MXPA99012085A - Treatment of insulin resistance with growth hormone secretagogues - Google Patents

Abstract

Estáinvención se refiere a procedimientos para el tratamiento de la resistencia a la insulina en un mamífero que comprende la administración de una cantidad eficaz de un compuesto de fórmula I (Ver Fórmula) donde las variables están definidas en la memoria descriptiva, o las mezclas estereoisómericas, los isómeros diastereoméricamente enriquecidos, diastereoméricamente puros, enantioméricamente enriquecidos enantioméricamente puros o las sales farmacéuticamente aceptables y profármacos de los mismos a dicho mamífero;dos compuestos de fórmula I son secretagogos de la hormona del crecimiento y como tales sonétiles para aumentar los niveles de la hormona del crecimiento endógena;en otro aspecto estáinvención proporciona determinados compuestos intermedios que sonútiles par la síntesis de los anteriores compuestos y determinados procedimientosútiles para la síntesis de dichos productos intermedios y los compuestos de fórmula 1;estáinvención se refiere asimismo a procedimientos que comprenden la administración a un ser humano o a otro animal de una combinación de un antagonista funcional de la somatostatina, corno un agonista alfa-2 adrenérgico y un compuesto de fórmula 1.

Description

TREATMENT OF INSULIN RESISTANCE BACKGROUND OF THE INVENTION Growth hormone (HC), which is secreted by the pituitary gland, stimulates the growth of all body tissues able to grow. In addition, it is known that growth hormone has the following basic effects on the metabolic processes of the body: 1. It increases the speed of protein synthesis in virtually all cells of the body. 2. It decreases the speed of the use of carbohydrates in the cells of the body; and 3. Increases the mobilization of free fatty acids and the use of fatty acids to produce energy. Growth hormone deficiency produces several medical disorders. In children it produces dwarfism. In adults, the consequences of an acquired HC deficiency are a large reduction in lean body mass and a concomitant increase in total body fat, especially in the trunk region. The reduction of skeletal and cardiac muscle mass and muscular power leads to a significant reduction in the ability to exercise. Bone density is also reduced. It has been seen that the administration of exogenous growth hormone is capable of reversing much of the metabolic changes.

The additional benefits of the therapy include the reduction in LDL cholesterol and a psychological improvement of well-being. In those cases in which higher levels of growth hormone were desired, the problem was usually solved by administering exogenous growth hormone or by administering an agent that stimulated the production and / or release of growth hormone. In any case, the peptide nature of the compound made its administration by injection necessary. Initially the source of growth hormone was from the extraction of pituitary glands from corpses. This resulted in an expensive product, with the added risk that a disease associated with the source of the pituitary gland could be transmitted to the growth hormone receptor (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone is available, which although it does not carry any risk of disease transmission, is still a very expensive product, which must be administered by injection or by a nasal spray. Most deficiencies of HC are caused by defects in the release of HC, not by primary defects in the synthesis of HC in the pituitary. Therefore, an alternative strategy to normalize serum HC levels is to stimulate their release from somatotrophs. An increase in secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and in the hypothalamus. As a consequence of this, what has been pursued has been the development of synthetic growth hormone releasing agents to stimulate the secretion of HC from the pituitary which may have some advantages over expensive and uncomfortable HC replacement therapy. Acting on physiological regulatory pathways, the most suitable agents would stimulate the pulsatile secretion of HC, thus avoiding, by means of negative feedback loops intact, excessive levels of HC associated with undesired secondary effects of the exogenous HC administration. The physiological and pharmacological stimulators of HC secretion are: arginine, L-3,4-dihydrophenylalanine (L-DOPA), glucagon, vasopressin and insulin-induced hypoglycaemia, as well as activities such as sleep and exercise , indirectly cause a release of the growth hormone of the pituitary, acting in some way on the hypothalamus, perhaps by decreasing the secretion of somatostatin or increasing the secretion of the known secretagogue, the growth hormone releasing factor (GHRF), or of a hormone releasing unknown endogenous growth hormone or all of them. Other compounds that stimulate the release of endogenous growth hormone have been developed, such as analogous peptide compounds related to GRF or the peptides of US Patent 4,411,890. These peptides, although they are considerably smaller than the growth hormones, remain susceptible to various proteases. As with most peptides, they have a low potential for oral bioavailability. WO 94/13696 is . < ßß¿j & < refers to certain spiropiperidines and homologs that promote the release of growth hormone. It has been reported that the compounds cited in WO 94/11012 and WO 94/13696 are useful for the treatment of osteoporosis in combination with parathyroid hormone or with a bisphosphonate. In one aspect, this invention relates to a method for the treatment of resistant disorders insulin, such as diabetes mellitus non-insulin dependent (NIDDM) and reduced glycemic control associated with obesity and aging in a mammal need, which comprises administering to said mammal an effective amount of a compound of formula I, defined below, or a pharmaceutically acceptable salt thereof. This invention relates to the use of secretagogue growth hormone releasing peptides specifically growth hormone (GHRP) or GHRP mimetics of formula I, defined below, to improve glycemic control. It is not expected that the agents that increase the levels of growth hormone (HC) have this effect, since it is well known that HC is diabetogenic in animals and in humans. In acromegalics, the utilization of glucose and the suppression of hepatic glucose production are altered (see Hansen, I., et al., Am J Physiol, 250: E269 (1986)). In this disease, in which excess HC occurs, impaired glucose and hyperinsulinemia have been reversed by pituitary surgery or chemotherapy, thus reducing HC levels (see Levin SR, et al., Am J Med, 57: 526 (1974), Feek, CM, et al., J Clin Endocrinol 22: 532 (1981)). Also, numerous studies have shown that the administration of HC to older subjects produces hyperglycemia, glucose intolerance and hyperinsulinemia (see Aloia, JF, et al., J Clin Endocrinol Metab, 43: 992 (1976); et al., J Clin Endrocrinol Metab, 67: 1312 (1988); Marcus, R., et al., J Clin Endocrinol Metab, 70: 519 (1990)). Therefore, HC therapy is contraindicated in those individuals with diabetes or at risk of diabetes. Obesity is the main risk factor for diabetes, being a large part of patients with obsessive NIDDM. Both disorders are characterized by high levels of circulating insulin and low levels of HC. It has been shown that treatment with GH deficient adults HC (Jorgensen, JOL, et al, Lancet 1. 1221 (1989)), obese women (Richelsen, B. et al, Am J Physiol., 266: E211 (1994) and elderly men (Rudman, D. et al., Horm Res 36 (Suppl 1): 73 (1991), produced an increase in lean body mass, hepatic and muscular mass, while This is why HC therapy for obesity would be appropriate if we exclude the diabetogenic effects of HC An alternative to the administration of exogenous HC is the therapy that stimulates the secretion of endogenous HC. seen that in patients ^ & ^ GHD and with intact pituitary and in older patients, there is a substantial reserve of HC in the pituitary, so that decreased serum GH levels is due to hyposecretion . The hyposecretion of HC in various clinical situations (obesity, advanced age, glucocorticoid suppression) is relatively resistant to stimulation by GHRH (Gertz, BJ, et al., J Clin Endocrinol Metab, 79: 745 (1994); Arvat, E., et al., J Clin. Endocrinol Metab, 79: 1440 (1994), Maccario M., et al., Metabolism, 44: 134 (1995)). In contrast, the administration of a GHRP or a combined administration of GHRH and GHRP in these patients can elicit an intense HC response (Aloi, J.A., et al., J Clin Endocrinol Metab, 79: 943; (1994)). Studies conducted with single doses of GHRPs have demonstrated the absence of an acute effect on circulating glucose or insulin levels. As usual, insulin and glucose have not been controlled in chronic studies, except to prove the absence of unfavorable changes (Jacks, T., et al., J Endocrinol, 143: 399 (1993)). Prior to the present invention, the use of GHRPs or GHRP mimetics to improve glycemic control had not been specifically explored. The method for the treatment of insulin resistance in a mammal comprising the administration of a compound of formula I is preferably carried out in those patients who have a hypothalamic-pituitary axis capable of responding in the form of HC secretions to the GHRPs and that they are diabetic (Type I or Type II), or that they are resistant to insulin, or that they have impaired glucose tolerance. In another aspect, this invention relates to methods for the treatment of congestive heart failure, obesity or weakness associated with advanced age in a mammal in need thereof, comprising administration to said mammal simultaneously, sequentially in any order or as a combination of a functional somatostatin antagonist, such as an alpha-2 adrenergic agonist, for example, clonidine, xylazine or medetomidine and a compound of formula I, defined below. In another aspect, this invention provides methods to accelerate the repair of bone fractures and wound healing, attenuate protein catabolic response after major surgery intervention and reduce cachexia and protein loss due to chronic disease in a mammal that need it, comprising administering to said mammal simultaneously, sequentially in any order or as a combination of an alpha-2 adrenergic antagonist, such as clonidine, xylazine or medetomidine and a compound of formula I, defined below. Clonidine is described in U.S. Patent No. 3,202,660 and its description is incorporated herein by reference, xylazine is described in U.S. Patent No. 3,235,550 and its description is incorporated herein by reference and medetomidine it is described in U.S. Patent No. 4,544,664, and its description is incorporated herein by reference. It has been shown that alpha-2 adrenergic agonists cause the release of endogenous growth hormone in dogs and in man (Celia et al., Life Sciences (1984), 34: 447-454; Hampshire J. Altszuler N. American Journal of Veterinary Research (1981), 42: 6, 1073-1076; Valcavi et al., Clinical Endocrinology (1988), 29: 309-316; Morrison et al., American Journal of Veterinary Research (1990) 51: 1, 65-70) and coadministration of an alpha-2 adrenergic agonist with a growth hormone releasing factor restores defective secretion of growth hormone in dogs. old (Arce et al., Brain Research (1990), 537: 359-362; Celia et al., Neuroendocrinology (1993), 57: 432-438). In another aspect, this invention provides a process for the synthesis of a compound of formula L-tartrate (3aR, 1 R) describing the procedure later.

Also, this invention relates to the processes for the preparation of certain intermediate compounds, shown below, which are useful in the synthesis of the compound of formula Z. The compounds of formula I used in the present invention and the compound of formula Z are described and claimed in the co-pending PCT application together with the present PCT / IB 96/01353 and having a filing date of December 4, 1996, assigned to the assignee hereof, wherein said compounds are described as possessing an activity of secretagogues of the hormone of the growth, increasing the level of hormone of the endogenous growth.

BRIEF DESCRIPTION OF THE INVENTION The compounds used in the processes of this invention have the formula I, or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein it is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (O) X6, (CH2) qN (X6) C (O) (CH2) t-A1, - (CH2) qN (X6) S02 (CH2 ) t-A1, - (CH2) qN (X6) SO2 (X6), - (CH2) qN (X6) C (O) N (X6) (CH2) t-A1, - (CH2) qN (X6) C (O) N (X6) (X6), (CH2) qC (O) N (X6) (X6), - (CH2) qC (O) N (X6) (CH2), - A1, - (CH2) qC (O) OX6, - (CH2) qC (O) O (CH2) rA1, - (CH2) qOX6, - (CH2) qOC (O) X6, - (CH2) qOC (O) (CH2) t-A1, - (CH2) qOC (O) -N (X6) (CH2) t-A1, - (CH2) qOC (O) N (X6) (X6), - (CH2) qC (O) X6, - (CH2) qC (O) (CH2) t-A1, - (CH2) qN (X6) C (O) X6, - (CH2) qN (X6) SO2N (X6) (X6), - (CH2) qS (O) mX6 , - (CH2) qS (O) m (CH2), - A1, -alkyl (C? -C10), - (CH2) t-A1, - (CH2) q-cycloalkyl (C3-C7), (CH2) q-Y1-alkyl (C? -C6), - (CH2) q-Y1-CH2) t-A1 or (CH2) q-Y1- (CH2) t-cycloalkyl (C3-C7); where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with alkyl (CrC), hydroxyl, alkoxy (CrC), carboxyl, -CONH2, -S (O) malky (C? -C6), -CO2 alkyl ester (C C4), 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S (O) m, -C (O) NX6-, -CH = CH-, -C = C-, -N (X6) C (O) -, -C (O) NX6-, - C (O) O-, -OC (O) N (X6) - or -OC (O) -; q is 0, 1, 2, 3 or 4; t is O, 1, 2 0 3; said group (CH2) q and the group (CH2) t may each be optionally substituted with hydroxyl, (C? -C4) alkoxy, carboxyl, -CONH2, -S (O) malky (C? -C6), - CO 2 (C 4) alkyl ester, 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro or 1 or 2 alkyl (C C 4); R2 is hydrogen, alkyl (CrC8), -alkyl (C0-C3) -cycloalkyl (C3-C8), -alkyl (C? -C4) -A1 or A1; wherein the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, C (O) OX6, -C (O) N (X6) (X6), -N (X6) (X6), -S ( O) malkyl (C C6), -C (O) A1, -C (O) (X6), CF3, CN or 1, 2 or 3 halogens; R3 is A1, alkyl (CrC? 0), -alkyl (d-CeJ-A1, -alkyl (Ci-Ce) -cycloalkyl (C3-C7), -alkyl (CrC5) -X1-alkyl (C1-C5), -alkyl (C C 5) -X 1 -alkyl (C 0 -C 5) -A 1 or -alkyl (C C 5) -X 1 -alkyl (d-CsJ-cycloalkyl (C 3 -C 7), wherein the alkyl groups in the definition of R 3 are optionally substituted with -S (O) malkyl (CrC6), -C (O) OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2, or 3 OX3; X1 is O, S (O) m, -N (X2) C (O) -, -C (O) N (X2) -, -OC (O) -, -C (O) O-, -CX2 = CX2-, -N (X2) C ( O) O-, -OC (O) N (X2) - or -C = C-; R4 is hydrogen, alkyl (Ci-Cß) or cycloalkyl (C3-C7) or R4 together with R3 and the carbon atom at which are attached form cycloalkyl (C5-C7), cycloalkenyl (C5-C7), a ring of 4 to 8 elements partially or totally saturated having from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, condensed with a ring of 5 or 6 elements partially saturated, totally unsaturated or fully saturated, which optionally has 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or alkyl (C-I-CT) O X4 together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached form a ring of five to seven elements: R6 is a bond or is where a and b are independently 0, 1, 2 or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C? -C6) alkyl; alkyl (CrC6) optionally substituted in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (O) malkyl (CrC6), -C (O) OX2, cycloalkyl ( C3-C7), -N (X2) (X2) and -C (O) N (X2) (X2); or the carbon carrying X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8, each alkylene bridge containing from 1 to 5 carbon atoms, provided that when an alkylene bridge is formed, then X5 or X5a, but not both, may be on the carbon atom and R7 or R8, but not both, may be on the nitrogen atom and with the proviso that when two alkylene bridges are formed, then X5 and X5a do not they can be on the carbon atom and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X5a and the carbon atom to which they are attached form a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; x ^ a ^? ¡l¡? [.. ivv | ..tl r, yftjtet «att« BA..ete Z1 is a link, O or N-X2, with the proviso that when a and b are both 0, then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (C-? - C6) alkyl; where the alkyl (C-i-Cß) optionally substituted in the definition of R7 and R8 is optionally independently substituted with A1, -C (O) O- alkyl (CrC6), -S (O) malkyls (CrC6), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 -O- C (O) alkyl (CIC-IO) or 1 to 3 alkoxy (C Cß); or R7 and R8 can be joined to form - (CH2) L- (CH2) r-; where L is C (X2) (X2), S (O) m or N (X2); 10 A1 each time it appears is independently cycloalkenyl (C5-C7), phenyl or a 4- to 8-part partially saturated, fully saturated or fully unsaturated ring, optionally having from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system Constituted by a 5 or 6 element ring partially saturated, totally unsaturated or fully saturated, optionally having from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a partially saturated 5 or 6 element ring, totally saturated or totally unsaturated, which optionally has from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently replaced, in one or optionally in both rings if A1 -'i "f ^ ^" * - J ^ is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3 , OCH3, -OX6, -C (0) N (X6) (X6), -C (O) OX6, oxo, alkyl (CrC6), nitro, cyano, benzyl, -S (0) malchyl (C C6), 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N (X6) (X6), -N (X6) C (O) (X6), -SO2N (X6) (X6) , -N (X6) SO2-phenyl, -N (X6) SO2 (X6), -CONX11X12, -SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, -NX6C- (O) X12, imidazolyl, thiazolyl and tetrazolyl, with the condition that if A1 is optionally substituted with methylenedioxy, then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted (C? -C6) alkyl; the optionally substituted (C C6) alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, alkoxycarbonyl (C -? - C6), -S (O) malky (C -? - C6), 1 to 5 halogens, 1 a 3 hydroxy, 1 to 3 alkanoyloxy (C? -C10) or 1 to 3 alkoxy (CrC6); X12 is hydrogen, (C? -C6) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl , F, CH3, OCH3, OCF3 and CF3; or X11 and X12 join to form (CH2) rL1- (CH2) r; where L1 is C (X2) (X2), O, S (O) m or N (X2); r each time it appears is independently 1, 2 or 3; X2 each time it appears is independently hydrogen, optionally substituted (Ci-Cβ) alkyl or optionally substituted (C3-C7) cycloalkyl, wherein the optionally substituted (CrC6) alkyl and (C3-C7) cycloalkyl optionally substituted in the definition of X2 they are optionally independently substituted with -S (O) malkyl (CrC6), -C (O) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (C-i-Cß); X6 is independently hydrogen, optionally substituted alkyl (CI-CT), halogenated alkyl (C2-Ce), optionally substituted cycloalkyl (C3-C), halogenated cycloalkyl (C3-C7), where optionally substituted alkyl (CrC6) and cycloalkyl (C3-C7) optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 alkyl (CrC), hydroxyl, (C? -C) alkoxy, carboxyl, CONH2, -S (O) malkyls (Ci-Cß) , (C -? - C) carboxylate or 1 H-tetrazol-5-yl alkyl ester; or when there are two groups X6 on an atom and both X6 are independently alkyl (C -? - C6), the two alkyl groups (CI-CT) can be optionally bound and, together with the atom to which the two groups X6 are linked , forming a ring of 4 to 9 elements, optionally having oxygen, sulfur or NX7; X7 is hydrogen or (C6) alkyl optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the proviso that: X6 and X12 can not be hydrogen when bound to C (O) or SO2 in the form C (O) X6, C (O) X12, SO2X6 or SO2X12; and when R6 is a bond, then L is N (X) 2 and each r in the definition (CH2) rL- (CH2) r- is independently 2 or 3. In one aspect, this invention provides a method for the treatment of insulin resistance in a mammal comprising administering to said mammal an effective amount of a compound of formula I, defined below, or stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or salts pharmaceutically acceptable and prodrugs thereof. A preferred method of the above method is when the disorder associated with insulin resistance is type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance or a syndrome or insulin resistance state. Another preferred method of the above method is when the disorder associated with insulin resistance is associated with obesity or advanced age. A preferred method of the above process is when said compound of formula I has the following formula ^^^ a ^^^ iw ^^^^^ ato - or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein R1 is -CH2-phenyl, R2 is methyl and R3 is - (CH2) 3- phenyl; R1 is -CH2-phenyl, R2 is methyl and R3 is -3-indolyl-CH2-; R1 is -CH2-phenyl, R2 is ethyl and R3 is -3-indolyl-CH2-; R1 is -CH2-4-fluoro-phenyl, R2 is methyl and R3 is -3-indolyl-CH2-; R1 is -CH2-phenyl, R2 is methyl and R3 is -CH2-O-CH2-phenyl, R1 is -CH2-phenyl, R2 is ethyl and R3 is -CH2-O-CH2-phenyl, R1 is -CH2- phenyl, R2 is -CH2CF3 and R3 is -CH2-O-CH2-phenyl, R1 is -CH2-4-fluoro-phenyl, R2 is methyl and R3 is -CH2-O-CH2-phenyl; R1 is -CH2-phenyl, R2 is t-butyl and R3 is -CH2-O-CH2-phenyl; R1 is -CH2-phenyl, R2 is methyl and R3 is -CH2-O-CH2-3,4-difluorophenyl. Another preferred method of the above process is when the compound of formula I has the formula or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein R 2 is methyl; A1 is 2-pyridyl; and R3 is -CH2-O-CH2-phenyl; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-O-CH2-3-chlorophenyl; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-O-CH2-4-chlorophenyl; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-O-CH2-2,4-dichloro-phenyl; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-O-CH2-3-chlorothiophene R2 is CH2CF3; A1 is 2-pihdyl; and R3 is -CH2-O-CH2-2,4-difluoro-phenyl; Another preferred method of the above process is when said compound of formula I or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof is the diastereomeric mixture 3a (R, S ), 1 (R), the diastereomer 3a (R), 1 (R) or the diastereomer 3a (S), 1 (R) of a compound selected from the group consisting of 2-amino-N- [1- (3a -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5-carbonyl) -4-phenyl-butyl] -isobutyramide, 2 -amino-N- [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) - 1- (1 H-indol-3-ylmethyl) -2-oxo-ethyl] -isobutyramide, 2-amino-N- [2- (3a-benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (1 H -indol-3-ylmethyl) -2-oxo-ethyl] -isobutyramide, 2-amino-N - [2- (3a- (4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-piraz olo [4,3-c] pyridin-5-yl] -1- (1 H -indol-3-ylmethyl) -2-oxo-ethyl] -isobutyramide, 2-amino-N- [2- (3a-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pihdin-5-yl) -1-benzyloxymethyl-2-oxo-ethyl] -isobutyramide , 2-amino-N- [2- (3a-benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo ^. S-cjpyridin-di-l-benzyloxymethyl ^ -oxo-ethylj-isobutyramide, 2-amino-N-. { 2- [3a-benzyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] piñdin-5 -yl] -1-benzyloxymethyl-2-oxo-ethyl} -sobutyramide, 2-amino-N-. { 1-Benzyloxymethyl-2- [3a- (4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pihdin-5 -yl] -2-oxo-ethyl} -isobutyramide, 2-amino-N- [2- (3a-benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine -5-yl) -1-benzyloxymethyl-2-oxo-ethyl] -isobutyramide, and 2-amino-N- [2- (3a-benzyl-3-oxo-2,3,3a, 4,6, 7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1-benzyloxymethyl-2-oxo-ethyl] -isobutyramide. A preferred method of the immediately preceding process is when said compound of formula I is the L-tartaric acid salt of 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. Another preferred method of the above process is a process wherein said compound of formula I or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof is the diastereomeric mixture 3a- ( R, S), - 1 (R), the enantiomer 3a- (R), 1- (R) or the enantiomer 3a- (S), 1- (R) of a compound selected from the group consisting of 2-amino -N- [1-benzyloxymethyl-2- (2-methyl-3-oxo-3a-pyridin-2-ylmethyl-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine -5-yl) -2-oxo-ethyl] -2-methyl-propionamide; 2-amino-N-. { 1- (3-chloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-pi-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- (4-chloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-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- (2,4-Dichloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-piñdin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -2,3,3a , 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-ii] -ethyl} -2-methyl-propionamide; 2-amino-N-. { 1- (4-chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- [3-oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -2,3 , 3a, 4,6,7-hexahydro-pyrazolo [3,4-c] pyridin-6-yl) -ethyl} -2-methyl-propionamide; and 2-amino-N-. { 1- (2,4-Dichloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-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; Another, even more preferred method of the above process further comprises administering to a mammal in need thereof a growth hormone releasing hormone or a functional analog thereof., which are prepared by methods known in the art, some examples of which are described in European Patent Publication No. EP 511 003. In another aspect, this invention provides pharmaceutically useful compositions for the treatment of insulin resistance in a mammal containing a pharmaceutically acceptable carrier and an effective amount of a compound of formula I, as shown below, or stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or pharmaceutically acceptable salts and prodrugs thereof.

In yet another aspect, this invention provides methods for increasing levels of endogenous growth hormone, comprising administering to a human and another animal in need thereof effective amounts of a functional somatostatin antagonist and a compound of formula I, as shown below, or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof. In another aspect, this invention provides methods for the treatment or prevention of congestive heart failure, obesity or weakness associated with advanced age in a mammal, comprising administering to a mammal in need thereof effective amounts of a functional antagonist of the somatostatin and a compound of formula I, as shown below, or stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or pharmaceutically acceptable salts and prodrugs thereof. From the immediately preceding procedure it is preferred when said functional somatostatin antagonist in an alpha-2 adrenergic agonist. The above procedure is preferred when said alpha-2 adrenergic agonist is selected from the group consisting of clonidine, xylazine and medetomidine. From the immediately preceding procedure it is preferred when said compound of formula I is the salt of L-tartaric acid of 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. This invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an amount of an alpha-2 adrenergic agonist and an amount of a compound of formula I, as defined above, or stereoisomeric mixtures, diastereomerically enriched isomers , diastereomerically pure, enantiomerically enriched or enantiomerically pure or the pharmaceutically acceptable salts or prodrugs thereof. Furthermore, this invention relates to methods for the treatment of insulin resistance in a mammal comprising administering to a mammal in need thereof an effective amount of a growth hormone-releasing peptide or a peptide-releasing peptide mimetic. growth hormone or a pharmaceutically acceptable salt thereof. In one aspect, this invention relates to the procedures described below, where the "*" indicates the stereochemical centers. A process for the preparation of the compound of formula k, .. ^. ^^^ ^ sa ^ tSu ^^^^ (K) comprising the reaction of compound of formula g, Free base (9) with the compound of formula j, (I) ? I? A ?, where Prt is an amine protecting group, in the presence of an organic base, a peptide coupling reagent and an inert solvent for the reaction, at a temperature from about -78 ° C to about -20 ° C. C, to give the compound of formula k. From the above procedure it is preferred when the peptide coupling reagent is the cyclic anhydride of 1-propanophosphonic acid and the compound of formula g has the R configuration, the compound of formula j has the R configuration and the compound of formula k has the configuration 3a- (R), 1- (R). A process for the preparation of the compound of formula Z, comprising the reaction of the compound of formula g, -, ^ f ^ aÉ t & * with the compound of formula j, (I) in the presence of an organic base, a peptide coupling reagent and a solvent inert to the reaction, at a temperature from about -78 ° C to about -20 ° C, to give the compound of formula k, (k) the deprotection of the compound of formula k to give the compound of formula I, (O the reaction of the compound of formula I with L-tartaric acid in an alcoholic solvent to give the compound of formula Z. From the above procedure it is preferred when the reactant of peptide coupling is the cyclic anhydride of 1-propanophosphonic acid and the compound of formula g has the R configuration, the compound of formula j has the R configuration and the compounds of formula k, I and Z have the configuration 3a- (R ), 1- (R) A process for the preparation of the compound of formula Free base (g) which comprises the reaction of the compound of formula f, $ ^ a »8 £ á with a base in an inert solvent at a temperature from about -50 to -10 ° C, in which the chirality of the benzyl group is maintained to give the compound of formula g. A process for the preparation of the compound of formula c, (c) comprising the reaction of the compound of formula b, (b) ~ ^^? * i? where Prt in an amine protecting group with an inorganic or organic base and benzyl bromide in a solvent inert to the reaction giving the compound of formula c. A process for the preparation of a compound of formula f, which comprises the reaction of the compound of formula e, (and) with L-tartaric acid in an organic solvent inert to the reaction.

This invention also provides the enantiomeric mixture R, S, the R-enantiomer or the S-enantiomer of the compound of formula where Prt is hydrogen or an amine protecting group. 10 DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of formula I, or the stereoisomeric mixtures, the diastereomerically enriched isomers, diastereomerically pure, enantiomerically enriched or enantiomerically pure or pharmaceutically acceptable salts and prodrugs thereof, used in the processes of the present invention can be obtained by methods known in the chemical art. In the above structural formulas and throughout the present application, the following terms have the indicated meanings, unless expressly indicated otherwise.

