Phenyl or pyridinyl substituted indazoles derivatives

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 s 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) 3_13 166-173, J. Med. Chem. (2003) 46 64-73, J. Med. Chem (1997) 40 996-o 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, fors example, US6323199). Such compounds can show a clear dissociation between antiinflammatory 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. {Modulators of the glucocorticoid receptor are0 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 LogD and thus an improved distribution volume in vivo. The systemic exposure of the compounds is also5 expected to be improved. Further 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:

wherein:

A is Ci _-6 alkyl, C _1-6 alkoxy, C _3-7 CyClOaIlCyI, C _1-6 haloalkyl, Ci _-6 alkylthio, Ci _-6 alkylC(O)-, Ci- ₆ alkyloxyC(O)-, NR ⁵ R ⁶ , NR ⁵ R ⁶ C(O)- or C _5- i ₀ heteroaryl, all optionally substituted by one or more substituents independently selected from halo, cyano, hydroxyl, C _1-4 alkyl, Ci- ₄ alkoxy and

R ⁵ and R ⁶ are independently selected from hydrogen, C^aUcyl, C _3-7 cycloalkyl, Ci- 6alkylC(0)- 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, Ci _-4 alkyl, Ci _-4 hydroxyalkyl-, Ci^alkylOC _M alkyl-, Ci^alkylthioC _M alkyl- or Ci^haloalkyl;

R ³ is C ₅ .i _O aryl, Cs-ioarylC _M alkyl-, C _5- i ₀ arylO-, Cs-ioaryloxyC _M alkyl-, C ₅ -ioheteroaryl-, Cs-ioheteroarylCi^aUcyl-, Cs.ioheteroarylC _M alkoxy- or C _{5- l} oheteroaryoxyCi^alkyl-, all of which are unsubstituted or optionally substituted by one or more substituents independently selected from B; B is hydroxyl, halo, cyano, Ci _-3 hydroxyalkyl-, C _3-6 CyClOaIlCyIO-, C _3- ecycloalkylthio-, Ci _-3 alkylS(O) _k -, C _1-4 haloalkyl or Q- ₄ haloalkoxy-, or B is one of the following groups which are linked to adjacent carbons on an aryl or heteroaryl ring (CH ₂ ) _t OCi _-4 alkylenylO(CH ₂ ) _v - or (CH ₂ ) _t O(CH ₂ ) _v -; k is O, 1; t and v are, independently, 0, 1, 2 or 3, and t and v are not both 0;

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 R ⁷ is hydrogen or Ci _-4 alkyl;

R and R are, independently, hydrogen, Ci _-4 alkyl (optionally substituted by one or two groups selected from hydroxyl, Ci _-4 alkoxy, NH ₂ , oxo, -C(O)NR ¹⁰ R ¹¹ , aIlCyI, - C(O)NR ¹⁰ CM alkyl, -NR ¹⁰ C(O)C _M aIlCyI, C _1-4 alkylthio, Cs-ioheterocyclyl, C _5- i ₀ aryl or C _{5- l} oheteroaryl),

C _3-7 cycloalkyl (optionally substituted by -C(O)NH ₂ ), Cs-ioheterocyclyl, C _5- i _O aryl, C _5- ioheteroaryl or -C(O)NR ¹⁰ R ¹ ' ;

whereby C _5-10 aryl or C _5- i ₀ heteroaryl are optionally substituted by halogen, C _M alkyl, Ci-

4alkoxy, CF ₃ , -OCF ₃ , hydroxy or cyano; and whereby any heterocyclyl is optionally substituted by Ci _-4 alkyl, -Ci _-4 alkoxy(Ci-4 alkyl), oxo or hydroxyl; 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, Ci-

₄ hydroxyalkyl-, C _1-4 alkyl, -C _M alkoxy(C _M alkyl) or -(CH ₂ ) _P C(O)NR ¹² R ¹³ ;

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are, independently, hydrogen or Ci _-4 alkyl; n and p are, independently, 0, 1, 2, 3 or 4; and

Y is hydrogen, halo, Ci^alkyl or C _1-4 haloalkyl; or a pharmaceutically acceptable salt thereof.

One embodiment relates to compounds of formula Ib

and A, 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, Ci- _δ haloalkyl optionally substituted by cyano;

R ¹ is Ci _-4 alkyl or Ci _-4 hydroxyalkyl;

R ³ is C _5- ioaryl or C _5- ioheteroaryl optionally substituted by Ci _-4 alkoxy;

X is O;

W is phenyl substituted by -C(O)NR ⁷ R ⁸ ; R ⁷ is hydrogen;

R ⁸ is Ci _-4 alkyl (optionally substituted by one or two groups selected from hydroxyl,

C(O)NH ₂ , -NHC(O)Ci _-4 alkyl, C _5- ioheterocyclyl, C _5- i _O aryl or C _5- ioheteroaryl),

C _3-7 cycloalkyl, C _5-10 heterocyclyl or Cs.ioheteroaryl, whereby any heterocyclyl is optionally substituted by Ci _-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] ^hydroxy alkyl or -C(O)NH ₂ ; and Y is hydrogen; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention provides a compound of formula Ia or Ib wherein A is Ci. ₆ haloalkyl. In a further embodiment A is Ci _-4 haloalkyl. In a further embodiment the present invention provides a compound of formula Ia or Ib wherein A is fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl or trifluoropropyl. In one embodiment A is difluoroethyl. In a further embodiment A is C _3-5 cycloalkyl substituted with cyano, hydroxyl or methoxy. In yet a further embodiment A cyclopropyl, cyclobutyl or cyclopentyl, optionally substituted with cyano. In another embodiment A is cyclopropyl substituted with cyano.

One embodiment of the present invention provides a compound of formula Ia wherein R ¹ hydrogen, Ci _-3 alkyl or Ci _-3 hydroxyalkyl;

In another embodiment R ¹ is methyl, ethyl or n-propyl, iso-propyl, n-butyl or iso-butyl. In a further embodiment R ¹ is methyl.

In another embodiment 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 sybstituted by halogen, C _1-3 alkyl, Ci _-3 alkoxy, CF ₃ , OCF ₃ , hydroxyl or cyano). In one embodiment R ³ is phenyl.

One embodiment of the present invention provides a compound of formula Ia or Ib wherein R ³ is pyridyl optionally substituted as recited above (for example optionally sybstituted by halogen, C _1-3 alkyl, C _1-3 alkoxy, CF ₃ , OCF ₃ , hydroxyl or cyano). In a further embodiment R ³ is pyridyl. In yet a further embodiment R ³ is pyridyl substituted with methoxy. In another embodiment 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. In a further embodiment 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, dimethyldioxooxazolidinylmethyl, methyldioxooxazolidinylethyl, dimethyldioxooxazolidinylethyl, indazolylmethyl , indazolylethyl, aminooxophenylmethyl, aminooxophenylethyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridinylmethyl, pyridinylethyl, indazolylmethyl or indazolylethyl. In another embodiment 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, oxopyrrolidinylmethyl, oxopyrrolidinylethyl, methyldioxooxazolidinylmethyl, dimethyldioxooxazolidinylmethyl, methyldioxooxazolidinylethyl, dimethyldioxooxazolidinylethyl, indazolylmethyl , indazolylethyl, aminooxophenylmethyl, aminooxophenylethyl, pyridinylmethyl, pyridinylethyl, indazolylmethyl or indazolylethyl. In another embodiment R ⁸ is hydroxyethyl, hydroxybutyl, aminooxoethyl, 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 Cs^cycloalkyl. In one embodiment 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. In one embodiment R ⁸ is oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl, tetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.

In another embodiment R ⁸ is dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.

A further embodiment of the present invention provides a compound of formula Ia or Ib 5 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. In one embodiment R ⁸ is pyridyl. o When 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 Ibs wherein W is phenyl substituted by -C(O)NR ⁷ R ⁸ ; and

R ⁷ and R ⁸ , together form pyrrolidinyl, oxopyrrolidinyl, carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide, piperidinyl, hydroxypiperidinyl, oxopiperidinyl, imidazolidinyl, oxoimidazolidinyl, hydroxyimidazolidinyl, piperazinyl, hydroxypiperazinyl or oxopiperazinyl. o hi one embodiment 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 IbS 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 0 pyrrolidinyl, piperidinyl or piperazinyl), the ring being optionally substituted by one or two groups selected from oxo, hydroxyl, C ₁ ^hydroxy alky 1 or -C(O)NH ₂ .

In one embodiment 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 .

In one embodiment 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.

One embodiment of the present invention provides a compound of formula Ia wherein:

A is Ci _-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, Ci _-6 haloalkyl, Ci _-6 alkylthio, Ci _-6 alkylC(O), Ci-

₆ alkyloxyC(O), NR ⁵ R ⁶ , NR ⁵ R ⁶ C(O) or C _5- i ₀ heteroaryl, all optionally substituted by one or more substituents independently selected from halo, cyano, hydroxyl, R ⁵ and R ⁶ are independently selected from hydrogen, C _h alky 1, C _3-7 cycloalkyl, Ci-

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 _h alky., Ci _-4 hydroxyalkyl, or

Ci. ₄ haloalkyl; R ³ is C _5- ioaryl, Cs-ioarylC _M alkyl, C _5- ioarylO, Cs-ioarylC _M alkoxy, C _5- ioaryloxyCi _-4 alkyl,

C _5- i ₀ heteroaryl, or C _5- ioheteroaryoxyCi.

₄ alkyl, all of which are unsubstituted or optionally substituted by one or more substituents independently selected from B;

B is hydroxyl, halo, cyano, C _3-6 cycloalkyloxyCi. ₄ alkyl, Cs-βcycloalkyloxy, C _3-6 cycloalkylthioCi. ₄ alkyl, C _3-

₆ cycloalkylthio, Ci _-3 alkylS(O) _k Ci-4alkyl, C]. ₃ alkylS(O) _k , or Ci _-4 haloalkoxy,

or B is one of the following groups which are linked to adjacent carbons on an aryl or heteroaryl ring (CH ₂ ) _t 0C _1-4 alkylenyl0(CH ₂ ) _v or (CH ₂ ) _t O(CH ₂ ) _v ; k is O, 1; t and v are, independently, 0, 1, 2 or 3, and t and v are not both 0; 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 Ci^alkyl;

R ⁷ is hydrogen or C _1-4 alkyl; R ⁸ and R ⁹ are, independently, hydrogen, Cj _-4 alkyl (optionally substituted by one or two groups selected from hydroxyl, Cj _-4 alkoxy, NH ₂ , oxo, C(O)NR ¹⁰ R ¹¹ , NR ¹⁰ Ci _-4 alkyl,

C(O)NR ¹⁰ C _1-4 alkyl, NR ¹⁰ C(O)Ci _-4 alkyl, CM alkylthio, C ₅ -ioheterocyclyl, C ₅ -i _O aryl or C _{5- l} oheteroaryl), C _3-7 cycloalkyl (optionally substituted by C(O)NH ₂ ), C _5- ioheterocyclyl, C _{5- l} oaryl, C _5- i ₀ heteroaryl or C(O)NR ¹⁰ R ¹¹ ; C _5- ioaryl or C _5- ioheteroaryl are optionally substituted by halogen, Ci _-4 alkyl, Ci _-4 alkoxy, CF ₃ , OCF ₃ , hydroxy or cyano; heterocyclyl is optionally substituted by Ci _-4 alkyl, Ci _-4 3IkOXy(Ci _-4 alkyl), oxo or hydroxyl; 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 oxo, hydroxyl, Ci _-4 hydroxyalkyl, Ci _-4 alkyl, Ci _-4 alkoxy^i^ alkyl) or (CH ₂ ) _P C(O)NR ¹² R ¹³ ;

R ¹⁴ and R ¹⁵ are, independently, hydrogen, Ci _-4 alkyl or Ci _-4 hydroxyalkyl; or R ¹⁴ and R ¹⁵ join to form a C _3-6 cycloalkyl ring;

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are, independently, hydrogen or Ci _-4 alkyl; n and p are, independently, O, 1 , 2, 3 or 4; Y is hydrogen, halo, Ci _-4 alkyl or Ci^haloalkyl; or a pharmaceutically acceptable salt thereof.

