Ghrelin receptor agonist for treatment of cachexia

Abstract

The present invention relates to use of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or the salt, for the manufacture of a medicament for the treatment of cachexia. The invention also relates to a method for the treatment of cachexia, comprising administering the compound of the present invention or a pharmaceutical composition comprising the same to a human or an animal. The invention further relates to use of said compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or the salt, in combination with one or more second active agents. Moreover, the invention relates to a pharmaceutical composition and a kit comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, for the treatment of said disease.

1 . A method for the treatment of cachexia, which comprises administering to a human or an animal an effective amount of one or more selected from the group consisting of a compound of the formula (I), a racemic-diastereomeric mixture and an optical isomer of said compound, and a pharmaceutically acceptable salt and a prodrug thereof 
       
         
           
           
               
               
           
         
         wherein 
         e is 0 or 1; 
         n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time; 
         Y is oxygen or sulfur; 
         R 1  is hydrogen, —CN, —(CH 2 ) q N(X 6 )C(O)X 6 , —(CH 2 ) q N(X 6 )C(O)(CH 2 ) t -A 1 , —(CH 2 ) q N(X 6 )SO 2 (CH 2 ) t -A 1 , —(CH 2 ) q N(X 6 )SO 2 X 6 , —(CH 2 ) q N(X 6 )C(O)N(X 6 )(CH 2 ) t -A 1 , —(CH 2 ) q N(X 6 )C(O)N(X 6 )(X 6 ), —(CH 2 ) q C(O)N(X 6 )(X 6 ), —(CH 2 ) q C(O)N(X 6 )(CH 2 ) t -A 1 , —(CH 2 ) q C(O)OX 6 , —(CH 2 ) q C(O)O(CH 2 ) t -A 1 , —(CH 2 ) q OX 6 , —(CH 2 ) q OC(O)X 6 , —(CH 2 ) q OC(O)(CH 2 ) t -A 1 , —(CH 2 ) q OC(O)N(X 6 )(CH 2 ) t -A 1 , —(CH 2 ) q OC(O)N(X 6 )(X 6 ), —(CH 2 ) q C(O)X 6 , —(CH 2 ) q C(O)(CH 2 ) t -A 1 , —(CH 2 ) q N(X 6 )C(O)OX 6 , —(CH 2 ) q N(X 6 )SO 2 N(X 6 )(X 6 ), —(CH 2 ) q S(O) m X 6 , —(CH 2 ) q S(O) m (CH 2 ) t -A 1 , —(C 1 -C 10 )alkyl, —(CH 2 ) t -A 1 , —(CH 2 ) q —(C 3 -C 7 )cycloalkyl, —(CH 2 ) q —Y 1 —(C 1 -C 6 )alkyl, —(CH 2 ) q —Y 1 —(CH 2 ) t -A 1  or —(CH 2 ) q —Y 1 —(CH 2 ) t —(C 3 -C 7 )cycloalkyl 
         (where the alkyl and cycloalkyl groups in the definition of R 1  are optionally substituted with (C 1 -C 4 )alkyl, hydroxyl, (C 1 -C 4 )alkoxy, carboxyl, —CONH 2 , —S(O) m (C 1 -C 6 )alkyl, —CO 2 (C 1 -C 4 )alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; 
         Y 1  is O, S(O) m , —C(O)NX 6 —, —CH═CH—, —C≡C—, —N(X 6 )C(O)—, —C(O)NX 6 —, —C(O)O—, —OC(O)N(X 6 )— or —OC(O)—; 
         q is 0, 1, 2, 3 or 4; 
         t is 0, 1, 2 or 3; 
         said (CH 2 ) q  group and (CH 2 ) t  group may each be optionally substituted with hydroxyl, (C 1 -C 4 )alkoxy, carboxyl, —CONH 2 , —S(O) m (C 1 -C 6 )alkyl, —CO 2 (C 1 -C 4 )alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C 1 -C 4 )alkyl); 
         R 2  is hydrogen, (C 1 -C 8 )alkyl, —(C 0 -C 3 )alkyl-(C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkyl-A 1  or A 1  (where the alkyl groups and cycloalkyl groups in the definition of R 2  are optionally substituted with hydroxyl, —C(O)OX 6 , —C(O)N(X 6 )(X 6 ), —N(X 6 )(X 6 ), —S(O) m (C 1 -C 6 )alkyl, —C(O)A 1 , —C(O)(X 6 ), CF 3 , CN or 1, 2 or 3 halogen); 
         R 3  is A 1 , (C 1 -C 10 )alkyl, —(C 1 -C 6 )alkyl-A 1 , —(C 1 -C 6 )alkyl-(C 3 -C 7 )cycloalkyl, —(C 1 -C 5 )alkyl-X 1 —(C 1 -C 5 )alkyl, —(C 1 -C 5 )alkyl-X 1 —(C 0 -C 5 )alkyl-A 1  or —(C 1 -C 5 )alkyl-X 1 —(C 1 -C 5 )alkyl-(C 3 -C 7 )cycloalkyl 
         (where the alkyl groups in the definition of R 3  are optionally substituted with —S(O) m (C 1 -C 6 )alkyl, —C(O)OX 3 , 1, 2, 3, 4 or 5 halogen, or 1, 2 or 3 OX 3 ; 
         X 1  is O, S(O) m , —N(X 2 )C(O)—, —C(O)N(X 2 )—, —OC(O)—, —C(O)O—, —CX 2 ═CX 2 —, —N(X 2 )C(O)O—, —OC(O)N(X 2 )— or —C≡C—); 
         R 4  is hydrogen, (C 1 -C 6 )alkyl or (C 3 -C 7 )cycloalkyl, or R 4  is taken together with R 3  and the carbon atom to which they are attached and form (C 5 -C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; 
         X 4  is hydrogen or (C 1 -C 6 )alkyl or X 4  is taken together with R 4  and the nitrogen atom to which X 4  is attached and the carbon atom to which R 4  is attached and form a five to seven membered ring; 
         R 6  is a bond or is 
       
