Dipeptide derivatives as growth hormone secretagogues

Abstract

This invention is directed to compounds of the formula and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis and/or frailty, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis and/or frailty when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of Formula I.

What is claimed is:  
     
       1. A compound of the formula:                    
       or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein 
       HET is a heterocyclic moiety of the formula                    
       Q is a covalent bond;  
       X is C═O or CH 2 ;  
       Y is CH 2 , O or NR 2 ;  
       Z is C═O;  
       R 1  is —(C 1 -C 10 )alkyl, —(CH 2 ) t —A 3 , or —(CH 2 ) q —(C 3 -C 7 ) cycloalkyl;  
       where A 1  is the definition of R 1  is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH 3 , OCH 3 , OCF 2 H, OCF 3  and CF 3 ; and  
       where the alkyl and cycloalkyl groups in the definition of R 1  are optionally subsituted with (C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, or 1, 2 or 3 fluoro groups;  
       q is 1 or 2;  
       t is 1 or 2;  
       said (CH 2 ) q  group and (CH 2 ) t  group in the definition of R 1  are optionally independently subsituted with hydroxy, (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 groups or 1 or 2 (C 1 -C 4 )alkyl groups;  
       R 2  is hydrogen, (C 1 -C 5 )alkyl or —(C 0 -C 2 )alkyl-(C 3 -C 8 )cycloalkyl;  
       where the alkyl groups and the cycloalkyl groups in the definition of R 2  are optionally substituted with 1, 2 or 3 fluoro groups;  
       R 3  is phenyl-CH 2 —O—CH 2 —, phenyl-CH 2 —S—CH 2 —, pyridyl-CH 2 —O—CH 2 —, thienyl-CH 2 —O—CH 2 —, thiazolyl-CH 2 —O—CH 2 —, phenyl-(CH 2 ) 3 — or 3-indolyl-CH 2 —; where the carbon atom bearing the substituent R 3  is of the (R)-configuration; where the aryl portion of the groups defined for R 3  is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH 3 , OCH 3 , OCF 2 H, OCF 3  and CF 3 ;  
       R 4  is hydrogen;  
       X 4  is hydrogen  
       R 6  is                    
       where a and b are each 0;  
       X 5  and X 5a  are each methyl  
       Z 1  is a bond;  
       R 7  and R 8  are each methyl.  
     
     
       2. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture of isomer thereof, or a pharmaceutically acceptable salt of the compound mixture, isomer or prodrug according to  claim 1  wherein # 
       Z is S(O) 2 ; Q is a covalent bond; X is CH 2 ; and  
       Y is CH 2  or NR 2 ; 
       R 2  is hydrogen, (C 1 -C 5 )alkyl or —(C 0 -C 2 )alkyl-(C 3 -C 8 )cycloalkyl;  
       where the alkyl and cycloalkyl groups in the definition of R 2  is optionally substituted with 1, 2 or 3 fluoro groups .  
     
     
       3. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 2  wherein Y is CH 2 . 
     
     
       4. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 3  wherein 
       R 1  is —CH 2 —A 1  is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH 3 , OCH 3 , OCF 2 H, OCF 3  and CF 3 ; and  
       R 3  is selected from the group consisting of 3-indolyl-CH 2 —, phenyl-(CH 2 ) 3 —, phenyl-CH 2 —O—CH 2 — and thiazolyl-CH 2 —O—CH 2 —, where the aryl portion of the groups defined for R 3  is optionally substituted with one to three substituents, each substituent being independently selected from the group consistion of methylenedioxy, F, Cl, CH 3 , OCH 3 , OCF 3 , OCF 2 H and CF 3 .  
     
     
       5. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 4  where the compound is the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer or the 3a(S),1(R) diastereomer of 2-amino-N-[2-(3a-benzyl-1,1-dioxo-hexahydro-1-thia-5,7a-diaza-inden-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide. 
     
     
       6. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiometrically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1  wherein 
       Z is C═O; Q is a covalent bond; X is CH 2 ; and Y is NR 2 ;  
       R 2  is hydrogen, (C 1 -C 5 )alkyl or —(C 0 -C 2 )alkyl-(C 3 -C 8 )cycloalkyl;  
       where the alkyl and cycloalkyl groups in the definition of R 2  are optionally substituted with 1, 2, or 3 fluoro groups .  
     
     
       7. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 6  wherein 
       R 1  is —CH 2 —A 1  phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH 3 , OCH 3 , OCF 2 H, OCF 3  and CF 3 ;  
       R 2  is hydrogen or (C 1 -C 3 )alkyl optional substituted with 1-3 fluoro groups; and  
       R 3  is selected from the group consisting of 3-indolyl-CH 2 —, phenyl-(CH 2 ) 3 —, phenyl-CH 2 —O—CH 2 — and thiazolyl-CH 2 —O—CH 2 —, where the aryl portion of the groups defined for R 3  is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH 3 , OCH 3 , OCF 3 , OCF 2 H and CF 3 .  
     
