Substituted Pyrrolidine Amides II

Abstract

which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.

1 . A compound according to general formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents —C 1-10 -alkyl; —C 3-10 cycloalkyl; —C 1-6 -alkylene-C 3-10 cycloalkyl; 3 to 7 membered heterocycloalkyl; —C 1-6 -alkylene-(3 to 7 membered heterocycloalkyl); aryl; —C 1-6 -alkylene-aryl; 5 or 6-membered heteroaryl; or —C 1-6 -alkylene-(5 or 6-membered heteroaryl); 
         R 2  represents —C(═O)—C 1-10 -alkyl; —C(═O)—C 3-10 -cycloalkyl; —C(═O)—C 1-6 -alkylene-C 3-10 -cycloalkyl; —C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)—C 1-6 -alkylene-(3 to 7 membered heterocycloalkyl); —C(═O)-aryl; —C(═O)—C 1-6 -alkylene-aryl; —C(═O)-(5 or 6-membered heteroaryl); —C(═O)—C 1-6 -alkylene-(5 or 6-membered heteroaryl); —S(═O) 1-2 —C 1-10 -alkyl; —S(═O) 1-2 —C 3-10 -cycloalkyl; —S(═O) 1-2 —C 1-6 -alkylene-C 3-10 -cycloalkyl; —S(═O) 1-2 -(3 to 7 membered heterocycloalkyl); —S(═O) 1-2 —C 1-6 -alkylene-(3 to 7 membered heterocycloalkyl); —S(═O) 1-2 -aryl; —S(═O) 1-2 —C 1-6 -alkylene-aryl; —S(═O) 1-2 -(5 or 6-membered heteroaryl); or —S(═O) 1-2 —C 1-6 -alkylene-(5 or 6-membered heteroaryl); 
         R 3  represents —C 1-10 -alkyl; —C 3-10 -cycloalkyl; —C 1-6 -alkylene-C 3-10 -cycloalkyl; aryl; —C 1-6 -alkylene-aryl; —C(═O)—C 1-10 -alkyl; —C(═O)—C 3-10 -cycloalkyl; —C(═O)—C 1-6 -alkylene-C 3-10 -cycloalkyl; —C(═O)-aryl; —C(═O)—C 1-6 -alkylene-aryl; —S(═O) 1-2 —C 1-10 -alkyl; —S(═O) 1-2 —C 3-10 -cycloalkyl; —S(═O) 1-2 —C 1-6 -alkylene-C 3-10 -cycloalkyl; —S(═O) 1-2 -aryl; or —S(═O) 1-2 —C 1-6 -alkylene-aryl; 
         R 4  represents —H; —F; —Cl; —Br; —I; —CN; —CH 3 ; —CF 3 ; —CF 2 H; —CFH 2  or cyclopropyl; 
         X represents N or CR 5 ; wherein R 5  represents —H; —F; —Cl; —Br; —I; —CN; —C 1-10 -alkyl or —C 3-10 -cycloalkyl; 
         Y represents N or CR 6 ; wherein R 6  represents —H; —F; —Cl; —Br; —I; —CN; —C 1-10 -alkyl or —C 3-10 -cycloalkyl; 
         Z represents N or CR 7 ; wherein R 7  represents —H; —F; —Cl; —Br; —I; —CN; —C 1-10 -alkyl or —C 3-10 -cycloalkyl; 
         wherein —C 1-10 -alkyl, —C 1-4 -alkyl and —C 1-6 -alkylene- in each case independently from one another is linear or branched, saturated or unsaturated; 
         wherein —C 1-10 -alkyl, —C 1-4 -alkyl, —C 1-6 -alkylene-, —C 3-10 -cycloalkyl and 3 to 7 membered heterocycloalkyl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from —F; —Cl; —Br; —I; —CN; —C 1-6 -alkyl; —CF 3 ; —CF 2 H; —CFH 2 ; —CF 2 Cl; —CFCl 2 ; —C(═O)—C 1-6 -alkyl; —C(═O)—OH; —C(═O)—OC 1-6 -alkyl; —C(═O)—NH 2 ; —C(═O)—NH(C 1-6 -alkyl); —C(═O)—N(C 1-6 -alkyl) 2 ; —OH; ═O; —OCF 3 ; —OCF 2 H; —OCFH 2 ; —OCF 2 Cl; —OCFCl 2 ; —O—C 1-6 -alkyl; —O—C(═O)—C 1-6 -alkyl; —O—C(═O)—O—C 1-6 -alkyl; —O—(CO)—NH(C 1-6 -alkyl); —O—C(═O)—N(C 1-6 -alkyl) 2 ; —O—S(═O) 2 —NH 2 ; —O—S(═O) 2 —NH(C 1-6 -alkyl); —O—S(═O) 2 —N(C 1-6 -alkyl) 2 ; —NH 2 ; —NH(C 1-6 -alkyl); —N(C 1-6 -alkyl) 2 ; —NH—C(═O)—C 1-6 -alkyl; —NH—C(═O)—O—C 1-6 -alkyl; —NH—C(═O)—NH 2 ; —NH—C(═O)—NH(C 1-6 -alkyl); —NH—C(═O)—N(C 1-6 -alkyl) 2 ; —N(C 1-6 -alkyl)-C(═O)—C 1-6 -alkyl; —N(C 1-6 -alkyl)-C(═O)—O—C 1-6 -alkyl; —N(C 1-6 -alkyl)-C(═O)—NH 2 ; —N(C 1-6 -alkyl)-C(═O)—NH(C 1-6 -alkyl); —N(C 1-6 -alkyl)-C(═O)—N(C 1-6 -alkyl) 2 ; —NH—S(═O)) 2 OH; NH—S(═O)) 2 —C 1-6 -alkyl; —NH—S(═O)) 2 —O—C 1-6 -alkyl; —NH—S(═O) 2 —NH 2 ; —NH—S(═O) 2 —NH(C 1-6 -alkyl); —NH—S(═O) 2 N(C 1-6 -alkyl) 2 ; —N(C 1-6 -alkyl)-S(═O) 2 —OH; —N(C 1-6 -alkyl)-S(═O) 2 —C 1-6 -alkyl; —N(C 1-6 alkyl)-S(═O) 2 —O—C 1-6 -alkyl; —N(C 1-6 -alkyl)-S(═O) 2 —NH 2 ; —N(C 1-6 -alkyl)-S(═O) 2 —NH(C 1-6 -alkyl); —N(C 1-6 -alkyl)-S(═O) 2 —N(C 1-4 -alkyl) 2 ; —SCF 3 ; —SCF 2 H; —SCFH 2 ; —S—C 1-6 -alkyl; —S(═O)—C 1-6 -alkyl; —S(═O) 2 —C 1-4 -alkyl; —S(═O) 2 —OH; —S(═O) 2 —O—C 1-6 -alkyl; S(═O) 2 —NH 2 ; —S(═O) 2 —NH(C 1-6 -alkyl); —S(═O) 2 —N(C 1-6 -alkyl) 2 ; —C 3-6 -cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5 or 6-membered heteroaryl; —O—C 3-6 -cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —O-phenyl; —O-(5 or 6-membered heteroaryl); —C(═O)—C 3-6 -cycloalkyl; —C(═O)-(3 to 6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5 or 6-membered heteroaryl); —S(═O) 2 —(C 3-6 -cycloalkyl); —S(═O) 2 -(3 to 6-membered heterocycloalkyl); —S(═O) 2 -phenyl or —S(═O) 2 -(5 or 6-membered heteroaryl); 
         wherein aryl and 5 or 6-membered heteroaryl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from —F; —Cl; —Br; —I; —CN; —C 1-6 -alkyl; —CF 3 ; —CF 2 H; —CFH 2 ; —CF 2 Cl; —CFCl 2 ; —C 1-4 -alkylene-CF 3 ; —C 1-4 -alkylene-CF 2 H; —C 1-4 -alkylene-CFH 2 ; —C(═O)—C 1-6 -alkyl; —C(═O)—OH; —C(═O)—OC 1-6 -alkyl; —C(═O)—NH(OH); —C(═O)—NH 2 ; —C(═O)—NH(C 1-6 -alkyl); —C(═O)—N(C 1-6 -alkyl) 2 ; —OH; ═O; —OCF 3 ; —OCF 2 H; —OCFH 2 ; —OCF 2 Cl; —OCFCl 2 ; —O—C 1-6 -alkyl; —O—C 3-6 -cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH 2 ; —NH(C 1-4 -alkyl); —N(C 1-6 -alkyl) 2 ; —NH—C(═O)—C 1-6 -alkyl; —N(C 1-6 -alkyl)-C(═O)—C 1-6 -alkyl; —NH—C(═O)—NH 2 ; —NH—C(═O)—NH(C 1-6 -alkyl); —NH—C(═O)—N(C 1-6 -alkyl) 2 ; —N(C 1-6 -alkyl)-C(═O)—NH(C 1-6 -alkyl); —N(C 1-6 -alkyl)-C(═O)—N(C 1-6 -alkyl) 2 ; —NH—S(═O) 2 —C 1-6 -alkyl; —SCF 3 ; —S—C 1-6 -alkyl; —S(═O)—C 1-6 -alkyl; —S(═O) 2 —C 1-6 -alkyl; —S(═O) 2 —NH 2 ; —S(═O) 2 —NH(C 1-6 -alkyl); —S(═O) 2 —N(C 1-4 -alkyl) 2 ; —C 3-6 -cycloalkyl; —C 1-4 -alkylene-C 3-6 -cycloalkyl; 3 to 6-membered heterocycloalkyl; —C 1-4 -alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl; 
         in the form of the free compound or a physiologically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 X represents CR 5 , Y represents CR 6 ; and Z represents CR 7 ; or   X represents N, Y represents CR 6 ; and Z represents CR 7 ; or   X represents CR 5 , Y represents N; and Z represents CR 7 ; or   X represents CR 5 , Y represents CR 6 ; and Z represents N; or   X represents N, Y represents N; and Z represents CR 7 ; or   X represents N, Y represents CR 6 ; and Z represents N; or   X represents CR 5 , Y represents N; and Z represents N; or   X represents N, Y represents N; and Z represents N.   
     