The alkyl groups include those alkyl groups of the desired length in a straight or branched configuration and which optionally may contain double or triple bonds. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl, butadienyl, hexenyl and the like. When the definition Co-alkyl appears in the definition, it indicates a simple covalent bond. The alkoxy groups include those alkoxy groups of the desired length in linear or branched configuration and which optionally may contain double or triple bonds. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, iopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxy and the like. The term "halogen" or "halo" includes the halogen atoms, fluorine, chlorine, bromine and iodine. The term "halogenated alkyl" includes an alkyl group as defined hereinabove substituted with one or more halogen atoms, as defined herein above. The term "halogenated cycloalkyl" includes a cycloalkyl group substituted with one or more halogen atoms, as defined herein above. The term "aryl" includes phenyl or naphthyl and the aromatic rings of 5-6 elements with 1 to 4 heteroatoms or bicyclic rings of 5-6 elements .. ^ .. ^ ¡^ ^ ^ ^ ^^^? Ñ ^^^ - ^ i - ^^^^^^^ i condensed with 1 to 4 heteroatoms of nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene (also known as thienium), furan, benzothiophene, tetrazole, indole, N-methylindol, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine and thiadiazole. The chemist skilled in the art will recognize that certain combinations of heteroatom-containing substituents cited in this invention define compounds that will be less stable under physiological conditions (for example those containing acetal or aminal linkages). According to this, said compounds are the least preferred. The term "prodrug" refers to compounds that are drug precursors and that once administered release the drug in vivo by some chemical or physiological processes (for example, a prodrug that is brought up to the physiological pH becomes the desired drug) . Examples of prodrugs are those which upon cleavage release the corresponding free acid, including said hydrolyzable ester-forming residues of the compounds of this invention, but not limited to, carboxylic acid substituents (e.g., R1 is - (CH2) qC ( O) X6, where X6, is hydrogen, or R2 or A1 contains carboxylic acid), wherein the free hydrogen is substituted by (C4) alkyl, (C2-C12) alkanoyloxymethyl, 1- (alkanoyloxy) (C-) C9) ethyl, 1-methyl- (1-alkanoyloxy) -ethyl with 5 to 10 carbon atoms, alkoxycarbonyl-oxymethyl with 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl with 4 to 7 carbon atoms, 1 methyl -1- (alkoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl with 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl with 4 to 10 carbon atoms, 3- phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-NN-alkylamino (C C2) alkyl (C2-C3) (such as β-dimethylaminoethyl), carbamoylalkyl ( C C2), N, N-dialkylcarbamoyl (CrC2) -alkyl (C C2) and piperidino-, pyrrolidino- or morpholinoalkyl (C2-C3). Other examples of prodrugs release an alcohol of formula I, in which the free hydrogen of the hydroxyl substituent (for example, R 1 contains hydroxyl) is replaced by alkanoyl (C 6 -C 6) oxymethyl, 1- (alkanoyloxy (CrC 6) ethyl, -methyl-1 - (alkanoyl (CrC6) -oxi) ethyl, alkoxy (CrC6) carbonyloxymethyl, N-alkoxy (C? -C6) -carbonylaminomethyl, succinoyl, alkanoyl (C? -C6), a-aminoalkanoyl (CrC4), arylacetyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in the proteins, P (O) (OH) 2, -P (O) (or (C6) alkyl) 2 or glycosyl (the radical resulting from the separation of the hydroxyl from the hemiacetal of a carbohydrate) The prodrugs of the compounds of formula I, wherein a carboxyl group is substituted in an acid carboxylic acid of formula I by an ester, can be prepared by combining the carboxylic acid with the appropriate alkyl halide in the presence of a of a base, such as potassium carbonate, in an inert solvent, such as DMF, at a temperature from about 0 ° C to about 100 ° C for about 1 to 24 hours. As ^? ^^ M ^^^? ^^^^ t ^ Tn ^? Alternatively, the acid is combined with the appropriate alcohol as a solvent in the presence of a catalytic amount of acid, such as concentrated sulfuric acid, at a temperature from about 20 ° C to 120 ° C, preferably at reflux, for about 1 hour to about 24 hours. hours. Another method is the reaction of the acid in an inert solvent, such as THF, by simultaneously removing water that is produced by physical means (eg, a Dean Stark trap) or chemicals (eg, molecular sieves). Prodrugs of the compounds of formula I, wherein an alcohol function has been derived in ether form, can be prepared by combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base, such as potassium carbonate, in an inert solvent. , as DMF, at a temperature from about 0 ° C to about 100 ° C for about 1 to about 24 hours. The alkanoylaminomethyl ethers can be obtained by reaction of the alcohol with a bis- (alkanoylamino) methane in the presence of a catalytic amount of an acid in an inert solvent, such as THF, according to the method described in US Pat. 4,997,984. On the other hand, these compounds can be prepared by the methods described by Hoffman et al., In J. Org. Chem. 1994, 59, p. 3530. Some of the previously defined terms may appear more than once in the previous formula and each time each term is presented it will be defined independently of the rest.

The following abbreviations are used throughout the specification and the appended claims, which have the following meanings: BOC t-butyloxycarbonyl BOP Benzotriazole-1-yloxytris hexafluorophosphate ( dimethylamino) phosphonium CBZ Benzyloxycarbonyl CDl N, N'-Carbonyldiimidazole CH2Cl2 Methylene Chloride 10 CHCl3 Chloroform DCC Dicyclohexylcarbodiimide DMF Dimethylformamide EDC 1- (3-dimethyl ethylcarbodiimide hydrochloride AcOET Ethyl acetate FMOC 9-Fluorenylmethoxycarbonyl h hours Hex hexane HOAT 1 -Hydroxy -7-azabenzotriazole 20 HOBT Hydroxybenzotriazole hydrate HPLC High pressure liquid chromatography MHz Megaherzium Mass spectrum iIffi'Ü a ^ a-Bi-.aa.

NMR Nuclear magnetic resonance PTH Parathyroid hormone TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TRH Thyrotropin releasing hormone TROC 2,2,2-Trichloroethoxycarbonyl The compounds used in a process of the present invention all have at least one asymmetric center, as indicated by the asterisk in structural formula I above. Other additional asymmetric centers may exist in the molecule depending on the nature of the different substituents that exist in the molecule. Each of said asymmetric centers will produce two optical isomers and it is provided that each of said optical isomers, in the form of separate, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, are included within the scope of the present invention. invention. In the case of the asymmetric center represented by the asterisk, it has been seen that the absolute stereochemistry of the most active isomer, and therefore, of the most preferred isomer, is that shown in formula IA. This preferred absolute configuration also applies to formula I. (the) With the substituent R4 as hydrogen, the spatial configuration of the asymmetric center corresponds to that of a D-amino acid. In most of the cases this is also designated as R configuration, although it may vary according to the values of R3 and R4 used when making the stereochemical assignments R or S. The compounds of formula I used in the methods of the present invention are generally isolated in form of its salts addition of pharmaceutically acceptable acids, such as salts derived from the use of inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methanesulfonic and the like. In addition, certain compounds Those containing an acid function, such as carboxy, can be isolated in the form of an inorganic salt in which the cotraion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as between the organic bases.

The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula I and contacting it with about 1 equivalent of the appropriate corresponding acid of the desired salt. The processing and isolation of the resulting salt are well known to those skilled in the art. The present invention includes within its scope pharmaceutical compositions containing, as an active ingredient, an amount for the treatment of insulin resistance of at least one of the compounds of formula I in combination with a pharmaceutically acceptable carrier. In addition, the present invention includes in its scope pharmaceutical compositions containing, as an active ingredient, at least one alpha-2 adrenergic agonist and at least one of the compounds of formula I in combination with a pharmaceutically acceptable carrier. Optionally, the pharmaceutical compositions may further comprise an anabolic agent together with at least one of the compounds of formula I or another compound having a different activity, for example, one that allows antibiotic growth or with other pharmaceutically active materials, wherein the combination reinforces the effectiveness and minimizes the side effects.

Assay for the stimulation of the release of HC from rat pituitary using the following protocol identifies compounds that have the ability to stimulate the secretion of HC from cultured cells of the rat pituitary. This test is also useful for comparing with standards in order to determine dosage levels. Cells are isolated from the pituitary of Wistar rats at six weeks of age. After decapitation, the anterior lobes are separated from the pituitary and transferred to a cold sterile Hank's balanced salt solution, without calcium or magnesium (HBSS). The tissues are finely ground, then subjected to two cycles of mechanically assisted enzymatic dispersion using 10U / ml of bacterial protease (EC 3.4.24.4, Sigma P-6141, St. Louis, Missouri) in HBSS. The enzyme-tissue mixture is stirred in a rotary flask at 30 rpm in an atmosphere of 5% C02 at about 37 ° C for about 30 minutes, with manual trituration after about 15 minutes and about 30 minutes using a 10-gauge pipette. ml. This mixture is centrifuged at 200 x g for about 5 min. Horse serum (35% final concentration) is added to the supernatant to neutralize the excess protease. The sediment is resuspended in fresh protease (10U / ml), agitated for approximately 30 minutes more in the previous conditions and manually ground and finally with a 23 gauge needle. Horse serum is added again (final concentration 35% ), the cells from both digests are then combined, pelleted (200 xg for approximately 15 minutes), resuspended in a culture medium (Dulbecco's Modified Eagle's Medium (DM), supplemented with 4.5 g / l glucose). , 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 100 U / ml nystatin and 50 mg / ml gentamicin sulfate, Gibco, Grand Island, New York) and became a count. Cells are plated at 6.0-6.5x104 cells per cm2 in 48-well Costar ™ plates (Cambridge, Massachusetts) and cultured for 3-4 days in culture medium. Just before the HC secretion test, the wells with the cells are washed twice with release medium, then equilibrated for about 30 minutes in a release medium (DM buffered with 25 mM Hepes, pH 7.4 containing albumin of bovine serum 0.5% at 37 ° C). The test compounds are dissolved in DMSO, then dilute in a previously heated release medium. The tests are done in quadruplicate. The assay is started by adding 0.5 ml of release medium (with vehicle or with the test compound) to each of the wells. The incubation is done at about 37 ° C for about 15 minutes, then it is finalized by removing the release medium, which is centrifuged at 2000 x g for about 15 minutes to eliminate the cellular matepal. The concentrations of rat growth hormone in the supernatants are determined by the standard radioimmunoassay protocol described below.

Rat Growth Hormone Measurement Rat growth hormone concentrations were determined by a double radioimmunoassay with antibodies using a reference preparation of rat growth hormone (NIDDK-rGH-RP-2) and an antiserum of the rat. Rat growth hormone obtained in monkey (NIDDK-anti-rGH-S-5) supplied by Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, CA). An additional part of rat growth hormone (1.5 U / mg, # G2414, Scripps Labs, San Diego, CA) was eluted to a specific activity of approximately 30 μCi / μg by the chloramine T method to be used as a tracer. Immune complexes were obtained by adding goat antiserum to the monkey IgG (ICN / Cappel, Aurora, OH) plus polyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%; collection was performed by centrifugation. This test has an operating range of 0.08-2.5 μg rat growth hormone per tube above basal levels.

Assay for the release of stimulated growth hormone exogenously in the rat after intravenous administration of the test compounds It is allowed to acclimate to Sprague-Dawley rats (Charles River Laboratory, Wilmington, MA) of twenty-one days to the conditions of the animal house (24 ° C, 12 h light cycle and 12 h dark) for approximately 1 week before testing the compound. All rats should have ad libitum access to water and a commercial ball diet (Agway Country Food, Syracuse, NY). The experiments are performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals. On the day of the experiment, the test compounds are dissolved in a vehicle containing 1% ethanol, 1 mM acetic acid and 0.1% bovine serum albumin in saline. Each test is performed in three rats. The rats are weighed and anesthetized by an intraperitoneal injection of sodium pentobarbital (Nembutol®, 50 mg / kg / body weight). Fourteen minutes after the administration of anesthesia, a blood sample is taken by making a cut at the tip of the tail and letting the blood drip into a microcentrifuge tube (blood sample for baseline, approximately 100 μl) . Fifteen minutes after the administration of the anesthesia, the test compound is administered by an intravenous injection into the caudal vein, with a total injection volume of 1 ml / kg of body weight. Additional blood samples are removed from the tail at 5, 10 and 15 minutes after administration of the compound. The blood samples are kept on ice until the separation of the serum by centrifugation (1430 x g for 10 minutes at 10 ° C). The serum is stored at -80 ° C until the determination of serum growth hormone by radioimmunoassay is performed as described above.

Determination of exogenously stimulated growth hormone release in dog after oral administration On the day of administration of the dose, the test compound is weighed to have the appropriate dose and dissolved in water. Doses are administered at a volume of 0.5-3 ml / kg by esophageal tube to 2-4 dogs for each dosing regimen. Blood samples (5 ml) are extracted from the jugular vein by direct puncture before administration of the dose and at 0.17, 0.33, 0.5, 0.75, 1, 2, 4.6, 8 and 24 hours after the administration of the dose using 5 ml vacutainers with lithium heparin. The plasma thus prepared is stored at -20 ° C until analysis.

Canine growth hormone measurement The concentrations of canine growth hormone are determined by a standard radioimmunoassay protocol using canine growth hormone (antigen for iodination and reference preparation AFP-1983B) and canine growth hormone antiserum obtained in mono (AFP-21452578) provided by Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, CA). A tracer is obtained by iodination of the chloramine T of the growth hormone to a specific activity of 20-40 μCi / μg. Immune complexes are obtained by adding goat antiserum to monkey IgG (ICN / Cappel, Aurora, OH) plus polyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%; the collection was performed by centrifugation. This test has an operating range of 0.08-2.5 μg canine HC / tube.

Determination of levels of canine growth hormone and insulin-like growth factor 1 in the dog after chronic oral administration Dogs receive the test compound daily for 7 or 14 days. Each day of the administration of the compound, the test compound is weighed to determine the appropriate dose and dissolved in water. The doses were administered at a volume of 0.5-3 ml / kg by esophageal tube to 5 dogs for each dosing regimen. Blood samples are taken on days 0, 3, 7, 10 and 14. Blood samples (5 ml) are obtained by direct puncture in the jugular vein before administration of the dose, 0.17, 0.33, 0.5, 0.754, 1, 2, 3, 6, 8, 12 and 24 hours after administration on days 0, 7 and 14 using 5 ml vacutainers with lithium heparin. Likewise, blood is drawn before the administration of the dose and 8 hours on days 3 and 10. The prepared plasma is kept at -20 ° C until analysis.

Female rat study This study evaluates the effect of chronic treatment with a GHRP mimetic on weight, body composition and non-fasting plasma concentrations of glucose, insulin, lactate and lipids in female deficient estrogen rats and without deficiency thereof . HE ^ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡Jtuu determines the acute response of serum HC levels to i.v. of the HC releasing agent on the last day of administration of the dose. Body weight is monitored weekly throughout the treatment period; additionally, the body composition and plasma levels of glucose, insulin, lactate, cholesterol and triglycerides are determined at the end of the treatment. The female virgin Sprague-Dawley rats were supplied by Charles River Laboratories (Wilmington, MA) and underwent a bilateral ovariectomy (Ovx) or sham surgery (Sham) at approximately 12 weeks of age. In the simulated operations, the ovaries were exteriorized and placed in the abdominal cavity. After surgery, rats were individually housed in 20 cm x 32 cm cages under standard animal conditions (approximately 24 ° C with a 12-hour light cycle and 12 hours of darkness). All rats had free access to water and a commercial ball diet (Agway ProLab 3000, Agway Country Food, Inc., Syracuse, NY). The experiment was carried out according to the NIH guide for the Care and Use of Laboratory Animals. Approximately seven months after the surgery, the Sham and Ovx rats were weighed and assigned randomly to the groups. The rats were administered daily by oral gavage 1 ml of vehicle (1% ethanol in distilled-deionized water), 0.5 mg / kg or 5 mg / kg of a growth hormone-releasing agent for 90 days. The rats were weighed at weekly intervals throughout the study. Twenty four «Aa *. After hours of the last oral dose, the acute response of serum growth hormone (HC) to the test agent was determined by the following procedure. The rats were anesthetized with 50 mg / kg sodium pentobarbital. The anesthetized rats were weighed and a blood sample was drawn for the baseline (-100 μl) of the caudal vein. The test agent (growth hormone releasing agent or vehicle) was then administered intravenously through the caudal vein in 1 ml. Approximately ten minutes after the injection, a second blood sample of 100 μl was extracted from the tail. The blood was allowed to clot at about 4 ° C then centrifuged at 2000 x g for about 10 minutes. The serum was stored at -70 ° C. The serum concentrations of growth hormone were determined by radioimmunoassay, as previously described. Following this procedure, each of the anesthetized rats was subjected to a total body scan by double-energy X-ray absorptiometry (DEXA, Hologic QDR 1000 / W, Waltham MA). A final blood sample was taken by cardiac puncture in heparinized tubes. The plasma was separated by centrifugation and ice cream was stored as described above. Plasma insulin is determined by radioimmunoassay using a kit from Binax Corp. (Portland, Maine). The interassay coefficient of variation is <; 10% Plasma levels of triglycerides, total cholesterol, glucose and lactate are measured using an Abbot VP ™ autoanalyzer and VP Super System® (Abbot Laboratories, Irving, Texas) using the systems . ? R & M;? I »& £ ^.,«? J? Í £ ¿, > of reagents for the Triglycerides, Cholesterol and Glucose Assay A-Gent ™ and a Sigma kit for lactate respectively. The activity of a growth hormone releasing peptide (GHRP) or mimetic of GHRP, such as the compound of formula I, which produces the plasma decrease of insulin, triglycerides, cholesterol and lactate, is determined by an analysis statistical test (unpaired test t) with the control group treated with the vehicle. The compounds of formula I used in a method of this invention can be administered orally, parenterally (for example, intramuscular, intraperitoneal, intravenous or subcutaneous injection or by implant), nasal, vaginal, rectal, sublingual or topical and can be formulated with pharmaceutically acceptable carriers to obtain the appropriate dosage forms for each route of administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier, such as sucrose, lactose or starch. Said dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also include buffering agents. The tablets and pills can be prepared additionally with enteric coatings.

The liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and syrups, the elixirs containing inert diluents commonly used in the art, such as water. In addition to the inert diluents, the compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents and sweetening, flavoring and perfuming agents. Preparations according to the invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, vegetable oils, such as olive oil and corn oil, gelatin and injectable organic esters, such as ethyl oleate. Such oral dosage forms may also contain adjuvants, such as preservatives, humectants, emulsifiers and dispersants. They can be sterilized, for example, by filtration through a bacterial retention filter, by incorporating sterilizing agents in the compositions, by irradiating the compositions, or by heating the compositions. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or in some other sterile injectable media immediately before use. Compositions for rectal or vaginal administration are preferably suppositories, which may contain, in addition to the . ^ .... ^^ A ^ fep aAa .. active substance, excipients such as cocoa butter or as wax for suppositories. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art. The dosage of the active ingredient in the compositions of this invention may be various; however, it is necessary that the amount of the active ingredient be such that an appropriate dosage form is obtained.

The selected dosage depends on the desired therapeutic effect, the route of administration and the duration of the treatment. Generally, daily dosage levels of between 0.0001 and 100 mg / kg body weight are administered to humans and other animals, e.g., mammals, for the effective release of growth hormone to occur. A, preferred dosage range for humans is 0.01 to 5.0 mg / kg body weight per day, which can be administered as a single dose or divided into multiple doses. A preferred dosage range in animals, other than humans, is from 0.01 to 10.0 mg / kg of body weight per day, which can be administered as a single dose or divided into multiple doses. A more preferred dosage range in animals, other than humans, is from 0. 1 to 5 mg / kg of body weight per day, which can be administered as a single dose or divided into multiple doses.

The preparation of the compounds of formula I used in a process of the present invention can be carried out by sequential or convergent synthetic routes. In the reaction schemes shown below, the detailed syntheses of the preparation of the compounds of the formula I are shown sequentially. Many of the protected amino acid derivatives are commercially available, where the protecting groups Prt, Z100 and Z200 are, for example, groups BOC, CBZ, benzyl, ethoxycarbonyl, CF3C (O) -, FMOC, TROC, trityl or tosyl. Other protected amino acid derivatives can be prepared by the methods described in the literature. Some 3-oxo-2-carboxy pyrrolidines and 4-oxo-3-carbonyl piperidines are commercially available, many other known pyrrolidines and 4-substituted piperidines being known in the literature. Many of the schemes illustrated below describe compounds containing Prt, Z100 or Z200 protecting groups. The benzyloxycarbonyl groups can be removed by various methods including, catalytic hydrogenation with hydrogen in the presence of a palladium or platinum catalyst in a protic solvent such as methanol. The preferred catalysts with palladium hydroxide on carbon or palladium on carbon. Hydrogen pressures can be used from 1-1000 psi; pressures of 10 to 70 psi are preferred. On the other hand, the benzyloxycarbonyl group can be removed by transfer hydrogenation.

The separation of the BOC protecting groups can be carried out using a strong acid, such as trifluoroacetic acid or hydrochloric acid, with or without the presence of a cosolvent such as dichloromethane, ethyl acetate, ether or methanol at a temperature from about -30 ° C to -70 ° C, preferably from about -5 to about 35 ° C. The benzylic esters can be separated from the amines by various methods including catalytic hydrogenation with hydrogen in the presence of a palladium catalyst in a protic solvent, such as methanol. Hydrogen pressures can be used from 1-1000 psi; pressures of 10 to 70 psi are preferred. The addition and separation of these and other protecting groups is discussed in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1981.

TTü ^^ - '^ - 1-- SCHEME 1 SCHEME 1: Protected amino acid derivatives 1 are commercially available in many cases, where the protective group Prt is, for example, the BOC group, FMOC or CBZ. Other amino acids can be prepared by the methods described in the literature. As illustrated in scheme 1, the coupling of the amines of formula 2 with protected amino acids of formula 1, where Prt is an appropriate protecting group, is conveniently carried out in an inert solvent, such as dichloromethane or DMF, by a reagent of coupling as EDC or DCC in the presence of HOBT or HOAT. In the case where the amine is present as the hydrochloride salt, it is preferable to add one or two equivalents of an appropriate base, such as triethylamine, to the reaction mixture. On the other hand, the coupling can be carried out with a coupling reagent, such as BOP, in an inert solvent, such as methanol. Said coupling reactions are generally carried out at temperatures from about -30 ° C to about 80 ° C, preferably from -10 ° C to about 25 ° C. For a discussion of other conditions used for coupling peptides, see Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., George Theime Verlag, 1974, Stuttgart. The separation of the unwanted by-products and the purification of the intermediate products is carried out by chromatography on silica gel, using flash chromatography (W. O Still, M. Kahn and A. Mitra, J. Org. Chem. 43 2923 1978), by crystallization or by grinding. The transformation of the compound of formula 3 into the intermediates of formula 4 can be carried out by separating the protective group Prt as described above. The coupling of the intermediates of formula 4 to the amino acids of formula 5 can be carried out as described above to give the intermediates of formula 6. The deprotection of amine 6 gives the compounds of formula 7.

SCHEME 2 SCHEME 2: On the other hand, the compounds of formula 7 can be prepared by a convergent route, as shown in scheme 2. The intermediate esters of formula 8 can be prepared by treating amino acids 1, where Prt is a suitable protecting group, with a base, such as potassium carbonate, followed by an alkyl halide, such as iodomethane in an appropriate solvent, such as DMF. Deprotection of the amine transforms 8 into 9. On the other hand, many amino acids of formula 9 are commercially available. Intermediate 10 is obtained by coupling 9 to amino acid 5. The ester of intermediate 10 can be converted to intermediate 11 by various methods known in the art; for example, the methyl and ethyl esters can be hydrolysed with lithium hydroxide in a protic solvent, such as aqueous methanol or aqueous THF at a temperature from about -20 ° C to 120 ° C, preferably about 0 ° C to 50 ° C. . In addition, removal of the benzyl group can be accomplished by various reducing methods, including hydrogenation in the presence of platinum or palladium catalyst in a protic solvent such as methanol. The acid 11 can then be coupled to the amine 2 giving the intermediates of formula 6. The transformation of 6 to 7 can be produced by separation of the protecting group Z200.

SCHEME 3 SCHEME 3: The esters of formula 6 can be converted to the intermediate acids of formula 13 by several of the methods known in the art; for example, the methyl and ethyl esters can be hydrolyzed with lithium hydroxide in a protic solvent, such as aqueous methanol or aqueous THF at a temperature from about -20 ° C to 120 ° C, preferably from about 0 ° C to 50 ° C . In addition, the removal of the benzyl group can be carried out by various reducing methods, including hydrogenation in the presence of platinum or palladium catalyst in a protic solvent such as methanol. The coupling of acid 13 to amine 16 generates the intermediates of formula 14. The transformation from 14 to 15 can be produced by separating the protective group Z 200 SCHEME 4 SCHEME 4: Esters of formula 17 can be prepared by treating an acid of formula 5 with hydroxysuccinimide in the presence of a coupling agent, such as EDC, in an inert solvent, such as methylene chloride, as illustrated in scheme 4. The treatment of an ester 17 with an amino acid of formula 11 in a solvent, such as dioxane, THF or DMF in the presence of a base, such as diisopropylethylamine produces 11. hn ^ tn? . ^ Asaaas ^ A ^^ SCHEME 5 SCHEME 5: As illustrated in scheme 5, alkylation of the diphenyloxazinone of formula 18 with cinnamyl bromide in the presence of bis (trimethylsilyl) amide generates 19, which is then converted to the acid (D) -2-amino -5-phenylpentanoic acid by separation of the protective group (Prt) and hydrogenation on PdCI2 catalyst.

SCHEME 6 H 28 SCHEME 6. The treatment of an ester of formula 21 with a base, such as sodium hydride, in a solvent, such as DMF, followed by an alkyl halide 22 generates a compound of formula 23, as illustrated in scheme 6. The treatment of a compound of formula 23 with a hydrazine of formula 24, such as hydrazine or methyl hydrazine, in a solvent, such as refluxing ethanol, ^^ ^^^ ^ ^^ j ^^^^^ z ^^ followed by the concentration and heating of the residue in toluene at or near reflux temperatures, produces a compound of formula 25. On the other hand, the 23 it can be treated with a salt of a hydrazine in the presence of sodium acetate in ethanol at reflux to give 25. The deprotection of the amine generates a compound of formula 28. The thioamides of formula 26 can be formed by treating the 25 with Lawesson's reagent in toluene or benzene at reflux. The separation of the protective group transforms the 26 into 27.

SCHEME 7 21 29 ^ ^^. ^^ a ^? '^ S ^^ TTm SCHEME 7 .. Treatment of a compound of formula 21 with a hydrazine of formula 24 in a solvent such as refluxing ethanol, followed by concentration and heating the residue in toluene at or near reflux temperatures produces the compounds of formula 29. On the other hand, 21 can be treated with a salt of a hydrazine in the presence of sodium acetate in refluxing ethanol to give the 29. Amide of formula 29 can be treated with a base such as sodium hydride in a solvent such as DMF followed by an alkyl halide to give 25. deprotection of the amine generates a compound of formula 28.

SCHEME 8 33 34 The reaction of a ketoester of formula 30 with a chiral amine, such as alpha-methylbenzylamine, with an appropriate aldehyde, such as formaldehyde, or the reaction of a vinyl ketoester of formula 31 with a chiral amine such as alpha-methylbenzylamine with a suitable aldehyde such as formaldehyde, affords a compound of formula 32 by reaction of double Mannich. The reaction of 32 with a hydrazine generates a chiral compound of formula 33. Deprotection of the nitrogen with hydrogen and an appropriate catalyst such as palladium affords compounds of formula 34.

SCHEME 9 87 88 SCHEME 9: The treatment of a compound of formula 81 with a reducing agent such as sodium borohydride and the protection of nitrogen gives a compound of formula 82. The protection of alcohol gives 83. The saponification of the ester gives a compound of formula 84. Reaction of 84 with thionyl chloride followed by treatment with diazomethane gives the homologous acid of formula 85. The esterification of 85 gives a compound of formula 86, in which O is deprotected and gives 87. Oxidation of 87 gives a ketone of formula 88. Reaction of 88 with a hydrazine, followed by deprotection of nitrogen gives a compound of formula 44.

SCHEME 10 SCHEME 10: Treatment of a compound of formula 35 with a base, with sodium hydride, in a solvent such as DMF, followed by treatment with diethyl carbonate generates the ethyl ester of compound 36. Deprotection of the amine transforms the 36 into 37 .

SCHEME 11 38 39 H 40 SCHEME 11: The treatment of the malonic ester of formula 38 with a base, such as sodium hydride, in a solvent such as DMF, and the subsequent hydrogenolysis of the benzyl group with hydrogen and a catalyst, such as palladium in an appropriate solvent, such as methanol, produces the ester of formula 39. Deprotection of the amine generates the compounds of formula 40. ^ ii fc ^? SCHEME 12 43 44 45 SCHEME 12: The treatment of a ketone of formula 41 with a secondary amine, such as piperidine, in an appropriate solvent, such as benzene, eliminating water, gives an enamine of formula 42. The alkylation of the enamine with a halogenated α-ester, as ethyl bromoacetate, in an appropriate solvent, such as benzene or THF, using an appropriate base, such as LDA or NaN (SiMe3) 2 gives a ketoester of formula 43. Reaction with hydrazine of formula 24 gives the compound of formula 44. Deprotection of nitrogen gives the compounds of formula 45. i i z i liiíai ii -Mi - ^ '- jf ^ * 8 ^ SCHEME 13 37 46 47 48 SCHEME 13: The treatment of a ketoester of formula 37 with a iodonium salt, such as diphenyliodonium trifluoroacetate, in an appropriate solvent, such as t-butanol, generates a ketoester of formula 46. Reaction of 46 with a hydrazine generates a compound of formula 47. Deprotection of nitrogen gives compounds of formula 48, see Synthesis, (9), 1984 p. 709 for a detailed description.

SCHEME 14 50 51 SCHEME 14: The treatment of a ketoester of formula 37, with an olefin, such as acrylonitrile, generates a ketoester of formula 49. The reaction of 49 with a hydrazine, generates a compound of formula 50. Deprotection of nitrogen gives compounds of formula 51 - ^^ H ^^ SCHEME 15 37 52 53 54 5 56 J¡jfá¡Í¡ & $ S tiÍÍ &iÍties iit ^^^^^^^^^ SCHEME 15: The treatment of a ketoester of formula 37 with allyl bromide and an appropriate base, such as sodium hydride, in an appropriate solvent, as DMF, it gives a ketoester of formula 52. The reaction of 52 with a hydrazine generates a compound of formula 53. The ozonolysis of 53 in an appropriate solvent, such as methylene chloride, followed by treatment with a reducing agent, such as dimethisulfoxide, gives an aldehyde of formula 54. Oxidation of 54 gives a carboxylic acid of formula 55. The Curtius rearrangement of 55, followed by hydrolysis of the isocyanate intermediate, gives a primary amine of formula 56. The treatment of a compound of formula 56 with an isocyanate or a carbamate gives a urea of formula 57. Deprotection of nitrogen gives the compounds of formula 58.

SCHEME 16 54 59 60 61 62 SCHEME 16: Treatment of a compound of formula 54 with a primary amine gives an imine of formula 59. Reduction of a compound of formula 59 gives a compound of formula 60. Treatment of a compound of formula 60 with an acylating agent gives a compound of formula 61. Deprotection of nitrogen gives the compounds of formula 62.

SCHEME 17 54 63 SCHEME 17: Treatment of a compound of formula 54 with a reducing agent, such as sodium borohydride, gives a compound of formula 63. Reaction of 63 with an acylating agent, such as isocyanate or carbamate, gives compounds of formula 64. The deprotection of the nitrogen gives compounds of formula 65. -: .- í & ^? s ¿k¿z? -.

SCHEME 18 67 SCHEME 18: Treatment of a compound of formula 63 with a phosphine, such as triphenylphosphine, and an azo compound, such as diethyl azodicarboxylate and an oxindole, gives a compound of formula 66. Deprotection of nitrogen gives the compound of formula 67. -g "* - * <» ** 2 * > * 3 ** ± - ~ * SCHEME 19 37 68 69 70 H SCHEME 19: Treatment of a ketoester of formula 37 with a chiral diol and an acid catalyst with removal of water in an appropriate solvent, such as benzene, yields a chiral ketal of formula 68. The alkylation of 68 with an alkyl halide in the presence of of a base such as LDA followed by an acid-catalyzed hydrolysis of the ketal gives the chiral ketoesters of formula 69. The reaction of 69 with a hydrazine generates chiral compounds of formula 70. Deprotection of nitrogen gives compounds of formula 71.

