Organic compounds

Abstract

The present disclosure relates to XIAP inhibitor compounds of the formula I.

1 . A compound of the formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H or C 1 -C 4  alkyl; 
         R 2  is H, or C 1 -C 4  alkyl which is unsubstituted or substituted by one or more substituents selected from halogen, —OH, —SH, —OCH 3 , —SCH 3 , —CN, —SCN and nitro; 
         R 3  is H, C 1 -C 4  alkyl, —CF 3 , —CH 2 —Z or R 2  and R 3  together form with the nitrogen form a C 3 -C 6  heteroaliphatic ring; 
         Z is H, —OH, F, Cl, —CH 3 ; —CF 3 , —CH 2 Cl, —CH 2 F or —CH 2 OH; 
         X is or a bicyclic structure selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where 
         A is —CH 2 , —CH—, N, O, or S; 
         X 1  is O, S, or NR a ; 
         R 4 , R a  and R b  are independently, H; C 1 -C 16  straight or branched alkyl; C 1 -C 16  alkenyl; C 1 -C 16  alkynyl; or C 1 -C 16  cycloalkyl; —(CH 2 ) 0-6 -phenyl; (CH 2 ) 0-6 -het; —O—C 1 -C 16  straight or branched alkyl, —S—C 1 -C 16  straight or branched alkyl; —N—C 1 -C 16  straight or branched alkyl; —O—C 1 -C 16  alkenyl; —S—C 1 -C 16  alkenyl; —N—C 1 -C 16  alkenyl —O—C 1 -C 16  cycloalkyl; —N—C 1 -C 16  cycloalkyl; —S—C 1 -C 16  cycloalkyl; —O—(CH 2 ) 0-6 -phenyl; —N—(CH 2 ) 0-6 -phenyl; —S—(CH 2 ) 0-6 -phenyl; —O—(CH 2 ) 0-6 -het; —N—(CH 2 ) 0-6 -het or —S—(CH 2 ) 0-6 -het wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R 4  and R a  may form a ring; 
         U is —R 5 ; —CH(R 5 )(R 6 ); —CO—N(R 5 )(R 6 ); —CO—O(R 5 ); —CO—S(R 5 ); —CS—N(R 5 )(R 6 ); —N(R 5 )—CO—N(R 5 )(R 6 ); —C 1 -C 5  alkyl-N(R 5 )(R 6 ); —C 1 -C 5 -alkyl-O(R 6 ) or —C 1 -C 5  alkyl-S(O) n (R 6 ) where n is 0, 1 or 2; 
         R 5  is H; C 1 -C 10  alkyl; C 3 -C 7  cycloalkyl; —(CH 2 ) 1-6 —C 3 -C 7  cycloalkyl; —C 1 -C 10  alkyl-aryl; —(CH 2 ) 0-6 -phenyl; —(CH 2 ) 0-6 —C 3 -C 7  cycloalkyl-(CH 2 ) 0-6 -phenyl; —(CH 2 ) 0-4 CH—((CH 2 ) 1-4 -phenyl) 2 ; —(CH 2 ) 0-6 —CH(phenyl) 2 , —C(O)—C 1 -C 10  alkyl; —C(O)—(CH 2 ) 1-6 —C 3 -C 7  cycloalkyl; —C(O)—(CH 2 ) 0-6 -phenyl; —(CH 2 ) 1-6 -het; —C(O)—(CH 2 ) 1-6 -het; —(CR 7 R 8 ) 0-2 -Aryl-V-Aryl; CHR 6 C(O)N(R 12 )(R 13 ); C(O)—NH—CH(R 11 )(R 14 ) or R 5  is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted; 
         or when U is —CO—N(R 5 )(R 6 ); —CS—N(R 5 )(R 6 ); —N(R 5 )—CO—N(R 5 )(R 6 ); or N(R 5 )—CO—N(R 5 )(R 6 ), R 5  and R 6  together with the N atom form an aromatic or aliphatic heterocycle; 
         R 7  and R 9  are independently H, halogen; C 1-7  alkyl; —OC 1-7  alkyl; C 1-7  cycloalkyl; or —OC 1-7  cycloalkyl wherein the alkyl, cycloalkyl substituents may be substituted or unsubstituted; 
         V is R 9 ; R 10 ; CR 9 R 10 ; —C(O)—; C(hal) 2 ; —O—; —N(H)—; N(alkyl); N(aryl); S; SO; or S(O) 2 ; 
         R 9  and R 10  are independently H, halogen, C 1-7  alkyl; —OC 1-7  alkyl; C 1-7  cycloalkyl; or —OC 1-7  cycloalkyl wherein the alkyl, cycloalkyl substituents may be substituted or unsubstituted; 
         R 6  is H; —C 1 -C 10  alkyl; —OH; —O—C 1 -C 10  alkyl; —(CH 2 ) 0-6 —C 3 -C 7  cycloalkyl; —O—(CH 2 ) 0-6 -aryl; —(CH 2 ) 0-6 -aryl; phenyl; —(CH 2 ) 1-6 -het; —O—(CH 2 ) 1-6 -het; —N(R 12 )(R 13 ); —CNOR 12 ; —S—R 12 ; —S(O)—R 12 ; —S(O) 2 —R 12 ; or —S(O) 2 —NR 12 R 13  wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted; 
