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Definitions

• the present invention relates to novel indazolyl 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) 313 166-173, J. Med. Chem. (2003) 46 64-73, J. Med. Chem. (1997) 40 996-1004, EP 0031954, EP 1190710 (WO 200124786), U.S. Pat. No. 5,861,401, U.S. Pat. No. 4,948,809, U.S. Pat. No. 3,992,441 and WO 99/33786.
• non-steroidal compounds interact with the glucocorticoid receptor (GR) and, as a result of this interaction, produce a suppression of inflammation (see, for example, U.S. Pat. No. 6,323,199).
• GR glucocorticoid receptor
• Such compounds can show a clear dissociation between anti-inflammatory and metabolic actions making them superior to earlier reported steroidal and non-steroidal glucocorticoids.
• the present invention provides further non-steroidal compounds as modulators (for example agonists, antagonists, partial agonists or partial antagonists) of the glucocorticoid receptor.
• glucocorticoid receptor ⁇ Modulators of the glucocorticoid receptor are disclosed in WO 2007/122165, WO 2008/076048 and WO 2008/043788. ⁇ These new compounds are contemplated to have improved properties such as selectivity or efficacy over the known compounds.
• These new compounds are also contemplated to have an improved low Log D and thus an improved distribution volume in vivo.
• the systemic exposure of the compounds is also expected to be improved.
• the compounds are contemplated to have a lower melting point and improved crystallinity compared to the known compounds.
• the present invention provides a compound of formula Ia:
• A is C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkylC(O)—, C 1-6 alkyloxyC(O)—, NR 5 R 6 , NR 5 R 6 C(O)— or C 5-10 heteroaryl, all optionally substituted by one or more substituents independently selected from halo, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl; R 5 and R 6 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylC(O)— and C 3-7 cycloalkylC(O)—, or R 5 and R 6 might form a ring with the nitrogen to which they are attached; R 1 is hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl-, C 1-4 alkylthio
• X is O or NH
• W is phenyl substituted by one or more substituents independently selected from —(CH 2 ) n C(O)NR 7 R 8 , —(CH 2 ) n NR 9 C(O)R 8 or —(CH 2 ) n C(O)NR 9 (CR 14 R 15 )C(O)NR 7 R 8 ; and W is optionally further substituted by halogen or C 1-4 alkyl;
• R 7 is hydrogen or C 1-4 alkyl;
• R 8 and R 9 are, independently, hydrogen, C 1-4 alkyl (optionally substituted by one or two groups selected from hydroxyl, C 1-4 alkoxy, NH 2 , oxo, —C(O)NR 10 R 11 , —NR 10 C 1-4 alkyl, —C(O)NR 10 C 1-4 alkyl, —NR 10 C 1-4 alkyl, C 1-4 alkylthio, C 5-10 heterocyclyl, C 5-10 aryl or C 5-10 heteroaryl),
• R 3 , R 7 and R 8 are defined as in compounds of formula Ia, or a pharmaceutically acceptable salt thereof.
• One embodiment relates to compounds of formula Ia or Ib, wherein:
• A is C 3-7 cycloalkyl, C 1-6 haloalkyl optionally substituted by cyano;
• R 1 is C 1-4 alkyl or C 1-4 hydroxyalkyl;
• R 3 is C 5-10 aryl or C 5-10 heteroaryl optionally substituted by C 1-4 alkoxy;
• X is O
• W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 is hydrogen;
• R 8 is C 1-4 alkyl (optionally substituted by one or two groups selected from hydroxyl, —C(O)NH 2 , —NHC(O)C 1-4 alkyl, C 5-10 heterocyclyl, C 5-10 aryl or C 5-10 heteroaryl), C 3-7 cycloalkyl, C 5-10 heterocyclyl or C 5-40 heteroaryl, whereby any heterocyclyl is optionally substituted by C 1-4 alkyl or oxo; or R 7 and R 8 , together with the nitrogen to which the are attached, form a 5- or 6-membered ring optionally comprising a second ring-nitrogen atom, the ring being optionally substituted by one or two groups selected from oxo, hydroxyl, C 1-4 hydroxyalkyl or —C(O)NH 2 ; and
• Y is hydrogen; or a pharmaceutically acceptable salt thereof
• A is C 1-6 haloalkyl.
