SA05260222A - A treatment method using specific growth hormone stimuli - Google Patents

Abstract

The invention relates to compounds of the formula: and to pharmaceutically acceptable salts (salts), where the alternatives are as specified in the specification, which are triggers for the secretion of growth hormone secretogogues and increase the level of the internal growth hormone. The compounds of this invention are useful in treating and preventing osteoporosis, hypotrophic heart failure, weakness associated with aging, obesity; increased speed of repair of bone fractures, poor response to metabolic demolition of protein, reduced wasting and protein loss due to chronic disease, increased wound healing speed, or increased healing speed Burn patients or patients who have undergone major surgery; improve muscle resistance and movement, maintain skin thickness, metabolic or renal balance. The compounds of the present invention are also useful in treating osteoporosis when used in an introduction with: a bisphosphonate repeater compound such as alendronate; estrogen, premarin, optionally progesterone, estrogen or anti-estrogen, or calcitonin, and beneficial drug formulations. In addition, the present invention relates to pharmaceutical compositions beneficial in increasing the production and internal release of growth hormone into another human or animal, including an effective amount of the compound of the present invention and a growth hormone secretion catalyst of 6-GHRP, GHRP-1, Hexarelin, a growth hormone release agent (IGF-2). , IGF-1, (GRF or B-HT920. The invention also related to intermediates useful in preparing compounds of Formula I.

Description

¥ A method of treatment with certain growth hormone secretion stimulants Full Description Background This application is a partial application of Application No. 97170581 filed with this office dated YY // Ahklam. The invention relates to dipeptide compounds that are stimulators of the secretion of growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis. stimulates growth hormone (GH) secreted by the pituitary gland; The growth of all viable body tissues. add to that; Growth hormone is known to have the following primary effects on the body building process:- 1 increase the rate of protein synthesis in essentially all cells of the body; - Decreased rate of utilization of carbohydrates in the body LIA; Ve *- Increased movement of free fatty acids and utilization of fatty acids for energy. Deficiencies in growth hormone result in many medical disorders. V (JULY) causes stunted growth In (pall) the results of growth hormone insufficiency include a profound decrease in lean body mass and a concomitant increase in total body fat, especially in the prominent region. A decrease in skeletal mass, heart muscle, and muscle resistance leads to a significant decrease in the energy of muscular effort. The vo decreases. Also bone density Administration of exogenous growth hormone has been shown to delay many anabolic changes Additional benefits of treatment include a decrease in LDL cholesterol and an improvement in physiological condition In cases where increased levels of growth hormone are desired the problem has generally been resolved by providing exogenous growth hormone or by taking Agent that stimulates the production and/or release of growth hormone. In both cases the nature of the peptidyl required the compound to be injected. © The source of the growth hormone was initially extracted from the pituitary glands of deceased subjects. This results in an expensive product and comes with a risk of disease transmission associated with the source emphysematous gland; Illiteracy to growth hormone recipient (a) disease L18005-0:©017581). nape; became alia synthetic growth hormone while carrying no risk of disease transmission; It is still a very expensive product that must be administered by injection or nasal spray. Most growth hormone insufficiency is caused by defects in growth hormone release that are not primarily vo. defects in the pituitary gland's production of growth hormone. So; An alternative way to normalize HGH serum levels is by stimulating its release from nutrients in the body. Increased growth hormone secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypophagic center. as a result; The development of synthetic growth hormone-releasing factors to stimulate pituitary growth hormone secretion has been pursued; It has multiple advantages other than the increased cost and inappropriateness of growth hormone replacement therapy. acting in parallel with physiological control pathways; Most of the desirable factors stimulate the secretion of pituitary growth hormone; Excess 0 levels of growth hormone associated with the undesirable side effects of exogenous growth hormone administration are avoided thanks to proper negative feedback. L-3,4-dihydroxyphenylalanine; The pituitary gland by acting Jia or somatostatin in some way on the SPC perhaps either to decrease secretion of somatostatin or hormone releasing hormone (GHRF) to increase secretion of a known growth hormone releasing factor stimulator or an unknown endogenous growth hormone or all of these. Other compounds that stimulate the release of endogenous growth hormone such as patent peptides or similar GRF peptides have been developed related to peptidyl compounds while being substantially smaller than US hormone peptides No. 451184956. These peptides are Varied As with most growth protease peptides, it is still susceptible to Protease enzymes to WO 94/13696 56M have low intestinal bioavailability. Certain signals and similar substances secrete the release of growth hormone. The compounds of the Ye spiropiperidines are of the general construction shown below.

CH3 CH; oy2

No HO oy Certain types of growth hormone release. These dipeptides are dipeptides WO 94/11012 indicated by the general structure: peptides

RIS 1 Rla 1 (Ho 1 Re p ke —C— rp C A) C01 No R14 RO where A is: A Reb Falaj Vehicles registered from 94/11012 WO and 94 /13696 It is useful in the treatment of osteoporosis © in combination with parathyroid hormone or bisphosphonate General description of the invention The invention provides compounds of the formula: R! i R3 Xe 7 yo CHD] (CHC |, Ne, RR Ea NF (CH)w 4 0 82 )0 mixtures of racemic-diastereomeric mixtures and isomers 0 Ophthalmic of the aforementioned compounds, salts, and prodrugs acceptable pharmacologically terminated where: © is zero or 1; “and each separately is 1 Ghia or oF, provided that wo and “both are not zeros At the same time; vo 7 is oxygen sulfur a RI 5 hydrogen «-(CH,)(N(X6)C(0)X® ”-CN hydrogen -(CHp)gN) X6)S0,X6 ¢-(CH;)gN(X®)SO,(CHy)-Al -(CH,)gN(X6)C(O)(CH,)-Al -(CHp)gN) X6)C(O)N(X6)(X) ¢-(CH,)N(XS)C(O)N(X6)(CH,)-A! “-(CH)4C(0)OX ?® «-(CH,)qC(OIN(XS)(CHy)-A! «-(CH,){C(OIN(X®)(X®)

° (CH,){0C(O)(CH,)-A! -(CH,){0C(0)X5 ~(CHy),0X® e-(CH,)C(O)O(CH,)-A! (CHp),C(0)XS ~(CH,),0C(O)N(X6)(X6) «~(CH,) OC(OIN(X6)(CH)-A! «-(CHp)N (X6)SO,N(XE)(XS) «(CH N(XS)C(0)OXS ¢-(CH,)(C(O)(CH,)-Al ~(C1-CioJalkyl = (C- C1g) dS -(CHy) S(O) CH) Al «~(CH,) S(O), X6 -(CHp)g=(Cs-Cr)eycloalkyl (CH,)g(C3-Cy) All Danry «(CHp)-Al m or alkyl +(CH,y)gY'(CHy) A! e~(CHy) Y1-(C;-Collalkyl {(CHy)-Y1-(C; -Co) alkyl £-(CHy)-Y'-(CHy)-(C3-Cy)eycloalkyl (CH) -Y!{(CHy)-(C5-Cy) cycloid in definition of cycloalkyl and the cyclic alkyl, in which the alkyl groups (C1-Cy) optionally replace the hydroxyl hydroxyl (C-Cylalkyl) with the alkyl (J-©) R! alkyl and 5(0(.)02- 0- -CONH, “carboxyl carboxyl” (C,-Cyalkoxy Ve “1H ¢-CO,(C;-Cyalkyl ester -CO,(C,-Cy) alkyl ester -S(0),, (C,-Cg)alkyl fluoro? or ¥1 fluoro or 1H-tetrazol-5-yl yl —0—{ 3 si -N(X6)C(0)- ¢-C=C - -CH=CH- “-C(O)NX6- S(O) 0 sa Y! ¢-0C(0)- Ar -OC(OIN(X6)- “-C(0)O- “- C(O)NXE- ;; J YY) is yellow vo ? or ??; 1 is the yellow ; 1 mentioned with (CH), and the (CH) group may optionally be substituted carboxyl group ¢ (C-Cy lalkoxy (r0©-0) hydroxyl alkyl hydroxyl (and©-r5)0(6-) and allelo5(0(,,)0-0); Alkyl ester (B0-:002)0- -CONH, ? or? Fluoro-0 (IH-tetrazol-5-yl tetrazol-#-yl-111 -CO,(C,-C,)alkyl ester); Y si 1 see fluoro a1 nol(©-,©); cyclic alkyl (and©-:0)- alkyl (C;-Cy) alkyl hydrogen is hydrogen 2 of the alkyl(and-0) -abolyl (Z-O0)-am-alkyl (YH-)-LH-Oaldrin-0)- (Co-Cs) in cycloalkyl and cycloalkyl, where alkyl groups (A! or Definition of vo

YO) Ar ON (CF; ctrem -C(0)A! -8(0),,(C,-Celalkyl -S(0),(C;-Ce) alkyl thalogen (pa) sia ¥ or

0 sa R3 for a measure (m0-0) and 0 sa R3)); Alkyl pain (©-0)- “-(C1-Ce)alkyl-A’ Circular alkyl -(C3-C7) Alkyl (6-0)- “-(C1-Ce)alkyl-( C3-Cq)ecycloalkyl (C3-Cq)-761-alkyl (F©-:0)- -A" «-(C1-Cs)alkyl-X'-(C;-Cs)alkyl -X'-(Co-Cs) alkyl ~(C1-Cs) nkhwala0u-m0)- !1-2 bollah (©:-0)- or alkyl dari <(C3-C7) alkyl (and ©-6)- 10 ee alkyl (and 0-, 0)- oldam(ben-y)-abollah (and-) 1-7 bollah (and 2-©)-?, where the alkyl groups are optionally substituted in the definition 183 with alkyl (F-6:R5)0()0- and God(M8)0(..)0-0-» 0(0763)- FY 0 £ or © chalogens or 10 or «OX3 v «-C(0)O- -OC(0)- «-C(O)N(X2)- «-N(X)C(0)- S(O), < 0 sa XI -OC(O)N(X2)- «-N(X2)C(0)0O- «-CX2=CX2- Ve r ¢-C=C- 4 is hydrogen Alkyl (Cj-Coalkyl (C1-Cg) or circular alkyl (C3-Cy) anoladma””(,©-and ©); or take 84 with 1203 together and the carbon atom bonded with them and form cyclic alkyl “(C5-Co)eyeloalkyl (C5-Cy) cycloidal alkyl (0-o0) 1 stump”ahaha©0,(00-f©); a ring with partially saturated members or fully saturated having 1 to vo 4 heteroatoms toms selected separately from the group consisting of “oxygen” sulfur and “nitrogen” or it is a circular A firing system consisting of a ring p0 with 0 or 1 members partially saturated or saturated (LIS welded to a 0 or 1 membered partially saturated ring that is not fully saturated or optionally fully saturated having from 1 to ; Heteroatoms selected separately from the group consisting of nitrogen Y. Sulfur sulfur and oxygen 4 is hydrogen or alkyl (C-Cgalkyl (C-Cg) or taken X4 with RY together and a nitrogen atom bonded to X4 and a carbon atom bonded to RY form a five to seven membered ring; A As _ RS is bond or is (CH2)a (CHa) ¢ Cua Yo 8 and 5 each being 0 (YO) ?;

and “X5 and 1458 are selected separately from the group consisting of Ni hydrogen fluoromethyl hydrogen Al «trifluoromethyl and the optionally substituted alkyl (C-Cglalkyl (C-Cg); optionally substituted alkyl (m©-,0) () optionally substituted C-Calkyl in the definition of X3 X55 with a substituent chosen from the group consisting of OX? ) 0- “-C(0)0X? kysyl dary (MNA-On) “(C5-Cy)eycloalkyl -C(ONXH)(X?) 5s -NXH(X?) or carbon carbon bearing XS or X52 forms one or two alkylene bridges with the nitrogen atom bearing 147 R35 where each alkylene bridge contains 1 to © atoms carbon “carbon atoms” provided that when Ve forms one alkylene bridge then it may be X5 or 1258 but not both on the R7 carbon atom or 188 but not both on the nitrogen atom And also on the condition that when two alkylene bridges are formed, then it cannot be 745 X52 on the carbon atom and it cannot be 187 and 1885 on the nitrogen atom. 'nitrogen atom vo' or X5 is taken together with X52 and the carbon atom attached to them and they form an 8 ring with ? to V partially saturated or saturated members (LIS) or a 4-membered P0 ring to A partially saturated or WIS saturated members having 1 to ; individually selected heteroatoms from the group composed of oxygen oxygen sulfur and nitrogen 'nitrogen' or 165 are taken together with X52 and the carbon atom bonded with them and form a Y system. A double circular ring system consisting of a p' ring with 0 or 1 Partially saturated or optionally fully saturated members having 1 or 1 heteroatoms selected separately from the group consisting of nitrogen, sulfur, and oxygen 0 fused to a “p” ring with 0 or “saturated members LIS molecules saturated or optionally unsaturated completely having 1 to ; heteroatoms selected separately from the group consisting of “nitrogen Yo sulfur and oxygen coxygen ZI is a bond O bond or N-X2 provided that Laie is bya both zeros then 71 is not N-X2 or 0;

A

(C1-Colakyl (C;-Cg) or alkyl hydrogen and 5 each separately is hydrogen 7 optionally substituted? the optionally substituted in (C-Coalkyl (C=C) where each separately Optionally alkyl alkyl -C(0)0~(C;-Cglalkyl) alkyl (0,0)-0(0)©- (Al and 1854 with R7 defined -S(0) ,(C1-Cy) ° o-,5)0()0-; 1 to * 1 halogen atoms chalogens to ¥ hydroxy 1 hydroxy to ¥ alkyl 0-C(0)(C ;-C alkyl -0-C(O)(C1-Crp) or 1 to ?alkoxy (and©-,©) te-tallo©-,©); or R85 R7 can be taken together to form ¢-(CH,),-L-(CHy),- where L mr (002(06,(5)0-R N(X?) 0 in each case on A unit is the Cs-Cpleycloalkenyl (C5-Cy) phenyl ring or a “p” ring with A to partially saturated members that are fully saturated or completely unsaturated optionally having 1 to heteroatoms Separately selected from the group consisting of oxygen sulfur and nitrogen ©010088; a bicyclic ring system consisting of a Siting © or 1 partially saturated members that are not fully saturated or optionally fully saturated 1 It has 1 to ; Maga atoms Individually selected heteroatoms from the group consisting of nitrogen, sulfur, and oxygen 0m fused to a p0 ring having 0 or 1 partially saturated members LS or optionally totally unsaturated having 1 to ; Individually selected heteroatoms from the group composed of nitrogen «©010086; sulfur or oxygen oxygen 0 uh in each case is optionally substituted in one p0 ring or both rings if Al is a binary ring system dy ia with Up to three alternatives, each alternative is selected separately from the group consisting of (OCF,H «OCF; «I Br «Cl «OCH; «CH; «CF, CTRM 0(11069069)- -C(0 OXE oxo Jl 0x0 “(C;-Cgalkyl (C;-Cy) nitro cyano cbenzyl alkyl -S(0)m(C-C) -1H “-S(0),,(C,-Cg)alkyl Yo tetrazole-*- yl “1H-tetrazol-5-yl phenyl” phenoxy Ji “phenoxy alkyl oxy” phenylalkyloxy halo chalophenyl methylenedioxy -SO,N(X6)(X) -N(X6)C(0)(X6) -N(X6)(X6) cmethylenedioxy q (CONX!1X12 -N(X6) S0,X6 ¢-N(X6)SO,-phenyl -N(X6)SOp-J yi

NX6SO,NX!IX12 NX6CONX!X!2 «NX6SO,X12 (-SO,NX!IX!2 itetrazolyl) or tetrazolyl thiazolyl cimidazolyl imidazolyl «-NX6C(0)X12 then optionally substituted methylenedioxy with methylenedioxy A, provided that if it is one; Cua is optionally? Definition to 1 alkyl (0-6)m(8)0- olellm8)0(,)0-0- “(C;-Calkoxycarbonyl 6) to 1 hydroxy alkanoyl to 1 hydroxy 8108608 halogen atoms; (Cy-Collalkyl (C1-Cg) alkyl chydrogen is hydrogen 2 provided that when cthienyl or thienyl furyl cimidazolyl imidazolyl ctiazolyl is optionally substituted with one to three X12 then chydrogen is hydrogen X12 not be yo

OCF; «OCH; «CH; Tel «Cl substituents selected separately from the group consisting of (CFs 5 ¢-(CHp),-L1-(CHp),- and 1612 together to form X11 or taken

NE?) 3 380.0 C(X2(X2)

OF or 1 ; 1 apart is dla in each # 2 alkyl (and 0-©) yl(0,0-2) chydrogen in each case is hydrogen 2 101l0,(0010 -.0) optionally substituted, where (C3-Cy) optionally substituted or the cyclic alkyl (m-,©) optionally substituted and the cyclic alkyl (C1-Cg) separately optionally replace the alkyl with the alkyl ( and optionally substituted 5(0(.)0-0-X2) in the definition of (C3-Co)eycloalkyl (f-f) “0X3 to ?1 or halogens to ©1 halogen atoms -C(0)OX3 «-S(0),,(C;-Coalkyl 0” ¢(C-Cglalkyl (C;-Cg) or alkyl hydrogen in each case is hydrogen 3

Ye replacing (Cy-Colalkyl (C1-Cg) alkyl <hydrogen separately is hydrogen 6 (C3-C7) cyclic alkyl ((Cy-Cy)halogenated alkyl (M06-:0) ) ( | jaa) Halogen dancer-(n-from) J SIL jaa) Yad Walala 010n(,0-.0) (CC) separately optionally Alkyl JS where it replaces (C4-C ,)-halogenatedeycloalkyl optionally substituted atoyl(m©-,©) and the cyclic alkyl (©-o) 1 and (0:010-f©) cycloalkyl (0:010-f©) hydroxyl substituent 0 hydroxyl (e©-,©); hydroxyl (C1 -Cg) or ?alkyl 1 by X6 optionally in defining -S(0)n(C1-Cq) alkyl «CONH, «carboxyl carboxylate» (C-Cylalkoxy (C-Cy) Alkoxy “carboxylate (C;-C4)alkyl ester carboxylate (C;-Cy) alkyl ester ¢-S(0),,(C-Cg)alkyl or ¢1H-tetrazol-5 -yl tetrazole-*- yl -1H or they are separately alkyl (m-0,0) X06 one and both atoms when there are two groups 146 on the Ve atom to optionally connect and; together with (Cp-Collalkyl), so the two alkyl groups (m©-,©) “(Cy-Colalkyl) with ; up to 9 members optionally having an oxygen atom ring attached to them; form an atom ring {NX7 sulfur sulfur oxygen ms Optionally substituted with C1-Clalkyl (C1-Cq) or the alkyl hydrogen is hydrogen 7 and thydroxyl hydroxyl Vo or ?; 1 he in each case is ““ provided that: or ;50 in C(O) when combined with hydrogen and 2012 cannot be hydrogen X6 and ¢80,X12 or SO,X6 «C(0)X!2 «C (0)X6 The figure is (11042) and each “in the definition of L when 146 is a bond of 5000, then 0.1 apart is ? or -(CHy),-L-(CH,),- containing these compounds which have “A” the preferred group of compounds; labeled “group is hydrogen RY is hydrogen 1701086©0; X4 The Cus shown here above is LST of formula 1 and for (--)? (C-C;) or the alkyl hydrogen is R7 hydrogen or methyl sulfate; ,6) 1 allele (J0-,©) optionally substituted with one or hydrogen is hydrogen RE vo hydroxyl two hydroxyl groups

(C- Cylalkyl (m©-,0) “phenyl phenyl” trifluoromethyl optionally substituted with (Cy-Cealkyl when the alkyl (m-0,6) is optionally substituted with m-hydroxyphenyl dndolyl indolyl phenyl imidazolyl Al08201tD1n wick “OX? ° -S(0)(C1-Cq) alkyl ((C5-Cq)cycloalkyl (C5-Cq) cyclic alkyl “p-hydroxyphenyl -C(OIN(XD) X?) sl -NX2)(X?) ¢-S(0)y(C;-Ce)alkyl and «(Cq-Cs)alkylene bridge (C;-Cs) come together to form an alkylene bridge R753 X5 or taken here above. (I) Other substituents not specified in “Group M” compounds are as specified in the formula A group of compounds that are preferred within “Group 0” which have formula 1 as shown CA labeled “group 13 contains compounds from group” chydrogen is zero; 165 and 7658 each separately have b hydrogen is Cus here above;. selects shydroxy (C,-Cylalkyl) alkyl (C,©-,©) anole (and ©-,©) or alkyl yl (and©-,©) hydroxy ?-indolyl-O013- “1-indolyl-CH,- of the group consisting of )= indolyl-112©- 3 «1-naphthyl-CH,- -CH ,-J—& -1 «3-indolyl-CH,- ?-indolyl-O011)-2-indolyl-CH,-0 «1-benzimidazolyl-CH,-benzimidazolyl-17--1 -2 -naphthyl-CH,- naphthyl-011- -7

J 8 -.)0-0,( Alkyl-2-benzimidazolyl-CH,-benzimidazolyl-0112-" Alkyl-2-pyridyl-(Ci-Cy)alkyl-pyridyl —Y Alkyl (C-,©)- - «phenyl-(Cy-Cy)alkyl- ;- pyridyl -(C-Cq) alkyl - 3-pyridyl-(C1-Caalkyl-pyridyl) =F - (C1-Cy) Alkyl (P0-0)- - «phenyl-CH,-S-CH,- phyl-CH,-S-CHp- «4-pyridyl-(C;-Cq)alkyl- ~~ 0 «phenyl-(Co-C3)alkyl-O-CH,- phenyl-(Co-C3) alkyl -O-CH,- thienyl-(C;-Cyq)alkyl- Juidh —Y -CH;- 5 «phenyl-CH,-O-phenyl-CHp- phenyl -CH,-O-J—— -CH,- ¢3-benzothienyl-CH,- from identification groups 183 with one to three aryl where the aryl part(s) optionally replaces the oxy SD Each substitution is selected separately from the group formed by methylene (Jil Yo .CF; 5 OCF,H «OCF; «OCH; «CHj «Cl Tel «methylenedioxy

1 A group of compounds; which are preferred within “group 78 of compounds; labeled having formula 1 as shown here OB “group ©”; containing compounds of “group 1 is zero or WY or 1 is zero ; © is 8 thydrogen above” where 184 is hydrogen or methyl methyl hydrogen and 1652 each separately is hydrogen 5 is X52 then hydrogen is not hydrogen X53 provided that when chydroxymethyl© thydrogen is hydrogen and hydrogen and 18 each of them is hydrogen 7

Js -CH,-S-CH,- “phenyl-CH,-0-CH,- phenyl-CH,-O-CH,- Hro R3 -CH,-J— ii = Y «1-naphthyl -CH,- -CH)-J——& -1 «-CH,-S-CH,-phenyl ¢3-indolyl-CH,- -CH,-Jd sa3) -* ar -(CH,) ;-phenyl -(CH,)3- «2-naphthyl-CH,- 0 (diay) with one to three R3 aryl identification groups where the aryl moiety is optionally replaced by “chloro” by a fluoro Each substituent is selected separately from the group consisting of fluororbeth. 1 contains the compounds of “group ©; which has formula 1 as 1-(0]2(-)0:-0©) is not M(0112)-cyclic alkyl Rl shown here above. where is i.e., alkyl (H©-6) and oleo-0); OCH; chydroxyl «(C-Cyalkyl (C-Cy) with an alkyl RY Definition of alkyl (and 5)0,)0-0- «CONH, «carboxyl carboxylate «(C;-Cyalkoxy (C1-Cy) «-CO, (C,-Cyalkyl ester -CO,(C-Cy) -5(0),(C1-Ce)alkyl fluoro to ¥1 fluoro or 1H-tetrazol-5-yl yl —o—Js 3 sii -1H “(Cy-C3) alkyl “(C3-Cg) cyclic alkyl chydrogen is hydrogen R20 is not Yo where (C-Cyalkyl (C-Cg) or alkyl phenyl J ¢-(Co-C;)alkyl-(C;-Cg)cycloalkyl

VY

or -CF;3 ¢hydroxyl with a hydroxyl (C1-Cylalkyl (C1-Cg) optionally substituted for the alkyl group of the halogen 1 to 1 N group of compounds; which are preferred within the “group ( 1 compounds; labeled 1. and 0 is sha containing compounds of 'group 1' (where CE is 'group of compounds; D' is another group of compounds; that are preferred within “group” are the compounds of “group 1” that have formula 1 as shown here CF named “group 1”; both are Win where m is zero; ode ¢-(CH,)-Al RI is “thiazolyl thiazolyl cthienyl phenyl” phenyl is RI in the definition of Al Cua which is optionally substituted with one to three pyrimidyl or pyridyl di 1 “OMe Me” Cl (F) substituents; each substituent is selected separately from the group consisting of tOCF,H 5 OCF; “CF, OR; 1 is yellow 1 phenyl-(CH,)s- phenyl-(CHy) );- “phenyl-CH,-O-CH,- phenyl-CH,-O-CH,- is R35 with one to aryl where the aryl moiety (3-indolyl-CHy-) optionally substitutes -CHy-di sad -" or 10 «OMe Me «Cl F three alternatives» each alternative is selected separately from the group consisting of .OCF,H or .OCF; «CF; vehicles; Named a 'F de gana', it is a group of compounds; which are preferred among those of formula 1 as shown here CF contain compounds of the “group ¢'G” group “-CH,-phenyl -CH,-J i is Rl methyl and 1452 each is methyl X53 where wie! 0 or thiazolyl-.011- -CH,-pyridyl pyridyl-112©- «-CH,-fluoro-phenyl fluoro-phenyl-O-011- t-butyl -t ethyl ethyl » methyl <hydrogen is R24 -CH,-thiazolyl .-CH,CF; or a group of compounds; which are preferred within 'Group 6' compounds; Labeled contains compounds from "group 0"; It has the form: (Gl "for a group vo

XT) R 0

EN oS 0 KR oH 0

:¥ mixtures of racemic-diastereomeric mixtures and optical isomers of the aforementioned compounds, where: Lg is -CH,-phenyl -CHy-J—sié 102 is methyl and 83 is -(CHa)3- J—it Al-Isatm- and (and 01)-; ° lg is phenyl-012- “-CHp-phenyl 12 is methyl and 1883 is = indolyl-0]12- ¢3-indolyl-CH,- lg is R? “-CHp-phenyl -CH,-J—ié is ethyl and 83 is ¥— CHp-Jd sail ¢3-indolyl-CH,- R! is ¢— fluoro — R? ~-CH,-4-fluoro-phenyl -CHp-Jsié is aR methyl .1 *- indolyl-01[2- ¢3-indolyl-CH,- a is R? “-CH,-phenyl -CH,-Jsié is methyl and 13 is -CHp-O-CHp-J—si8 ¢-CH,-O-CH,-phenyl C is “- CH,-phenyl -CH,-Jsé 182 is ethyl and T is -CH,-O-CH,-J—s ¢-CH,-O-CH,-phenyl vo c is R? "-CH,-phenyl -CH,-J—i is -CH-CF; 13 is -CHy-O-CHp-J—s ¢-CH,-O-CH,-phenyl L is ¢— fluoro- ‎R? -CHy-4-fluoro-phenyl -CH,-Jsié is methyl and 1883 is ¢-CH,-O-CH,-phenyl -CH,-0-CH,-Js Lee is “-CHy -phenyl -CH,-Jié 182 is -t-butyl t-butyl and 1883 is phenyl-:0-011-:011- ¢-CH,-O-CH,-phenyl 0 or R! "-CHp-phenyl -CHp-Jsé 182 is methyl and 18 is -difluoro-CH,-0-CH,-3,4-di-fluoro-phenyl -CH, -O-CH,-i is a diastereomeric mixture of -1-amino —a¥)=Y]-N-—(R,S) benzyl-7-methyl-7 - exo-7: 40778707 -hexahydro-pyrazolo[?;?-m]pyridine- ve#-yl)-1-(08-(;;-difluoro-benzyloxymethyl)-7-exo-ethyl] - 7- Methyl-propionamide

Yo 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-0x0-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c] [pyridin-5-yl)-1-(R)-(3,4-difluoro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl- propionamide (S)-a¥ 5 (R)=a¥ It is preferred within the “!0 group” of compounds and the separate .diastereomeric mixture isomers are preferred from the stereoisomer mixture of 0 compounds; The name 'G Ae gana' is a group of compounds; Which is preferred within the above shown LST contains compounds of 'group 6' with formula 'H'. R35 -CHy-phenyl -CH,-Js where 18 is -27(-1[7-unima -Y «diastereomeric mixture] The mixture of stereoisomers is benzyl-7-methyl-+-exo-7 :3:5:27:2:7-hexahydro-pyrazolo[??-8]pyridine-(8,8(0-carbonyl)-;-phenyl-(08)-butyl]-isobutyramide 0-2 -amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-0x0-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin Separate -5-carbonyl)-4-phenyl-(R)-butyl}-isobutyramide (S)-a¥ 5 (R)—a¥ from the compounds and the "H" isomers are preferred within the "group". diastereomeric mixture 1 A group of compounds that are preferred within the “© group” of compounds named