         R 12  and R 13  are independently H; C 1 -C 10  alkyl; —(CH 2 ) 0-6 —C 3 -C 7  cycloalkyl; —(CH 2 ) 0-6 —(CH) 0.1 (aryl) 1-2 ; —C(O)—C 1 -C 10  alkyl; —C(O)—(CH 2 ) 1-6 —C 3 -C 7  cycloalkyl; —C(O)—O—(CH 2 ) 0-6 -aryl; —C(O)—(CH 2 ) 0-6 —O-fluorenyl; —C(O)—NH—(CH 2 ) 0-6 -aryl; —C(O)—(CH 2 ) 0-6 -aryl; or —C(O)—(CH 2 ) 1-6 -het, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted; or a substituent that facilitates transport of the molecule across a cell membrane, or R 12  and R 13  together with the nitrogen are het; 
         where R 11  and R 14  are C 1-7  alkyl; —(CH 2 ) 0-6 -phenyl; or amide; 
         aryl is phenyl, naphthyl, or indanyl which is unsubstituted or substituted; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of formula (II) according to  claim 1  wherein
 R 1  is H or C 1 -C 4  alkyl; 
 R 2  is H or C 1 -C 4  alkyl; 
 R 3  is H or C 1 -C 4  alkyl; 
 X is a bicyclic structure selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where 
         A is —CH 2 , —CH—, N, O, or S; 
         X 1  is O, S, or NR a ; 
         R 4 , R a  and R b  are independently, H; C 1 -C 16  straight or branched alkyl; or —(CH 2 ) 0-6 -phenyl wherein phenyl is unsubstituted with halo; 
         U is —R 5 ; —CH(R 5 )(R 6 ); C 1 -C 5  alkyl-N(R 5 )(R 6 ); or —CO—N(R 5 )(R 6 ); 
         R 5  is H; alkyl; —(CH 2 ) 0-6 -phenyl; —C(O)—C 1 -C 10 alkyl; —C(O)—(CH 2 ) 0-6 -phenyl; —(CR 7 R 8 ) 0-2 -Aryl-V-Aryl; CHR 6 C(O)N(R 12 )(R 13 ); or C(O)—NH—CH(R 11 )(R 14 ); 
         R 7  and R 8  are independently H, halogen; C 1-7  alkyl; —OC 1-7  alkyl; C 1-7  cycloalkyl; or —OC 1-7  cycloalkyl; 
         V is —C(O)—; C(hal) 2 ; —O—; —N(H)—; N(alkyl); N(aryl); S; SO; or S(O) 2 ; 
         R 9  and R 10  are independently H, halogen, C 1-7  alkyl; —OC 1-7  alkyl; C 1-7  cycloalkyl; or —OC 1-7  cycloalkyl; 
         R 6  is H; —C 1 -C 10  alkyl; —OH; —O—C 1 -C 10  alkyl; —(CH 2 ) 0-6 -phenyl; —(CH 2 ) 0-6 -aryl-; —O—(CH 2 ) 0-6 -aryl; phenyl; —(CH 2 ) 1-6 -het; —O—(CH 2 ) 1-6 -het; —N(R 12 )(R 13 ); —CNOR 12 ; —S—R 12 ; —S(O)—R 12 ; —S(O) 2 —R 12 ; or —S(O) 2 —NR 12 R 13 ; 
         R 12  and R 13  are independently H, or C 1 -C 10  alkyl; 
         where R 11  and R 14  are C 1-7  alkyl; —(CH 2 ) 0-6 -phenyl; or amide; 
         aryl is phenyl, naphthyl, or indanyl which is unsubstituted or substituted; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of formula (II) according to  claim 1  wherein
 R 1 , R 2  and R 3  are independently H or C 1 -C 4  alkyl; 
 X is a bicyclic structure selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where 
         A is —CH 2 , —CH—, N, O, or S; 
         X 1  is O, S, or NR a ; 
         R 4 , R a  and R b  are independently, H; C 1 -C 16  straight or branched alkyl; or —(CH 2 ) 0-6 -phenyl; 
         U is —R 5 ; —CO—N(R 5 )(R 6 ) or C 1 -C 5 alkyl-N(R 5 )(R 6 ); 
         R 5  is H; —(CH 2 ) 0-6 -phenyl; Aryl-V-Aryl; or C(O)—NH—CH(R 11 )(R 14 ) wherein aryl or phenyl may be substituted or unsubstituted; 
         V is —O—; 
         R 6  is H; —C 1 -C 10  alkyl; —OH; —O—C 1 -C 10  alkyl; —O—(CH 2 ) 0-6 -phenyl; —(CH 2 ) 0-6 -phenyl; indanyl or phenyl; 
         where R 11  and R 14  are C 1-7  alkyl; —(CH 2 ) 0-6 -phenyl; or amide; 
         aryl is phenyl, naphthyl, or indanyl which is unsubstituted or substituted; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 .- 5 . (canceled) 
     