SCHEME 20 37 72 H 71 FIGURE 20: Treatment of a ketoester of formula 37 with a chiral amino acid ester, such as the tert-butyl ester of va na, yields a chiral enamine of formula 72. The alkylation of 72 with an alkyl halide in the presence of a base, such as LDA, followed by the acid-catalyzed hydrolysis of the enamine of the chiral ketoesters of formula 69. The reaction of 69 with a hydrazma generates the chiral compounds of formula 70. Deprotection of nitrogen gives the compounds of formula 71.

SCHEME 21 chiral H 71 SCHEME 21: The deprotection of the nitrogen of the 25 gives compounds of formula 28. The formation of the salt of 28 with a chiral acid gives a mixture of diastereomeric salts of formula 73. The crystallization of the salts ^ «TeAí ^. ^^ i- ^ i? yea i., .... ^^ diastereomeric gives the acid salt of the chiral compounds of formula 70. The decomposition of the salt 70 with the base liberates the chiral compounds of Formula 71 SCHEME 22 28 25 , 100 75 74 SCHEME 22: Alkylation of compounds of formula 25 with an allylic acetate in the presence of an appropriate catalyst such as palladium tetrakis (triphenylphosphine) affords compounds of formula 74. Deprotection of i ^ aaaa .. ^? JS? ^ Ma? m s ^ md nitrogen gives the compounds of formula 75, see Tetrahedron (50), p. 515, 1994, for a detailed discussion.

SCHEME 23 H 80 SCHEME 23: Treatment of a cetodiéster of formula 76 with an alkyl halide in the presence of a base such as sodium hydride, followed by acid catalyzed hydrolysis and decarboxylation, followed by esterification with methyliodide and a suitable base affords a compound of formula 77. Reaction of a compound of formula 77 with an appropriate aldehyde, such as formaldehyde and benzylamine affords a compound of formula 78. Reaction of a compound of formula 78 a hydrazine generates the chiral compounds of formula 79. Deprotection of nitrogen gives compounds of formula 80.

SCHEME 24 SCHEME 24: The treatment of an amine of formula 23 with an acid of formula 11 in an inert solvent, such as dichloromethane or DMF, by a ^^^ ^^ - ^ i ^ ^ ím '^ coupling reagent such as EDC EPPC in the presence of HOBT affords compounds of formula 89. Reaction of compounds of formula 89 with a hydrazine generates compounds of formula 6. Deprotection of nitrogen gives the compounds of formula 7. aZ¿.Si¿8¡¿¿¡¡ ¿¿¿SCHEME 25 93 92 93 92 ^^^^^^ ^ ^ ^^^^ SCHEME 25: The treatment of a hydroxyacetoacetate ester of formula 90 with an alkyl halide in the presence of an appropriate base, such as sodium hydride, gives the compounds of formula 91. The reaction of 91 with a hydrazine generates the compounds of formula 92. The O-alkylation of the oxygen of the carbonyl of 92 gives the 93, which is converted into the halide 94. The displacement of the halide X by the cyanide ion gives the nitrile 95. The reduction from 95 gives the primary amine 96, which is deprotected and cyclized in the presence of formaldehyde to give the 28.

SCHEME 26 99 28 SCHEME 26: The treatment of a protected beta-keto aminovalerate, such as 97, with an alkyl halide in the presence of an appropriate base, such as sodium hydride, gives the compounds of formula 98. The reaction of the compounds of formula 98 with a Hydrazine generates the compounds of formula 99. Deprotection of the compounds of formula 99 gives the primary amines of formula 100. Cyclization of the compounds of formula 100 in the presence of formaldehyde gives the compounds of formula 28.

SCHEME 27 23rd R ^ NHNH- ^^^ J? ^^^^ aí ^^^ Z ^? ^^ Sié ^? ^^^ ^ j ^ SCHEME 27: The treatment of the amine of formula 23a with an acid, such as 1, in the presence of EDC and HOAT, in a solvent suitable, provides ketoesters of formula 23b. The ketoester 23b can be treated with a hydrazine salt in the presence of sodium acetate in refluxing ethanol to give the hydrazines of formula 23c. Deprotection under appropriate conditions gives the amines of formula 4. The coupling of the intermediates of formula 4 with the amino acids of formula 5 can be carried out as described above to give the intermediates of formula 6. Deprotection of amine 6 gives the compounds of formula 7.

SCHEME 28 SCHEME 28: Prt represents an amine protecting group that is known to those skilled in the art. Prt has been used instead of BOC to illustrate the preferred protective group, but the use of BOC should not considered as limiting the scope of this description. Also, although the scheme illustrates the synthesis of the compound of formula m using particular isomers, other isomers and / or isomeric mixtures are also within the scope of the present disclosure.

Step A. To a solution of hydrochloride of 4-0x0-piperidine-3-carboxylic acid ethyl ester in an organic solvent inert to the reaction, such as IPE, THF, methylene chloride and AcOEt, with or without water as co-solvent, preferably IPE and water, an inorganic or organic base is added, such as TEA, DMAP, a hydroxide or a carbonate, preferably TEA, followed by an amino protecting group, preferably (Boc) 20. The mixture is stirred for about 1-24 hours, preferably overnight, preferably under nitrogen. The organic phase is separated and processed according to standard procedures known to those skilled in the art and concentrated to give the desired product in the form of crystals.

Step B. To a solution of 3-ethyl-1-tert-butyl ester of 4-oxo-piperidin-1,3-dicarboxylic acid in an organic solvent, such as THF, IPE, an alcohol, DNF or DMSO, preferably DMF, a Inorganic or organic base, such as TEA, DMAP, a hydroxide or a carbonate, preferably lithium carbonate, is added, followed by benzyl bromide. The mixture is heated to about 25-100 ° C, preferably 60 ° C, and stirred for about 1-24 hours, preferably 20 hours. The reaction mixture is then cooled to room temperature and extracted with an organic solvent such as IPE, toluene, THF or AcOEt and processed according to standard procedures known to those skilled in the art to give the desired product.

Step C. To a solution of 3-benzyl-4-oxo-piperidin-1,3-dicarboxylic acid 3-ethyl-1-tert-butyl ester in an organic solvent, as an alcohol, THF or toluene, methylhydrazine is added, followed by an acid, such as sulfuric acid, HCl, AcOH or TsOH, preferably acetic acid at about 0 ° C to room temperature. The reaction mixture is slowly heated to about 40-100 ° C, preferably at about 65 ° C, it is stirred for 3-10 hours, preferably about 7.5 hours. After cooling to room temperature, the organic layer is washed with 10% sodium bicarbonate and processed according to standard procedures known to those skilled in the art and concentrated to give the desired product.

Step D. The concentrated solution of step C is mixed with an organic solvent such as IPE, cooled to about 10-10 ° C, preferably 0 ° C, an acid, such as MeS03H, TFA or HCl, preferably HCl gas, is repeatedly introduced, and stirring at room temperature until hydrolysis is complete. The mixture is concentrated, an organic solvent is added, such as methylene chloride, IPE or THF, followed by a base, such as a hydroxide, a carbonate, preferably NH 4 OH. The mixture is then extracted with methylene chloride, IPE or THF and concentrated to give the desired compound.

Step E. To a solution of 3a-benzyl-2-methyl-2,3a, 4,5,6,7-hexahydro-pyrazolo [4, 3-c] pyridin-3-one in an acetone / water mixture ( water 1% to 11%, preferably water 5% in acetone), L-tartaric acid is added. The mixture is heated to 25-60 ° C, preferably to about 50 ° C and is preferably stirred overnight. The reaction mixture is cooled to preferably 10-15 ° C and the precipitates are filtered, washed with acetone / cold water and dried to give the desired compound.

Step G. 2-Aminoisobutyric acid, a base such as a hydroxide, preferably 1 N NaOH, (Boc) 20 and an organic solvent, are mixed as THF, IPE or dioxane and stir at room temperature overnight. The reaction mixture is diluted with an organic solvent, such as ethyl acetate, and adjusted to about pH 3 to 7 by adding an aqueous acid, such as HCl. The organic phase is separated and processed according to standard procedures known to those skilled in the art to give the desired product.

Step H. To a solution of 2-amino-3-benzyllooxiproponic acid in water and an inorganic or organic base, preferably TEA, 2.5-dioxo-pyrrolidin-1-yl-2-tert-ester is added. butoxycarbonylamino-2-methyl-propionic acid, in an organic solvent such as THF. The mixture is preferably stirred overnight at preferably room temperature, preferably under nitrogen. An aqueous acid, such as a 10% citric acid solution, is added to the mixture. The mixture is stirred for several minutes, then diluted with an organic solvent, such as ethyl acetate. The organic phase is separated from the mixture and processed according to standard procedures known to those skilled in the art and concentrated to give the desired product.

Steps F and I. To a solution of the L-tartrate of 3a- (R) -benzyl-2-methyl-2,3a, 4,5,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one, in an organic solvent such as ethyl acetate at about -78 to -20 ° C, preferably about 66 ° C, a base, such as TEA, is added. The mixture is stirred for 1-24 hours, preferably approximately 1.5 hours. After ^ Z.zz:?: To remove the precipitated salt, 3-benzyloxy-2- (2-tert-butoxycarbonylamino-2-methylpropionylamino) -propionic acid and a base, such as TEA, are added at about -50 up to 0 ° C, preferably about 35 ° C, followed by the addition of a reagent for the coupling of peptides, preferably the cyclic anhydride of 1-propanophosphonic acid (PPAA) in ethyl acetate. The mixture is stirred for about 1-6 hours, preferably about 2 hours at -50 ° C to 0 ° C, preferably from about -20 ° C to about -27 ° C, then slowly increasing the temperature to preferably about 0 °. C. The reaction mixture is poured into water and extracted with an organic solvent such as IPE and the organic layer is separated and processed according to standard procedures known to those skilled in the art to give the desired product.

Step J. To a solution of the tert-butyl ester of the acid. { 1- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1 - (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl] -1-methyl-ethyl} -carbamic in an organic solvent, such as methylene chloride, from about 10 to about 10 ° C, preferably about 0-5 ° C, TFA is added maintaining preferably the temperature below about 5 ° C. The temperature is then increased to room temperature, the mixture is stirred for about 1-6 hours, preferably about 3 hours. The methylene chloride is replaced by another organic solvent such as ethyl acetate. The mixture is then adjusted to a pH of 7 to 9, preferably a pH of 8, with an aqueous base, as a saturated sodium bicarbonate solution and then processed according to standard procedures known to those skilled in the art. to give the desired product.

Step KA a solution of 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] -2-methyl propionamide from step I in an alcohol, such as methanol, (L) - (+) - acid is added Tartaric and the mixture is stirred overnight. The resulting solution is filtered and concentrated. An organic solvent is added, such as IPE or ethyl acetate, and the excess alcohol is azeotropically removed. The solid which is isolated is dissolved in ethyl acetate and the solution is refluxed, then allowed to cool to room temperature to give the crystals of the desired product. The following examples are provided only for the purpose of illustrating the invention and are not intended to be limitations of the disclosed invention.

GENERAL EXPERIMENTAL PROCEDURES: Amicon silica 30 μM, 60 Á pore size, was used for column chromatography. Melting points were recorded on a Buchi 510 apparatus and given uncorrected. The proton and carbon NMR spectra were recorded on a Varian XL-300, on a Bruker AC-300, on a Varian Unity 400 or on a Bruker AC-250 at 25 ° C. Chemical shifts are expressed in parts per million downstream of trimethylsilane. The particle beam mass spectra were obtained on a Hewlett-Packard 5989A spectrometer using ammonia as a source of chemical ionization. For the dissolution of the initial sample, chloroform or methanol was used. The liquid secondary ionic mass spectra (LSIMS) were obtained on a Kratos ConcepM S high resolution spectrometer using cesium ion bombardment on a sample dissolved in a dithioerythritol and dithiothreitol 1: 5 mixture or on a thioglycerol matrix. For the dissolution of the initial sample, chloroform or methanol was used. The data given are the sums of 3-20 scans calibrated against cesium iodide. TLC analyzes were carried out using E. Merck Kieselgel 60 F 254 silica plates visualized (after elution with the solvent (s) indicated by staining with ethanolic phosphomolybdic acid and heating on a hot plate) General procedure A (for coupling peptides EDC is used): A 0.2-0.5 M solution of the primary amine (1.0 equivalent) in dichloromethane (or a primary amine hydrochloride and 1.0-1.3 equivalents of triethylamine) is treated sequentially with 1.0-1.2 equivalents of the partner of carboxylic acid coupling, 1.5-1.8 equivalents of hydroxybenzotriazole hydrate (HOBT) or HOAT and 1.0-1.2 equivalents (stoichiometrically equivalent to the amount of carboxylic acid) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and the mixture is stirred overnight in an ice bath (the ice bath is allowed to warm up so that the reaction mixture is generally maintained at about 0-20 ° C. for approximately 4-6 h and approximately at 20-25 ° C for the remaining period). The mixture is diluted with ethyl acetate or other solvent, as specified, and the resulting mixture is washed twice with 1N NaOH, twice with 1 N HCl (if the product is not basic), once with brine, dried Na 2 SO and concentrated giving the crude product, which is purified as specified. The carboxylic acid component can be used as the dicyclohexylamine salt to couple to the primary amine or the latter hydrochloride; in this case, triethylamine is not used.

EXAMPLE 1 2-Amino-N- hydrochloride. { 1 (R) -benzyloxymethyl-2-r3a- (R) -4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6-hexahydro-pJra2? Lor4,3-c1pyridin-5 -in-2-oxo-ethyl) -isobutyramide and 2-Amino-N- Hydrochloride. { 1 (R) -benzyloxymethyl-2-f3a-S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolor-4,3-clpyridin- 5-ill-2-oxo-ethyl) -isobutyramide.

A. 3-ethyl-1-tert-butyl ester of 4-oxo-piperidin-1,3-dicarboxylic acid. A mixture of 8.00 g (38.5 mmol) of 4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride, 9.23 g (42.4 mmol) of di-tert-butyl dicarbonate and 3.89 g (38.5 mmol) of triethylamine in 150 mL of THF were stirred at room temperature for approximately 72 h. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed three times with 10% aqueous HCl, a saturated aqueous solution of sodium bicarbonate and brine, dried over MgSO4 and concentrated to give 10.0 g of 1A as a white solid. . MS (Cl, NH3) 272 (MH +).

B. 3- (R, S) - (4-Fluoro-benzyl) -4-oxo-piperidin-1,3-dicarboxylic acid 3-ethyl ester 1-tert-butyl acid To a solution of 2.00 g (7.4 mol) of 1A in 10 ml of DMF were added 282 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for approximately 15 min. A solution of 1.39 g (7.4 mmol) of 4-fluorobenzyl bromide in 7 ml of DMF was added to the stirring solution and the mixture was stirred for about 72 h at room temperature. The mixture was diluted with ethyl acetate and washed once with water and four times with brine, dried over MgSO4 and concentrated to give 2.8 g of 1 B. MS (Cl, NH3) 380 (MH +).

C. 3a- (R, S) - (4-Fluoro-benzyl) -2-methyl-3-oxo-2,3,3aA67-hexahydro-pyrazolor4,3-clpridin-5-tert-butyl ester carboxylic A mixture of 2.54 g (6.7 mmol) of 1B and 309 mg (6.7 mmol) of methylhydrazine in 100 ml of ethanol was heated to reflux for about 8 h. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated to reflux for about 17 h. The mixture was concentrated and the residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate: hexane 18:82 v / v) to (ethyl acetate: hexane 75:25 v / v) giving 1.0 g of 1C as a colorless oil. MS (Cl, NH3) 362 (MH +).

D. Trifluoroacetate of 3a- (R. SH4-fluoro-benzin-2-methyl-2,3,3a.4,5,6,7-hexahydro-pyrazolo | 4,3-clpiridin-3-one A 1.00 g (2.8 mmoles) of 1C was added 10 ml of trifluoroacetic acid at about 0 ° C and the mixture was stirred for about 1 h, ethyl acetate was added and the mixture was concentrated to give 1.0 g of 1D.MS (Cl, NH3) 263 ( MH + > E. (R) -3-Benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -propionic acid A 1.83 g (6.2 mmoles) of Nt-BOC-O-benzyl-D-serine in 35 ml of DMF was added 1.02 g (7.4 mmoles) of potassium carbonate followed by 0.92 g (6.5 mmoles) of iodomethane. The mixture was stirred overnight at about 24 ° C under a nitrogen atmosphere. The reaction mixture was diluted with 200 ml of water and extracted three times with ethyl acetate. The combined organic fractions were washed five times with water and once with brine, dried over MgSO4 and concentrated. The crude (R) -3-benzyloxy-2-tert-butoxycarbonyl-amino-propionic acid methyl ester was dissolved in 15 ml of cold trifluoroacetic acid at about 0 ° C and the mixture was stirred for about 2 h. The mixture was concentrated and the residue was diluted with 1 N NaOH and extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4 to give 0.84 g (4.02 mmol) of the (R) -2-amino-3-benzyloxy-propionic acid methyl ester, which was coupled at 0.81 g (4.02 mmol). of Nt-BOC-α-methylalanine giving 1.80 g of the (R) -3-benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -propionic acid methyl ester. The crude product was dissolved in 20 ml of THF: water 4: 1 and a solution of 335 mg (7.98 mmoles) of lithium hydroxide hydrate in 1 ml of water was added to the solution and the mixture was stirred overnight. room temperature. The mixture was concentrated and the residue was diluted with ethyl acetate and acidified with aqueous HCl and extracted three times with ethyl acetate. The organic extracts were combined and washed once with brine, dried over Na 2 SO and concentrated giving 1.60 g of 1E as an oil, which solidified upon standing. 1 H NMR (CDCl 3 300 MHz) d 7.30 (m, 5 H), 7.10 (d, 1 H), 5.07 (br s, 1 H), 4.68 (m, 1 H), 4.53 (q, 2 H), - 39 (m, 1 H), 3.68 (m, 1 H), 1.3-1.5 (m, 15 H).

F. (1- {1 (R) -benzyloxy-methyl-2-f3a- (R, S) - (4-fluoro-benzy-2-methyl-3-oxo-2-tert -butyl ester, 3.3a.4,6,7-hexahydro-pyrazolof4.3-c1pyridin-5-ill-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid According to the method indicated in the General Procedure A, 193 mg (0.51 mmoles) of 1 D and 196 mg (0.51 mmoles) of 1E were coupled giving a mixture of diastereomers. The residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate: hexane 1: 1 v / v) to 100% ethyl acetate to give 60 mg of the less polar 1 F 1 isomer and 100 mg of the isomer 1 F 2 more polar. MS (Cl, NH3) 624 (MH +) for both isomers.

G. 2-amino-NM (R) -benzyloxymethyl-2-r3a- (R) - (4-f) uoro-benzyl) -2-methyl-3-oxo-2.3.3a.4,6,7 hydrochloride hexahydro-pyrazolof4,3-c1pyridin-5-ill-2-oxo-ethyljisobutyramide To 60.0 mg (0.10 mmol) of the 1-F-1 isomer in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was added. stirred at room temperature for approximately 2 h. The mixture was concentrated and the residue was precipitated in ethanol / hexane to give 50 mg of the 1G 1 isomer as a white powder. MS (Cl, NH3) 524 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.32 (m, 5 H), 7.12 (m, 2 H), 6.91 (m, 2 H), 5.15 (m, 1 H), 4.54 (s, 2 H), 3.78 (m, 2 H), 3.02 (m, 7 H), 2.66 (m, 2 H), 1.57 (s, 6 H).

H. 2-amino-N- (1 (R) -benzyloxymethyl-2-r3a- (S) - (4-fluoro-benzyl-2-methyl-3-oxo-2.3.3a.4.6.7) hydrochloride hexahydro-pyrazoloyl-4,3-c1pyridin-5-ill-2-oxo-ethyljisobutyramide To 100 mg (0.16 mmol) of the 1F 2 isomer in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature. The mixture was concentrated and the residue was precipitated in ethanol / hexane to give 60 mg of the 1H 2 isomer as a white powder: MS (Cl, NH 3) 524 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.32 (m, 5 H), 7.08 (m, 2 H), 6.95 (m, 2 H), 6.80 (m, 2 H), 5.30 (m, 1 H), 4.61 (m, 3 H), 3.80 (m, 2 H), 2.58 (m, 3 H), 1.58 (s, 6 H).

EXAMPLE 2 2-amino-N-r2-r3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3aA6,7-hexahydro-pyrazole-4,3-hydrochloride c1pyridin-5-n-1 (R) - (1 H -indol-3-ylmethyl) -2-oxo-ethylisobutyramide A. (R) -2-amino-3-r (1 H-indol-3-iQ-propionic acid) methyl ester 4.92 g (16.2 mmol) of Nat-BOC-D-tryptophan in 100 ml of DMF were added 2.46 g (17.8 mmol) of potassium carbonate followed by 2.41 g (17.0 mmol of iodomethane and the mixture was stirred overnight at 24 ° C under nitrogen) The reaction mixture was diluted with water and extracted three times with acetate The combined organic fractions were washed five times with 500 ml of water and once with brine, dried over MgSO4 and concentrated to give 4.67 g of a white solid to the methyl ester of (R) -2-tert. crude butoxycarbonylamino-3- (1H-indol-3-yl) -propionic acid was added 15 ml of cold trifluoroacetic acid at about 0 ° C and the mixture was stirred for about 2 h. The mixture was concentrated and the residue was diluted with NaOH 1 N and extracted three times with ethyl acetate.The combined organic extracts were washed with brine and dried over Na 2 SO giving the (R) -2-amino-3- (1 H -indol-3-yl) -propionic acid methyl ester as an orange oil with a quantitative yield.

B. (R) -2- (2-tert-Butoxycarbonyl-amino-2-methyl-propionylamino) -3- (1 H -indol-3-yl) -propionic acid methyl ester The crude product from step 2A 1.55 g (7.1 mmol) was coupled to 1.44 g (7.1 mmol) of Nt-BOC-α-methylalanine according to Procedure A to give an oil, which was purified by chromatography on silica gel using to elute a gradient of ethyl acetate to 10%, 20%, 30%, 40% and 50% in hexane. 1.32 g of (R) -2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -3- (1 H -indol-3-yl) -propionic acid methyl ester were recovered.

C. (R) -2- (2-tert-Butoxycarbonylamino-2-methyl-propionylamino) -3- (1 H -indol-3-yl) -propionic acid To a solution of 1.03 g (2.64 mmol) of 2B in 10 ml of THF was added 381 mg (9.1 mmol) of lithium hydroxide hydrate in 2 ml of water and the mixture was stirred overnight at room temperature. The excess THF was removed by evaporation and the basic aqueous mixture was extracted three times with ethyl acetate and then acidified to pH 4 with acetic acid or dilute hydrochloric acid. The product was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4 and evaporated giving 1.03 g of 2C as an orange foam. MS (Cl, NH3) 390 (MH +). 1 H NMR (CDCl 3 300 MHz) d 7.61 (d, 1 H), 7.48 (d, 1 H), 7.27 (t, 1 H), 7.10 (t, 1 H), 4.81 (s at, 1 H), 3.35 ( m, 1 H), 1.49 (s, H), 1.32 (s, 9 H).

D. (1-r2-y3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo- 2.3.3a.4.6.7-hexahydro-pyrazole-4-tert-butyl ester -clpyridin-5-ill-1 (RW1 H-indol-3-ylmethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl) -carbamic acid According to the method indicated in General Procedure A, 193 mg were coupled (0.51 mmoles) of 1D and 200 mg (0.51 mmoles) of 2C and the residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate: hexane 1: 1 v / v) to ethyl acetate 100 % yielding 230 mg of 2D, MS (Cl, NH3) 633 (MH +).

E. 2-amino-N-f2-r3a- (R, S) - (4-fluoro-benzyl) -2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolor4 hydrochloride. 3-c1pyridin-5-in-1 (R) - (1 H -indol-3-ylmethyl-2-oxo-etyl-isobutyramide) To 230 mg (0.36 mmoles) of 2D in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for about 2 h.The mixture was concentrated and the residue was precipitated from ethanol / hexane giving 130 mg of 2E as a white powder MS (Cl, NH3) 533 (MH +). NMR (CD3OD): (partial) d 7.79 (d, 1 H), 7.48 (m, 1 H), 7.33 (m, 2 H), 7.19-6.77 (m, 7 H), 6.54 (m, 1 H) , 5.17 (m, 1 H), 4.02 (m, 1 H), 3.11-2.68 (m, 6 H), 2.47 (m, 2 H), 2.03 (m, 2 H), 1.59 (m, 6 H) .

EXAMPLE 3 2-amino-N-r2-r3a- (R, S) -benzp-2-methyl-3-oxo-2.3.3a, 4,6,7-hexahydro-pyrazoloyl-4,3-clpyridin-5 in-1 (R) - (1 H-indol-3-ylmethyl) -2-oxo-etip-isobutyramide A. 4-Oxo-piperidin-1,3-dicarboxylic acid 3-methyl-1-tert-butyl ester To a mixture of 7.00 g (36.2 mmol) of 4-oxo-p-rperidin-3-carboxylic acid methyl ester and 8.82 (72.3 mmoles) of 4,4-dimethylaminopipdine in 200 ml of methylene chloride at about 0 ° C, a solution of 7.88 g (36.2 mmoles) of ditertiary butyl dicarbonate in 150 ml of methylene chloride was added. for approximately 30 min. The mixture was warmed to room temperature and then stirred for about 17 h. The mixture was concentrated and the residue was diluted with chloroform and washed three times with 10% aqueous HCl, a saturated aqueous solution of sodium bicarbonate and brine, dried over MgSO0 and concentrated to give 9.18 g of a light yellow oil.

B. 3- (R. S) -benzyl-4-oxo-p? Peridin-1, 3- dicarboxylic acid methyl ester-3-tert-butyl acid To a solution of 5.00 g (19.4 mmol) of 3A in 10 ml from DMF was added 745 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for approximately 15 min. A solution was added via a cannula.

Then, 3.32 g (19.4 mmoles) of benzyl bromide in 15 ml of DMF was added to the stirring solution and the mixture was stirred for about 42 h at room temperature. The mixture was diluted with ethyl acetate and washed once with water and four times with brine, dried over MgSO4 and concentrated to give 6.0 g of 3B as a yellow oil. MS (Cl, NH3) 348 (MH +).

C. 3a- (R. S) -benzD-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazole-4,3-clpyridin-5-tert-butyl ester A mixture of 4.00 g (11.5 mmol) of 3B and 530 mg (11.5 mmol) of methylhydrazine in 100 ml of ethanol was heated to reflux for about 8 h. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated to reflux for about 17 h. The mixture was concentrated and the residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate: hexane 15:85 v / v) to (ethyl acetate: hexane 75:25 v / v) giving 2 , 6 g of 3C as a colorless oil. MS (Cl, NH3) 344 (MH +).

D. 3a- (R, S) -benzyl-2-methyl-2,3a, 4,5,6,7-hexahydro-pyrazolor4,3-c1pyridin-3-one A 2.60 g (7.6 mmoles) of 3C were added 20 ml of trifluoroacetic acid at about 0 ° C and the mixture was stirred for about 2.5 h. Ethyl acetate was added and the solution was washed with NaOH 6N, dried over MgSO4 and concentrated giving 1.8 g of 3D. MS (Cl, NH3) 244 (MH +).

E. (1-f2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2,3.3a.4.6.7-hexahydro-pyrazolor4.3-clpyridine tert-butyl ester -5-in-1 (R) - (1 H-indol-3-ylmethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl) -carbamide In accordance with the method set forth in General Procedure A, 125 mg (4.6 mmoles) of 3C and 1.75 g (0.51 mmoles) of 2C were coupled and the residue was purified by chromatography on silica gel using an elution gradient of (ethyl acetate: hexane 6: 4 v / v) to 7% methanol in ethyl acetate giving 150 mg of 3E.F. 2-amino-N-r2-f3a- (R. S) -benzyl-2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazoleof4,3-clpridine-5-hydrochloride -yl) -1 (RH1 H-indol-3-ylmethyl) -2-oxo-etn-isobutyramide To 150 mg (0.24 mmoles) of 3E in 15 ml of ethanol was added 5 ml of concentrated HCl and the mixture was mixed. stirred at room temperature for approximately 3 h. The mixture was concentrated and the residue crystallized from ethanol / hexane to give 100 mg of 3F. MS (Cl, NH3) 515 (MH +). 1 H NMR (CD3OD) d 7.20-6.91 (m, 9 H), 6.56 (m, 1 H), 5.17 (m, 1 H), 4.05 (m, 1 H), 2.96 (s, 3 H), 2.62 ( m, 1 H), 2.38 (m, 1 H), 2.06 (m, 2 H), 1.61 (m, 8 H).

EXAMPLE 4 2-amino-N-r2-r3a- (R) -benzyl) -2-methyl-3-oxo-2,3,3a.4.6.7- hexahydro-pyrazolor4,3-clpyridin-5-yl hydrochloride ) -1 (R) -benzyloxymethyl-2-oxo-etn-isobutyramide and 2-amino-N-r2- (3a- (S) -benzyl) -2-methyl-3-oxo-2,3-hydrochloride , 3a? 617-hexahydro-pyrazolor4,3-clpyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-etm-isobutyramide A. H-2- (3a- (R S) -benzyl-2-methyl-3-oxo-2,3,3a.4,6,7-hexahydro-pyrazoloyl-4-tert-butyl ester -c1pyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl] -1-methyl-ethyl} -carbámico According to the method indicated in the General Procedure A, 1.12 g (4.6 mmoles) of 3C and 1.75 g (0.51 mmoles) of 1E were coupled giving a mixture of diastereomers. The residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate: hexane 1: 1 v / v) to 100% ethyl acetate to give 350 mg of the less polar 4A isomer and 250 mg of the 4A isomer 2 more polar. MS (Cl, NH3) 606 (MH +) for both isomers.