CHyds "group ]; contains compounds of "group 0" where !18 is indolyl-and Y=011 is R35 -CH,-4-fluoro-phenyl or -fluoro-phenyl-E11 ©- -CH,-phenyl .3-indolyl-CH,- ~a¥)=Y]-N- ul From?- diastereomeric mixture Ye (8O5)-benzyl-7 -methyl-7-oxo-7:3652707:7-hexahydro-pyrazolo[?;?-8]pyridine-(indole-?-ylmethyl)-7-oxo-ethyl]-isobutyramide-111(-)8 (-1-)li-0© 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-0x0-2,3,3a,4,6,7- hexahydro-pyrazolo[4,3-c]pyridin-5-y1)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo0-ethyl}-isobutyramide and 27-(5) uncoupled ( R)=a¥ of compounds and T isomers are preferred within the "group Ye.diastereomeric mixture preferred from the mixture of stereoisomer materials

The mixture of gall is a diastereomeric mixture of ?-amino-7-[7-(27- –(R.S)benzyl-7-ethyl-7-exo-07:7:27:7:7; -hexahydro-pyrazolo[?;6-7]pyridine-,-0yl)-1-(08-(111-indole-7-ylmethyl)-7-oxo-ethyl]-2-amino-N isobutyramide -[2-(3a-(R,S)-benzyl-2-ethyl-3-0x0-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5 -yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo0-ethyl]- ° isobutyramide is preferred within the 'T' group of compounds and is the (S) isomer a¥ 5 (R)=a¥ discrete is preferred from the .diastereomeric mixture. The diastereomeric mixture of ?- ‎—a¥)=Y]-N- sul 0 (59O68)-(4-fluoro-benzyl)-?-methyl-?-oxo-70364087:7:7-hexahydro-pyrazolo[?;7-m]pyridine-*-TH) (R= (de indole) -?-yl-methyl)-7-oxo-ethyl]-isobutyramide 2-amino-N-[2-(3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-0x0- 2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo -ethyl]- isobutyramide vo is preferred within the 'T' group of compounds and the separate (R)—a¥ and 57-27) isomers are preferred from the stereoisomeric mixture.diastereomeric mixture A group of compounds is preferred among “group 0” compounds; named "Group 7"; Contains compounds of “group 6” where !18 is phenyl-011- -CH,-phenyl or ¥.4-fluoro- -CH,-4-fluoro-phenyl -CH,-J— i And 1283 O-CH,-O-CH;-phenyl-CH,-O-CHj;- is a diastereomeric mixture of ?1-amino-17-[7- (27-(R,S)benzyl-7-methyl-?-exo-770462767:71-hexahydro-pyrazolo[;;?-6]pyridine-(-0yl)-1-(048- Benzyl oxymethyl-7-oxo-ethyl]-isobutyramide 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-0x0-2,3,3a,4, 6,7-hexahydro-pyrazolo Yo [4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide

So it is preferred within the “L group” of compounds, and the separate isomers “27-(8) and 87-(8) are preferred from the mixture of stereoisomeric materials “diastereomeric mixture.” The isomer 27-(8) is more preferred than the isomer 27-(8) The preferred salt of isomer 87-(08 is the salt of L-tartaric acid. ° The mixture of stereoisomeric substances is diastereomeric mixture of ?- ~a¥)=Y]-N- sul —(R,S)benzyl-7-ethyl-7-oxo-7056548767:7-hexahydro-pyrazolo[;;8-7]pyridine--0yl)-1-(8)-benzyloxy Methyl-7-oxo-ethyl]-isobutyramide 2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-0x0-2,3,3a,4,6,7 -hexahydro-pyrazolo [4,3-c]pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide 0 is preferred among the "group J" compounds The separate (R)=aY and 97-27 isomers are preferred from the stereoisomeric mixture. Diastereomeric mixture is the stereoisomeric mixture of –a¥]-Y}-N- sid —Y —(R,S)benzyl-3?-exo-7-(7707-trifluoro-ethyl)-770487:07:7-hexahydro-pyrazolo[;;7-m]pyridine-*-yl]-1 -(08-benzyl-oxymethyl-?-oxo-ethyl)-

0 isobutyramide 2-amino-N-{2-[3a-(R,S)-benzyl-3-0x0-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4 ,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl} - isobutyramide is preferred within "group L". " of the compounds and the separate isomers 87-(08 5 ‎(S)-a¥©) are preferred from the diastereomeric mixture and the isomer is (R)-a¥

preferred over the isomer ?8-(9). The stereoisomeric mixture of 7-amino-17-[1-(8)-benzyl-oxymethyl-7-[27-(5,5)-(?-fluoro-benzyl)-7-methyl- 3-oxo-71304:27:07:71-hexahydro-pyrazolo[;;6-7]pyridine-*-yl]-7-oxo-ethyl)-isobutyramide 2-amino-N-{1-(R )-benzyloxymethyl-2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo- Ye 2,3,3a,4,6,7-hexahydro-pyrazolo] 4,3-c[pyridin-5-yl]-2-oxo0-ethyl} -isobutyramide

Ya

It is preferred within the “group [” of compounds and the separate isomers 27-(8) and 27-(5). - Amino diastereomeric mixture The mixture of stereoisomers is benzyl-7-:6-butyl-7-exo-70766487:7:7-hexahydro-pyrazolo[7:4-] -05.5(pyridine-*- yl)-1-(08-benzyl-oxymethyl-7-oxo-ethyl]-isobutyramide 0 2-amino-N-[2-(3a-(R,S)-benzyl-2-tert-butyl-3- 0x0-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide and-97 87) discrete (R)—a ¥ compounds and isomers aT is preferred within the "group". labeled Ve saw an) where p is 'D' contains compounds of the CK group ¢-(CH,)-Al is RI ¢) cthiazolyl JJ cthienyl phenyl It is phenyl RI in the definition of Al where it is which is optionally substituted with one to three pyrimidyl A and pyridyl “OMe Me Cl©” Each substituent is selected separately from the group consisting of “diy vo ¢OCF,H 5 OCF; «CF; or 1 is yellow 1 -(CH,);-phenyl -(CH,);- “-CH,-O-CH,-phenyl-CH,-O-CH, - and 3 is with one to aryl where optionally the aryl part (3-indolyl-CH,-) or *- indolyl-F013- (OMe Me «Cl F) of Gi Saal optionally substitutes three substituents; Each substituent is selected separately from the group © OCF,H ar OCF; “CF;” of compounds; labeled K The group of compounds that are preferred within “group” and 7650 are each X5-methylated. Cum "> are these compounds of the "CL group" group «-CH,-4-fluoro-phenyl -CH,-Jxé - fluoro-4 «-CH,-phenyl is phenyl- Y011- RI ¢methyl is R25 -CH,-thiazolyl hydrogen or thiazolyl-.11©- -CH,-pyridyl pyridyl-E011- Yo -CH,CF; or t-butyl butyl -t obey; Ji «methyl methyl hydrogen

A group of vehicles that are preferred within “.1 group” of vehicles; Labeled "group A" are compounds of "group L" where Rl is "-CH,-phenyl -CHy-J—182 is hydrogen or methyl and 1623 is .-CH, -0-CH,-phenyl -CH,-O-CH,-Jsié The diastereomeric mixture of ?-amino –a¥)=Y]-N- -(R,S) © benzyl-3-—Velet lero ssl hexahydro-pyrazolo[?;?-8]pyridine-*-yl)-(08)-1benzyl-oxymethyl-7-oxo-ethyl]-isobutyramide 2-amino-N-[2-(3a-(R,S)-benzyl-3-0x0-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c] pyridin- 5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is preferred within the "[" group; the separate (R)—a¥ and 57-27) isomers are preferred from the material mixture The stereoisomer is a diastereomeric mixture and the (R)-aY isomer is preferred over the (5)-87. Another group of compounds; which are preferred within “group A” vehicles; labeled Me gana contains compounds of 'group M' that have formula 1 as shown here lel where b is zero; X5 and 1458 each separately form alkyl hydrogen m (F0-©6) or oleZ0-©) or an alkyl (J©-©) hydroxy thydroxy(C;-Cy)alkyl selects 83 from the group formed from) = indolyl-O4a©- “l-indolyl-CH,- ?- indolyl-O011- “2-indolyl-CH,- ?- indolyl-O011- “1-naphthyl-CH,- - CH,-J—&5 -1 3-indolyl-CH,- 1 “2-naphthyl-CH,- -CH,-J—a& -7 benzimidazolyl-O011-“1-benzimidazolyl-CH,- “-benzimidazolyl-W011- 2-benzimidazolyl-CH,- -alkyl J— 8 -(C}-Cy) cphenyl-(Ci-Coalkyl- 0 -alkyl ~(C1-Cs) 7-pyridyl 2-pyridyl-(C1-Ca)alkyl-(O-R0)- ?- pyridyl 3-pyridyl-(C1-Ca)alkyl-(C1-Cyq) 4;- pyrisdyl-1-polyolazine-0)-anindrum-4 (-CH,-S-CH,-phenyl-(CHy-S-CHy-)-alkyl (0-0)-thienyl-( Cy-Ca)alkyl- -O0-611- Alkyl (©-M0)-phenyl «phenyl-(Co-C3)alkyl-O-CHa- -CH,-O-J— -CH,- phyl- .tn-Isdam-1-0112-0 Jig yu support -0 -CH,- -CH,-O-CH,- «3-benzothienyl-CHp- +00 yenyl -CH,-O-CH ,- «thienyl-CH,-O-CH,- thiazolyl -CH,-O-CH,- «thiazolyl-CH,-O-CHp-pyridyl» pyridyl-CH,- O-CH,-

1

J— 18 -O-CH,-CH, 5 -1-011-0-07jaa) ys -CH,-O-CH- ¢phenyl-O-CH,-CH, with one to three RI From the definition of aryl groups where the aryl part(s) is optionally replaced by each substitution that is selected separately from the group consisting of methylene dioxy (Jil Rothel. OCF,H «OCF; «OCH; «CH; » Cl of the “multiple” compounds each ° of the compounds labeled M The set of compounds that are preferred within the “group of formula 1” as shown here eM contains the compounds of the “group ¢M” “group is zero; 6 is 1 WE) is zero; 7 is 8 thydrogen is RY hydrogen being dum above; or methyl hydrogen each on Unity hydrogen X52 Dz is X58, then it is not hydrogen, provided that when 145 is hydrogen, chydroxymethyl 0 is oxygen, Y hydrogen, each of them is hydrogen R85 187 thydrogen hydrogen “propyl” Propyl cethyl ethyl “methyl methyl chydrogen is hydrogen R? oxygen -CHp-s or cyclic propyl CF3 “-CH,CF3 “t-butyl -t ¢i-propyl propyl -i phenyl is the phil of Rl in the definition Al where ¢«CH,-A' is R! ¢-CH,-cyclopropyl which is pyrimidyl or pyridyl cthiazolyl thiazolyl thienyl ve optionally substituted with one to three substituents; Each substituent is selected separately from the group -CHy-O-CH,- 5— a R® 4 ¢OCF,H 5 OCF; «CF; Me © consisting of “CHy-Jid ss —Y “phenyl-(CHy)s- phenyl -(CHy)s- “phenyl-CH,-O-CHy-phenyl tabazolyl -CH,-O-CH,- «thienyl-CH,-O-CHy linyl -CH,-O-CHj «3-indolyl-CH,- -CH,-O-CHy- «pyridyl-CH,- O-CHp-pyridyl-CH,-O-CH,- «thiazolyl-CH,-O-CHp- T0 where cphenyl-O-CH,-CH; phenyl -O-CHp-CH, pyrimidyl-CH,-O-CHy- pyrimidyl with one to three 0« each substituent being separately selected from aryl optionally substituted for the aryl moiety .OCF,H 3 OCF ; «CF; “OMe Me (Cl F) The group of compounds; which are preferred within “Group 74 of compounds; labeled having Formula 1 as shown JM! contains the compounds of “Group ¢'N For the Yo group or “ethyl ethyl” methyl is R2 methyl and 1458 each is methyl appendage: 0; X5 where wake is optionally substituted with one or three substituents; each substituent is selective phenyl is Al ¢-CH,CF;

AR

R3 ¢OCF,H3OCF; «CF; «OMe (Me «Cl F) separately from the group consisting of or phenyl-(CH;)3- phenyl -(CH,);- «phenyl-CH,-O-CH,- phenyl -CH)-O-CH)- He optionally replaces the aryl fragment 8171 with one Cua thienyl-CH,-O-CHa- thienyl -CH,-O-CHa- «OMe (Me «Cl F into three substituents. Each substituent is selected separately from the group consisting of OCF,H. JM! labeled "group ©0"; contains compounds from "ethyl group" methyl Jie is R2 tmethyl and 1658 each is methyl X5 where dled here optionally substituted with 3-pyridyl or “- pyridyl 2-pyridyl is 7-pyridyl Al or 11:01©-;

Me Cl F one substituent to two substituents. Each substituent is selected separately from the group consisting of ve “phenyl-CH,-O-CH;- phenyl-CH,-O-CH,- R3 11 :R00; «CF; OMe where thienyl-CHy-O-CHa- replaces thienyl-CH,-O-CH,- or phenyl-(CHa)s- phenyl -(CHa)s- with one to three Substitutes » Each substituent is selected separately from the aryl optionally the aryl part .OCF,H 5 OCF; «CF; OMe MeCl The group consisting of L is another group of compounds; which are preferred within the “Group!18 compounds; which have Formula 1 as MD labeled “Group 0”; Contains compounds of the “cmethyl group 182 ¢methyl and 1458 each being the X5-methyl shown here above. Where optionally substituted with one or three substituents” each phenyl substituent is phenyl Al or 11201©-; cethyl

OCF; «CF; OMe Me «Cl© is separately selected from the group consisting of -CH,-O-CH,-a «2-pyridyl-CH,-O-CHp- pyridyl -1 -011.-0 -01.- hr R3 ¢OCF,H,0 with one to aryl pyridyl -0-011-:3-01771071-011 where optionally substitutes the aryl moiety - “OMe Me (Cl F) each substitute be selected separately from the group consisting of (ily three) .OCF,H 5 OCF; “CF,” a group of compounds; that are preferred within “group 0” of compounds; labeled “group 0 contains Compounds of "group 0" having the formula: Yo

XT) Ro

N NH; x 0 KR 0 H 1

B mixtures of racemic-diastereomeric mixtures and optical isomers of the aforementioned compounds, where: R? is the methyl conformation; A' is ?- 2-pyridyl and 13 is *- chloro-phenyl-O[0-01-R011- ¢-CH,-O-CH;-3-chloro-phenyl R? 0 is “CH,CF;am is ?- 2-pyridyl and 13 is -CH,-0-CHp-J—¢-CH,-O-CH,-phenyl p is A" "CHCF3 is 7-pyridyl 2-pyridyl and 18 is ;-chloro- -CH,-0-CHy-dié ¢-CH,-O-CH,-4-chloro-phenyl is A' < CH,CF; is 7-pyridyl 2-pyridyl and 13 is 07;-dichloro-0phenyl-:0-011-,011- ¢-CH,-0-CH ,-2,4-di-chloro-phenyl R? is R11:07©; A' is ?- pyridyl 2-pyridyl and 13 is #*-chloro- ¢-CH,-O- CH,-3-chloro-thiophene -CH,-O-CH,- (ys R? is A' «CH,CF; is 7-pyridyl 2-pyridyl F183 is 7a;- AB = fluoro- .-CH,-0O-CH,-2,4-di-fluoro-phenyl -CH,-O-CH,-J,# vo 7-amino «(R)-V]-N-benzyl oxymethyl-7-(7-methyl-?-oxo-27-(8,8)-pyridine-"-ylmethyl-7:304:27) :7:7-hexahydro-pyrazolo[;;6-7]pyridine-*-yl)-7-oxo-ethyl]-7-methyl-propionamide 2-amino-N-[1-(R)- benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2- ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c] [pyridin-5-yl)-2-oxo-ethyl]-2- methyl-propionamide Y. Preferred within the “© group” of compounds, and the separate (S)=aY 5 (R)=a¥ isomers are preferred from the mixture of stereoisomeric materials. —¥)-(R)-) }-N-chlorobenzyl oxy-methyl)-7-oxo-7-[7-oxo-87-(5,5)-pyridine-7-ylmethyl-ve 7 -(7:7:-trifluoro-ethyl)-7704830707-hexahydro-pyrazolo[?;7-”]pyridine-,-0yl]-ethyl)-7-methyl-propionamide yy

2-amino-N-{1-(R)-(3-chlorobenzyloxy-methyl)-2-ox0-2-[3-0x0-3a-(R,S)-pyridin-2- ylmethyl-2-(2 ,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5- yl]-ethyl}-2-methyl-propionamide and-27 (5) The discrete (R)=a¥ is preferred within the “© group” of compounds and isomers are

E. Preferred from the mixture of stereoisomeric materials .diastereomeric mixture is the mixture of gall diastereomeric mixture of ——Y amino —£)-(R)-1}-N- chloro-benzyl oxy -methyl)-7-oxo-7-[3-oxo-27-(58,8)-pyridine-"-ylmethyl-7-(7:7:7-trifluoro-ethyl)-7505:270707-hexahydro - Pyrazolo[?;8-7] pyridine-

-0-yl]-ethyl)-7-methyl-propionamide

2-amino-N-{1-(R)-(4-chloro-benzyloxy-methyl)-2-ox0-2-[3-0x0-3a-(R,S)-pyridin- Ve 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- The separate propionamide (S)-at 5 (8)-87 is preferred among the “group 0” compounds and isomers

Preferred from the mixture of stereoisomeric materials ‎.diastereomeric mixture

b The steric diastereomeric mixture of 7-amino —£0Y)-(R)-1}-N-dichlorobenzyl oxymethyl)-"-oxo-7-[?-oxo-27 -(8,9)-pyridine-?"-ylmethyl-7-(7:707-trifluoro-ethyl)-7:540870707-hexahydro-pyrazolo[4,6-7]pyridine-*-yl]-ethyl );-7-methyl-propionamide

2-amino-N-{1-(R)-(2,4-dichlorobenzyloxymethyl)-2-oxo0-2-[3-0x0-3a-(R,S)-

pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c] Y.

pyridin-5-yl]-ethyl }-2-methyl-propionamide

It is preferred within the “© group” of compounds and the separate (R)=a¥ and 27-(5) isomers are preferred from the .diastereomeric mixture

The stereoisomeric mixture of ——Y amino-7<-(1-(8)-(;-

-1-Nidirib chloro-thiophene-? trifluoro-ethyl)-75656270707-hexahydro-pyrazolo[3:4-m]pyridine-"-yl]-ethyl)-7-methyl-propionamide

2-amino-N-{1-(R)-(4-chloro-thiophen-2-ylmethoxymethyl)-2-ox0-2-[3-0x0-3a- (R,S)-pyridin-2 -ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro- pyrazolo[4,3-c]pyridin-6-yl]-ethyl } -2-methyl-propionamide is preferred within the "© group" of compounds and the separate (S)=a¥ 5 (R)=a¥ isomers are

© A favorite of the .diastereomeric mixture is the mixture of gall diastereomeric mixture of 7-amino ~£Y)-(R)-V}-N-difluoro-benzyyloxy -methyl)-7-oxo-7-[7-oxo-87-(8,8)-pyridine-"-ylmethyl-7-(70707-trifluoro-ethyl)-7:507:27:7:7 - hexahydro-pyrazolo[4:"-]pyridine-*-yl]-ethyl)-?-methyl-propionamide 2-amino-N-{1-(R)-(2,4-difluoro-benzyloxy-methyl) )-2-oxo-2-[3-0x0-3a-(R,S)- Ye 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 is preferred within the “© group” of compounds and is the (S) isomer. =aY 5 (R)=a¥ separated preferably from J gall diastereomeric mixture .diastereomeric mixture > The group of compounds containing useful intermediates in the manufacture of compounds of formula (I) is of the formula: R! OCH (CH) AA rR” N (ID) racemic-diastereomeric mixtures and optical isomers of the aforementioned compounds and acceptable salts pharmacologically O terminator where © is zero or ov 2:9 and “each separately is 1 Ghia or oF provided that w is not and” both are zero at the same time; RI is pbb and the gene “-(CH,)N(X6)C(0)X6 “-CN hydrogen ~(CHp)N(X6)SO0,X6 ¢-(CH,)N(X6) )SO5(CH,)-Al ¢-(CH,)(N(X?)C(O)(CHp)-A' «-(CH,)N(X6)C(O)N(X6) (X®) ««(CHp)gN(XE)C(O)N(XO)(CHy)-A! (CH, CO)OXS -(CH,),CON(XO)CHp)-A! (CH), CONXO(XS) vo

Yo «-(CH,)40C(O)(CHy)-A! «-(CH,),0C(0)X$ «-(CH,)OX6 «-(CH)(C(O)O(CHy)-A! «-(CHp),C(O)X® « « -(CH,)qOC(O)N(X6)(X®) ¢-(CH,)qOC(O)N(X6)(CH,)-Al -(CHp)N(XO)SO,N(X6) ((X6)¢-(CHy)N(XS)C(0)OXE ¢-(CH,)qC(O)(CHy)-Al «(C1-Cip)alkyl -(C-Cyp)desl¢-) CHp)4S(0)(CHp) Al ¢ +(CHy)S(0) XE -(CHp)¢-(C3-Cr)eycloalkyl ~(CH,)(C3-Cy) Danery J SU «(CHp) )-Al 00 or Alkyl -(CH,)4-Y1-(CHy)-Al ««(CH,)g-Y1-(C;-Cyglalkyl -(CH,)¢-Y1-(C;-) Cq) alkyl t-(CHy)g-Y!-(CH,)-(C5-C7)eycloalkyl -(CH,)g-Y!-(CHy)-(C3-Cq) cyclic in definition of cycloalkyl and a cyclic alkyl, in which the (C1-Cy) alkoxy hydroxyl groups optionally substituted with an alkyl (J0-©) prime (J0-,); hydroxyl RI! and 5)0(,)0-6 - Jl -CONH, <carboxyl carboxyl “(C;-Cy)alkoxy 0 tetrazole-H-yl-1H “-CO,(C-Cylalkyl ol-Lu-R5)0()0-alkyl (b) -0)6©- «-C(O)NXS6- ¢S(0),, <O is Y!¢fluoro to ?lor 1 see 1H-tetrazol-5-yl -stolarm0 - Ar “-C(0)0- CTARM -N(X6)C(0)- “-C=C- “-CH=CH- ?; JY) ? or ;; 1 is yellow 7 Oia aq ¢-OC(O)- 0” to 1 mentioned with the (CH), and the (CHp)g group may optionally substitute the hydroxyl hydroxyl group Vo. (C-Cyplalkyl (C1-Cy) alkyl Y or 1 “fluoro fluoroalkyl (0-:5)0,)0-CONH, “carboxyl (J-R6)n”Gl0 -0)carboxylate-111(J00,)0-0-. or ester alkyl ester (Cy-0:0:)0©- -8(0),(Cy-Ce)alkyl ¢1H-tetrazol-5-yl tetrazol-#-yl f)- Alkyl (C-Cylalkyl (C-Cg) Alkyl chydrogen is R? Ye (C1-Caalkyl-A! “(C1-Ca) JV A (C-C3)alkyl-( C3-Cs)cycloalkyl -(Co-Cs) in cycloalkyl and cycloalkyl cycloalkyls where the alkyl groups are optionally substituted with Al or N(X6)(X6) RVT and TOL)- -C(O) OX® chydroxyl definition 1682 by hydroxyl to 1 or CN “CF; ctrum”-C(0)A!alkyl (m26-:0)e(5)0-ollom20-r0)m (0) s thalogen © Yo phenyl halogen atoms ((C5-Cy)eycloalkenyl (Cs-Cq) in each individual case the alpha is circular Al or completely unsaturated having WIS partially saturated members A saturated A or a P ring related to phenyl

optionally 1 to ; Heteroatoms selected separately from the group consisting of oxygen coxygen sulfur sulfur and nitrogen or a circular Aid ring system consisting of a ring with © or 6 partially saturated members completely unsaturated or optionally fully saturated having 1 to ; Separately selected heteroatoms from the group consisting of cnitrogen, sulfur, and coxygen fused to ring 108 having * or > partially saturated members wholly saturated or optionally totally unsaturated having 1 to ; Hetero-atoms 85 1) Selected separately from the group consisting of nitrogen, sulfur, or oxygen, soxygen, in each separate case, optionally substituted in one 108 ring or both Ve rings if Al was the system p0 bicyclic ring system; With up to three (ila) each substituent is individually selected from the set consisting of Tel (OCF,H (OCF), «I (Br «Cl -C(0)OXS -C(OIN(XE)(XE) ) “-OX6” OCH; “CH;” CF, oxar “0x0 alkyl” (Cy -Cg)alkyl (C,-Co) nitro “nitro cyano” benzyl alkyl -S(0),(C-Cg) -1H “-S(0),(Ci-Cg)alkyl tetrazol-*-“1H-tetrazol-5-yl phenyl” Ji “phenoxy vo alkyl oxy” phenylalkyloxy halophenyl chalophenyl methylenedioxy “and -SO,N(X6)(X6) “-N(X6)C(0)(X6) -N(X6)SO,X6 «-N(X6)SO,-phenyl -N(X6)SOp-d— sd ok NX6SO,NX!IX12 NXSCONXIIX12 ~~ «NX6S0,X12 »-SO,NX !IX12 -NX6C(O)X12 imidazolyl thiazolyl or ctetrazolyl Y. Provided that if AT is optionally substituted with methylenedioxy then it can only be substituted with methylene one methylenedioxy dioxy; Cua 1511 is hydrogen or optionally substituted 1(C1-Cg)(C1-Cg)alkyl (and,0-0) optionally substituted? m0-,0) optionally substituted Yo in definition of !381 with “phenyl Jub phenoxy alkoxy carbonyl (m-0,0) “(C,-C)alkoxycarbonyl alkyl 1 -8(0),(C;-Collalkyl - S(0)(C;-Cq) to

d© halogen atoms 1 chalogens to “? 1 hydroxy to the oxy cannoyl (C;-C jo) no<hrm ald©-,6) or 1 to ¥ croxy ¢ (C;-Cgalkoxy (C;-Cg) 2 is hydrogen alkyl hydrogen (F0-R6) anolol(F-©); X12 is optionally substituted with one to three substituents selected separately from the group consisting of “Cl each OCF; “OCH; “CH; ¢CF3 3” or X12, X11 are taken together to form (CH) LI-(CHy),- Na MR (SO), 0 «C(X2)(X2) Ar N(X2) Ve # In each case is YO ? ;

2 In each case, an optionally substituted alkyl hydrogen (C;-Cgalkyl (C-Cg) or an optionally substituted cyclic alkyl (C3-Cpleyeloalkyl (CC)) each separately optionally substituted for the alkyl (C© -,©) 1101 O(0-,©) optionally substituted and optionally substituted (C3-C)eyeloalkyl (C5-C) in definition 762 with S(O) (C1-Ce) alkyl

©OX3 to ?1 or halogens to © 1 halogen atoms -C(0)OX? 1 By Allah (m©-,8)0© (0-” 0

3 In each case, hydrogen or alkyl (m©-:0) ¢ (C,-Cgalkyl

6 In each case, the alkyl chydrogen (C,-Cq) of Waldo-0 is optionally substituted with a (Cy-Co)halogenated alkyl cyclic (b-with) Jada (C3-Cy)eycloalkyl optionally alkyl-dary (C3-Cp)- sim hb

(C,-Co) where each optionally substitutes for the (C3-Cy)-halogenatedeycloalkyl cyclic 0 (and ©-f) 1 and 610: »(,©-and 0) the substituted JS anoleh (©,0-m ) optionally substituted for the 0-0 villin); )0()0-alkyl «CONH, «carboxyl carboxyl Alkyl Y or 1 or 1H-tetrazol-5-yl (J-00:)0- 0-,002)- » 111- Tetrazole-*- yl

Yo (t-t©) (C1-Coalkyl or

When there are two XO groups on one atom and both X6 are an alkyl and (2-0) “(C-Collalkyl) then the two alkyl groups (C1-Cq) (C-,©) can connect Optionally and ; together with