• A is C 1-4 haloalkyl.
• the present invention provides a compound of formula Ia or Ib wherein A is fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl or trifluoropropyl.
• A is difluoroethyl.
• A is C 3-5 cycloalkyl substituted with cyano, hydroxyl or methoxy.
• A is cyclopropyl substituted with cyano.
• One embodiment of the present invention provides a compound of formula Ia wherein R 1 hydrogen, C 1-3 alkyl or C 1-3 hydroxyalkyl;
• R 1 is methyl, ethyl or n-propyl, iso-propyl, n-butyl or iso-butyl. In a further embodiment R 1 is methyl.
• R 1 is hydroxymethyl, hydroxyethyl or hydroxypropyl or hydroxybutyl. In a further embodiment R 1 is hydroxymethyl.
• One embodiment of the present invention provides a compound of formula Ia or Ib wherein R 3 is phenyl optionally substituted as recited above (for example optionally substituted by halogen, C 1-3 alkyl, C 1-3 alkoxy, CF 3 , OCF 3 , hydroxyl or cyano).
• R 3 is phenyl
• R 3 is pyridyl optionally substituted as recited above (for example optionally substituted by halogen, C 1-3 alkyl, C 1-3 alkoxy, CF 3 , OCF 3 , hydroxyl or cyano).
• R 3 is pyridyl.
• R 3 is pyridyl substituted with methoxy.
• R 3 is methoxypyridin-3-yl.
• One embodiment of the present invention provides a compound of formula Ia wherein X is O.
• One embodiment of the present invention provides a compound of formula Ia or Ib wherein R 7 is hydrogen, methyl or ethyl. In another embodiment R 7 is hydrogen.
• R 7 is methyl
• One embodiment of the present invention provides a compound of formula Ia or Ib wherein W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 is hydrogen; and R 8 is hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminooxomethyl, aminooxoethyl, aminooxopropyl, aminomethyloxomethyl, aminomethyloxoethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetylaminomethyl, acetylaminoethyl, oxoimidazolidinylmethyl, oxoimidazolidinylethyl, oxopyrrolidinylmethyl, oxopyrrolidinylethyl, oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl, oxotertahydrofuranyl, tertahydrofuranyl, methyldioxooxazolidinylmethyl, dimethyldioxooxazolid
• R 8 is hydroxyethyl, hydroxybutyl, aminooxoethyl, aminomethyloxoethyl, aminooxopropyl, cyclopentyl, acetylaminoethyl, oxoimidazolidinylethyl, tetrahydrothiophenyl, oxopyrrolidinylethyl, dioxidotetrahydrothiophenyl, oxotertahydrofuranyl, tertahydrofuranyl, dimethyldioxooxazolidinylethyl, indazolylmethyl, aminooxophenylethyl, pyridinyl or pyridinylmethyl.
• One embodiment of the present invention provides a compound of formula Ia or Ib wherein A is difluoroethyl or cyclopropyl substituted with cyano; R 1 is methyl or hydroxymethyl; R 3 is phenyl or pyridyl substituted with methoxy; X is O; Y is hydrogen;
• W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 is hydrogen; and
• R 8 is hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminooxomethyl, aminooxoethyl, aminooxopropyl, aminomethyloxomethyl, aminomethyloxoethyl, acetylaminomethyl, acetylaminoethyl, oxoimidazolidinylmethyl, oxoimidazolidinylethyl, to oxopyrrolidinylmethyl, oxopyrrolidinylethyl, methyldioxooxazolidinylmethyl, dimethyldioxooxazolidinylmethyl, methyldioxooxazolidinylethyl, dimethyldioxooxazolidinylethyl, indazolylmethyl, indazolyleth
• R 8 is hydroxyethyl, hydroxybutyl, aminooxoethyl, is aminomethyloxoethyl, aminooxopropyl, acetylaminoethyl, oxoimidazolidinylethyl, oxopyrrolidinylethyl, dimethyldioxooxazolidinylethyl, indazolylmethyl, aminooxophenylethyl or pyridinylmethyl.
• a further embodiment of the present invention provides a compound of formula Ia or Ib wherein A is difluoroethyl or cyclopropyl substituted with cyano; R 1 is methyl or hydroxymethyl; R 3 is phenyl or pyridyl substituted with methoxy; X is O; Y is hydrogen;
• W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 is hydrogen; and
• R 8 is C 5-6 cycloalkyl.