For the avoidance of doubt, 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.

In another aspect the present invention provides compounds selected from:

1 -( {3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 - yl]phenyl } carbony l)-D-prolinamide,

N-[( 1 S,2R)-2- {[ 1 -(3- { [(2R)-2-carbamoylpyrτolidin-l -yl]carbonyl}phenyl)- 1 H-indazol-5- yl]oxy}-l-methyl-2-phenylethyl]ethanediamide, 3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yl]-

N-(2-hydroxyethyl)benzamide,

N-(2-amino-2-oxoethyl)-3-[5-({(lR,2S)-2-[(2,2-difluoropro panoyl)amino]-l- phenylpropyl} oxy)- 1 H-indazol- 1 -yl]benzamide,

N-[( 1 S)-2-amino- 1 -methyl-2-oxoethyl]-3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl } oxy)- 1 H-indazol- 1 -yl]benzamide,

N-[2-(acetylamino)ethyl]-3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 - phenylpropyl} oxy)- 1 H-indazol- 1 -yl]benzamide,

3-[5-( {( lR,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yl]-

N-[2-(2-oxoimidazolidin- 1 -yl)ethyl]benzamide, 2,2-difluoro-N-[(lS,2R)-2-{[l-(3-{[(2R)-2-(hydroxymethyl)pyr rolidin-l- yl]carbonyl}phenyl)- 1 H-indazol-5-yl]oxy} - 1 -methyl-2-phenylethyl]propanamide,

2,2-difluoro-N-[(l S,2R)-2- {[ 1 -(3- { [(3R)-3-hydroxypyrrolidin- 1 -yl]carbonyl} phenyl)- 1 H- indazol-5-yl]oxy} - 1 -methyl-2-phenylethyl]propanamide,

3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yl]- N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide,

1 -( {3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 - yl]phenyl}carbonyl)-L-prolinamide,

2,2-difluoro-N- {( 1 S,2R)- 1 -methyl-2-[(l - {3-[(3-oxopiperazin- 1 -yl)carbonyl]phenyl} - 1 H- indazol-5-yl)oxy]-2-phenylethyl}propanamide, 3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yl]-

N-[2-(2-oxopyrrolidin- 1 -yl)ethyl]benzamide,

3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yl]-

N- [2-(5 , 5 -dimethyl-2,4-dioxo- 1 ,3 -oxazolidin-3 -yl)ethyl]benzamide,

3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- lH-indazol- 1 -yl]- N-( 1 , 1 -dioxidotetrahydrothiophen-3-yl)benzamide,

3-[5-( {( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yl]-

N-( 1 H-indazol-3-ylmethyl)benzamide,

N-[( 1 R)-2-amino-2-oxo- 1 -phenylethyl]-3-[5-( {(1 R,2S)-2-[(2,2-difluoropropanoyl)amino]-

1 -phenylpropyl} oxy)- 1 H-indazol- 1 -yljbenzamide,

N-(2-amino-2-oxoethyl)-3-[5-({(lR,2S)-2-[(2,2-difluoropro panoyl)amino]-l- phenylpropyl } oxy)- 1 H-indazol- 1 -yl]-N-methylbenzamide, N-(3-amino-3-oxopropyl)-3-[5-({(lR,2S)-2-[(2,2-difluoropropa noyl)amino]-l- phenylpropyl} oxy)- 1 H-indazol- 1 -yljbenzamide,

(4R)-l-({3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]- l-phenylpropyl}oxy)-lH- indazol- 1 -yljphenyl} carbonyl)-4-hydroxy-L-prolinamide,

1 - { [3-(5- { [( 1 R,2S)-2- { [( 1 -cyanocyclopropyl)carbonyl]amino} - 1 -phenylpropyl] oxy } - 1 H- indazol- 1 -yl)phenyl] carbonyl } -D-prolinamide, or a pharmaceutically acceptable salt thereof.

In a further aspect the present invention provides compounds selected from:

N-cyclopentyl-3-(5- { [( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3- yl)propyl]oxy} - 1 H-indazol- 1 -yl)benzamide,

3-(5- { [( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3-yl)propyl]oxy } -

1 H-indazol- 1 -yl)-N-pyridin-3-ylbenzamide,

3-(5- { [( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3-yl)propyl]oxy} -

1 H-indazol- 1 -yl)-N-( 1 , 1 -dioxidotetrahydrothiophen-3-yl)benzamide, 3-(5-{[(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l-(6-methoxy pyridin-3-yl)propyl]oxy}- lH-indazol-l-yl)-N-(tetrahydrofuran-3-yl)benzamide,

3-(5- { [( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3-yl)propyl]oxy} -

1 H-indazol- 1 -yl)-N-(2-hydroxybutyl)benzamide,

N-cyclopentyl-3-(5-{[(lR,2S)-2-[(2,2-difluoropropanoyl)am ino]-3-hydroxy-l-(6- methoxypyridin-3-yl)propyl]oxy } - 1 H-indazol- 1 -yl)benzamide, and

3-(5- { [( 1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3-yl)propyl]oxy } -

1 H-indazol- 1 -yl)-N-(pyridin-3-ylmethyl)benzamide, 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 'C _1-6 ' 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 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. The term "Co" in C _0-4 alkyl refers to a situation where no carbon atom is present.

The term 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 .

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, iso-butoxy, 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 _1-6 cycloaUcyr' may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In this specification, unless stated otherwise, the term "heterocycloalkyl" or "heterocyclyl" 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. The term "Ci- _δ heterocycloalkyl" may be, but is not limited to pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrothiophenyl oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or tertahydrofuranyl.

In this specification, unless stated otherwise, the term "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.

In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine (fluoro), iodine (iodo), chlorine (chloro) or bromine (bromo).

In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with halo as defined above. The term "Ci- ₆ haloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, difluoroethyl, trifiuoromethyl, chloromethyl, dichloromethyl, trichloromethyl or fiuorochloromethyl.

The term "Ci _-3 haloalkylO" or "Qohaloalkoxy" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.

In this specification, unless stated otherwise, the term "thioalkyl" means an alkyl group as defined above, which is substituted with sulphur atom. The term "Ci- ₆ thioalkyl" may include, but is not limited to methylsulfanyl, ethylsulfanyl or propylsulfanyl.

The term "cycloalkylthio" means a sulphur atom substituted with a cycloalkyl as defined above such as for instance cyclopropylsulfanyl.

The term "C _M alkylthioalkyl" means a alkyl group with a sulphur atom between the carbon atoms. The term "d^alkylthioC _M alkyl" may include, but is not limited to ethylsulfanylmethyl.

In this specification, unless stated otherwise, the term "C _5- ioaryl" or aryl refers to an aromatic or partial aromatic group having 5 to 10 carbon atoms such as for example, phenyl or naphthyl. The term "C _5- i ₀ aryloxy" or "Cs.ioarylO" refers to for example phenoxy.

In this specification, unless stated otherwise, the term "Cs.ioheteroaryl" or 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, 5 thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, benzofuryl, benzothienyl, dioxabicyclodecatrienyl, quinolinyl or isoquinolinyl.

When aryl (for example phenyl) or heteroaryl is substituted by (CH ₂ ) _t OCi. 4alkylenyl0(CH ₂ ) _v or (CH ₂ ) _t O(CH ₂ ) _v ; wherein t and v are, independently, 0, 1, 2 or 3, but t io and v are not both 0; these substituents can be, for example, CH ₂ OCH ₂ O, OCH ₂ O, OCH ₂ CH ₂ O or OCH ₂ CH ₂ linking adjacent carbons on the aryl or heteroaryl ring.

For the avoidance of doubt a group R ³ defined as C _5- ioaryl e.g. phenyl, substituted with a group Ci- ₂ alkylS(O)k includes a phenyl substituted with methylsulphonyl group.

I ₅

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.

₂ o Compounds of the present invention have been named with the aid of computer software (ACDLabs 10.06/Name(IUPAC)).

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

₂₅ 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

30 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. 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^V-dibenzylethylamine, choline or 2-aminoethanol or amino acids for example lysine or arginine.

The compounds of the invention, or a pharmaceutically acceptable salt thereof, may exist in solvated, for example hydrated, as well as unsolvated forms, or as cocrystals and the present invention encompasses all such forms.

Process

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. For example using as an intermediate a compound of formula (Ic) or (Id):

wherein R ¹ , R ³ , X and Y are defined as above, and Z is A-C(O) or A-S(O) ₂ . 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 . Alternatively, 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):

with acylation reagents of formula (Ilia), (HIb) or (IIIc)

(IIIc) wherein R ¹ , R ³ , A, X and Y are defined above, W is as defined above or can be a group that can be converted into W as defined above, and 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 HATU 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 In(Ci _-6 alkyl)amine, for example diisopropylethylamine, or pyridine) and at a suitable temperature (such as -10° to 5O ⁰ C).

A compound of formula (II) can be prepared according to step a, b or c. a) A compound of formula (II) can be prepared by coupling a compound of formula (IV) wherein W and Y are as defined above and L ² is a leaving group (such as halogen or triflate) with a compound of formula (V)

wherein R ¹ and X are defined above and G corresponds to R ³ or a protected precurser 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 fert-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 12O ⁰ C).

Or, b) A compound of formula (II) can be prepared by reacting a compound of formula (VII)

with a compound of formula (VIII)

wherein R ¹ , X, W and Y are defined above, G corresponds to R ³ or a protected precurser 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 5O ⁰ C), followed by a subsequent reductive amination step using or adopting literature methods.

Or, c) a compound of formula (II) may be prepared by reacting a compound of formula (VIII) with a compound of formula (IX)

CX)

wherein 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.

As a specific case of a compound of formula (V), a compound of formula (X) might be used to prepare a compound of formula (II) wherein R ¹ and G are defined as in compounds of formula (V).

Compounds of formula (X) may be prepared by reacting a nucleophile G-M with a carbonyl compound of formula (XI) followed reduction and subsequent deprotection of the intermediate of formula (XII)

wherein 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. The addition of the nucleophile may be performed in a suitable aprotic solvent such as THF at moderate temperature between -10 and 5O ⁰ C. The following reduction and deprotection steps might be carried out by using or adopting literature methods.

Alternatively, compounds of formula (X) may be prepared by a reaction of a nuceophile G- M with an aldehyde of formula (XIII) and a subsequent deprotection.

wherein 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.

Another way to prepare a compound of formula (X) is the reaction of a nitroalkyle of formula (XIV) with an aldehyde of formula (XV), followed by reduction of the nitro function

wherein R ¹ , R ³ and G are as defined above. Both steps may be carried out by following or adopting literature methods.

Medical use Because of their ability to bind to the glucocorticoid receptor the compounds of the invention are useful as anti-inflammatory agents, and can also display antiallergic, immunosuppressive and anti-proliferative actions. Thus, 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):

(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, for example 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 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 5 processes: acute lymphatic leukaemia malignant lymphoma lymphogranulomatoses lymphosarcoma o extensive metastases, mainly in breast and prostate cancers

(xv) Endocrine diseases, which coincide with inflammatory, allergic and/or proliferative processes: endocrine orbitopathy thyrotoxic crisis s de Quervain's thyroiditis

Hashimoto's thyroiditis

Hyperthyroidism

Basedow's disease

Granulomatous thyroiditis o 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 5 (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. o 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-HT ₃ -antagonist in cytostatic-agent-induced vomiting.

(xx) Pains of inflammatory origins, e.g., lumbago

Without prejudice to the foregoing, the compounds of the invention can also be used to treat disorders such as: 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, 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, 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 a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, for use in therapy (such as a therapy described above).

In yet another aspect the present invention provides the use of a compound 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). In a further aspect 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).

In one aspect 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.

In a still further aspect 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.

In another aspect 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. In another aspect 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 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.

In the context of the present specification, 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. 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. An agonist may be a full or partial agonist. 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 Ia, 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 another aspect the present invention provides 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. One embodiment relates to the use of 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 acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition can comprise from 0.05 to 99 %w (per cent by weight), for example from 0.05 to 80 %w, such as from 0.10 to 70 %w (for example from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition.

A pharmaceutical composition of the present invention can be administered in a standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. Thus, a 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 1O g of active ingredient. In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous, intraarticular or intramuscular injection.

