX (Panvera, Part number P2814, stored at -700C initially but once thawed stored at room temperature). Avoid repeated freeze/thaws for all reagents. The GR Screening buffer 1OX comprises 10OmM potassium phosphate, 20OmM sodium molybdate, ImM EDTA and 20% DMSO.
Test compounds (iμL) and controls (iμL) in 100% DMSO were added to black polystyrene 384-well plates (Greiner low volume black flat-bottom, part number 784076). 0% control was 100%DMSO and 100% control was lOμM Dexamethasone. Background solution (8μL; assay buffer 1OX, Stabilizing Peptide, DTT and ice cold MQ water) was added to the background wells. GS Red solution (7μL; assay buffer 10X3 Stabilizing Peptide, DTT, GS 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 wells. The plate was sealed and incubated in a dark at room temperature for 2hours. The plate was read in an Analyst plate reader (LJL Biosystems/Molecular Devices Corporation) or other similar plate reader capable of recording fluorescence polarization (excitation wavelength 530nm, emission wavelength 59OnM and a dichroic mirror at 561nm). The IC50 values were calculated using XLfit model 205. IC50 values are presented below for certain Examples.
Figure imgf000053_0001

Claims

1. A compound of formul Laa ((II))::
Figure imgf000054_0001
wherein:
A is phenyl, naphthyl, pyridinyl, furyl, thiazolyl, thienyl, thiophene, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl, dihydrobenzofuranyl, quinolinyl or isoquinolinyl, optionally substituted by one or more substituents independently selected from halo, Ci-6 alkyl, Ci-6 alkoxy, C1-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, benzyloxy, nitro, cyano, C(O)2H5 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, S(O)2(N-linked heterocyclyl), C(O)(C1-4 alkyl), C(O)(C1-4 haloalkyl), C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), NR10R11, isoxazolyl, oxazolyl, phenoxy (optionally substituted by halo, C1-6 alkyl, Ci-6 alkoxy, Ci-4 thioalkylthioalkyl, C1. 4 haloalkyl, CM haloalkoxy, nitro, cyano, C(O)2H, C(O)2(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Cw alkyl), S(O)2N(C1-4 alkyl)2, C(O)(Cx-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, d-6 alkoxy, C1-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy, 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(C1-4 alkyl), C(O)N(Cj-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR16R17), pyridinyloxy (optionally substituted by halo, C1-S alkyl, C1-S alkoxy, C1-4 thioalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, 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(0)NH(CM alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)(C1-4 alkyl) OrNR18R19), pyrazolyl (optionally substituted by halo, C1-6 alkyl, C1-6 alkoxy, C1-4 thioalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, nitro, cyano, 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(C1-4 alkyFh, C(O)(C1-4 alkyl), benzyloxy, C(O)NH2, C(O)NH(Cx-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)(Ci-4 alkyl) OrNR20R21) or tetrahydrofuranyl (optionally substituted by Ci-6 alkyl); and when A is phenyl adjacent ring carbons may be joined through a group: OCH2O3 OCH2CH2O or OCH2CH2; R10, R11, R14, R15, R16, R17 5 R18, R19, R20 and R21 are independently selected from hydrogen, Ci-4 alkyl or C3-7 cycloalkyl; R1 is hydrogen;
R2 is hydrogen, C1-4 alkyl, Ci-4haloalkyl, C3-7 cycloalkyl or C3-7 cyclohaloalkyl; R3 is hydrogen, Ci-4 alkyl or Ci-4 haloalkyl; R3a is hydrogen or Ci-4 alkyl; R4 is hydrogen, halogen, C1-4 alkyl or C1-4 haloalkyl; W is hydrogen or phenyl, C3-7 cycloalkyl, thienyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl optionally substituted by one or more substituents independently selected from halo, Ci-6 alkyl (optionally substituted by Ci-6 alkoxy), Ci-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, Ci-4s haloalkoxy, nitro, cyano, OH, C(O)2H3 C(O)2(Cx-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, benzyloxy, imidazolyl, 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 alkyl) or NR12R13; X is CH2, CH(Ci-4 alkyl), O, S, S(O), S(O)2 or NH; Y is hydrogen, halo, Cx-S alkyl, C1-6 alkoxy, Ci-4 thioalkyl, Ci-4 haloalkyl, C1-4 haloalkoxy,0 nitro, cyano, OH, C(O)2H, C(O)2(Cx-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Cj-4 alkyl)2, benzyloxy, imidazolyl, 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) OrNR22R23; and R12, R13, R22 and R23 are independently selected from hydrogen, C1-4 alkyl or C3-7 cycloalkyl; 5 or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein A is phenyl, thiazolyl, tbiophene, pyrazolyl, imidazolyl, oxazolyl, indolyl, benzothiophenyl, benzothiazolyl, dihydroisoquinolinyl, benzothiadiazolyl or dihydrobenzofuranyl optionally substituted by one or moreo substituents independently selected from halo, Cx-6 alkyl, Ci-6 alkoxy, Ci-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, benzyloxy, cyano, S(O)2(C1-4 alkyl), S(O)2(N- linked heterocyclyl), C(O)(Cj-4 haloalkyl), NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), oxazolyl, phenyl, pyrazolyl (optionally substituted by halo, C1-6 alkylor Ci-4 haloalkyl).