• R 8 is cyclopentyl.
• a further embodiment of the present invention provides a compound of formula Ia or Ib wherein A is difluoroethyl or cyclopropyl substituted with cyano; R 1 is methyl or hydroxymethyl; R 3 is phenyl or pyridyl substituted with methoxy; X is O; Y is hydrogen;
• W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 is hydrogen; and
• R 8 is C 5-6 heterocyclyl, optionally substituted by methyl, ethyl or oxo.
• R 8 is oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl, tetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.
• R 8 is dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.
• a further embodiment of the present invention provides a compound of formula Ia or Ib wherein A is difluoroethyl or cyclopropyl substituted with cyano; R 1 is methyl or hydroxymethyl; R 3 is phenyl or pyridyl substituted with methoxy; X is O; Y is hydrogen;
• W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 is hydrogen; and
• R 8 is C 5-6 heteroaryl.
• R 8 is pyridyl.
• R 7 and R 8 together with the nitrogen to which they are attached, form a 5- or 6-membered ring which optionally comprises a second ring-nitrogen atom, said ring is, for example, pyrrolidinyl, piperidinyl or piperazinyl.
• One embodiment of the present invention provides a compound of formula Ia or Ib is wherein W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 and R 8 together form pyrrolidinyl, oxopyrrolidinyl, carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide, piperidinyl, hydroxypiperidinyl, oxopiperidinyl, imidazolidinyl, oxoimidazolidinyl, hydroxyimidazolidinyl, piperazinyl, hydroxypiperazinyl or oxopiperazinyl.
• R 7 and R 8 together form carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide or oxopiperazinyl.
• Another embodiment of the present invention provides a compound of formula Ia or Ib wherein A is difluoroethyl, amide or cyclopropyl substituted with cyano; R 1 is methyl or hydroxymethyl; R 3 is phenyl or pyridyl substituted with methoxy; X is O; Y is hydrogen; W is phenyl substituted by —C(O)NR 7 R 8 ;
• R 7 and R 8 together with the nitrogen to which the are attached, form a 5- or 6-membered ring optionally comprising a second ring-nitrogen atom (for example the ring is pyrrolidinyl, piperidinyl or piperazinyl), the ring being optionally substituted by one or two groups selected from oxo, hydroxyl, C 1-4 hydroxyalkyl or —C(O)NH 2 .
• R 7 and R 8 together form pyrrolidinyl, oxopyrrolidinyl, carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide, piperidinyl, hydroxypiperidinyl, oxopiperidinyl, imidazolidinyl, piperazinyl, hydroxypiperazinyl, oxopiperazinyl, tetrahydrothiophenyl, oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.
• R 7 and R 8 together form carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide or oxopiperazinyl.
• One embodiment of the present invention provides a compound of formula Ia wherein Y is hydrogen.
• A is C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 alkylC(O), C 1-6 alkyloxyC(O), NR 5 R 6 , NR 5 R 6 C(O) or C 5-10 heteroaryl, all optionally substituted by one or more substituents independently selected from halo, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl; R 5 and R 6 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylC(O) and C 3-7 cycloalkylC(O), or R 5 and R 6 might form a ring with the nitrogen to which they are attached; R 1 is hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkylthioC 1-4 alkyl or C 1-4 haloalkyl; R 3 is C 5-10 aryl, C 5-10
• X is O or NH
• W is phenyl substituted by one or more substituents independently selected from (CH 2 ) n C(O)NR 7 R 8 , (CH 2 ) n NR 9 C(O)R 8 or (CH 2 ) n C(O)NR 9 (CR 14 R 15 )C(O)NR 7 R 8 ; and W is optionally further substituted by halogen or C 1-4 alkyl;
• R 7 is hydrogen or C 1-4 alkyl;
• R 8 and R 9 are, independently, hydrogen, C 1-4 alkyl (optionally substituted by one or two groups selected from hydroxyl, C 1-4 alkoxy, NH 2 , oxo, C(O)NR 10 R 11 NR 10 C 1-4 alkyl, C(O)NR 10 C 1-4 alkyl, NR 10 C(O)C 1-4 alkyl, C 1-4 alkylthio, C 5-10 heterocyclyl, C 5-10 aryl or C 5-10 heteroaryl), C 3-7 cycloalkyl (
• the present invention relates to any compound falling within the scope of compounds of formula Ia or Ib and any one specific compound mentioned below.