B. 2-Amino-N-2 - (3a- (R) -benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazoloyl-4,3-hydrochloride clpiridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethylisobutyramide 250 mg (0.41 mmol) of the 4A 1 isomer in 15 ml of ethanol was added with 5 ml of concentrated HCl and the mixture was stirred at room temperature. environment for about 5 h. The mixture was concentrated and the residue was precipitated from ethanol / hexane and dried under vacuum to give 130 mg of 4B isomer 1. MS (Cl, NH3) 506 (MH +). 1 H NMR (CD 3 OD): d 7.33 (m, 5 H), 7.14 (m, 5 H), 5.22 (m, 1 H), 4.57 (m, 3 H), 3.80 (m, 2 H), 3.14 (m , 1 H), 3.04 (s, 3 H), 2.96 (m, 2 H), 2.61 (m, 2 H), 1.63 (m, 7 H).

O 2-amino-N-r2- (3a- (S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-p¡razolof4 hydrochloride, 3-Clpyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethylisobutyramide To 250 mg (0.41 mmol) of the 4A 2 isomer in 15 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for about 5 h. The mixture was concentrated and the residue was precipitated from ethanol / hexane and dried under vacuum to give 120 mg of the 4C 2 isomer. MS (Cl, NH3) 506 (MH +). 1 H NMR (CD 3 OD): d 7.31 (m, 5 H), 7.13 (m, 5 H), 6.78 (m, 1 H), 5.28 (m, 1 H), 4.62 (m, 3 H), 3.81 (m , 2 H), 3.14 (m, 1 H), 2.62 (m, 3 H), 1.58 (m, 7 H).

D. 2-amino-N-r2- (3a- (R) -benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazole-4,3-methanesulfonate Clpyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethylisobutyramide Saturated aqueous sodium bicarbonate was added to 3.60 g (6.6 mmol) of the 4B 1 isomer and the mixture was extracted with ethyl acetate . The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate, cooled to about 0 ° C and 0.43 ml (6.6 mmoles) of methanesulfonic acid was added and the mixture was stirred for about 0.5 h. Hexane (200 ml) was added to the solution and the mixture was stirred for about 1 h and filtered to give 3.40 g of a white solid. The solid crystallized from 3% aqueous ethyl acetate to give 2.55 g of the 4D 1 isomer as a crystalline solid. MS (Cl, NH3) 506 (MH +).

EXAMPLE 5 2-Amino-NH - (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolor-4,3-c-pyridine-5-carbonyl hydrochloride ) -4-phenyl- (R) -butyne-isobutyramide and 2-amino-N-ri- (3a- (S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6-Hydrochloride, 4,6 , 7-hexahydro-pyrazolor4,3-clpyridine-5-carbonyl) -4-phenyl- (R) -butyne-isobutyramide A. 2-Oxo-5,6-diphenyl-3- (3-phenol-allyl) -morpholine-4-carboxylic acid t-butyl ester To a solution at approximately -78 ° C of 13.8 g (70.0 mmol) ) of cinnamyl bromide and 4.94 g (14.0 mmol) of t-butyl- (2S) carboxylate, 3R) - (+) - 6-oxo-2,3-diphenyl-4-morpholine in 350 ml of anhydrous THF was added 28 ml (28 mmol) of 1 M sodium bistrimethylsilylamide in THF. The mixture was stirred at about -78 ° C for about 1.5 h and then poured into 750 ml of ethyl acetate. The mixture was washed twice with brine, dried over MgSO4 and concentrated to give a yellow oil. The oil was stirred in 150 ml of hexane overnight and the precipitated solid was then collected by filtration giving 3.2 g of 5A as a white solid.

B. 5 (S). 6 (R) -diphenyl-3 (R) -3 (phenyl-allyl) -morpholin-2-one 2.97 g (6.33 mmoles) of 5A were added 20 ml of trifluoroacetic acid at about 0 ° C and the mixture was stirred for about 2 h and then concentrated. The residue was dissolved in water and made alkaline with aqueous NaOH until a pH of 10 was maintained. The mixture was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO and concentrated to give a orange oil which was purified by chromatography on silica gel (ethyl acetate: hexane 10:90 v / v) giving 880 mg of 5B as a white solid.

C. 2- (R) -amino-5-phenyl-pentanoic acid A mixture of 440 mg (1.19 mmol) of 5B and 120 mg of palladium chloride in 20 ml of ethanol and 10 ml of THF was hydrogenated at 45 psi during approximately 16 h. The mixture was filtered through diatomaceous earth and concentrated and the residue was triturated with ether to give 240 mg of 5C as a white solid.

D. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester To a suspension of 5.0 g (24.6 mmol) of Nt-BOC-a-methylalanine in 13.5 ml of sodium chloride. methylene was added 3.40 g (29.6 5 mmoles) of N-hydroxysuccinamide and 5.65 g (29.6 mmoles) of EDC. The suspension was stirred for about 17 h at room temperature. The mixture was diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate and brine was washed twice with water. It was dried over MgSO and concentrated. The product was purified by chromatography on silica gel (1: 1 v / v ethyl acetate: hexanes) to give 5.2 g of the title compound of this part D as a white solid.

E. (R) -2- (2-tert-Butoxycarbonylamino-2-methyl-propylamino) -5-phenyl-pentanoic acid A mixture of 203 mg (1.05 mmol) of 5D, 378 mg (1.26 mmol) of 5C and 434 mg (3.36 mmoles) of diisopropylethylamine in 2 ml of DMF was stirred overnight. The mixture was diluted with ethyl acetate and extracted twice with 1N HCl. The aqueous phase was extracted once with ethyl acetate. The combined organic extracts were washed three times with water and once with brine. The mixture was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using 80% chloroform in hexane followed by 100% chloroform followed by 10% methanol in chloroform to give 127 mg of 5E. ^ í ta¡ ^? x! ^^ -í-, F. (1- [1- (3a- (R, S) -benzyl-2-methyl-3-oxo-2,3-tert -butyl ester) , 3a, 4,6,7-hexahydro-pyrazolor4,3-clpiridin-5-carbonyl) -4-phenyl- (R) -butylcarbamoyl-1-methyl-ethyl) -carbamic acid According to the method indicated in the General Procedure A, 130 mg (0.53 mmoles) of 3C and 200 mg (0.53 mmoles) of 5E were coupled giving a mixture of diastereomers. The residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate: hexane 1: 1 v / v) to 100% ethyl acetate to give 40 mg of the less polar 5F 1 isomer and 40 mg of the 5F isomer 2 more polar. MS (Cl, NH3) 604 (MH +) for both isomers.

G. 2-amino-NH - (3a- (RVbenzyl-2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrrazolor4,3-clpyrdin-5-carbonp 4-Phenyl- (R) -butyl isobutyramide To 40 mg (0.07 mmol) of the 5F 1 isomer in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for about 4 h. The mixture was concentrated and the residue was precipitated in methylene chloride / hexane, dried in vacuo to give 30 mg of the 5G 1 isomer. MS (Cl, NH 3) 504 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.19 (m, 10 H), 4.37 (m, 1 H), 3.02 (m, 6 H), 2.67 (m, 4 H), 1.83 (m, 4 H), 1.62 (s, 6 H), 1.28 (m, 1 H) ).

¿Jfi & H. 2-amino-N-l - (3a- (S -benzyl-2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolo [4.3-clpridine-5-carbonyl] hydrochloride] -4-phenyl- (R) -butyl isobutyramide To 40 mg (0.07 mmol) of the 5F 2 isomer in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for about 4 h. The residue was concentrated and the residue was precipitated in methylene chloride / hexane, dried under vacuum to give 30 mg of the 5H 2 isomer. MS (Cl, NH 3) 504 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.25 (m, 9) H), 6.88 (m, 1 H), 3.04 (s, 3 H), 2.71 (m, 4 H), 2.48 (m, 2 H), 1.75 (m, 4 H), 1.62 (m, 6 H) , 1.28 (m, 1 H).

EXAMPLE 6 2-amino-N-r2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6-hexahydro-pyrazolor-4,3-c-pyridin-5-yl hydrochloride ) -1- (R) -benzyloxymethyl-2-oxo-ethyl-1-isobutyramide A. (1-r2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2,3.3a.4.6.7-hexahydro-pyrazolof4,3-clpyridin-5-tert-butyl ester -yl) -1- (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl) -carbamic acid According to the method indicated in General Procedure A, 200 mg (0.82 mmol) were coupled. of 3C and 320 mg (0.82 mmoles) of 1E giving a mixture of diastereomers. The residue was purified by chromatography on silica gel using an elution gradient from (ethyl acetate). see ethyl: hexane 1: 1 v / v) to 10% methanol in ethyl acetate to give 170 mg of 6A.

B. 2-amino-N-r2- (3a- (R, S) -benzyl-2-methyl-3-oxo-2.3.3a, 4.6.7-hexahydro-pyrazolof4,3-clpyridin-5-yl hydrochloride ) -1- (R) -benzyloxymethyl-2-oxo-etyl-isobutyramide To 170 mg (0.28 mmoles) 6A in 20 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for about 2.5 h. The mixture was concentrated and the residue was precipitated in ethanol / hexane to give 70 mg of 6B. MS (Cl, NH3) 506 (MH +). 1 H NMR (CD 3 OD): d 7.32 (m, 5 H), 7.16 (m, 1 H), 5.22 (m, 1 H), 4.67 (m, 1 H), 4.55 (m, 2 H), 3.79 (m , 2 H), 3.12 (m, 2 H), 3.00 (m, 6 H), 2.71 (m, 3 H), 1.56 (m, 8 H).

EXAMPLE 7 2-amino-N-f2- (3a-benzyl-2-ethyl-3-oxo-2, 3, 3a.4.6.7- hexahydro-pyrazolof4,3-c1pyridin-5-yl) -1-hydrochloride - (1H-indol-3-methylmethyl) -2-oxo-etin-isobutyramide A. 3a- (R, S) -benzyl-2-ethyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrrazolo [4.3-clpyridine-5-carboxylic acid tert -butyl ester A 555 mg (1.60 mmol) 3B in 27 ml of ethanol was added 240 mg of (1.60 mmol) of ethylhydrazine oxalate and the mixture was heated to reflux for about 4 h. The mixture was concentrated and the residue was purified by chromatography on silica gel using an elution gradient from (hexane: ethyl acetate 10: 1 v / v) to (hexane: ethyl acetate 3: 7 v / v) giving 357 mg of 7A. MS (Cl, NH3) 358 (MH +).

B. 3a- (R. S) -benzyl-2-ethyl-3-oxo-2.3.3a, 4.6,7-hexahydro-pyrazolor4.3-c1pyridin-3-one To 350 mg (0.98 mmoles) of 7A in 3 ml of ethanol was added 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for about 2 h. The mixture was concentrated giving 257 mg of 7B. MS (CI, NH3) 258 (MH +).

C. (1-r2- (3a- (R, S) -benzyl-2-ethyl-3-oxo-2.3.3a.4.6.7- hexahydro-p¡razolof4,3- tert -butyl ester clpyridin-5-yl) -1- (RH 1 H -indol-3-ylmethyl) -2-oxo-ethylcarbamoyl-1-methyl-et? l) -carbamic 15 According to the method indicated in the general procedure A, 82 mg (0.28 mmoles) of 7B and 100 mg (0.26 mmoles) of 2C were coupled and the residue was purified by chromatography on silica gel using an elution gradient from 100% methylene chloride to 2% methanol in Methylene chloride giving 110 mg of 7C. MS (Cl, NH3) 629 (MH +). . a¿¿S ^^ - aZ.ZA ^ D. 2-amino-N-r2- (3a- (R. S) -benc? l-2-ethyl-3-oxo-2.3.3a, 2-hydrochloride, 4.6 .7-hexahydro-p? Razolor4.3-clpridin-5-yl) -1- (R) - (1 H -indol-3-ylmethip-2-oxo-etn-isobutyramide 100 mg (0.15 mmoles) of 7 C in 2 ml of ethanol was added 1 ml of concentrated HCl and the mixture was stirred at room temperature for about 2 h The mixture was concentrated giving 72 mg of 7D as a colorless foam MS (Cl, NH3) 529 (MH +).

EXAMPLE 8 2-amino-N-r2- (3a- (R) -benzyl-2-ethyl-3-oxo-2,3,3a-6,7-hexahydro-pyrazolof 4-clpyridin-5-yl) -1- (R) hydrochloride ) -benzyloxymethyl-2-oxo-etn-isobutyramide and 2-amino-N-r2- (3a- (S) -benzyl-2-ethyl-3-oxo- 2,3,3a.4,6 hydrochloride. , 7-hexahydro-pyrazolor413-c1pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl-isobutyramide A. (1-f2- (3a-benzyl-2-ethyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolo r4,3-c1-pyridin-5-iO) tert-butyl ester -1- (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic acid According to the method indicated in general procedure A, 85 mg (0.29 mmol) of 7B and 100 mg were coupled ( 0.26 mmoles) of 1 E giving a mixture of diastereomers The residue was purified by chromatography on silica gel using an elution gradient from 100% methylene chloride to 2% methanol in methylene chloride to give 6 mg of the 8A isomer. less polar and 11 mg of the more polar 8A 2 isomer MS (Cl, NH3) 620 (MH +) for both isomers.

B. 2-amino-N-f2- (3a- (R) -benzyl-2-ethyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolof4,3-clpyridin-5-yl) hydrochloride 1- (R) -benzyloxymethyl-2-oxo-etn-isobutyramide To 5.7 mg (0.009 mmol) of the 8A 1 isomer in 1 ml of ethanol was added 0.4 ml of concentrated HCl and the mixture was stirred at room temperature for about 3 h. The mixture was concentrated giving 4.7 mg of 8B isomer 1. MS (Cl, NH3) 520 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.41-7.05 (m, 10 H), 5.20 (m, 1 H), 4.61 (m, 1 H), 4.52 (s, 2 H), 3.71 (m, 1 H ), 3.60 (m, 1 H), 2.61 (m, 3 H), 1.39 (m, 9 H).

O 2-amino-N-r2- (3a- (S) -benzyl-2-ethyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolohydrochloride [4,3-c1pyridin-5- il) -1- (R) -benzyloxymethyl-2-oxo-etill-isobutyramide To 10 mg (0.016 mmol) of the 8A 2 isomer in 1 ml of ethanol was added 0.4 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 3 h. The mixture was concentrated giving 8 mg of 8C isomer 2. MS (Cl, NH3) 520 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.43-7.00 (m, 10 H), 6.81 (m, 1 H), 5.32 (m, 1 H), 4.63 (m, 2 H), 4.53 (m, 1 H ), 3.72 (m, 1 H), 1.37 (m, 9 H).

EXAMPLE 9 2-Amino-N-r2- (2-benzyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolof 4,3-clpridin-5-yl) hydrochloride - 1 - (R) -benzyloxymethyl-2-oxo-etn-isobutyramide A. 2-Benzyl-3-hydroxy-2,4,6,7-tetrahydro-pyrazolo [4,3-clpyridine-5-carboxylic acid tert-butyl ester A mixture of 800 mg (3.11 mmol) of 3B and 495 mg (3.11 mmol) of Benzylhydrazine dihydrochloride and 423 mg (3.11 mmol) of sodium acetate trihydrate in 15 ml of ethanol was heated to reflux for about 17 h. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated to reflux for 48 h. The mixture was diluted with ethyl acetate and washed with brine, dried over MgSO 4 and concentrated and the residue was purified by chromatography on silica gel using 100% ethyl acetate followed by 5% methanol in methylene chloride giving 530 mg of 9A as a light brown solid. MS (Cl, NH3) 330 (MH +).

B. 2-benzyl-4.5.6.7-tetrahydro-2H-pyrrazolor4.3-clpyridin-3-ol To 411 mg (1.24 mmol) of 3E in 30 ml of ethanol were added ml of concentrated HCl and the mixture was stirred at room temperature for about 30 min. The mixture was concentrated, and the residue crystallized from methanol / ethyl acetate to give 353 mg of 9B. MS (Cl, NH3) 230 (MH +).

C. (1-r2- (2-Benzyl-3-hydroxy? -2,4,6,7-tetrahydro-pyrazoloyl-4-cyridyl-5-yl) -1-R-tert-butyl ester benzyloxymethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic acid According to the method indicated in General Procedure A, 100 mg (0.38 mmol) of 9B and 145 mg (0.38 mmol) of 1 E were coupled and the The residue was purified by chromatography on silica gel (methylene methochloride 95: 5 v / v) to give 42 mg of 9C as a white solid: MS (Cl, NH3) 592 (MH +).

D. 2-amino-N-r2- (2-benzyl-3-oxo-2,3,3a, 4,6,7-hexahydro-p¡razolof4,3-c1pyridin-5-yl) hydrochloride - 1- (R) -benzyloxymethyl-2-oxo-etn-isobutyramide To 42 mg (0.07 mmol) of 9D in 20 ml of ethanol was added 6 ml of concentrated HCl and the mixture was stirred at room temperature for about 30 min. The mixture was diluted with concentrated ethanol and the residue precipitated from methanol / ethyl acetate to give 35 mg of 9D as a white solid. MS (Cl, NH3) 492 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.41-7.16 (m, 10 H), 5.19 (m, 3 H), 4.48 (m, 4 H), 3.88 (m, 1 H), 3.74 (m, 2 H ), 2.68 (m, 2 H), 1.58 (m, 6 H).

EXAMPLE 10 2-amino-N- (2-r3a- (R) -benzyl-3-oxo-2- (2,2,2-trifluoro-etin-2,3.3a.4,6-hexahydro-pyrazolor) hydrochloride -c1pyridin-5-n-1- (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide and 2-amino-N- (2-r3a- (S) -henoii-3-oxo-2-hydrochloride (2,2,2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolor4,3-c1pyridin-5-l, 1- (R) -benzyl-methyl-2 -oxo-ethyl) -isobutyramide A. 3a- (R. S) -benzyl-3-oxo-2- (2.2.2-trifluoro-eti0-2,3,3a, 4,6,7-hexahydro-pyrazolo r4) tert-butyl ester 3-C1-pyridine-5-carboxylic acid A mixture of 840 mg (2.42 mmol) of 3B and 276 mg (2.42 mmol) of 2,2,2-trifluoroethylhydrazine (70% in water) in 20 ml of ethanol was heated to reflux for about 5 h and then concentrated The residue was dissolved in 40 ml of toluene and heated to reflux for about 17 h The mixture was concentrated and the residue was purified by chromatography on silica gel (hexane: ethyl acetate 9: 1 v / v) giving 703 mg of 10A as a yellow oil, MS (Cl, NH3) 412 (MH +).

B. 3a- (R, S) -benzyl-2- (2.2.2-trifluoro-ethyl) -2.3.3a.4.5.6.7-hexahydro-pyrazolor4,3-clpiridin-3-one A 600 mg (1.46 mmole) from 10A to about 0 ° C, 3 ml of cold trifluoroacetic acid was added and the mixture was stirred for about 3 h, allowing the solution to reach room temperature. The mixture was concentrated and the residue dissolved in water and the solution was basified to pH 11 with 5N NaOH and then saturated potassium carbonate. The solution was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated giving 345 mg of 10B as an opaque oil. MS (Cl, NH3) 312 (MH +).

C. (1- {2-R3a- (R S) -benzyl-3-oxo-2- (2.2.2-trifluoroethylene) -2,3,3a-tert -butyl ester, 4,6,7-hexahydro-p¡razolof4l3-clpiridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid According to the method indicated in General procedure A, 137 mg (0.44 mmoles) of 10B and 167 mg (0.44 mmoles) of 1 E were coupled giving a mixture of diastereomers. The residue was purified by chromatography on silica gel using an elution gradient from 100% methylene chloride to 5% methanol in methylene chloride to give 128 mg of the less polar 10C 1 isomer and 63 mg of the more polar 10C 2 isomer. MS (Cl, NH3) 674 (MH +) for both isomers.

D. 2-amino-N- (2-f3a- (R) -benzyl-3-oxo-2- (2.2.2-trifluoro-ethyl) -2.3.3a, 4,6,7-hexahydro-pyrazole-4,3 hydrochloride -c1pyridin-5-n-1- (R) -benzyloxymethyl-2-oxo-etiD-isobutyramide To 120 mg (0.18 mmoles) of the 10C 1 isomer in 3.5 ml of ethanol was added 1.5 ml of concentrated HCl and the mixture was mixed. The mixture was stirred at room temperature for about 2 h. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ faat ^ fe ^ - ^ ^^^ teA ^^^^^^^^ mg of the 10D 1 isomer as a grayish powder. MS (Cl, NH3) 574 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.31 (m, 5 H), 7.18 (m, 5 H), 5.21 (m, 1 H), 4.57 (m, 3 H), 4.26 (m, 1 H), 4.08 (m, 1 H), 3.79 (m, 2 H), 3.09 (m, 4 H), 2.65 (m, 2 H), 1.63 (m, 6 H).

E. 2-amino-N- (2- [3a- (S -benzyl-3-oxo-2- (2.2.2-trifluoro-ethyl) -2,3,3a, 4,6,7 hydrochloride -hexahydro-pyrrazolo [4,3-c] pyridin-5-ill-1- (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide 53 mg (0.079 mmol) of the 10C 2 isomer 3.5 ml of ethanol was added to 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for about 2 h.The mixture was concentrated to give 41 mg of the 10E 2 isomer as a pale yellow solid: MS (Cl, NH3) 574 ( MH +). 1 H NMR (CD 3 OD): (partial) d 7.33 (m, 5 H), 7.15 (m, 4 H), 6.81 (m, 1 H), 5.30 (m, 1 H), 4.67 (m, 4 H), 4.15 (m, 2 H), 3.77 (m, 2 H), 3.09 (m, 3 H), 2.64 (m, 3 H), 1.58 (m, 6 H). ? j ^ g ^ s.jf EXAMPLE 11 2-amino-N-r2- (3a- (R) -benzyl-2-tert-butyl-3-oxo-2,3,3a? 6,7-hexahydro-methanesulfonate -pyrazolor4,3-c1pyridin-5-yl) -1 - (R) -benzyloxymethyl-2-oxo-etyl-isobutyramide and 2-amino-N-r2- (3a- (S) -benzyl-2-tert. -butyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolor4,3-c1pyridin-5-ih-1- (R) -benzyloxymethyl-2-oxo-etin-isobutyramide A. 3a- (R, S) -benzyl-2-tert-butyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolo [4,3-c1pyridin-5-tert -butyl ester] At 2.07 mg (5.95 mmoles) of 14B in 40 ml of ethanol, 0.97 g (7.7 mmol) of tert-butylhydrazine hydrochloride and 0.63 g (1.7 mmol) of sodium acetate were added and the mixture was heated to about 70 g. ° C for approximately 17 h. The mixture was cooled and the solution was decanted from the precipitate and concentrated. The residue was dissolved in 80 ml of toluene and heated to reflux for about 6 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (hexane: ethyl acetate 9: 1 v / v) to give 1.7 g of 11 A. MS (Cl, NH3) 386 (MH +).

B. 3a- (R. S) -benzyl-2-tert-butyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolof4.3-clpyridin-3-one To 535 mg (1.39 mmol) of To 20 ml of methylene chloride was added 225 μl of methanesulfonic acid and the mixture was stirred for about 1.5 h at room temperature. The mixture was diluted with ethyl acetate and washed two times with 1 N NaOH and once with brine, dried over Na2SO4 and concentrated to give 246 mg of 11B. MS (Cl, NH3) 286 (MH +).

C. (1-f2- (3a- (R, S) -benzyl-2-tert-butyl-3-oxo-2,3,3a.4.6.7-hexahydro-pyrazole-4,3-tert-butyl ester clpridine-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl) -carbamic acid According to the method indicated in general procedure A, 246 mg (0.86 mmol) were coupled. ) of 11 B and 328 mg of 14F giving a mixture of diastereomers. The residue was purified by chromatography on silica gel (hexane: ethyl acetate 6: 4 v / v) to give 250 mg of the less polar 11C 1 isomer and 90 mg of the more polar 11C 2 isomer. MS (Cl, NH3) 648 (MH +) for both isomers.

D. Methanesulfonate of 2-amino-N-f2- (3a- (R) -benzyl-2-tert-butyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolo [4.3-clpyridine] -5-p-1- (R) -benzyloxymethyl-2-oxo-etm-isobutyramide. To 210 mg (0.32 mmol) of the 11C 1 isomer in 15 ml of methylene chloride at about 0 ° C was added 28 μl (0.44 mmol) of methanesulfonic acid The ice bath was removed and the mixture was stirred for about 3 h, diluted with 15 ml of diethyl ether and the solid precipitate was collected by filtration to give 100 mg of the 11 D 1 isomer. (Cl, NH3) 548 (MH +). 1 H NMR (CD3OD): (partial) d 7.33 (m, 5 H), 7.27-7.07 (m, 5 H), 5.21 (m, 1 H), 4.54 (m, 3 H), 3.86 (m, 3 H), 3.10 (m, 4 H), 2.61 (s, 3 H), 1.62 (m, 6 H), 1.18 (s, 9 H).

E. Methanesulfonate of 2-am? No-N-f2- (3a- (S) -benzyl-2-tert-butyl-3-oxo-2,3,3a, 4.6,7-hexahydro-pyrazole-4,3-clp Ridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide. To 85 mg (0.13 mmoles) of the 11C 2 isomer in 10 ml of methylene chloride at about 0 ° C was added. μl (0.32 mmoles) of methanesulfonic acid. The ice bath was removed and the mixture was stirred for about 3 h, diluted with 20 ml of diethyl ether and the solid precipitate was collected by filtration to give 46 mg of the 11E2 isomer. MS (Cl, NH3) 548 (MH +) . 1 H NMR (CD 3 OD): (partial) d 8.28 (da, 1 H), 7.32 (m, 5 H), 7.18 (m, 4 H), 6.84 (m, 1 H), 5.31 (m, 1 H), 4.60 (m, 3 H), 3.70 (m, 3 H), 3.18-2.92 (m, 3 H), 2.68 (s, 3 H), 1.57 (m, 6 H), 1.13 (s, 9 H).

"**" W (* EXAMPLE 12 2-Amino-Np - (R) - (1 H -indol-3-ylmethyl) -2- (2-methyl-3-oxo-3a- (R, S) dihydrochloride -pyridin-2-ylmethyl-2,3,3a, 4,6,7-hexahydro-pyrazolor4,3-c1pyridin-5-yl) -2-oxo-etill-isobutyramide A. 4-Oxo-3- (R, S) -pyridin-2-ylmethyl-piperidin-1,3-dicarboxylic acid 3-methyl-1-tert-butyl ester To a solution of 2.00 g (7.8 mmol) of 3A in 32 ml of THF 468 mg (11.7 mmol) of sodium hydride (60% oil dispersion) was added at about 0 ° C and the mixture was stirred for about 30 min. A solution of 762 mg (6.0 mmoles) of 2-picolyl chloride in 5 ml of THF was added to the stirring solution for about 5 min, followed by the addition of 432 mg (2.6 mmoles) of potassium iodide. The ice bath was removed and the mixture was heated for about 17 h at reflux. The mixture was diluted with ethyl acetate and washed once with water and once with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using (ether: hexane 6: 4 v / v) followed by (ethyl acetate: hexane 6: 4 v / v) to give 1.2 g of 12A. MS (Cl, NH3) 349 (MH +).

B. 2-Methyl-3-oxo-3a- (R, S) -pyridin-2-ylmethyl-2,3,3a, 4,6,7-hexahydro-pyridolof 4,3-tert-butyl ester Clpyridine-5-carboxylic acid A mixture of 1.20 g (3.45 mmol) of 12A and 159 mg (3.45 mmol) of methylhydrazine in 20 ml of ethanol was heated to reflux for about 6.5 h. The mixture was concentrated and the residue was dissolved in 25 ml of toluene and heated to reflux for about 17 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (65:35 v / v ethyl acetate: hexane) to give 450 mg of 12B. MS (Cl, NH3) 345 (MH +).

C. 2-Methyl-3a- (R. S) -pyridin-2-ylmethyl-2,3,3a.4.6.7-hexahydro-pyrazoloyl-4,3-c'-pyridin-3-one dihydrochloride A mixture of 450 mg (1.30 mmol) of 12B in 2 ml of 4M HCl / dioxane was stirred at room temperature for approximately 4.5 h. The mixture was concentrated giving 450 mg of 12C. MS (Cl, NH3) 245 (MH +).

D. Tert-butyl acid ester. { 1- [1- (1- (R) -H-indol-3-ylmethyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazole-4,3- c1pyridin-5-yl) -2-oxo-ethylcarbamoyl-1-methyl-ethyl) -carbamic acid According to General Procedure A, 108 mg (0.31 mmol) of 12C and 122 mg (0.31 mmol) of 2C were coupled. and the residue was purified by chromatography on silica gel (ethyl acetate: methanol 95: 5 v / v) to give 118 mg of 12D. MS (Cl, NH3) 66 (MH +).

E. 2-amino-N-f1- (RH 1 H -indol-3-ylmethyl) -2- (2-methyl-3-oxo-3a- (R, S) -pyridin-2-ylmethyl-2,3-dihydrochloride. 3a.4,6,7-hexahydro-pyrazolor4.3-c1pyridin-5-yl) -2-oxo-ethylisobutyramide A mixture of 110 mg (0.18 mmoles) 12D in 1 ml of 4M HCl / dioxane was stirred at room temperature for 17 h. The mixture was concentrated giving 51 mg of 12E. MS (Cl, NH3) 516 (MH +). 1 H NMR (CD3OD): (partial) d 8.91-8.52 (m, 2 H), 8.04 (m, 2 H), 7.76-7.50 (m, 3 H), 6.82 (m, 1 H), 4. 62 (m, 1 H), 3.36 (s, 3 H), 1.63 (s, 6 H).

