LXR modulators with bicyclic core moiety
The present invention relates to bicyclic compounds (e.g. indoles) containing a sulfonyl moiety, which bind to the liver X receptor (LXRα and/or LXKβ) and act preferably as inverse agonists of LXR.
1. A method for the prophylaxis and/or treatment of diseases amenable for treatment with LXR modulators, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I)
a glycine conjugate, tauro conjugate, enantiomer, diastereomer, tautomer, N-oxide, solvate, prodrug or pharmaceutically acceptable salt thereof,
wherein
is an annelated 5- to 6-membered cycle forming a 6-membered aryl or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, wherein this cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, SF 5 , NO 2 , C 1-6 -alkyl, oxo, C 0-6 -alkylene-OR 11 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 11 , C 0-6 -alkylene-NR 11 S(O) 2 R 11 , C 0-6 -alkylene-S(O) 2 NR 11 R 12 , C 0-6 -alkylene-NR 11 S(O) 2 NR 11 R 12 , C 0-6 -alkylene-CO 2 R 11 , O—C 1-6 -alkylene-CO 2 R 11 , C 0-6 -alkylene-O—COR 11 , C 0-6 -alkylene-CONR 11 R 12 , C 0-6 -alkylene-NR 11 —COR 11 , C 0-6 -alkylene-NR 11 —CONR 11 R 12 , C 0-6 -alkylene-O—CONR 11 R 12 , C 0-6 -alkylene-NR 11 —CO 2 R 11 and C 0-6 -alkylene-NR 11 R 12 ,
wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl; and
wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, and
wherein the new formed cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
is selected from the group consisting of 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S, 6- to 14-membered aryl and 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF 5 , NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 21 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 21 , C 0-6 -alkylene-NR 21 S(O) 2 R 21 , C 0-6 -alkylene-S(O) 2 NR 21 R 22 , C 0-6 -alkylene-NR 21 S(O) 2 NR 21 R 22 , C 0-6 -alkylene-CO 2 R 21 , O—C 1-6 -alkylene-CO 2 R 21 , C 0-6 -alkylene-O—COR 21 , C 0-6 -alkylene-CONR 21 R 22 , C 0-6 -alkylene-NR 21 —COR 21 , C 0-6 -alkylene-NR 21 —CONR 21 R 22 , C 0-6 -alkylene-O—CONR 21 R 22 , C 0-6 -alkylene-NR 21 -CO 2 R 21 and C 0-6 -alkylene-NR 21 R 22 ,
wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl,
and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N, and
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl,
and wherein optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5- to 6-membered unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N,
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
is selected from the group consisting of 6- or 10-membered aryl and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S,
wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, SF 5 , NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 31 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-(6-membered aryl), C 0-6 -alkylene-(5- to 6-membered heteroaryl), C 0-6 -alkylene-S(O) n R 31 , C 0-6 -alkylene-NR 31 S(O) 2 R 31 , C 0-6 -alkylene-S(O) 2 NR 31 R 32 , C 0-6 -alkylene-NR 31 S(O) 2 NR 31 R 32 , C 0-6 -alkylene-CO 2 R 31 , O—C 1-6 -alkylene-CO 2 R 31 , C 0-6 -alkylene-O—COR 31 , C 0-6 -alkylene-CONR 31 R 32 , C 0-6 -alkylene-NR 31 —COR 31 , C 0-6 -alkylene-NR 31 —CONR 31 R 32 , C 0-6 -alkylene-O—CONR 31 R 32 , C 0-6 -alkylene-NR 31 —CO 2 R 31 and C 0-6 -alkylene-NR 31 R 32 ,
wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N, and
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
is selected from the group consisting of 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S, 6- to 14-membered aryl and 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,
wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF 5 , NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 21 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 21 , C 0-6 -alkylene-NR 21 S(O) 2 R 21 , C 0-6 -alkylene-S(O) 2 NR 21 R 22 , C 0-6 -alkylene-NR 21 S(O) 2 NR 21 R 22 , C 0-6 -alkylene-CR 41 (═N—OR 41 ), C 0-6 -alkylene-CO 2 R 21 , O—C 1-6 -alkylene-CO 2 R 21 , C 0-6 -alkylene-O—COR 21 , C 0-6 -alkylene-CONR 21 R 22 , C 0-6 -alkylene-NR 21 —COR 21 , C 0-6 -alkylene-NR 21 —CONR 21 R 22 , C 0-6 -alkylene-O—CONR 21 R 22 , C 0-6 -alkylene-NR 21 —CO 2 R 21 and C 0-6 -alkylene-NR 21 R 22 ,
wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, CO—OC 1-4 -alkyl, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N, and
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
and wherein optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5- to 6-membered unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N,
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
wherein has a substituent from above in 1,2-orientation regarding to the connection towards
or has an annelated additional cycle in 1,2-orientation;