3. A compound according to claim 1 wherein A is phenyl optionally substituted by one or 5 more substituents independently selected from halo, C1-6 alkyl, C1-6 alkoxy, C1-4 haloalkyl,
Ci-4 haloalkoxy, C3-6 cycloalkyl, pyridinyloxy, benzyloxy, cyano, S(O)2(C1-4 alkyl), S(O)2(N-lώked heterocyclyl), C(O)(C1-4 haloalkyl), NHC(O)(C1-4 alkyl), NHC(O)(C3-6 cycloalkyl), oxazolyl, phenyl, pyrazolyl (optionally substituted by halo, C1-6 alkyl or C1-4 haloalkyl). 0
4. A compound according to any one of claims 1 to 3 wherein R1 is hydrogen;
R2 is hydrogen or C1-4 alkyl; R3 is hydrogen; s R3a is hydrogen, and R4 is hydrogen.
5. A compound according to any one of claims 1 to 4 wherein
W is hydrogen, phenyl or pyrimidinyl optionally substituted by one or more halo. 0
6. A compound according to any one of claims 1 to 5 wherein X is CH2, O or NH.
7. A compound according to any one of claims 1 to 5 wherein X is O. s
8. A compound according to any one of claims 1 to 7 wherein Y is hydrogen or halo.
9. A compound selected from
JV-[(2S)-l-[l-(4-flxιorophenyl)mdazol-5-yl]oxypropan-2-yl]-2,4,6-trimethyl- benzenesulfonamide; 0 JV-[(25)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,4,6-trimethyl- benzenesulfonamide; N-[(21S)-l-[[l-(4-Fluorophenyl)indazol-5-yl]amino]propan-2-yl]-2,4,6-trimetliyl- benzenesulfonamide;
N"-[(25)-l-[6-CMoro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,3-dihydrobenzoforaα-
5-sulfonamide; N-[(2iS)-l-[l-(4-Fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
JV-[(25)-l-[6-Chloro-l-(4-fl.uorophenyl)indazol-5-yl]oxypropan-2-yl]-3,4-diinethyl- benzenesulfonamide;
N-[(25)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-methyl-2-phenyl- l,3-thiazole-5-sulfonamide;
N-[(25)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide;
N-[(25)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l-methyl-indole-5- sulfonamide; 3-Chloro-iV-[(2iS)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2- yl]benzenesulfonamide;
N-[(2S)- 1 -[ 1 -(4-fluorophenyl)indazol-5-yl]oxyproρan-2-yl]-3-
(trifluoromethyl)benzenesulfonamide;
N-[(2S)-l -[6-chloro- 1 -(4-fluoropb.enyl)indazol-5-yl]oxypropan-2-yl]-5- 1 ,2-oxazol-5-yl- thiophene-2-sulfonamide; l-Cyclopentyl-iV-[(2iS)-l-[l-(4-fluoroplienyl)indazol-5-yl]oxyρropan-2-yl]-3,5-dimethyl- pyrazole-4-sulfonamide;
Ν-[(2^)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methoxy- benzenesulfonamide; l-(Difluorometh.yl)-N-[(2iS)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-5-inethyl- pyrazole-4-sulfonamide;
N-[(25)-l-[6-chloro-l-(4-fluoroplienyl)indazol-5-yl]oxypropan-2-yl]-2,5-dimethoxy- benzenesulfonamide;;
N-[(2JS)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3,4-dimethyl- benzenesulfonamide;
N-[(21S)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l,5-dimethyl-pyrazole-4- sulfonamide; N-[(2ιS)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-ylJ-4-pyrazol-l-yl- benzenesulfonamide;
N-[(25)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3,5-dimethyl- benzenesulfonamide; N-[(2JS}-l-[6-Chloro-l-(4-fluoroρhenyl)indazol-5-yl]oxypropan-2-yl]-8-thia-7,9- diazabicyclo[4.3.0]nona-2,4,6,9-tetraene-5-sulfonamide;
3-Chloro-iV-[(2iS)-l-[l-(4-fl.uorophenyl)indazol-5-yl]oxypropan-2-yl]benzenesulfonamide;
5-Chloro-7V-[(25)-l-[l-(4-fliiorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methyl- benzothiophene-2-sulfonamide; N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methoxy- benzenesulfonamide;
N-[(2iS)-l-[6-Chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-phenoxy- benzenesulfonamide;
N-[(2<S)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]benzothiazole-6- sulfonamide;
N-[(25)-l-[l-(4-fluoropb.enyl)indazol-5-yl]oxypropan-2-yl]-4-plienyl-benzenesulfonatnide;
N-[(25)-l-[6-chloro-l-(4-fluorophenyl)mdazol-5-yl]oxypropan-2-yl]-2-(232,2- trifluoroacetyl)-3 ,4-dihydro- 1 H-isoquinoline-7-sulfonamide;
N-[(21S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l-methyl-indole-5- sulfonamide;
N-[(25)-l-[6-cb.loro-l-(4-fluorophenyl)iαdazol-5-yl]oxypropan-2-yl]-l;3 -dimethyl- pyrazole-4-sulfonamide;