EXAMPLE 13 2-amino-NM - (R -benzyloxymethyl-2- (2-methyl-3-oxo-3a- (R, S) -pyridin-2-ylmethyl-213,3a, 4-dihydrochloride, 6-hexahydro-pyrazolor4,3-c1pyridin-5-yl) -2-oxo-ethylisobutyramide A. (1-p- (R) -benzyloxymethyl) -2- (2-methyl-3-oxo-3a- (R, S) -pyridin-2-ylmethyl-2,3,3a, 4,6,7-hexahydro-pyrazolo-4,3-c1-pyridin-5-yl) -2-oxo-ethylcarbamoin-1-methyl ethyl) -carbamic According to General Procedure A, 86 mg were coupled (0.27 mmoles) of 12C and 103 mg (0.27 mmoles) of 1 E and the residue was purified by chromatography on silica gel (ethyl acetate: hexane 95: 5 v / v) giving 82 mg of 13A. '** £? & amp; & amp; -B 2-amino-N-f1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3a- (R, S) - dihydrochloride pyridin-2-methyl-2,3,3a, 4,6,7-hexahydro-pyrazolof4,3-clpyridin-5-yl) -2-oxo-ethylisobutyramide A mixture of 75 mg (0.12 mmol) of 13A in 1 ml of HCl 5M / dioxane was stirred at room temperature for 17 h. The mixture was concentrated giving 80 mg of 13B. MS (Cl, NH3) 507 (MH +). 1 H NMR (CD 3 OD): (partial) d 8.78 (m, 1 H), 8.46 (m, 1 H), 8.13-7.82 (m, 2 H), 7.32 (m, 5 H), 4.57 (m, 3 H), 3.96 (m, 1 H), 3.82 (m, 2 H), 1.63 (m, 6 H).

EXAMPLE 14 2-amino-N-22- (3a- (R, -benzyl-2-methyl-3-oxo-2,3,3a, 4,6J-hexahydro-pyrololor 4,3-c1pyridin- 5-l) -1- (R) - (benzyloxymethyl) -2-oxo-etinsobutyramide A. 4-Oxo-piperidin-1,3-dicarboxylic acid 3-methyl-1-tert-butyl ester 15 To a mixture of 100.0 g (516.4 mmol) of 4-oxo-pyridin-3-methyl ester carboxylic acid and 63 g (516.4 mmoles) of 4,4-dimethylaminopiperidine in 1 l of methyl chloride at about 0 ° C was added a solution of 113.0 g (516.4 mmoles) of di-tert-butyl dicarbonate in 100 ml of chloride of methylene for approximately 90 min. The mixture was slowly warmed to room temperature and then stirred for about 19 h. The mixture was washed three times with 10% aqueous HCl, a saturated aqueous solution of sodium bicarbonate and brine, dried over MgSO and concentrated giving 130.5 g of 14A as ^ ¡& ^? ^ S? S ^^ > ^^ á ^^ si & ^^ A &^ t¿ ^ í «¡J. ^^^ «-,, M ^^^^^^^^^^ ^ ^ ^ ^ ^ ^^^ S ^ kAÍ ^ AM an amorphous solid. 1 H NMR (CD 3 OD): d 4.03 (a, 2 H), 3.74 (s, 3 H), 3.56 (t, 2 H), 2.36 (t, 2 H), 1.42 (2.9 H).

B. 3- (R) -benzyl-4-oxo-piperidin-1,3-dicarboxylic acid 3-methyl-1-tert-butyl ester To a stirred suspension of 11.7 g (293 mmol) of sodium hydride 60% washed twice with 100 ml of hexane) in 100 ml of DMF was added a solution of 65.4 g (254 mmoles) of 14A in 150 ml of DMF at about 0 ° C for about 45 min. The ice bath was removed and the mixture was stirred at room temperature for approximately 45 min. The mixture was again cooled to about 0 ° C and 35.2 ml (296 mmoles) of benzyl bromide in 200 ml of DMF was added dropwise to a stirring solution and the mixture was stirred for about 23 h at room temperature. To the solution, 550 ml of water was carefully added and the mixture was stirred for about 30 min. The mixture was extracted three times with ethyl acetate and the combined organic extracts were washed five times with water, once with brine, dried over MgSO4 and concentrated giving 98 g of a yellow oil. The oil crystallized from hexane giving 71 g of 14B as a white solid. MS (Cl, NH3) 348 (MH +). 1 H NMR (CDCl 3): (partial) d 7.23 (m, 3 H), 7.13 (m, 2 H), 4.58 (m a, 1 H), 4.18 (a, 1 H), 3.63 (s, 3 H), 3.28-2.96 (m, 4 H), 2.72 (m, 1 H), 2.43 (m, 1 H), 1.44 (s, 9 H).

C. 3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazoloyl-4,3-clpyridine-5-carboxylic acid tert-butyl ester. A mixture of 47.0 g (135 mmol) of 14B, 38.9 g (270 mmol) of methylhydrazine sulfate and 44.3 g (540 mmol) of sodium acetate in 900 ml of ethanol was heated to reflux for about 17 h under nitrogen. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed three times with water and once with brine, dried over MgSO4 and concentrated to give a yellow oil. The oil was stirred in 750 mL of hexane for about 3 h giving 41.17 g of 14C as a white solid. MS (Cl, NH3) 344 (MH +). 1 H NMR (CDCl 3): (partial) d 7.19 (m, 3 H), 7.05 (m, 2 H), 4.61 (m, 2 H), 3.24 (m, 1 H), 3.09 (s, 3 H), 3.01 (m, 1 H), 2.62 (m, 4 H), 1.52 (s, 9 H).

D. 3a- (R, S) -benzyl-2-methyl-2,3,3a, 4,5,6,7-hexahydro-pyrrazolo f4,3-clpyridin-3-one hydrochloride. Anhydrous HCl was bubbled through through a solution of 24.55 g (71.5 mmoles) of 14 C in 800 ml of diethyl ether at about 0X for about 12 min. The mixture was stirred for about 3 h, during which time a precipitate formed. The solid precipitate was collected by filtration to give 19.2 g of 14D. MS (Cl, NH3) 244 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.25 (m, 3 H), 7.05 (m, 2 H), 3.77 (m, 2 H), 3.51 (d, 1 H), 3.25 (m, 1 H), 3.17 (m, 3 H), 3.03 (s, 3 H), 2.81 (m, 1 H).

E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester To a stirring solution of 100.0 g (492 mmoles) of Boc-a-methylalanine and 94.0 g (492 mmoles) ) of EDC in 2 I of methylene chloride at about OX were added in portions 56.63 g (492 mmoles) of N-hydroxysuccinamide and the reaction was allowed to warm to room temperature. The mixture was stirred for approximately 24 h and was washed twice with a saturated aqueous sodium bicarbonate solution and brine, dried over Na2SO4 and concentrated to give 124.0 g of 14E as a white solid. 1 H NMR (CDCl 3): d 4.96 (a, 1 H), 2.82 (s, 4 H), 1.66 (s, 6 H), 1.48 (s, 9 H).

F. 3- (R) -benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -propionic acid A mixture of 50.5 g (168 mmol) of 14E, 33.5 g (168 mmol) of O-benzyl D-serine and 51.05 g (505 mmoles) of triethylamine in 400 ml of dioxane and 100 ml of water was heated at about 45 ° C for about 16 h. The mixture was diluted with ethyl acetate and acidified to pH 2 with acetic acid. The layers were separated and the organic phase was washed with brine, dried over Na2SO4 and concentrated to give 650 g of 14F as a white solid. 1 H NMR (CD 3 OD): (partial) d 7.55 (d, 1 H), 7.29 (m, 5 H), 4.52 (m, 1 H), 4.48 (s, 2 H), 3.84 (d of d, 1 H ), 3.69 (d of d, 1 H), 1.42 (s, 6 H), 1.38 (s, 9 H). ^^ gS & f ^^^^^^ ^^^^^^^^ - T G. L-tartrate of 3a- (R -benzyl-2-methyl-2.3.3a.4.5,6,7-hexahydro- pyrazolof4,3-clpiridin-3-one A mixture of 5.00 g (20.6 mmol) of the free base of 14D and 3.09 g (20.6 mmol) of L-tartaric acid in 80 ml of acetone and 3.2 ml of water was heated under nitrogen at about 70X for about 70 h, during which time the reaction mixture was converted to a slurry and another 20 ml of acetone was added.The reaction mixture was cooled slowly to room temperature and then filtered. collected was washed with acetone and dried in vacuo giving 7.03 g of 14G as a white solid.

H. 3a- (R) -benzyl-2-methyl-2,3,3a, 4,5,6,7-hexahydro-pyrazolo [4,3-c1pyridin-3-one To a suspension of 5.00 g ( 12.7 mmoles) of 14G in 80 ml of methylene chloride at about 0X was added 1.72 ml (25.4 mmoles) of ammonium hydroxide and the mixture was stirred for about min. The cold solution was filtered and used immediately in the next step.

I. (tert-Butyl ester of (1-r2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazoloid-4,3-cipyridin) 5-yl) -1- (R) - (benzyloxymethyl) -2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic A mixture of 4.83 g (12.7 mmol) of 14F, the solution of 14H, 2.60 g (19.1 mmoles) of HOAT and 2.45 g (12.8 mmoles) of EDC was stirred at about OX under nitrogen for about 1 h and then warmed to room temperature and stirred for about 16 h.The mixture was filtered and the filtrate was washed with saturated aqueous bicarbonate and water, dried over MgSO4 and concentrated giving 7.35 g of 141 as a white solid.

J. 2-Amino-N-r2- (3a- (R) -benzyl-2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolof4,3-clpyridin-5-yl) -1 - (R) - (benzylloxymethanol) -2-oxo-ethyl-1-butbutyramide. To 755 mg (1.25 mmol) of 141 in 7 ml of methylene chloride at about OX was added 3.5 ml of cold trifluoroacetic acid and The mixture was stirred for about 1 h at about OX. The mixture was allowed to warm to room temperature and was stirred for about 2 h. The mixture was concentrated and co-evaporated twice with toluene. The residue was dissolved in chloroform and washed twice with saturated aqueous sodium bicarbonate and once with water and brine. The mixture was dried over MgSO4 and concentrated to give 594 mg of 14J as an oil.

EXAMPLE 15 2-Amino-Np - (R) -benzyloxymethyl-2- (2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolor-4,3-c1pyridin-5-yl) hydrochloride - 2-oxo-et¡n¡sobutyramide A. 2-Methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrrazolo [4,3-c-pyridine-5-carboxylic acid tert -butyl ester A mixture of 3.00 g (11.66 g) mmoles) of 3A and 537 mg (11.66 mmol) of methylhydrazine in 100 ml of ethanol was heated to reflux for about 17 h. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated to reflux for about 17 h. The mixture was diluted with ethyl acetate and washed twice with brine, dried over MgSO and concentrated. The residue was purified by chromatography on silica gel using an elution gradient from 100% ethyl acetate to 5% methanol in methylene chloride giving 2.28 g of 15A as a white solid. 1 H NMR (CD 3 OD): d 4.20 (s, 2 H), 3.67 (t, 2 H), 3.43 (s, 3 H), 2.58 (t, 2 H), 1.48 (s, 9 H).

B. 2-Methyl-2,3,3a.4.5.6,7-hexahydro-pyrazolor4.3-clpiridin-3-one hydrochloride A 510 mg (2.01 mmol) of 15A in 30 ml of ethanol was added ml of concentrated HCl and the mixture was stirred at room temperature for about 35 min. The mixture was concentrated and the residue crystallized from methanol / ethyl acetate to give 425 mg of 15B as a yellow solid. 1 H NMR (CD 3 OD): d 4.27 (s, 2 H), 3.71 (s, 3 H), 3.56 (t, 2 H), 3.05 (t, 2 H).

C. (1-r1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-2.3.3a.4.6,7-hexahydro-pyrazolof4.3-clpyridyl) tert-butyl ester 5-yl) -2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic acid According to the method indicated in the General Procedure A, 100 mg (0.53 mmoles) of 15B and 202 mg (0.53 mmoles) of 1E were coupled and the residue was purified by chromatography on silica gel (methylene chloride: methanol 95: 5 v / v) to give 54 mg of 15C as a white solid. EM (Cl, NH3) 516 (MH +).

D. 2-amino-N-f1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazoloyl-4-clpyrdin-5-chlorohydrate; l) -2-oxo-ethyl-1-butbutramide A 54 mg (0.10 mmol) of 15C in 30 ml of ethanol were added ml of concentrated HCl and the mixture was stirred at room temperature for about 40 min. The mixture was concentrated and the residue was precipitated from methanol / ethyl acetate to give 50 mg of 15D. MS (Cl, NH3) 416 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.28 (m, 5 H), 5.18 (m, 1 H), 4.69- 4.38 (m, 4 H), 3.88 (m, 1 H), 3.73 (m, 2 H ), 3.68 (s, 2 H), 3.61 (m, 1 H), 2.67 (m, 1 H), 1. 57 (s, 6 H).

EXAMPLE 16 2-Amino-N-r2- (2-benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolor4,3-clpyridin-5-yl) -1- hydrochloride (R ) - (1H-indol-3-ylmethyl) -2-oxo-etinisobutyramide A. 2-Benzyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo-4,3-clpyridine-5-carboxylic acid tert-butyl ester A mixture of 800 mg (3.11 mmol) of 3A and 495 mg (3.11 mmol) of benzylhydanzine dihydrochloride in 15 ml of ethanol was heated to reflux for about 17 h. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated to reflux for about 48 h. The mixture was diluted with ethyl acetate, washed twice with brine, dried over NaSO and concentrated. The residue was purified by chromatography on silica gel using an elution gradient from 100% ethyl acetate to 5% methanol in methylene chloride giving 530 mg of 16A as a brown solid. MS (Cl, NH3) 330 (MH +).

B. 2-Benzyl-2,3,3a, 4,5,6,7-hexahydro-pyrazoloyl-3,3-cpyridin-3-one hydrochloride. To 411 mg (1.24 mmol) of 16A in 30 ml of ethanol was added. ml of concentrated HCl and the mixture was stirred at room temperature for about 30 min. The mixture was concentrated and the residue crystallized from methanol / ethyl acetate to give 353 mg of 16B as a yellow solid. MS (Cl, NH3) 230 (MH +). 1 H NMR (CD 3 OD) d 7.26-7.40 (m, 5 H), 5.22 (s, 2 H), 4.12 (s, 2 H), 3.53 (t, 2 H), 3.00 (t, 2 H).

C. (R) -2- (2-tert-Butoxycarbonylamino-2-methyl-propionylamino) -3- (1 H -indol-3-yl) -propionic acid To a stirring solution of 30.6 g (0.15 mmoles) of D-tryptophan, 30.4 g (0.30 mmol) of N-methylmorpholine in 450 ml of dioxane: water (4.1) were added 45.0 g (0.15 mmol) of 14E and the mixture was stirred for about 72 h. The excess dioxane was removed by evaporation and water and ethyl acetate were added to the mixture. The pH of the solution was adjusted to 3 with concentrated HCl and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue crystallized from ethyl acetate / hexanes to give 37.0 g of an off-white solid.

D. Tert-butyl acid ester. { 1-f2- (2-benzyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolof4,3-c1pyridin-5-yl) -1- (R) - (1 H -indole -3-ylmethyl) -2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic acid According to the method indicated in General Procedure A, 100 mg (0.38 mmol) of 16B and 202 mg (0.53 mmol) were coupled. 16 C and the residue was purified by chromatography on silica gel (methylene chloride: methanol 95: 5 v / v) to give 45 mg of 16D as a white solid. EM (Cl, NH3) 601 (MH +).

E. 2-amino-N-r2- (2-benzyl-3-oxo-2.3.3a.4.6,7-hexahydro-pyrazolo [4.3-c1pyridin-5-yl] -1 hydrochloride (RH1 H- ndol-3-ylmethyl) -2-oxo-etnisobutyramide To 45 mg (0.07 mmol) of 16 D in 60 ml of ethanol was added 20 ml of concentrated HCl and the mixture was stirred at room temperature for about 35 min. The mixture was concentrated and the residue was precipitated in methanol / ethyl acetate to give 30 mg of 16E. 1 H NMR (CD 3 OD): (partial) d 7.40 (m, 4 H), 7.25 (m, 3 H), 7.11 (m, 2 H), 6.96 (m, 2 H), 6.81 (m, 1 H), 5.38 - 4.93 (m, 3 H), 4.46 (m, 1 H), 4.22 (m, 1 H), 3.96 (m, 1 H), 3.69 (m, 1 H), 3.18 (m, 1 H), 2.28 (m, 1 H), 1.57 (s, 6 H), 1.38 (m, 1 H).

EXAMPLE 17 2-Amino-N-R 1 -benzyloxymethyl-2- (2,3-dimethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolor-4,3-clpyridin-5-yl hydrochloride ) -2-oxo-etinsobutyramide A. 3-Methyl-4-oxo-piperidin-1,3-dicarboxylic acid 3- (R, S) -methyl-1-tert-butyl ester To a solution of 2.00 g (7.77 mmoles) of 3A in 30 ml of DMF was added 308 mg (7.77 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for about 25 min. To the stirred solution was added 0.50 ml (7.77 mmol) of methyl iodide and the mixture was stirred for about 17 h at room temperature. The mixture was diluted with ethyl acetate and washed once with water and four times with brine, dried over MgSO and concentrated. The residue was purified by chromatography on silica gel (hexane: ethyl acetate 7: 3 v / v) to give 1.75 g of 17A as a clear oil. MS (Cl, NH3) 272 (MH +).

B. 2,3- (R, S) -dimethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrrazol-4,3-clpyridine-5-carboxylic acid tert-butyl ester A mixture of 1.62 g (9.50 mmol) of 17A and 435 mg (9.50 mmol) of methylhydrazine in 30 ml of ethanol was heated to reflux for about 4 h. The mixture was concentrated and the residue was dissolved in 50 ml of toluene and heated to reflux for about 14 h. The mixture was diluted with ethyl acetate and washed twice with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography on silica gel (hexane: ethyl acetate 7: 3 v / v) to give 1.00 g of 17B as a white solid. MS (Cl, NH3) 268 (MH +).

O 2.3a- Hydrochloride (R, S) -dimet? L-2,3,3a, 4,5,6,7-hexahydro-pyrazolor4,3-clpiridin-3-one To 1.00 g (3.74 mmol) of 17B in 40 ml of ethanol were added 8 ml of concentrated HCl and the mixture was stirred at room temperature for about 35 min. The mixture was concentrated and the residue crystallized from methanol / ethyl acetate to give 850 mg of 17C as a white solid. EM (CI, NH3) 168 (MH +).

D. (1-f1- (R) -benzyloxymethyl-2- (2.3a- (R, S) -3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolor4.3-c1pyridin tert-butyl ester -5-p-2-oxo-ethylcarbamo? -l-1-methyl-ethyl-carbamic acid According to the method outlined in General Procedure A, 150 mg (0.74 mmol) of 17C and 514 mg (1.35 mmol) were coupled. of 1E and the residue was purified by chromatography on silica gel (hexane: ethyl acetate 85:15 v / v) to give 185 mg of 17D as a white solid.

E. 2-amino-Np- (R) -benzyloxymethyl-2- (2,3a- (R, S) -dimethyl-3-oxo-2,3,3a, 416,7-hexahydro-p-hydrochloride ? razolor4,3-clp? ridin-5-yl) -2-oxo-ethylisobutyramide To 173 mg (0.33 mmoles) of 17B in 40 ml of ethanol was added 15 ml of concentrated HCl and the mixture was stirred at room temperature for about 1 hour. The mixture was concentrated and the residue was diluted with chloroform and washed with saturated aqueous sodium bicarbonate and brine, dried over Na 2 SO and the residue was purified by chromatography on silica gel using an elution gradient from 100% ethyl acetate until 10% diethylamine in ethyl acetate. The residue was dissolved in ethanol and acidified with aqueous HCl. The mixture was concentrated and the residue crystallized from methanol / ethyl acetate to give 65 mg of 17E as a white solid. MS (Cl, NH3) 502 (MH +). 1 H NMR (CD 3 OD): (partial) d 7.32 (m, 5 H), 5.14 (m, 1 H), 4.53 (m, 3 H), 3.71 (m, 3 H), 2.97 (m, 1 H), 2.83 (m, 1 H), 2.57 (m, 1 H), 1.98 (m, 2 H), 1.61 (m, 6 H), 1.38 (s, 3 H). ¡^^ gi? EXAMPLE 18 2-Amino-N-r2- (3a- (R) -benzyl-3-oxo-2.3.3a, 4.6, 7-hexahydropyrazolof4,3-c1pyridin-5-yl) -1- (R) hydrochloride ) -benzyloxymethyl-2-oxo-etinsobutyramide and 2-amino-N-r2- (3a- (S) -benzyl-3-oxo-2,3,3a-1,4,6,7-hexahydro-5-pyrazolohydrochloride] 413-c1pyridin-5-yl) -1 - (R) -benzyloxymethyl-2-oxo-ethylisobutyramide * A. 3-Benzyl-4-oxo-p -peridin-3-carboxylic acid methyl ester To 200 mg (0.58 mmoles) of 3B to about OX was added 5 ml of cold trifluoroacetic acid and the mixture was stirred for approximately 1 h. The mixture was concentrated and the residue was co-evaporated with ethyl acetate in hexane. To the residue 2N NaOH was added to make it alkaline and the mixture was extracted with chloroform. The combined organic extracts were dried over MgSO4 and concentrated giving 18A with a quantitative yield. 15 B. Methyl ester of 3- (R S) -benzyl-1-f3-benzyl-2- (R) - (2-tert-butoxycarbonylamino-2-methyl-propionylamino) propion? Ll-4- oxo-piperidin-3-carboxylic acid According to the method indicated in the General Procedure A, 1.77 g (7.16 mmoles) of 18A and 3.04 g (8.0 mmoles) of 14F were coupled giving a mixture of diastereomers. The residue was purified by chromatography on silica gel (hexane: ethyl acetate 7: 3 v / v) giving 820 mg of the '& * -t tSsM isomer 18B 1 less polar and 1.14 g isomer 18B 2 more polar. MS (Cl, NH3) 611 (MH +) for both isomers.

C. (1- [2- (3a- (R. S) -benzyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolo [4,3-c1pyridin-5-yl] tert-butyl ester ) -1- (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic acid To a solution of 820 mg (1.32 mmol) of isomer 18B 1 in 13 ml of ethanol were added 342 (2.63 mmol) ) of hydrazine sulfate and 431 mg (5.26 mmol) of sodium acetate and the mixture was heated to reflux for about 17 h.The mixture was concentrated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. it was dried over MgSO4 and concentrated The residue was purified by chromatography on silica gel using an elution gradient from 75% ethyl acetate in hexane to 100% ethyl acetate to give 550 mg of 18C 1 isomer. Dissolution of 1.14 g (1.86 mmol) of 18B 2 isomer in 20 ml of ethanol was added 485 mg (3.73 mmol) of hydrazine sulfate and 613 mg (7.48 mmol) of sodium acetate and the mixture was it was refluxed for approximately 17 h. The mixture was concentrated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate / hexane 75:25 v / v) to give 710 mg of the 18C 2 isomer.

D. 2-amino-N-r2- (3a- (R) -benzyl-3-oxo-2,3.3a.4.6.7-hexahydro-pyrazolo [4,3-clpyridin-5-yl] -1 hydrochloride - (R) -benzyloxymethyl-2-oxo-etlylsobutyramide To 200 mg (0.34 mmol) of the 18C 1 isomer in 12 ml of ethanol was added 6 ml of concentrated HCl and the mixture was stirred at room temperature for about 2.5 h. The mixture was concentrated and coevaporated three times with ethanol to give 20 mg of the 18D isomer 1. MS (Cl, NH3) 492 (MH +). 1 H NMR (CD 3 OD): (partial) d 8.42 (da, 1 H), 7.35 (m, 5 H), 7.18 (m, 5 H), 5.23 (m, 2 H), 4.91 (m, 1 H), 4.54 (m, 4 H), 3.80 (m, 2 H), 3.63 (m, 1 H), 3.12 (m, 1 H), 3.07 (m, 3 H), 2.61 (m, 3 H), 1.62 ( m, 6 H), 1.39 (m, 1 H).

E. 2-amino-N-f2- (3a- (S) -benzyl-3-oxo-2,3,3a, 416,7-hexahydro-pyrazolor-4,3-clpyridin-5-yl-1-hydrochloride - (R) -benzyloxymethyl-2-oxo-ethyljisobutyramide To 200 mg (0.34 mmoles) of the 18C 2 isomer in 12 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for about 2.5 h. The mixture was concentrated and coevaporated three times with ethanol to give 30 mg of the 18E 2 isomer. MS (Cl, NH 3) 492 (MH +). 1 H NMR (CD 3 OD): (partial) d 8.29 (day, 1 H), 7.30 ( m, 5 H), 7.11 (m 4 H), 6.88 (m, 1 H), 5.29 (m, 1 H), 4.92 (m, 1 H), 4.62 (m, 3 H), 3.91 - 3.70 (m , 3 H), 3.22 -2.95 (m, 3 H), 2.66 (m, 3 H), 1.57 (m, 6 H), 1.30 (m, 1 H), 0.89 (m, 1 H).

EXAMPLE 19 2-amino-N-H - (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3a- (R, S) -thiazol-4-ylmethyl-2,3,3a, 4,6,7-hexahydro-pyrazolor4,3-c1pyridin-5-yl) -2-oxo-ethylisobutyramide A. 4-Oxo-3- (R, SHiazol-4-ylmethyl-piperidin-1,3-dicarboxylic acid) 3-ethyl ester 1-tert-butyl acid of a solution of 300 mg (1.10 mmol) of 1A in 5 ml from THF to about OX, 67 mg (1.66 mmol) of sodium hydride (60% oil dispersion) was added and the mixture was stirred for about 30 min.A solution of 204 mg (1.21 mmol) of 4-chloromethylthiazole (Hsiao) was added. , C. N; Synth, Comm.20, page 3507 (1990)) in 5 ml of THF to the cold solution, followed by 87 mg (0.53 mmol) of potassium iodide and the mixture was heated to reflux for about 17 h The mixture was diluted with water and extracted with ethyl acetate.The combined organic extracts were dried over Na2SO and concentrated and the residue was purified by chromatography on silica gel (hexane: ethyl acetate 7: 3 v / v ) giving 90 mg of the title compound: MS (Cl, NH3) 648 (MH +).

B 2-Methyl-3-oxo-3a- (R, S) -thiazol-4-ylmethyl-2,3,3a.4,6,7-hexahydro-pyrazolo [4,3-clpyrid] tert-butyl ester N-5-carboxylic acid To 90 mg (0.24 mmol) of 19A in 2 ml of ethanol was added 11.2 mg (0.24 mmol) of methylhydrazine and the mixture was heated to reflux for about 17 h. An additional amount of 33.6 mg (0.72 mmol) of methylhydrazine was added and the mixture was heated to reflux for about 7 h. The mixture was concentrated and the residue was dissolved in 3 ml of toluene and heated to reflux for about 17 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (hexane: ethyl acetate 6: 4 v / v) to give 44 mg of 19B. MS (Cl, NH3) 648 (MH +) C. 2-Methyl-3a- (R. S) -thiazol-4-ylmethyl-2,3,3a.4,5,6,7-hexahydro-pyrazolo [4.3-clpyridin-3-one] dihydrochloride A mixture of 44 mg (0.10 mmol) of 19B in 1 mL of 4M HCl in dioxane was stirred at room temperature for approximately 4 h. The mixture was concentrated and co-evaporated with methylene chloride to give 40 mg of 19C. MS (CI, NH3) 251 (MH +).

D. Tert-butyl acid ester. { 1-f1 - (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3a- (R. S) -thiazol-4-ylmethyl-2,3,3a, 4,6,7-hexahydro-pyrazolof4 .3-chlorpyridin-5-yl) -2-oxo-ethylcarbamoyl-1-methyl-ethyl-carbamic acid According to the method outlined in General Procedure A, 40 mg (0.12 mmol) of 19C and 39 mg were coupled. (0.12 min) of 14F and the residue was purified by chromatography on silica gel (ethyl acetate: hexane 9: 1 v / v) to give 40 mg of 19D. MS (Cl, NH3) 613 (MH +).

E. 2-amino-N-f1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3a- (R. S) -thiazol-4-ylmethyl-2,3,3a, 4-dihydrochloride , 6,7-hexahydro-pyrazoloyl-4,3-clpridin-5-yl) -2-oxo-ethylisobutyramide A mixture of 40 mg (0.06 mmol) of 19 D in 1 mL of 4M HCl in dioxane was stirred at room temperature for approximately 5 h. The mixture was concentrated and co-evaporated with methylene chloride to give 40 mg of 19E. MS (CI, NH3) 513 (MH +).

EXAMPLE 20 Salt of the L-tartaric acid of 2-amino-N-f2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a-6,7-hexahydro-pyrazole-4,3- c1pyridin-5-yl) -1 (R) - (benzyloxymethyl) -2-oxo-ethylisobutyramide To 4.6 g of the title compound of Example 14 in 20 ml of methanol was added a solution of 1.36 g of L-tartaric acid in 20 ml of methanol at about OX. The mixture was warmed to room temperature, stirred for 40 min and concentrated in vacuo. The residue was diluted with 220 ml of ethyl acetate, heated to reflux for about 15 h, then stirred at about 72X for about 18 h. The mixture was cooled to room temperature and filtered to give 5.78 g of the title compound as a colorless crystalline solid.

EXAMPLE 21 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidin-1-carboxylic acid tert-butyl ester A. 3-Benzyl-4-oxo-piperidin-1-carboxylic acid tert-butyl ester A mixture of the β-ketoester (4480 mg, 12.9 mmol) and LiCl (1100 mg, 25.8 mmol) was heated in DMF ( 2.0 ml) at approximately 120X for approximately 17 h. The reaction mixture was cooled to room temperature and extracted with AcOEt (3 x 100 ml). The combined extracts were dried and concentrated in vacuo. The crude product was chromatographed on SiO2 using 20% ethyl acetate / hexanes giving 1320 mg of the desired product as a yellow oil. 1 H NMR (250 MHz CDCl 3) d 7.4 (m, 1 H), 4.2 (m, 1 H), 3.4 (m, 1 H); 3.3 (dd, 1 H), 3.05 (dd, 1 H), 2.7 (m, 1 H), 2.55 (m, 4 H), 1.5 (s, 9 H); MS (APCI): 190 (M + 1-BOC).