• the present invention provides compounds selected from:
• the present invention provides compounds selected from:
• C 1-6 means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
• alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.
• C 1-4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or t-butyl.
• C 0 in C 0-4 alkyl refers to a situation where no carbon atom is present.
• alkylenyl refers to a straight or branched chain alkyl group linking two other atoms. It is, for example, CH 2 or CH 2 CH 2 .
• alkoxy refers to radicals of the general formula O—R, wherein R is selected from a hydrocarbon radical.
• alkoxy may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, iso-butoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
• cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
• C 1-6 cycloalkyl may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• heterocycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system having one or more heteroatoms independently selected from O, N or S.
• C 1-6 heterocycloalkyl may be, but is not limited to pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrothiophenyl oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.
• a 5- or 6-membered ring optionally comprising a second ring-nitrogen atom refers to heterocycloalkyl as defined above and may be, but is not limited to pyrrolidinyl, prolinamide or piperazinyl.
• halo and “halogen” may be fluorine (fluoro), iodine (iodo), chlorine (chloro) or bromine (bromo).
• haloalkyl means an alkyl group as defined above, which is substituted with halo as defined above.
• C 1-6 haloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl or fluorochloromethyl.
• C 1-3 haloalkylO or “C 1-3 haloalkoxy” may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
• thioalkyl means an alkyl group as defined above, which is substituted with sulphur atom.
• C 1-6 thioalkyl may include, but is not limited to methylsulfanyl, ethylsulfanyl or propylsulfanyl.
• cycloalkylthio means a sulphur atom substituted with a cycloalkyl as defined above such as for instance cyclopropylsulfanyl.
• C 1-4 alkylthioalkyl means a alkyl group with a sulphur atom between the carbon atoms.
• C 1-4 alkylthioC 1-4 alkyl may include, but is not limited to ethylsulfanylmethyl.
• C 5-10 aryl or aryl refers to an aromatic or partial aromatic group having 5 to 10 carbon atoms such as for example, phenyl or naphthyl.
• C 5-10 aryloxy or “C 5-10 arylO” refers to for example phenoxy.
• C 5-10 heteroaryl refers to a mono- or bicyclic aromatic or partially aromatic ring with 5 to 10 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulphur.
• Heteroaryl is, for example, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, furyl, thienyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, benzofuryl, benzothienyl, dioxabicyclodecatrienyl, quinolinyl or isoquinolinyl.
• a group R 3 defined as C 5-10 aryl e.g. phenyl, substituted with a group C 1-2 alkylS(O) k includes a phenyl substituted with methylsulphonyl group.
• Compounds of the invention 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.
• Compounds of the invention may be converted to a pharmaceutically acceptable salt thereof, such as an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulphate, acetate, ascorbate, benzoate, fumarate, hemifumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate, p-toluenesulphonate, benzenesulphonate, ethanesulphonate, 2-naphthalenesulfonate, mesytilenesulfonate, nitric acid, 1,5-naphthalene-disulphonate, p-xylenesulphonate, aspartate or glutamate.
• an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulphate, acetate, ascorbate, benzoate, fumarate, hemifumarate,
• 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-methylpiperidine, N-ethylpiperidine, piperazine, procaine, dibenzylamine, N,N-dibenzylethylamine, choline or 2-aminoethanol or amino acids for example lysine or arginine.
• 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-methylpiperidine, N-ethylpiperidine, piperazine, procaine, dibenz
• the compounds of the invention, or a pharmaceutically acceptable salt thereof, may exist is in solvated, for example hydrated, as well as unsolvated forms, or as cocrystals and the present invention encompasses all such forms.
• the compounds of the invention can be prepared using or adapting methods disclosed in the art, or by using or adapting the method disclosed in the Example below.
• Starting materials for the preparative methods are either commercially available or can be prepared by using or adapting literature methods.
• a process for the synthesis of a compound of formula Ia or Ib can comprise using an acid/amine coupling reaction disclosed in WO 2007/122165, WO 2008/043788 or WO 2008/076048.