Ya

; To 4 members having a cldring that forms an XO ring with which two groups are linked: an atom atom, i.e. 7 rhea; optionally substituted with hydrogen is hydrogen 7 or ?; hydrogen cannot be hydrogen X12 5 6 and ¢50,X12 or SO,X6 «C(0)X!2 «C(0)X6 of the form -CH=CH-J—uié is not R', then hydrogen is hydrogen R? be laa ie .-CH=CH-pheny]l labeled (IT) A group of intermediate compounds favored among the preceding groups of Formula 8 contains compounds where *” is zero or; “Hawa;! Alkyl (C=C) or Alkyl -(CH)-A' to ? 1 fluoro 1 oleh©6 (,©-.©) with (C3-Cy) and cyclic alkyl (C-Coalkyl (©-©) to ? Substituents selected separately 1 with RE in Define AL and optionally replace fluoro ve {OCF,H 5 OCF; “CF; methoxy Me Cl from the group formed by the alkyl tal” (C3-C7) cyclic alkyl (Cy-Cylalkyl ( C-Cg) an alkyl chydrogen is R2 hydrogen or phenyl-alkyl (and 0-6) “phenyl” (Cy-Cj)alkyl-(C;3-C7)cycloalkyl (Co-Cs) to 1 with phenyl and phenyl alkyl where the alkyl groups (C-Cy)alkyl-phenyl .methoxy and methoxy OH “CF3 F” optionally substituted by ?selected substituents separately from the group consisting of -© 131 contains Ac pans' labeled CAA A group of compounds preferred among compounds "group is zero; !14 is pyridyl-and 011-© 1 is W where is "AA de sand" on Compounds of -CH,-phenyl -CH,-J—sé sf “-CH,-thiazolyl -CH,-J— 5 ji “-CH,-pyridyl fluoro substituents to ?substitutes selected separately from the group consisting of 1 fluoro optionally with olazine-©) or phenyl (C;-C4) alkyl hydrogen and 12 ¢chloro hydrogen and Yo chloro in phenyl or phenyl (C,-Cylalkyl optionally substituted for alkyl groups (B©-©) by Cua phenyl

Define R with 1 to ? Substitutes selected separately from the group consisting of 000:000 fluorohydroxy or methoxy The compounds that are preferred within the “group 1313” compounds are the mixture of diastereomeric mixtures of Cua compounds. 1 sa phenyl-S011- -CH,-phenyl© and 1282 is a methyl or a hydrogen and the separate (S)-a¥ (R)—a¥ isomers are favored from the stereoisomer mixture .diastereomeric mixture Another group of intermediate compounds preferred in the manufacture of compounds of formula ( ) which has the formula: R! 0=(CH2)e| (CH2)n 200 1 0 (CH2)w 00 Mixtures of racemic-diastereomeric mixtures and optical isomers of the aforementioned compounds, where 27190 is methyl “CBZ BOC methyl” TROC 100 “CF3C(O)- triethyl tetosyl arum CH3;C(0)- R benzyl J—ju optionally substituted optionally substituted with cmethoxy dimethoxy or nitro p is zero or 1; Swan of them separately is 1 hia or; provided it is not 0 - “ and “ are both zeros at the same time; (CH) N(X6) C(O)X «-CN «hydrogen (ssp 4 5 aR! (CH) N(XE)S0,XS e<(CH)N(X6)SO(CHy)-A! -(CH)N(X6)C(O)(CHy)-A! «-(CHp)N(X6)C(O)N(X0)(X©) ¢-(CHp)N(XS) C(O)N(XS)(CH,)-A! (CH,)C(O)OXS (CH), CONXE)CH,)-A! <(CH,) COIN(X6)(XS) ~(CH,)OC(O)(CHy)-A! «=(CH,), 0C(0)X6 ¢-(CH,)qOX® (CH) C(O)O(CHY-A! 0 «-(CH,){C(0)X6 «- (CH,)qOC(O)N(X6)(X®) ¢-(CH,)qOC(O)N(XE)(CH,)-Al ~(CH,)N(X6)SON(X6) )(X6) (CH) N(XO)C(0)OX® «~(CH,)oC(O)CHy)-A! ~(C1-Cro)alkyl -(C;-C1g) dS - (CH,) S(O) (CHA! +(CH,)gS(0),X «-(CHz)¢-(C3-Cy)cycloalkyl -(CH,)-(C5-C7) (5 o— Jl «-(CH,)-Al

Y. Or alkyl <(CHy)g-Y!-(CHp)-A! «-(CHyp)g-Y'-(C;-Cglalkyl -(CH,),-Y1-(Cy-Cg) alkyl t-(CH,)q-Y (CH, )-(C3-C; )eyeloalkyl (CH,)g-Y'-(CH,)(C3-Cy) cyclic in the definition of cycloalkyl and cycloalkyl, where the alkyl groups (C1-Cy) are optionally replaced by the hydroxyl alkyl hydroxyl (C,-Cyalkyl Al with an alkyl (J©-R©) alkyl and 5)0(.)4-0- <-CONH, “carboxyl carboxyl ((C1-Cy)alkoxy 0” 1H -CO,(C;-Cyalkyl ester -COH(C,-Cy) alkyl jiu) -8(0),(C,-Coalkyl ¢fluoro 5,58 or ? Y 0 or 1H- tetrazol-5-yl yl —0—{ ji

N(X6)C(O)- -C=C- -CH=CH- «-C(O)NX6- m. Murphy sa YI ¢-0C(0)- Ar -OC(O)N(X6)- «-C(0)0- «-C(O)NX6- ;; of YY) is zero Ve

F? or 1 yellow at mentioned with (CHy); It may optionally substitute (0110) with the alkoxy carboxyl group (0-0)n<scZ0-0); hydroxyl carboxyl (B00:)0-0- Jul -8(0),,(C;-Cg)alkyl -8(0),,(C;-C) alkyl -CONH, fluoro to? Fluoro1 (1H-tetrazol-5-yl tetrazol-#-yl-1H ; -CO,(C,-C,)alkyl vo {(Cy-Cylalkyl (C1-Cp) alkyl Y OR 1 or oleyl(0,-ol); cyclic alkyl (F-0:0)-alkyl (C-Cg) is hydrogen 1770:0860 alkyl 2 -(C1-Cyalkyl-A' M -)- JS since (Cy-C3)alkyl-(C3-Cg)cycloalkyl (0-m)- in cycloalkyl and cycloalkyl, where the alkyl groups are optionally replaced by cA! N(X6)(X6) ~C(OIN(X6)(X6) «-C(O)OX6 hydroxyl by hydroxyl RZ definition © ?1 ar CN «CF; «-C (0)(X%) -C(O)A!alkyl 0-.5)0(0)(0)(0-0-0)(0)m(0)s or ?halogen 60p1810;phenyl(Cs -Cy)cycloalkenyl separately The block is circular (0-and 0) Alls in each Al or completely unsaturated have LIS saturated Lf ja members saturated A with; to ring or ring phenyl individually selected from the group consisting of heteroatoms into; optionally 1 m hetero-atoms binary ring system or ring system nitrogen and sulfur oxygen with © or 1 Partially saturated members that are not completely saturated or completely saturated ring A circular consisting of a ring

Optionally add 1 to ; Heteroatoms selected separately from the group consisting of nitrogen, sulfur, sulfur, and oxygen 20m fused with ring 0 or 1 molecularly saturated members, completely saturated or optionally completely unsaturated, having 1 to ; Heterotoms selected separately from the group consisting of nitrogen 0100860 sulfur 0e sulfur or oxygen soxygen AAT each case optionally substituted in one 1108 ring or both rings if Al is a ring system ring system bi-circular; With up to three (Jia) each substituent is individually selected from the set consisting of «OCF;<I (Br «Cl (F 007.11; -C(0)OX6 « -C(OIN(X6)(X6) (-OX6 “OCH; “CH; “CF; oxo JS 0x0 nitro gi “(C1-Cg)alkyl (C;-Co) ve cyano cbenzyl alkyl -S) 0),,(C-Cq) -1H ¢-5(0)(C;-Ce)alkyl tetrazol-*-yl “1H-tetrazol-5-yl” phenyl phenylalkyloxy halophenyl chalophenyl 2-oxy-SO,N(X6)(X6) “-N(X6)C(O)(X6) “-N(X6)(X) methylenedioxy (CONX!X12 (-N(X6)SO,X6 «-N(X6)SO,-phenyl -N(X6)SOp-d— -NX6SO,NX!1X12 «-NX6CONX11X12 »-NX6S0,X12 «-SO,NX11X12 Vo -NX6C(O)X!2 imidazolyl dimidazolyl thiazolyl or tetrazolyl itetrazolyl provided that if AT is optionally substituted with methylenedioxy then ( Se substituted only with one methylenedioxy methylene; where XI is hydrogen or an alkyl (m©-,©) (C;-Coalkyl optionally substituted for Ye; each optionally substituted Optionally substituted alkyl (C1-Collalkyl (C=C) f Identification of XH with cphenyl phenoxy cphenoxy alkoxy carbonyl (C1-Cg) γ-(0)-0)alkyl (0-0(F)-0)(0-Allyl(5-0) (0(.)0-» 1 to © atoms 1 halogens to 7-hydroxy 1-hydroxy to ? The cannoyl-oxy Yo (m©-t©) (C-Cpg)alkanoyloxy or 1 to 0 alkoxy (m©-:6) ((C1-Collalkoxy 2) is a chydrogen Alkyl “(C;-Cgalkyl (C1-Cq) phenyl” phenyl thiazolyl ctiazolyl imidazolyl 20010820171 furyl or thienyl cthienyl provided that when

YY

optionally substituted with one to three X12 the hydrogen is hydrogen X12 not being OCF; «OCH; «CH; Each «Cl substituent selected separately from the group consisting of ¢CFy 5 (~(CH,),-L1{(CHy),- together to form X12, X11 or taken as L4 ( SO), © «C(XH)(X?) I pass °

OF or 1 7 in each case # (C1-Coalkyl M6-©) hydrogen separately Ala hydrogen in each 2 is optionally substituted where (C3-Co) is substituted optionally substituted eycloalkyl (C3-Cr) or cyclically alkyl each separately optionally substituted alkyl (m©-,©) 71 (m0-,©) and cycloidal alkyl (m©-:5)0, Optionally substituted XE (6-), (C3-Coleycloalkyl (C5-Cr) 0 (0X3 to 1 halogens) or halogens to 0 1 halogen atoms (C(0)OX3) f)-,5)0(.)0-; §(C,-Cglalkyl (C;-Cg) or alkyl hydrogen separately is hydrogen Aa in every 3 (C,-Cg) The alkyl (and ©-0) chydrogen separately is Alla hydrogen in each 6 (C3-Cq) cyclic alkyl “(C,-Ce)halogenated alkyl (C,-Co) optionally substituted alkyl halogenated halogen-(-f) g — optionally substituted; the (C3-Cy)eycloalkyl he alkyl he is each optionally substituted for the alkyl m-0)¢(C5-Cy)-halogenatedeycloalkyl 1,1l0© (67610-F0) optionally substituted (C3-Cq) oleate (0,0-) and the cyclic alkyl “(C1-C alkoxy) (b©-r©) hydroxyl by hydroxyl XO is optionally in the definition of the alkyl -8(0),,(C-Cg)alkyl (and-0-R5)0()6- «CONH, «carboxyl carboxylate or ? 1 Alkyl or 1H-tetrazol-5-yl (M-)E00-OlZAM©-,02)0©-. 111- Tetrazole-#- yl 0 or ¢(C1-Cy)alkyl (-r) (CC) are one X6 alkyl and both atoms on the XO atom when there are two groups to contact voluntarily and; Together with (C1-Celalkyl oleh (m0-,0); the two alkyl groups (m©-,©) bonded with them may have two groups 166; they form a 4- to 4-membered nucleus having an atom atom (NX ? or sulfur sulfur oxygen optionally oxygen |” 1 mol (0,0-m) optionally substituted with (C-Cq) or alkyl hydrogen is XT or ?; 1 and in each case shall be zero; thydroxyl hydroxyl vv provided that: or ,50 in C(O) when bonded with hydrogen and 1012 cannot be hydrogen 6 ¢ 80,X12 see S0,X6 «C(0)X!2 «C(0)X6 Figure -CH=CH-J— is not R! then hydrogen when 82 is hydrogen ¢-CH=CH -phenyl©

BOC then 2190 is not “-“CH,-CH=CH-Ph is R's H is R? when it is

BOC When 182 is 11 and a 18 is then 7190 is not and BOC is 2190 then 2190 is not -CH,-C(CH3)=CH, is R's 11 is R? When it is .011:0(0)- then 71909 is not “CH; and 18 is phenyl R? when it is

Ac gana’ named (TI) are preferred compounds within the preceding group of compounds of formula 1; “©” is zero or 1; 10 He Cua These compounds CC 'CBZ benzyl benzyl cmethyl methyl BOC mo 0 ¢-(CHy)q-(C3-Cr)cycloalkyl -(CHz)g-(C3-C7) A cyclic alkyl chydrogen is hydrogen RI in which the alkyl groups (C1-Cyplalkyl (C1-C pg) are optionally substituted by the alkyl -(CH)-A' fluoro Y to 1 (R©- t) oligolytic(j,©-,©) and cyclic alkyl (0-r0) anolelation 0(:010-and©) with 0 separately selected substituents from Y to 1 with RT in definition AT and optionally substituted 0 ¢ OCF,H 5 OCF; “CF; “OMe Me the group consisting of each of the cyclic alkyl (C-Cylalkyl (C-Cg) alkyl hydrogen) is hydrogen 2 or phenyl-alkyl (0-,) phenyl “(Co-Cj)alkyl-(C3-Cq)cycloalkyl (Co-Cs) alkyl to 1 with phenyl And the alkyl phenyl phosphate-1 by Allah (and -0,©) where the alkyl groups 0 and .016 .OH (CF; 7) are optionally substituted by individually selected substituents from the group consisting of (DD named 'group ( 'CC' is a group of preferred compounds within the 'group sae' compounds is BOC where 7100 is 'CC de sans' containing these compounds of or phenyl- and -CH,-thiazolyl 011 Thiazolyl-01[2-] «-CH,-pyridyl nil; !1581 is pyridyl-011- to * individually selected substituents from group constituent 1 0-0-0- optionally substituted with 0 (-0) alkyl hydrogen is R24 ¢chloro hydrogen and a fluoro of fluoro(C1-Cylalkyl (C1-Cy) where phenyl or phenyl alkyl groups are optionally replaced by (C-Cyalkyl)

Ye to 7 substituents selected separately from group 1 in definition 182 with phenyl or phenyl methoxy and hydroxy fluoro from fluoro is the mixture of stereoisomers "DD" The preferred compounds within the "group" compounds and 1782 is -CH,-phenyl from compounds where !18 is a phenyl-E011- diastereomeric mixture and the separate isomers 87-(8) and 99-27 are thydrogen or hydrogen methyl methyl _ 0 .diastereomeric mixture A preferred mixture of stereoisomer materials containing this (I) also another group of compounds useful in the manufacture of compounds of the formula Compounds of the formula:

R I R ¥ 7200 Cal Aral 9" Elk

Nd | RS REO

Iv) and racemic-diastereomeric mixtures isomers of racemic-diastereomeric mixtures 0 (CF3C(0)- «CBZ 802] have 7790 optical Cua of the mentioned compounds 38 optionally substituents that substitute benzyl or benzyl tosyl etrityl triethyl 1120© FMOC nitro sis or dimethoxy optionally cmethoxy with methoxy; 1 is zero or © and both are zeros in the same W provided that it is not oY or 1 apart is yellow Lge for" and every 10 the time; sulfur or sulfur oxygen is oxygen 7"-(CH,)N(X6)C(O)X® «-CN hydrogen (pag ——— Ammo ~(CHpN(X6)S0,X6 «~(CH,) N(X6)SO,(CH,)-A' (CH) N(X6)C) O)(CHy)-A!(CH)N(X6)C(O)N(X6)(XS) «(CH N(X6)C(ON(XS)(CHp-Al +0 «-(CH, (4C(0)OX* «-(CH,)C(OIN(X6)(CHy)-A' «-(CH,)C(O)N(X6)(X®) «-(CH,){ OC(O)(CHp)-A! «-(CHp),0C(0)X® «-(CH,) 0X? «-(CHp),C(O)O(CHp)-A! «-( CHp),C(0)X?8 ~(CHp){OC(O)N(X6)(X8) ¢-(CHp)qOC(OIN(X6)(CHp)-A' -(CH)NXOSO,N (X6)(X) «-(CHp)gN(X®)C(0)OX6 «-(CHp)4C(O)(CHp)-A! ~(C1-Cip)alkyl ~(C1-C 1g) JS) (CHp)(S(O) (CHA! (CH)S(O) X8 vo vo «-(CHy)q-(C3-Cr)eycloalk yl -(CHy)o-(C3-C1) kyssel dari -(CH,)-A! Or Alkyl -(CHy)g-Y!-(CHp)-A! «-(CH)g-Y'-(C;-Cg)alkyl -(CH,)g-Y'-(C-Cg) alkyl ¢-(CH,)g-Y-(CHy)-(C3 -Cy)cycloalkyl -(CHy)4-Y1-(CHy)-(C3-Cy) is cyclic in the cycloalkyl and the cycloalkyl is optionally replaced by Cua (C1=Cy) alkyl groups with a chydroxyl With Kale (H©-:6) Anulfli©-,©); Hydroxyl Rl definition 0 Alkyl (F-0-R5)0(0-(.) <-CONH, «carboxyl carboxyl ¢(C1-Cy)alkoxy alkyl (B-02)6©-allolla(J0) -,©)02©- 111-tetrazole-*- yl ¢-8(0),,(C;-Co)alkyl ¢fluoro or ¥fluoro Y-1 or 1H-tetrazol-5-yl - N(X6)C(0)- -C=C- «-CH=CH- -C(O)NX6- Anhydrous. throw ¢-OC(0)- § -OC(O)N(X6)- «-C(O)O- ctarm ). ;; JY is yellow 1-7-? or ?; -COy(C}-Cy) alkyl ester ¢-8(0)(C;-Co)alkyl -S(0)y(C1-Cg) alkyl ester -~CONH, Vo fluoro Y ?or 0 (IH-tetrazol-5-yl tetrazol-#-yl-1H “-CO,(C;-Cy)alkyl ester oleh (0-:0); (C;-Cy) Alkyl Y R 1 R efluoro (and©-,6) atollahli-,©-0); )- -(C1-Cy) (©-m)-oldmaben (and-yn)-1 and yl (R0-Mo0)t-alkyl in the cycloalkyl and the cycloalkyl, where the alkyl groups are optionally substituted by Al. or ©

N(X6)(X6) -C(O)N(X6)(X6) -C(0)OX6 hydroxyl by RZ hydroxyl Definition 1 1 § CN (CF; “-C(O)(X) ®) «-C(O)A!¢-8(0),(C,-Coalkyl -S(0)(C;-Co) alkyl thalogen cpa sila or ?-(C1-Ce) alkyl-A' +(C-Cg) alkyl -A' «(C-C glalkyl (C;-Cyg) alkyl Al bitter R3

X!(C1-Cs) alkyl «(C-Cg)alkyl-(C3-Cr)eycloalkyl (Ci-Ce) alkyl -(C3-Cr) alkyl ve «(C1-Cs) Alk-X'-(Cp-Cs) Alk-A! (C-Cs)alkyl-X'-(C;-Cs)alkyl -(Ci-Cs) alkyl

Alkyl-(C-Cs)-(C-Cs)-(Co-Csalkyl-A') or -(C3-C7) alkyl -X'+(C-Cs) alkyl (and ©-): 6)- ¢-(C;-Cs)alkyl-X'-(C;-Cs)alkyl-(C3-Cq)cycloalkyl z where the alkyl groups in the definition of RY are optionally replaced with an alkyl ( M©-:5)0,,)0- Alwalala (m)-,5)0(,,)0-; 1 “-C(O)OX3 to © halogens or 1 to ¥ “0X3 “-CX2=CX2- “-C(0)0- “-<OC(0)- “ -C(O)N(X?)- «-N(X2)C(0O)- «S(0), © bitter XI ° -C=C- R -OC(O)N(X2) )- «-N(X2)C(0)O- (C4-Cy) or cyclic alkyl (C;-Coalkyl (C1-Cq) an alkyl chydrogen is the hydrogen of RY bonded to a carbon atom or 184 is taken with 103 together and the carbon atom ¢(C;3-Cy)cycloalkyl cycloalkyl (b-b) «(C5-Coleyeloalkyl (Cs-Cy) and they form a cycloalkyl Lagan ((C5-Cq)cycloalkenyl 0 A ring with A to partially saturated or fully saturated members having 1 to 1 heteroatoms selected separately from the group consisting of coxygen, sulfur, and nitrogen. Or it is an i aA fring system consisting of a 0 or 1 member p0 ring partially saturated or fully saturated welded to a © or 7 member ring partially saturated; LIS unsaturated or optionally fully saturated having from 1 to; ve heteroatoms selected separately from the group consisting of nitrogen sulfur sulfur and oxygen soxygen 4 is hydrogen or a Alkyl (C)-Collalkyl (C-Cg) or X* is taken with Lae RY and a nitrogen atom bonded to 354 and a carbon atom bonded to RY forming a ring with five to seven members; XX _ 28 AN 1 ¢ (CH2)a (CH2)b OR is the bond RS Y bond? or #; Alkyl Al dtrifluoromethyl fluoromethyl

The optionally substituted XS in the definition of Cp-Collalkyl (C;-C) optionally substitutes the alkyl (F©-R5)0(0)- (OX?Al) with a substituent chosen from the group consisting of X05 vo

Yv «(C3-C)eycloalkyl (C3-Cy) alkyl dary «-C(0)0OX2 ¢-S(0),,(C,-Cg)alkyl ¢-C(OIN(X2)(X? ) 5 -N(X2)(X?) with an alkylene bridge forming a quinine bridge X58 9 165 bearing carbon or carbon Each alkylene bridge contains Cua R85 72200 carrying a nitrogen atom Nitrogen or X5 provided it may be carbon atoms to © 1 carbon atoms on an alkylene bridge ° and may be 2200 or 185 but not carbon atom but not both on carbon atom 8 0100860? atom both on the nitrogen atom bonded with them and form a carbon atom ring and carbon atom X52 together with X5 or take A members partially saturated or fully saturated members; or a p0 ring with ; to 1 having ¥ to ring selected each separately heteroatoms to; heteroatoms 1 partially saturated or fully saturated have ve (nitrogen and nitrogen sulfur oxygen from the group formed by oxygen bonded with them and form A carbon atom system with a carbon atom X52 together with X53 or take a circular binary consisting of a “p” ring (with 0 or 1 partially saturated members) or a ring system a ring selected separately from heteroatoms 1 or 1 heteroatoms optionally completely saturated with 0m oxygen fused with sulfur The group consisting of nitrogen ©010088; sulfur vo 1 or optionally totally unsaturated having LIS saturated ola ring p0 with 0 or 76 saturated members selected separately from the group made up of nitrogen heteroatoms to ; heteroatoms and oxygen 7860-:0?; sulfur sulfur nitrogen 71 both are zero then bya is Laie provided that (N-X2 or O bond is bond 71 or 0; N-X2 is not an optionally substituted 1; (C1-Cglalkyl or alkyl (m©-,0) hydrogen is the optionally substituted hydrogen 5 (C-Colalkyl) where each separately optionally substitutes for an alkyl (0,6-m) Alkyl -C(0)0-(C,-Cg)alky!l Alkyl (F,6,-26)-0(0)- Al with R¥ in definition 0 to 1 chalogens to © 1 halogen atoms (and©-:8)0(0-) and (0-,8)0,)0-1 to ?alkyl (f:0-,0 ()6)©-0- Atolle:©-:©)(0)©-0- or chydroxy hydroxy vo or #(Cy-Cglalkoxy (C1-Cg) to ?alkoxy

Ya

Phenyl ((C5-Cq)cycloalkenyl (Cs-Cq) In each case separately the cycloalkenyl Al is completely saturated or completely unsaturated having (ja) saturated members A or a 4- to p-ring phenyl selected separately from the group consisting of heteroatoms to; 1 heteroatoms optionally a binary ring system or a ring system “nitrogen and nitrogen sulfur oxygen” circular consisting of p0 ring with 0 or 1 partially saturated members wholly unsaturated or wholly saturated © selected separately from the group constituting heteroatoms to; optionally 1 heteroatoms having or a © Caring and 0m oxygen fused to a ring sulfur sulfur cnitrogen of nitrogen into; 1 hetero-atoms or optionally unsaturated atoms having LIS partially saturated members sulfur-saturated nitrogen selected separately from the group made up of nitrogen 85 soxygen or oxygen sulfur 0 one or both rings separately optionally substituted in an Ala ring in each ring pair; with up to three substituents; a ring system is an Al ring system if it rings The two rings (OCF,H «OCF; «I Br «Cl (F) each substituted for J Make a selection separately from the group consisting of

JS «0x0 OXO -C(O)OXS6 -C(OIN(XE)(X6) KADF «OCH; «CH; «CF; -S(0),,(C1-C¢) alkyl cbenzyl cyano nitro nitro (C 1-Celalkyl (C-Cy) Vo phenoxy phenyl 1H-tetrazol-5-yl tetrazole-*-yl-1H «-S(0),,(C1-Cyg)alkyl methylene chalophenyl halo fil «phenylalkyloxy phenylalkyloxy 016707 -SO,N(X6)(X6) -N(X6)C(O)( X6) «-N(X6)(X6) cmethylenedioxy oxy il (CONX!1X12 «-N(X6)SO,X6 «-N(X6)SO,-phenyl -N(X6)SOp-d sé «- NX6SO,NX11X12 «-NX6CONX!11X12 «-NX6S0,X12 «-SO,NX 11X12 Ye itetrazolyl or tetrazolyl thiazolyl imidazolyl «-NX6C(0)X12 then methylenedioxy optionally substituted with methylene dioxy AT provided that if it is one; ve oleh (m-0,©) optionally substituted (CC) optionally substitutes each alkyl (C1-Cq) phenoxy carbonyl phenoxy phenyl with XM phenyl in definition

Ya to 1¢-S(0),,(C-Cgalkyl -S(0),(C-Cg) alkyl ¢(C-Cg)alkoxycarbonyl to 1-hydroxy cannoyl to ?hydroxy 1 chalogens ©¢ (Cy-Cgalkoxy (C1-Cg) halogen atoms) to 1 alkyl (f:©-t©) nodm ramselell©-,.©) or an alkyl phenyl thiazolyl (M ©-,0) Alolala (©,-0); phenyl chydrogen is hydrogen 2

Laie provided that cthienyl or thienyl furyl furyl cimidazolyl imidazolyl ctiazolyl 0 is optionally substituted with one to three X12 the chydrogen is hydrogen X12 not being OCF; «OCH; «CH; © «Cl Substituents selected separately from the group consisting of ¢CF3 (CH), -L1{(CHy),- together to form X12, X11 or taken

N(X2) R (SO), and C(XD(X2) Br LI 0

OF separately is 1; ? Or Ala in each # or (-0) (C;-Cg) alkyl hydrogen separately Ala hydrogen in every 2 optionally substituted where (C5-Coleycloalkyl (C3-Cy) is substituted optionally substituted or the optionally substituted cyclic alkyl and the cyclic alkyl (Cy-Cglalkyl optionally the alkyl (m©-,0) saa each on the optionally substituted in definition 762 with the alkyl and 0-,5(0)(,, ) 0- (C3-Coleyeloalkyl (C5-C) 0 « 0X3 to ?1 or halogens to © 1 halogen atoms «-C(O)OX3 ¢-8(0),,(Cy- Ce)alkyl or alkyl (m©-©) 1 and for Aquarius 0-)?; hydrogen separately is hydrogen Alla in each 3 son (m©-©) (C1-Cg) separately is hydrogen 60p 0:08: RT; Alla alkyl in every 6 (C3-C7) cyclic alkyl “(Cyp-Cy)halogenated alkyl (C,-Cg) optionally substituting a cyclic halogenated alkyl (-m) ) J&L laa) substituting (C3-Co)eycloalkyl 0 optionally for the alkyl (0,©2-) saa al-8108602160710-(0-and-0)); Where both the optionally substituted and the ring-alkyl (m©-:0) 1 and 0, (67016-and 0) substitute the (Cp-Collalkyl {(C1-C)alkoxy (C1-Cy) optionally alkoxy hydroxyl in the definition 765 by alkyl hydroxyl “-8(0),(C,-Celalkyl (um©-0)m(5)0-”CONH, “carboxyl alkyl carboxyl Y or 1) or 1H-tetrazol-5-yl (H0-,02)0©-.111-tetrazol-*-yl-COy(Ci-Cy) Yo or “(C1-Cy)alkyl ( T-).