       
         
           
           
               
               
           
         
         (where a and b are independently 0, 1, 2 or 3; 
         X 5  and X 5a  are each independently selected from the group consisting of hydrogen, trifluoromethyl, A 1  and optionally substituted (C 1 -C 6 )alkyl; 
         the optionally substituted (C 1 -C 6 )alkyl in the definition of X 5  and X 5a  is optionally substituted with a substituent selected from the group consisting of A 1 , OX 2 , —S(O) m (C 1 -C 6 )alkyl, —C(O)OX 2 , (C 3 -C 7 )cycloalkyl, —N(X 2 )(X 2 ) and —C(O)N(X 2 )(X 2 ); 
         or the carbon bearing X 5  or X 5a  forms one or two alkylene bridges with the nitrogen atom bearing R 7  and R 8  wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X 5  or X 5a  but not both may be on the carbon atom and R 7  or R 8  but not both may be on the nitrogen atom and further provided that when two alkylene bridges are formed then X 5  and X 5a  cannot be on the carbon atom and R 7  and R 8  cannot be on the nitrogen atom; 
         or X 5  is taken together with X 5a  and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, 
         or X 5  is taken together with X 5a  and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; 
         Z 1  is a bond, O or N—X 2 , provided that when a and b are both 0 then Z 1  is not N—X 2  or O); 
         R 7  and R 8  are independently hydrogen or optionally substituted (C 1 -C 6 )alkyl (where the optionally substituted (C 1 -C 6 )alkyl in the definition of R 7  and R 8  is optionally independently substituted with A 1 , —C(O)O—(C 1 -C 6 )alkyl, —S(O) m (C 1 -C 6 )alkyl, 1 to 5 halogen, 1 to 3 hydroxy, 1 to 3 —O—C(O)(C 1 -C 10 )alkyl or 1 to 3 (C 1 -C 6 )alkoxy); or 
         R 7  and R 8  can be taken together to form —(CH 2 ) r -L-(CH 2 ) r —; where L is C(X 2 )(X 2 ), S(O) m  or N(X 2 ); 
         A 1  for each occurrence is independently (C 5 -C 7 )cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; 
         A 1  for each occurrence is independently optionally substituted, in one or optionally both rings if A 1  is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF 3 , OCF 2 H, CF 3 , CH 3 , OCH 3 , —OX 6 , —C(O)N(X 6 )(X 6 ), —C(O)OX 6 , oxo, (C 1 -C 6 )alkyl, nitro, cyano, benzyl, —S(O) m (C 1 -C 6 )alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, —N(X 6 )(X 6 ), —N(X 6 )C(O)(X 6 ), —SO 2 N(X 6 )(X 6 ), —N(X 6 )SO 2 -phenyl, —N(X 6 )SO 2 X 6 , —CONX 11 X 12 , —SO 2 NX 11 X 12 , —NX 6 SO 2 X 12 , —NX 6 CONX 11 X 12 , —NX 6 SO 2 NX 11 X 12 , —NX 6 C(O)X 12 , imidazolyl, thiazolyl and tetrazolyl, provided that if A 1  is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy 