N-[(2iS)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-5-l,2-oxazol-5-yl-thiopliene-2- sulfonamide; iV-[(2>S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,3-dihydrobenzofuran-5- sulfonamide; iV-[5-[[(2iS)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]sulfamoyl]-2- methyl-phenyljcyclopropanecarboxamide; iV-[(2<S)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3?5-dimethyl- benzenesulfonamide;
N-[(21S)-l-[l-(4-fiuorophenyl)indazol-5-yl]oxypropan-2-yl]-4-pyrazol-l-yl- benzenesulfonamide; iV-[(251)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropaB-2-yl]-4-pyrrolidin-l- ylsulfonyl-benzenesulfonamide;
N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,5-dimethoxy- benzenesulfonamide; . iV-[(25)-l-[l-(4-fluorophenyl)iQdazol-5-yl]oxypropan-2-yl]-3,5-dimetliyl-l,2-oxazole-4- sulfonamide;
N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-l,5-dimethyl-pyrazole-4- sulfonamide;
N-[4-[[(25)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2- yl]sulfamoyl]ρhenyl]acetamide;
N-[(2iS)-l-[l-(4-Fluorophenyl)indazol-5-yl]oxypropan-2-yl]benzothiazole-6-sulfonamide;
4-Cyano-N"-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]benzenesulfonamide; iV-[(2iS)-l-[l-(4-fluorophenyl)itidazol-5-yl]oxypropan-2-yl]-4-phenoxy- benzenesulfonamide; N-[(2S)~l -[I -(4-fluoroplienyl)indazol-5-yl]oxypropan-2-yl]-2-(252,2-trifiuoroacetyl)-3,4-
Jz/zy^ro-lH-isoquinoline-7-sulfonamide;
N-[(25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-3-methylsulfonyl- benzenesulfonamide ;
N-[(2S)~ 1 -[6-chloro- 1 -(4-fluorophenyl)indazol-5-yl]oxypropan-2-ylj- 1 ,2-dimethyl- imidazole-4-sulfonamide;
7V-[(2)S)-l-[l-(4-fiuorophenyl)indazol-5-yl]oxypropan-2-yl]-5-[l-methyl-5-
(trifluoromethyl)pyrazol-3-yl]thiophene-2-sulfonamide; iV-[5-[[(2)S)-l-fl-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]sulfamoyl]-2-methyl- phenyljcyclopropanecarboxamide; N-[(2ιS)-l-[l-(4-fluorophenyl)indazol-5-yl]oxyρropan-2-yl]-l,3-diineth.yl-pyrazole-4- sulfonamide; iV-[(25)-4-[l-(4-fluorophenyl)indazol-5-yl]butan-2-yl]-2,4,6-trimethyl- benzenesulfonamide;
2,436-Trimethyl-Ν-[(2S)-4-(l-pyrimidin-5-ylindazol-5-yl)butan-2-yl]benzenesulfonamide; or, iV-[(2S)-l-[6-chloro-l-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-4-propyl- benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, and a pharmaceutically acceptable adjuvant, diluent or carrier.
11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9 for use in therapy.
12. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of a glucocorticoid receptor mediated disease state.
13. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of an inflammatory condition.
14. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of asthma.
15. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of COPD.
16. A method of treating a glucocorticoid receptor mediated disease state, an inflammatory condition, an asthmatic condition and/or COPD, 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 as claimed in any one of claims 1 to 9.
17. A combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, and one or more agents selected from the list comprising:
• a PDE4 inhibitor; • a selective β.sub2. adrenoceptor agonist;
• a muscarinic receptor antagonist;
• a steroid;
• a modulator of chemokine receptor function; or,
• an inhibitor of p38 kinase function.
18. Processes for the preparation of compounds of formula (I); (a) by coupling a compound of formula (II):
Figure imgf000061_0001
with a compound of formula (III):
VL1 (ill)
A Nb U wherein L1 is a leaving group, in a suitable solvent, in the presence of a suitable base, or (b) by coupling a compound of formula (IV):
Figure imgf000061_0002
wherein L2 is a leaving group with a compound of formula (V):
R1 f R3a
% VΨ XH (V) u in a suitable solvent, in the presence of a suitable base or (c) by coupling a compound of formula (VI):
Figure imgf000062_0001
with a compound of formula (VII):
Figure imgf000062_0002
wherein L is a leaving group, in a suitable solvent, in the presence of a suitable base.
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