     
         6 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (II) according to  claim 1 . 
     
     
         7 . A method of treating a proliferative disease which comprises administering a therapeutically effective amount of a compound of formula (II) according to  claim 1  to a mammal in need of such treatment. 
     
     
         8 . A method of  claim 7 , wherein the mammal is a human. 
     
     
         9 . A process to prepare compound of formula (II) according to  claim 1  comprising the steps of
 (a) coupling of an amine HXU with a t-Boc-L-amino acid or its derivative using a peptide coupling agent; and 
 (b) removing t-Boc with trifluoroacetic acid. 
 
     
     
         10 . The process according to  claim 9 , wherein the coupling agent is DCC/HOBt or HBTU/HOBt. 
     
     
         11 . A compound selected from the group consisting of
 (1S,9S)-9-((S)-2-Methylamino-butyrylamino)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (1S,9S)-9-((S)-2-Methylamino-propionylamino)-6,10-dioxo-octahydro-pyridazino[1,2][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (1S,9S)-9-((S)-2-Methylamino-propionylamino)-10-oxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (1S,8S)-8-((S)-2-Methylamino-propionylamino)-9-oxo-hexahydro-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (1S,8S)-8-((S)-2-Methylamino-butyrylamino)-5,9-dioxo-hexahydro-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (1S,8S)-8-((S)-2-Methylamino-propionylamino)-5,9-dioxo-hexahydro-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (1S,8S)-8-((S)-2-Methylamino-butyrylamino)-9-oxo-hexahydro-pyrazolo[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide;   (3S,6S,8aS)-6-((S)-2-Methylamino-propionylamino)-5-oxo-octahydro-indolizine-3-carboxylic acid phenethyl-amide;   (3R,6S,8aS)-6-((S)-2-Methylamino-propionylamino)-5-oxo-hexahydro-thiazolo[3,2-a]pyridine-3-carboxylic acid phenethyl-amide;   (6S,10aS)-6-((S)-2-Methylamino-propionylamino)-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid phenethyl-amide;   (Z)-(3S,6S,10aR)-6-((S)-2-Methylamino-propionylamino)-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid phenethyl-amide;   (S)-6-((S)-2-Methylamino-butyrylamino)-5-oxo-1,2,3,5-tetrahydro-indolizine-3-carboxylic acid phenethyl-amide;   (S)-6-((S)-2-Methylamino-propionylamino)-5-oxo-1,2,3,5-tetrahydro-indolizine-3-carboxylic acid phenethyl-amide;   (S)-6-((S)-2-Methylamino-propionylamino)-5-oxo-1,2,3,5-tetrahydro-indolizine-3-carboxylic acid (2-cyclohexyl-ethyl)-amide;   (S)-2-Amino-N-{1-[((S)-1-carbamoyl-2-phenyl-ethylcarbamoyl)-methyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl}-propionamide; and   (S)-2-Amino-N-{1-[((S)-1-carbamoyl-2-phenyl-ethylcarbamoyl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl}-propionamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . A compound selected from the group consisting of