     
         3 . The compound according to  claim 2 , wherein optionally present R 5  represents —H; optionally present R 6  represents —H; and/or optionally present R 7  represents —H 
     
     
         4 . The compound according to  claim 1 , wherein
 R 1  represents —C 3-10 -cycloalkyl; —C 1-6 -alkylene-C 3-10 -cycloalkyl; aryl; or 5 or 6-membered heteroaryl.   
     
     
         5 . The compound according to  claim 1 , wherein
 R 2  represents —C(═O)—C 1-10 -alkyl; —C(═O)—C 3-10 -cycloalkyl; —C(═O)—C 1-6 -alkylene-C 3-10 -cycloalkyl; —C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)-(5 or 6-membered heteroaryl); —S(═O) 2 —C 1-10 -alkyl; —S(═O) 2 —C 3-10 -cycloalkyl; —S(═O) 2 —C 1-6 -alkylene-C 3-10 -cycloalkyl; or —S(═O) 2 -(5 or 6-membered heteroaryl).   
     
     
         6 . The compound according to  claim 1 , wherein
 R 3  represents —C 1-10 -alkyl; —C 3-10 -cycloalkyl; —C 1-6 -alkylene-C 3-10 -cycloalkyl; aryl; —C 1-6 -alkylene-aryl.   
     
     
         7 . The compound according to  claim 1 , wherein
 R 4  represents —H.   
     
     
         8 . The compound according to  claim 1 , wherein
 R 1  represents
 cyclopropyl, unsubstituted; 
 —CH 2 -cyclopropyl, unsubstituted; 
 phenyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, cyclopropyl and —OCH 3 , wherein phenyl is optionally annealed to a dioxolane ring by a substituent —O—CH 2 CH 2 —O—; or 
 pyridyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, and —OCH 3 . 
   
     
     
         9 . The compound according to  claim 1 , wherein
 R 2  represents
 —C(═O)—C 1-10 -alkyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, and —Br; 
 —C(═O)-cyclopropyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, and —OCH 3 ; 
 —C(═O)-cyclobutyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN and —OCH 3 ; 
 —C(═O)-2-tetrahydrofuranyl, unsubstituted; 
 —C(═O)-(5- to 6-membered heteroaryl), wherein said 5- to 6-membered heteroaryl is selected from the group consisting of thiazolyl, pyrazolyl, oxazolyl and 1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, isoxazolyl, isothiazolyl, wherein in each case said 5- to 6-membered heteroaryl is unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, ═O, and —OCH 3 ; 
 —S(═O) 2 —C 1-10 -alkyl, unsubstituted; 
 —S(═O) 2 -cyclopropyl, unsubstituted; 
 —S(═O) 2 —CH 2- cyclopropyl, unsubstituted; or 
 —S(═O) 2 -(5- to 6-membered heteroaryl), wherein said 5- to 6-membered heteroaryl is selected from the group consisting of thiazolyl, pyrazolyl, oxazolyl and 1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, isoxazolyl, isothiazolyl, wherein in each case said 5- to 6-membered heteroaryl is unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, ═O, and —OCH 3 . 
   
     
     
         10 . The compound according to  claim 1 , wherein
 R 3  represents
 —C 1-10 -alkyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, and —Br; 
 cyclohexyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, and —Br; 
 —CH 2 -cyclopropyl, unsubstituted; 
 —CH 2 -cyclohexyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, and —Br; 
 phenyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, and —OCH 3 ; or 
 —CH 2 -phenyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, and —OCH 3 . 
   