When there are two X6 groups on one atom and both X6 are an alkyl (C1-Cg) Allah(m0-,©0); It is permissible for the two alkyl groups (C-Collalkyl (C1-Cq) to bond optionally and; together with the atom atom attached to them two groups 366 form a ring p1108 with; to 5 members that optionally has oxygen sulfur sulfur or NX ? 7° is a hydrogen or an alkyl (0,0-m) 1 ele(0,0-m) optionally substituted with a hydroxyl thydroxyl and “ in each Alla separately is zero; 1 or OY Provided that: 06 cannot be hydrogen when bonded with C(O) or SO, in the form ¢80,X12 4 SO,X6 «C(0)X!2 «C(0) (X6 and 1 when RY is a bond then L is NOX?) and every # in the definition of -,(12©)sa(112©)- is 1 or . The preferred compounds from the previous compounds of formula (IV) are the compounds Cua is yellow; Y is tO 181 is phenyl-0112- “-CH,-phenyl 182 is methyl or n¢thydrogen is 1;” is 1; R3 is R* ¢-CH,-O-CH,-phenyl -CH,-O-CH,-Jué is Ve hydrogen x? thydrogen is hydrogen. R® thydrogen is “C(CH3)y- 7220 is 300 RY is hydrogen. This invention provides: A method of increasing endogenous growth hormone levels in a human or other animal involving the administration of this human or other animal for an effective amount of a compound of the formula]; Ye a drug combination useful for increasing the endogenous production or release of growth hormone in humans or animals aT comprising an inert carrier and an effective amount of a compound of the formulation ]; A drug composition useful for increasing the production or endogenous release of a growth hormone in a human or other animal includes an inert substance; An effective amount of a Formula 1 compound and another growth hormone releasing stimulant such as B-HT920 (IGF-2 (IGF-1 “GHRP-1” Hexarelin “GHRP-6), Growth Hormone Releasing Factor (GRF) Yo or methyl thereof) A method for the treatment or prevention of osteoporosis involving the administration to a person or other animal in need of such treatment or prevention of a quantity of a compound of the formula [Aad] in the treatment or prevention of osteoporosis;

A method of treating or preventing osteoporosis involves the administration of a human or other animal with osteoporosis a combination of a bisphosphonate such as alendronate, and most preferably a bisphosphonate ibandronate and a compound of formula A

° A method of treating or preventing osteoporosis that involves the use of a human or other animal with osteoporosis

A combination of an estrogen or Premarin®, a Formula 1 compound, and optionally a progesterone, fprogesterone

A method for increasing levels of 1061-1 in an IGF-1-deficient human or other animal includes administration of a compound of the formula [;

0 A method for treating osteoporosis involves the administration of a human or other animal with osteoporosis to a combination of an agonist or an antiestrogen (estrogen) such as tamoxifen, cdroloxifene, raloxifene, idoxifen, and a compound of the formula ];

A particularly preferred method for the treatment of osteoporosis involves the administration of a human or other animal with osteoporosis to a combination of an anti-estrogen or anti-estrogen such as:

‎—AY Todd fluoro-phenyl)-41-0-(7-pipyridine-1-yl-ethoxy)- - 2) cis

tetrahydro-naphthalene-?"-ol; Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7, 8-tetrahydro- naphthalene-2-ol; (-)-huh-- —Y)- Eom dis pyrrolidine-1-yl-ethoxy)phenyl]-4:71:0-tetra

0 | hydrophthalene-?”- and l;

(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-

tetrahydronaphthalene-2-ol;

cis-phenyl-5-[; -(7-pyrrolidine-1-yl-ethoxy)-phenyl]-407056050-tetrahydrophthalene-1-ol;

cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8- Yo

tetrahydronaphthalalene-2-ol;

-"1[-1-©5 pyrrolodinoethoxy-?'-pyridyl]-?-phenyl-7-hydroxy-507:701-tetrahydronaphthalene; cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4- tetrahydronaphthalene; - tetrahydroisoquinoline; 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4- tetrahydroisoquinoline; cis )2 — hydroxy Emo (di -( 7-piperidine-1-yl-ethoxy)-phenyl]-67:5:5/- 0 tetrahydrophthalene-7-ol;cis-6-(4-hydroxyphenyl)-5-[4-(2) -piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8- tetrahydronaphthalene-2-ol; or 1-("-ethoxyphenyl pyrrolidinol)-7-phenyl-7- HYDROXY-070701;- tetrahydroisoquinoline; 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4- Vo tetrahydroisoquinoline; and a compound of formula [; a method for the treatment of osteoporosis Bone and includes the intake of a human or other animal with osteoporosis of both calcitonin and a compound of Formula [;.9 a method for increasing muscle mass; and includes the intake of a human or other animal needing this treatment of an amount of a compound of Formula 1 effective in stimulating the secretion of endogenous growth hormone And a method for stimulating growth in cases of children with growth hormone deficiency, which includes the child with growth hormone deficiency taking a compound of formula T that is effective in stimulating the secretion of endogenous growth hormone Yo. This invention also provides a method for treating or Preventing the occurrence of diseases or conditions that can be treated or prevented with growth hormone, including the intake of a human or other animal plating for this treatment or prevention of an amount of a compound of formula I affecting the stimulation of endogenous growth hormone secretion.

In the aspect of AT, this invention provides methods for treating or aie congestive heart failure; weakness associated with age; Obesity includes the intake by humans or animals in need of such treatment or withholding of an amount of a compound of Formula 1 affecting the stimulation of endogenous growth hormone secretion; For the current approach, the disease or condition that is being treated or prevented is preferably congestive heart failure; or weakness oo associated with advancing age. In the aspect of OAT, this invention provides methods to increase the speed of bone fracture repair; The response to protein catabolism is impaired after major surgery; Reduce wasting and protein loss resulting from chronic diseases such as AIDS and cancer; AU speeds up wounds; It increases the speed of recovery in burn patients or patients who underwent surgeries gS and includes eating a human or 0 animal AT in need of this treatment of an amount of a compound of formula 1 affecting the stimulation of endogenous growth hormone secretion. For the current method, it is the method It is preferred to use it to speed up the repair of broken bones or to speed up the recovery of patients who have undergone major surgeries. In terms of clad AT, this invention provides ways to improve muscle strength; its movement; maintaining skin thickness; metabolic homeostasis and renal homeostasis; It includes the intake of a human or other animal in need 1 of this treatment for a quantity of a compound of protective element 1 that is effective in stimulating the secretion of endogenous growth hormone. As for the current compounds that stimulate the secretion of growth hormone, they are stable under different physiological conditions and can be taken parenterally. Through the nose (by inhalation) or orally. Detailed Description of the Invention ‎Ye The ordinary skilled realizes that some of the substitutes included in this invention lack chemical stability; When one combines with another or with different atoms in compounds. These compounds, which lack chemical stability, are not favored. In general, compounds of formula 1 can be made in a number of ways, including methods known in Osi chemistry for the production of compounds. The particular methods for making the compounds of Formula 1 give further features [Ye] of this invention and are illustrated in the following reaction programs. In previous structural formulas and during the current application; The following terms have certain meanings unless otherwise expressed.

Alkyl groups mean that alkyl groups include a certain length in a straight or branched form and can optionally contain double or triple bonds 50005. Examples of alkyl groups are methyl ethyl cethyl propyl isopropyl butyl-sec-butyl tertiary butyl pentyl pentyl 0 isopentyl cisopentyl hexyl isofemmexyl cisohexyl allyl ethinyl cethynyl propenyl butadienyl cbutadienyl hexenyl <hexenyl etc. When Coalkyl Cords is present in the definition; It means a single covalent bond. In particular, alkoxy groups are meant to include 0 alkoxy groups of a certain length in straight or de ia form and optionally contain double or triple bonds. Examples of alkoxy groups are methoxy cethoxy ¢PIOPOXY isopropoxy (“9001:000; DULOXY” cisobutoxy “tertiary manat” pentoxy) pentoxy disopentoxy chexoxy 5-jill cisohexoxy oxy aallyloxy 7-propynyloxy «2-propynyloxy | 'halogen' or 'halo' to include halogen atoms, fluorine, chlorine, bromine, and iodine. The term 'halogenated alkyl' means to include a group An alkyl as defined here above substituted by one or more halogen atoms as defined here above.The term “halogenated cycloalkyl” is meant to include a cycloalkyl group substituted by one or ASI of halogen atoms as defined here above.The term “aryl” is meant to include phenyl naphthyl and vo© rings and 1 aromatic member with 1 to ; heteroatoms or circular double rings with 0 or 1 members fused to 1 to ; Heteroatoms of nitrogen (nitrogen sulfur or oxygen) Examples of heterocyclic aromatic rings are to “thienyl furan” (also known as thienyl Thiophene pyridine N-indole ctetrazole tetrazole benzothiophene 10082016 17- formyl indole N-methylindole pyrimidine Pyrimidine cthiazole thiazole benzimidazole <N-formylindole .thiadiazole and thiadiazole H0

A chemist of ordinary skill realizes that certain combinations of heteroatom-containing substituents included in the present invention are compounds that will be less stable in physiological conditions (eg containing acetal or 81-nt-aminyl bonds). accordingly; These compounds are less

Ve The phrase “prodrug” refers to compounds that are the source materials for drugs, which after ingestion, the drug is excreted in the living body through some chemical and physiological processes

(Example: prodrugs adjusted to the physiological pH level that convert to the required form of the drug). Examples of prodrugs upon partition yield the appropriate free acid and these hydrolyzable ester-forming residues of the compounds of the present invention include but are

~(CH,){C(0),X® is RI (as “carboxylic acid” is not limited to carboxylic acid substituents vo containing carboxylic acid Al or R2 or containing hydrogen Inductively "76 is hydrogen."

(carboxylic acid where the free hydrogen is replaced by an alkyl (B-6) “(Cy-Cyalkyl alkanoyl oxymethyl (N0-U6) ((C,-Cyp)alkanoyloxymethyl 1-(alkanoyl oxy) ) -1 ((Cy-Co)1-(alkanoyloxy)ethyl (C4-Co) Ji methyl-1-(alkanoyloxy) 1-methyl-1-(alkanoyloxy)ethyl Ji 0 has from * to 01 carbon atoms alkoxycarbonyloxymethyl his from? to + carbon atoms 1-(alkoxycarbonyloxy)ethyl his

From to 1 carbon atoms -1 carbon atoms methyl-1-(alkoxycarbonyloxy)ethyl 1-methyl-1-(alkoxycarbonyloxy)ethyl has from *# to A carbon atoms “carbon atoms

¥ has N-(alkoxycarbonyl)aminomethyl 17-(alkoxycarbonyl)aminomethyl Yo (sal carbonyl) escola(-0(-1) carbon atoms to 4 carbon atoms 01 has 4 to 1-(N-(alkoxycarbonyl)amino)ethyl enyl

£1 «4-crotonolactonyl crotono-lactyl - 4 «3-phthalidyl phthalidyl —¥ «carbon atoms alkyl aminos (C-C3) alkyl cgamma-butyrolacton-4-yl gamma-butyrolactocon-4 - yl (eg Pega-di-N,N+(C;-Cy)alkylamino(C,-Cs)alkyl remote -NN-(C;-C2)alkyl (0-:0)- carbamoyl ¢(B-dimethylaminoethyl) JL

NN- AL alkyl (0-,0)-carbamoyl alkyl-(0-,0)(alk1 0-(0-)870877001) ; 1 0 piperidinio »pyrrolidino or (C-C3)mL-0) Other examples of prodrugs that release an alcohol of formula [A] are other examples of prodrugs that release an alcohol of the formula [a]. where the free hydrogen is substituted for the hydroxyl substituent (eg L contains 0 hydroxyl) with the 1-oxymethyl alkanoyl (C,-Cgalkanoyloxymethyl (C,-Cq) ((J©- (©) alkanoyl-oxy)ethyl-1 ¢1-((C;-Cg)alkanoyloxy)ethyl methyl-1-(f-0-2) alkanoyl oxy)ethyl c1-methyl-1-((C;-) Cg)alkanoyloxy)ethyl (0,0-M) “(Cp-Cealkoxycarbonyloxymethyl) (N-(C,-Cg)alkoxy-carbonylaminomethyl N-(C;-Cg) succinoyl 100[1H06?;alkanoyl 1(M6-0) “(Ci-Cglalkanoyl) alkanoyl (C;-C4)amino(C;-C,)alkanoyl arylacetyl and “- aminoacyl co-aminoacyl or “- aminoacyl-0-aminoacyl Cus a-aminoacyl-ai-aminoacyl are parts E »- aminoacyl (g-aminoacyl) mentioned separately, any of the natural L-amino acids (Lid) found in proteins (P(O)OH), (alkyl -PO)O (C-Colalkyl), -PO)((C1-Co)O R glycosyl 0 (the hydroxyl radical of the hemiacetal (carbohydrate) of the carbohydrate) The prodrugs in this The invention where the carboxyl group in the carboxylic acid of formula (I) is replaced by an ester, which can be prepared by combining carboxylic acid and the appropriate alkyl halide in the presence of Jie base 0 potassium carbonate in an inert solvent DMF Jie at a temperature ranging from about 0°C to 100°C for a period ranging from one hour to about YE hours. By the Aly method the acid is combined with a suitable alcohol as a solvent in the presence of a catalytic amount of

An acid such as concentrated sulfuric acid at a temperature of about Te to 00 C; preferably with steam re-condensation for a period of one hour to about YE hours. The other method is acid Jeli in An inert solvent such as THF is accompanied by the removal of the resulting water by physical methods (Jie (Dean Stark trap) or chemical (Jie) molecular sieves).

o The prodrugs in this invention are Cus the function of alcohol, alcohol, which is derived in the form of ether, which can be prepared by combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base such as potassium carbonate potassium carbonate in the presence of an inert solvent, DMF Jie, at a temperature of about 0 C to 100 C for a period of about one hour to about YE hours. can get

0 on alkanoylaminomethyl ethers 68165, alkanoylaminomethyl by reacting the alcohol with 8-(alkanoylamino)methane, bis-(alkanoylamino)methane, in the presence of a catalytic amount of acid in an inert solvent such as THF according to the method described in the patent American invention number 4. in an alternative way These compounds can be prepared by the methods described by:

Hoffman et al. in J.

Org.

Chem. 1994, 59, p. 3530. ve Some of the previously defined terms can occur more than once in the previous form, and in the event that they occur, each term will be defined alone without the others. Throughout the standard and the appended claims, abbreviations with the following meanings are used: BOC: -t t-butyloxycarbonyl 0 benzotriazole-1-yloxy tris (dimethylamino)phosphonium hexafluorophosphate benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate | 0 CBZ: benzyloxycarbonyl -N'«N: CDI carbonyl-diimidazole N,N'-carbonyldiimidazole:CH,Cl: methylene chloride: CHCl3: chloroform chloroform

Dicyclohexylcarbodiimide Dicyclohexylcarbodiimide DCC: Yo dimethylformamide DMF: Dimethylformamide

B -©(-1 (EDC dimethylaminopropyl)-7-ethylcarbodiimide hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc ethyl acetate FMOC: = Fluorenylmethoxycarbonyl 9-fluorenylmethoxycarbonyl th ° h:Hex hexane -1 HOAT: HYDROXY-7-azabenzotriazole 1-hydroxy-7-azabenzotriazole 1:Hydroxybenzotriazole hydrate hydroxybenzotriazole hydrate: HPLC high pressure liquid chromatography 1 27 megahertz Cada: MS mass spectrum: NMR nuclear magnetic resonance 1: Parathyroid hormone (48 2 jlall) TFA trifluoroacetic acid: THF vo tetrahydrofuran TLC: thin layer chromatography TRH: hormone thyrotropin releasing hormone -YeYeY TROC: 2,2,2-trichloroethoxycarbonyl The compounds in All of the present invention contain at least one asymmetric center 0 as denoted by an asterisk in the structure of formula T above. Additional asymmetric centers can exist on the molecule depending on the nature of the different substituents on the molecule. Each asymmetric center gives two optical isomers. What is meant is that all these optical isomers separate pure or partially pure as optical isomers; Racemic mixtures or mixtures of stereoisomer binary materials would fall within the scope of the present invention. In Als the asymmetric center and die crossed by the star; It was found that the absolute stereochemistry of the most active Ye, and thus the preferred isomer, is indicated in the formula JA. This absolute conformation also applies to the formula [].

¢9 R! i R} Xe i. SOG Ed NR N.

Eps | SRS SN (CH2)w R* 0 27g (A) with substituent 144 in the form of hydrogen The spatial configuration of the asymmetric center corresponds to that in (1-amino acid D-amino acid in . In many cases it is denoted as 18 but this will vary depending on the values of 183 and 1844 used to make the R or 5 for the stereochemical symbols.

° Current compounds are generally preferred in the form of pharmacologically acceptable acid addition salts such as salts resulting from the use of inorganic and organic acids. Examples of these are hydrochloric acid 000106 nitric sulfuric sulfuric phosphoric: 0M 0109 formic cacetic trifluoroacetic probiotic propionic maleic D-succinic L-tartaric (L-tartaric) cmalonic methane

0 cmethanesulfonic etc. In addition to that; Certain compounds having a carboxy acidic function can be separated into their inorganic salts and in which the opposite-ion can be selected from sodium (potassium), lithium, calcium, magnesium, etc.; as well as from membership rules.

Pharmacologically acceptable salts are formed by taking about 1 equivalent of a compound of formula (1) and contacting it with

ge 10 is about 1 equivalent of the appropriate acid corresponding to the required salt. Composition and separation of the resulting salt

Well known to those of ordinary skill in the art.

Compounds of Formula (D) that secrete growth hormone are useful exogenously (extrahomally) in the form of a unique means of understanding how growth hormone secretion is regulated at the pituitary level. They include use in the evaluation of several factors believed or known to influence paralytic growth hormone secretion

0 _ age; sex; Jal go Nutrition; glucose; amino acids; Fatty acids; As well as cases of fasting and non-fasting. Furthermore; The compounds in this invention can be used to evaluate the ability of other hormones to alter growth hormone secretion. For example, it has been proven that somatostatin inhibits the secretion of growth hormone.

The compounds of formula T can be given to animals as well as humans to secrete the growth hormone Ye in the body. The compounds are useful for treating symptoms related to growth hormone deficiency and stimulate growth

Oa or enhance eating efficiency in animals raised for meat production to improve carcass quality; To increase milk production in dairy cattle, to improve bone and wound healing, and to improve the functions of vital organs. For example, turkeys; Farm animals (such as opal gall (the compounds in this invention can be given 0 sheep; pigs; horses; cattle etc.) In addition, these compounds can be administered to human subjects in vitro as a diagnostic method to directly determine if 1 compounds of formula (JB) the pituitary gland is capable of secreting growth hormone.

Loa lial can be taken internally by children. Blood samples are taken before and after this intake. It is possible, 0, for the presence of growth hormone. Comparing the amounts of growth hormone in each of these samples will be the most direct way to determine the ability of the patient's pituitary gland to secrete growth hormone. The scope of this invention includes pharmaceutical formulations comprising as the primary active agent at least one of the compounds of formula 1, together with a pharmaceutically acceptable carrier. Optionally combinations Metabolic building material in addition to - at least - one of the compounds of the pharmaceutical Lad may include _ 1 Formula 1 or other compounds that exhibit different activity such as an antibiotic that allows growth or a substance for the treatment of osteoporosis or With other active pharmaceutical substances, where in combination it activates efficiency and reduces side effects. stilbestrol 0 of E types enkephalins anabolic steroids anabolic steroids theophylline compounds listed in US Patent No. Such as Zyranol 5 compounds thus incorporate their contents as a reference; such as Sulbenox TAYE in US Patent No. 441184960 is described herein; thus peptides and peptides of sulbenox Ye ¢ their contents incorporate as a reference.

The growth hormone-releasing stimulants of this invention are in combination with other growth hormone-releasing stimulants such as GH-releasing peptides GHRP-1 3 GHRP-6 as described in US Patent No. (££V VARY) their contents herein incorporate for reference; and publications B-HT920 5 WO 89/07111 “WO 89/07110” as well as the newly discovered hexarelin ©GHRP-2 as described in WO 93104081 or growth hormone-releasing hormone (GHRH) also ( GRF and its analogues or growth hormone and its analogues or somatomeding including IGF-2 5 1061-1 or adrenergic agonists (po ala) such as clonidine or Jie SHTID serotonin agonists sumitriptan or depressants somatostatin or inhibit its secretion such as physostigmine and pyridostigmine «pyridostigmine | 0 Useful for increasing the level of endogenous growth hormone in mammals. The combination of growth hormone-releasing stimulants in this invention with GRE results in a synergistic increase in endogenous growth hormone. As it is known to those skilled in this coll, the known and potential uses of growth hormone are different and multiple; See "Human Growth Hormone", Strobel and Thomas, Pharmacological Reviews, 4, pg. 1-34 (1994); T. Rosen et al., Horm Res, 1995; 43: p.p. 93-99; M. Degerblad et al., vo

European Journal of Endocrinology, 1995; 133: pp. 180-188; J. O. Jorgensen,

European Journal of Endocrinology, 1994, 130: pp. 224-228; K.C. Copeland et al.,

Journal of Clinical Endocrinology and Metabolism, Vol. 78 No. 5, p. 1040-1047;

J.A. Aloi et al., Journal of Clinical Endocrinology and Metabolism, Vol. 79 No. 4, p. 943-949; F. Cordido et al., Metab. Clean. Exp., (1995), 44(6), pp. 745-748; K.M. Y.

Fairhall et al., J. Endocrinol., (1995), 145(3), pp. 417-426; R.M. Frieboes et al.,

Neuroendocrinology, (1995), 61(5), pp. 584-589; and M. Llovera et Malaga Int. J.

Cancer, (1995), 61(1), pp. 138-141. Therefore, taking the compounds of this invention for the purposes of stimulating endogenous growth hormone secretion could have the same effects or uses of growth hormone itself. These different uses of growth hormone Ye ld age; In the treatment of adults with JUS deficiency, it can be summarized as follows: Activate growth hormone secretion in the treatment of “glucocorticoids” in growth hormone and prevent the catabolic side effects of glucocorticoids oY osteoporosis; activate the immune system (immune system); Wound healing speed increases; Increases the speed of repairing bone fractures; treatment of growth retardation; Treatment of congestive heart failure as described in (Example of method for testing the effectiveness of WO stimuli and 95/28174 WO 95128173 PCT Publications) Growth hormone secretion in the treatment of congestive heart failure is described in:

R. Yang et al., Circulation, Vol. 92, No. 2, p.262, 1995), ° treatment of acute or chronic renal failure or insufficiency; Treatment of physiological short stature, including children with growth hormone deficiency; Treatment of short stature associated with chronic diseases; Treating obesity; Accelerating recovery and reducing Tumer. The Prader-Willi offer to treat growth retardation associated with prolonged hospitalization for burn patients or after major surgeries such as those of the gastrointestinal tract; treatment of intrauterine growth retardation; abnormal body composition; hypersecretion of the parathyroid glands and Cushing's disease; replaces growth hormone in stressed patients; Treatment of formation other than Alzheimer’s delay, sleep disorders, “Noonans disease of normal bones and cartilage”; presentation of wound healing; psychological and social deprivation; treatment of pulmonary insufficiency and dependence on artificial respiration; reduces the response to protein catabolism after major surgeries “Treatment of symptoms of malabsorption.” Reduces wasting and protein loss resulting from chronic diseases such as cancer or AIDS. Increases 1 over ALS (TPN nutrition) speed of weight gain and exogenous protein gain in patients on a) Ua ) dissemination of pall stems includes a non-intestinal route); treatment of hyperinsulinemia Langerhans); adjunctive therapy to induce ovulation and to prevent and treat gastric and duodenal ulcers; Activation of thymus and prevention of thymus function decline with age; Adjunctive therapy for patients on chronic renal gail dialysis; Treating immunosuppressed patients and promoting an antibody response _ © after vaccination; improving muscle strength; increased muscle mass; its movement and maintenance of skin thickness, blood, metabolic, and renal balance in the frail of the elderly; activate bone-producing cells; bone rebuilding and cartilage growth; Treatment of neurological diseases such as lateral sclerosis related to (Guillian-Barre) peripheral nerves caused by drugs and muscular dystrophy; multiple sclerosis; cerebrovascular accidents and Yo-deficiency diseases; activating the immune system in pets and treating progression disorders Age in celal animals, stimulating growth in farm animals, and increasing wool growth in sheep. aay oy

It is well known to those skilled in the art that many compounds are now used in an attempt to treat the ailments or therapeutic indications mentioned above. the union of these therapeutic substances; some of which were mentioned above; With a growth stimulant that leads to the structural and metabolic properties required of these different pharmaceutical substances. In these combinations of therapeutic substances and stimulants for the secretion of growth hormone in this invention from ‎oad 0 taken separately or in sequence or at the same time in a dose ranging from one in a hundred to several times the effective dose when using these compounds and substances that stimulate secretion alone. The combination therapy to prevent osteoporosis; preventing osteoporosis; reduce bone fractures; activation of bone fracture healing; Activation of bone formation and an increase in bone mineral density may occur with a combination of bisphosphonates and growth hormone-releasing substances in this invention; hail WO 95/11029 PCT Discussion of combination therapy with bisphosphonates and growth hormone-releasing agents. The use of bisphosphonates

085 for these purposes has been re-examined for example; By: Hamdy, N.A.T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends In Endocrinol.

Matab., 1993, 4, pages 19-25. bisphosphonates with these benefits include - but not only - alendronate JS ctiludronate “is adi” alendronate methicil (APD-dimethyl risedronate) Etidronate <YM-175 cetidronate cclodronate pamidronate BM-210995 5 pamidronate (ibandronate) according to gileld, the daily oral dose ratio of bisphosphonate ranges between 1 mg and 1 mg 0 And the daily oral dose of substances that stimulate the secretion of growth hormone in this invention ranges from 101 mg / kg to Yo mg / kg of body weight that the patient takes to obtain treatment

Effective for osteoporosis.