In one embodiment a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered orally.

In another embodiment a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered by inhalation.

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 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. For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD, asthma or allergic rhinitis a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, 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, formoterol, 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 modulator of chemokine receptor function (such as a CCRl receptor antagonist);

• an inhibitor of p38 kinase function;

• an inhibitor of matrix metalloproteases, such as targeting MMP-2, -9 or MMP- 12; or,

• an inhibitor of neutrophil serine proteases, such as neutrophil elastase or proteinase 3.

In another embodiment of the invention where such a combination is for the treatment of COPD, asthma or allergic rhinitis, 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. 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 sequencially. Or they may be administered separately.

The following Examples illustrate the invention. The following abbreviations are used in the Examples:

The following Examples illustrate the invention:

TFA Trifluoroacetic acid;

THF Tetrahydrofuran

DCM Dichloromethane HPLC High Performance Liquid Chromatography;

LC/MS Liquid Column Chromatography / Mass Spectroscopy;

GC Gas Chromatography

DMSO Dimethylsulfoxide;

APCI-MS Atmospheric Pressure Chemical Ionisation Mass Spectroscopy; NMP l-methyl-2-pyrrolidinone

DIEA N,N-diisopropylethylamine

HATU O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HBTU 2-( 1 H-benzo[d] [1 ,2,3]triazol- 1 -yl)- 1 , 1 ,3,3-tetramethylisouronium hexafluorophosphate(V) r.t. Room temperature, which is a temperature in the range from of 16°C to 25°C

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 DMSO-cfc (H 2.50 ppm) were used as internal references. Alternativly, NMR spectra were recorded on a Varian Inova Unity

500MHz instrument. Proton-NMR experiments were acquired using dual suppression of residual solvent peak and H ₂ O.

The following methods was used for chiral SFC analysis:

Using an Analytical Method Development System from Thar Technologies, Inc. Using CO ₂ as mobile phase with MeOH as modifier and pressure at 150 bar. Columns used was kept at +37°C by using an column oven. Detection was carried out on 254nm.

Chiral SFC (method A) Chiralpak ^® AS, 0.46x25cm column, 30% MeOH, 3 mL/min.

Chiral SFC (method B) Chiralpak ^® IB, 0.46x25cm column , 35% MeOH, 2 mL/min.

The following method was used for LC/MS analysis: 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.

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 HPLC analysis:

LC Method A: HPLC method A was performed with Agilent 1100 series machines on

Kromassil © C18 5μm 3.0xl00mm 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 5μm 3.0xl00mm 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.

Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

Preparative HPLC system A: Column: XBridge C18, dimention (150 X 30mm, 5μm packing), 20ml/min solvent speed and gradient 20% to 90 % MeCN (0.1 TFA) in Water (0.1% TFA) over 20 min)

Example 1

1 -( {3-[5-( {( 1 R,2S)-2-rf2,2-difluoropropanoyl ^' )aminol- 1 -phenylpropyll oxyV 1 H-indazol- 1 - yliphenvUcarbonvD-D-prolinamide

In a 10 mL round-bottomed flask, 2,2-difluoropropanoic acid (25.04 mg, 0.23 mmol), and 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethy lisouronium hexafluorophosphate(V) (90 mg, 0.24 mmol) were dissolved in DMF (1.5 mL). At room temperature N-ethyl-N-isopropylpropan-2 -amine (0.051 mL, 0.31 mmol) was slowly added via a syringe. After 10 min continoued stirring (R)-l-(3-(5-((lR,2S)-2-amino-l- phenylpropoxy)-l H-indazol- l-yl)benzoyl)pyrrolidine-2-carboxamide (Ia, 100 mg, 0.21 mmol) in THF (0.5 mL) was added and stirring was continued over night. The mixture was diluted with ethyl acetate and washed with sat. aq. sodium bicarbonate and brine. After drying over sodium sulfate and removal of the volatiles the crude was dissolved in acetonitril / water (1:1) and subjected to HPLC-purification [Kromasil 100 C18, acetonitril/water 35:65 to 65:35]. After freeze drying 34 mg (29%) of a colourless powder were obtained. APCI-MS: m/z 576.2 [MH ⁺ ]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (IH, d), 8.21 (0.7H, s), 8.19 (0.3H, s), 7.89 (0.6H, s), 7.82 (0.6H, m), 7.78 - 7.72 (1.3H, m), 7.63 (IH, t), 7.56 (IH, t), 7.45 - 7.39 (2.7H, m), 7.38 - 7.20 (5.3H, m), 7.13 (IH, m), 6.96 (0.7H, s), 6.91 (0.3H, s), 5.28 (IH, d), 4.37

(0.7H, m), 4.23 (1.3H, m), 3.65 - 3.56 (1.3H, m), 3.51 - 3.34 (0.7H, m; partially covered by water signal), 2.19 (IH, m), 1.93 - 1.73 (3H, m), 1.49 (3H, t), 1.32 (3H, d). LC (method A) rt = 9.40 min LC (method B) rt = 8.43 min

1 - (| ^" 3-(5- { IY 1 R,2SV2-amino- 1 -phenylpropylioxy) - 1 H-indazol- 1 -yl ^* )phenyl]carbonvU -D- prolinamide (Ia)

In a 100 mL round-bottomed flask, tert-butyl (lR,2S)-l-(l-(3-((R)-2- carbamoylpyrrolidine- 1 -carbonyl)phenyl)- 1 H-indazol-5-yloxy)- 1 -phenylpropan-2- ylcarbamate (Ib, 472 mg, 0.81 mmol) was dissolved in ethyl acetate (12 mL). At room temperature hydrogen chloride (3 mL, 6N in iso-propanol) was added and stirring was continued for 20 h. Thereafter temperature was raised to 5O ⁰ C and stirring was continued for an additional hour. The mixture was transferred to a separation funnel and extracted with water and 0.5M aq. hydrogen chloride. The aquous phases were combined and basified with sodium carbonate. Ethyl acetate was added to the mixture and the phases were separated. The organic phase was extracted once more with ethyl acetate and the combined organic phases were washed with brine and dried over sodium sulfate. After removal of the volatiles the residue was taken up in dioxane / water (1:2) and freeze dried to obtain a yield 284 mg of colourless powder (73 %). APCI-MS: m/z 484.1 [MH ⁺ ] 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (IH, s), 8.17 (IH, s), 7.89 (IH, s), 7.82 (IH, d), 7.78 - 7.70 (2H, m), 7.62 (IH, t), 7.55 (IH, t), 7.42 (2H, m), 7.38 - 7.21 (6H, m), 7.15 (IH, m), 6.98 - 6.89 (IH, m), 5.11 (IH, d), 4.37 (IH, dd), 4.21 (OH, m), 3.61 (2H, m), 3.47 (IH, m), 3.18 (IH, quintet), 2.18 (IH, m), 1.93 - 1.74 (3H, m), 1.07 (3H, d).

Tert-butyl IT 1 S.2RV2- {[ 1 -(3- ( [f 2RV2-carbamoylpyrrolidin- 1 -yll carbonyl) phenyl)- 1 H- indazol-5-ylloxy) -1 -methyl-2-phenylethyl]carbamate (Ib)

To a solution of 3-(5-((lR,2S)-2-(tert-butoxycarbonylamino)-l-phenylpropoxy)- lH- indazol-l-yl)benzoic acid (Ic, 461 mg, 0.95 mmol) and 2-(3H-[l,2,3]triazolo[4,5- b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (378 mg, 0.99 mmol) in DMF (3 mL) N-ethyl-N-isopropylpropan-2-amine (0.313 mL, 1.89 mmol) was

added dropwise at room temperature and a slight exothermic reaction was observed. After strirring at room temperature for 1 hour the mixture was diluted with ethyl acetate and washed with brine, 0.5M hydrochloric acid, brine, aqu. sat. sodium bicarbonate and again brine. Drying over sodium sulfate and evaporation of the solvent the residue was dissolved in a dioxane-water mixture (1 :2) and freezedried to give 477 mg (86%) of a colourless solid.

APCI-MS: m/z 528.1 [MH+-C4H9], 584.1 [MH ⁺ ]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.20 (0.7H, s), 8.18 (0.3H, s), 7.90 (0.7H, s), 7.82 (0.7H, d), 7.78 - 7.72 (1.4H, m), 7.63 (IH, t), 7.56 (IH, t), 7.46 - 7.28 (5.3H, m), 7.28 - 7.19 (2H, m), 7.09 (IH, m), 7.00 (IH, d), 6.98 - 6.90 (IH, m), 5.25 (IH, d), 4.37 (0.7H, dd), 4.21 (0.3H, dm), 3.84 (IH, dd), 3.60 (1.3H, m), 3.47 (0.7H, m), 2.19 (IH, m), 1.94 - 1.74 (3H, m), 1.28 (9H, s), 1.17 (3H, d).

3 - [5 -( { ( 1 R,2S)-2- [(tert-butoxycarbonyl)amino] - 1 -phenylpropyl } oxy)- 1 H-indazol- 1 - yllbenzoic acid (Ic)

In a 50 mL round-bottomed flask was dissolved isobutyl 3-(5-((lR,2S)-2-(tert- butoxycarbonylamino)-l-phenylpropoxy)-l H-indazol- l-yl)benzoate (Id, 1.23 g, 2.26 mmol) in 1,4-dioxane (10 mL) and water (2 mL) to give a colorless solution. Aquous sodium hydroxide (2M, 3.3 mL) was added and the solution was heated to 8O ⁰ C for 1 h. The mixture was concentrated in vacuo, diluted with water to approx. 100 mL and washed with MTBE. The organic phase was extracted with 0.5M aq. sodium hydroxide. The aquous phases were combined, acidified with 2M hydrochloric acid and extracted with ethyl acetate. After evaporation of the organic phase the product was obtained as a yellow oil. Dissolving in acetonitril / water (1 :1) and freezedrying yielded 980 mg (89%) of a colourless solid. APCI-MS: m/z 488.2 [MH ⁺ ]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (IH, t), 8.06 (2H, d), 8.02 (2H, s), 7.97 (2H, d), 7.70 - 7.59 (2H, m), 7.47 - 7.33 (7H, m), 7.33 - 7.21 (7H, m), 6.98 (IH, m), 5.51 - 5.37 (IH, m), 4.09 (IH, m), 1.46 (9H, s), 1.18 (3H, d).

2-Methylpropyl 3-r5-(((lR,2S)-2-r(tert-butoxycarbonyl)amino]-l-phenylpropyU oxy)-lH- indazol-l-yllbenzoate (Id)

In a 25 niL round-bottomed flask was isobutyl 3-(5-((lR,2S)-2-amino-l-phenylpropoxy)- lH-indazol-l-yl)benzoate (Ie, 1.10 g, 2.48 mmol) and di-tert-butyl dicarbonate (0.627 mL, 2.73 mmol) dissolved in THF (5 mL). At O ⁰ C triethylamine (0.516 mL, 3.72 mmol) was added dropwise. The ice bath was removed and stirring was continued over night. The mixture was diluted with ethyl acetate (80 mL) and washed with sat. aq. ammonium acetate and with brine. After drying over sodium sulfate and removal of the solvents the crude was obtained as an pale yellow oil and subjected to flashchromatography on silica gel (heptane/MTBE=5:4). 1.23 g (91%) of the product were obtained as a colourless foam. APCI-MS: m/z 544.3 [MH ⁺ ]

Isobutyl 3-(5-(( 1 R,2S)-2-amino- 1 -phenylpropoxy)- 1 H-indazol- 1 -vpbenzoate (1 e)

A 15 mL vial was charged with cesium carbonate (1.043 g, 3.20 mmol), (lR,2S)-2-amino- 1-phenylpropan-l-ol (0.181 g, 1.20 mmol), 2-(dimethylamino)acetic acid (0.052 g, 0.50 mmol), copper(I) iodide (0.048 g, 0.25 mmol) and butyronitrile (3.8 mL) and heated at 85 ⁰ C for 30 min.