L is selected from the group consisting of a bond, C 1-6 -alkylene, C 2-6 -alkenylene, C 2-6 -alkinylene, 3- to 10-membered cycloalkylene, 3- to 10-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S, 6- or 10-membered arylene and 5- to 10-membered heteroarylene containing 1 to 4 heteroatoms independently selected from N, O and S,
wherein alkylene, alkenylene, alkinylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF 5 , NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 41 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 41 , C 0-6 -alkylene-NR 41 S(O) 2 R 41 , C 0-6 -alkylene-S(O) 2 NR 41 R 42 , C 0-6 -alkylene-NR 41 S(O) 2 NR 41 R 42 , C 0-6 -alkylene-CO 2 R 41 , O—C 1-6 -alkylene-CO 2 R 41 , C 0-6 -alkylene-O—COR 41 , C 0-6 -alkylene-CONR 41 R 42 , C 0-6 -alkylene-NR 41 —COR 41 , C 0-6 -alkylene-NR 41 —CONR 41 R 42 , C 0-6 -alkylene-O—CONR 41 R 42 , C 0-6 -alkylene-NR 41 —CO 2 R 41 and C 0-6 -alkylene-NR 41 R 42 ,
wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
and wherein optionally two adjacent substituents on the arylene and heteroarylene moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N, and
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
R 1 is selected from the group consisting of H, halogen, CN, SF 5 , NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 41 , Y—C 0-6 -alkylene-(3- to 6-membered cycloalkyl), Y—C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), Y—C 0-6 -alkylene-(6-membered aryl), Y—C 0-6 -alkylene-(5- to 6-membered heteroaryl), C 0-6 -alkylene-S(═O)(—R 41 )═N—R 75 , X—C 1-6 -alkylene-S(═O)(—R 41 )═N—R 75 , C 0-6 -alkylene-S(O) n R 41 , X—C 1-6 -alkylene-S(O) n R 41 , C 0-6 -alkylene-S(═NR 71 )R 41 , X—C 1-6 -alkylene-S(═NR 71 )R 41 , C 0-6 -alkylene-S(O)(═NR 71 )R 41 , X—C 1-6 -alkylene-S(O)(═NR 71 )R 41 , C 0-6 -alkylene-S(═NR 71 ) 2 R 41 , X—C 1-6 -alkylene-S(═NR 71 ) 2 R 41 , C 0-6 -alkylene-NR 41 S(O) 2 R 41 , X—C 1-6 -alkylene-NR 41 S(O) 2 R 41 , C 0-6 -alkylene-S(O) 2 NR 41 R 42 , X—C 1-6 -alkylene-S(O) 2 NR 41 R 42 , C 0-6 -alkylene-NR 41 S(O) 2 NR 41 R 42 , X—C 1-6 -alkylene-NR 41 S(O) 2 NR 41 R 42 , C 0-6 -alkylene-SO 3 R 41 , X—C 1-6 -alkylene-SO 3 R 41 , C 0-6 -alkylene-CO 2 R 41 , X—C 1-6 -alkylene-CO 2 R 41 , C 0-6 -alkylene-O—COR 41 , X—C 1-6 -alkylene-O—COR 41 , C 0-6 -alkylene-CONR 41 R 42 , X—C 1-6 -alkylene-CONR 41 R 42 , C 0-6 -alkylene-CONR 41 OR 41 , X—C 1-6 -alkylene-CONR 41 OR 41 , C 0-6 -alkylene-CONR 41 SO 2 R 41 , X—C 1-6 -alkylene-CONR 41 SO 2 R 41 , C 0-6 -alkylene-NR 41 —COR 41 , X—C 1-6 —C 0-6 -alkylene-NR 41 —COR 41 , C 0-6 -alkylene-NR 41 —CONR 41 R 42 , X—C 1-6 -alkylene-NR 41 —CONR 41 R 42 , C 0-6 -alkylene-O—CONR 41 R 42 , X—C 1-6 -alkylene-O—CONR 41 R 42 , C 0-6 -alkylene-NR 41 —CO 2 R 41 , X—C 1-6 -alkylene-NR 41 —CO 2 R 41 , C 0-6 -alkylene-NR 41 R 42 , and X—C 1-6 -alkylene-NR 41 R 42 ,
wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
and wherein optionally two adjacent substituents on the aryl and heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S and N, and
wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 , R 51 are independently selected from H and C 1-4 -alkyl,
wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, SO 3 H, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
or R 11 and R 12 , R 21 and R 22 , R 31 and R 32 , R 41 and R 42 , respectively, when taken together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms independently selected from O, S and N; and
wherein the new formed cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, SO 3 H, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
R 71 is independently selected from H, CN; NO 2 , C 1-4 -alkyl and C(O)—OC 1-4 -alkyl,
wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, CO 2 H, CO 2 —C 1-4 -alkyl, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, SO 3 H, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
R 75 is independently selected from C 1-4 -alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6-membered aryl and 5- to 6-membered heteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, Me, Et, CHF 2 , CF 3 , OH, oxo, CO 2 H, CONHCH 2 CO 2 H, CONH(CH 2 ) 2 SO 3 H, SO 3 H, OMe, OEt, OCHF 2 , and OCF 3 ;
X is independently selected from O, NR 51 , S(O) n , S(═NR 71 ), S(O)(═NR 71 ) and S(═NR 71 ) 2 ;
Y is independently selected from a bond, O, NR 51 , S(O) n , S(═NR 71 ), S(O)(═NR 71 ) and S(═NR 71 ) 2 ;
n is independently selected from 0 to 2;
and with the proviso, that the following structures are excluded:
2. The method according to claim 1 , wherein
is selected from
wherein is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl, O-halo-C 1-4 -alkyl, NH 2 , NHC 1-4 -alkyl, N(C 1-4 -alkyl) 2 , SO 2 —C 1-4 -alkyl and SO 2 -halo-C 1-4 -alkyl.