The compounds in this invention can be combined with estrogen antagonists/inhibitors in mammals. slo is an estrogen antagonist/inhibitor that can be used as a second compound in this invention. The vo term estrogen agonist/antagonist means compounds that bind with estrogen receptors and prevent bone degeneration and bone loss. In particular, estrogen inhibitors are defined here as chemical compounds that are able to bind with (SU) o estrogen receptors in mammalian tissues and mimic the actions of estrogen in one or more tissues. Estrogen inhibitors are defined here as chemical compounds that are able to bind with receptor sites. Estrogen in mammalian tissues.It stops the actions of estrogen in one or more of the tissues.These activities can be determined by those skilled in the art according to standard tests and include test methods for estrogen receptor binding sites, standard histomorphometry of bone, and a densitometer 0 Eriksen E.F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S.J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals,

Inv. Radiol., 1996, 31(1): 50-62: Wahner H.W. and Fogelman I., The Evaluation of

Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin 1

Dunitz Ltd., London 1994, pp. 1-296). A variety of these compounds are described and referenced below but other estrogen antagonists/inhibitors are well known to those of skill in the art. The —¥ “phenol (phenol: droloxifene is a preferred estrogen being droloxifene hia conducive/[71-41-1-(chaymethylamino)ethoxy]-phenyl]-?- phenyl-1-butyl] -0 and the compounds (((E)¢3-[1-[4-(2-dimethylamino)ethoxy]-phenyl]-2-phenyl-1-butenyl]- (merged here for reference). 0147471 relating to it described in US Patent No

Jy) tamoxifen Another preferred antagonist/antiestrogen is tamoxifen methyl SB diphenyl-1-butyl)phenoxy)-1111--710(-7-(-?; cethanamine amine? -hydroxy-, -7-(2) 2-(-4-(1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl | 0 (0:1) 2-hydroxy-1,2 ,3-propanetricarboxylate 70;-propane terticarboxylate and related compounds described in US Patent No. £07101 (herein incorporated 4-hydroxy tamoxifen by reference). Another related compound is ;-hydroxytamoxifen described in US Patent No. 677775? (incorporated herein for reference).—1] cmethanone The preferred antagonist/anti-estrogen is raloxifene 010<178:06::(methanone Yo-pipredinyl)ethoxy]-1(-7[- hydroxy-7-(4-hydroxyphenyl)benzo[0]thine-7-yl[;phenyl]-hydrochloride;

00 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy] phenyl]-hydrochloride,

Described in US Patent No. 45,185,314 (incorporated herein for reference). Another preferred estrogen antagonist/antagonist is tidoxiphene pyrrolidine” oo 1-41-1-[11-(?-iodophenyl)-7-phenyl-1-butyl]phenoxy[ethyl] pyrrolidine, 1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl] described in US Patent No. 58,749,166 (incorporated herein by reference). Another preferred estrogen inhibitor/antagonist includes compounds as described in Publicly Assigned US Patent No. 000Y ENVY (herein incorporated as a translator). The particularly favored compounds described here are: wt-+-(;-fluoro-phenyl)-*-[?-(7-piperidine-1-yl-ethoxy)-phenyl]-4097:3:6 -tetrahydro-naphthalene-7- tds cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7, 8-tetrahydro- naphthalene-2-ol; 1(-)-mask->-phenyl-5-[;-(7-pyrrolidine-1-yl-ethoxy)-phenyl]-4076705-tetra am 5 — naphthalene-7-ol; (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- naphthalene-2-ol; mY meals mY) Elmo - dad 0-5 yl-ethoxy)-phenyl]-801705609-tetrahydro0phthalein-?"-ol;cis-6-phenyl-5-[4-(2-pyrrolidin) -1-yl-ethoxy)-phenyl]-5,6,7,8- tetrahydronaphthalene-2-ol; cis )"= pyrrolidineethoxy-7"-pyridyl]-7-phenyl-7-hydroxy- 007070;- tetrahydronaphthalene; cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4- Yo tetrahydronaphthalene; of tetrahydronaphthalene; TENT mug pun pyrrolidinoethoxyphenyl)-7-(4;"-fluorophenyl)-7--';(-1hydrisoquinoline; 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl) -6-hydroxy-1,2,3,4- tetrahydroisoquinoline; cis ° tetrahydro-naphthalene-"-ol; cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8 -tetrahydro-naphthalene-2-ol; ethoxyphenyl pyrrolidinol)-7-phenyl-7-hydroxy-007070;-tetrahydro ME) isoquinoline. 0 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3, 4- tetrahydroisoquinoline. Another US Patent No. estrogen describing estrogen antagonist(s) for EYTYAVE (merged herein by reference). US Patent No. 4 discloses phenyl-—Y and 2-phenyl-3-aroyl-benzothiophene derivatives of 2-phenyl-3-aroyl-benzothiophene-1. oxide Orylbenzothiophene-1-oxide -* The following paragraphs provide preferred dosage ratios for antisorption agents. The amount of antiresorption agents used is determined by their ability to prevent bone loss. This ability is determined by means of the body's handling of each compound and the minimum and maximum effective dose thereof to prevent bone loss using the method as mentioned above. 8 Generally the effective dose for the active in this invention; For example for the treatment of osteoporosis (when used with a compound of formula 1 in estrogen by estrogen antagonists/inhibitors 001 mg/kg/ to #1 preferably cas mg/kg/You to 100 of this invention) ranging from 0,1 day to droloxifene in particular; The effective dose for drloxifene is ~11 mg/kg/day; preferably 50 to ov 001 to 01 ranging from raloxifene in particular; The effective dose of raloxifene is 10 mg/kg/day, preferably 0.1 to 0.1 mg/kg/day, with tamoxifen in particular; The effective dose of tamoxifen is up to mg/kg/day. 1.1 mg/kg/day and is particularly preferred; The effective dose of substances: ° fluoro-phenyl)-1-5; -(7-biperidene-1-yl-ethoxy)-phenyl]-097:5:5/- — 2) cis tetrahydro-naphthalene-?"-ol; cis-6-(4-fluoro-phenyl )-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- naphthalene-2-ol; quaternary AY edad (-)-8l» -- phenyl-41-5-(7-pyrrolidine-1-yl-ethoxy)-0 hydro-naphthalene-7-ol; (-)-cis-6-phenyl-5-[4-(2-) pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- naphthalene-2-ol; - tetrahydro AVEO NH-7-phenyl-8-[;-(7-pyrrolidine) -1-yl-ethoxy)- naphthalene-?"- ol;0 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7 ,8-tetrahydro-naphthalene-2-ol; phenyl-7-hydroxy-007070;- tetra = Y= [da pn Vm oS Si gd 5 ja 1] cis hydronephthalene; cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2- phenyl-6-hydroxy-1,2,3,4- Y. tetrahydronaphthalene; pyrrolidinoethoxyphenyl)-7-(4;"-fluorophenyl)-7-hydroxy-070701;-tetra-';(-1-hydroisoquinoline;1-(4'-pyrrolidinoethoxyphenyl)-2-(4" -fluorophenyl)-6-hydroxy-1,2,3,4- tetrahydroisoquinoline; — 2) cis tetrahydrophthalene-7-ol;oA cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7, 8-tetrahydronaphthalene-2-ol; OR 1-(;-ethoxyphenyl pyrrolidinol)-7-phenyl-7-hydroxy-0407070-tetrahydrisoquinoline

1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline 0

It ranges from 00001 to 100 mg/kg/day, preferably 0.001 to 100 mg/kg/day. In particular; The effective dose of a substance; - Hydroxy tamoxifen, 4-hydroxy tamoxifen

ranging from 150,001 to 100 mg/kg/day; Preferably 1000 to 100 mg/kg/day. Compounds with the ability to stimulate growth hormone secretion from pituitary cells of cultured brain 0 were determined using the following method. This test is also useful for comparison with measurements to determine dose levels. Cells were dissociated from the pituitary glands of 6-week-old male Wistar rats. after detaching the head; The anterior lobes of the pituitary gland are separated in sterile cold balanced salt solution, Hank's, without calcium or magnesium (11355). Then the tissues are finely minced; then they are subjected to two cycles of automated coenzyme distribution using 01 units/mL of Bacterial Protease (EC 3.4.24.4, Sigma P-6141) 1 in 11355. The tissue and enzyme mixture was stirred in a spinning flask at 1 rpm in CO; fo atmospheric at about 17"C for approx. 01 minutes, crushed by hand after about 11 minutes for about ye minutes using 10 milliliters in a pipette This mixture was centrifuged 87700 for about minutes Horse serum was added to the supernatant to neutralize the excess protease. The small grains are resuspended in fresh protease; stirred for about 0 - 10 minutes under the previous conditions; crushed manually and finally through a YY gauge needle again added the horse serum and the cells from the digested materials unite and turn into small grains (107*p for about Vo min); washed; resuspended in culture medium and counted. Cells were singled out on 0716.5-60 cells/Yau in $A bowls from Will Costar and are grown for '-; Lowy Days (D-MEM) Dulbecco's Modified Eagle plus £0.0g/l glucose 701 glucose Yog serum (las 77.5 bovine whey) 71 iia nonessential amino acids; 001 units/mL nystatin and © 1 mg/mL gentamicin sulfate before a secretion test

Growth hormone.

eq min at medium 0 Immediately before calibration the culture vessels are washed twice; Then it is equilibrated for about a period of time and Vet contains pH Hepes mM Yo neutralized by D-MEM (diluted bovine serum albumin at 71” * hurricane). The tested compounds were dissolved in Leo and then diluted in absolute medium before heating. Calibrations are performed four times. The titration begins with the addition of 0 mL of absolute medium (via transfer applicator or tested compound) to each culture vessel. done © 1 min; It ends with removal of the culture medium; incubation for about 11 ty at a temperature of about 11 minutes to remove cellular material. Yo concentrations for about gXY eee which are centrifuged rat growth hormone in the float were determined by a standard method for determining radioimmunity and antiserum (NIDDK-TGH-RP-2) using the growth hormone reference preparation. In mice, growth hormone in mice made in monkeys (115-5-5:-0110112-200 taken from Dr. 0) and growth hormone for mice (Harbor-UCLA Medical Center, Torrence, Calif.) A. Parlow is added. Iodine (Calif. “San Diego” Scripps Labs “G2414 # mg [san 51,0) supplemental chloramine µC/µg approximately by the chloramine method 01 reaches a specific activity to be used as a tracer. Immunocomplexes produced by adding anti-goat serum to 180 T monkeys “polyethylene glycol in addition to polyethylene glycol (Organon Teknika, Durham, N.C.) d to a final concentration of 75”, and centrifuged. This is 0.000-00000 by weight. Molecular assay has an action range of 0.056-7.9 mcg of rat growth hormone per tube over time. Reference: 0.4 greater than sail baseline levels. Active compounds stimulate hormone secretion.

Cheng, K., Chan, W.-S., Barreto, Jr., A., Convey, E.M., Smith, R.G. 1989. Titration of growth hormone secretion in rats after exogenously stimulating them with intravenous administration of the tested compounds Ye on 71-day-old Sprague-Dawley Fatran Ad (Charles River Laboratory, Wilmington, Mass.) 11 hour light; VY allowed to acclimate under limited rearing conditions (£7'C; Cycle allowed to have access to water and eat of il about a week before the compound test. Each sad dark) ve as desired. (Agway Country Food, Syracuse, N.Y.) Commercial in the form of small granules for the protection and use of laboratory animals. These trials are conducted under NIH guidance.

Te 1 cethanol 71 ethanol on the day of the experiment; The tested compounds were dissolved in a carrier containing bovine serum albumin in saline solution. 720.1 and acetic acid 1 mM acetic acid Each compound tested with number = 7. Mice are weighed and anesthetized by proton injection with sodium ,

VE (mg/kg body weight). After 00 (Nembutol) sodium pentobarbital pentobarbital and allows the blood to flow into the tube of the JA device blood by cutting the tip Ae minutes of taking the anesthetic; taken © minutes after ingestion of the anesthetic Vo (approximately μl). 001 Aaa) microcentrifuge (blood sample 1 milliliter/ALS The tested compound is injected intravenously into the tail vein and the volume of the injected volume min after Voy ingests 0 1 0 kg of body weight. Additional blood samples are taken from the tail at (g x VET) compounded. Blood samples are kept on ice until serum separation by centrifugation (10 minutes at 10*C). The serum is stored at -80*C until the percentage of growth hormone 01 duration 0 is determined in the serum by the radioimmunoassay method as mentioned previously and will be mentioned below. Evaluation of growth hormone secretion after its activation from the outside in dogs after oral administration on the day of the trial; The tested compound is weighed to determine the appropriate dose and dissolved in water. Doses taken in a volume of 1.0 milliliters/kg by four dogs fed by gastric tube for each sample system. After deal blood samples (¥ milliliters) were collected from the jugular vein by venipuncture immediately before 1 hours after the dose using a container Suction Ag ch cf oY 1 boat near Alarat (IV ink) The prepared plasma is stored at a temperature of lithium heparin? Milliliters containing lithium heparin temperature -<0 *"C until analysis. Measurement of growth hormone In dogs, canine growth hormone concentrations were determined by a standard radioimmunoassay method using Y. antagonist (AFP-1983B). Serum for growth hormone in dogs reared in monkeys traceable to produce (Harbor-UCLA Medical Center, Torrence, Calif.). We obtain immunocomplexes by adding anti-goat serum 0-01 Yo plus polyethylene glycol (Organon Teknika, Durham, N.C.) monkey IgG to the JET to Final Concentration 70.000-000010 Gram Molecular Weight polyethylene glycol

to *,? 104 μg. Extraction is done by centrifugation. This titration works in a range of canine growth hormone per tube. injection into cha) The compounds in this invention can be administered orally and non-orally ed intramuscularly into the peritoneal membrane; into a vein under the skin or by implant); Nasal; Formulated with a pharmaceutically approved carrier for administration (Sag rectal; sublingual or surface routes) 0 dosage forms appropriate for each route of administration. Solid dosage forms for oral administration include capsules; tablets; Pills, powders and granules In these solid dosage forms, the active compound is mixed with at least one of starch or starch, lactose, sucrose, sucrose, Jie, an inert, pharmaceutically permitted carrier. These dosage forms also include as in normal application additional substances other than these diluents. Pills and tablets may be further prepared with an enteric outer coating. Suspensions; Jad Liquid doses for enteric administration include lozenges; syrups; approved elixirs containing inert artefact diluents such as ve water In addition to these inert diluents, the compounds may also contain additional substances such as wetting agents, emulsifiers, and with flakes and sweeteners; Flavor and odor. The compounds according to this invention for non-intestinal administration include pure aqueous solutions, propylene glycol Jie and non-aqueous; suspensions or emulsions. Examples of non-aqueous solvents Vegetable oil, such as vegetable oil, polyethylene glycol, propylene glycol 0, organic injectable esters and esters, gelatin, olive and corn oil; Gelatin, such as ethyl oleate 18 and 01 _ Alaa. These dosage forms may also contain additional substances such as preservatives; wet Emulsified and distributed. They can be sterilized by, for example, filtration through a bacteria-trapping filter or incorporation of sterile materials into formulations; By (JB) exposure of the formulations to radiation; or by heating the formulations. Also they may be made into solid, sterile Ye formulations which may be dissolved in sterile water; or some other sterile medium which is injected immediately prior to use.

1y Compositions for rectal and vaginal administration are preferably suppositories which may contain; in addition to the active substance. formulations administered intranasally or sublingually are also preferred with standard affinities well known in the art. The doses of the active substance in these formulations of the present invention may vary but ; The important thing is that ° we get the amount of active substance in the form of an appropriate dose. The doses chosen depend on the desired pharmacological effect; By way of ingestion” and for a duration of mg/kg of body weight in 1001 treatments. in general; Dose levels between 0009 to today are administered to humans and other animals; The preferred dose ranges from 1 to © 101 mg/kg body weight per day, which can be taken as a single dose or divided into several doses. The preparation of Formula 1 compounds in This invention can be made by sequential or combined formation methods. The formations that explain the preparation of formula 1 compounds in a sequential form are shown in the reaction programs shown below. Many protected amino acid derivatives are commercially available as the protecting groups are vo ethoxy benzyl benzyl “CBZ BOC and 2200 be for example; 7100 Prt groups The otosyl or trityl tosil “TROC (FMOC ¢-CF3C(O)” ethoxycarbonyl carbonyl oxo-Yan derivatives of other protected amino acids can be prepared by written methods. The 4-oxo-?-carboxyl 3-0x0-2-carboxyl pyrrolidines carboxylpyrrolidines-" pyrrolidines are commercially available and pyrrolidines 4-0x0-3-carboxyl piperidines 0-substituted related are known in the literature. - 4 other piperidines and piperidines

Prt Many of the programs described below describe compounds that contain protect groups that can be removed by benzyloxycarbonyl and 2200. The benzyl oxycarbonyl groups 0 in the presence of a palladium hydrogen catalyst can be produced in several ways, including; Catalytic hydrogenation with hydrogen methanol 00808001. Jie catalysts in protonated solvent platinum, palladium ve or palladium carbon on palladium hydroxide preferred is palladium hydroxide psi 0001-1 Ali Carbon «©8:00. The hydrogen pressures of palladium

1y is a pound per square inch. in an alternative way The group 70-01 can be employed to prefer pressures than it can be removed by hydrogenation of the carrier. benzyloxycarbonyl benzyl oxycarbonyl can be done using a strong acid such as tertiary acid BOC The removal of protection groups with or without hydrochloric acid or hydrochloric acid trifluoroacetic acid fluoroacetic ether cethyl acetate ethyl acetate “dichloromethane” the presence of an auxiliary solvent such as dichloromethane © at a temperature of about -<10”*C to 007*C preferably about methanol Or methanol ether -** C to about ©7 "C. It can be removed by several methods, amines from amines, benzyl esters, benzyl esters in palladium, in the presence of a 4 hydrogen palladium catalyst Catalytic hydrogenation with hydrogen includes psi 0001-1 may use hydrogen from methanol a solvent such as methanol 0 psi Addition and removal of protection groups Ve to 10 pressures of Other Juni discussed by: 1. Greene in Protective Groups in Organic Synthesis, John Wiley & Sons, New

York, 1981.

PRNA MG 1 144 R34—N—Prt 5 1 S No 4 (CH y WHO) (CHa nit i — yalla COOH LKR NN 0 \ 0 N -Npo 2 3 ¢ 2 ¢ |[ ¢ RiX40 RS vert 0 base repair RS 00 00 HOOC-R6-N-7200 N.w HC) (CH2)n 5 1 wH2C) ( ) CH2)n Hla Nla 0 \ 0 \ um N-N_, N-N 6 3[ 4 ¢ RixX40 RS Tech El Ta CO Ns w(H2C) (CH2)n Najla 0 \ um N-N 7 program: 1 The protected amino acid derivatives 1 are available in several cases (lat where the protective group Prt is; for example “Jia FMOC groups” BOC or .CBZ 0 Other amino acids can be prepared by methods described in the literature.As shown in program 1 of the recombinant procedure a conjugate of 1165 amines of formula Y with protected amino acids of formula 10 where Prt It is a suitable protection group; in an inert solvent tie dichloromethane or DMF by means of a reagent consortium such as EDC or DCC in the presence of HOBT or 101. In the case of the presence of the amine As hydrochloride salt 0 it is better to add one or two equivalents of a suitable base such as triethyl amine to the reaction mixture to. By the Say Aly method, conjugation occurs with a recombinant reagent BOP Jie in an inert solvent such as methanol 06018001. Conjugation reactions generally take place at temperatures

Raised a temperature from about Alem to about 880*C; Preferably -100*C to about ©7*C. For a discussion of other terms used to combine peptides see: Houben-Weyl, Vol.

XV, part II, E.

Wunsch, Ed., George Theime Verlag, 1974, Stuttgart.

Still, M.

Kahn and A.

Mitra, J.

Org.

Chem. 43 2923 1978) by crystallization or crushing. Can a compound transfer be made from the formula? to intermediate compounds of Formula 4 by removing the 0 protecting group as described above. (Say) Conjugation of intermediates of formula ; into amino acids of formula © as described above to give intermediates of formula a Removing the amine protection 1 amine yields compounds of formula 7. Program 1 RS OOC- R6-N-7200 RAX4 RAX4 RAX4 H 5 »= ——— COOH COOR COOR H 9 8 ¢ 1 [3 H,0) CH (Hn qom and 0 vartem RS and curtem LG 66_70 1-60 727 11 JH R3+N—LRON-Z COOR COOH 0 N-N 2 KX 2 11 16 RS 0 CURT RIX40 RS R34+ —N—LRO-N-H 60 µl CO CO a l (wH20) (CH2)n > wH20) (CH2)n yPa “SR 0 0 N-Np, m 1-3 7 ¢ 6 ¢ v0 program iY alternatively; Compounds of Formula 1 can be prepared by a one-way route as shown in the program “. Intermediate esters of Formula A can be prepared by processing

amino acids 0, where protecting group is an appropriate protecting group; With a base such as potassium carbonate then an alkyl halide such as jodomethane in a suitable solvent DMF Jie removing the protection of the amine JIB compound + to compound A by the method of (Aly), many Amino acids of formula 9 are commercially available Intermediate compound 01 0 is generated from the conjugate of compound 9 to an amino acid © The ester of intermediate compound 01 can be converted to the intermediate acid 11 by a number of known methods In the art; for example, 006191 methyl esters and a wethyl ether of lithium hydroxide can be hydrolyzed in a protonated solvent Jie aqueous methanol or aqueous THF at a temperature of about Ble to Asi Ye preferably about 0 °C to 0 *" °C. In addition 0 to this; removal of de gana benzyl can be achieved by a number of reductive methods including hydrogenation in the presence of a platinum or palladium catalyst in protonated solvent such as methahol.Then the acid 11 can be combined into an amine ?to give intermediate compounds of

Formula 6. The transition of compound 1 to compound 7 can be achieved by removing de gana of protection 2200.

program ? COOH m001 CO CO CILX40 RE CH,X4O RS R3-N—L-R6-N-7200 RON Lge Nz200 HNX!clap 00 wah CO Ns 1 wH2C) (CH2) n wH2C) (CH2)n Nella Nella 1 \ NN © DL 'R2 12 2 6 NX 1 NX 1 0 00 RS CH X40 RS and TARMUS 6 spots R34-N—LLRO-N -7200 CO CO Ne —_—) XN.w(H2C) (CH2)n w(H2C) (CH2)n yba yba \ \ N-N, 0 N-N 0 1 1 15 (14 programs) “: esters of formula 1 can be converted into intermediate acids of formula VY by a number of methods known in the art; for example, methyl or ethyl esters can be hydrolyzed with Lithium hydroxide in a protonated solvent such as manic methanol or THF ambient at a temperature from about 0 45007 to 1"0"C; preferably about sie sia to 0**C. In addition to that Removal of the benzyl group can be achieved by a number of reductive methods including hydrogenation in the presence of a platinum or palladium catalyst in the protonated solvent Jie methanol 016168001. The conjugation of the acid VY to the amine amine 11 0 Generates intermediate compounds of formula VE Compound transfer can be achieved; 1 L Compound 11 by removing the Z200 protection group

TA

program; 0 4-4

HO-N 8 RX sold 0 L.E

RS 0 1 COOH RS x4 0 R8 Plaster of Nations §0 1 | pol NL pe 7200

QCOOH

N, oo 17 17 Program: Esters of formula VY can be prepared by treating an acid of formula © with hydroxysuccinimide in the presence of a conjugate agent such as EDC in an inert solvent Jie methylene chloride as shown in the program. Treating a VV ester with an amino acid of formula 1 in a solvent such as THF “dioxane” or DMF in the presence of a base such as diisopropylethylamine yields compound 11.2 G ali ax —. AL M oo Prt” CL HOS “NH, — 0 18 19 20 1 Program 10 As shown in Program © The alkylation of diphenyloxazinone of formula VA with cinnamyl bromide In the presence of sodium bis(trimethylsilyl)amide it generates compound 19 which converts to (0)-7-amino = 0-(D)-2-amino phenylpentaenoic acid -5-phenylpentanoic acid (PAC) to remove the protecting group and hydrogenation over a catalyst 0

Program M 1 0 0 CO,Me CO,Me , Base Rl R”NHNH, .1 N 2. RIX N 4 > 00 0 22 ¢ 00 p 23 21 R? R? / / N-N N-N, S E Go R! R!8 l R2 Lawesson Reagent—¥ 7! N J 2 027 0 E R!N R? L100 / 0 | 25 R! N H 28 Program: 1 Treating an ester of formula 11 with a base such as sodium hydride in a solvent such as DMF and then an alkyl halide YY an alkyl halide generates a compound of formula 0 ?? As shown on the TV program Treating a compound of formula YT with a hydrazine of formula Jie YE hydrazine or methyl-hydrazine in a reconstituted Jie ethanol solvent condensation Followed by concentration and heating of the residue in toluene at temperatures with or near vapor re-condensation yielding a compound of formula Yo. Alternatively, compound YY can be treated with a salt of hydrazine in the presence of sodium acetate. acetate 0 in ethanol whose vapor is re-condensed to give compound ©?. Removing the amine protection generates a compound of formula YA that can form thioamides of formula 17

First, by treating the YO compound with a Lawesson reagent in toluene or recondensed benzene. Removing protecting group Ji compound 176 to XY compound program Mg 7 2 0 CO,Me Nh R?NHNH 0 Base 1 . 2 N 24 2 RX | h 00 N h 00 29 21 R?R?N-N N-N 0 0 — R!N R h 00 N 22 25 0 Program 7: The treatment of a compound of formula 71 with hydrazine of formula YE in recondensed ethanol Jie solvent; Followed by concentration and heating of the residue in toluene at temperatures with or close to re-condensation of the vapor resulting in compounds of the formula AKD by the Aly method. The YO compound can be treated with a salt of hydrazine in the presence of sodium acetate In ethanol whose vapor is recondensed to give a compound YA, an amide 0 p010e of the formula YA can be treated with a base such as sodium hydride in a solvent DMF Js followed by an alkyl halide and an alkyl halide compound YO Removing the amine protection yields a compound of formula YA

except program A NH, 0 0 Ph] wn OMe Me 0 Lowe 0 GC CO, Me 3 ¢ R! 2 NH, N R NHNH, Phu Pho 24 OMe __— 37 m eq.

CHO 1 a CH, 31 R? / R? is N / 0 p ~N R! Hy ) 0 R! WH N nl Ph H Me 34 33 1A mali The reaction of the ketoester of formula 01 with a chiral amine as Alpha-methylbenzylamine alpha-methylbenzylamine with a suitable aldehyde Je 0 formaldehyde or the reaction of a keto-phenyl ester: 61061 vinyl of formula “1” with a chiral amine such as Alpha-methylbenzylamine with a suitable aldehyde Jie formaldehyde gives a compound of formula YY through a double Mannich reaction. The reaction of a compound YY with hydrazine generates A chiral compound of formula YY. Removal of nitrogen protection with hydrogen and a suitable catalyst such as 0 palladium yields compounds of formula YE.

No program q m OH m © yg and CO, Et CO, Et 00 5 00 % 82« 81 OPrt* OPrt* R! R!C F CO, Et CO,H MN 00 00 A 84« 82 OPrt* OPrt* R R CO,H CO, Et F — N N 7100 7100 86« 85 OH 0 C R CO, Et CO, Et — and N N 7100 280 8 8 ¢ 7 8 ' R? R? NNO NNO — R R! N ps H “44 Program: Treatment of a compound of formula A with a sodium borohydride reducing agent and nitrogen protection yields a compound of Formula 87. The protection of the alcohol alcohol gives compound 87. Saponification of the ester: 8518 gives a compound of formula AE. The reaction of compound Af with thionyl chloride followed by treatment with diazomethane gives a similar acid of Formula LAC The esterification of compound 85 gives a compound of formula AT which undergoes deprotection-0 to give compound 87. The oxidation of compound AY gives

A ketone of the formula LAA The reaction of compound AA with hydrazine followed by removal of nitrogen protection yields a compound of the formula £4 mg 001 0 0 0 Aco R A CO,R L Base 1. —_— Ray n( INN Ww no hand 2.(RO),CO n( l n( AN Prt rt H 37 3€ 35 0 Program :01 N Treating a compound of formula V0 with a base such as sodium hydride in a solvent DMF Jie followed by treatment with diethylcarbonate generates an ethyl ester from compound YT The removal of the amine Alea amine converts compound 1 to compound XY Program AR 0 0 o CO,R OEt 1. Base Play Sp n( NN 0 2. H, n( In yw 7100 and 9 7100 CO,R 3 CO: 1 39 W A CO,R n()< N Ow H 40 0 Program: 11 N malonic ester treatment ester of formula YA with a base such as sodium hydride in a DMF Jie solvent and subsequent hydrolysis of a benzyl group with hydrogen and a palladium Jie catalyst in a suitable solvent such as methanol methanol produces an ester of formula (YA) The removal of les amine is amine Generate compounds of formula m

Our program VY Rahm 0 R! 1 R aS with semen charge 2.11 N 00 l 200 42 41 3[ ' R? R? o RO 0 A 0 oN 0 for 2111111 in | AA Qo God N N p 00 H 200 44« 43 Program VY The treatment of a ketone of formula 41 with a secondary amine such as piperidine in a suitable solvent Jie Benzene with water removal gives enamine (enamine 0 formula 47. An alkyl enamine with an alpha-haloester such as ethylbromoacetate in a suitable solvent such as benzene or THF using a suitable base LDA Jie or f(11011)511/16 gives a ketoester of formula '. Reaction with hydrazine of formula YE gives the compound of formula 44. The removal of the nitrogen protection Nitrogen gives compounds of formula 46.1 pRNA mg lm co,Et 0 0 CO, Et Ph,I" 05 07 Ph 3CO, N 2 t-BuOH 7100 00 3 6 37 R? R? / / N-N N-N 0 | 0 — Ph Ph N.