A 3 mL vial was charged with isobutyl 3-(5-iodo-lH-indazol-l-yl)benzoate (If, 0.420 g, 1 mmol) and butyronitrile (0.8 mL) and heated to 60 ⁰ C for 10 min. The Iodoindazole solution was transferred to the catalyst mixture in one portion. The vessel was rinsed with butyronitrile (0.4 mL) and this solution was transferred to the

5 catalyst mixture as well. The reaction mixture was then stirred at 85 °C overnight, cooled and filtered through a plug of silica using ethyl acetate/methanol (9/1) as eluent. The solvents were evaporated at reduced pressure and the crude product was purified by flash chromatography on silica, using a gradient of ethyl acetate in heptane (both solvents containing 2% TEA) as eluent to give the title compound (70 mg, 16 %). io APCI-MS: m/z = 444.2 [MH+]

¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (IH, t), 8.06 (IH, s), 8.01 (IH, d), 7.96 (IH, d), 7.68 (2H, dd), 7.43 (2H, d), 7.37 (2H, t), 7.29 (2H, m), 7.11 (IH, d), 5.18 (IH, d), 4.16 (2H, d), *(lHin solvent peak), 2.11 (IH, m), 1.2 (3H, d), 1.05 (6H, d). LC (method A) it = 10.9 min

I ₅

Isobutyl 3-(5-iodo-lH-indazol-l-yP)benzoate (If)

A 50 mL.s flask was charged with sodium carbonate (0.700 g, 6.60 mmol), 3-(5-iodo-lH- indazol-l-yl)benzoic acid (2.185 g, 6 mmol) and NMP (15 mL) at 40 °C with magnetic 20 stirring. After a couple of minutes l-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added in one portion. After one hour at 40°C, the temperature was raised to 55 ⁰ C and another portion of l-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added. The stirring was continued overnight.

After cooling, the reaction mixture was partitioned between water and ethyl acetate. The 25 organic phase was washed twice with water, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to afford the title compound as a syrup (2.5 g, 99 %). The product solidified to a beige material upon standing.

APCI-MS: m/z = 421 [MH+]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (IH, t), 8.19 (IH, d), 8.16 (IH, d), 8.07 (IH, dt), 7.92

(IH, ddd), 7.70 (IH, dd), 7.64 (IH, t), 7.56 (IH, d), 4.17 (2H, d), 2.12 (IH, m), 1.05 (6H, d).

LC (method A) rt = 17.6 min

Example 2

N-rf 1 S.2RV2- m -(3- { r(2RV2-carbamoyrpyrrolidin- 1 -yllcarbonvU phenylV 1 H-indazol-5- ylloxyl - 1 -methyl-2-phenylethyllethanediamide

The title compound was prepared according to the protocol described for example 2, starting from 2-amino-2-oxoacetic acid (17.62 mg, 0.20 mmol) and (R)-l-(3-(5-((lR,2S)- 2-amino- 1 -phenylpropoxy)- 1 H-indazol- 1 -yl)benzoyl)pyrrolidine-2-carboxamide (87 mg, 0.18 mmol). Yield after freeze drying: 14 mg (14%) of a colourless powder. APCI-MS: m/z 555.1 [MH ⁺ ] 1H NMR (400MHz, DMSOd ₆ ) δ 8.57 (IH, d), 8.22 (0.7H, s), 8.20 (0.3H, s), 7.93 (IH, s), 7.87 (0.7H, s), 7.82 (0.7H, d), 7.77 - 7.72 (2.3H, m), 7.63 (IH, m), 7.55 (IH, m), 7.44 - 7.39 (2.7H, m), 7.38 - 7.28 (2.7H, m), 7.27 - 7.20 (2H, m), 7.12 (IH, m), 6.96 (0.7H, m), 6.92 (0.3H, m), 5.40 (IH, d), 4.36 (0.7H, m), 4.21 (1.3H, m), 3.60 (1.3H, m), 3.46 (0.7H, m), 2.19 (IH, m), 1.92 - 1.74 (3H, m), 1.28 (3H, d). LC (method A) rt = 7.58 min LC (method B) rt = 7.08 min

Example 3

3-[5-({(lR,2S ^" )-2-[(2,2-difluoropropanoyl ^' )amino ^' |-l-phenylpropyl)oxy)-lH-indazol-l-yl]- N-fσ-hydroxyethvDbenzamide

A solution of 3-[5-( {(1 R,2S)-2-[(2,2-difluoropropanoyl)amino]- 1 -phenylpropyl} oxy)- 1 H- indazol-l-yl]benzoic acid (3a) in DCM 3 niL and NMP 0.1 mL was added to a mixture of HBTU (127 mg, 0.33 mmol) and 2-aminoethanol (30 mg, 0.50 mraol). TEA (0.140 mL, 1.00 mmol) was added to the mixtures and the solution was stirred over weekend. 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%). APCI-MS: m/z = 523 [MH ⁺ ]

¹ H NMR (300 MHz, DMSOd ₆ ) δ 8.72 (IH, d), 8.61 (IH, t), 8.22 (IH, d), 8.16 (IH, t), 7.89 - 7.82 (2H, m), 7.78 (IH, d), 7.64 (IH, t), 7.44 - 7.39 (2H, m), 7.37 - 7.31 (2H, m), 7.29 - 7.20 (2H, m), 7.13 (IH, d), 5.28 (IH, d), 4.74 (IH, t), 4.27 - 4.18 (IH, m), 3.52 (2H, q), 3.43 - 3.38 (2H, m), 1.49 (3H, t), 1.32 (3H, d). LC (method A) it = 9.5 min LC (method B) rt = 8.9 min

3-[5-( {( 1 R,2S)-2-F(2,2-difluoropropanoyl)aminol- 1 -phenylpropyl) oxy)- 1 H-indazol- 1 - yl]benzoic acid (3a)

Isobutyl 3-[5-[(lR,2S)-2-(2,2-difluoropropanoylamino)-l-phenyl-propox y]indazol-l- yl]benzoate (Ie) (1.97 g, 3.68 mmol) was dissolved in MeOH (10 mL) and THF (10.00 mL), lithium hydroxide (0.264 g, 11.03 mmol) dissolved in water (10.00 mL) was added to the solution and stirred over night at room temperature. The mixture was diluted with

water and washed with TBME, acidified (2M HCl) and extracted with EtOAc x 2, the organic phases were combined and dried with Na ₂ SO ₄ , filtered, evaporated to obtain the title compound (1.760 g, 100 %) as dry film. APCI-MS: m/z = 480 [MH ⁺ ] s ¹ H NMR (400 MHz, DMSO-Ci ₆ ) δ 13.22 (IH, s), 8.71 (IH, d), 8.25 - 8.20 (2H, m), 8.02 - 7.97 (IH, m), 7.92 (IH, d), 7.77 (IH, d), 7.69 (IH, t), 7.42 (2H, d), 7.34 (2H, t), 7.28 - 7.21 (2H, m), 7.14 (IH, d), 5.29 (IH, d), 4.27 - 4.18 (IH, m), 1.49 (3H, t), 1.32 (3H, d).

Example 4 o N-(2-amino-2-oxoethyl)-3-r5-(((lR,2S ^' )-2-[(2,2-difluoropropanoyl)amino1-l- phenylpropyl } oxyV 1 H-indazol- 1 -ylibenzamide

Prepared similarly to Example 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and glycinamide hydrochloride. s APCI-MS: m/z = 536 [MH ⁺ ]

¹ H NMR (300 MHz, DMSO-de) δ 8.87 (IH, t), 8.72 (IH, d), 8.22 (IH, d), 8.19 (IH, t), 7.91 - 7.84 (2H, m), 7.81 (IH, d), 7.66 (IH, t), 7.44 - 7.38 (2H, m), 7.37 - 7.31 (2H, m), 7.29 - 7.20 (3H, m), 7.14 (IH, d), 7.05 (IH, s), 5.28 (IH, d), 4.29 - 4.17 (IH, m), 3.83 (2H, d), 1.49 (3H, t), 1.32 (3H, d). 0 LC (method A) it = 9.1 min LC (method B) rt = 8.6 min

Example 5

N-rαSV2-amino-l-methyl-2-oxoethyl]-3-r5-({(lR,2SV2-r(2.2-di fluoropropanoyl)aminol- ₅ 1 -phenylpropyll oxy)- 1 H-indazol- 1 -ylibenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and L-alaninamide hydrochloride. APCI-MS: m/z = 550 [MH ⁺ ]

¹ H NMR (300 MHz, DMSOd ₆ ) δ 8.71 (IH, d), 8.63 (IH, d), 8.22 (IH, d), 8.21 (IH, t), 7.91 - 7.85 (2H, m), 7.79 (IH, d), 7.64 (IH, t), 7.44 - 7.39 (2H, m), 7.37 - 7.31 (2H, m), 7.28 - 7.20 (3H, m), 7.13 (IH, d), 6.99 (IH, s), 5.28 (IH, d), 4.48 - 4.38 (IH, m), 4.28 - 4.17 (IH, m), 1.49 (3H, t), 1.36 - 1.30 (6H, m). LC (method A) rt = 9.5 min LC (method B) rt = 8.9 min

Example 6

N-r2-(acetylamino)ethyll-3-r5-({(lR.2SV2-r( ^' 2,2-difluoropropanovnaminol-l- phenylpropyl } oxy)- 1 H-indazol- 1 -yllbenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl} oxy)-l H-indazol- l-yl]benzamide (3a) and N-(2-aminoethyl)acetamide.

APCI-MS: m/z = 564 [MH ⁺ ]

¹ H NMR (400 MHz, DMSO-de) δ 8.73 - 8.64 (2H, m), 8.22 (IH, s), 8.15 (IH, s), 7.97 (IH, t), 7.88 - 7.79 (3H, m), 7.64 (IH, t), 7.42 (2H, d), 7.34 (2H, t), 7.28 - 7.20 (2H, m), 7.14

(IH, d), 5.28 (IH, d), 4.23 (IH, q), 3.34 - 3.28 (2H, m), 3.21 (2H, q), 1.80 (3H, s), 1.49

(3H, t), 1.32 (3H, d).

LC (method A) rt = 9.4 min

LC (method B) rt = 8.9 min

Example 7

3-[5-( ((I R.2S)-2-[(2,2-difluoropropanoyl)amino1- 1 -phenylpropyll oxy)- 1 H-indazol- 1 -yll- 5 N-[ ^" 2-(2-oxoimidazolidin- 1 -vDethyllbenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl} oxy)-l H-indazol- l-yl]benzamide (3a) and l-(2-aminoethyl)imidazolidin-2- one. o APCI-MS: m/z = 591 [MH ⁺ ]

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 - 8.66 (2H, m), 8.22 (IH, d), 8.13 (IH, t), 7.89 - 7.84 (IH, m), 7.83 - 7.76 (2H, m), 7.64 (IH, t), 7.44 - 7.39 (2H, m), 7.34 (2H, t), 7.29 - 7.20 (2H, m), 7.13 (IH, d), 6.26 (IH, s), 5.28 (IH, d), 4.29 - 4.18 (IH, m), 3.45 - 3.34 (2H, m), 3.27 - 3.15 (6H, m), 1.49 (3H, t), 1.32 (3H, d). s LC (method A) rt = 9.4 min LC (method B) rt = 8.9 min

Example 8

2.2-DJfIuOrO-N-[C 1 S.2RV2- ( \1 -(3 - { r( ^" 2R)-2-(hvdroxymethyl)pyrrolidin- 1 -o yllcarbonvU phenyl)- 1 H-indazol-5-ylloxy) - 1 -methyl-2-phenylethylipropanamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl} oxy)-l H-indazol- l-yl]benzamide (3a) and (2R)-pyrrolidin-2-ylmethanol.