     
       8. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 7  where the compound is the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R) diasteromer of the 8a(S),1(R) diastereomer of 2-amino-N-[2-(8a-benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide. 
     
     
       9. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound mixture, isomer or prodrug according to  claim 1  wherein 
       Z is C═O; Q is a covalent bond; X is CH 2 ; and Y is O.  
     
     
       10. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 9  wherein 
       R 1  is —CH 2 —A 1  is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH 3 , OCH 3  OCF 2 H, OCF 3  and CF 3 ; and  
       R 3  is selected from the group of 3-indolyl-CH 2 —, phenyl-(CH 2 ) 3 —, phenyl-CH 2 —O—CH 2 — and thiazolyl-CH 2 —O—CH 2 —, where the aryl portion of the groups defined for R 3  is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH 3 , OCH 3 , OCF 3 , OCF 2 H and CF 3 .  
     
     
       11. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 10  where the compound is the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R) diastereomer or the 8a(S),1(R) diastereomer of the compound selected from the group consisting of 
       2-amino-N-[2-(8a-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,  
       2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-thiazol-4-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide and  
       2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-3-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide.  
     
     
       12. A compound according to  claim 1  wherein 
       Z is C═O or S(O) 2 ; Q is a covalent bond; X is C═O; and Y is NR 2 ;  
       R 2  is hydrogen, (C 1 -C 5 )alkyl or —(C 0 -C 2 )alkyl-(C 3 -C 8 )cycloalkyl;  
       where the alkyl and cycloalkyl groups in the definition of R 2  are optionally substituted with 1, 2 or 3 fluoro groups .  
     
     
       13. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 12  wherein 
       Z is C═O; R 1  is —CH 2 —A 1 , where A 1  in the definition of R 1  is phenyl or pyridyl where said phenyl or pyridyl is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH 3 , OCH 3 , OCF 2 H, OCF 3  and CF 3 ; and  
       R 3  is phenyl-CH 2 —O—CH 2 —, pyridyl-CH 2 —O—CH 2 —, phenyl-(CH 2 ) 3 —, 3-indolyl-CH 2 — or thiazolyl-CH 2 —O—CH 2 —, where the aryl portion of the groups defined for R 3  is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH 3 , OCH 3 , OCF 3 , OCF 2 H and CF 3 .  
     
     
       14. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 13  wherein 
       R 2  is hydrogen or (C 1 -C 3 )alkyl where the alkyl group is optionally substituted with 1-3 fluoro groups.  
     
     
       15. A compound of a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture of isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 14  wherein 
       R 3  is phenyl-CH 2 —O—CH 2 — or phenyl-(CH 2 ) 3 —, where the phenyl in the definition of R 3  is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH 3 , OCH 3 , OCF 3 , OCF 2 H and CF 3 .  
     
     
       16. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 15  wherein 
       R 1  is —CH 2 —A 1  where A 1  is phenyl, 2-pyridyl, 3-pyridyl, optionally substituted with 1-3 fluoro groups or 1-3 Chloro chloro groups;  
       R 2  is methyl or ethyl where the ethyl group is optionally substituted with 1-3 fluoro groups; and  
       R 3  is phenyl-CH 2 —O—CH 2 —, where the phenyl is optionally substituted with 1-3 fluoro groups, 1-3 Chloro chloro groups or 1-2 CF 3  groups.  
     
     
       17. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 16  where the compound is the 1(R),8a(R,S) diastereomeric mixture, the 1(R),8a(R) diasteromer or the 1(R),8a(S) diastereomer of 2-amino-N-{1-(2, 4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-pyridin-3-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       18. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 16  wherein 
       R 1  is —CH 2 —A 1  where A 1  is phenyl optionally substituted with 1-2 chloro groups of 1-2 fluoro groups; and  
       R 2  is methyl or —CH 2 CF 3 ; and  
       R 3  is phenyl-CH 2 —O—CH 2 —, optionally substituted with 1-3 fluoro groups, 1-3 chloro groups or 1-2 CF 3  groups .  
     
     
       19. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 18  where the compound is selected from the group consisting of 
       2-amino-N-[2-(8a-(R,S)-benzyl-2-methyl-1,3-dioxohexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,  
       2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(R,S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide and  
       2-amino-N-{2-[8a-(R,S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide.  
     
     
       20. The compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 19  where the compound is 2-amino-N-[2-(8a-(R)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide. 
     