N 100 Hus 20 Program: 1 “dallas is a ketoester of formula 1” with an iodonium salt as Jud diphenyliodonium trifluoroacetate 11101010866116 in solvent

Suitable for Jie +- butanol t-butanol generates a ketoester of the formula LET The reaction of compound 7 with hydrazine generates a compound of the formula LEY The removal of nitrogen protection gives compounds Of the formula ¢£A see 709 (Synthesis, (9), 1984 p. for a detailed description. AR Program 8E 0 0 CN (NO) Pr CO, Et CN (NO) > N HY N 00 27 00 2 49 ¢ 7 3 2 2 / m N-N N-N 0 | — 0 CN (NO,) CN (NOy) N H 00 l e 51 50« VE Program Treating a ketoester of Formula 17 with an acrylonitrile Jia olefin generates a ketoester of Formula 4. The reaction of £9 with alg hydrazine A compound of formula 0. Removing the nitrogen protection yields compounds of formula 0 (vi

Yo Berna Mug 0 0 084

CO, Et <> and A 00 A 00 37 2

R? R? // 0 is 0

CHO

~~ —> — for N 100 00 z SB 2 «54

R? R? //

N-N N-N 0 | 0

CO,H is NH, Yb 20 55 Mao 6

R? R? //

N-N, N-N, 0 | 0

H 6+6 H 6-6 1_5 Hl Nxx hd nd

Nioo 0 N 0 2.6 57 Ho 5g allyl bromide with allyl bromide 717 of the formula ketoester program 130 The treatment of the keto ester gives DMF in a suitable solvent such as sodium hydride Jie and a suitable base A compound of hydrazine is generated by the reaction of © with hydrazine, the ester keto: 16606516 of the formula, ozone 02006, in a suitable solvent such as methylene chloride of the compound dallas of the formula, dimethylsulfide, followed by treatment with A reducing agent such as methylene chloride of formula 84. The oxidation of compound 08 gives an aldehyde carboxylic acid giving an aldehyde of formula ©©. A brief rearrangement of compound 00 followed by hydrolysis of carboxylic acid of formula 06. The treatment of the primary amine with isocyanate 16 gives primary amine 0 giving urea 768 of formula 07. The removal of isocyanate is compound of formula 071 with isocyanates

OA from formula GUS jo gives nitrogen protection

Lal Program Mg 5 ‎R? R? / / N-N N-N 0 | 0 for “ CHO > ~ NX Noo “59 54 mL R? R? / / N-N N-N o 9 | 0 and L or NHX® N X 6 6 Doo ' 60 Noo ' 61 X R? / N-N = vo x Mi 1 Program: 11 N Composite Treatment of formula 4© with a primary amine gives an imine of formula 8. Reduction of a compound of formula 09 gives a compound of formula 1. A 0 treatment of a compound of formula 61 with an acylation agent gives a compound of formula 1. Removing the nitrogen protection yields compounds of formula AY with an encapsulated program R? R? / / N-N N-N 0 | 0 “D JP CHO i 63 ml 4 1 ml R R / / N-N, N-N, Mohlam Thi 176 0 Les 0 68 L in Doo Program AY The treatment is composed of Formula o¢ with reducing agent Je sodium borohydride 0 gives a compound of formula LAY The reaction of compound 7 with an acylation agent such as

Ya

Removing gE gives compounds of formula carbamate or carbamate isocyanate isocyanate 10 gives compounds of formula nitrogen lea

YA Barna Mag

R? R? (CL

N-N N-N 0 No 0 o _ ET L PPh;, DEAD ~TSN l 00 l 00 63 5 / R «66

N-N 0 o 7 HS N

N

H

“67 Jie phosphine. Treating a compound of Formula 17 with phosphine DA program 0 diethylazodicarboxylate and a diethyl azo dicarboxylate compound triphenyl phosphine nitrogen. Removal of the nitrogen protection IN gives a compound of formula oxindole And oxynidol AY gives the compound of the formula va 8 program mg 0 0 0

CO, Et CO, Et

R 1. R'X 2.11 1 1 27 00 27 00 37 «68 0 R? 0, Et / “a, N-N “R' yeh | and

N 4 7100 1 «69 L 00 / R? 70

N-N 0 “u Rl i 71 chiral diol with chiral diol TV of the formula ketoester program 119 The treatment of the keto ester gives ketalcare the benzene and an acid catalyst with the removal of water in a suitable solvent such as benzene in the presence of An alkyl halide with an alkyl halide TA that the alkylation of the LTA compound of the formula chiral ketal 0 chiral sa gives ketal esters followed by hydrolysis catalysis - an acid for the ketal LDA base such as generates hydrazine compounds Of Formula 1 The reaction of compound 15 with hydrazine chiral ketoesters yields compounds of formula nitrogen protection aly) N.70 of chiral formula AA

Program mouth 01 t-BuO> SON 0 CO, Et X NH 1. Base t-BuO2C” “NH; COEt 2 RX 1 3.H No Noo 00 A z 2 37 R? J 0 Et 7 ,0 0 and “Rl R! b R N 4 for 7100 70 69« R? ed / N-N 0 1 N H 7 Program: 01 The treatment of the ketoestor of the formula TV with a Jie chiral amino acid ester valine ester -t valine t-butyl ester gives a chiral enamine of formula 77. The alkylation of VY compound with an alkyl halide in the presence of LDA Jie base followed by catalytic-acid hydrolysis Enamine gives JIS chiral esters of formula 18 The reaction of compound 64 with hydrazine generates chiral compounds of formula WY The removal of Alea nitrogen gives compounds of formula RA

A

AR Berna Mag

R? 12 / / Y N-N 0 E 0 —_—

R! R

N N

Ho Hoe nah R? > / 1 8

I (Co 0 ol) crystallized Rl

R! N

N. . H*chiral acid

H * chiral acid 70

R? rd 13 / Base

N-N0

K’R! for 4

YA yield compounds of formula Yo of a nitrogen compound Program 1?: The removal of the nitrogen protection gives a mixture of chiral acid JS salts with TA acid forming a salt of the ied da ld compound to crystallize Salts of VY substances of the formula diastereomeric salts stereoisomer. If the decomposition of .71 of the formula chiral gives an acid salt of diastereomeric salts

RA of the formula chiral salt nor with a base releases chiral compounds

AY

YY Program R? R2

A HA

L cel[ - RT S"SN0Ac 0 L _ E and

Pd(PPh;), Hala R

Pi 00 to 00

R2 2 // N-N 0 1 N\—R

NN R N

N H

7100 (74 75 allylic acetate with lylic acetate YO). The alkylation of compounds of formula 1YY is palladium tetrachys (dimethylphosphine) Je in the presence of a suitable catalyst to give compounds of formula 7; palladium tetrakis(triphenylphosphine) eo (Tetrahedron (50) p. 515, 1994) give compounds of formula 45 see nitrogen

AY

9 Barna Mag

CO, Et 1 2 1. Base, RX R 2. Acid tp — 3. CH;l, Base 0 COE (R' = benzyl) 0 CO,Me 76 77 0 Re 1 and | And no 016 _ 8

Ph1

Ph. 78 792

R?

NNO od

N

H

“80 with alkyl halide V1 of the ketodiester formula. The treatment of the keto diester YY program is followed by catalytic hydrolysis - sodium hydride in the presence of a base such as alkyl halide and an appropriate base that gives methyliodide acid and decarboxylation; followed by esterification with methyl iodide 0

Jie suitable aldehyde with aldehyde VV The reaction of a compound of formula YY a compound of formula and benzylamine 6 gives a compound of formula 8. The reaction of formaldehyde with formaldehyde of formula 79. A chiral is generated Keral hydrazine compounds with hydrazine VA is a compound of the formula

Av compounds of formula give nitrogen removal nitrogen protection

At 164 Program 0 R 0 for LASER

N R H

0BSN

R

N3>

N + CO,H > RE” ~z20 c R 0 0

H x4 (CH,)w™ "> (CH,),

R! 23 RE R 0 «89 0 R 0 R 4

R* R* f 0 c R’ 0 h (CH), (CH) N(CH),

R! R \ 0 WW

N Ng SR? ' ¢ 7 in an inert solvent 11 with acid of formula YY of formula amine Treatment of amine YE program or EDC Je with coupling reagent DMF or dichloromethane Jie with Ad The reaction of compounds of the formula LAA gives compounds of the formula HOBT in the presence of DCC ° giving nitrogen generates compounds of the formula +. The removal of nitrogen protection is hydrazine

blood prona mg Yo 0 0 0 0 OH 0 OH NR 91 9 AR AR 1 —N N—N / ANP _ Aon OH R OH R 3 9 ' 92 ¢ JR 2 NN — 1 —N py / OR and AP on Xx RH CN HR 95 ¢ 94 4 2 N—N . . IN remove group J 1. R z —_— 0 OR 2.CH,0 Rl R NH H,N 28 96 1Y0 mali Hydroxyacetoacetate ester processing Sodium hydride of formula 0 with an alkyl halide in the presence of a suitable base, Jie, sodium hydride 0 yields compounds of formula 91. The reaction of 91 with hydrazine yields compounds of formula 7. The 0-alkylation of the carbonyl oxygen of compound AY gives compound AY which converts to halide 54. Substitution of the X halide with a cyanide ion yields nitrile 55. Reduction 40 yields primary amine 47 whose protection is removed and subjected to cyclization in the presence of formaldehyde to give compound JA

A

1 Program MG 0 0 py CO, Et > CO, Et

Boc—N Boc—N ~ A

H H 1 97 9g RK

R2 2 / R Asl F J / OH NN Shah 7 | 0 0 tn 5 and —

NH1R

R N

Boc NH, H 99 100 28 beta-keto-protected aminovalerate program *?: The treatment of beta-keto aminovalerate = protected sodium hydride Ja in the presence of a suitable base alkyl halide with alkyl halide ay as compound With A gives compounds of formula 58. Reaction of compounds of formula sodium hydride © 99 yields compounds of formula 44. Deprotection of compounds of formula hydrazine in 001 Recycling of compounds of formula .001 of the formula primary amines gives primary amines

YA gives compounds of the formula formaldehyde in the presence of formaldehyde

AY

Program 3 4 0 R: R Xt 0 0 Bab P then 8 PW Nain, (CHy)( (CH), HO, C we 2n

N 72 + 2 N CO,Me

H Prt mh o ' 0 23 ¢ 'A 0

R3 R4 x4 A R4 x4 0 N together be 0

N< to remove protection (CHa) SS WHC (CH) \ 0 \ 0

N-N N-N DBA RS R 23 HOOC-RO-N-72% 4 8 0 68 R3 for JL AAA A A

R3 +N —LRO-N-7200 R 3 co 0

No Remove Protect (H,C) “(CHa 20m (CH2)n.” No R! \ 0 Nya N-N

N-N 21 A 4 R 7 in the presence of 1 by an acid such as compound YY of the formula amine The processing of amine VV is a program of the formula ?" b. The keto-esters and 1101 in a suitable solvent give keto esters EDC in the presence of sodium acetate hydrazine B "can be treated with hydrazine salt ketoester 0 of hydrazines re-condensed vapor to give ethanol hydrazines in ethanol Sodium acetate of formula 4. The amines Deprotection under suitable conditions yields YY amines of formula © amino acids Intermediate compounds of formula can conjugate with amino acids

AA amine occurs as previously described to give intermediate compounds of formula 1. Removing the amine protection 7. gives compounds of formula The following examples are provided for the purpose of further illustration only and are not intended to limit the invention described. General experimental procedure ° 01 µm; 01 amicon silica used.

Buchi 510 perforation; For column chromatographic analysis. Melting temperatures are taken on an instrument and are not corrected. Proton and carbon NMR fields are recorded at Bruker AC-250 or Varian Unity 400 “Bruker AC-300” Varian XL-300 temperature ©1°C. Chemical changes are expressed in ppm of the field from Trimethyl 0 beam parts from a spectrophotometer JIS Ceylon P0701607151180. We obtain ical analyzers as a source of chemical ionization. To dissolve ammonia using ammonia Hewlett-Packard 5989 we obtain analyzes as a whole .methanol or methanol chloroform Aad chloroform Analyzer with Demonstrable Power Kratos Concept-18 from the Liquid Secondary Ion System (LSIMS) uses a mixture of binary 5:1 sprayed onto a dissolved sample of high cesium ion using cesium ion ve or in dithiothreitol and dithioerythritol .methanol methanol chloroform to dissolve the initial sample use chloroform 108170©01. Meters calibrated against cesium iodide YeoF The listed information They are obtained from E. Merck Kieselgel 60 F254 plates seen by TLC analyzes of silica iodide cesium (after Separation by solvent(s) required) by dye by 715 phosphomolybdic acid v. and heating on a hot plate. ethanolic phosphomolybdic acid Ethanolic phosphomolybdic acid 9-07 solution (EDC) using peptide of general procedure A (equivalent dichloromethane synthesis) in dichloromethane 1( primary amine ) of a primary amine — equivalent of 1,7-1 and primary amine hydrochloride (or equivalent primary amine hydrochloride of 1,7-1 acid) treated respectively by triethylamine ( vo equivalents HYDRIDE VAY, 0 OTHER BOTTOMATIC; carboxylic acid HOAT R (HOBT) hydroxybenzotriazole hydrate

1,YY equivalents (chemical equivalent of an amount of carboxylic acid -”(-1-dimethylaminopropyl)-”- Jf)carbodiimide hydrochloride (EDC) 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture is stirred overnight in an ice trough (the ice trough allows it to liad so the reaction mixture is kept at 0 temperature about hia 0 455007 for about 1-8 hours and a temperature of about 7-175"*C for the remainder). The mixture is diluted with ethyl acetate or other solvent as to be specified; the resulting mixture is washed twice with 1 N NaOH; twice with 1 N HCI (if the product is basic); hydrochloride from (AY) ¢ in which case triethylamine is used as an example 1 "-amino-21-(1(8)-benzyl oxymethyl-7-[©2-] (08-(?- Fluoro-Benzyl)-? -methyl-?-vo-exo-77:50722:7-hexahydro-pyrazolo[?;?-8]pyridine-*-yl]-7-exo-ethyl (-isobutyramide hydrochloride and 7-amino-7<-) 1(8)-benzyl oxymethyl-7-[2-(8)-(1-fluorobenzyl)-7"-methyl-7-oxo-75:5:27:27-hexahydro-pyrazolo[?;?- 8]pyridine-0—yl]-?-oxo-ethyl)-isobutyramide hydrochloride 2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)- 2-methyl-3-oxo- 2.3.3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramide \E hydrochloride and 2 -Amino-N-{1-(R)-benzyloxymethyl-2-[3a-(S)-(4-flucrobenzyl)- 2-methyl-3-0x0-2,3.3a.4.6.7-hexahydro- pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl } - isobutyramide hydrochloride (a);- oxo-piperidin-0*-dicarboxylic acid (tert)butyl ester”-ethyl Ester 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester Yo was stirred at room temperature for about 177 hours a mixture of A (g (YA0) milligrams) ) of ;-oxo-piperidin-7-carboxylic acid ethyl ester hydrochloride; YY g a. milligrams (TAL) g TAY 5 butyl dicarbonate” tert JS (milligrams) of the mixture concentrate and the residue was dissolved in THF milliliters of triethyl amine in aqueous sodium bicarbonate solution 700 Al HCL; ethyl acetate and washed three times each time with 1g of a solid color 01 and concentrated to give (MgSO, saturated; brine; dried over . 7777 (CI, NH;) MS White. Ester -©:-1 3-(R.S)-(4-Fluoro-benzyl)-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester

YAY In milliliters of 1117 add 01 mmol (1a in Vif) g Ye to a solution of 10 mmol) of sodium hydride (dispersible oil 170) and stir the mixture at Vif (mg) To the stirred solution a solution of 1.74 g (4,000 ml mol 11 at room temperature) of = fluorobenzylbromide was stirred in gram DMF in 7 milliliters of h at room temperature. The mixture was diluted with ethyl acetate and washed once VY for approx. and concentrated to give 7.8 g of MgSO, with water and four times with brine; dried over 1 (MH*) 0” (Cl, NH ;) MS hexahydro- —V Tefal Ve — fluoro-benzyl)-7-methyl-7-oxo —£)-(R,S)av(c)pyrazolo[;;?-6] Pyridine--carboxylic acid:©-butyl ester 3a-(R.S)-(4-Fluoro-benyzl)-2-methyl-3-0x0-2.3,3a.4.6,7-hexahydro-pyrazolo[4,3- c]pyridine -5-carboxylic acid tert-butyl ester 0 mMol 1 VY) g Y.08 hours mixture of A heated with re-condensation for about 100 milliliters of methyl hydrazine in TY (gram) of 1b and 7095 mg mL of toluene and heated with recondensation of 100 ethano to. The mixture is concentrated and the residue is dissolved in an hour. The mixture was concentrated and the residue was purified by vapor chromatography for about 1 vol/vol (ethyl acetate: hexane) to AVIVA silica gel using a graded separation of 1 g Yo from 1 g as clear, colorless oil. 1 vol/vol. The volume of ethyl acetate: hexane) to give MS (711 (0111) (0111) Yo:vo) NH3)

Hexahydropyrazolo[;;?-6] 17066564087 27-(5E0)-(;-fluoro-benzyl)-7-methyl-7:(3)pyridine-?-one-trifluoroacetate 3a-(R.S) )-(4-Fluoro-benzyl)-2-methyl-2.3a.4.5.6.7-hexahydropyrazolo[4,3-c] pyridin-3-one trifluoroacetate (mL trifluoroacetate 10 mmol) from c added VA) 1 g to fluoroastic at about 0°C and the mixture was stirred for about 1 hour. Ethyl acetate is added

MH") 7767 (CL, NH;) MS .d 1 g of 1 and concentrate the mixture to give (H)(8)-”-benzyl-oxy-7-(7-:©-butoxycarbonylamino-7- methyl-propionyl (amino)- propionic acid (R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)- Ye propionic acid 1 mL of Yo Benzyl-1-serine in -BOC-N (mmol) from (TY) g VAY to (1.0 mmol) potassium carbonate then 0.57 g (VE) 0.17 g is added DMF under ale milligram atmosphere) of iodomethane. The mixture was stirred overnight at approx. and extracted three times with ethyl acetate. cele mL Yoo nitrogen. The reaction mixture was diluted with ve washed organic matter united five times with water and once with brine; dried over and concentrated. Dissolve (8)-”-benzyl-oxy-7-©1-butoxycarbonyl-amino-acid in 1850 mL of cooled trifluoroacetic acid at about zero C 11 propionic methyl ester in 1 N NaOH and the mixture was stirred for about two hours. The mixture was concentrated and the residue was diluted with and extracted three times with ethyl acetate. The combined organic extracts were washed with a 0 mM solution of (8)-7-amino-£,0Y) 144 g brine and dried over 1182507 to give benzyl-oxy-propionic acid methyl ester the product that conjugates With 87 g (0.07 mM -* mole) of 0-300-17-methylalanine giving 1.80 g of (8)-3-benzyl-oxy-7-butoxycarbonylamino-7-methyl- propionylamino)propionic acid methyl ester.-tert-Y) water and add a solution of 728 mg (0.548 mL THF 1:4 mL of 01 in pall product Ye mL water is dissolved into the solution and stirred the mixture by 1 mol) of lithium hydroxide hydrate overnight at room temperature. The mixture was concentrated and the residue was diluted with ethyl acetate, acidified with aqueous ay, and extracted three times with ethyl acetate. The organic extracts were combined and the HCI washed once with brine; 111121 (CDCl; 300MHz) 6 7.30(m,5H), 7.10(d,1H), 5.07(bs,1H), 4.68( m,1H), 4.53(q,2H), 4.09(m,1H), 3.68(m,1H), 1.3-1.5(m,15H). ° oxymethyl-benzyl-7-[23-(5,8)-(?-fluoro-benzyl)-?-methyl-?- RYN)(f)hexahydro-pyrazolo[;6-7] pyridine-*-yl]-7-oxo-ethyl -1776046877:7-esco-butyl ester (tert-methyl-ethyl)-carbamic acid -1-((R)-(1-{1-(R)-) Benzyloxymethyl-2-[3a-(R.S)-(4-fluoro-benzyl)-2-methyl-3-oxo- 2.3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl [-2-oxo-ethylcarbamoyl}-1- 01 methyl-ethyl)-carbamic acid tert-butyl ester mg (+100 mmol) of VAT according to the method in general procedure (a); Mg (,91 ; mM) of 1H conjugates to give a mixture of stereoisomer binary materials. The residue 1197 and Da1 is purified by silica gel chromatography using a gradient separation of (111 volume]/volume (and 1 (the least polar) is 1 mg of the isomer 01 ethyl acetate to give 7000 ethyl acetate/hexane). to 1 of both isomers (MH*) 7 (and 1111,a©); MS (and 1) is more polar 1 mg than isomer 0011o benzyl-oxymethyl-7-[27-( 8-(?-fluoro-benzyl)-7-methyl- —(R))IN- sd -" (g) oxo-77042707:7-hexahydropyrazolo[;;?-8]pyridine-*- yl]-7-oxo-ethyl)-” isobutyramide hydrochloride 2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl -3-oxo- 9 2.3.3a.4.6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl }isobutyramide hydrochloride 10 mL ethanol added in (1,1) mmol) of the nV isomer) 10 mg to mL of 1101 concentrate and stir the mixture at room temperature for about 2 hours. Concentrate as a powder (1g) 1 mg of isomer 050 of the mixture and precipitate The residue from ethanol/hexane to give Ye .01117 (oY ¢ (Cl, NH;) MS) is white.

THNMR(CD;OD): (partial) 6 7.32(m,5H), 7.12 (m,2H), 6.91(m,2H), 5.15(m,1H), 4.54(s,2H), 3.78(m,2H), 3.02(m,7H), 2.66(m,2H), 1.57(s,6H).(h)7-—(R)VI-N-sind-7-oxymethylbenzyl -[23-(5)-(?-fluoro-benzyl)-?-methyl-*-oxo-7734007771-hexahydropyrazole[;;6-7]pyridine-*-yl]-7-oxo-0 ethyl)-isobutyramide hydrochloride 2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo- 2.3.3a .4.6.7-hexahydropyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl } -isobutyramide hydrochloride to 100 mg (+07 mmol) isomer of ? (1f) In 10 milliliters of ethanol add 0? milliliters of 1101 concentrate and stir the mixture at room temperature for about two hours. The mixture was concentrated and a residue of 10 aad ethanol/hexane precipitated from the isomer of ? (1H) As a white powder. MH") oY ¢ (Cl, NH;) MS THNMR(CD;0D): (partial) 6 7.32(m,5H), 7.08 (m,2H), 6.95(m,2H), 6.80(m ,2H), 5.30(m,1H), 4.61(m,3H), 3.80(m,2H), 2.58(m, 3H), 1.58(s,6H). x Example Y —£)-(R,S)-av]-Y]-N-sis —¥(fluoro-benzyl)-7"-methyl-3?- —Vleta@V VY — su Sof hexahydro-[ e-Ye £1 1s Jom pyridine-*-yl]-1(08-(111-indole-7-ylmethyl)-?- sus-ethyl[-isobutyramide hydrochloride 2-Amino-N-[ 2-[3a-(R.S)-(4-fluoro-benzyl)-2-methyl-3-o0x0-2,3.3a.4,6,7-hexahydro- pyrazolo[4,3-c]pyridin- 5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]- Y. isobutyramide hydrochloride —Y-R)(i)amino-7-[111-indole (-7-yl)-propionic acid methyl ester (R)-2-Amino-3-[1H-indol-3-yl)-propionic acid methyl ester to £87 g (Y1,Y) milligram) of -D-BOC-t-0-N tryptophan in lle 001 DMF (Yo added 7.47 g 1 V,A mMg) of potassium carbonate then 7.41 g VY (mM) of iodomethane; The mixture was stirred overnight at iil YE under nitrogen atmosphere. The reaction mixture was diluted with cola and extracted three times with ethyl acetate. tl material

United Organics five times with 9000 milliliters of water and once with saline”; It was dried over MgSO, and concentrated to give 5.17 g of a white solid. To (08)-6:1-7-butoxycarbonylamino-7-(111-indole-“*-yl)-propionic acid methyl ester crude Vo mL of cold trifluoroacetic acid at about 0”C was added and the mixture was stirred for about two hours. 0 suture concentrate, the residue was diluted with 1 N NaOH, and extracted three times with ethyl acetate. The combined organic extract of gall was washed with brine and dried over 1187507 to give (5)-7-amino-?-(111-indole-7-yl)-propionic acid methyl ester as an orange colored oil in quantitative yield. (b) ()-7-(16-7-butoxycarbonylamino-7'-methyl-7-propionylamino)-3 ?-(111-0,indole-”-yl)-propionic acid methyl ester ( R)-2-(2-tert-Butoxycarbonylamino-2-methyl-2-propionylamino)-3-(1H-indol-3- yl)-propionic acid methyl ester conjugate to the crude product of ?A 09 g VY ) milligrams) to 1.44 g (VY) milli-mol) of -0-BOCHN-methylalanine according to procedure (a) to give oil which was purified by 1 silica gel chromatography using a graded level of 6700 07700770 7450 and 25 ethyl acetate in hexane for the filtrate.Recover 1.77 g of (7-068-(16:1-7-butoxycarbonylamino-7-methyl-propionylamino)-7-(111-indole-7-yl) propionic acid methyl ester.(c)(8)-7-(7-©-butoxycarbonylamino-7-methyl-propionylamino)-7-(111-indole-*-yl)-(R)-propionic acid 2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)- Y. propionic acid to a solution of 0.17 g (1,14 lle) mole) of 7b in 10 milliliters THF Add TAY mg (9.1 milligrams) of lithium hydroxide hydrate in 7 milliliters of water and stir the mixture overnight at room temperature. 7 Excess is removed by evaporation; The base aqueous mixture, Yo, was extracted three times with ethyl acetate; then acidified to pH; With dilute acetic or hydrochloric acid. The product was extracted with ethyl acetate and the organic extracts qo g of 1 g were washed as a foam of color 0.17 and evaporated to give MgSO, combined with brine; Dried over (MH") 790 (Cl, NH3) MS orange. THNMR(CDCl; 300MHz) 6 7.61(d, 1H), 7.48(d,1H), 7.27(t,1H), 7.10(t , 1H), 4.81(bs,1H), 3.35(m,1H), 1.49(s,6H), 1.32(s,9H).fluoro-benzyl)-7-methyl-7-oxo-7:504087: 077- hexa —£)-(R,S)-a*)-Y[-V}(3) hydro-pyrazolo[?;8-7]pyridine-*-yl]-1-(08-( 111-indole-7-ylmethyl]-?-oxo-butyl ester tert carbamic acid {dB ethyl carbamoyl]-1-methyl-{1-[3-(3a-(R.S)-) (4-Fluoro-benzyl)-2-methyl-3-0x0-2,3,3a.4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-( 1H-indol-3-ylmethyl]-2-oxo-ethylcarbamoyl]- 1-methyl-ethyl}-carbamic acid tert-butyl ester Ve mg (00+ mmol) of VAY according to the method described in the general procedure ( a) The residue was conjugated and purified by X chromatography (aX mg (51 mmol) of Yoo-do vol/vol ethyl acetate:hexane) to ethyl acetate (VY) silica gel using graded separation of (MH?) 177 (Cl, (and 111 MS .2Y) mg of 7710 to give 0 oxo-Fd ie (e) = amino[055-21-1-(;-fluoro-benzyl) -?- 0 hexahydro-pyrazolo[?7-H]b Ridin-*-yl]-1-(08-(111-indole-?-7:27 yl-methyl)-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-[3a-] (R.S)-(4-fluoro-benzyl)-2-methyl-3-ox0-2,3.3a.4,6,7-hexahydro- pyrazolo[4.3-¢]pyridin-5-y1]-1-(R )-(1H-indol-3-ylmethyl)-2-oxo-ethyl]- isobutyramide hydrochloride Y. Milliliters of ethanol added; 01 in 10 milligrams (of YT) to 771 mg milliliters of 1101 concentrate and stir the mixture at room temperature for about two hours. The mixture was concentrated as a white powder of AY 111 mg and the residue was precipitated from ethanol/hexane to give (0111 oYY (Cl, NH;) MS).

ITHNMR(CD;0D): (partial) 8 7.79(d,1H), 7.48(m,1H), 7.33(m,2H), 7.19-6.77 Yo (m,7H), 6.54(m,1H), 5.17 (m,1H), 4.02(m, 1H), 3.11-2.68(m,6H), 2.47(m,2H), 2.03(m,2H), 1.59(m,6H).