APCI-MS: m/z = 563 [MH ⁺ ]

¹ H NMR (300 MHz, DMSOd ₆ ) δ 8.71 (IH, d), 8.20 (IH, d), 7.82 - 7.72 (3H, m), 7.61 (IH, t), 7.50 - 7.38 (3H, m), 7.37 - 7.30 (2H, m), 7.28 - 7.19 (2H, m), 7.13 (IH, d), 5.28 (IH, d), 4.30 - 4.08 (2H, m), 3.61 - 3.57 (IH, m), 3.50 - 3.35 (4H, m), 2.01 - 1.80 (3H, m), 1.77 - 1.62 (IH, m), 1.49 (3H, t), 1.32 (3H, d). LC (method A) rt = 10.5 min LC (method B) rt = 9.6 min

Example 9 2,2-Difluoro-N-r(lS,2R)-2-{ri-π-{r(3RV3-hvdroxypyrrolidin-l -yllcarbonvnphenvn-lH- indazol-5-ylloxyl-l-methyl-2-phenylethyllpropanamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and (3R)-pyrrolidin-3-ol. APCI-MS: m/z = 549 [MH+]

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.71 (IH, d), 8.21 (IH, d), 7.84 - 7.73 (3H, m), 7.62 (IH, t), 7.51 - 7.46 (IH, m), 7.44 - 7.39 (2H, m), 7.37 - 7.30 (2H, m), 7.28 - 7.20 (2H, m), 7.13 (IH, d), 5.28 (IH, d), 4.37 - 4.30 (IH, m), 4.28 - 4.16 (2H, m), 3.64 - 3.51 (2H, m), 3.46 - 3.43 (IH, m), 3.30 - 3.26 (IH, m), 2.01 - 1.74 (2H, m), 1.49 (3H, t), 1.32 (3H, d). LC (method A) rt = 9.4 min LC (method B) rt = 8.8 min

Example 10

3-r5-((( ^' lR.2S)-2-r(2.2-difluoropropanoyl ^' )amino]-l-phenylpropyπoxy)-lH-indazol-l-yl1- N- [(3 R)-2-oxotetrahydrofuran-3 - ylibenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and (3R)-3-aminodihydrofuran- 2(3H)-one hydrochloride. APCI-MS: m/z = 563 [MH ⁺ ]

¹ H NMR (400 MHz, DMSO-Ci ₆ ) δ 9.16 (IH, d), 8.71 (IH, d), 8.23 (IH, s), 8.18 (IH, s), 7.95 - 7.91 (IH, m), 7.85 (IH, d), 7.79 (IH, d), 7.69 (IH, t), 7.42 (2H, d), 7.34 (2H, t), 7.28 - 7.21 (2H, m), 7.14 (IH, d), 5.29 (IH, d), 4.85 - 4.77 (IH, m), 4.45 - 4.40 (IH, m), 4.32 - 4.20 (2H, m), 2.50 - 2.44 (IH, m), 2.40 - 2.30 (IH, m), 1.49 (3H, t), 1.32 (3H, d). LC (method A) rt = 10.7 min LC (method B) rt = 10.0 min

Example 11

1 -( (3-[5-( {( 1 R,2S)-2-r(2,2-difluoropropanovDamino1- 1 -phenylpropyll oxy)- 1 H-indazol- 1 - yllphenyl ) carbonvD-L-prolinamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl} oxy)-l H-indazol- l-yl]benzamide (3a) and L-prolinamide. APCI-MS: m/z = 576 [MH ⁺ ] 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.71 (IH, d), 8.21 (IH, s), 7.90 - 7.79 (IH, m), 7.75 (IH, d), 7.66 - 7.52 (2H, m), 7.46 - 7.39 (2H, m), 7.37 - 7.30 (3H, m), 7.29 - 7.20 (3H, m), 7.13 (IH, d), 6.98 - 6.90 (IH, m), 5.28 (IH, d), 4.40 - 4.33 (IH, m), 4.28 - 4.17 (IH, m), 3.66 - 3.41 (2H, m), 2.24 - 2.11 (IH, m), 1.94 - 1.71 (3H, m), 1.49 (3H, t), 1.37 - 1.27 (3H, m). LC (method A) rt = 9.4 min

LC (method B) rt = 8.7 min

Example 12

2,2-Difluoro-N- {( 1 S.2RV 1 -methyl-2-[T 1 - (3-IT3-oxopiperazin-l -vPcarbonyllphenvU- 1 H- indazol-5-yl)oxy1-2-phenylethvUpropanamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and piperazin-2-one.

APCI-MS: m/z = 562 [MH ⁺ ] 1H NMR (400 MHz, DMSO-de) δ 8.71 (IH, d), 8.21 (IH, d), 8.13 (IH, s), 7.86 - 7.82 (IH, m), 7.80 - 7.74 (2H, m), 7.64 (IH, t), 7.44 - 7.39 (3H, m), 7.34 (2H, t), 7.28 - 7.19 (2H, m),

7.13 (IH, d), 5.28 (IH, d), 4.27 - 4.18 (IH, m), 4.15 - 3.92 (2H, m), 3.39 - 3.34 (2H, m),

3.29 - 3.19 (2H, m), 1.49 (3H, t), 1.32 (3H, d).

LC (method A) rt = 9.1 min LC (method B) rt = 8.6 min

Example 13

3-F5-C {( 1 R,2S)-2-r(2,2-difluoropropanoyl)aminol- 1 -phenylpropyU oxyV 1 H-indazol- 1 -yli-

N-[2-(2-oxopyrrolidin- 1 -vDethylibenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and l-(2-aminoethyl)pyrrolidin-2-one hydrochloride.

APCI-MS: m/z = 590 [MH ⁺ ] 1H NMR (300 MHz, DMSO-de) δ 8.74 - 8.66 (2H, m), 8.22 (IH, d), 8.10 (IH, t), 7.89 -

7.75 (2H, m), 7.64 (IH, t), 7.44 - 7.39 (2H, m), 7.37 - 7.30 (2H, m), 7.29 - 7.19 (3H, m),

7.14 (IH, d), 5.28 (IH, d), 4.28 - 4.18 (IH, m), 3.44 - 3.27 (6H, m), 2.16 (2H, t), 1.95 -

1.84 (2H, m), 1.49 (3H, t), 1.32 (3H, d).

LC (method A) rt = 9.9 min LC (method B) rt = 9.2 min

Example 14

3-[5-( {(1 R,2S)-2-F(2,2-difluoropropanoyl)aminol- 1 -phenylpropyl j oxy ^* )- 1 H-indazol- 1 -yli- N-r2-(5,5-dimethyl-2,4-dioxo-L3-oxazolidin-3-yl)ethyllbenzam ide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl} oxy)-l H-indazol- l-yl]benzamide (3a) and 3-(2-aminoethyl)-5,5-dimethyl-

1 ,3-oxazolidine-2,4-dione hydrochloride.

APCI-MS: m/z = 634 [MH ⁺ ] 1H NMR (300 MHz, DMSOd ₆ ) δ 8.83 (IH, t), 8.72 (IH, d), 8.22 (IH, d), 8.04 (IH, t),

7.89 - 7.84 (IH, m), 7.80 - 7.71 (2H, m), 7.64 (IH, t), 7.44 - 7.40 (2H, m), 7.37 - 7.31 (2H, m), 7.29 - 7.19 (2H, m), 7.14 (IH, d), 5.28 (IH, d), 4.28 - 4.18 (IH, m), 3.64 - 3.58 (2H, m), 3.55 - 3.48 (2H, m), 1.49 (3H, t), 1.45 (6H, s), 1.32 (3H, d).

LC (method A) rt = 11.7 min LC (method B) rt = 10.8 min

Example 15

3-[5-( (f lR,2SV2-|Y2,2-difluoropropanoyr)amino1- 1 -phenylpropyU oxy)- 1 H-indazol- 1 -yl]-

N-(l,l-dioxidotetrahydrothiophen-3-yl)benzaniide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and tetrahydrothiophen-3 -amine 1,1- dioxide.

APCI-MS: m/z = 597 [MH ⁺ ]

¹ H NMR (400 MHz, DMSO-Ci ₆ ) δ 8.90 (IH, d), 8.71 (IH, d), 8.23 (IH, s), 8.19 - 8.16 (IH, m), 7.92 - 7.89 (IH, m), 7.85 (IH, d), 7.77 (IH, d), 7.67 (IH, t), 7.44 - 7.40 (2H, m), 7.36 -

7.31 (2H, m), 7.28 - 7.21 (2H, m), 7.14 (IH, d), 5.28 (IH, d), 4.78 - 4.66 (IH, m), 4.29 -

4.17 (IH, m), 3.52 (IH, dd), 3.39 - 3.33 (IH, m), 3.25 - 3.15 (IH, m), 3.10 (IH, dd), 2.49 -

2.40 (IH, m), 2.29 - 2.16 (IH, m), 1.49 (3H, t), 1.32 (3H, d)

LC (method A) rt = 10.6 min

LC (method B) rt = 10.0 min

Example 16

3-f 5-( {( 1 R,2S)-2-r(2,2-difluoropropanoyl ^* )amino1- 1 -phenylpropyl) oxy)- 1 H-indazol- 1 -yll- N-( 1 H-indazol-3 -ylmethyl)benzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and l-(lH-indazol-3-yl)methanamine. APCI-MS: m/z = 609 [MH+]

¹ H NMR (300 MHz, DMSO-de) δ 9.27 (IH, t), 8.71 (IH, d), 8.21 - 8.18 (2H, m), 7.90 - 7.80 (2H, m), 7.77 (2H, d), 7.64 (IH, t), 7.51 - 7.46 (IH, m), 7.44 - 7.39 (2H, m), 7.37 - 7.29 (3H, m), 7.28 - 7.18 (2H, m), 7.13 (IH, d), 7.10 - 7.03 (2H, m), 5.27 (IH, d), 4.85 (2H, d), 4.28 - 4.17 (IH, m), 1.49 (3H, t), 1.31 (3H, d). LC (method A) rt = 11.6 min LC (method B) rt = 11.2 min

Example 17

N-rπRV2-amino-2-oxo-l-phenylethvn-3-r5-(l(lR.2S)-2-r(2,2 -difluoropropanoyl)amino1- 1 -phenylpropyl I oxy)- 1 H-indazol- 1 -ylibenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and (2R)-2-amino-2- phenylethanamide hydrochloride. APCI-MS: m/z = 612 [MH ⁺ ]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (IH, d), 8.72 (IH, d), 8.22 (2H, d), 7.94 - 7.86 (2H, m), 7.78 (IH, d), 7.72 (IH, s), 7.64 (IH, t), 7.53 (2H, d), 7.42 (2H, d), 7.38 - 7.20 (8H, m), 7.14 (IH, d), 5.65 (IH, d), 5.29 (IH, d), 4.24 (IH, dd), 1.50 (3H, t), 1.32 (3H, d). LC (method A) rt = 11.1 min LC (method B) rt = 10.5 min

Example 18

N-(2-amino-2-oxoethylV3-r5-( ^' ((lR.2SV2-r(2,2-difluoropropanoyl')aminol-l- phenylpropyU oxy)- 1 H-indazol- 1 -yll-N-methylbenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and N-methylglycinamide hydrochloride.

APCI-MS: m/z = 550 [MH ⁺ ]

¹ K NMR (300 MHz, DMSOd ₆ ) δ 8.71 (IH, d), 8.20 (IH, s), 7.84 - 7.56 (4H, m), 7.51 -

7.29 (6H, m), 7.28 - 7.20 (2H, m), 7.19 - 7.10 (2H, m), 5.28 (IH, d), 4.27 - 4.17 (IH, m),

4.04 (IH, s), 3.83 (IH, s), 2.96 (3H, s), 1.49 (3H, t), 1.32 (3H, d).

LC (method A) rt = 9.0 min

LC (method B) rt = 8.4 min

Example 19

N-(3-amino-3-oxopropyl)-3-[5-({(lR,2S)-2-[(2,2-difluoropr opanoyl)aminol-l- phenylpropyl I oxyV 1 H-indazol- 1 - yllbenzamide

Prepared similarly to Exampel 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl} oxy)-l H-indazol- l-yl]benzamide (3a) and beta-alaninamide hydrochloride. APCI-MS: m/z = 550 [MH ⁺ ]

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.74 - 8.66 (2H, m), 8.22 (IH, d), 8.14 (IH, t), 7.89 - 7.74 (3H, m), 7.64 (IH, t), 7.45 - 7.30 (5H, m), 7.29 - 7.20 (2H, m), 7.13 (IH, d), 6.83 (IH, s), 5.28 (IH, d), 4.27 - 4.18 (IH, m), 3.46 (2H, dd), 2.37 (2H, t), 1.49 (3H, t), 1.32 (3H, d). LC (method A) rt = 9.1 min LC (method B) rt = 8.6 min

Example 20 f4RVl-a3-r5-({riR.2SV2-r(2.2-difluoropropanovnamino1-l-pheny lpropylloxy)-lH- indazol- 1 -yl]phenyl) carbonvD-4-hydroxy-L-prolinamide

Prepared similarly to Example 3 from 3-[5-({(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l- phenylpropyl}oxy)-lH-indazol-l-yl]benzamide (3a) and (4R)-4-hydroxy-L-prolinamide.