     
       21. The compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug drug according to  claim 19  where the compound is 2-amino-N-[2-(8a-(s)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide. 
     
     
       22. The compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 19  where the compound is 2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(R)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       23. The compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 19  where the compound is 2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       24. The compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 19  where the compound is 2-amino-N-{2-[8a-(R)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       25. The compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 19  where the compound is 2-amino-N-{2-[8a-(S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       26. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound mixture, isomer or prodrug according to  claim 16  wherein 
       R 1  is —CH 2 —A 1  where A 1  is 2-pyridyl optionally substituted with 1-2 chloro groups; and  
       R 2  is methyl or —CH 2 CF 3 ; and  
       R 3  is phenyl-CH 2 —O—CH 2 —, optionally substituted with 1-3 fluoro groups, 1-3 chloro groups or 1-2 CF 3  groups .  
     
     
       27. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 26  where the compound is 
       2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,  
       2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,  
       2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1, 3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,  
       2-amino-N-[2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide or  
       2-amino-N-{1-(R)-(4-chloro-benzyloxymethy)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2oxo-ethyl}-2-methyl-propionamide.  
     
     
       28. A compound of a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug drug according to  claim 27  where the compound is 2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide. 
     
     
       29. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 27  where the compound is 2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide. 
     
     
       30. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 27  where the compound is 2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       31. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 27  where the compound is 2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahdyro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       32. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 27  where the compound is 2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       33. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 27  where the compound is 2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       34. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 27  where the compound is 2-amino-N-[2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide. 
     
     
       35. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 27  where the compound is 2-amino-N-[2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide. 
     
     
       36. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 27  where the computer is 2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       37. A compound or a prodrug of such compound or a pharmaceutically acceptable salt of the compound or a prodrug according to  claim 27  where the compound is 2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       38. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1  wherein Z is C═O; Q is a covalent bond; X is C═O; and Y is CH 2 . 
     
     
       39. A compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 38  wherein 
       R 1  is —CH 2 —A 1  where A 1  is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH 3 , OCF 2 H, OCF 3  and CF 3 ; and  
       R 3  is selected from the group consisting of 3-indolyl-CH 2 —, phenyl-(CH 2 ) 3 —, phenyl-CH 2 —O—CH 2 — and thiazolyl-CH 2 —O—CH 2 —, where the aryl portion of the groups defined for R 3  is optionally substituted with one to three substituents, each being independently selected from the group consisting of methylenedioxy, F, Cl, CH 3 , OCH 3 , OCF 3 , OCF 2 H and CF 3 .  
     
     
       40. A compound of a prodrug of such compound or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 39  where the compound is the 1(R), 8a(R,S) diastereomeric mixture, the 1(R),8a(R) diastereomer or the 1(R), 8a(S) diastereomer of 2-amino-N-{1-benzyloxymethyl-2-[8a-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo [1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide. 
     
     
       41. The L-tartrate salt of the compound of  claim 31 . 
     
     
       42. The pharmaceutical composition useful for treating osteoporosis and/or frailty which comprises a pharmaceutically acceptable carrier, an amount of calcitonin and an amount of a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1 . 
     
     
       43. A pharmaceutical composition useful for treating osteoporosis and/or frailty which comprises a pharmaceutically acceptable carrier, an amount of a bisphosphonate compound and an amount of a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1 . 
     
     
       44. A pharmaceutical composition useful for treating osteoporosis and/or frailly which comprises a pharmaceutically acceptable carrier, an amount of estrogen or Premarin®, an amount of a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1  and, optionally, an amount of progesterone. 
     
     
       45. A method for treating osteoporosis and/or frailty which comprises administering to a human or other animal in need of such treatment an amount of a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1  which is effective in treating osteoporosis and/or frailty. 
     
     
       46. A method for treatment of osteoporosis and/or frailty which comprises administering to a human or other animal with osteoporosis and/or frailty effective amounts of a bisphosphonate compound and a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound mixture, isomer or prodrug according to  claim 1 . 
     
     
       47. A method for the treatment of osteoporosis and/or frailty according to  claim 46  wherein the bisphosphonate compound is alendronate. 
     
     
       48. A method for the treatment of osteoporosis and/or frailty according to  claim 46  wherein the bisphosphonate compound is ibandronate. 
     
     
       49. A method for the treatment of osteoporosis and/or frailty which comprises administering to a human or other animal with osteoporosis and/or frailty effective amounts of estrogen or Premarin® and a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug according to  claim 1  and, optionally progesterone. 
     
     
       50. A method for the treatment of osteoporosis and/or frailty which comprises administering to a human or other animal with osteoporosis and/or frailty effective amounts of calcitonin and a compound or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound mixture, isomer or prodrug according to  claim 1 .