Example » ¥— amino-7[1-1-(8,572-87)-_benzyl-7-methyl-?-oxo-7000568707:7-hexahydro-pyrazolo[;;?-6]pyridine-*-yl)- 1168-(111-indole-?-yl-methyl)-?-oxoethyl]-isobutyramide 2-Amino-N-[2-(3a-(R.S)-benzyl-2-methyl-3-0x0-2.3.3a). 4,6,7-hexahydro-° pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxoethyl]-isobutyramide (a); 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester to a mixture of 7 g (YY) milli-mol) of 4-oxo-piperidine-?"- 0-carboxylic acid methyl ester AMY (g lle YLT) mole) of 4©;-dimethylaminopyridine in 70000 Milliliters of methylene chloride at about 0”C a solution of 1.88 g lle YY (mole) of tert HB butyl dicarbonate in 101 milliliters of methylene chloride is added over about 0” minutes. ly the mixture to room temperature and then anneal for about wo hours. the mixture was concentrated and the residue was diluted with chloroform and washed three times with ila 110170 0 saturated aqueous sodium bicarbonate solution and brine; It was dried over 14880, and concentrated to give 4 g of pure yellow oil. (b) *-(8,5-benzyl-;-oxo-piperidine-701-dicarboxylic acid -1:-1 butyl ester =F Methyl Sind 3-(R.S)-Benzyl-4 -oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester Y. To a solution of 19.4 g (milligram)?a in 01 ml DMF was added 145 mg Vo (mmol) of sodium hydride (oil dispersed 47) and the mixture was stirred at room temperature for about 11 minutes. A solution of 3.97 g (19.4 mmol) was added. of benzylbromide in 11 milliliters DMF to the solution stirred with a syringe and the mixture stirred for about EY vo hour at room temperature The mixture was diluted with ethyl acetate and washed once with water and four times with brine; dried above 850 and concentrated to give 1 g of GF as a yellow oil. (MH") Y£A (CL, NH;) MS av benzyl-?-methyl-7-oxo-72:587:7-hexahydropyrazolo ‎ ~(R,S)-a¥(c)butyl ester tert[4,6-7]-pyridine-*-carboxylic acid 3a-(R.S)-Benzyl-2-methyl-3- 0x0-2,3.3a.4,6,7-hexahydropyrazolo[4,3-c]-pyridine- 5-carboxylic acid tert-butyl ester H. Mixture of; g (11.0 mmol) Rami) of A ad heated with re-evaporation of 0 mL ethanol. Concentrate 100 mg (11.0 mmol) of methyl hydrazine in 0 5 ml of toluene and heat with vapor re-condensation for about 100 minutes of the mixture and dissolve the residue in an hour. The mixture was concentrated and the residue was purified by silica gel chromatography using VY separation. Volume/volume of ethyl acetate: (Y0:V0 (volume/volume of ethyl acetate: hexane) to A0IVO) graded from

MH") 44 (Cl, NH;) MS as a clear, colorless oil. at hexane) to give 7.6 g of 0-benzyl-7-methyl-7654:87:71-hexahydro-pyrazolo [;; 6-7] pyridine- —(R,S)=aV (d) ov 3a-(R.S)-Benzyl-2-methyl-2.3a.4.5.6.7-hexahydro-pyrazolo[4.3-c] pyridin-3-one milliliter of triglyceride 01 milligram af) of VT) is added to 7.60 g of fluoroacetic at about 0 °C and the mixture is stirred for about two and a half hours. g of standard VA; dried over 14850 0, concentrated to give 1 NaOH and washed the solution with Ji (MH*) 74 (Cl, NH;) MS *d (e) (1-[7- (©97-2,-_benzyl-7-methyl-7-oxo-725870707-hexahydro-pyrazolo[;;6-7]pyridine-*-yl)-118-(111-indole-7-ylmethyl) )-7-oxoethylcarbamoyl]-butyl ester tert carbamic acid {df methyl--1|0 {1-[2-(3a-(R.S)-Benzyl-2-methyl-3- o0x0-2,3,3a,4.6,7-hexahydro-pyrazolo [4,3-c]pyridin-5-y1)-1R-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl]-1-methyl- ethyl} -carbamic acid tert-butyl ester mg (£1.1 mmol) of 170 according to the method in general procedure (a); conjugate mmol ) of “7c” and the residue was purified by analysis of 01) g MYO aYxo silica gel chromatography using a gradient separation of (17 vol/v ethyl acetate: hexane) aT 101 mg to 797 methanol in ethyl acetate to give aA hexa —Velef@l ro — gu So methyl-?- —Y=diju —(R,S)=a¥)-Y]-N- sid -7 (5) indole-? - ylmethyl)-7'-oxo — ethyl]-(-1H)-TR-(s-hydro-pyrazolo[;?-6]pyridine-* isobutyramide hydrochloride 2-Amino-N-[2 -(3a-(R.S)-benzyl-2-methyl-3-0x0-2.3,3a,4.6,7-hexahydro- pyrazolo[4,3-c]pyridin-5-y])-1R-(1H-indol -3-ylmethyl)-2-oxo-ethyl]-isobutyramide 0 hydrochloride ethanol Add 10 milliliter (le 10 milligrams) of *e in 11 051 mg TE) to the concentrate and stir the mixture at 0°C room temperature for about ? hours. The mixture concentrates and the HCI crystallizes

MH") 01 (CL, NH;) MS .5¥ mg of 001 ethanol/hexane residue to give

IHNMR(CD;0D): § 7.20-6.91(m,9H), 6.56(m,1), 5.17(m,1H), 4.05(m,1H), 2.965 Ve 3H), 2.62(m,1H), 2.38(m,1H), 2.06(m,2H), 1.61(m,8H). £ Example benzyl-7-methyl-7-oxo-77:527:67:7-hexahydro- —(R)=a¥)=Y]-N-sisal -"pyrazolo[;;" -8]pyridine-1-yl)-1-(08-benzyl oxymethyl-?-oxo-ethyl]- isobutyramide hydrochloride and 7-amino-7-[7-(23-(6)-benzyl-7) Methyl-?-oxo-hexahydro-pyrazolo[;;6-7]pyridine-*-yl)-1-(08-benzyl-oxy” Vee allelel Methyl-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-0x0-2.3.3a.4.6,7-hexahydro-pyrazolo[4,3-c]pyridin-1-y1)-1 -(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride and 2-Amino-N-[2-(3a-(S )-benzyl-2-methyl-3-0x0-2.3.32.4.6.7- Y hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]- isobutyramide hydrochloride hydro-Lu Sa - 54 7: benzyl-7- methyl-?-arrocamro-t —(R,S)—a¥)-Y¥]-) } 0 pyrazolo[?;?-6]pyridine-*-yl)-1-(08-benzyloxymethyl) -7-oxo-ethylcarbamoyl]-butyl ester tert carbamic acid {df methyl- -1 Yo

{1-[2-(3a-(R.S)-benzyl-2-methyl-3-0x0-2.3.3a.4.6.7-hexahydro-pyrazolo[4.3-c] pyridin-5-y1)-1 -(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl }- carbamic acid tert-butyl ester according to the procedure in the general procedure of) conjugate VY g (£51 mmol) gram) of 0 “ag and #la, 1 g (1.0 millimole) of 1 e to give a mixture of stereoisomer binary materials. The residue was purified by silica gel chromatography using a gradient separation of fan V1 (ethyl acetate volume: hexane) to ethyl acetate 7001 to give Tor mg of the less polar isomer 1 (?a)

You i mg of the more polar isomer 7 (4a). (MH*) 011 (CLNH;) MS for both isomers. (b) “-amino-1-[7-(27-(08-benzyl-7-methyl-?-oxo-7056652767:7-hexahydro-feet lds don 0pyridine-*-yl)-1-) (8)-benzyl-oxymethyl-?-oxo-[Jf isobutyramide hydrochloride 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-0x0-2,3.32) .4,6,7-hexahydro- pyrazolo[4,3-c]pyridin-5-yD-1-(R )-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride to Yor mg EY) milligrams) of 1 isomer (;a) in 11 milliliters of ethanol add © milliliters HCL concentrate and stir the mixture at room temperature for about © hours. The mixture is concentrated and the ethanol/hexane residue precipitates and dried by vacuum to yield 171 mg of the isomer 1(kb).e(CL,NH;)MS T L(MH*) - IHNMR(CD;0D): § 7.33(m,5H). ), 7.14(m,5H), 5.22(m,1H), 4.57(m, 3H), 3.80 (m,2H), 3.14(m, 1H), 3.04(s,3H), 2.96(m, 2H), 2.61(m, 1H), 1.63(m,7H).0(c)—Y amino-7<-71-(27-(98)-benzyl-?-methyl-3- − Velefaalel oY = gu Sof hexahydropyrazole[;;?-6]pyridine-*-yl)-1-(04-oxymethyl-7-oxo-ethyl]-isobutyramide hydrochloride [2-Amino-N-] 2-(3a-(S )-benzyl-2-methyl-3-0x0-2.3.3a,4,6,7-hexahydro- pyrazolo{4.3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo -ethyl]-isobutyramide Yo hydrochloride

Yeu milliliters of ethanol 11 mmol) of the ¥ isomer (;a) in 141 mg Yoo to concentrate and stir the mixture at room temperature for about ½ hours. HCl concentrate 0 milliliters added 171 mg of the mixture and the ethanol/hexane residue was precipitated and dried by vacuum to give 119 vol ©+% (Cl, NH;) MS (kg). 1 esd

IHNMR(CD;0D): 8 7.31(m,5H), 7.13(m,5H), 6.78(m,1H), 5.28(m,1H), 4.62° (m,3H), 3.81(M,2H) , 3.14(m,1H), 2.62(m,3H), 1.58(m,7H). - Amino-71[1-17-(27-(8)-_benzyl-7-methyl-3?-oxo-77606468767:7-hexahydro -Y(3)pyrazolo[;;?-6]pyridine -*-yl)-1-(08-benzyl-oxymethyl-7-oxo-ethyl]- isobutyramidemethanesulfonate 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-) 3-0x0-2.3.3a.4.6.7-hexahydro-pyrazolo Ve[4.3-¢]pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide methanesulfonate aqueous sodium bicarbonate added saturated to 7.60 g (11 mmol) of its isomer and the mixture was extracted with ethyl acetate. The organic layer is dried over 14880 C and concentrated. Dissolve 1 (2) 1 milliliter (11 ml EY) of the residue in ethyl acetate, cool to about 0 °C and add _1 mol) of methanesulfonic acid and stir the mixture for about half an hour. Add 1 milliliter of hexane ) to the solution and the mixture was stirred for about one hour and filtered to give 3,460 g of 001) to give 7.55 g of 77 Sle as a white solid. The solid was recrystallized from ethyl acetate (MH?) © +% (Cl , NH;) MS (;d) as a white crystalline solid. -8(-27(-1[-<7-unima-"pyrazolo[;6-7]pyridine-#-carbonyl)-?-phenyl-(08-butyl]-isobutyramide hydrochloride benzyl-7 -methyl-?-oxo-7:305087:707-hexahydro--(57-27(1[-N- sisal -7f pyrazolo];?-6]pyridine-*-carbonyl)- ;-phenyl-(08-butyl]-isobutyramide hydrochloride 2-Amino-N-[1-(3a-(R)-benzyl-2-methyl-3-0x0-2,3,3a.4.6,7-hexahydro -pyrazolo Yo [4,3-c]pyridin-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramide hydrochloride and 2-

011

Amino-N-[1-(3a-(S)-benzyl-2-methyl-3-0x0-2,3.3a.4.6.7-hexahydro-pyrazolo]4,3-c]pyridine-5-carbonyl)-4- phenyl-(R)-butyl]-isobutyramide hydrochloride (a)”-oxo-5;>-diphenyl-7-(*-phenylallyl)-morpholine-carboxylic acid 4-butyl ester 2-0Oxo0-5 ,6-diphenyl-3-(3-phenylallyl)-morpholine-carboxylic acid t-butyl ester 0 to a solution at about -78*C of 1.8 g Vo (mmol) of cinnamoyl bromide and 94,? g VE (mmM) of t-butyl-(28,38)-(+)-oxo-FX diphenyl-;-morpholine carboxylate in You mL anhydrous THF added YA milliliters (YA) milligrams) of 1 mM bis-trimethylsilylamide sodium in 0 THF The mixture is stirred at about -7/8*C for about an hour and a half then poured into Vou milliliters of ethyl acetate. Wash the solution twice with saline; It was dried over 148807 and concentrated to give a yellow oil. The oil was stirred in 101 mL hexane overnight and the precipitated solid was collected by filtration to give 3.7 g of 10 white solid. —(R)1«(S)° (=)diphenyl-08(7)-(”-phenyl-allyl)-morpholine-7-one 5(S).6(R)-Diphenyl-3 (R)-(3-phenyl-allyl)-morpholin-2-one Yo to 7.59 g (0.77 mmol) of M.010 mL of trifluoroacetic acid was added at about 0°C and the mixture was stirred for about 2 hours Then he concentrates. The residue was dissolved in water and became basic with aqueous 118011 until the pH was maintained at 0.01. The mixture was extracted three times with ethyl acetate and the combined organic extracts were washed with ©_brine; It was dried over 14880, and concentrated to give an orange-colored oil which was purified by silica gel chromatography (0 (400 v/v ethyl acetate/hexane) to give AM mg of bear as a white solid. (c) 7-(8-amino-*-phenyl-pentanoic acid 2-(R)-Amino-5-phenyl-pentanoic acid Yo) hydrogenated at 0 pounds per square inch for about 1 hour mixture of 446 mg V (09 mmol) of bVY 5 mg palladium chloride in 71 mL ethanol and 10 mL tqr

YoY

Vio the mixture is filtered through detoy ash and concentrated; The residue was pulverized with ether to give THF from 1 mg Hg as a white solid. Butoxycarbonylamino-7-methyl-propionic acid 7;*-dioxo-tert-Y(d)yl ester -1-nidilorib 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2.5-dioxo-pyrrolidin-1-yl ° ester 013.0 mmol) of 0-300-11-methylalanine in Y £.71) to a slurry of © g N hydroxychloroquine mL of methylene chloride add 7.50 g (?9.3 mmol) of approximately 117 hours sad stir the slurry LEDC mM) of YR 1) succinimide and 0.10 g cela solution at room temperature. The mixture was diluted with ethyl acetate and washed twice both with 0 saturated sodium bicarbonate and saline. It is dried over 14850 C and concentrated. The product was purified by analyzing 5.7 g of compound silica gel chromatography (1:31 v/v ethyl acetate: hexanes) Title for Part D as a white solid. (E) ((-7-) 7-:©-butoxycarbonylamino-7-methylpropionylamino)-*-phenyl-pentanoic acid (re 1.7 mg) TVA 030 stirred overnight mixture of 707 mg (1.00 mmol) ) of mM) of diisopropyl ethyl (VT) from 0g f;7; mg N 1 1101 The mixture was diluted with ethyl acetate and extracted twice with DMF Amine in ? milliliters The aqueous phase was extracted once with ethyl acetate. The collected organic extracts were washed three times with water and once with brine. The mixture was dried over 148807 and concentrated. © The residue was purified by silica gel chromatography using chloroform 74860 in hexane then mg of *H.117# in chloroform to give 701 then methanol 7001 chloroform (f) (-11-(? 2,5-(a)-benzyl-7-methyl-7-oxo-70305:27:7:71-hexahydro-pyrazolo[;6-7]pyridine-k-carbonyl (-;-phenyl-) 8)-butylcarbamoyl]-1-methyl-ethyl)-butyl ester tert carbamic acid Yo

{1-[1-(3a-(S.R)-Benzyl-2-methyl-3-0x0-2,3,3a.4,6,7-hexahydro-pyrazolo[4,3-c] pyridine-5) -carbonyl)-4-phenyl-(R)-butylcarbamoyl]-1-methyl-ethyl} -carbamic acid tert-butyl ester according to the method described in the general procedure off) conjugate 11 mg (50 + mL mo) of Yer g atv 0 mg 0 OF) milligrams) of 8e to give a mixture of stereoisomer binary materials. The residue was purified by silica gel chromatography using a gradient separation of 1:1 (vol/v ethyl acetate:hexane) to ethyl acetate 7000 to give £0 mg of the least polar isomer 1 (*f) and £0 mg Which isomer? The most polar (50) MS (BTL11 (MH?) 014 (Cl, for both

the two isomers. 0(g)7-amino-7<-[1-(87-(8-benzyl-7-methyl-?-oxo-7070056877:71-hexahydro-pyrazolo[;;?-6]pyridine) -carbonyl)-; -hexahydro- pyrazolo[4,3-c]pyridine-carbonyl)-4-phenyl-(R)-butyl] -isobutyramide hydrochloride b to 56 mg (0 mM Y) of isomer 1 (*f) in 10 milliliters from Ishaul is added; milliliters of HCL concentrate and stir the mixture at room temperature for about ; hours. The mixture was concentrated and the residue of methylene chloride/hexane was precipitated and dried by vacuum to give 0 mg of the isomer 1 (FZ). MH") 14 (CL, NH3) MS IHNMR(CD;0D): (partial) § 7.19(m,10H), 4.37(m, 1H), 3.02(m,6H), 2.67(m, 4H) ), 1.83(m,4H), 1.62(s,6H), 1.28(m, 1H).0(h)7-amino--[1-(8(7-27)-benzyl-7) -methyl-?- Veal oF Y= gu Sf hexahydro-pyrazolo?;6-7]pyridine-©-carbonyl)-;-phenyl-(8)-butyl]-isobutyramide hydrochloride 2-Amino-N- [1-(3a-(S)-benzyl-2-methyl-3-o0x0-2.3,32,4.6,7-hexahydro- pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl -(R)-butyl]-isobutyramide hydrochloride Yo to 56 mg (Y) (0 mmol) of isomer 7 (50) in 10 milliliters of ethanol is added; milliliters of concentrated HCI are added and the mixture is stirred at room temperature for about hours.

Voit The mixture was concentrated and the residue of methylene chloride / hexane was precipitated and dried by vacuum to give

MH") 004 (CLNH;) MS mg of the ¥ (h) isomer." 0

THNMR(CD;0D): (partial) 7.25(m,9H), 6.88(m,1H), 3.04(s,3H), 2.71(m,4H), 2.48(m,2H), 1.75(m,4H ), 1.62(m,6H), 1.28(m, 1H). 1 Example ° Hydro- La -1776587:7:7-and SCO —Y-Jiie Benzyl-7- ~(R,S)=a¥)~Y]-N- sisal —¥ Pyridine -*-yl)-1-(08-oxymethyl-benzyl-?-oxo-ethyl]- TeV 8] os isobutyramide hydrochloride 2-Amino-N-[2-(3a-(R.S)-benzyl-2) -methyl-3-0x0-2.3,32.4.6,7-hexahydro-pyrazolo [4,3-¢]pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl] -isobutyramide 01 hydrochloride - 71-(27-(5,J6-benzyl-7-methyl-?-oxo-703665:87:7:7-hexahydro-0 pyrazolo[?;6-7]pyridine-*-yl)-1 -(08-benzyl oxymethyl-7-oxo-ethylcarbamoyl]-methyl-ethyl;-carbamic acid +:16-butyl ester-1 {1-[2-(3a-(R.S)-benzyl-2) -methyl-3-0x0-2.3.3 a.4.6.7-hexahydro-pyrazolo[4,3-c]vo pyridin-5-yl)-1-(R )-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl -ethyl}- carbamic acid tert-butyl ester mm) of 0 AY) mg 001 according to the procedure described in general procedure (a); conjugate mmol) of 1 e to give a mixture of stereoisomers (AT) “c and 1© mg volume/1:1) The residue was purified by silica gel chromatography using a graded separation of ©

JU of 171 mg in ethyl acetate to give 701 vol ethyl acetate: hexane) to methanol-71[1-11-(56,27-59])-benzyl-7-methyl-?-oxo-17: 5665870707- hexa sud —Y (b)pyridine-*-yl)-1-(8)-benzyl oxymethyl-?-oxo-ethyl]- [eV E] sls Hom - hydroisobutyramide 2-Amino-N-[2-(3a-(R.S)-benzyl-2-methyl-3-0x0-2.3.3a.4.6.7-hexahydro- Yo pyrazolo[4,3-c]pyridin-5-yl) hydrochloride )-1-(R )-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride

10 milliliters of ethanol © 1 milliliter Yo (mmol) of ?a in + TA) 171 mg is added to the concentrate and the mixture is stirred at room temperature for about two and a half hours. The mixture HCI 05 (Cl, (MS) was concentrated in mg of Av. Vr and the ethanol/hexane residue was precipitated to give (MH).

IHNMR (CD;0D): 6 7.32(m,5H), 7.16(m,5H); 5.22(m,1H), 4.67(m,1H), 4.55° (m,2H), 3.79 (m,2H), 3.12(m,2H), 3.00(m,6H), 2.71(m,3H), 1.56(m,8H). 1 Example Hexahydro-pyrazolo —Y Tefal eV Y= suf ethyl-3- Y= yu —a¥)-Y]-N- sisal -" pyridine-*-yl (-1-) 111- Indole-7-yl-methyl)-7-oxo-ethyl]-isobutyramide [e-Vet] hydrochloride 0 2-Amino-N-[2-(3a-benzyl-2-ethyl-3-0x0-) 2.3,3a.4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide hydrochloride [o-£¥] sls om benzyl-?-ethyl-7-oxo-7:7507:7:71-hexahydro- —(R,S)-aV 0 butyl ester -tert pyridine©carboxylic acid 3a-(R.S) )-Benzyl-2-ethyl-3-0x0-2.3 .3a,4.6,7-hexahydro-pyrazolo[4,3-c]pyridine-5- Vo carboxylic acid tert-butyl ester mg Yoo in 77 milliliters of ethanol is added QF mmol) from 0 ) to 000 mg mmol) of ethyl hydrazine oxalate and the mixture is heated at room temperature (VT) for about hours.The mixture is concentrated and the residue is purified by volume gel chromatography hexane / volume: ethyl acetate) to (7: vol/vol 1:01) smelica using a graded separation of

MH") 008 (Cl, NH;) MS .IV mg of TOV hexane/ethyl acetate) to give (b)27-(5kh)-benzyl-7-ethyl-75:66487:71-hexahydro -pyrazolo[?;7-e]pyridine-“one 3a-(R,S)-Benzyl-2-ethyl-3-ox0-2,3a.4.5.6.7-hexahydro-pyrazolo[4,3-c] ] pyridine-3- One Yo

Yo

V0 ethanol oe SLY mM) of 7a in 113A) 7500 mg was added to the concentrate and the mixture was stirred at room temperature for about 2 hours. The mixture concentrated HCL in milliliters of (0117(( YoA (Cl, NH3) MS) mg of YOV lap.) to give (C) (71-1-(83-(8,0-y-benzyl-?-) ethyl-?-oxo-737:7:7-hexahydropyrazolo[?;*-8]pyridine-*-yl)-1-(08-(111-indole-*-ylmethyl)-7-oxo -ethyl 0-butyl ester (tert-methyl-ethyl)-carbamic acid-1-]lyumabric {1-[2-(3a-(R.S)-benzyl-2-ethyl-3-0x0-2.3.3a .4.6.7-hexahydropyrazolo[4,3-c]pyridin-5-y1)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1 -methyl-ethyl}- carbamic acid tert-butyl ester mM) from A) 7 mg AY according to the procedure described in general procedure (a); Ye mM) from C is conjugated and the residue is purified by analysis of (YT) Lap and 100 mg to 77 methanol in 7001 silica gel chromatography using gradient separation of methylene chloride (MH) 674 (CL, 1111145 —aV) mg of 011 methylene chloride to give benzyl-?- ethyl-?-oxo -17030287077- hexa =(R,S)=a¥)-Y]-N-(d)7-aminohydropyrazolo[;;?-6]pyridine-*-yl)-5-(8 (-(1-indole-?-ylmethyl)-?-oxo-0-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-(3a-) (R,S)-benzyl)-2-ethyl-3-0x0-2.3 J3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-y1)-5-(R)-(1- indol-3-ylmethyl )-2-ox0-ethyl]- isobutyramide hydrochloride milliliter 1 mg (010 milligrams) of 1 g in ? 100 mL ethanol was added to Ye 100 mg VY concentrate and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give HCI (MH*) 0*1 (CI, NH3) MS from Ed as a colorless foam. Example: M-benzyl-7-ethyl-3-oxo-7:55087:0707-hexa hydro —(R)=a¥)-Y]-N-sisal -”pyrazolo[;;”-8]pyridine-*-yl)-1-(08-benzyl-oxymethyl-?-oxo-ethyl] -ve isobutyramide hydrochloride and 7-amino-71-17-(23-(8)-benzyl-?-ethyl-?-oxo-

01 hexahydropyrazolo[?;”-m]pyridine-*-yl)-1-(08)-benzyl oxy 07 methyl-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2 -(3a-(R)-benzyi-2-ethyl-3-0x0-2.3.3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2 -oxo-ethyl]-isobutyramide hydrochloride and 2-Amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-0x0-2.3,3a,4.6.7-°hexahydro-pyrazolo[4.3- c]pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]- isobutyramide hydrochloride (oxo-171:3:5:87:7:7-hexahydro- -Y-J 8) benzyl-?- —a¥)-Y]-V} 0 pyrazolo[7;?-6]pyridine--yl)-1-(08-benzyl-oxymethyl-7-oxo-ethylcarbamoyl]-

Jind butyl tert methyl-ethyl;-1-carbamic acid | 0 {1-[2-(3a-Benzyl-2-ethyl-3-0x0-2,3 .3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yD)-1-(R) -benzyloxymethyl-2-oxo-ethylcarbamoyl]-1 -methyl-ethyl}-carbamic acid tert-butyl ester mg (+19 mmol) of A according to the method in general procedure (a); mm) of 1H conjugates to give a mixture of stereoisomer binary materials. (oY) Fr and 100 mg 0 71001 residue were purified by silica gel chromatography using a graded separation of methylene chloride (1A) from 11 mg of the less polar (1A) 1 to methanol 77 in methylene chloride to give 6 mg of isomer of both isomers. =Y]-N-sud -7(b)[Odpyrazolo[?;?-8]pyridine-*-yl)-1-(08-benzyl-oxymethyl-7-oxo-Y isobutyramide 2-Amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-0x0-2,3.32,4.6.7-hexahydro-pyrazolo]4,3-c]pyridin-5-y1) hydrochloride -1-(R)-benzyloxymethyl-2-oxo-ethyl] -isobutyramide hydrochloride mL of 1-in-(IA) ethanol 1 mg (008 mmol) of the OV isomer to 0 mL of 1101 concentrate and the mixture was stirred at room temperature for about 1.4 yo added HO (CI, NH;) MS (mol). 1 hour. The mixture was concentrated to give 7, ; mg of an isomer

01

THNMR(CD;OD): (partial) 8 7.41-7.05(m,10H), 5.20(m,1H), 4.61(m,1H), 4.52 (s,2H), 3.71(m, 1H), 3.60( m,1H), 2.61(m,3H), 1.39(m,9H). hexa-17:6-0527:7:7-usco =Y=d 8) benzyl-?- =(S)-a¥)=-Y]-N- sual =Y (c) Hydro-pyrazolo[;6-7]pyridine-*-yl)-1-(08-benzyl oxymethyl-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-( 3a-(S)-benzyl-2-ethyl-3-0x0-2,3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-y1)-1-(R)-benzyloxymethyl-2- oxo-ethyl]-isobutyramide hydrochloride milliliters of ethanol 1 in (IN) mg (0001+ milligrams) of isomer ?01 to concentrate and stirred at room temperature for about ? HCL 1.4 mL of HCl (MH*) oY + (CLNH;) MS (A) is added. 1 mg of the A isomer concentrates the mixture to give 0

IHNMR(CD;0D): (partial) 8 7.43-7.00(m,10H), 6.81(m,1H), 5.32(m, 1H), 4.63 (m,2H), 4.53(m,1H), 3.72( m,1H), 1.37(m,9H). Example ?amino-14-[7-(7-benzyl-7-oxo-7:706548767:71-hexahydro-pyrazolo[a;?-6]-"pyridine-*-yl)-1 -(08-benzyl-oxymethyl-7-oxo-ethyl]-isobutyramide hydrochloride 0 2-Amino-N-[2-(2-benzyl-3-0x0-2,3.3a.4.6.7-hexahydro-pyrazolo[ 4.3-¢]pyridin-5- yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride pyridin-*-acid [e-TeE] ols 3m benzyl-7-hydroxy-7 :7:467- tetrahydro- (1) butyl ester -tert carboxylic acid 2-Benzyl-3-hydroxy-2.4,6.7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid 0 tert -butyl ester mm TV) a mixture of 800 mg 117 h heated with vapor re-condensation for about 1 mmol) of benzylhydrazine dihydrochloride YI (g) of £905 mg ml of 11 milligrams (of sodium acetate trihydrate in 1,1) and 77 mg milliliters of toluene and heated with re-condensation of 100 to ethanol. The mixture was concentrated and the residue was dissolved in vo steam for about 8 hours. The mixture is diluted with ethyl acetate and washed with brine; dried 7000 over 14850, concentrated and the residue purified. using silica gel chromatography

a Ethyl acetate and then methanol 70 in methylene chloride to give + 14 mg OF as a light brown solid. YY. (Cl, NH;) MS (0111. (b)—Y benzyl-75:041-tetrahydro]211- [e-Ved] ols 3 sm pyridine-?- ol 2-Benzyl- 4.5.6.7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-ol o to (£3 mg YE) milligrams of Yoo bat mL ethanol added 10 mL of 1101 concentrate and stir the mixture at room temperature for about 00 minutes. The mixture was concentrated and the methanol/ethyl acetate residue crystallized to give 57 mg MS of (MH) 001 (Cl, NH;) (c) 71-11-(?-benzyl-?-hydroxy-7: 35:71- tetrahydro-pyrazolo[?-6]0pyridine-*-yl)-1-68-benzyl oxymethyl-7-oxo-ethylcarbamoyl]-1-methyl-ethyl)-acid carbamic tert butyl ester {1-[2-(2-Benzyl-3-hydroxy-2.4.6.7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-R-benzyloxymethyl-2 -oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester vo according to the method described in general procedure (a); 001 mg YA (+ mMol) of 5 mg VEO (0 mg (mM YA) of 1H were conjugated and the residue was purified by silica gel chromatography (0:90 v/v methanol: methylene chloride) to give £Y mg of 4g as a white solid. (Cl, NH;) MS 7H(011.(d)7-amino-<-[7-(7-benzyl-”-oxo-7606487:7:71-hexahydro-[e-Ye£ ] sd 5 om 0 pyridine-*-yl)-(08-benzyl-oxymethyl-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-(2-benzyl-3-0x0-) 2.3,3a,4,6,7-hexahydro-pyrazolo[4.3-¢ |pyridin-5- yD)-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride (to 7; mg eV) mmol) of 80% 710 mL ethanol add 1 mL HCI concentrate and stir the mixture at room temperature for about 0 min. dilute the mixture with vo ethanol; The residue of methanol/ethyl acetate was concentrated and precipitated to give 1 mg TO as a white solid. MH") £4Y (Cl, NH3) MS

YY.