3. The method according to claim 1 , wherein
is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl, cyclopentyl, cyclohexyl, bicyclopentyl, bicyclooctyl, bicycloheptyl, pentacyclooctyl and piperidinyl,
wherein the cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl, O-halo-C 1-4 -alkyl, C 1-4 -alkyl-OH and halo-C 1-4 -alkyl-OH; and wherein optionally two adjacent substituents on the phenyl ring form together a —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCF 2 O— and —OCH 2 O— group.
4. The method according to any claim 1 , wherein
is selected from phenyl, pyridyl and thiophenyl; wherein phenyl, pyridyl and thiophenyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl and O-halo-C 1-4 -alkyl; and wherein residue -L-R 1 is linked in 1,3-orientation regarding the connection towards
and L is not a bond.
5. The method according to claim 1 , wherein
-L-R 1 is selected from
wherein the cycle is unsubstituted or further substituted with 1 to 4 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl, O-halo-C 1-4 -alkyl, C 1-4 -alkyl-OH, halo-C 1-4 -alkyl-OH, SO 2 —C 1-4 -alkyl and SO 2 -halo-C 1-4 -alkyl; and wherein optionally two adjacent substituents on the phenyl ring form together a —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCF 2 O— and —OCH 2 O— group.
6. The method according to claim 1 , wherein
R 1 is selected from CO 2 H, tetrazole, CH 2 CO 2 H, OCH 2 CO 2 H, SO 2 CH 2 CO 2 H, CHMeCO 2 H, CMe 2 CO 2 H, C(OH)MeCO 2 H, CONHSO 2 Me and CONH(OH); and optionally the glycine and tauro conjugate thereof.
7. The method according to claim 1 , wherein
-L-R 1 is selected from
and optionally the glycine and tauro conjugate thereof.
8. The method according to claim 1 , wherein
is selected from the group consisting of
wherein
R 2 is selected from Me, F, Cl, CN, OMe, CHO, CHF 2 , CF 3 , SO 2 Me,
and
wherein is optionally further substituted with 1 to 2 substituents selected from the group consisting of F, Cl, CN, Me, OMe, CHO, CHF 2 and CF 3 .
9. The method according to claim 1 , wherein
is selected from the group consisting of
10. The method according to claim 1 , wherein Formula (I) contains a substituent selected from the group consisting of CO 2 H, tetrazole, CONHSO 2 Me and CONH(OH); and optionally the glycine and tauro conjugate thereof.
11. The method according to claim 1 selected from
or a glycine conjugate or tauro conjugate thereof; and
an enantiomer, diastereomer, tautomer, N-oxide, solvate, prodrug or pharmaceutically acceptable salt thereof.
12. The method according to claim 1 , wherein the disease is selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hyper-cholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications, and unwanted side-effects of long-term glucocorticoid treatment in diseases.
13. The method according to claim 1 , wherein
L-R 1 is
wherein the cycle is unsubstituted or further substituted with 1 to 4 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O—C 1-4 -alkyl, O-halo-C 1-4 -alkyl, C 1-4 -alkyl-OH, halo-C 1-4 -alkyl-OH, SO 2 —C 1-4 -alkyl and SO 2 -halo-C 1-4 -alkyl; and wherein optionally two adjacent substituents on the phenyl ring form together a —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCF 2 O— and —OCH 2 O— group.
14. The method according to claim 1 , wherein
R 1 is C 0-6 -alkylene-CO 2 R 41 or C 0-6 -alkylene-CONR 41 R 42 , or a glycine conjugate or tauro conjugate thereof.
15. The method according to claim 1 , wherein
R 1 is COOH, or a glycine conjugate or tauro conjugate thereof.
16. The method according to claim 1 , wherein
R 1 is C 0-6 -alkylene-CONR 41 R 42 .
17. The method according to claim 16 , wherein
R 41 and R 42 are independently selected from H and C 1-4 alkyl, wherein C 1-4 alkyl is unsubstituted or substituted with CO 2 H.
18. The method according to claim 1 , wherein
L-R 1 is
or a glycine conjugate or tauro conjugate thereof.
19. The method according to claim 1 , where the compound is a glycine conjugate.
20. The method according to claim 1 , wherein the compound is
21. The method according to claim 1 , wherein the compound is
or a glycine conjugate thereof.
22. The method according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. The method according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The method according to claim 12 , wherein the disease with unwanted side-effects of long-term glucocorticoid treatment is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, and asthma.