B. 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidin-1-carboxylic acid tert-butyl ester A solution of the product from step A of example 21 above (1320 mg, 4.56 mmol), pyrrolidine (972 mg , 13 mmol) and p-toluenesulfonic acid (33 mg) in benzene (30 ml) was refluxed through 3 A molecular sieves for approximately 17 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in benzene (10 ml) and cooled to approximately 0X. Methyl bromoacetate (1530 mg, 10 mmol) was added slowly. The reaction mixture was slowly allowed to warm to room temperature and then heated to reflux for about 17 h, at which time H20 (5 ml) was added. After refluxing for a further 2 h, the reaction mixture was cooled to room temperature and extracted with AcOEt (3 x 100ml). The combined organic extracts were dried and concentrated in vacuo. The crude residue was chromatographed on Si02 gel using 15% ethyl acetate / hexanes to give 280 mg of the product. 1 H NMR (250 MHz CDCl 3) d 7.35 (m, 5H), 4.5 (m, 1 H), 3.8 (s, 3 H), 3.4 (dd, 1 H), 3.1 (m, 1 H), 2.85 (m , 4 H), 2.6 (m, 1 H), 2.4 (m, 1 H), 1.5 (s, 9 H); MS (APCI): 362 (M + 1).

EXAMPLE 22 Ester 1-6-oxo-1-phenyl-cyclohexane-1,3-dicarboxylic acid 3-tert-butyl methyl ester A solution of diphenylmercury (890 mg, 2.5 mmol) in CHCl3 (4 ml) under N2 was heated to approximately 40X. Lead tetraacetate (1110 mg, 2.5 mmol) was added in small portions and the yellow-green solution was stirred at about 40 ° C for approximately 0.5 h. The? -cetoester (520 mg, 2.0 mmol) was then added, followed by pyridine (0.2 ml, 2.5 mmol). After 5h at about 40X, the reaction mixture was concentrated in vacuo and the residue was dissolved in ether (100ml) and filtered. The filtrate was washed with 3N H2SO4 (3x), dried and concentrated to give 616 mg of a yellow solid. Flash chromatography on Si02 gel using 25% ethyl acetate / hexanes gave 368 mg of the desired product. 1 H NMR (400 MHz CDCl 3) d 7.15 (m, 5 H), 4.4 (s, 2 H), 3.7 (s, 5 H), 2.6 (s, 2 H), 1.5 (s, 9 H). MS (APCI): 334 (M + 1). ^^^^ ... ^^ t ^ ^ S ^ S ^? Úi tS ^ i ^^ l ^^^^ EXAMPLE 23 (D) -2-amino-3- (2,4-dichloro- benzyloxy) -propionic A. Acid- (D) -2-tert-butoxycarbonyl-3- (2, 4-dichloro-benzyloxy) -propionic acid To a stirred solution of boc-D-serine (8.2 g, 40 mmol) in DMF (75 ml) at about OX was added NaH (60% dispersion, 3.2 g, 80 mmol ) for approximately a period of 10 minutes. The reaction mixture was stirred for about 1.75 h at about OX, then about 0.25 h at room temperature. After cooling to approximately 0X, a solution of 2,4-dichlorotoluene (5.56 ml, 40 mmol) in DMF (5 ml) was added dropwise. The reaction mixture was allowed to warm to 23X and stirred for approximately 17 h, then partitioned between diisopropyl ether and 10% HCl. The aqueous solution was extracted with diisopropyl ether (2x). The combined extracts were washed with saturated aqueous brine, dried and concentrated to give 14.75 g of the crude product, which was used without further purification. 1 H NMR (400 MHz CDCl 3) d 7.6-7.2 (m, 3 H), 5.4 (d, 1 H), 4.6 (s, 2 H), 4.0 (d, 1 H), 3.8 (dd, 2 H), 1.1 (s, 9 H). MS (APCI): 264.266 (M + 1. M + 2). * aiaitaiWM ^ teWJtjJa6i ^ 8aa-? ^ ts & ^^^^^^^^ m -...

B. (D) -2-amino-3- (2,4-dichloro-benzyloxy) -propionic acid hydrochloride The product from step A of example 23 above (14.7 g, 40 mmol) was stirred in 4M HCl / dioxane ( 100 ml) for approximately 17 h. The reaction mixture was concentrated in vacuo to give 12 g of a pale yellow solid (100%). MS (APCI): 265 (M + 1).

EXAMPLE 24 Example 24, which has the formula shown below wherein R1 is -CH2-phenyl and R2 is methyl, was synthesized analogously to the procedures described above in Examples 3C to 3F using the title compound of Example 21 as the starting material. Both diastereomers were isolated, R, R and S, R (* indicates the other stereoisomeric center at carbon C-3 of the previous structure). E.M. (M + 1) = 520; EM method = bombardment of particles.

EXAMPLES 25 and 26 Examples 25 and 26 have the formula shown below, wherein for both examples 25 and 26, R1 is phenyl and R2 is methyl, where example 25 is the R, R isomer and example 26 is the S, R isomer. Examples 25 and 26 were synthesized analogously to the procedures described in Examples 3C to 3F using the title compound of Example 22 as a starting material, followed by chromatographic separation of the two separated isomers. E.M of each example (M + 1) = 493; EM method = bombardment of particles.

EXAMPLES 27-159 Examples 27 to 159 listed in the following table were prepared according to the scheme illustrated below by coupling the appropriately substituted pyraZine-piperidine of formula I (in the following scheme) with the derivative (D) -OBnSer II (in the following scheme) of analogous to the procedures described in examples 3E and 3F.

The pyrazothion piperidines of formula I were prepared analogously to the procedures described in Examples 3B and 3C with the appropriate alkylating agent and alkylhydrazine; the derivatives (D) -OBnSer (II) were prepared in three steps analogously to the procedures described in Example 23A, Example 23B and Example 5F. - ^ uzriy ^ S »s« * \ iü. i & amp; amp; & Note: in the above table, the designation of the isomer refers to the stereochemistry at the C-3 position (indicated with the "*" in the structure) of the pyrazole-piperidine group; d1 and d2 refer to the isomers that have been separated chromatographically; d1, 2 refers to the mixture of isomers. The abbreviations used in the table above are: Fe is phenyl; PB is particle bombardment and APCI is chemical ionization at atmospheric pressure. The following NMR data are those of the compounds indicated in the table above.

EXAMPLE 37 1 H NMR (400 MHz, d 4 -MeOH): d 7.2 (m, 5 H). 5.2 (t 1 H 4.6 (m, 3 H), 3.8 (d, 2 H), 3.1 (d, 1 H), 3.0 (s, 3 H), 2.6 (dd, 2 H), 1.6 (s, 6 H).

EXAMPLES 67 AND 68 1 H NMR (300 MHz, d 4-MeOH): d 8.85 (s, 1 H), 8.6 (t, 1 H), 8.1 (d, 1 H), 8.0 (t 1 H), 7.35 (s, 5 H), 5.15 (s, 1 H), 4.6 (sa, 3 H), 3.85 (m, 2 H), 3.65 (m, 2 H), 3.2 (s) , 3 H), 2.75 (m, 2 H), 1.65 (s, 6 H).

EXAMPLE 128 1 H NMR (400 MHz, d 4 -MeOH): d 8.8 (s, 1 H), 8.6 (s, 1 H). 8.5 (t, 1 H). 7.96 (t, 1 H), 7.9 (d, 1 H), 7.45 (d, 1 H), 7.33 (d, 1 H), 5.2 (s, 1 H), 4.6 (s, 3 H, 4.4 (m, 1 H), 4.2 (m, 2 H), 3.9 (m, 4 H), 3.5 (m), 3.2 (m 2 H, 2.8 (dd, 2 H), 1.6 (s, 6 Hl) EXAMPLES 129 AND 130 1 H NMR (400 MHz, d 4 -MeOH): d 8.76 (s, 1 H), 8.50 (t, 1 H), 7.92 (dt, 2 H), 7. 43 (q, 1 H, 6.90 (t, 1 H), 5.20 (m, 1 H), 4.90 (m), 4.30 (m, 1 H), 4.20 (m, 1 H), 3.7-3.4 (m), 3.30 (s, 2 H), 3.20 (m, 1 H), 2.80 (dd, 2 H), 1.60 (s, 6 H) EXAMPLE 137 1 H NMR (300 MHz, d 4 -MeOH): d 8.7 (1. 1 H), 8.45 (t, 1 H), 7.9 (t, 2 H), 7.25 (m, 4 H), 5.2 (m, 1 H 4.95 (d, 1 H), 4.6 (s 2 H), 4.3 (m, 1 H), 3.8 (t, 2 H 3.5 (dd, 2 Hi, 2.8 (m, 1 H. 2.8 (dd, 2 H, 1.6 (s, 6 H) EXAMPLE 138 1 H NMR (400 MHz, d 4 -MeOH): d 8.8 (dd, 1 H). 8.6 ís. 1 HOUR). 8.5 ít 1 m 7.95 ÍL 1 H), 7.9 (s, 1 H). 7.3 (s.1 H), 7.0 s, 1 H). 5.2 ís. 1 I H). 4.85 yes, 3 HV, 4.4 (m, 1 H), 4.18 ym,, 1 H). 3.8 (m, 2 H). 3.5 (dd, 2 H), 3.2 id, 2 H), 2.8 (dd.2H), 1.6Is, 6H) EXAMPLES 141 and 142 1 H NMR 300 300 MHz, d 4 -MeOH): δ 8.75 (m, 1 H), 8.5 μm, 1 H, 7.9 (m, 2 H), 7.3 (s 2 H), 5.2 yr, 1 H), 4.65 yr, 1 H, 4.55 yr, 2 H), 4.35 yr, 1 H, 4.20 yr. 1 H). 3.8 ít, 1 H), 3.5 ídd, 2 H), 3.15 id. 1 H), 2.8 (dd.2 H), 1.6 (s, 2 H) EXAMPLES 160-179 Examples 160 to 179 shown in the following table were prepared according to the scheme illustrated below by coupling the suitably substituted pyrazole piperidine I (in the scheme) with the derivative (D) -Trp (III) (see Example 2C) of analogous to the procedures described in examples 3E and 3F.

Note: in the table above, the designation of the isomer refers to techemistry at the C-3 position (indicated with the "*" in the structure) of the pyrazole-piperidine group; d1y d2 refers to the isomers that have been separated chromatographically; d1, 2 refers to the mixture of isomers.

EXAMPLES 180-183 The examples 180 183 shown in the following table were prepared according to the scheme illustrated below by coupling the pyrazole-piperidine I suitably substituted with the intermediate acid IV analogously to the procedures described in Examples 3E and 3F.

The intermediate acid (IV) was prepared by treating an amino acid with the product of Example 5D using the established procedure described in Example 5F.

^ A? Note: in the above table, the designation of the isomer refers to the stereochemistry at the C-3 position (indicated with the "*" in the structure) of the pyrazole-piperidine group; d1 and d2 refers to the isomers that have been separated chromatographically; d1, 2 refers to the mixture of isomers.

EXAMPLE 184 L-Tartrate 2-amino-N-r2- (3a-IR -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolor-4,3-c1pyridin-5-yl) ) -1-ÍR) -benzyloxymethyl-2-oxo-ethyl-1-2-methyl-propionamide A. 4-Oxo-piperidin-1,3-dicarboxylic acid-1-tert-butyl ester 3-dicarboxylic acid ester of a 4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride (100 g, 0.482 mol) in IPE (725 ml) and water (360 ml) were added slowly TEA (63.5 g, 0.627 moles), followed by (Boc) 2 O (115.7 g, 0.53 moles). The mixture was stirred overnight under nitrogen. The organic phase was separated and washed with water and dried over Na 2 SO 4 and concentrated in vacuo to give the desired product as crystals (142.9 g, yield 109%) containing a small amount of IPE). ^^ ..-. zsínüíá B. Ester 3-benzyl-4-oxo-piperidin-1,3-dicarboxylic acid 1-tert-butyl ester To a solution of 3-ethyl-1-tert-butyl 4-ethyl ester -oxo-piperidin-1,3-dicarboxylic acid (73.36 g, 0.27 mol) in DMF (734 ml) was added lithium carbonate (50 g, 0.676 mol) followed by benzyl bromide (55.44 g, 0.324 mol). The mixture was heated to about 60X and stirred for about 20 hours. The reaction mixture was then cooled to room temperature and extracted with IPE, washed with water and dried over magnesium sulfate. After filtering and concentrating in vacuo, a solid was obtained. Recrystallization of the crude product from hexane gave a white solid (33.6 g, 38.2% yield).

O 3a-benzyl-2-methyl-2,3,3a, 4,5,6,7-hexahydro-pyrazolor4,3-c1pyridin-3-one To a solution of ethyl 3-tert-butyl 3-butyl ester Benzyl-4-oxo-piperidin-1,3-dicarboxylic acid (1935.97 g, 5.36 moles) in toluene (9700 ml) was slowly added methylhydrazine (292.2 ml, 5.63 moles), followed by acetic acid (235 ml, 5.68 moles) at approximately 8X. The reaction mixture was slowly heated to about 65X and stirred for about 7.5 hours. After cooling to room temperature, the organic layer was washed with 10% sodium bicarbonate. After cooling to room temperature, the organic layer was washed with 10% sodium bicarbonate, water and a saturated NaCl solution and concentrated in vacuo to low volume. The reaction was repeated on the same scale twice. Concentrated product solutions were combined and mixed with IPE (50 I), cooled to approximately OX, HCl gas was repeatedly introduced and stirred at room temperature overnight until the deprotection was complete. The mixture was concentrated in vacuo to about half the original volume, methylene chloride (24 1) was added, followed by NH OH (22 1). The mixture was then extracted with methylene chloride and concentrated to low volume (6 to 7 1). Hexane (20 1) was added and the mixture was cooled to about 15-20X. The free base product was collected in the form of crystals and dried under vacuum (2985 g total), yield 84.8%).

D. L-Tartrate of 3a- (R) -benzyl-2-methyl-2,3,3a, 4,5,6,7-hexahydro-pyrazolo [4,3-clpipdn-3-one To one solution of 3a-benzyl-methyl-2,3,3a, 4,5,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one (100 g, 0.41 mol) in a mixture of acetone / water (970 ml / 120 ml) was added L-tartaric acid (67.55 g, 0.45 moles). The mixture was heated to approximately 50X and stirred overnight. The reaction mixture was cooled to about 10-15X and the precipitates were filtered, washed with cold ketone / water and dried in vacuo. The product was obtained as a white solid (157.8 g, yield 97.83%, 99%).

E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid. 2-aminoisobutyric acid (140 g, 1.36 mol), 1 N NaOH (1620 ml, 1.63 mol) (Boc) 20 (375 ml, 1.63 mol) were mixed. and THF 420 ml and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (700 ml) and adjusted to a pH of about 3.0 by adding 6N HCl. The separated organic phase was washed with a saturated NaCl solution and concentrated to about 1/4 of the original volume. After dealing with hexane, the white solid product was isolated and collected (125.8 g, 45.44% yield). An additional 7.8 g of the product was collected from the mother liquor.

F. 2,5-Dioxo-pyrrolidin-1-yl ester of -tert-butoxycarbonylamino-2-methyl-propionic acid To a solution of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (100 g, 9,492 moles) and anhydrous succinic (60.02 g, 0.522 mol) in methylene chloride (1000 ml) was added EDC (100.09 g, 0.522 mol) while stirring under nitrogen. The mixture was stirred under nitrogen overnight. The reaction mixture was then diluted with ethyl acetate (1 L), washed with a saturated solution of sodium bicarbonate and water, then concentrated in vacuo to a low volume. In the solution, white crystals were precipitated, which were collected by filtration and dried in vacuo to give the product (104.9 g + 23.7 g, 89.5% yield).

G. 3- (R) -benzyloxy-2- (2-tert-butoxycarbon-lamino-2-methyl-propionylamino) -propionic acid To a solution of 2-amino-3-benzyloxy-propionic acid (26.2 g, 0.113 moles) ) in water (101.8 ml) and TEA (28.53 g, 0.282 moles) was added 2,5-dioxo-pyrrolidin-1-yl ester of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (33.94 g, 0.133 moles) ) in THF (407 ml). The mixture was stirred overnight at room temperature under nitrogen. A solution of 10% citric acid (500 ml) was added to the mixture. The mixture was stirred for another 10 min, then diluted with ethyl acetate (500 ml). The organic phase was separated from the mixture and washed with water and a saturated NaCl solution and then concentrated in vacuo to give a thick oil. The crude oil was treated with IPE / hexane (50/50) and cooled to approximately 10X to give a white solid product (42.3 g, yield 98.4%).

H. (1-r2- (3a- (R) -benzyl-2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolof4,3-c1pyridin-5-yl) tert-butyl ester -1- (R) -benzyloxymethyl-2-oxo-ethylcarbamoin-1-methyl-ethylPcarbamic acid To a solution of L-tartrate of 3a- (R) -benzyl-2-methyl-2,3a, 4,5,6, 7-hexahydro-pyrazolo [4,3-c] pyridin-3-one (10.81 g, 0.0275 moles) in ethyl acetate (216.2 ml) at about -66X was added TEA (8.43 ml, 0.0605 moles). The mixture was stirred for about 1.5 hours, after removing the precipitated salt by filtration, 3- benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propylamino) -propionic acid (8.7 g, 0.0229 mol) and TEA (19.15) were added. ml, 0.1374 moles) at about -35X, followed by the dropwise addition of 50% PPAA in ethyl acetate (27.5 ml, 0.0458 moles) The mixture was stirred for about 2 hours from about -20X to about -27X, then 1.5 hours at a time when the temperature was slowly increased until approximately The reaction mixture was poured into water and extracted with IPE, washed with a 7% NaCI solution and concentrated in vacuo. The crude oil obtained was treated with IPE / hexane (50/50) to allow crystallization. The product was obtained as a white solid (10.3 g, yield 74.3%).

I. 2-amino-N-r2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo r4,3-clp? Ridin- 5-p-1- (RVbenzyloxymethyl-2-oxo-etn-2-methyl-propionamide) To a solution of tert-butyl ester of acid. {1- [2- (3a- (R) -benz? l-2-methyl-3-oxo-2,3,3a, 4,5,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2 -oxo-ethylcarbamoyl-1-methyl-ethyl} -carbamic acid (10.3 g, 0.017 mol) in methylene chloride (68.6 ml) at about 0-5X was added TFA (35 ml) to keep the temperature below about The temperature was then increased to room temperature The mixture was stirred for about 3 hours The methylene chloride was replaced by ethyl acetate as solvent The mixture was then adjusted to about pH 8 with a saturated solution of bicarbonate Sodium was then washed with saturated NaCl and concentrated in vacuo to a low volume, a white solid product was obtained after a mixture with IPA and then with hexane (7.4 g, 86.1% yield). HPLC showed a product containing 0.2% diastereomer.

J. L-Tartrate of 2-amino-N-22- (3a- (R) -benzyl-2-methyl-3-oxo-2.3.3a.4.6.7-hexahydro-pyrazolo f4,3-c] pyridine -5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl-2-methyl-propionamide To a solution of 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] -2 methyl-propionamide from step I (385 g, 0.761 mol) in methanol (4000 ml) was added L - (+) - tartaric acid (114.5 g, 0.761 mol) and the mixture was stirred overnight. The resulting cloudy solution was filtered yielding a clear solution, which was concentrated to remove most of the solvent. Ethyl acetate (total 12 L) was added and the remaining methanol was azeotropically removed between about 63X and 72X. The solid that was isolated was dissolved in ethyl acetate and the solution was refluxed for about 16 hours, then allowed to cool to room temperature overnight. The product was collected as a white solid (482.3 g, 96.8% yield). P.F. 174-176X.

EXAMPLE 185 L - (+) - 2-amino-Nf 1 - (2,4-difluoro-benzyloxymethyl) -2-oxo-2-r3-oxo-3a-pyridin-2-methyl-2-tartrate 1,2,2,2-trifluoro-ethyl) -2.3.3a, 4,6,7-hexahydro-pyrazolo r4,3-clpyridin-5-yl-1-ethyl} -2-methyl-propionamide A. 4-Oxo-3-pyridin-2-ylmethyl-piperidin-1,3-dicarboxylic acid-1-tert-butyl ester 3-oxo-3-pyridin-3-dicarboxylic acid ester 3-oxo-3-ethyl ester piperid-n-1,3-dicarboxylic acid (10.34 g, 38.2 mmol) in DMF (40 ml) at approximately OX was added picolyl chloride hydrochloride (5.7 g, 34.7 mmol), potassium carbonate (14.4 g, 104.1 mmol) and Potassium iodide (5.76 g, 34.7 mmol). After stirring at about OX for about 2 hours, the ice bath was removed and DABCO (973 mg, 8.68 mmol) was added. The reaction mixture was stirred for about 30 min and poured into a mixture of water and IPE. The organic layer was separated and washed with NaHCO 3 and saturated aqueous NaCl, dried over Na 2 SO 4 and concentrated in vacuo. The crude residue crystallized from hexanes to give a white solid (8.19 g, 65% yield). 1 H NMR (CDCl 3) d 1.17 (t, 3 H), 1.48 (s, 9 H), 1.55 (s, 2 H), 2.61 (m, 1 H), 2.71 (m, 1 H), 3.31-3.50 ( m, 3 H), 4.11 (d, 2 H), 4.49 (d, 1 H), 7.06 (sa, 1 H), 7.17 (d, 1 H), 7.54 (m, 1 H), 8.40 (s, 1 HOUR).

Sxt * a? Uu? Ij tííSt? & Za B. 3-Oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro-eti0-2) tert-butyl ester, 3,3a, 4,6,7-hexahydro-pyrazolo f4.3-d pyridine-5-carboxylic acid A 70% aqueous solution of CF3CH2NHNH2 (325 ml, 1986 mole) (obtained from Aldrich) was extracted with toluene (3 x 1200 ml) To a solution of the product from step A (600 g, 1.655 mol) in toluene (900 ml), the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethylhydrazine were first added, followed by acid. acetic acid (121.4, 1986 moles) The reaction mixture was heated to about 70X for about 2 hours, then another extraction with toluene of aqueous 2,2,2-trifluoroethyl hydrazine 70% (50 g) was added. The reaction mixture was heated to about 80X for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHCO3 (2L). The toluene layer was separated and washed with saturated aqueous NaCl (2 I). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol / water gave the desired product as a white solid (609.5 g). 1 H NMR (CDCl 3) d 1.50 (s, 9 H), 2.53 (d, 1 H), 2.70 (br s, 2 H), 2.88 (br s, 1 H), 3.97 (m, 1 H), 4.19 (m, 1 H), 4.46 (sa, 1 H), 4.63 (sa, 1 H), 7.06 (m, 2 H), 7.51 (m, 1 H), 8.34 (m, 1 H).

C. 3a-pyridin-2-ylmethyl-2- (2.2.2-trifluoro-etn-2.3a, 4.5.6.7-hexahydro-p¡razole r4.3-c1pyridin-3-one) Acid was added dropwise methanesulfonic acid (11.6 g, 121 mmol) to a solution of the product from step B (10 g, 24.2 mmol) in CH 2 Cl 2 (100 ml) for about 30 minutes The reaction mixture was stirred for about 1 hour, then cooled to OX was added and then triethylamine (18.6 ml, 133.1 mmol) was added via an addition funnel The mixture was allowed to warm to room temperature for about 1 hour, diluted with more CH2CI2 and washed with saturated aqueous NaCl, dried over Na2S0 it was filtered and concentrated in vacuo to give the product as a white solid (7.2 g) 1 H NMR (CDCl 3) d 2.51-2.72 (m, 4 H), 3.35 (m, 2 H), 3.49 (m, 2 H), 4.03 (m, 1 H), 4.25 (m, 1 H), 7.08 (d, 2 H), 7.51 (t, 1 H), 8.37 (d, 1 H).

D. (D) -Tarate of 3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro-etn-2,3a.4,5,6,7-hexahydro-pyrazolo [4,3-c1pyridin- 3-one In a dry, nitrogen-purged 5 I round bottom flask equipped with a mechanical stirrer, (D) - (-) tartaric acid (129 g, 0.86 moles) was added to the product from step C (243 g). , 0.78 moles) in acetone / water (9: 1, 2430 ml) at about 17X The mixture was stirred at room temperature overnight, filtered, the solid was collected and washed with cold acetone and dried in vacuo. The product was obtained as a yellow solid (284 g, 78.8% yield).

E. 2-tert-Butoxycarbonyllamino-3- (2,4-difluoro-benzyloxy) -propionic acid To a solution of N-Boc- (D) -serine (452 g, 2.2026 moles) in a THF mixture ( 7 I) and DMF (3 I) at about OX was added a solution of potassium tert-butoxide (515.8 g, 4.5963 moles). The reaction mixture was stirred at about OX for about 30 min, then 2,4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After warming to room temperature, the reaction mixture was concentrated in vacuo to remove THF. The reaction mixture was partitioned between 4.5 I of H20 and 4.5 I of IPE. The layers were separated and the pH of The aqueous layer was adjusted with 1 N HCl to about 3. The aqueous layer was extracted twice with 4 I of IPE. The organic solution was dried over Na 2 SO 4 and concentrated in vacuo to give a yellow waxy solid (518.0 g, yield 70.9%). 1 H NMR (CDCl 3) d 1.44 (s, 9 H), 3.73 (m, 1 H), 3.94 (d, 1 H), 4.44 (s, 1 H), 4.54 (s, 2 H), 5.34 (m, 1 H), 6.78 (m, 1 H), 6.84 (m, 1 H), 7.30 (m, 1 H).

F. Methanesulfonic acid salt of 2-amino-3- (2,4-difluoro-benzyloxy) -propionic acid To a solution of step E (1.19 g, 3.59 mmole) in CH2Cl2 / IPE (1: 1, 12 ml) methanesulfonic acid (1.72 g, 17.95 mmol) was added via syringe for approximately 10 minutes. Immediately a solid precipitated in the solution. After about 1 hour, the solid is filtered and washed with a mixture of CH2Cl2 / IPE (1: 1) yielding 939 mg of the product (yield 80%).

G. 2- (2-tert-Butoxycarbonylmannien-2-methyl-propionyl-amino) -3-, 2,4-difluoro-benzyloxy-propionic acid To a solution of the product from step F (520 mg, 1.46 mmol) in THF / water (4: 1, 10 ml) was added 2,5-dioxo-pyrrolidin-1-yl ester of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (438 g, 1.46 mmole) and triethylamine (369 mg, 3.65 mmole) ). The reaction mixture was stirred at room temperature for about 1 hour and quenched with a 10% aqueous citric acid solution (10 ml). After about 15 min, ethyl acetate (50 ml) was added, the organic layer was separated and washed with saturated aqueous NaCl, dried over Na 2 SO and concentrated in vacuo to give a foam (534.1 mg, 88% yield). 1 H NMR (CD3OD) d 1.38 (br s, 15 H), 3.77 (d, 1 H), 3.92 (d, 1 H), 4.52 (m, 3 H), 6.92 (m, 1 H), 7.41 (m, 1 H), 7.58 (d, 1 H).

H. (1- {1- (2,4-D-Fluoro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-pyridin-2-ylmethyl-2-tert -butyl ester. -(2, 2,2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo-4,3-clpyridin-5-yl-ethylcarbamo-P-1-methyl-ethyl) -carbamic acid (a ) The product of step D (517 g, 1.12 moles) was added to about -6X to ethyl acetate (5170 ml) in a dry, nitrogen-purged 12-l round bottom flask equipped with a mechanical stirrer. The solution was cooled to about -40X, then triethylamine (398 mL, 2.86 mmol) was added for about 45 minutes. The reaction mixture was stirred for about 90 min, at a temperature between about -50X and about -40X, filtered through a nitrogen-purged 22 l round bottom flask, washed with ethyl acetate (2068 ml, pre-chilled). to about -50X) giving the free base as a white solid. (b) The product of step G (425 g, 1.02 mole) was added at about -30X to an ethyl acetate solution containing the product of step H (a), triethylamine (654 ml, 4.69 moles) and PPAA ( 50% in ethyl acetate, 916 ml, 1.53 moles). The reaction mixture was stirred for about 1 hour, washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give the product as an oil (636 g, yield: 87.8%).

I. 2-amino-N. { 1- (2,4-difluoro-benzyloxymethip-2-oxo-2-r3-oxo-3a-pyridin-2-ylmethyl-2- (2.2.2-trifluoro-ethyl) -2.3.3a, 4,6,7 -hexahydro-pyrazolo Í4.3-C1 pyridin-5-l1-etiP-2-methyl-propionamide Methanesulfonic acid (258.3 ml, 3.98 moles) was added dropwise at about 15X for about 55 minutes to the producer of step H ( 566 g, 0.796 mol) in CH2CI2 (11.320 ml) in a dry 22 liter round bottom flask purged with nitrogen and equipped with a mechanical agitator. The mixture was stirred for about 40 minutes at about 20X, then saturated aqueous NaHCO3 (8,490 ml) was added until a pH of about 7.8 was reached. The organic layer was separated, washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give an oily product (388.8 g, 80% yield).

J. L - (+) - 2-amino-N- tartrate. { 2,4-difluoro-benzyloxymethiP-2-oxo-2-f3-oxo-3a-pyrid? N-2-methyl-2- (2.2.2-trifluoro-ethyl) -2,3,3a.4.6,7 -hexahydro-pyrazolo Í4.3- clpiridin-5-n-etiP-2-methyl-propionamide To a solution of the product of step I (370 g, 0.6 mol) in methanol (4070 ml) in a round bottom flask of 12 I equipped with a mechanical stirrer, L - (+) - tartaric acid (90 g, 0.6 moles) was added. The reaction mixture was stirred for about 90 min to about 22X, filtered and concentrated. The crude product was diluted with ethyl acetate (4.560 ml), heated to about 70X and allowed to cool slowly to room temperature for about 17 hours. The solid was filtered and dried to give white crystals, mp 188-189X (348.46 g, 76% yield). 1 H NMR (MeOH, d 4) d 8.28 (d, 1 H), 7.59 (t, 1 H), 7.41 - 7.39 (m, 1 H), 7.18 - 7.13 (m, 1 H), 6.92 (t, 1 H ), 5.2 (t, 1 H), 4.56 (sa, 3 H), 4.36 (s, 2 H), 4.31 - 4.25 (m, 1 H), 4.13 - 4.25 (m, 1 H), 4.13 - 4.06 ( m, 1 H), 3.78 (d, 2 H), 3.21 (t, 1 H), 3.18 - 2.96 (m, 2 H), 2.65 - 2.55 (m, 2 H), 1.57 (d, 6 H). MS: MH + 611. [a] 589 + 22.03 (c = 11.9, MeOH).