 N-[(4S,7S)-4-(Indan-2-yloxymethyl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-propionamide;   N-((4S,7S)-6,10-Dioxo-4-phenethylsulfanylmethyl-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl)-2-methylamino-propionamide;   N-[(4S,7S)-6,10-Dioxo-4-(2-phenyl-ethanesulfinylmethyl)-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-propionamide;   N-[(4S,7S)-6,10-Dioxo-4-(2-phenyl-ethanesulfonylmethyl)-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-propionamide;   N-[(4S,7S)-6,10-Dioxo-4-(3-phenoxy-phenyl)-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-propionamide;   N-{(4S,7S)-4-[3-(4-Fluoro-phenoxy)-phenyl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-2-methylamino-propionamide;   N-[(4S,7S)-4-(3-Benzoyl-phenyl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-propionamide;   N-[(4S,7S)-4-(3-Benzoyl-phenyl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-butyramide;   N-[(4S,7S)-4-(Indan-2-yloxymethyl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-butyramide;   N-((4S,7S)-6,10-Dioxo-4-phenethylsulfanylmethyl-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl)-2-methylamino-butyramide;   N-[(4S,7S)-6,10-Dioxo-4-(2-phenyl-ethanesulfinylmethyl)-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-butyramide;   N-[(4S,7S)-6,10-Dioxo-4-(2-phenyl-ethanesulfonylmethyl)-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-butyramide;   N-[(4S,7S)-6,10-Dioxo-4-(3-phenoxy-phenyl)-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-2-methylamino-butyramide;   N-{(4S,7S)-4-[3-(4-Fluoro-phenoxy)-phenyl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-2-methylamino-butyramide;   N-[(3S,6S,10aS)-3-(Indan-2-yloxymethyl)-5-oxo-decahydro-pyrrolo[1,2-a]azocin-6-yl]-2-methylamino-propionamide;   2-Methylamino-N-((3S,6S,10aS)-5-oxo-3-phenethylsulfanylmethyl-decahydro-pyrrolo[1,2-a]azocin-6-yl)-propionamide;   2-Methylamino-N-[(3S,6S,10aS)-5-oxo-3-(2-phenyl-ethanesulfinylmethyl)-decahydro-pyrrolo[1,2-a]azocin-6-yl]-propionamide;   2-Methylamino-N-[(3S,6S,10aS)-5-oxo-3-(2-phenyl-ethanesulfonylmethyl)-decahydro-pyrrolo[1,2-a]azocin-6-yl]-propionamide;   2-Methylamino-N-[(3S,6S,10aS)-5-oxo-3-(3-phenoxy-phenyl)-decahydro-pyrrolo[1,2-a]azocin-6-yl]-propionamide;   N-{(3S,6S,10aS)-3-[3-(4-Fluoro-phenoxy)-phenyl]-5-oxo-decahydro-pyrrolo[1,2-a]azocin-6-yl}-2-methylamino-propionamide;   N-[(3S,6S,10aS)-3-(3-Benzoyl-phenyl)-5-oxo-decahydro-pyrrolo[1,2-a]azocin-6-yl]-2-methylamino-propionamide;   N-[(3S,6S,10aS)-3-(3-Benzoyl-phenyl)-5-oxo-decahydro-pyrrolo[1,2-a]azocin-6-yl]-2-methylamino-butyramide;   2-Methylamino-N-[(3S,6S,10aS)-5-oxo-3-(2-phenyl-ethanesulfonylmethyl)-decahydro-pyrrolo[1,2-a]azocin-6-yl]-butyramide;   2-Methylamino-N-((3S,6S,10aS)-5-oxo-3-phenethylsulfanylmethyl-decahydro-pyrrolo[1,2-a]azocin-6-yl)-butyramide   2-Methylamino-N-[(3S,6S,10aS)-5-oxo-3-(3-phenoxy-phenyl)-decahydro-pyrrolo[1,2-a]azocin-6-yl]-butyramide;   N-[(3S,6S,10aS)-3-(Indan-2-yloxymethyl)-5-oxo-decahydro-pyrrolo[1,2-a]azocin-6-yl]-2-methylamino-butyramide;   N-{(3S,6S,10aS)-3-[3-(4-Fluoro-phenoxy)-phenyl]-5-oxo-decahydro-pyrrolo[1,2-a]azocin-6-yl}-2-methylamino-butyramide;   N-[(3S,6S,9aS)-3-(Indan-2-yloxymethyl)-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl]-2-methylamino-propionamide;   