     
     
         11 . The compound according to  claim 1 , wherein
 R 1  represents phenyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, cyclopropyl and —OCH 3 ; and/or   R 2  represents —C(═O)—C 1-6 -alkyl; —C(═O)-cyclopropyl; or —C(═O)-cyclobutyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, and —Br; and/or   R 3  represents fluoro-phenyl.   
     
     
         12 . The compound according to  claim 1 , selected from the group consisting of
 1 2,2-difluoro-N-[rac-(2R,3S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   2 2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   3 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   4 2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-oxo-pyrrolidin-3-yl]propanamide   5 2,2-difluoro-N-[rac-(2R,3S)-2-(2,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   6 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3,4-difluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   7 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]propanamide   8 N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropane-carboxamide   9 N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropane-sulfonamide   10 N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanesulfonamide   11 2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   12 N-[(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propanamide   13 1-methyl-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   14 1-fluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   15 N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide   16 N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide   17 N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl-]1-(trifluoromethyl)cyclopropanecarboxamide   18 1-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   19 N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclobutanecarboxamide   20 2,2-difluoro-N-[(2S,3R)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   21 2,2-difluoro-N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   22 1-methyl-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   23 1-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   24 2,2-difluoro-N-[(2S,3R)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   25 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   26 2,2-difluoro-N-[rac-(2R,3S)-2-(3,5-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   27 2,2-difluoro-N-[rac-(2R,3S)-5-oxo-2-phenyl-1-(1-phenylindazol-5-yl)pyrrolidin-3-yl]propanamide   28 N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclo-propanecarboxamide   29 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-cyanophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   30 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-cyanophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   31 2,2-difluoro-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   32 N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclobutanecarboxamide   33 2,2-difluoro-N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   34 N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   36 2,2-difluoro-N-[rac-(2S,3S)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   37 1-cyclopropyl-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide   38 2,2-difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]propanamide   39 N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide   42 2,2-difluoro-N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   43 N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   45 1:1 mixture of (1 S,2S)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and (1 S,2S)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   46 rac-(1 S,2R)-2-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   48 2,2-difluoro-N-[rac-(2S,3R)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   49 N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   51 N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanesulfonamide   52 2-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   53 N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   54 N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   55 N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   56 1:1 mixture of (1R,2R)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and (1R,2R)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   61 N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   62 N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   63 1:1 mixture of (1R,2R)-2-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide and (1R,2R)-2-fluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   65 N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide   66 N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]acetamide   67 N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   68 2,2-difluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   69 2,2-difluoro-N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   70 1-fluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide   71 N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide   72 2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]propanamide   73 1-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide   74 N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-cyclopropanecarboxamide   75 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4,4-difluorocyclohexyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   76 2,2-difluoro-N-[rac-(2R,3S)-1-(1-cyclohexylindazol-5-yl)-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   77 2,2-difluoro-N-[rac-(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-(1-methylindazol-5-yl)-5-oxo-pyrrolidin-3-yl]propanamide   78 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(2,2-difluoroethyl)indazol-5-yl]-2-(2-fluoro-5-methoxy-phenyl)-5-oxo-pyrrolidin-3-yl]propanamide   79 2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   80 2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   81 2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   82 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(cyclopropylmethyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   84 2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4,4-difluorocyclohexyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide   85 2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   86 2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   87 2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide   88 N-[(2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl]-2,2-difluoropropanamide   89 2,2-difluoro-N-[rac-(2R,3S)-2-ethyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide   90 2,2-difluoro-N-[rac-(2R,3R)-2-(cyclopropylmethyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide   91 2-cyclopropyl-N-[(2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]acetamide   92 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide   93 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-1H-imidazole-2-carboxamide   94 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-2-methyloxazole-5-carboxamide   95 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-5-methylthiazole-4-carboxamide   96 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]pyrimidine-2-carboxamide   97 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]nicotinamide   98 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]oxetane-3-carboxamide   99 N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]thiazole-5-sulfonamide   100 N-[rac-(2R,3R)-2-(5-chlorothiophen-2-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]cyclopropanesulfonamide   101 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-b]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide   102 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-c]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide   103 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide   in each case in the form of the free compound or a physiologically acceptable salt thereof.   
     
     
         13 . A pharmaceutical dosage form comprising a compound according to  claim 1 . 
     
     
         14 . A method for treatment and/or prophylaxis of pain and/or inflammations in a subject, comprising a step of administering the subject a compound according to  claim 1 . 
     
     
         15 . The method according to  claim 14  for the treatment and/or prophylaxis of asthma, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia rheumatica, giant cell arteritis, Sjögren syndrome, Duchenne muscular dystrophy, vasculitis, Behçet's disease, ulcerative colitis and/or Crohn's disease.