EXAMPLE A The following are the results of the "Female Rat Study" described hereinabove, in which the rats were administered the compound secretagogue of HC salt of L-tartaric acid of 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] -pyridin-5-l) -1- (R) - (benzyloxymethyl) -2-oxo-ethyl] -isobutyramide.

TABLE 1 Average plasma levels of insulin and metabolites after daily administration of a GHRP mimetic dose for three months Non-fasting blood samples were collected from the rats at the time of sacrifice. An asterisk (*) indicates a value significantly different from that of the group treated with the corresponding vehicle.

»AjSgaagg3fc? i ^ £ ^ vÁ? a (p <0.05).

The data in Table 1 show that this treatment is associated with a dose-related decrease in plasma glucose and / or insulin levels, which is in line with an improvement in glycemic control and insulin sensitivity due to this treatment. The treatment also associated a tendency in terms of the decrease in plasma levels of lactate, cholesterol and triglycerides, which agrees with an improvement in the control of the lipid and metabolic profile as a consequence of a greater sensitivity to insulin achieved with this treatment.

Claims (26)

1. NOVELTY OF THE INVENTION
3. The use of a compound of formula 1 or stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure isomers, enriched or enantiomerically pure enantiomers or pharmaceutically acceptable salts and prodrugs thereof, wherein it is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (O) X6, - (CH2) qN (X6) C (O) (CH2) t-A1, - (CH2) qN (X6) S02 ( CH2) rA1, - (CH2) qN (X6) S02 (X6), - (CH2) qN (X6) C (O) N (X6) (CH2) rA1, - (CH2) qN (X6) C (O) N (X6) (X6), - (CH2) qC (O) N (X6) (X6), - (CH2) qC (O) N (X6) (CH2) t-A1, - (CH2) qC (O ) (X6), - (CH2) qC (O) O (CH2) t-A1, - (CH2) qOX6, - (CH2) qOC (O) X6, - (CH2) qOC (O) (CH2) t- A1, - (CH2) qOC (O) -N (X6) (CH2) t-A1, - (CH2) qC (O) N (X6) (X6), - (CH2) qC (O) X6, - ( CH2) qC (O) (CH2) t-A1, - (CH2) qN (X6) C (O) X6, - (CH2) qN (X6) S02N (X6) (X6), - (CH2) q S ( 0) mX6, - (CH2) q S (0) m (CH2) t-A1, -alkyl (C C10), - (CH2) t -A1, - (CH2) q-cycloalkyl (C3-C7), ( CH2) q-Y1 -alkyl (C? -C6), - (CH2) q-Y1-CH2) t-A1, or (CH2) q -Y1- (CH2) -cycloalkyl (C3-C7); where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with alkyl (CrC4), hydroxyl, alkoxy (CC), carboxyl, -CONH2, -S (0) m alkyl (CrC6), -C02 alkyl ester (C1 -C4), IH-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S (0) m, -C (0) NX6-, -CH = CH-, C = C-, -N (X6) C (O) -, -C (0) NX6-, C ( O) O-, -OC (0) NX6-, or -OC (O) -; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said group (CH2) q and the group (CH2) t may each be optionally substituted with hydroxyl, alkoxy (CrC4), carboxyl, -CONH2, S (0) m alkyl (C6), -C02 alkyl ester ( C C4), IH-tetrazol-5-yl or 1, 2 or 3 fluoro or 1 or 2 alkyl (C4); R2 is hydrogen, (C? -C8) alkyl, (C0-C3) alkyl- (C3-C8) -cycloalkyl, -alkyl (CrC4), -A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition R2 are optionally substituted with hydroxyl, C (0) OX6-, -C (0) N (X6) (X6), -N (X6) (X6), -S ( 0) m alkyl (CrC6), -C (0) A1, -C (O) (X6), CF3, CN or 1, 2 or 3 halogens; R3 is A1, alkyl (CC? 0), alkyl (CrC6)-A1, -alkyl (C6) -cycloalkyl (C3-C7), -alkyl (C1-C5) -X1-alkyl (C5), -X1 -alkyl (C C5), -alkyl (C C5) -X1 -alkyl (C0-C5) -alkyl or -alkyl (C1-C5) -X1"(C1-C5) -cycloalkyl (C3-C7) alkyl wherein the alkyl groups in the definition of R3 are optionally substituted with -S (0) m alkyl (d-C6), -C (O) OX3, 1, 2,3,4, or 5 halogens, or 1, 2 , or 3 OX3; X1 is O, S (0) m, -N (X2) C (O) -, -C (O) N (X2) -, -OC (O) -, -C (O) O -, -CX2 = CX2-, -N (X2) C (O) -, -OC (O) N (X2) - or -C = C-, R4 is hydrogen, (C6) alkyl or cycloalkyl (C3-) C7) or R4 together with R3 and the carbon atom to which they are attached form (C5-C7) cycloalkyl, a ring of 4 to 8 elements partially or totally saturated 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 ring of 5 or 6 elements partially or totally saturated, totally unsaturated or tota saturated, which optionally has 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C6) alkyl or X4 together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached form an aryl of five to seven elements: R6 is a bond or is where a and b are independently 0, 1, 2 or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted alkyl (C-i-Ce); the (Ci-Cβ) alkyl optionally substituted in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (0) malchyl (d-Cß), -C (0) OX2 , (C3-C7) cycloalkyl, -N (X2) (X2) and - C (0) N (X2) (X2); or the carbon carrying X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8, each alkylene bridge containing 1 to 5 carbon atoms containing, provided that when an alkylene bridge is formed, then X5 or X5a, but not both, may be on the carbon atom and R7 or R8, but not both, can be on carbon atom and R7 or R8, but not both, can be on the nitrogen atom and with the proviso that two alkylene bridges are also formed, then X5 and X5a can not be on the carbon atom and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X a and the carbon atom to which they are attached form a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or N-X2, with the proviso that when a and b are both 0, then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (dC6) alkyl; wherein the (d-Cß) alkyl optionally substituted in the definition of R7 and R8 optionally independently substituted with A1, -C (O) O-alkyl (d-Cß), -S (0) malkyl (d-C6), to 5 halogens, 1 to 3 hydroxy, 1 to 3 -OC (0) alkyl (C C -io) or 1 to 3 alkoxy (CrC6); or R7 and R8 can be joined to form - (CH2) rL- (CH2) r; where L is C (X2) (X2), S (0) m or N (X2); Al each time it appears is independently cycloalkenyl (C5-C), phenyl or a ring of 4 to 8 elements partially saturated, fully saturated or totally unsaturated, 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 ring of 5 or 6 elements, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently substituted, in one and optionally in both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, - OX6, -C (0) N (X6) (X6), -C (O) OX6, oxo, alkyl (d-Ce), nitro, cyano, benzyl, - S (0) maltoyl (Ci-d.), IH-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N (X6) (X6), -N (X6) C (0) (X6) , -S02N (X6), -N (X6) S02-phenyl, -N (X6) S02 (X6), -CONX11X12, -S02NX11X12, -NX6S02X12, -NX6CONX11X12, -NX6S02, NX11X12, -NX6C- (0) X12 , imidazolyl, thiazolyl and tetrazolyl, with the proviso that if A1 is optionally substituted with methylenedioxy, then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted alkyl (d-Cß); the optionally substituted (d-Cß) alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, alkoxycarbonyl (d-Cß), -S (0) malky (d-C6), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 alkanoyloxy (d-do) or 1 to 3 alkoxy (d-C6); X12 is hydrogen, (d-C6) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3, or X11 and X12 join to form (CH2) r-L1- (CH2) r; where L1 is C (X2) (X2), O, S (0) m or N (X2); r each time it appears is independently 1, 2, or 3; X2 each time it occurs is independently hydrogen, optionally substituted alkyl (d-C6) or optionally substituted cycloalkyl (C3-C), wherein the optionally substituted (d-C6) alkyl and the optionally substituted (C3-C7) cycloalkyl is the definition of X2 are optionally independently substituted with -S (0) maltyl (d-C6), -C (O) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (d-Cß); X6 is independently hydrogen, optionally substituted alkyl (CrC6), halogenated alkyl (C2-CQ), optionally substituted cycloalkyl (C3-C7), halogenated cycloalkyl (C3-C) where optionally substituted (d-C6) alkyl and cycloalkyl ( C3-C7) optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 alkyl (CC), hydroxyl, alkoxy (d-C4), carboxyl, CNOH2, -S (0) malchyl, alkyl ester (dd) carboxylate or 1 H-tetrazol-5-yl; or when there are two groups X6 on an atom and both X6 are independently alkyl (d-Cß), the two alkyl groups (d-C6) can be optionally attached and, together with the atom to which the two groups X6 are bound, form a ring of 4 to 9 elements, optionally having oxygen, sulfur or NX7; X7 is hydrogen or (d-C6) alkyl optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the proviso that: X6 and X12 can not be hydrogen when bound to C (O) or S02 in the form C (0) X6, C (0) X12 or SOX6 S02X12; and when R6 is a bond, then L is N (X) 2 and each r in the definition (CH2) rL- (CH2) r- is independently 2 or 3, for the manufacture of a medicament for treating insulin resistance in a mammal. 2. The use according to claim 1, wherein said compound of formula I has the following formula or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts or prodrugs thereof, wherein R1 is -CH2-phenyl, R2 is methyl and R3 is - (CH2) 3-phen ?the; R1 is -CH2-phenyl, R2 is methyl and R3 is -3-indolyl-CH2; R1 is -CH2-phenyl, R2 is ethyl and R3 is -3-indolyl-CH2; R1 is -CH2-4-fluoro-phenyl, R2 is methyl and R3 is -3-indolyl CH2; R1 is -CH2-phenyl, R2 is methyl and R3 is -CH2-0-CH2-phenol, R1 is -CH2-phenyl, R2 is ethyl and R3 is -CH2-0- CH2-phenol, R1 is -CH2-phenyl, R2 is CH2CF3 and R3 is -CH2-0- CH2-phenyl, R1 is -CH2-4-fluoro-phenyl, R2 is methyl and R3 is -CH2-0-CH2-phenol; R1 is -CH2-phenyl, R2 is t-butyl and R3 is -CH2-0- CH2-phenyl, R1 is -CH2-phenyl, R2 is methyl and R3 is -CH2-0- CH2-3,4-difluorophenyl 3 The use according to claim 1, wherein said compound of formula I has the formula or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein R 2 is methyl; A1 is pyridyl; and R3 is -CH2-0- CH2-phenyl; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-0-CH2-3-chloro-phenyl; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-0-CH2-4-chloro-phenol; R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-0-CH2-2,4-dichloro-phenyl; R2 is CH2CF3; tAi fe¿ &g: -? A1 is 2-pyridyl; and R3 is -CH2-0-CH2-3-chloro-thiophene or R2 is CH2CF3; A1 is 2-pyridyl; and R3 is -CH2-0-CH2-2,4-difluoro-phenyl.
4. 4. The use according to claim 1, wherein said compound of formula I or the stereoisomeric mixtures, the isomers
5. 5 diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure or the pharmaceutically acceptable salts and prodrugs thereof is the diastereomeric mixture 3a (R, S), 1 (R), the diastereomer 3a (R), 1 (R) or the diastereomer 3a (S), 1 (R) of a compound selected from the group 10 constituted by 2-amino-N- [1- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5 -carbonyl) -4-phenyl-butyl] -isobutyramide, 2-amino-N- [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazole [4,3-c] pyridin-5-yl) -1- (1 H- indol-3-ylmethyl) -2-oxo-ethyl] -isobutyramide, 2-amino-N- [2- (3a-benzyl) 2-Ethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 - (1 H -indol-3-ylmethyl) - 2-oxo-15-ethyl] -isobutyramide, 2-amino-N- [2- (3a- (4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydro-pyrazolo [4,3-c] p? ridin-5-yl) -1- (1 H -indol-3-ylmethyl) -2-oxo-ethyl] -isobutyramide, 2-amino-N- [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1-benzyloxymethyl-2-oxo- ethyl] -isobutyramide, 2-amino-N- [2- (3a-benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4.3- 20 c] pyridin-5-yl) -1-benzyloxymethyl-2-oxo-ethyl] -isobutyramide, 2-amino-N-. { 2- [3a-benzyl-3-oxo-2- (2,2,2, -trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3- c] pyridin- 5-yl) -1-benzyloxymethyl-2-oxo-et? L] -isobutyramide, 2-amino-N-. { 1-Benzyloxymethyl-2- [3a- (5-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro- ^ I ^ ^ ^^^^^ sgz ^^^^^^^^^^^ pyrazolo [4,3-c] pyridin-5-yl] -2-oxo-ethyl} -isobutyramide, 2-amino-N- [2- (3a-benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine -5-yl) -1-benzyloxymethyl-2-oxo-ethyl] -isobutyramide, and 2-amino-N- [2- (3a-benzyl-3-oxo-2,3,3a, 4,6,7- hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1-benzyloxymethyl-2-oxo-ethyl] -isobutyramide. 5. The use according to claim 4, wherein said compound is the L-tartaric acid salt of 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.
6. 6. The use according to claim 1, wherein said compound of formula I or the stereoisomeric mixtures, the diastereomerically enriched isomers, diastereomerically pure, enantiomerically enriched or enantiomerically pure or the pharmaceutically acceptable salts and prodrugs thereof is the diastereomeric mixture 3a- (R, S), 1- (R), the enantiomer 3a- (R), 1- (R) or the enantiomer 3a- (S), 1- (R) of a compound selected from the group consisting of 2-amino-N- [1-benzyloxymethyl-2- (2-methyl-3-oxo-3a-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-. { 1-3-chloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-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- (4-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -2,3,3a, 4, 6,7-hexahydro-p -razolo [4,3-c] pyridin-5-yl] ethyl} -2-methyl-propionamide; 2-amino-N-. { 1- (2,4-Dichloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-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- (4-Chloro-thiophen-2-ylmethoxymethyl) -2-oxo-2- [3-oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -2,3 , 3a, 4,6,7-hexahydro-pyrazolo [3,4-c] pyridin-6-yl] -ethyl} -2-methyl-propionamide; and 5 2-amino-N-. { 1- (2,4-Dichloro-benzyloxymethyl) -2-oxo-2- [3-oxo-3a-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.
7. 7. The use of a growth hormone releasing hormone or of a functional analogue thereof, for the manufacture of a medicament to be used in combination with the medicament of claim 1, for the treatment of resistance to insulin in a mammal.
8. 8. A pharmaceutical composition useful for the treatment of insulin resistance in a mammal containing a pharmaceutically acceptable carrier and an effective amount of a compound of formula I or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched isomers S ^ £ ia ^ "ig ^". ^^ a ^^ - ^ tfa ^ c ,, ^. < Sa.,, _, "" -. -, ^^ ^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ or enantiomerically pure or the pharmaceutically acceptable salts and prodrugs thereof, wherein it is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) C (0) (CH2) t-A1, - (CH2) qN (X6) S02 ( CH2) t-A1, - (CH2) qN (X6) S02 (X6), - (CH2) qN (X6) C (0) N (X6) (CH2) tA \ - (CH2) qN (X6) C ( 0) N (X6) (X6), (CH2) qC (0) N (X6) (X6), - (CH2) qC (0) N (X6) (CH2) t-A1, - (CH2) qC ( 0) OX6, - (CH2) qC (0) 0 (CH2) »- A1, - (CH2) qOX6, - (CH2) qOC (0) X6, - (CH2) qOC (0) (CH2) rA1, - (CH2) qOC (0) -N (X6) (CH2) rA1, - (CH2) qOC (0) N (X6) (X6), - (CH2) qC (0) X6, - (CH2) qC (0 ) (CH2) t-A1, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) S02N (X6) (X6), - (CH2) qS (0) mX6, - ( CH2) qS (0) m (CH2) rA1, -alkyl (d-Cio), - (CH2) rA1, - (CH2) q-cycloalkyl (C3-C7), (CH2) q-Y1-alkyl (d-) C6), - (CH2) q-Y1- (CH2), - A1 or (CH2) qY1- (CH2) t-cycloalkyl (C3-C7); wherein the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted by (C? -C4) alkyl, hydroxyl, (C1-C4) alkoxy, carboxyl, -CONH2, -S (0) malkyl (d-Cß), - C02 alkyl ester (C? -C4), 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S (0) m, -C (0) NX6 -, - CH = CH-, -C = C-, -N (X6) C (0) -, -C (0) NX6-, - C (0) 0-, -OC (0) N (X6) - or -OC (O) -; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said group (CH2) q and the group (CH2) t may each be optionally substituted with hydroxyl, alkoxy (CrC4), carboxyl, -CONH2, -S (0) malkyl (d-C6), -C02 alkyl ester (d-C4), 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro or 1 or 2 alkyl (dd); R2 is hydrogen, alkyl (CrC8), alkyl (C0-C3) -cycloalkyl (C3-C8), -alkyl (C? -C4) -A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, C (0) OX6, -C (0) N (X6) (X6), -N (X6) (X6), -S ( 0) malchyl (C C6), -C (0) A1, -C (0) (X6), CF3, CN or 1, 2 or 3 halogens; R3 is A1, alkyl (d-C10), -alkyl (d-C6), -A1, -alkyl (C6) -cycloalkyl (C3-C7), -alkyl (d-C5) -X1-alkyl (d- C5), -alkyl (C5) -X1 -alkyl (C0-C5) -A1 or -alkyl (C5) -X1- (C1-C5) -cycloalkyl (C3-C7) alkyl; wherein the alkyl groups in the definition R3 are optionally substituted with -S (0) maltyl (C C6), -C (0) OX3, 1, 2,3,4 or 5 halogens, or 1, 2, or 3 OX3; X1 is O, S (0) m, -N (X2) C (0) -, -C (0) N (X2) -, -OC (O) -, -C (0) 0-, -CX2 = CX2-, -N (X2) C (0) 0-, -OC (0) N (X2) - or -C = C-; R4 is hydrogen, alkyl (CrC6) or cycloalkyl (C3-C7) or R4 together with R3 and the carbon atom to which they are attached form cycloalkyl (C5-C7), cycloalkenyl (C5-C7), a ring of 4 to 8 partially or fully saturated elements 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 ring of 5 or 6 elements partially or fully saturated, condensed with a ring of 5 or 6 elements partially saturated, totally unsaturated or fully saturated, which optionally has 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or alkyl (CrC6) or X4 together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached form a ring of five to seven elements: R6 is a bond or is where a and b are independently 0, 1, 2, or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted alkyl (d-C6); optionally substituted alkyl (d-C6) in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (0) maltyl (d-C6), -C (0) OX2 , (C3-C7) cycloalkyl, -N (X2) (X2) and -C (0) N (X2) (X2)or the carbon carrying X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8, each alkylene bridge containing from 1 to 5 carbon atoms, provided that when an alkylene bridge is formed, then X5 and X5a, but not both, may be on the carbon atom and R7 or R8, but not both, may be on the nitrogen atom and with the proviso that when two alkylene bridges are formed, then X5 and X5a they can not be on the carbon atom and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X5a and the carbon atom to which they are attached form a bicyclic ring system constituted by a ring of 5 or 6 elements partially or totally saturated, having optionally 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z is a bond, O or N-X2, with the addition that when a and b are both 0, then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (dC6) alkyl; wherein the (d-C6) alkyl optionally substituted in the definition of R7 and R8 is optionally independently substituted with A1, -C (0) 0 -alkyl (d-C6), -S (0) maltyl (C Cß), to 5 halogens, 1 to 3 hydroxy, 1 to 3 -0-C (0) alkyl (Ci-do) or 1 to 3 alkoxy (d-Cß); or R7 and R8 can be joined to form - (CH2) rL- (CH2) r; where L is C (X2) (X2), S (0) m or N (X2); Al each time it appears is independently cycloalkenyl (C5-C7), phenyl or a ring of 4 to 8 elements partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a 5 or 6 element ring partially saturated, totally unsaturated or fully saturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed by a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently substituted, on one or optionally on both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3 , OCF2H, CF3, CH3, OCH3, -OX6, -C (0) N (X6) (X6), -C (0) OX6, oxo, alkyl (d-C6), nitro, cyano, benzyl, -S ( 0) malkyl (d-Cß), 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N (X 6) (X 6), -N (X 6) C (0) (X 6), -S02N (X6) (X6), -N (X6) S02-phenyl, -N (X6) S02 (X6), -CONX11X12, -S02NX11X12, -NX6S02X12, -NX6CONX1 X12, -NX6S02NX11X12, -NX6C- (0) X12, imidazolyl, thiazolyl and tetrazolyl, with the proviso that if A1 is optionally substituted with methylenedioxy, then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted (C -Cß) alkyl; the optionally substituted alkyl (CrCβ) defined for X11 is optionally independently substituted with phenyl, phenoxy, alkoxycarbonyl (CrCβ), - S (0) malto (d-Cβ), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3-alkanoyloxy (d-do) or 1 to 3 alkoxy (CrCβ); X12 is hydrogen, alkyl (CrC6), phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X11 and X12 join to form (CH2) r-L1- (CH2) r; where L1 is C (X2) (X2), O, S (0) m or N (X2); r each time it appears is independently 1, 2 or 3; X2 each time it occurs is independently hydrogen, optionally substituted (C-C6) alkyl or optionally substituted (C3-C7) cycloalkyl, wherein optionally substituted alkyl (CrCß) and (C3-C7) cycloalkyl optionally substituted in the definition of X2 they are optionally independently substituted with -S (0) malkyl (d-Cß), -C (0) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (d-Cß); X6 is independently hydrogen, optionally substituted alkyl (CrCß), halogenated alkyl (C2-C6), optionally substituted cycloalkyl (C3-C7), halogenated cycloalkyl (C3-C7), wherein optionally substituted alkyl (CrCß) and cycloalkyl (C3-) C) optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 (d-C4) alkyl, hydroxyl, alkoxy (dd), carboxyl, CONH, -S (0) malchyl (CrCß), alkyl ester (dd) ) carboxylate or 1 H-tetrazol-5-yl; or when there are two groups X6 on an atom and both X6 are independently alkyl (CrC6), the two alkyl groups (d-C6) can be optionally attached and, together with the atom to which the two groups X6 are attached, form a ring from 4 to 9 elements, optionally having oxygen, sulfur or NX7; X7 is hydrogen or alkyl (CrCß) optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the proviso that: X6 and X12 can not be hydrogen when bound to C (O) or S02 in the form C (0) X6, C (0) X12, S02X6 or S02X12; and when R6 is a bond, then L is N (X) 2 and each r in the definition (CH2) rL- (CH2) r is independently 2 or 3.
9. 9.- The use of a functional somatostatin antagonist in combination with a compound of formula I or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein it is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) C (0) (CH2) t-A1, - (CH2) qN (X6) S02 ( CH2), - A1, (CH2) qN (X6) S02 (X6), - (CH2) qN (X6) C (0) N (X6) (CH2) t-A1, - (CH2) qN (X6) C (0) N (X6) (X6), - (CH2) qC (0) N (X6) (X6), - (CH2) qC (0) N (X6) (CH2) t-A1, - (CH2) qC (0) OX6, - (CH2) qC (0) 0 (CH2) »- A1, - (CH2) qOX6, - (CH2) qOC (0) X6, - (CH2) qOC (0) (CH2), -A1, - (CH2) qOC (0) -N (X6) (CH2) t-A1, - (CH2) qOC (0) N (X6) (X6), - (CH2) qC (0) X6, - (CH2) qC (0) (CH2), - A1, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) S02N (X6) (X6), - (CH2) qS ( 0) mX6, (CH2) qS (0) m (CH2) t-A1, -alkyl (d-do), - (CH2) rA1, - (CH2) q-cycloalkyl (C3-C7), (CH2) q Y1-alkyl (d-C6), - (CH2) q-Y1-CH2) t-A1 or (CH2) q-Y1- (CH2) t-cycloalkyl (C3-C7); where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with alkyl (dd), hydroxyl, alkoxy (dd), carboxyl, -CONH2, -S (0) m alkyl (CrC6), -C02 alkyl ester (C C4), 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S (0) m, -C (0) NX6-, -CH = CH-, -C = C-, -N (X6) C (0) -, -C (0) NX6-, - C (0) 0-, -OC (0) N (X6) - or -OC (O) -; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said group (CH2) q and the group (CH) t may each be optionally substituted with hydroxyl, alkoxy (dd), carboxyl, -CONH2, -S (0) m alkyl (C6), -C02 alkyl ester (d-C4), 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro or 1 or 2 alkyl (dC); R2 is hydrogen, alkyl (d-Ca), -alkyl (C0-C3) -cycloalkyl (C3-C8), -alkyl (d-d) -A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, C (0) OX6, -C (0) N (X6) (X6), -N (X6) (X6), -S (0) m alkyl (C? -C6), -C (0) A1, -C (0) (X6), CF3, CN or 1, 2 or 3 halogens; R3 is A1, (C1-C10) alkyl, -alkyl (CrC6) -A1, -alkyl (CrCß) -cycloalkyl (C3-C7), -alkyl (d-C5) -X1-alkyl (C1-C5), - alkyl (d-C5) -X1-alkyl (C0-C5) -A1 or -alkyl (d-C5) -X1-alkyl (d-CsJ-cycloalkyl (C3-C7); where the alkyl groups in the definition of R3 they are optionally substituted with -S (0) maltyl (CrCß), -C (0) OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2, or 3 OX3; X1es O, S (0) m, -N (X2) C (0) -, - C (0) N (X2) -, -OC (O) -, -C (0) 0-, -CX2 = CX2-, -N (X2) C ( 0) 0-, -OC (0) N (X2) - or - CsC-; R4 is hydrogen, alkyl (d-C6) or cycloalkyl (C3-C) or R4 together with R3 and the carbon atom to which they are together they form cycloalkyl (C5-C7), cycloalkenyl (Cß-d), a ring of 4 to 8 elements partially or totally saturated having from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, condensed with a ring of 5 or 6 elements partially saturated, totally unsaturated or fully saturated, which optionally has 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or alkyl (CrCβ) or X 4 together with R 4 and the nitrogen atom to which X 4 is attached and the carbon atom to which R 4 is attached form a ring of five to seven elements: R 6 is a bond or is where a and b are independently 0, 1, 2 or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted alkyl (d-C6); the alkyl (CrCß) optionally substituted in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (0) malkyl (d-Cß), -C (0) OX2, cycloalkyl (C3-C7), -N (X2) (X2) and - C (0) N (X2) (X2); or the carbon carrying X5 or X5a form one or two alkylene bridges with the nitrogen atom bearing R7 and R8, each alkylene bridge containing from 1 to 5 carbon atoms, with the proviso that when an alkylene bridge is formed, then X5 or X5a, but not both, can be on the carbon atom and R7 or R8, but not both, can be on the nitrogen atom and with the proviso that when two alkylene bridges are formed, then X5 and X5a do not they can be on the carbon atom and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X5a and the carbon atom to which they are attached form a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed by a partially saturated or fully unsaturated 5 or 6-element ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or N-X2, with the proviso that when a and b are both 0, then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (dC6) alkyl; wherein the alkyl (CrCß) optionally substituted in the definition of R7 and R8 is optionally independently substituted with A1, -C (0) 0-alkyl (CrCß), -S (O) malky (CrC6), 1 to 5 halogens, 3-hydroxy, 1 to 3 -0-C (0) alkyl (CC? 0) or 1 to 3 alkoxy (d-Cß); or R7 and R8 can be joined to form - (CH2) r-L- (CH2) r; where L is C (X2) (X2), S (0) m or N (X2); Al each time it appears is independently cycloalkenyl (C5-C7), phenyl or a ring of 4 to 8 elements partially saturated, fully saturated or completely unsaturated, 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 or totally unsaturated or fully saturated 5 or 6 element ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed by a ring of 5 or 6 elements partially saturated, totally saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently substituted, in one or optionally in both rings A1 is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3 , OCF2H, CF3, CH3, OCH3, -OX6, -C (0) N (X6) (X6), -C (0) OX6, oxo, (C6) alkyl, nitro, cyano, benzyl, -S (0 ) malkyl (d-Cß), 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N (X6) (X6), -N (X ^) C (0) (X6), -S02N (X6) (X6), -N (X6) S02-phenyl, -N (X6) S02 (X6), -CONX11X12, -S02NX11X12, -NX6S02X12, -NX6S02X12, -NX6CONX11X12, -NX6S02NX11X12, -NX6C- ( 0) X12, imidazolyl, thiazolyl and tetrazolyl, with the proviso that if A1 is optionally substituted with methylenedioxy, then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted alkyl (CrCß); the optionally substituted (dC) alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, alkoxycarbonyl (CrCβ), S (0) malkyl (d-Cβ), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3-alkanoyloxy (Crdo) or 1 to 3 alkoxy (d-Cß); X12 is hydrogen, alkyl (CrCß), phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, OCH3, OCF3, and CF3; or X11 and X12 join to form (CH2) rL1- (CH2) r; where L1 is C (X2) (X2), O, S (0) m or N (X2); r each time it appears is independently 1, 2 or 3; X2 each time it occurs is independently hydrogen, optionally substituted alkyl (CrCß) or optionally substituted (C3-C7) cycloalkyl, wherein optionally substituted alkyl (CrCß) and (C3-C7) cycloalkyl optionally substituted in the definition of X2 are optionally independently substituted with -S (0) malchyl (CrCß), -C (0) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (CrC6); X6 is independently hydrogen, optionally substituted (dCS) alkyl, halogenated (C2-C6) alkyl, optionally substituted (C3-C7) cycloalkyl, halogenated (C3-C7) cycloalkyl, where optionally substituted (C -C) alkyl and (C3-C7) cycloalkyl optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 alkyl (dd), hydroxyl, alkoxy (dd), carboxyl, CONH2, -S (0) malkyl (d-Cß), ester of alkyl (CrC 4) carboxylate or 1 H-tetrazol-5-yl; or when there are two groups X6 on an atom and both X6 are independently alkyl (CrCß), the two alkyl groups (CrCβ) can be optionally bound and, together with the atom to which the two groups X6 are attached, form a ring of 4 to 9 elements, which optionally has oxygen, sulfur or NX7; X7 is hydrogen or alkyl (CrC6) optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the condition of; X6 and X12 can not be hydrogen when bound to C (O) or S02 in the form C (0) X6, C (0) X12, S02X6 or S02X12; and when 5 R6 is a bond, then L is N (X) 2 and each r in the definition (CH2) rL- (CH2) r is independently 2 or 3 for the manufacture of a medicament for increasing the levels of growth hormone endogenous in a human being or other animal. 