         (where X 11  is hydrogen or optionally substituted (C 1 -C 6 )alkyl; 
         the optionally substituted (C 1 -C 6 )alkyl defined for X 11  is optionally independently substituted with phenyl, phenoxy, (C 1 -C 6 )alkoxycarbonyl, —S(O) m (C 1 -C 6 )alkyl, 1 to 5 halogen, 1 to 3 hydroxy, 1 to 3 (C 1 -C 10 )alkanoyloxy or 1 to 3 (C 1 -C 6 )alkoxy; 
         X 12  is hydrogen, (C 1 -C 6 )alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X 12  is not hydrogen, X 12  is optionally substituted with one to three substituents independently selected from the group consisting of C 1 , F, CH 3 , OCH 3 , OCF 3  and CF 3 ; 
         or X 11  and X 12  are taken together to form —(CH 2 ) r -L 1 -(CH 2 ) r —; 
         where L 1  is C(X 2 )(X 2 ), O, S(O) m  or N(X 2 )); 
         r for each occurrence is independently 1, 2 or 3; 
         X 2  for each occurrence is independently hydrogen, optionally substituted (C 1 -C 6 )alkyl, or optionally substituted (C 3 -C 7 )cycloalkyl, where the optionally substituted (C 1 -C 6 )alkyl and optionally substituted (C 3 -C 7 )cycloalkyl in the definition of X 2  are optionally independently substituted with —S(O) m (C 1 -C 6 )alkyl, —C(O)OX 3 , 1 to 5 halogen or 1 to 3 OX 3 ; 
         X 3  for each occurrence is independently hydrogen or (C 1 -C 6 )alkyl; 
         X 6  is independently hydrogen, optionally substituted (C 1 -C 6 )alkyl, (C 2 -C 6 )halogenated alkyl, optionally substituted (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )-halogenated cycloalkyl, where optionally substituted (C 1 -C 6 )alkyl and optionally substituted (C 3 -C 7 )cycloalkyl in the definition of X 6  is optionally independently substituted with 1 or 2 (C 1 -C 4 )alkyl, hydroxyl, (C 1 -C 4 )alkoxy, carboxyl, CONH 2 , —S(O) m (C 1 -C 6 )alkyl, carboxylate, (C 1 -C 4 )alkyl ester, or 1H-tetrazol-5-yl; or 
         when there are two X 6  groups on one atom and both X 6  are independently (C 1 -C 6 )alkyl, the two (C 1 -C 6 )alkyl groups may be optionally joined and, together with the atom to which the two X 6  groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX 7 ; 
         X 7  is hydrogen or (C 1 -C 6 )alkyl optionally substituted with hydroxyl; and 
         m for each occurrence is independently 0, 1 or 2; 
         with the proviso that: 
         X 6  and X 12  cannot be hydrogen when it is attached to C(O) or SO 2  in the form C(O)X 6 , C(O)X 12 , SO 2 X 6  or SO 2 X 12 ; and 
         when R 6  is a bond then L is N(X 2 ) and each r in the definition —(CH 2 ) r -L-(CH 2 ) r — is independently 2 or 3. 
       