APCI-MS: m/z = 592 [MH ⁺ ]

¹ H NMR (300 MHz, DMSO-d*) δ 8.71 (IH, d), 8.22 (IH, d), 7.91 - 7.89 (IH, m), 7.86 - 7.81 (IH, m), 7.74 (IH, d), 7.64 (IH, t), 7.58 - 7.53 (IH, m), 7.50 - 7.47 (IH, m), 7.44 -

7.39 (2H, m), 7.37 - 7.30 (2H, m), 7.28 - 7.20 (2H, m), 7.14 (IH, d), 6.96 (IH, s), 5.28

(IH, d), 4.46 (IH, t), 4.27 - 4.18 (2H, m), 3.81 - 3.73 (IH, m), 3.36 - 3.33 (2H, m), 2.21 -

2.10 (IH, m), 1.95 - 1.84 (IH, m), 1.49 (3H, t), 1.32 (3H, d).

LC (method A) rt = 8.3 min LC (method B) rt = 7.8 min

Example 21

1 - (F3-(5- { f( 1 R,2S)-2- { IY 1 -cyanocvclopropyDcarbonyl] amino} - 1 -phenylpropylioxy) -IH- indazol- 1 -vDphenyllcarbonyll -D-prolinamide

The title compound was prepared according to the protocol described for Example 1, starting from 1-cyanocyclopropanecarboxylic acid (23.76 mg, 0.21 mmol) and (R)-l-(3-(5-

(( 1 R,2S)-2-amino- 1 -phenylpropoxy)- 1 H-indazol- 1 -yl)benzoyl)pyrrolidine-2-carboxamide

(94 mg, 0.19 mmol). Yield after freeze drying: 53 mg (47%) of a colourless powder.

APCI-MS: m/z 577.1 [MH ⁺ ]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (0.7H, s), 8.20 (0.3H, s), 8.04 (1.3H, d), 7.90 (0.7H, s), 7.82 (0.7H, d), 7.75 (1.3H, d), 7.63 (1.3H, t), 7.55 (IH, t), 7.42 (3H, d), 7.36 -

7.29 (3.3H, m), 7.24 (3H, m), 7.13 (1.3H, m), 6.98 (0.7H, s), 6.93 (0.3H, s), 5.34 (IH, d),

4.37 (0.7H, m), 4.22 (1.3H, m), 3.65 - 3.57 (1.3H, m), 3.47 (0.7H, m), 2.19 (IH, m), 1.93 -

1.73 (3H, m), 1.45 (2H, m), 1.29 (3H, d), 1.20 (IH, m).

LC (method A) rt = 9.36 min LC (method B) rt = 8.31 min

Example 22

N-cyclopentyl-3-(5-(r(H?.25 ^f )-2-r(2,2-difluoropropanoyl)amino1-l-(6-methoxypyridin-3-

To N-[(1R,2S)- 1 - { [ 1 -(3-bromophenyl)- 1 H-indazol-5-yl]oxy} - 1 -(6-methoxypyridin-3- yl)propan-2-yl]-2,2-difluoropropanamide (20 mg, 37μmol), cyclopentylamine (4.4 mg, 51μmol), Tri-t-butylphosphoniumtetrafluoroborat (2.1 mg, 7μmol) and trans- bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(I I) (5.6 mg, 7μmol) in 1 ml THF was added molybdenum hexacarbonyl (4.6 mg, 18μmol). 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 100%) to yield 6.7 mg (32 %) of N-cyclopentyl-3-(5-{[(7/?,25)-2-[(2,2-difluoropropanoyl)amin o]-l- (6-methoxypyridin-3-yl)propyl]oxy } -1 H-indazol- 1 -yl)benzamide ES+MS: m/z 578 [MH ⁺ ]

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.20 (d, IH), 8.05 (dd, IH), 8.01 (s, IH), 7.81 (m, IH), 7.72 (d, IH), 7.66 (d, IH), 7.60 (dd, IH), 7.57 (t, IH), 7.15 (dd, IH), 6.98 (d, IH), 6.75

(d,lH), 6.67 (br, IH), 6.15 (br, IH), 5.36 (d, IH), 4.41 (m, IH), 4.38 (m,lH), 3.92 (s, 3H), 2.10 (m, 2H), 1.77 (t, 3H), 1.64-1.74 (m., 4H), 1.52 (m, 2H), 1.29 (d, 3H).

r(lS)-2-(methoxymethylamino}-l-methyl-2-oxoethyll-carbami c acid t-butyl ester

Boc-Ala-OH (20Og, 1057 mmol) in 3400 ml dichloromethane were cooled to 0°C. 1,1'- Carbonyldiimidazol (205,7g, 1268 mmol) was added in multiple portions over 30 min and stirring was continued for 30 minutes at 0 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 ⁰ C. After stirring for 14 hours at room temperature the mixture was diluted with 4 L t-butyl methyl ether and washed with IM HCl solution (2 times 800 ml, 15 min stirring, then phase separation), saturated NaHCO ₃ solution (1,3 L) and brine (1,3L). After drying over Na ₂ SO ₄ the solvent was removed i.vac, and the white crystalline product purified by recrystallization in 500 ml t- butyl methyl ether to yield 217,8 g (89%)of /(7S)-2-(methoxymethylamino)-l-methyl-2- oxoethyl]-carbamic acid t-butyl ester.

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 5.25 (br, IH), 4.67 (dq, IH), 3.76 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.30 (d, 3H).

r(lS)-2-(6-methoxy-3-i)yriclinyl)-l-methyl-2-oxoethyll-ca rbamic acid t-butyl ester

To 248ml Isopropylmagnesium chloride (2M in THF, 496 mmol) were added 20,97g (495 mmol) lithium chloride and the resulting suspension was stirred for 60min at room temperature. At 0° to 1O ⁰ C 93g (495 mmol) 5-Brom-2-methoxypyridin were added over 30 min and stirred for 60min at room temperature. In parallel 91,9 Ig (396 mmol) [(lS)-2- (methoxymethylamino)-l-methyl-2-oxoethyl] carbamic acid t-butyl ester were suspended

in 425 ml THF and over 40 min at 20° bis 25°C 198 ml isopropylmagnesium chlorid (2M in THF, 396 mmol) were added and stirred for additional 15 minutes at room temperature. The clear LiCl/5-Brom-2-methoxypyridin/iPrMgBr solution was slowly added to the Weinreb amid suspension at 20° to 25°C and stirred over night. The reaction mixture was

5 cooled to 2°C and added slowly to a mixture of 70 ml cone. HCl and 210 ml water at 2°C. While the addition an external cooling bath at -15°C was used to keep the internal temperature in the range of 0° to 5°C. The pH was adjusted to 5 and 210 ml tert.-butyl methyl ether were added and the mixture stirred for 15min at room temperature, phases were separated and the organic phase was washed with water (210 ml) and brine (210 ml).o The solvent was evaporated and the residue resolved in 130 ml THF.1050 ml n-heptane were added and the mixture was heated to 6O ⁰ C to form a single phase. The volume was reduced to 675 ml and the mixture cooled to room temperature over 1 h and cooled to 2°C over 30 min. After 60 min at 2°C the product is filtered of and dried in vacuum to yield 87,45 g [(lS)-2-(6-methoxy-3-pyridinyl)-l-methyl-2-oxoethyl]-carbami c acid t-butyl ester.s ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.81 (d, IH), 8.14(dd, IH), 6.81 (d, IH), 5.52 (br, IH), 5.18 (dq, IH), 4.01 (s, 3H), 1.44 (s, 9H), 1.40 (d, 3H).

[(lS,2R)-2-Hydroxy-2-(6-methoxy-3-pyridinyl)-l-methylethy l]-carbamic acid t-butyl ester

o To [(lS)-2-(6-methoxy-3-pyridinyl)-l-methyl-2-oxoethyl]-carbami c acid t-butyl ester. (102 g, 364 mmol) in 2-propanol (310 mL) and toluene (475 mL) was added aluminum tri iso-propylate (44,6 g, 218 mmol) . The reaction mixture was stirred at 50°C for 72 hours and water (220 ml) ethyl acetate (550 ml) were added. The mixtures pH is adjusted to 4 (10 ml 6M HCl) and extracted with ethyl acetate (first phase sep. was decanted). The5 organic phase is washed with brine (220 ml), dried over MgSO ₄ , the solvent is removed i.vac, and the product purified by chromatography on silica gel (3000g, ethyl acetate in hexane 0% to 50% . Yield 100,7 g (98 %) [(lS,2R)-2-Hydroxy-2-(6-methoxy-3-pyridinyl)- l-methylethyl]-carbamic acid t-butyl ester. 1H-NMR (300 MHz, CDCl ₃ ); δ = 8.07 (d, IH), 7.56 (dd, IH), 6.72 (d, IH), 4.75 (m, IH),0 4.57 (d, IH), 3.98 (m, IH) 3.92 (s, 3H), 3.81 (br, IH), 1.44 (s, 9H), 1.00 (d, 3H).

ClR.2S)-2-Amino- 1 -ϊ6-methoxypyridin-3-\llpropan- l-ol

To [(7iS',2/?)-2-Hydroxy-2-(6-methoxy-3-pyridinyl)-l-methylethy l]-carbamic acid t-butyl ester (33 g, 117mmol) in 290 mL 1,4-dioxane was added 292 ml HCl in 1,4-dioxane (4 M, 1168 mmol) and the mixture was stirred for two hours at room temperature. The solvent is removed i.vac, and the residual HCl salt tree times coevaporated with 100 mL toluene. The residue (32,53 g) was suspended in 325 mL acetonitrile and 176,2 g K ₂ CO ₃ was added and the mixture was stirred over night at 60 ⁰ C. After cooling to room temperature the suspension was filtered through a path of cellites and the solid residues were washed with additional 500 ml acetonitrile. Acetonitile filtrates were combined and the solvent was removed i.vac to yield 8,35 g (39,2 %) (77?,2S)-2-Amino-l-[6-methoxypyridin-3-yl]propan-l-ol as free base. The cellites with the residue were suspended in additional 750 mL acetonitrile and additional 100 g K ₂ CO ₃ were added. Stirring at 60 ⁰ C was repeated over night. After cooling to room temperature the suspension was filtered through an additional path of cellites and the solid residues were washed with additional 500 ml acetonitrile. Combination of filtrates yields 8,45 g (39,6 %) (7i?,25)-2-amino-l-[6-methoxypyridin-3-yl]propan-l-ol as free base, 16.8 g overall. 1H-NMR (300 MHz, CDCl ₃ ); δ = 8.05 (d, IH), 7.57 (dd, IH), 6.71 (d, IH), 4.47 (d, IH), 3.91 (s, 3H), 3.13 (dq, IH), 0.94 (d, 3H).

ClR.2S)-I - ffl - β-Bromophenyl)- lH-indazol-5-ylloxy} - l-(6-methoxypyridin-3-yl)propan-2- amine

(7i?,25)-2-Amino-l-[6-methoxypyridin-3-yl]propan-l-ol (200 mg, 0.79 mmol), copper(I)iodide (30 mg, 0.16 mmol), N,N-dimethylglycin (32 mg, 0.31 mmol) and caesium carbonate (512 mg, 1.57 mmole) were suspended in butyronitrile (1.6 mL). The reaction vessel was capped and the mixture was stirred at 110 ⁰ C for 2 hours. Then l-(3-

bromophenyl)-5-iodoindazole (266 mg, 0.79 mmole)was added and heating to 130 ⁰ C was continued for 20 hours. The solvent was removed i.vac, and the product purified by chromatography on silica gel. (ethyl acetate in hexane 0 to 100%, then methanol in ethyl acetate 10%) to yield 307 mg (86%) (7i?,2S)-l-{[l-(3-Bromophenyl)-lH-indazol-5- 5 yl]oxy}- l-(6-methoxypyridin-3-yl)propan-2-arnine.