10. The use of a functional somatostatin antagonist in combination with a compound of formula I or stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or pharmaceutically acceptable salts and prodrugs thereof, wherein it is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (0) X6, - OlSi ?? & ..3Í? AuSSif¡¡ ^^^^^^^^^^^^^^ S ^^ M ^^^^^^^^ (CH2) qN (X6) C (0) (CH2) t- A1, - (CH2) qN (X6) S02 (CH2), - A1, - (CH2) qN (X6) S02 (X6), - (CH2) qN (X6) C (0) N (X6) (CH2) , -A1, - (CH2) qN (X6) C (0) N (X6) (X6), (CH2) qC (0) N (X6) (X6), - (CH2) qC (0) N (X6) ) (CH2) t-A1, - (CH2) qC (0) OX6, - (CH2) qC (0) 0 (CH2) rA1, - (CH2) qOX6, - (CH2) qOC (0) X6, - ( CH2) qOC (0) (CH2) t-A1, - (CH2) qOC (0) -N (X6) (CH2) t-A1, - (CH2) qOC (0) N (X6) (X6), - (CH2) qC (0) X6, - (CH2) qC (0) (CH2) t-A1, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) S02N (X6) (X6), - (CH2) qS (0) mX6, - (CH2) qS (0) m (CH2) t-A1, -alkyl (d-do), - (CH2), - A1, - (CH2) q-cycloalkyl (C3-C7), (CH2) q-Y1-alkyl (CrC6), - (CH2) q-Y1-CH2) t-A1 or (CH2) q-Y1- (CH2) t-cycloalkyl (C3) -C); where the alkyl and cycloalkyl groups in the definition of R are optionally substituted with alkyl (dd), hydroxyl, (C4) alkoxy, carboxyl, -CONH2, -S (0) malchyl (CrCß), -C02 alkyl ester (dd) ), 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S (0) m, -C (0) NX6-, -CH = CH-, -C = C-, -N (X6) C (0) -, -C (0) NX6-, - C (0) 0-, -OC (0) N (X6) - or -OC (O) -; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said group (CH2) q and the group (CH2) t may each be optionally substituted with hydroxyl, alkoxy (dd), carboxyl, -CONH2, -S (0) malkyl (d-Cß), -C02 alkyl ester (d-C4), 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro or 1 or 2 alkyl (CrC4); R 2 is hydrogen, alkyl (d-C 8), -alkyl (C 0 -C 3) -cycloalkyl (C 3 -C 8), alkyl (d-C) -A 1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, C (0) OX6, -C (0) N (X6) (X6), -N (X6) (X6), -S ( 0) malchyl (C C6), -C (0) A1, -C (0) (X6), CF3, CN or 1, 2 or 3 halogens; R3 is A1, (d-C10) alkyl, -alkyl (C? -C6) -A1, -alkyl (CrC?) -cycloalkyl (C3-C7), -alkyl (CrC5) -X1-alkyl (CrC5), -alkyl (d-C5) -X1 -alkyl (C0-C5) -A1 or - _ ^ ea ^^^^^^ »^^» ^ rf¡iiMa > i. ^ - a-tt ^ a.J «^^ a ^^ a ^ -. to. - »~ w» -ig ^ a «w.J ^ i ^^ a ^ < A < "(C5) alkyl-X1-alkyl (CrC5) -cycloalkyl (C3-C7); where the alkyl groups in the definition of R3 are optionally substituted with -S (0) maltyl (d-C6), -C (0) OX3, 1, 2, 3, 4, or 5 halogens or 1, 2, or 3 OX3; X1 is O, S (0) m, -N (X2) C (0) -, -C (0) N (X2) -, -OC (O) -, -C (0) 0-, -CX2 = CX2-, N (X2) C (0) 0-, -OC (0) N (X2) - or -C = C; R4 is hydrogen, (C6-C6) alkyl or (C3-C7) cycloalkyl or R4 together with R3 and the carbon atom to which they are attached form cycloalkyl (C5-C7), cycloalkenyl (C5-C7), a ring of 4 to 8 elements partially or totally saturated 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 ring of 5 or 6 elements partially or totally saturated, condensed with a 5 or 6 element ring partially saturated, totally unsaturated or fully saturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or alkyl (CrC6) or X4 together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached form a ring of five to seven elements: R6 is a bond or is where a and b are independently 0, 1, 2, or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted alkyl (d-Cß); the alkyl (CrCß) optionally substituted in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (0) malqu? lo (C? -C6), -C (0) OX2, cycloalkyl (C3-C7), -N (X2) (X2) and -C (0) N (X2) (X2); or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 or R8, each alkylene bridge containing from 1 to 5 carbon atoms, with the proviso that when an alkylene bridge is formed, then X5 or X5a, but not both, may be on the carbon atoms and R7 or R8, but not both, may be on the nitrogen atom and with the proviso that when two alkylene bridges are formed, then X5 and X5a do not they can be on the carbon atom and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X5a and the carbon atom to which they are attached form a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or N-X2, with the proviso that when a and b are both 0, then Z is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted alkyl (CrCβ); wherein the alkyl (CrCß) optionally substituted in the definition of R7 and R8 is optionally independently substituted with A1, -C (0) 0-alkylene (d-Cß), -S (O) malky (d-Cß), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 -0-C (0) alkyl (d-C10) or 1 to 3 alkoxy (C Cß); or R7 and R8 can be joined to form - (CH2) r-L- (CH2) r; where L is C (X2) (X2), S (0) m or N (X2); Al each time it appears is independently cycloalkenyl (C5-C7), phenyl or a ring of 4 to 8 elements partially saturated, fully saturated or totally unsaturated, 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 ring of 5 or 6 elements, optionally having from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a ring of 5 or 6 elements partially saturated, totally saturated or totally unsaturated, optionally from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently replaced, in one or optionally in both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, -OX6, - C (0) N (X6) (X6), oxo, (d-C6) alkyl, nitro, cyano, benzyl, - 5 S (0) malchyl (CrCß), 1 H-tetrazol-5-yl, phenyl, phenoxy , phenylalkyloxy, halophenyl, methylenedioxy, -N (X6) (X6), -N (X6) C (0) (X6), -S02N (X6) (X6), -N (X6) S02-phenyl, -N ( X6) S02 (X6), -CONX11X12, -S02NX11X12, -NX6S02X12, -NX6CONX11X12, -NX6S02NX11X12, -NX6C- (0) X12, midazolyl, thiazolyl and tetrazolyl, with the proviso that if A1 is optionally substituted with methylenedioxy,
10. 10 then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted alkyl (CrCß); the optionally substituted alkyl (CrCß) defined for X11 is optionally or independently substituted with phenyl, phenoxy, alkoxycarbonyl (CrCβ), - S (0) malkyl (d-Cβ), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 alkanoyloxy (d-do) 15 or 1 to 3 alkoxy (d-Cß); X12 is hydrogen, alkyl (d-Cß), phenyl thiazolyl, midazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH 3, OCH 3, OCF 3 and CF 3; or X11 and X12 join to form (CH2) r-L1- (CH2) r; where 20 L1 is C (X2) (X2), O, S (0) m or N (X2); r each time it appears is independently 1, 2 or 3; X2 each time it appears is independently hydrogen, optionally substituted alkyl (CrCß) or optionally substituted cycloalkyl (C3-C7), where the alkyl (d-Cß) ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^ fe ^^ »^^, ^. ^ j - ^. *. », .. - - ^ ^ g ^ B ^ i ^ s ^ ^ optionally substituted and the (C3-C7) cycloalkyl optionally substituted in the definition of X2 are optionally independently substituted with -S (0) malkyl (C C6), -C (0) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (CrCß); X6 is independently hydrogen, optionally substituted alkyl (CrCß), halogenated alkyl (C-C6), optionally substituted cycloalkyl (C3-C), halogenated cycloalkyl (C3-C7), where optionally substituted (d-C) alkyl and cycloalkyl (C3-C) optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 alkyl (d-C4), hydroxyl, alkoxy (d-C4), carboxyl, CONH2, -S (0) malkyl (CrCβ ), alkyl (dd) carboxylate ester or 1 H-tetrazol-5-yl ester; or when there are two groups X6 on an atom and both X6 are independently alkyl (CrC6), the two alkyl groups (CrCβ) can be optionally attached and, together with the atom to which the two groups X6 are attached, form a ring of 4 to 9 elements, which optionally has oxygen, sulfur or NX7; X7 is hydrogen or alkyl (CrCß) optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the proviso that: X6 and X12 can not be hydrogens when bound to C (O) or S02 in the form C (0) X6, C (0) X12, S02X6 or S02X12; and when R6 is a bond, then L is N (X2) and each r in the definition (CH2) rL- (CH2) r is independently 2 or 3 for the manufacture of a medicament for the treatment or prevention of congestive heart failure , obesity or weakness associated with advanced age in a mammal.
11. 11. The use according to claim 10, wherein said functional somatostatin antagonist is an alpha-2 adrenergic agonist. 12. The use according to claim 11, wherein said alpha-2 adrenergic agonist is selected from the group consisting of clonidine, xylazine and medetomidine. 13. The use according to claim 12, wherein said compound of formula I is the salt of L-tartaric acid of 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. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an amount of an alpha-2 adrenergic agonist and an amount of a compound of formula I
12. Or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein, is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) C (0) (CH2), - A1, - (CH2) qN (X6) S02 ( CH2) rA1, - (CH2) qN (X6) S02 (X6), - (CH2) qN (X6) C (0) N (X6) (CH2) t-A1, - (CH2) qN (X6) C ( 0) N (X6) (X6), (CH2) qC (0) N (X6) (X6), - (CH2) qC (0) N (X6) (CH2) t-A1, - (CH2) qC ( 0) OX6, - (CH2) qC (0) 0 (CH2) t-A1, - (CH2) qOX6, - (CH2) qOC (0) X6. - (CH2) qOC (0) (CH2) rA1, - (CH2) qOC (0) -N (X6) (CH2) t -A1, - (CH2) qOC (0) N (X6) (X6), - (CH2) qC (0) X6, - (CH2) qC (0) (CH2), - A1, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) S02N (X6) (X6), - (CH2) qS (0) mX6, - (CH2) qS (0) m (CH2), - A1, -alkyl (d-d0), - (CH2) t-A1, - (CH2) q-cycloalkyl (C3-C7), (CH2) qY -alkyl (Ci-Cß), - (CH2) q-Y1- (CH2) rA1 or - (CH2) q-Y1- (CH2) t-cycloalkyl (C3) -C7); where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with alkyl (dC), hydroxyl, alkoxy (dd), carboxyl, -CONH2, -S (0) malchyl (CrCß), -C02 alkyl ester (dd) , 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S (0) m, -C (0) NX6-, - CH = CH-, -C = C-, -N (X6) C (0) -, -C (0) NX6-, - C (0) 0-, -OC (0) N (X6) - or -OC (O) -; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said group (CH2) q and the group (CH2) t, may each be optionally substituted with hydroxyl, alkoxy (dC), carboxyl, -CONH2, -S (0) malchyl (CrC6), -C02 alkyl ester ( dd), 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro or 1, or 2 alkyl (dC); R2 is hydrogen, alkyl (CrC8), -alkyl (C0-C3) -cycloalkyl (C3-C8), -alkyl (C4) -A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, C (0) OX6, -C (0) N (X6) (X6), -N (X6) (X6), -S ( 0) malkyl (d-C6), -C (0) A1, -C (O) (X6), CF3, CN or 1, 2 or 3 halogens;
13. , * Jbta & o9ti * Yes.
14. R3 is A1, (C1-C10) alkyl, -alkyl (C6) -A1, -alkyl (CrCS) -cycloalkyl (C3-C7), -alkyl (C5) -X1 -alkyl (C5), -alkyl (CrC5) -X1-(C0-C5) alkyl-A1 or -alkyl (CrC5) -X1-alkyl (CrC5) -cycloalkyl (C3-C7); where the alkyl groups in the definition of R3 are optionally substituted with -S (0) maltyl (d-C6), -C (0) OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3; X1 is O, S (0) m, -N (X2) C (0) -, -C (0) N (X2) -, -OC (O) -, -C (0) 0-, -CX2 = CX2-, NX2) C (0) 0-, -OC (0) N (X2) - or -C = C-; R 4 is hydrogen, alkyl (d-Cß) or cycloalkyl (C 3 -C 7) or R 4 together with R 3 and the carbon atom to which they are attached form cycloalkyl (C 5 -C 7), cycloalkenyl (C 5 -C 7), a ring of 4 8 elements partially or totally saturated 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 ring of 5 or 6 elements partially or totally saturated, condensed with a 5 or 6 element ring partially saturated, totally unsaturated or fully saturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or alkyl (d-Cß) or X4 together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached form a ring of five to seven elements: R6 is a bond or is _ ^ jHB «^^ | g ^ ai S ^ '* ^. sa» g «iMal» MM ^ ~ a .- ^ ~. < ai * gagRi iÉ ^ a¿8St < t where a and b are independently 0, 1, 2 or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted alkyl (d-C6); the (d-Cß) alkyl optionally substituted in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (0) maltyl (d-C6), -C (0) OX2 , (C3-C7) cycloalkyl, -N (X2) (X2) and - C (0) N (X2) (X2); or the carbon carrying X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8, each alkylene bridge containing from 1 to 5 carbon atoms, provided that when an alkylene bridge is formed, then X5 or X5a, but not both, may be on the carbon atom and R7 or R8, but not both, may be on the nitrogen atom and with the proviso that when two alkylene bridges are formed, then X5 and X5a do not they can be on the carbon atom and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X5a and the carbon atom to which they are attached form a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a ring of 5 or 6 elements v4: 4 partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or N-X2, with the proviso that when a and b are both 0, then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (d-C) alkyl; wherein the alkyl (d-Cß) optionally substituted in the definition of R7 and R8 is optionally independently substituted with A1, -C (0) 0-alkyl (d-Cß), S (0) malkyl (d-Ce), to 5 halogens, 1 to 3 hydroxy, 1 to 3 -0-C (0) alkyl (d-C10) or 1 to 3 alkoxy (CrCß); or R7 and R8 can be joined to form - (CH2) r-L- (CH2) r; where L is C (X2) (X2), S (0) m or N (X2); Al each time it appears is independently cycloalkenyl (Cs-C), phenyl or a ring of 4 to 8 elements partially saturated, fully saturated or totally unsaturated, 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 ring of 5 or 6 elements, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or totally unsaturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently substituted, on one or optionally on both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3 , OCF H, CF3, CH3, OCH3, -OX6, -C (0) N (X6) (X6), -C (0) OX6, oxo, alkyl (C6), nitro, cyano, benzyl, -S ( 0) malchyl (CrCß), 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N (X6) (X6), -N (X6) C (0) (X6), -S02N (X6) (X6), -N (X6) S02-phenyl, -N (X6) S02 (X6), -CONX11X12, -S02NX11X12, -NX6S02X12, -NX6CONX11X12, -NX6X02NX11X12, -NX6C- (0) X12, imidazolyl , thiazolyl and tetrazolyl, with the proviso that if A1 is optionally substituted with methylenedioxy, then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted (C -Cß) alkyl; the optionally substituted (d-Cß) alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, alkoxycarbonyl (d-Cß), - S (0) malkyl (CrCß), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3-alkanoyloxy (d-Cio) or 1 to 3 alkoxy (d-Cß); X12 is hydrogen, (d-Cß) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH 3, OCH 3, OCF 3 and CF 3; or X11 and X12 join to form (CH2) r-L1- (CH2) r; where L1 is C (X2) (X2), O, S (0) m or N (X2); r each time it appears is independently 1, 2 or 3; X2 each time it appears is independently hydrogen, optionally substituted alkyl (CrCß) or optionally substituted cyclo (C3-C7) cycloalkyl, wherein optionally substituted (CrCß) and optionally substituted (C3-C) cycloalkyl in the definition of X2 are optionally independently substituted with -S (0) malchyl (CrC6), -C (0) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (d-Cß); X6 is independently hydrogen, optionally substituted alkyl (d-C6), halogenated alkyl (C2X6), optionally substituted cycloalkyl (C3-C7), halogenated cycloalkyl (C3-C), where optionally substituted (d-C6) alkyl and cycloalkyl (C3-C7 optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 alkyl (-C), hydroxyl, (C1-C4) alkoxy, carboxyl, CONH2, -S (0) malkyl (CrC6), (C 1 -C 4) alkylcarboxylate or 1 H-tetrazol-5-yl; or when there are two groups X6 on an atom and both X6 are independently alkyl (CrCß), the two alkyl groups (d-Cß) can be optionally attached and, together with the atom to which the two groups X6 are bound, form a ring from 4 to 9 elements, optionally having oxygen, sulfur or NX7; X7 is hydrogen or alkyl (CrCß) optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the proviso that: X6 and X12 can not be hydrogen when bound to C (O) or SO2 in the form C (O) X6, C (O) X12, SO2X6 or SO2X12; and when R6 is a bond, then L is N (X2) and each r in the definition (CH2) rL- (CH2) r is independently 2 or 3.
15. 15. The use according to claim 1, wherein The disorder associated with insulin resistance is type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance or an insulin resistance syndrome or condition.
16. 16. The use according to claim 1, wherein the disorder associated with insulin resistance is obesity or advanced age.
17. 17. The use of a growth hormone releasing peptide or a growth hormone releasing peptide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of insulin resistance in a mammal.
18. 18. A process for the preparation of the compound of formula k, (K) comprising the reaction of the compound of formula g, Free base (g) with the compound of formula j, (I) where Prt is an amide protecting group, in the presence of an organic base, a peptide coupling reagent and an inert solvent for the reaction, at a temperature from about -78X to about -20X, to give the compound of formula K.
19. 19. A method according to claim 18, wherein the peptide coupling reagent is the cyclic anhydride of 1-propanophosphonic acid and the compound of formula g has the configuration R, the compound of formula j has the configuration R and the compound of formula k has the configuration 3a- (R) , 1- (R).
20. 20. - A process for the preparation of the compound of formula Z, which comprises the reaction of the compound of formula g, with the compound of formula j, (I) »¿t ^ lfes & - Ksl ^^^^? ^^ íH ^ tiJj in the presence of an organic base, a peptide coupling reagent and an inert solvent for the reaction, at a temperature from about -78X to about -20X, to give the compound of formula k, (k) the deprotection of the compound of formula k to give the compound of formula I, (I) the reaction of the compound of formula I with L-tartaric acid in an alcoholic solvent to give the compound of formula Z.
21. 21. - A method according to claim 20, wherein the peptide coupling reagent is the cyclic anhydride of 1-propanophosphonic acid and the compound of formula g has the R configuration, the compound of formula j has the R configuration and the compounds of formula k, I and Z have the configuration 3a- (R), 1- (R).
22. 22. A process for the preparation of the compound of formula g which comprises the reaction of the compound of formula f, with a base in an inert solvent at a temperature from about -50 to -10X, wherein the chirality of the benzyl group is maintained to give the compound of formula g.
23. 23. A process for the preparation of the compound of formula c, (c) comprising the reaction of the compound of formula b, (b) where Prt is an amine protecting group with an inorganic or organic base and benzyl bromide in a solvent inert to the reaction giving the compound of formula c. - ** -
24. 24.- A procedure for the preparation of a compound of formula f, which comprises the reaction of the compound of formula e, 15 (e) with L-tartaric acid in an organic solvent inert to the reaction.
25. 25. The enantiomeric mezcal R, S, the R-enantiomer or the S-enantiomer of the compound of formula < As ^ z ^, .. ,,? .ziU7? & isi ». where Prt is hydrogen or an amine protecting group.
26. 26.- The use of a compound of formula I or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof, wherein is 0 or 1; n and w are each independently 0, 1 or 2; with the proviso that w and n are not at the same time 0; And it's oxygen or sulfur; R1 is hydrogen, -CN, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) C (0) (CH2) t-A1, - (CH2) qN (X6) S02 ( CH2) t-A1, - (CH2) qN (X6) S02 (X6), - (CH2) qN (X6) C (0) N (X6) (CH2) t-A1, - (CH2) qN (X6) C (0) N (X6) (X6), (CH2) qC (0) N (X6) (X6), - (CH2) qC (0) N (X6) (CH2) t-A1, - (CH2) qC (0) OX6, - (CH2) qC (0) 0 (CH2) t-A1, - (CH2) qOX6, - (CH2) qOC (0) X6, - (CH2) qOC (0) (CH2) t -A1, - (CH2) qOC (0) -N (X6) (CH2) t-A1, - (CH2) qOC (0) N (X6) (X6), - (CH2) qC (0) X6, - (CH2) qC (0) (CH2) rA1, - (CH2) qN (X6) C (0) X6, - (CH2) qN (X6) S02N (X6) (X6), - (CH2) qS (0) mX6, - (CH2) qS (0) m (CH2) t-A1, -alkyl (CrC10), - (CH2), - A1, - (CH2) q- cycloalkyl (C3-C7), (CH2) q- Y 1 -alkyl (C C 6), - (CH 2) q-Y 1 -CH 2) t-A1 or - (CH 2) q- Y 1 -CH 2) t-cycloalkyl (C 3 -C 7); where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with alkyl (dd), hydroxyl, alkoxy (d-C4), carboxyl, -CONH2, -S (0) malkyl (d-Cß), -C02 ester of I rent J ^^^^^^^ > > ^^^^^^^ (d-d), 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is 0, S (0) m, -C (0) NX6-, -CH = CH-, -C = C, -N (X6) C (0) -, -C (0) NX6-, -C (0) 0-, -OC (0) N (X6) - or -OC (O) -; q is 0, 1, 2, 3, or 4; t is 0, 1, 2 or 3; said group (CHz) q and the group (CH2) t may each be optionally substituted with hydroxyl, alkoxy (dd), carboxyl, -CONH2, -S (0) malkyl (d-C6), -C02 alkyl ester (dd), 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro or 1 or 2 alkyl (dd); R2 is hydrogen, (C? -C8) alkyl, -C0-C3 alkyl- (C3-C8) cycloalkyl, -C (C4) alkyl or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, C (0) OX6, -C (0) N (X6) (X6), -N (X6) (X6), -S ( 0) malchyl (CrC6), -C (0) A1, -C (0) (X6), CF3, CN or 1, 2 or 3 halogens; R3 is A1, (C1-C10) alkyl, -alkyl (d-Cß) -A1, alkyl (CrC6) -cycloalkyl (C3-C7), -alkyl (d-C5) -X1-alkyl (C5), - (C C5) -X1 alkyl- (C0-C5) -A1- or (d-C5) alkyl-X1-alkyl (CrC5) -cycloalkyl (C3-C7) alkyl; where the alkyl groups in the definition of R3 are optionally substituted with -S (0) maltyl (d- C6), -C (0) OX3, 1, 2, 3"4 or 5 halogens, or 1, 2, or 3 OX3; X1 is 0, S (0) m, - N (X2) C (0) -, -C (0) N (X2) -, -OC (O) -, -C (0) 0-, -CX2 = CX2-, -N (X2) C (0) 0-, - OC (0) N (X2) - or -C = C-; R4 is hydrogen, (C6) alkyl or (C3-C7) cycloalkyl or R4 together with R3 and the carbon atom to which they are attached form cycloalkyl (C5-C7), cycloalkenyl (C5-C7), a ring of 4 to 8 elements partially or totally saturated 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 ring of 5 or 6 elements partially or totally saturated, condensed with a 5 or 6 element ring partially saturated, totally unsaturated or fully saturated, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or alkyl (d-C6) or X4 together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached form a ring of five to seven elements: R6 is a bond or is where a and b are independently 0, 1, 2, or 3; X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted alkyl (CrCß); the alkyl (CrCß) optionally substituted in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S (0) malchyl (d-C6), -C (0) OX2, cycloalkyl (C3-C7), -N (X2) (X2) and - C (0) N (X2) (X2); or the carbon carrying X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8, each alkylene bridge containing from 1 to 5 carbon atoms, provided that when an alkylene bridge is formed, then X5 or X5a, but not both, may be on the carbon atom and R7 or R8, but not both, may be on the nitrogen atom and with the proviso that when two alkylene bridges are formed, then X5 and X5a do not they can be on the atom of carbon and R7 and R8 can not be on the nitrogen atom; or X5 together with X5a and the carbon atom to which they are attached form a ring of 3 to 7 elements partially or totally saturated, or a ring of 4 to 8 elements partially or totally saturated having 1 to 4 heteroatoms independently selected from the group group consisting of oxygen, sulfur and nitrogen; or X5 together with X5a and the carbon atom to which they are attached form a bicyclic ring system consisting of a ring of 5 or 6 elements partially or totally saturated, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, totally saturated or totally unsaturated, which optionally has 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or N-X2, with the proviso that when a and b are both 0, then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted alkyl (CrCβ); wherein the alkyl (CrCß) optionally substituted in the definition of R7 and R8 is optionally independently substituted with A1, -C (0) 0-alkyl (d-C6), -S (0) malky (d-Cß), 1 a 5 halogens, 1 to 3 hydroxy, 1 to 3 -0-C (0) alkyl (Crdo) or 1 to 3 alkoxy (CrCβ); or R7 and R8 can be joined to form - (CH2) rL- (CH2) r; where L is C (X2) (X2), S (0) m or N (X2); Al each time it appears is independently cycloalkenyl (C5-C7), phenyl or a ring of 4 to 8 elements partially saturated, fully saturated or totally unsaturated, 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 ring of 5 or 6 elements, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with a 5 or 6 element ring partially saturated, fully saturated or completely unsaturated, optionally tending from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 each time it appears is optionally independently substituted, on one or optionally on both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent being independently selected from the group consisting of F, Cl, Br, I, OCF3 , OCF2H, CF3, CH3, OCH3, -OX6, -C (0) N (X6) (X6), -C (0) OX6, oxo, alkyl (d-C6), nitro, cyano, benzyl, -S ( 0) malchyl (CrC6), 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N (X6) (X6), -N (X6) C (0) (X6), -S02N (X6) (X6), -N (X6) S02-phenol, - N (X6) S02 (X6), - CONX11X12, -S02NX1 X12, -NX6S02X12, -NX6CONX1 X12, - NX6C- (0) X12, Midazolyl, thiazolyl and tetrazolyl, with the proviso that if A1 is optionally substituted with methylenedioxy, then it can only be substituted with a methylenedioxy; wherein X11 is hydrogen or optionally substituted alkyl (d-Cß); the optionally substituted alkyl (d-Cß) defined for X11 is optionally independently substituted with phenyl, phenoxy, alkoxycarbonyl (CrC6), -S (0) malkyls (CrCß), 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 alkanoyloxy (C1-C10) or 1 to 3 alkoxy (CrC6); X12 is hydrogen, alkyl (dC6), phenyl, thiazolyl, imidazolyl, furyl or thienyl, with the proviso that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group constituted 5 for Cl, F, CH 3, OCH 3, OCF 3 and CF 3; or X11 and X12 join to form (CH2) rL1- (CH2); where L1 is C (X2) (X2), O, S (0) m or N (X2); r each time it appears is independently 1, 2 or 3; X2 each time it appears is independently hydrogen, optionally substituted alkyl (CrCß) or optionally substituted cycloalkyl (C3-C7), where the alkyl (d-Cß) Optionally substituted and the (C3-C) cycloalkyl optionally substituted in the definition of X2 are optionally independently substituted with -S (0) maltyl (d-Cß), -C (0) OX3, 1 to 5 halogens or 1-3 OX3; X3 each time it appears is independently hydrogen or alkyl (CrC6); X6 is independently hydrogen, optionally substituted alkyl (CrCβ), Halogenated alkyl (C2-C6), optionally substituted cycloalkyl (C7-C3), halogenated cycloalkyl (C3-C7), wherein optionally substituted alkyl (CrCß) and (C3-C7) cycloalkyl optionally substituted in the definition of X6 is optionally independently substituted with 1 or 2 alkyl (dC4), hydroxyl, alkoxy (dd), carboxyl, CONH2, -S (0) malchyl (d-Cß), Alkyl (d-d) carboxylate or 1 H-tetrazol-5-yl; or when there are two groups X6 on an atom and both X6 are independently alkyl (CrC6), the two alkyl groups (CrC6) can be optionally attached and, together with the atom to which the two groups X6 are attached, form a ring of 4 to 9 - d ^^^ á? i? -. ^ T ^ 7sx.-í -. ^ -.--. elements, optionally having oxygen, sulfur or NX7; X7 is hydrogen or alkyl (CrCß) optionally substituted with hydroxyl; and m each time it appears is independently 0, 1 or 2; with the proviso that: X6 and X12 can not be hydrogen when bound to C (O) or S02 in the form C (0) X6, C (0) X12, S02X6 or S02X12; and when R6 is a bond, then L is N (X) 2 and each r in the definition (CH2) rL- (CH2) r- is independently 2 or 3 for the manufacture of a medicament for the treatment of sleep disorders in a mammal. ^^^^^^^^^^^^^^^^^^^^^ SUMMARY OF THE INVENTION This invention relates to methods for the treatment of insulin resistance in a mammal comprising the administration of an effective amount of a compound of formula I wherein the variables are defined in the specification, or the stereoisomeric mixtures, the diastereomerically enriched, diastereomerically pure, enanitomically enriched or enantiomerically pure isomers or the pharmaceutically acceptable salts and prodrugs thereof to said mammal; the compounds of formula I are secretagogues of growth hormone and as such are useful for increasing the levels of endogenous growth hormone; in another aspect this invention provides certain intermediate compounds that are useful for the synthesis of the above compounds and certain methods useful for the synthesis of said intermediates and the compounds of formula I; this invention also relates to procedures | ^ a ^? * Please note that they comprise administration to a human or other animal of a combination of a functional somatostatin antagonist, such as an alpha-2 adrenergic agonist and a compound of formula I. PF / all * P99 / 1430F