• a compound of the invention can be prepared if an acid of formula (Ic) is reacted with an amine of formula HNR 7 R 8 or HNR 9 (CR 14 R 15 )C(O)NR 7 R 8 .
• a compound of the invention can be prepared by reaction of an amine of formula (Id) with an acid as defined by HOC(O)R 8 .
• the compounds of formula (Ic) and (Id) can be synthesised from protected precursors such as alkylesters for the synthesis of (Ic), or from an N-protected precursor of NR 9 H such as NR 9 BOC or N 3 for the preparation of (Id).
• One embodiment relates to a process for the preparation of compounds of formula Ia or Ib by coupling a compound of formula (II):
• W is as defined above or can be a group that can be converted into W as defined above
• L 1 is a leaving group ⁇ such as halogen (for example chloro) or, when L 1 ⁇ OH, a leaving group generated by reaction of a coupling reagent (such as HART with a carboxylic acid) ⁇ .
• the reaction may be performed in a suitable solvent (such as pyridine, THF or DMF), in the presence of a suitable base (such as a tri(C 1-6 alkyl)amine, for example diisopropylethylamine, or pyridine) and at a suitable temperature (such as ⁇ 10° to 50° C.).
• a compound of formula (II) can be prepared according to step a, b or c.
• a compound of formula (II) can be prepared by coupling a compound of formula (IV)
• R 1 and X are defined above and G corresponds to R 3 or a protected precursor to R 3 .
• the reaction can be performed in a suitable solvent (such as an aromatic solvent, for example toluene) or a polar, aprotic solvent, such as DMF or butyronitril, in the presence of a suitable base (such as a alkali metal alkoxide (for example sodium tert-butoxide) or, cesium carbonate, such as mediated by a suitable metal catalyst such as Copper(I) iodide at a suitable temperature (for example in the range 80° to 120° C.).
• a suitable solvent such as an aromatic solvent, for example toluene
• a polar, aprotic solvent such as DMF or butyronitril
• a suitable base such as a alkali metal alkoxide (for example sodium tert-butoxide) or, cesium carbonate, such as mediated by a suitable metal catalyst such as Copper(I) iodide
• a compound of formula (II) can be prepared by reacting a compound of formula (VII)
• R 1 , X, W and Y are defined above, G corresponds to R 3 or a protected precursor to R 3 , and L 3 is a leaving group (such as halogen, mesylate or tosylate).
• the reaction can be performed in a suitable solvent (such as DCM, 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 ⁇ 10 to 50° C.), followed by a subsequent reductive amination step using or adopting literature methods.
• a suitable solvent such as DCM, DMF or acetonitrile
• a suitable base such as an alkali metal carbonate, for example cesium carbonate or potassium carbonate
• a compound of formula (II) may be prepared by reacting a compound of formula (VIII) with a compound of formula (IX)
• R 1 and R 3 are as defined above, and PG is a suitable protecting group such as BOC, mesyl or tosyl or related carbonyl- or sulfonyl residues.
• the reaction can be performed in a suitable solvent such as DCM or toluene in the presence of a suitable base such as NaH or KOtBu, followed by a deprotection step using or adopting literature methods.
• R 1 and G are defined as in compounds of formula (V).
• R 1 , R 3 , G and PG are as defined above, and L is a leaving group (such as alkoxy, methoxy(methyl)amino), M is a metal such as Li or Mg-halide.
• L is a leaving group (such as alkoxy, methoxy(methyl)amino)
• M is a metal such as Li or Mg-halide.
• compounds of formula (X) may be prepared by a reaction of a nucleophile G-M with an aldehyde of formula (XIII) and a subsequent deprotection.
• R 1 , R 3 , G and PG are as defined above, and M is a metal such as an alkali metal (e.g. Li) or Mg-halide.
• the reaction may be performed by following disclosed protocols for addition of carbanions to aldehydes.
• a compound of formula Ia, 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):
• 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
• ARDS adult 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
• Rheumatic diseases/auto-immune diseases/degenerative joint diseases which coincide with inflammatory, allergic and/or proliferative processes: all forms of rheumatic diseases, for example rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, collagenoses, Behçet's disease reactive arthritis inflammatory soft-tissue diseases of other origins arthritic symptoms in degenerative joint diseases (
• iv Vascular inflammations (vasculitides) Panarteritis nodosa, temporal arteritis, erythema nodosum Polyarteris nodosa Wegner's granulomatosis Giant-cell arteritis
• Dermatological diseases which coincide with inflammatory, allergic and/or proliferative processes: atopic dermatitis (mainly in children) exfoliative dermatitis, psoriasis erythematous diseases, triggered by different noxae, for example radiation, chemicals, burns, etc.