2-Methylamino-N-[(3S,6S,9aS)-5-oxo-3-(2-phenyl-ethanesulfonylmethyl)-octahydro-pyrrolo[1,2-a]azepin-6-yl]-propionamide;   N-[(3S,6S,9aS)-3-(3-Benzoyl-phenyl)-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl]-2-methylamino-propionamide;   2-Methylamino-N-{(3S,6S,9aS)-5-oxo-3-[3-((Z)-propenyl)-4-vinyl-cyclopent-3-enyloxymethyl]-octahydro-pyrrolo[1,2-a]azepin-6-yl}-butyramide;   2-Methylamino-N-[(3S,6S,9aS)-5-oxo-3-(2-phenyl-ethanesulfonylmethyl)-octahydro-pyrrolo[1,2-a]azepin-6-yl]-butyramide;   2-Methylamino-N-((3S,6S,9aS)-5-oxo-3-phenethylsulfanylmethyl-octahydro-pyrrolo[1,2-a]azepin-6-yl)-propionamide;   2-Methylamino-N-[(3S,6S,9aS)-5-oxo-3-(3-phenoxy-phenyl)-octahydro-pyrrolo[1,2-a]azepin-6-yl]-propionamide;   N-[(3S,6S,9aS)-3-(3-Benzoyl-phenyl)-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl]-2-methylamino-butyramide;   2-Methylamino-N-((3S,6S,9aS)-5-oxo-3-henethylsulfanylmethyl-octahydro-pyrrolo[1,2-a]azepin-6-yl)-butyramide;   2-Methylamino-N-[(3S,6S,9aS)-5-oxo-3-(3-phenoxy-phenyl)-octahydro-pyrrolo[1,2-a]azepin-6-yl]-butyramide;   2-Methylamino-N-[(3S,6S,9aS)-5-oxo-3-(2-phenyl-ethanesulfinylmethyl)-octahydro-pyrrolo[1,2-a]azepin-6-yl]-propionamide;   N-{(3S,6S,9aS)-3-[3-(4-Fluoro-phenoxy)-phenyl]-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl}-2-methylamino-propionamide;   2-Methylamino-N-[(3S,6S,9aS)-5-oxo-3-(2-phenyl-ethanesulfinylmethyl)-octahydro-pyrrolo[1,2-a]azepin-6-yl]-butyramide;   N-{(3S,6S,9aS)-3-[3-(4-Fluoro-phenoxy)-phenyl]-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl}-2-methylamino-butyramide;   N-[(3S,6S,8aS)-3-(Indan-2-yloxymethyl)-5-oxo-octahydro-indolizin-6-yl]-2-methylamino-propionamide;   2-Methylamino-N-[(3S,6S,8aS)-5-oxo-3-(2-phenyl-ethanesulfonylmethyl)-octahydro-indolizin-6-yl]-propionamide;   2-Methylamino-N-((3S,6S,8aS)-5-oxo-3-phenethylsulfanylmethyl-octahydro-indolizin-6-yl)-propionamide;   2-Methylamino-N-[(3S,6S,8aS)-5-oxo-3-(2-phenyl-ethanesulfinylmethyl)-octahydro-indolizin-6-yl]-propionamide;   2-Methylamino-N-[(3S,6S,8aS)-5-oxo-3-(3-phenoxy-phenyl)-octahydro-indolizin-6-yl]-propionamide;   N-{(3S,6S,8aS)-3-[3-(4-Fluoro-phenoxy)-phenyl]-5-oxo-octahydro-indolizin-6-yl}-2-methylamino-propionamide;   N-[(3S,6S,8aS)-3-(3-Benzoyl-phenyl)-5-oxo-octahydro-indolizin-6-yl]-2-methylamino-propionamide;   N-[(3S,6S,8aS)-3-(3-Benzoyl-phenyl)-5-oxo-octahydro-indolizin-6-yl]-2-methylamino-butyramide;   N-[(3S,6S,8aS)-3-(Indan-2-yloxymethyl)-5-oxo-octahydro-indolizin-6-yl]-2-methylamino-butyramide;   2-Methylamino-N-((3S,6S,8aS)-5-oxo-3-phenethylsulfanylmethyl-octahydro-indolizin-6-yl)-butyramide;   2-Methylamino-N-[(3S,6S,8aS)-5-oxo-3-(2-phenyl-ethanesulfinylmethyl)-octahydro-indolizin-6-yl]-butyramide;   2-Methylamino-N-[(3S,6S,8aS)-5-oxo-3-(2-phenyl-ethanesulfonylmethyl)-octahydro-indolizin-6-yl]-butyramide;   2-Methylamino-N-[(3S,6S,8aS)-5-oxo-3-(3-phenoxy-phenyl)-octahydro-indolizin-6-yl]-butyramide; and   N-{(3S,6S,8aS)-3-[3-(4-Fluoro-phenoxy)-phenyl]-5-oxo-octahydro-indolizin-6-yl}-2-methylamino-butyramide;   or a pharmaceutically acceptable salt thereof.