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.21 (d, IH), 7.98 (d, IH), 7.83 (t, IH), 7.60 (m, 3H), 7.44 (ddd, IH), 7.35 (t, IH), 7.19 (dd, IH), 7.02 (d, IH), 6.72 (d, IH), 5.23 (d, IH), 3.89 (s, 3H), 3.54 (dq, IH), 1.27 (d, 3H)

io N-\(1R, 2S)- 1 - ( r 1 -(3-bromophenvD- 1 H-indazol-5-ylloxyl - 1 -(6-methoxypyridin-3- yl)propan-2-yll-2,2-difluoropropanamide

l,l'-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. (7i?,2S)-l-{[l-(3-bromophenyl)-lH- i ₅ indazol-5-yl]oxy}-l-(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. (ethyl acetate in hexane 0 to 40%) to yield 205 mg (56%) N-[(/iζ25)-l-{[l-(3- bromophenyl)-lH-indazol-5-yl]oxy}-l-(6-methoxypyridin-3-yl)p ropan-2-yl]-2,2-

20 difiuoropropanamide.

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.19 (d, IH), 8.00 (d, IH), 7.86 (t, IH), 7.64 (d, IH), 7.63 (m, IH), 7.60 (dd, IH), 7.46 (ddd, IH), 7.37 (t, IH), 7.16 (dd, IH), 6.97 (d, IH), 6.76 (d, IH), 6.67 (br, IH), 5.36 (d, IH), 4.39 (dq, IH), 3.92 (s, 3H), 1.77 (t, 3H), 1.28 (d, 3H).

2 ₅ Example 23 3 -(5- { UlR, 2 _l SV2-r(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3 - yltoropylioxyl - 1 H-indazol- 1 -yl)-N-(pyridin-3-yl)benzamide

To N-[(/i?, 2S)- 1 - { [ 1 -(3-bromophenyl)- 1 H-indazol-5 -yl]oxy } - 1 -(6-methoxypyridin-3- yl)propan-2-yl]-2,2-difluoropropanamide (37 mg, 68μmol), 3-aminopyridine (19.2 mg, 204μmol), tri-t-butylphosphoniumtetrafluoroborat (8.9 mg, 31μmol) and trans-

5 bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II ) (10.3 mg, 14μmol) in 1.9 ml THF was added molybdenum hexacarbonyl (12.5 mg, μmol). 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%) too yield 22 mg (55%) 3-(5-{[(7i?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(6-methox ypyridin- 3-yl)propyl]oxy } - lH-indazol- 1 -yl)-N-(pyridin-3-yl)benzamide. ES+MS: m/z 587 [MH ⁺ ]

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.74 (d, IH), 8.41 (d, IH), 8.31 (m, 2H), 8.20 (m, 2H), 7.89 (d, IH), 7.86 (d, IH), 7.68 (d, IH), 7.64 (t, IH), 7.61 (dd, IH), 7.33 (dd, IH), 7.17s (dd, IH), 6.99 (d, IH), 6.75 (d, IH), 6.68 (d, IH), 5.37 (d, IH), 4.40 (dq, IH), 3.92 (s, 3H), 1.77 (t., 3H), 1.25 (d, 3H).

Example 24

3-(5-{r(ii?.2 ₁ S ^f )-2-[(2,2-difluoropropanoyl)aminol-l-(6-methoxypyridin-3-yl) propyl]oxy}-ϋ

To N-[(7i?, 2S)- 1 - { [ 1 -(3-bromophenyl)- 1 H-indazol-5-yl]oxy } - 1 -(6-methoxypyridin-3- yl)propan-2-yl]-2,2-difluoropropanamide (40 mg, 73 μmol), tetrahydrothiophen-3-amine 1,1-dioxide (13 mg, 135μmol), tri-t-butylphosphoniumtetrafluoroborat (2.6 mg, 9μmol) ₅ and trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipallad ium(II) (2.8 mg, 14μmol)

in 2 mL THF was added molybdenum hexacarbonyl (9.3 mg,35 μmol). 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, 135μmol), tri-t-butylphosphoniumtetrafluoroborat (1.3 mg, 4μmol) and trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipallad ium(II) (1.4 mg, 2μmol) were added and microwave radiation was continued for 8 minutes. Then the solvent was removed i.vac, and the product purified by chromatography on silica gel (ethyl acetate in hexane 0% to 30% then additional 5 % methanol) to yield 6.5 mg (14%) 3-(5-{[(lR,2S)-2- [(2,2-difluoropropanoyl)amino]- 1 -(6-methoxypyridin-3-yl)propyl]oxy } - lH-indazol- 1 -yl)- N-( 1 , 1 -dioxidotetrahydrothiophen-3 -yl)benzamide . ES+MS: m/z 628 [MH ⁺ ] 1H-NMR (300 MHz, CDCl ₃ ); δ = 8.20 (d, IH), 8.11 (d, IH), 8.01 (s, IH), 7.85 (m, IH), t

7.71 (d, IH), 7.63 (t, IH), 7.60 (dd, IH), 7.16 (dd, IH), 7.08 (m, IH), 6.99 (d, IH), 6.76 (d, IH), 6.67 (d, IH), 5.36 (d, IH), 5.00 (m, IH), 4.39 (dq, IH), 3.92 (s, 3H), 3.47 (m, IH), 3.29 (m, IH), 3.16 (m, 2H), 2.63 (m, IH), 2.44 (m IH), 1.77 (t, 3H), 1.29 (d, 3H).

Example 25

3-(5-{f(7i?,25^-2-r(2,2-difluoropropanoyl)aminol-l-(6-methox ypyridin-3-yl)propylloxy}-lH- indazol-l-yl)-N-(tetrahvdrofuran-3-yl ^' )benzamide

To N-[(7i?, 2S)- 1 - { [ 1 -(3-bromophenyl)- 1 η-indazol-5-yl]oxy } - 1 -(6-methoxypyridin-3- yl)propan-2-yl]-2,2-difluoropropanamide (37 mg, 68μmol), 3-aminotetrahydrofuran (18 mg, 204μmol), tri-t-butylphosphoniumtetrafluoroborat (8.8 mg, 31 μmol) and trans- bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(I I) (10.3 mg, 14μmol) in 1.5 mL THF was added molybdaenhexacarbonyl (12.5 mg, 47 μmol). 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-{[(7i?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(6- methoxypyridin-3 -yl)propyl]oxy } - 1 H-indazol- 1 -y l)-N-(tetrahydrofuran-3 -yl)benzamide . ES+MS: m/z 580 [MH ⁺ ]

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.20 (d, IH), 8.08 (dd, IH), 8.02 (s, IH), 7.83 (m, IH), 5 7.71 (m, IH), 7.67 (d, IH), 7.60 (dd, IH), 7.58 (t, IH), 7.16 (dd, IH), 6.99 (d, IH), 6.76 (d, IH), 6.66 (br, IH), 6.43 (br, IH), 5.36 (d, IH), 4.75 (m, IH), 4.40 (dq, IH), 4.01 (m,lH), 3.92 (s, 3H), 3.91 (m, IH), 3.83 (m, 2H), 2.38 (m, IH), 1.95 (m, IH), 1.77 (t, 3H), 1.29 (d, 3H).

io Example 26

3-(5-{r(H?,25 ^f )-2-r(2,2-difluoropropanoyl)amino1-l-(6-methoxypyridin-3-yl) propyl]oxy}-

To N- [(Zi?, 2S)- 1 - {[ l-(3-bromophenyl)-l H-indazol-5-yl]oxy} - 1 -(6-methoxypyridin-3- i ₅ yl)propan-2-yl]-2,2-difluoropropanamide (50 mg, 92μmol), l-amino-2-butanole (25 mg, 275μmol), tri-t-butylphosphoniumtetrafluoroborat (12 mg, 41μmol) and trans- bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(I I) ( mg, 7μmol) in 2 mL THF was added molybdenum hexacarbonyl (17 mg, 64μmol). The microwave vessel was closed and radiated in a microwave reactor (CEM discover) at 150 W and 125°C for 10 minutes 20 (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-{[(ii?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(6-methox ypyridin-3-yl)propyl]oxy}- 1 H-indazol- 1 -yl)-N-(2-hydroxybutyl)benzamide . ES+MS: m/z 582 [MH ⁺ ] 2 ₅ ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.20 (d, IH), 8.11 (s, IH), 8.01 (s, IH), 7.82 (m, IH),

7.73 (d, IH), 7.66 (d, IH), 7.60 (dd, IH), 7.57 (t, IH), 7.16 (dd, IH), 6.98 (d, IH), 6.75 (d, IH), 6.74 (br, IH), 6.66 (br, IH), 5.36 (d, IH), 4.40 (dq, IH), 3.92 (s, 3H), 3.76 (m, IH),

3.74 (dddd, IH), 3.34 (dddd, IH), 1.77 (t, 3H), 1.57 (m, 2H),1.29 (d, 3H), 1.00 (t, 3H).

Example 27

N-cvclopentyl-3-(5-(F(7i?, 25V2-r(2.2-difluoropropanovnamino1-3-hvdroxy-l-(6- methoxypyridin-3-yl)propyl ^" |oxy) - 1 H-indazol- 1 -vDbenzamide

To N-[( 1 R,2S)- 1 - { [ 1 -(3-bromophenyl)- lH-indazol-5-yl]oxy} -3-tert-butoxy- 1 -(6- methoxypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (37 mg, 60μmol), cyclopentylamine (7.1 mg, 84μmol), Tri-t-butylphosphoniumtetrafluoroborat (3.5mg, 12μmol) and trans-bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalla dium(II) (9.1 mg, io 12μmol) in 1.6 ml THF was added molybdenum hexacarbonyl (7.6 mg, 29μmol). 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-{[(7i?,25)-3-ter/-butoxy-2-[(2,2- i ₅ difluoropropanoyl)amino]-l -(6-methoxypyridin-3-yl)propyl]oxy} - 1 H-indazol- 1 -yl)-N- cyclopentylbenzamide, which were treated with 178 μl trifluoroacetic acid in 0.6 ml dichloromethane over 18 hours at room temperature. Saturated sodium hydrogen carbonate solution was added, the mixture was stirred virgously and extracted with ethyl acetate after 30 minutes. Then the solvent was removed i.vac, and the product purified by preparative

20 thin layer chromatography on silica gel (ethyl acetate 100%) to yield 15 mg of N- cyclopentyl-3-(5-{[(7i?,25)-2-[(2,2-difluoropropanoyl)amino] -3-hydroxy-l-(6- methoxypyridin-3-yl)propyl]oxy} - 1 H-indazol- 1 -yl)benzamide. ES+MS: m/z 594 [MH ⁺ ] 1H-NMR (400 MHz, CDCl ₃ ); δ = 8.17 (d, IH), 8.02 (s, IH), 7.97 (s, IH), 7.77 (d, IH),

2s 7.69 (d, IH), 7.66 (dd, IH), 7.61 (d, IH), 7.56 (t, IH), 7.08 (dd, IH), 6.98 (d, IH), 6.74 (d, IH), 6.24 (d, IH), 5.42 (d, IH), 4.42 (ddd, IH), 4.35 (m, IH), 4.20 (d, IH), 3.90 (s, 3H), 3.78 (m, IH), 2.76 (br, IH), 2.11 (m, 2H), 1.66 (t, 3H), 1.64-1.74 (m., 4H), 1.52 (m, 2H).

carbamic acid, [(I S)-I-[H. l-dimethylethoxy)methyll-2-(methoxymethylamino)-2-oxoethyll- , 9H-fluoren-9-ylmethyl ester

FMOC-SER(TBU)-OH (50 g, 130 mmol) in 320 ml dichloromethane were cooled to 0 ⁰ C. 1,1'- Carbonyldiimidazol (28.3 g, 175 mmol) were added in multiple portions and stirring was continued for 30 minutes at 0°C. Triethylamine (24,2 ml, 175 mmol) was added followed by N,O-dimethyl hydroxylamine mono hydrochloride (17 g, 175 mmol) in multiple portions and stirring was continued for 30 minutes at 0 ⁰ C. After stirring for 14 hours at room temperature the mixture was diluted with 400 ml t-butyl methylether and washed with IM HCL solution (2 times 100 ml), saturated NaHCO ₃ solution and brine. After drying over Na ₂ SO ₄ the solvent was removed i.vaα, and the product purified by chromatography on silica gel (ethyl acetate in hexane, 0% to 70%) to yield 39,2 g of carbamic acid, [(lS)-l-[(l,l-dimethylethoxy)methyl]- 2-(methoxymethylamino)-2-oxoethyl]-, 9H-fluoren-9-ylmethyl ester (92%). 1H-NMR (300 MHz, CDCl ₃ ); δ = 7.76 (d, 2H), 7.61 (m, 2H), 7.40 (dd, 2H), 7.3 l(dd, 2H), 5.68 (d, IH), 4.87 (br, IH), 4.36 (d, 2H), 4.24 (t, IH), 3.78 (s, 3H), 3.62 (m, 2H), 3.25 (s, 3H), 1.16 (s, 9H).