• 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
• vascular diseases vulvitis inflammatory hair loss such as alopecia greata 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
• 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 ulceris 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 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
• Blood diseases which coincide with inflammatory, allergic and/or proliferative processes: acquired haemolytic anemia thrombocytopenia such as for example idiopathic thrombocytopenia M.
• 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
• Endocrine diseases which coincide with inflammatory, allergic and/or proliferative processes: endocrine orbitopathy thyrotoxic crisis de Quervain's thyroiditis Hashimoto's thyroiditis
• the compounds of the invention can also be used to treat disorders such as: diabetes type I (insulin-dependent diabetes), Guillain-Barré 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, granulocyte transfusion, 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, Butter's Syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic
• diabetes type I insulin-
• CHF congestive heart failure
• congestive heart failure refers to a disease state of the cardiovascular system whereby the heart is unable to efficiently pump an adequate volume of blood to meet the requirements of the body's tissues and organ systems.
• CHF is characterized by left ventricular failure (systolic dysfunction) and fluid accumulation in the lungs, with the underlying cause being attributed to one or more heart or cardiovascular disease states including coronary artery disease, myocardial infarction, hypertension, diabetes, valvular heart disease, and cardiomyopathy.
• diastolic congestive heart failure refers to a state of CHF characterized by impairment in the ability of the heart to properly relax and fill with blood.
• systolic congestive heart failure refers to a state of CHF characterized by impairment in the ability of the heart to properly contract and eject blood.
• physiological disorders may present as a “chronic” condition, or an “acute” episode.
• chronic means a condition of slow progress and long continuance.
• a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease.
• acute means an exacerbated event or attack, of short course, followed by a period of remission.
• the treatment of physiological disorders contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear.
• the present invention provides a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, for use in therapy (such as a therapy described above).
• the present invention provides the use of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a glucocorticoid receptor mediated disease state (such as a disease state described above).
• the invention provides the use of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an inflammatory condition (such as an arthritic).
• an inflammatory condition such as an arthritic
• the invention provides the use of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a respiratory disorder.
• the invention provides the use of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma.
• the invention provides the use of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of COPD.
• the present invention provides a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, for use in treating an inflammatory condition, respiratory disorder, asthma and/or COPD.
• the present invention further provides a method of treating a glucocorticoid receptor is mediated disease state (such as a disease state described above), 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 Ia, or a pharmaceutically acceptable salt thereof.
• a glucocorticoid receptor is mediated disease state (such as a disease state described above), 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 Ia, or a pharmaceutically acceptable salt thereof.
• the term “therapy” and “treatment” also includes prophylaxis and prevention unless there are specific indications to the contrary.
• the terms “therapeutic” and “therapeutically” should be construed accordingly.
• 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.
• An agonist may be a full or partial agonist.
• disorder unless stated otherwise, means any condition and disease associated with glucocorticoid receptor activity.
• said active ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, (active ingredient) and a pharmaceutically acceptable adjuvant, diluent or carrier.
• a pharmaceutical composition comprising a compound of formula Ia, or a pharmaceutically acceptable salt thereof, for treating a glucocorticoid receptor mediated disease state (such as a disease state described above), an inflammatory condition, respiratory disorder, asthma and/or COPD.
• a further aspect the present invention provides a process for the preparation of said composition comprising mixing the active ingredient with a pharmaceutically to acceptable adjuvant, diluent or carrier.
• the pharmaceutical composition can comprise from 0.05 to 99% w (percent by weight), for example from 0.05 to 80% w, such as from 0.10 to 70% w (for example from 0.10 to 50% w), of active ingredient, all percentages by weight being based on total composition.
• a pharmaceutical composition of the present invention can be administered in a is standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
• a compound of formula Ia, 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 10 g of active ingredient.
• composition of the invention is one suitable for intravenous, subcutaneous, intraarticular or intramuscular injection.
• a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof is administered orally.
• a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof is administered by inhalation.
• Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ -cyclodextrin may be used to aid formulation.
• Tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
• the invention further relates to a combination therapy or composition wherein a compound of formula Ia, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula Ia or Ib, 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.
• a compound of formula Ia or Ib, or a pharmaceutically is acceptable salt thereof can be combined with one or more agents for the treatment of such a condition.
• the one or more agents is selected from the list comprising:
• a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof can be administered by inhalation or by the oral route and the other agent, e.g. xanthine (such as aminophylline or theophylline) can be administered by inhalation or by the oral route.
• the other agent e.g. xanthine (such as aminophylline or theophylline)
• xanthine such as aminophylline or theophylline
• a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, and the other agent, e.g xanthine may be administered together. They may be administered sequentially. Or they may be administered separately.
• NMR spectra were recorded on a Varian Mercury-VX 300 MHz instrument or a Varian Inova 400 MHz instrument. The central peaks of chloroform-d (H 7.27 ppm), acetone (H 2.05 ppm), dichloromethane-d2 (H 5.32 ppm) or DMSO-d 6 (H 2.50 ppm) were used as internal references. Alternatively, NMR. spectra were recorded on a Varian Inova Unity 500 MHz instrument. Proton-NMR experiments were acquired using dual suppression of residual solvent peak and H 2 O.
• LC Method A HPLC method A was performed with Agilent 1100 series machines on Kromassil ⁇ C18 5 ⁇ m 3.0 ⁇ 100 mm colum. Aqueous phase was water/TFA (99.8/0.1) and organic phase was acetonitrile/TFA (99.92/0.08). Flow was 1 ml/min and gradient was set from 10 to 100% of organic phase during 20 minutes. Detection was carried out on 220, 254 and 280 nm.
• LC Method B HPLC method B was performed with Agilent 1100 series machines on XTerra® RP 8 5 ⁇ m 3.0 ⁇ 100 mm colum. Aqueous phase was 15 nM NH3 in water and organic phase was acetonitrile. Flow was 1 ml/min or 0.6 ml/min when indicated and gradient was set from 10 to 100% of organic phase during 20 minutes. Detection was carried out on 220, 254 and 280 nm.
• the mixture was diluted with 15% NaHSO 4 (2 ml), the organic layer was separated (phase separator) and the water layer was back extracted with DCM 3 mL, the combined organic layers were evaporated.
• the crude product was dissolved in MeCN 3 mL and purified by mass directed autopreparartion using Preparativ HPLC system A, the pure fractions were combined and freeze dried to obtain the title compound (40 mg, 46%).
• Boc-Ala-OH 200 g, 1057 mmol
• 3400 ml dichloromethane 3400 ml dichloromethane were cooled to 0° C.
• 1,1′-Carbonyldiimidazol (205.7 g, 1268 mmol) was added in multiple portions over 30 min and stirring was continued for 30 minutes at 0° C.
• Triethylamine (175.8 ml, 1268 mmol) was added over 20 min at 2° C. followed by N,O-dimethyl hydroxylamine mono hydrochloride (123.7 g, 1268 mmol) in multiple portions and stirring was continued for 30 minutes at 0° C.
• 1,1′-Carbonyldiimidazol (217 mg, 1.34 mmol) was added to 2,2-difluorpropionic acid (111 mg, 1.0 mmol) in 4 mL THF and stirred for 7 hours.
• (1R,2S)-1- ⁇ [1-(3-bromophenyl)-1H-indazol-5-yl]oxy ⁇ -1-(6-methoxypyridin-3-yl)propan-2-amine (304 mg, 0.67 mmol) in THF (2 mL) was added and stirring was continued for 64 hours at room temperature. The solvent was removed i.vac., and the product purified by chromatography on silica gel.
• the microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125° C. for 6 minutes (5 minutes ramp time). Then the solvent was removed i.vac., and the product purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 22 mg (55%) 3-(5- ⁇ [(1R,25)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)propyl]oxy ⁇ -1H-indazol-1-yl)-N-(pyridin-3-yl)benzamide.
• the microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125° C. for 6 minutes (5 minutes ramp time). Additional tetrahydrothiophen-3-amine 1,1-dioxide (13 mg, 135 ⁇ mol), tri-t-butylphosphoniumtetrafluoroborat (1.3 mg, 4 ⁇ mol) and trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(H) (1.4 mg, 2 ⁇ mol) were added and microwave radiation was continued for 8 minutes.