     
     
         2 . A method for the treatment of cachexia, which comprises administering to a human or an animal an effective amount of one or more selected from the group consisting of a compound of the formula (II), a racemic-diastereomeric mixture and an optical isomer of said compound, and a pharmaceutically acceptable salt and a prodrug thereof 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —(C 1 -C 3 )alkyl-phenyl, —(C 1 -C 3 )alkyl-pyridyl —(C 1 -C 3 )alkyl-quinolinyl or —(C 1 -C 3 )alkyl-thiazolyl, where the phenyl in R 1  is optionally substituted with one or two substituents selected from the group consisting of halo, CF 3 , CH 3  and phenyl; 
         R 2  is —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-CF 3 ; 
         R 3  is —(C 1 -C 4 )alkylindolyl, —(C 1 -C 4 )alkylphenyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl-Ar, —(C 1 -C 4 )alkyl-S—(C 1 -C 4 )alkyl-Ar, where Ar is phenyl, thienyl, thiazolyl, pyridyl, pyrimidinyl or benzisoxazolyl, said Ar is optionally substituted with one or two substituents selected from the group consisting of halo, OCF 3 , CF 3  and CH 3 ; and 
         R 6  is —C(X 5 )(X 5 ), where X 5  is —(C 1 -C 6 )alkyl. 
       
     
     
         3 . The method according to  claim 1 , wherein the compound is selected from the group consisting of the following compounds:
 2-amino-N-(1-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl(R)-butyl]-isobutyramide;   2-amino-N-[1-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl(R)-butyl]-isobutyramide;   2-amino-N-[1-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl(R)-butyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[1-(R)-benzyloxymethyl-2-(3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[1-(R)-benzyloxymethyl-2-(3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[1-(R)-benzyloxymethyl-2-(3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R,S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[2-(3a-(S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide;   2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(3-chloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(3-chloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyri din-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(3-chloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(4-chloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(4-chloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyri din-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(4-chloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(2,4-dichloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(2,4-dichloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(2,4-dichloro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(4-chloro-thiophen-2-ylmethoxymethyl)-2-oxo-2-(3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,5,7-hexahydro-pyrazolo[3,4-c]pyridin-6-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(4-chloro-thiophen-2-ylmethoxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,5,7-hexahydro-pyrazolo[3,4-c]pyridin-6-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(4-chloro-thiophen-2-ylmethoxymethyl)-2-oxo-2-(3-oxo-3a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,5,7-hexahydro-pyrazolo[3,4-c]pyridin-6-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R,S)-pyri din-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(3,4-difluoro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide;   2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(3,4-difluoro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide; and   2-amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(3,4-difluoro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide.   
     
     
         4 . The method according to  claim 1 , wherein the compound is selected from the group consisting of the following compounds:
 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide; and   2-amino-N-[1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide;   or is a pharmaceutically acceptable salt thereof.   
     
     
         5 . The method according to  claim 1 , wherein the cachexia is cancer cachexia, tuberculous cachexia, diabetic cachexia, hemodyscrasia-associated related cachexia, endocrine disease-associated cachexia, chronic obstructive pulmonary disease-associated cachexia, chronic kidney disease-associated cachexia, cardiac failure-associated cachexia, infectious disease-associated cachexia, or acquired immunodeficiency syndrome-associated cachexia. 
     
     
         6 . The method according to  claim 1 , wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with one or more second active agents. 
     
     
         7 . The method according to  claim 6 , wherein the second active agents are any of a chemotherapeutic agent, an immunotherapeutic agent, a drug which is documented as having an ameliorating effect on cachexia in an animal model or clinical practice, and a diuretic agent. 
     
     
         8 . (canceled) 
     
     
         9 . A pharmaceutical composition for the treatment of cachexia, comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A kit for the treatment of cachexia, comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The kit according to  claim 10 , which further comprises one or more kinds of second active agents and a container. 
     
     
         12 . A commercial package comprising a pharmaceutical composition containing a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a written matter associated with said pharmaceutical composition, the written matter stating that said pharmaceutical composition can or should be used for treating cachexia.