9H-fIuoren-9-ylmethyl [C2S)-3-tert-butoxy-l -(6-methoxypyridin-3-yl)-l -oxopropan-2- yllcarbamate

64 ml Isopropylmagnesium chloride (2M in THF, 128 mmol) were added to 5-Brom-2- methoxypyridin (10 g, 53 mmol) and carbamic acid, [(lS)-l-[(l,l-dimethylethoxy)methyl]-2-

(methoxymethylamino)-2-oxoethyl]-, 9H-fluoren-9-ylmethyl ester (18. Ig, 43 mmol) in 55 ml THF at -15°C and stirred over night while the mixture was warmed to room temperature. The reaction mixture was cooled to 2°C and added slowly to a 2M HCl-ice mixture and stirred vigorously. The pH was adjusted to 5 and the aqueous phase extracted with ethyl acetate. After drying over Na ₂ SO ₄ the solvent was removed i.vac, and the product purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 100%) to yield 3.28 g (13%) 9H- fluoren-9-ylmethyl [(2S)-3 -tert-butoxy- 1 -(6-methoxypyridin-3 -yl)- 1 -oxopropan-2- yljcarbamate.

¹ H-NMR (300 MHz, CDCl ₃ ); δ - 8.82 (d, IH), 8.16 (dd, IH), 7.77 (d, 2H), 7.63 (m, 2H), 7.41 (dd, 2H), 7.32 (dd, 2H), 6.81 (d, IH), 5.95 (d, IH), 5.29 (m, IH), 4.40 (d, 2H), 4.25 (t, IH), 4.02 (s, 3H), 3.76 (dd, IH), 3.66 (dd, IH), 1.02 (s, 9H).

9H-fluoren-9-ylmethyl f(lR, 2S)-3-tert-butoxy- 1 -hydroxy- 1 - (6-methoxypyridin-3-yl)propan- 2-yll carbamate

9H-fluoren-9-ylmethyl [(2S)-3-tert-butoxy- 1 -(6-methoxypyridin-3-yl)- 1 -oxopropan-2- yljcarbamate (2.26 g, 4.76 mmol) in 2-propanol (4.4 mL) and toluene (6 mL) was added aluminum tri iso-propylate (300 mg, 1.4 mmol) . The reaction mixture was stirred at 65°C for 72 hours, additional aluminum tri iso-propylate (300 mg, 1.4 mmol) was added and stirring was continued for 24 hours. Water was added, the mixture was stirring for 15 minutes and extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ , the solvent is removed i.vac, and the product purified by chromatography on silica gel (ethyl acetate in hexane 0% to 100% ) to yield 1.46 g (65%) 9H-fluoren-9-ylmethyl [(lR,2S)-3- tert-butoxy- 1 -hydroxy- 1 -(6-methoxypyridin-3-yl)propan-2-yl]carbamate. 1H-NMR (300 MHz, CDCl ₃ ); δ = 8.18 (s, IH), 7.78 (d, 2H), 7.66 (m, 3H), 7.41 (dd, 2H), 7.32 (dd, 2H), 6.75 (d, IH), 5.64 (d, IH), 4.91 (m, IH), 4.41 (m, 2H), 4.23 (m, 2H), 3.93 (s, 3H), 3.50 (dd, 2H), 1.18 (s, 9H).

(lR,2S)-2-amino-3-tert-butoxy-l-(6-methoxyOyridin-3-yl)pr opan-l-ol

To 9H-fluoren-9-ylmethyl [(/i?,2S)-3-tert-butoxy- 1 -hydroxy- 1 -(6-methoxypyridin-3- yl)propan-2-yl]carbamate (2.38 g, 5.0 mmol) in 19 mL N,N-dimethylformamid was added piperidine (4.9 mL, 50 mmol) at room temperature. The reaction mixture was stirred 20 hours at room temperature. The reaction mixture was added to ice-water and the precipitate removed by filtration through cellites followed by careful washing of the solids with water. The aqueous filtrate was extracted with 10% methanol in dichloromethane and the organic phase was dried over Na ₂ SO ₄ . The solvent was removed i.vac, and the product purified by chromatography on silica gel. (methanol in dichloromethane 0% to 10%) to yield 426 mg (34 %) (IR, 2S)-2-amino-3 -tert-butoxy- 1 -(6-methoxypyridin-3-yl)propan- 1 -ol. 1H-NMR (400 MHz, CDCl ₃ ); 6 = 8.13 (d, IH), 7.63 (dd, IH), 6.76 (d, IH), 4.62 (d, IH), 3.94 (s, 3H), 3.47 (dd, IH), 3.35 (dd, IH), 3.09 (m, IH), 1.20 (s, 9H).

(lR,2S)-l-{[l-(3-bromophenyl)-lH-indazol-5-ylloxy}-3-tert -butoxy-l-(6-methoxypyridin-3- yl)proyan-2-amine

(ii?,2S)-2-Amino-3-tert-butoxy-l-(6-methoxypyridin-3-yl)p ropan-l-ol (350 mg, 1.38 mmol), copper(I)iodide (52 mg, 0.28 mmol), N,N-dimethylglycine (57 mg, 0.55 mmol) and caesium carbonate (896 mg, 2.75 mmole) were suspended in butyronitrile (2.9 mL). The reaction vessel was capped and the mixture was stirred at 110 °C for 2 hours. Then l-(3-bromophenyl)-

5-iodoindazole (465 mg, 1.38 mmole) was added and heating to 130 ⁰ C was continued for 20 hours. The mixture was filtered through cellites followed by careful washing of the solids with 10% triethylamine in methanol. The solvent was removed i.vac, and the product purified by chromatography on silica gel. (ethyl acetate in dichloromethane 0 to 100%, then methanol in ethyl acetate 10% + 1% triethylamine) to yield 122 mg (17%) (7i?,25)-l-{[l-(3-bromophenyl)- lH-mdazol-5-yl]oxy}-3-ter/-butoxy-l-(6-methoxypyridin-3-yl)p ropan-2-amine. 1H-NMR (300 MHz, CDCl ₃ ); δ = 8.22 (d, IH), 8.01 (d, IH), 7.86 (t, IH), 7.67 (dd, IH), 7.62 (ddd, IH), 7.60 (d, IH), 7.45 (ddd, IH), 7.36 (t, IH), 7.13 (dd, IH), 7.04 (d, IH), 6.75 (d, IH), 5.18 (d, IH), 3.91 (s, 3H), 3.58 (dd, IH), 3.50 (dd, IH), 3.37 (m, IH), 1.20 (s, IH)

N-r(lR,2S)-l-{ri-β-bromophenyl)-lH-indazol-5-ylloxy}-3-t ert-butoxy-l-(6- methoxypyridin-3-yl)propan-2-yl1-2, 2-difϊuoropropanam ide

l,l'-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. (7i?,25)-l-{[l-(3-bromophenyl)- lH-indazol-5-yl]oxy}-3-tert-butoxy-l-(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. Water and ethyl acetate were added, the mixture was stirred vigorously, extracted with ethyl acetate after 30 minutes and washed with brine. The solvent was removed i.vac, and the product purified by chromatography on silica gel. (ethyl acetate in hexane 0 to 50%) to yield 52 mg (37%) N-[(7λ,25)-l-{[l-(3-bromophenyl)-lH-indazol-5- yl]oxy}-3-/er/-butoxy-l-(6-methoxypyridin-3-yl)propan-2-yl]- 2,2-difluoropropanamide. ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.13 (d, IH), 8.02 (d, IH), 7.86 (t, IH), 7.71 (dd, IH), 7.63 (ddd, IH), 7.61 (d, IH), 7.45 (ddd, IH), 7.37 (t, IH), 7.13 (dd, IH), 7.06 (d, IH), 6.76 (br, IH), 6.72 (d, IH), 5.27 (d, IH), 4.51 (m, IH), 4.01 (dd, IH), 3.89 (s, 3H), 3.49 (dd, IH), 1.57 (t, 3H), 1.18 (s, 9H).

Example 28

3-(5- { [(/i?,2iSV2-|Y2.2-difluoropropanoyl)amino ^' l- 1 -(6-methoxypyridin-3-yl)propyl ^" loxy) - 1 H-indazol- 1 -yl)-N-(pyridin-3 -ylmethvDbenzamide

To N-[(1R, 2S)- 1 - { [ 1 -(3-bromophenyl)- 1 H-indazol-5-yl]oxy } - 1 -(6-methoxypyridin-3- yl)propan-2-yl]-2,2-difluoropropanamide (50 mg, 92μmol), 3-aminomethylpyridine (30 mg, 275μmol), tri-t-butylphosphoniumtetrafluoroborat (12 mg, 41μmol) and trans- bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II ) (13.9 mg, 18μmol) in 2 ml THF was added molybdenum hexacarbonyl (17 mg, 64 μmol). 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-{[(/i?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(6-methox ypyridin-3- yl)propyl]oxy} - 1 H-indazol- 1 -yl)-N-(pyridin-3-ylmethyl)benzamide. ES+MS: m/z 601[MH ⁺ ]

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 8.62 (br, IH), 8.55 (br, IH), 8.19 (d, IH), 8.12 (m, IH), 8.00 (s, IH), 7.84 (d, IH), 7.74 (m, 2H), 7.67 (d, IH), 7.58 (m, 2H), 7.29 (dd, IH), 7.15 (dd, IH), 6.98 (d, IH), 6.75 (d, IH), 6.69 (m, 2H), 5.35 (d, IH), 4.68 (d, 2H), 4.39 (dq, IH), 3.92 (s, 3H), 1.76 (t., 3H), 1.28 (d, 3H).

Assay

Human Glucocorticoid Receptor (GR) Assay

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). In the GR radioligand binding assay, test compounds were serially diluted in semi-log steps (10 concentrations) with a final concentration of 10 μM. Test compounds (lμL) and

controls (lμL) 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 μM

Dexamethasone.

The full length GR was diluted to a final concentration of 3.3% (0.495 mg/ml) in assay buffer (2OmM Tris-HCl, ImM EDTA, 10% (w/v) Glycerol, 2OmM Sodium molbydate, pH 7.4). 45 μL 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 (7nM final assay concentration) and 5 μL 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.

50 μL ice-cold charcoal solution (pH 7.4: 2% Charcoal, 0,2% Dextran T70 in 2OmM Tris- HCl, ImM EDTA and 2OmM Sodium molbydate) was added to each well and the samples were mixed on plate shaker for 5 minutes. The plate was then centrifuged for 1.5 min at 1500 rpm, the samples (80 μL) were transfered from each well to a filter plate (Millipore, 0.45 μm, MHVBN45) on a vacuum manifold and then collected into new plates (Greiner, 96 well white/transparent, 655095). The filter plate was washed once with 20μl of water and then 100 μL 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. The data obtained from each replicate experiment were analysed using the software ActivityBase, version 5.4.3 (ID Business Solutions Ltd) and IC ₅₀ values were calculated. Ref: Necela, BM, Cidlowski, JA, Trends Pharmacol Sci, 24: 58, 2003