• CEM discover tetrahydrothiophen-3-amine 1,1-dioxide
• tri-t-butylphosphoniumtetrafluoroborat 1.3 mg, 4 ⁇ mol
• trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(H) 1.4 mg, 2 ⁇ mol
• the microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125° C. for 10 minutes (5 minutes ramp time. Then the solvent was removed i.vac., and the product purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 11 mg (30%) 3-(5- ⁇ [(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)propyl]oxy ⁇ -1H-indazol-1-yl)-N-(tetrahydrofuran-3-yl)benzamide.
• the microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125° C. for 10 minutes (5 minutes ramp time). Then the solvent was removed i.vac., and the product purified by chromatography on silica gel (ethyl acetate in hexane 0% to 100%) to yield 35 mg (66%) 3-(5- ⁇ [(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)propyl]oxy ⁇ -1H-indazol-1-yl)-N-(2-hydroxybutyl)benzamide.
• the microwave vessel was closed and radiated in microwave reactor (CEM discover) at 150 W and 125° C. for 6 minutes (5 minutes ramp time). Then the solvent was removed i.vac., and the product purified by preparative thin layer chromatography on silica gel (ethyl acetate in hexane 50%) to yield 15 mg of 3-(5- ⁇ [1R,2S)-3-tert-butoxy-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)propyl]oxy ⁇ -1H-indazol-1-yl)-N-cyclopentylbenzamide, which were treated with 178 ⁇ l trifluoroacetic acid in 0.6 ml dichloromethane over 18 hours at room temperature.
• 1,1′-Carbonyldiimidazol (74 mg, 0.46 mmol) was added to 2,2-difluorpropionic acid (50 mg, 0.46 mmol) in 1.2 mL THF and stirred for 3 hours.
• (1R,2S)-1- ⁇ [1-(3-bromophenyl)-1H-indazol-5-yl]oxy ⁇ -3-tert-butoxy-1-(6-methoxypyridin-3-yl)propan-2-amine (120 mg, 0.23 mmol) in THF (1.2 ml) was added and stirring was continued for 20 hours at room temperature.
• the microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125° C. for 10 minutes (5 minutes ramp time). Then the solvent was removed i.vac., and the product purified chromatography on silica gel (hexane/ethyl acetate 0 to 100%) to yield 19 mg (35%) 3-(5- ⁇ [(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)propyl]oxy ⁇ -1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide.
• the radioligand GR binding assay is based on a competition assay using 3H -labeled Dexamethasone.
• Dexamethasone is known to bind in the ligand binding domain of GR and compete for binding with endogenous ligands like e.g. cortisol (Necela, 2003).
• test compounds were serially diluted in semi-log steps (10 concentrations) with a final concentration of 10 ⁇ M.
• Test compounds (1 ⁇ L) and controls (1 ⁇ L) in 100% DMSO were added to 96 Greiner V-bottom polypropylene plates. 0% control was 6.7% DMSO (final concentration in assay) and 100% control was 6.7 ⁇ M Dexamethasone.
• GR full length GR was diluted to a final concentration of 3.3% (0.495 mg/ml) in assay buffer (20 mM Tris-HCl, 1 mM EDTA, 10% (w/v) Glycerol, 20 mM Sodium molybdate, pH 7.4). 45 ⁇ L of GR was added to each well and the plates were incubated for 15 min at room temperature.
• 3H -dexamethasone solution was diluted to a concentration of 70 nM in assay buffer (7 nM final assay concentration) and 5 ⁇ L was added to each well. The samples were mixed for 5 min using a plate shaker at 700 rpm, before incubation for 2 h at room temperature.
• the plate was then centrifuged for 1.5 min at 1500 rpm, the samples (80 ⁇ L) were is transferred from each well to a filter plate (Millipore, 0.45 ⁇ m, MHVBN45) on a vacuum manifold and then collected into new plates (Greiner, 96 well white/transparent, 655095).
• the filter plate was washed once with 20 ⁇ l of water and then 100 ⁇ L of scintillation liquid was added to each well and mixed by incubation on plate shaker for 5 min. Radioactivity was measured in a 1450 Microbeta Trilux Reader (Wallac) counting cpm for 2 minutes per well.

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