THNMR(CD;OD): (partial) 7.41-7.16(m,10H), 5.19(m,3H), 4.48(m,4H), 3.88(m,1H), 3.74(m,2H), 2.68(m ,2H), 1.58(m,6H). 01 Ex. Fluoro-ethyl)- DE YY eX) Yu Sf Amino-1-(7-[23-(08-benzyl-?--"hexahydro-pyrazolo[;;?-e] Pyridine-*-yl]-1-(08-benzyl-oxy-750 5-0-lysene methyl-7-oxo-ethyl)-isobutyramide hydrochloride and 7-amino--(7-[83-(8)-) oxo-7-(707,7-trifluoro-ethyl)-7577207-hexahydro-pyrazolo[:?-8]pyridine-*-yl]-1-(08-benzyl oxymethyl-7-oxo- ethyl)-isobutyramide hydrochloride 2-Amino-N-{2-[3a-(R)-benzyl-3-0x0-2-(2,2 2-trifluoro-ethyl)-2,3.3a.4.6.7-hexahydro- pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl }- 01 isobutyramide hydrochloride and 2-Amino-N-{2-[3a-(S)- benzyl-3-0x0-2-(2.2.2- trifluoro-ethyl)-2.3.3a.4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2 -oxo-ethyl} -isobutyramide hydrochloride hexa - 64 ale trifluoro-enyl)-07 - 7 oY )=Y— benzyl-?-oxo —(R,S)-a¥ 0 butyl ester tert hydropyrazolo[;;?-8]pyridine--carboxylic acid 0 3a-(R,S)-Benzyl-3-0x0-2-(2,2.,2-trifluoro-ethyl)-2,3. 3a,4.6.7-hexahydro-pyrazolo[4,3-c]pyrid in-5-carboxylic acid tert-butyl etser Gla (mol 1.27) mg Afr heated with vapor re-condensation for about © hours mixture of trifluoroethyl (XY = X X mmol) of YoY ) in grams) of B and 7726 mg, in 40 milliliters of ethanol, then concentrated. The residue was dissolved in 10 in (slo AV) hydrazine for 0 hours. The mixture was concentrated and the residue was purified, 117 toluene, and heated with re-condensation of the vapor for a period of about, by silica gel chromatography (9:1 v/v hexane: ethyl acetate) to give 07 mg of

MH") 17 (CI, NH;) MS as a yellow oil. Hexahydro pyrazolo[;;6-7]pyridine-?-one Yo 3a-(R.S)-Benzyl-2-(2,2 2-trifluoroethyl)-2.3a,4.5.,6,7-hexahydro- pyrazolo[4,3-c]pyridin-3-one

arr

Add * mL 39° jaa at about 01 mol) of lle 1187) 001 mg to cold trifluoroacetic acid and stir the mixture for about ¥ hours; Leave the solution to reach room temperature. The mixture is concentrated, the residue is dissolved in water, the solution is made alkaline to N, and then saturated with potassium carbonate. The solution was extracted three © NaOH with pH 11 times with ethyl acetate and the combined organic extracts were washed with brine; It is dried over 0 (MH*) 701 (CL, NH3) MS over 10 mg of 10b as an opaque oil. YEO and concentrated to give MgSO4 (GB) (1-(7-[2-(5,a-benzyl-? - oxo-7-(707:7-thanefluoro-ethyl)-benzyl oxy “RI dh pyridine-*- [e-Tet] sls jl om - hexahydro-57 tert butyl ester Carbamic acid (Ji methyl-7-oxo-ethylcarbamoyl)-1-methyl-(1-{2-[3a-(R,S)-Benzyl-3-0x0-2-(2,2,2-trifluoro) -ethyl)-2.3.3a,4.6.7-hexahydro-01 pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl }-1- methyl-ethyl)- carbamic acid tert-butyl ester (88 mmol) of 171 mg according to the method in general procedure (a); conjugate a mixture of stereoisomers. aad (1 mmol) of out £) 1797 and 0 mg, the residue was purified by silica gel chromatography using gradient separation of methylene chloride-1 (a) +) the less polar 1 mg of isomer 178 to methanol 705 in methylene chloride to give 0 Both (MH*) 174 (Cl, NH;) MS E(C01) and 17 mg of the more polar ¥ isomer the two isomers trifluoro-ethyl)-VY) YmSf benzyl-*- — (R)—av]=Y}-N- sua l = Y(3)pyridine-*-yl]-1-(08-oxy-benzyl [e-Yet] ls Som 0:407a-hexahydro-0 000 methyl-7-oxo-ethyl)- Isobutyramide hydrochloride 2-Amino-N-{2-[3a-(R)-benzyl-3-0x0-2-(2,22-trifluoro-ethyl)-2.3.32.4.6.7-hexahydro-pyrazolo[4,3-c] [pyridin-5-yI]-1-(R )-benzyloxymethyl-2-oxo-ethyl } - isobutyramide hydrochloride dsl ve in (101 mL) of the VA isomer) mg 171 to Yo concentrated and stirred the mixture at room temperature for about two hours. HCL concentrate V,0 mL is added

11 (Cl, NH3) MS mixture to give 94 mg of the ¥ (10D) isomer as an off-white powder. (0/4) 011.

THNMR(CD;0D): (partial) 6 7.31(m,5H), 7.18(m,5H), 5.21(m,1H), 4.57(m,3H), 4.26(m,1H), 4.08(m, 1H), 3.79(m,2H), 3.09(m,4H), 2.65(m,2H), 1.63(m,6H). (e) 7-amino-l<-(?-[23-(8)-benzyl-?-oxo-7-(7707-trifluoro-ethyl)-oo-hexahydro-pyrazolo[;;?- 6]pyridine-*-yl]-1-(08-benzyl-oxy-5methyl-7-oxo-ethyl)-isobutyramide hydrochloride 2-Amino-N-{2-[3a-(S)-benzyl-3- 0x0-2-(2,2 2-trifluoro-ethyl)-2,3.3a.4.6.7- hexahydro-pyrazolo[4.3-¢]pyridin-5-y1]-1-(R)-benzyloxymethyl-2 -oxo-ethyl }- isobutyramide hydrochloride Ve to oY mg +i VA (mM) of isomer 7 (10g) in Yio mL ethanol added 0.0 mL HCL Concentrate and stir the mixture at room temperature for about two hours. Jalal concentrates to give 1 mg of the 7" isomer (10E) as a light yellow solid. (Cl, NH;) MS .01117(oV¢

IHNMR(CD;0D): (partial) 6 7.33(m,5H), 7.15(m,4H),6.81(m,1H), 5.30(m, 1H), vo 4.67(m,4H), 4.15(m ,2H), 3.77(m,2H), 3.09(m,3H), 2.64(m,3H), 1.58(m,6H). 11 Example “-amino-11-[7-(27-(08-benzyl-7-:-butyl-?-oxo-7:564870771-hexahydro-pyrazolo[;;?-6]pyridine-*) -yl)-1-(08-benzyl oxymethyl-7-oxo-ethyl]-0 isobutyramidemethanesulfonate and 7-——(S)—a¥)—YI-N-sisal benzyl-7-© 1-Butyl-?-oxo-777 hexahydro-pyrazolo[?;8-7]pyridine-*-yl)-1-(08-benzyl-oxymethyl-7-oxo-ethyl]-2-isobutyramidemethanesulfonate Amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-0x0-2.3 .3a.4.6,7-hexahydro- pyrazolo[4,3-c]pyridin-5- yl)-1-(R )-benzyloxymethyl-2-oxo-ethyl]-isobutyramide methanesulfonate and 2-Amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-oxo - Yo 2.3.3a.4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide methanesulfonate

0(a)*-(9e)-benzyl-7--butyl-7-oxo-77:457:7:71-hexahydropyrazolo butyl ester tert[?6-7]pyridine-*-acid Carboxylic 3a-(R.S)-Benzyl-2-tert-butyl-3-0x0-2,3,3a.4,6.7-hexahydropyrazolo[4,3-c]pyridin- 5-carboxylic acid tert-butyl ester g 1.57 mL ethanol add 50 g (0.90 mmol) of 1b; in 7.197 ° to 7.197 °M (VY) butylhydrazine hydrochloride 0.15 g tert ml mole) of (7, hr.) 117 grams) of sodium acetate is cooled and the mixture is heated at about 107 * C for about a period of about, the mixture is filtered and the solution is filtered from the precipitate and concentrated. The residue was dissolved in 80 milliliters of toluene for hours. The mixture is concentrated and the residue is purified by a solution of 1 and heated with re-condensation of the vapor for a period of about

ANY hexane:ethyl acetate) to give 1.7 g of aaa silica gel chromatography) 1:9 v/0(MH*)T (Cl, NH;) MS [e-¥e£] ody 3 om Hydro- La —VeloctalY-dis —tert—Y—dy i —(R,8)=a¥ (B) 3a-(R.S)-Benzyl-2-tert-butyl-2,3 ,3a.4.6,7-hexahydro-pyrazolo[4,3-¢]pyridin-3-one mM methylene chloride in Yoo 11 is added to 576 mg (1.74 mmol) of μL of methanic acid sulfonic and stirred the mixture for about an hour and a half at a temperature of 9 N and 1 NaOH once, at room temperature. The mixture was diluted with ethyl acetate and washed twice with (CL, NHy) MS i) mg TET with saline; It was dried over 112507 and concentrated to give 011117(YA-(“52-2y)-benzyl-7-:“butyl-”-oxo-765877:7-hexahydro 7-11(c)0 pyrazolo [?;?-6]pyridine-*-yl)-1-(08-benzyl oxymethyl-7-oxo-ethylcarbamoyl]-butyl ester tert-methyl-ethyl)-carbamic acid-1{1 -[2-(3a-(R.S)-Benzyl-2-tert-butyl-3-0x0-2.3.3a,4.6.7-hexahydro-pyrazolo[4.3-c]pyridin-5-yl)-1-(R )-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1 -methyl-ethyl}- carbamic acid tert-butyl ester Yo (mg) of AT (mg YER conjugate of) according to the method described in the general procedure To give a mixture of two-space materials. The residue was purified by VE analysis of 11 mg TYAS

YY ¢ silica gel chromatography (7: ; v/v hexane/ethyl acetate) to give You mg of the less polar isomer 1 (11g) and 90 mg of the isomer ? The most polar (1A). TEA (Cl, NH) MS (MH) for both isomers. —(R)=a¥)=Y]-N-sisal -7(3)benzyl-7--butyl-?-oxo-71:30527:7:71-hexa0hydro-pyrazolo[ ;;6-7]pyridine-*-yl)-1-(8)-benzyl oxymethyl-7-oxo-ethyl]-isobutyramidemethanesulfonate 2-Amino-N-[2-(3a-(R) -benzyl-2-tert-butyl-3-0x0-2.3.32.4.6,7-hexahydro-pyrazolo [4,3-c]pyridin-5-y])-1-(R)-benzyloxymethyl-2-oxo -ethyl]-isobutyramide methanesulfonate 1 to 100 mg TY (mM) of isomer 1 (11 g) in vo mL methylene chloride at about 0 C. YA is added μl (88+ mmol) of methanesulfonic acid.The ice bath was removed and the mixture stirred for about −hours; diluted with lll Vo diethyl ether and the precipitate was collected by filtration to give 100 mg of its isomer 1(1d). (Cl, NH;) MS mH (MH*) : IHNMR(CD;OD): (partial) 6 7.33(m,5H), 7.27-7.07(m,5H), 5.21(m, 1H), 4.54(m, vo 3H), 3.86(m,3H), 3.10(m,4H), 2.61(s,3H), 1.62(m,6H), 1.18(s,9H). ( e)—(S)=a¥)=-YI-N- sid —Y benzyl-7-):©-butyl-7- —VeletaatoFe¥— gulf hexahydropyrazolo[;;?-6] Pyridine-*-yl)-1-(08)-benzyl-oxy Methyl-7-oxo-ethyl]-isobutyramidemethanesulfonate 2-Amino-N-[2-(3a-(S)-benzyl-2-tert-butyl-3-0x0-2.,3 .3a,4.6). 7-hexahydro-pyrazolo Y. [4,3-c]pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide methanesulfonate to 85 mg (Y ) 1 milligram) of an isomer? (11c) In 01 milliliters of methylene chloride at about 0C add 1? μl TY (milligram) of Yemethanesulfonic acid. The ice bath is removed and the mixture is stirred for about ½ hours; It was diluted with lille Yo diethyl ether and the precipitate was collected by filtration to give £71 mg of the isomer ? (11E).(Cl,NH;)MS Ke.(MH*).

1100 1111/1 :(010,00) (partial) 6 8.28(br d,1H), 7.32(m,5H), 7.18(m,4H), 6.84(m,1H), 5.31(m,1H), 4.60(m,3H), 3.70(m,3H), 3.18-2.92(m,3H), 2.68(s,3H), 1.57(m,6H), 1.13(s,9H). 11 Example —(R,S)=a¥— gu Sl indole-7-ylmethyl)-7-(7-methyl-7--111(-08(-1[-14-unima) 1-0-1-)lypyridine-7-ylmethyl-7:6:4627:7.71-hexahydro-pyrazoloa;;?-6]pyridine-*-oxo-ethyl]-isobutyramide dihydrochloride 2-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-0x0-3a-(R,S)-pyridin-2-ylmethyl-2.3. 3a.4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-y)-2-oxo-ethyl]-isobutyramide dihydrochloride 01-carboxylic SLD (a);-oxo-7-(08, 5-pyridin-7-ylmethyl-piperidin-00*- acid methyl ester = F-16-1-butyl ester 4-0x0-3-(R.S)-pyridin-2-ylmethyl-piperidin-1, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester Add 8; THF mL YY mmol) of ViA to a solution of ¥ g vo mmol) of Sodium hydride (dispersed oil 410) at about 0°C (11.7 mg mg) + 1 mMg) VAY min. A solution of 1 is added and the mixture is stirred for approx. to the stirred solution within for about ¾ minutes; then THF"-picolell chloride in ¾ milliliters (milligrams) of potassium iodide is added. Ice bath removed and mixture heated for 1 yo) mg YY hr with steam re-condensed. Dilute mixture with ethyl acetate and wash once with about 117 Ye water and once with brine; Dried above 2850 and concentrated. The residue was purified by silica gel chromatography using (£57 vol/v ether/hexane) and then (£57 vol/vol acetate (MH?) 4 (Cl, g of 1"A. 148) and 0.7 111 ethyl:hexane) to give methyl-?-oxo-27-(14,95)-pyridine-7-ylmethyl-7:3:0427:07071-hexa-1(b)hydro-pyrazolo [;;?-6]pyridin-*--carboxylic acid :6-butyl ester Ye 2-Methyl-3-0x0-3a-(R,S)-pyridin-2-ylmethyl-2.3,3a.4,6 ,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

¥,£80) 0.01g Heat with re-condensation for about six and a half hours a mixture of

Yo mg (, 45 mmol) of methylhydrazine in 1959, NY mole) of lle toluene and heated with re-condensation of Yo to ethanol. The mixture is concentrated and the residue is dissolved in an hour. The mixture was concentrated and the residue was purified by gel vapor chromatography 117 for approximately (CL, (and 1111 MS vol/vol ethyl acetate/hexane) to give 00 mg of 7 Yolo) silica 0 (MH) 36 (c) = methyl-07-(08,9-pyridine-?-ylmethyl-76555:8727-hexahydro-pyrazole[?6-7]pyridine-?-one-dihydrochloride 2-Methyl-3a -(R.S)-pyridin-2-ylmethyl-2,3a.4.5.6.7-hexahydro-pyrazolo[4,3-c]pyridin-3-one dihydrochloride 1

VY) mg 4900 was stirred at room temperature for about four and a half hours a mixture of mm) of 11b in ¥ milliliters of 1101; Grammolecular/dioxane. Yéo (:113,A6) MS Ga 17 mg of 450 mixture was concentrated (0111.0111) to give indole-”-ylmethyl (-7-(?-methyl-?-oxo-27-(9) ,.)- -11-08(-1(-11-((d)pyridine-?-ylmethyl-756448307:7-hexahydro-pyrazolo[?;?-]pyridine-*-yl) -?-0 butyl ester tert-oxo-ethylcarbamoyl]-1-methyl-ethyl)-carbamic acid {1-[1-(1-(R)-H-Indol-3-ylmethyl)-2 -(2-methyl-3-0x0-3a-(R.S )-pyridin-2-ylmethyl- 2.3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo -ethylcarbamoyl]-1- methyl-ethyl}-carbamic acid tert-butyl ester mg YY 5 c 17 mmol) of TY) mg 018 conjugate of) according to general procedure 0 mmol Grammy) from “C and the residue was purified by silica gel chromatography 71”

TN (CL, NH) MS VY mg of 118 v/v ethyl acetate/methanol) to give (0111.0:40) —a¥= su Sl indole-”-ylmethyl(-7-)? -methyl-?- -111(-0p(-1J-N-sid -7(e)pyridine-7-ylmethyl-75:4:2777-hexahydro-pyrazolo[?;?-8] pyridine-*- -05,8(ve yl)-7-oxo-ethyl]-isobutyramide dihydrochloride

A 2-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-ox0-3a-(R.S)-pyridin-2- ylmethyl- 2,3,3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]- isobutyramide dihydrochloride was stirred at room temperature for 11 hours mixture of 111 mg lk +A (mol 0 gram) of 71d in 1 milliliter of 1101; Grammolecular/dioxane. Concentrate the mixture to give

)© mg of ?a1ah. MH") 0016 (Cl, NH3) MS IHNMR(CD;0D): (partial) 5 8.91-8.52(m,2H), 8.04(m,2H), 7.76-7.50(m, 3H), 6.82 (m,1H), 4.62(m,1H), 3.36(s,3H), 1.63(s,6H). Example 0 0 ?-amino-[1-(08-benzyl) oxymethyl-7-(?-methyl-7-oxo-8,5-27)-pyridine-"-ylmethyl-0560407:71-hexahydro-pyrazolo[;;6-7]pyridine-7"-oxo -ethyl]-isobutyramide dihydrochloride 2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-ox0-3a-(R,S)-pyridin-2- ylmethyl- 2,3a.4.5.6.7-hexahydro-pyrazolo[4,3-c]pyridin-2-oxo-ethyl]- isobutyramide dihydrochloride vo-8(-11-1(1)benzylSo methyl-7 -(7-methyl-1-oxo-27-(014,5-pyridine-7-ylmethyl-770402:7-hexahydro-pyrazolo[?;"-h]pyridine-*-yl)-7-oxo -ethylcarbamoyl]-1-methyl-ethyl4-carbamic acid tert-butyl ester {1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-0x0-3a-(R.S )-pyridin -2-ylmethyl- 2,3.3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl )-2-ox0-ethylcarbamoyl]-1- Y.methyl-ethyl}-carbamic acid tert-butyl ester according to general procedure (a); AT conjugate 0 mg YY) mL j mole) of 11c and 7710 mg (YY) + mmol) of 1e ig the residue was chromatographically silica gel (0:40 v/v ethyl acetate: hexane) to give AY mg of 1a. (b)=Yamino-a<-[1-(18-benzyl aSo methyl-7-(7-methyl-7-oxo-27-(5-Ra])-pyridine-"-yl Methyl-77640830:7-hexahydro-pyrazolo[?8-7]pyridine-*-yl)-?1-sus-ethyl]-isobutyramide dihydrochloride

No 2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-0x0-3a-(R,S)-pyridin-2- ylmethyl-2.3,3a.4, 6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]- isobutyramide dihydrochloride was stirred at room temperature for about 11 hours a mixture of VO mg lle VY (Verine Grammy) of NY in 1 mL of HCL; Grammolecular/dioxane. The mixture was concentrated to give 0 mg of AAP. MH") * 11 (Cl, NH) MS (partial) & 8.78(m,1H), 8.46(m,1H), 8.13-7.82 (m,2H), 7.32 :(0,00) 11111 ( m,5H), 4.57(m,3H), 3.96(m,1H), 3.82(m,2H), 1.63(m,6H). Ji 16 —Y=dyji —(R)=a¥ )~Y]-N-sid -Y 0 methyl-?-oxo-7065573:7071-hexa goin — eV El pyridine-*-yl)-1-(8-benzyl-oxymethyl-?- oxo-ethyl]-isobutyramide 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-0x0-2,3.32,4.6.7-hexahydro-pyrazolo [4.3-c] [pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide oe (1)-oxo- “YO gum” dicarboxylic acid tert) butyl ester =F methyl ester 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester to a mixture of 0.01 g (E) 0 mmol fC oxo- Piperidine-*-carboxylic acid methyl ester and 71 g OVE (mmol) of 4;?-dimethylaminopyridine in one liter of methylene chloride at about 0°C add a solution of VY 54 00 g milligrams) of tert SUE butyl dicarbonate in 100 milliliters of methylene chloride over about 90 minutes. Lay the mixture slowly to room temperature and then stir for about VA 1 hour. The mixture was washed three times each time with aqueous HCL 701; saturated aqueous sodium bicarbonate solution and brine; It was dried over 14850 and concentrated to give 101.5 g of IVE as an amorphous solid. 4.03(br,2H); 3.74(s,3H), 3.56(t,2H), 2.36(t,2H), 1.42(s,9H). Yo:lol 0) 11111 (b) 7-(08-benzyl-?-oxo-piperidin-0*-dicarboxylic acid tert)butyl ester *- methyl ester

10 3-(R)-Benzyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester mmol) of sodium hydride (YAT dispersed oil) g VY To a stirred suspension of 65.4 mL DMF is added 001 mL hexane) in 001 washed twice with 0 at about zero C through DMF 1001 mMg) of (0a in TOE) approx 0 ½ min. Remove the ice bath and stir the mixture at room temperature for approx 0 ½ min. The mixture is re-cooled to about 0”C and 35.7 milliliters (199 mmol) are added dropwise To the stirred solution and stir the mixture for about DMF (milliliter Yoo gram) of benzyl bromide in and stir the mixture ele 50 0 milliliters at room temperature. To the solution YY is carefully added and the extracted materials are washed Ji min. The mixture was extracted three times with 00” organic acetate of about 0 duration five times with water; once with brine; It was dried over 14850, and concentrated as OVE gm of VY to give 98 gm of yellow oil. The oil crystallizes from hexane to give

MH") Y£A (Cl, NH;) MS is a white solid.

IHNMR (CDCl,): (partial) 8 7.23(m,3H), 7.13(m,2H), 4.58(br m,1H), 4.18(br,1H), 3.63(s, 3H), 3.28-2.96 ( m,4H), 2.72(m, 1H), 2.43(m,1H), 1.44(s,9H). vo oxo-7:3:4307:7-hexahydro-pyrazolo —V=dse benzyl-7- ~(R)-a¥ (=) tert [?;6-7] pyridine-k-carboxylic acid 3a-(R)-Benzyl-2-methyl-3-0x0-2,3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-3- carboxylic acid tert-butyl ester g EY hr under nitrogen mixture of VY heated with vapor re-condensation for about Y. mmol) of hydrazine sulfate (0 g) YAY (VE mmol) from 1 Yo) 6 lbs methyl (40?© mmol) of sodium acetate in 100 mL ethanol. The mixture was concentrated, the residue was dissolved in ethyl acetate, washed three times with water and once with

Vo and concentrate to give a yellow oil. The oil is stirred into the MSOs brine; dried over gm of ; 01g as a white solid. 51.17 h to give YO mL hexane for about 117 ve (Y¢ (Cl, NH;) MS)

11

IHNMR(CDCL,): (partial) 8 7.19(m,3H), 7.05(m,2H), ft)4.61 m,2H), 3.24(m, 1H), 3.09(s,3H), 3.01( m, 1H), 2.62(m,4H), 1.52(s,9H). Pyridine-?- fe-Yet] slo il pms ous Benzyl-7-methyl-7054:27:77-hexa —(R,S)=a¥(3)one hydrochloride 3a-(R.S) -Benzyl-2-methyl-2.3,3a,4.6.7-hexahydropyrazolo[4,3-c]pyridin-3-one ° hydrochloride (mM) from (V1.0) g YE,00 through a solution of JY 1101 pumps bubbles from min. 11 in 800 milliliters diethyl ether at about 0C for about 04C stirred the mixture for about ¥ hours; During this time a white precipitate is formed. Article collection

MH") 74 (CL NH) MS solidified by filtering to give 19.79 g of 4 Ed. 0

ITHNMR(CD;0D): (partial) 8 7.25(m,3H), 7.05(m,2H), 3.77(m,2H), 3.51(d, 1H), 3.25(m,1H), 3.17(m, 3H), 3.03(s,3H), 2.81(m,1H). Methyl-propionic acid 7;*- dioxo “Y= ginal Butoxycarbonyl-6:1-7 (2) yl-ester -1-nidilorib 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2,5-dioxopyrrolidin-1-yl ester d.g (£3 mmol) of ©0-30-methylamine and 94 g 001 to a stirred solution of 1 liter of methylene chloride at about 0'm is added 1 (97; mmol) of 200 in mol) of 17-hydroxysuccinimide in batches and then let the reaction le g (57; 7 h) and wash twice each time with TE to warm to Room temperature.The thread is stirred for about 11 saturated aqueous sodium bicarbonate and brine solutions;dried over 118250 and concentrated to give 0 as a white solid.AVE g of

THNMR(CDCly): 8 4.96(br,1H), 2.82(s,4H), 1.66(s,6H), 1.48(s,9H). Benzyloxy-7-(0:6-7-butoxycarbonylamino-7-methyl-propionylamino)-(R)-V(f)propionic acid 3-(R)-Benzyloxy-2 -(2-tert-butoxycarbonylamino-2-methyl-propionylamino)- Yo propionic acid

171 m0 mmol) of 1 TA) of a mixture of 0.00 g Bitte heated at about mmol) of 0-benzyl-0-serine”; and 01.00 g (010 mM VIA) g ?,0 mL dioxane and 100 mL water. The mixture is diluted with 4000 g) of triethylamine V with acetic acid. The layers are separated and the condition is washed with 1 ethyl acetate, acidified to a pH of 1 gm as a solid 1500 over 118250 and concentrated to give the organic hind with brine; 0 with a white colour.

IHNMR(CD;0D): (partial) 6 7.55(d,1H), 7.29(m,5H), 4.52(m,1H), 4.48 (s,2H), 3.84(d of d,1H), 3.69( dof d,1H), 1.42(s,6H), 1.38(s,9H). Pyridine-?-[oY o£ ol 5 hexahydro- —Yeleoct cae Y—ddisa benzyl-7- ~(R)-a ¥ (J) 1,1-tartrate 0 3a-( R)-Benzyl-2-methyl-2.3a.4,5.6.7-hexahydro-pyrazolo[4,3-c]pyridin-3-one L- tartrate mmol) of free base from 14d and 50g You) to a mixture of © g water lle VY 5 mL acetone Av tartaric in -L mmol (of 005 mmol) during this time the mixture becomes dela Ve heated under nitrogen at about 17 *C for about ve additional acetone.The reaction mixture is slowly cooled to 01ºC.The reaction is a thick suspension and added at room temperature and then filtered.The solid is washed with acetone and collected and dried by vacuum to give a white solid. VE g of 17 benzyl-7-methyl-77055837-hexahydro-pyrazolo[;?-m]pyridine-?- ~(R)=a¥(h)9pwn3a-( R)-Benzyl-2-methyl-2,3a.4.5.6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one in 80 mM methylene chloride at 5VE mM) from 1" ,7) to a suspension of (gm) milliliters (769.4 mmol) of ammonium hydroxide (0.77 about 0”C) is added per minute. The cold solution is filtered And it is used directly in the next step.‎ 11 The mixture is stirred for about, benzyl-?-methyl-”-oxo-765:87:7:71-hexahydro- —(R)=a¥)-Y]-V } (i)ve pyrazolo[;;”-6]pyridine-*-yl)-11-(04-benzyl oxymethyl-7-oxo-ethylcarbamoyl]-butyl ester tert carbamic acid {df methyl--1

Monetization {1-[2-(3a-(R)-Benzyl-2-methyl-3-0x0-2.3.3a.4.6,7-hexahydro-pyrazolo[4.3-c] pyridin-5-yl)- 1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl } - carbamic acid tert-butyl ester was stirred at about 4h 6° hia under nitrogen for about one hour a mixture of § AY, 1 mmol (17.7 g) of 0; solution of 1 H; 1.10 g (190 mmol) of 5 Y.60 (HOAT 1.8 g) mmol) of EDC then ly to room temperature and stirred for about 11 hours. The mixture was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate and water; dried over 1850, and concentrated to give VFO g of 1 vol. As a white solid. ?;?-]pyridine-*-yl)-1-(08-benzylmethyl-7-oxo-ethyl]-isobutyramide 2-Amino-N-[2-(3a-(R)-benzyl-2-) methyl-3-0x0-2.3.3a.4.6.7-hexahydro-pyrazolo [4,3-c]pyridin-5-y1)-1-(R)-benzylmethyl-2-oxo-ethyl]-isobutyramide to Veo 1,Y0 mg (milligram) of ;1p in 1mL methylene chloride at approx. 0.¥ mL of cold trifluoroacetic acid was added and the mixture was stirred for about vo 1 hour at about 0°C. Leave the mixture to warm to room temperature and stir for about two hours. The mixture was concentrated and covalently 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 148507 and had 0494 mg of ; 1 What kind of oil? 1 Ji vo *-amino-]-[11-(8-benzyl-oxyethyl-7-(7-methyl--oxo-7:366407:7:71-hexahydro-pyrazoloa);;? -H]pyridine-*-yl)-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[1-(R)-benzyloxyethyl-2-(2-methyl-3-0x0-2,3, 3a.4,6,7-hexahydro- pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramide hydrochloride “Vel a@Veret = ssf —¥=di = (i ) hexahydro-pyrazolo[?;?-] om cpm vo carboxylic acid tert butyl ester 2-Methyl-3-0x0-2.3.3a.4,6.7-hexahydro-pyrazolo[4,3-c [pyridin-5-carboxylic acid tert-butyl ester

17 hours a mixture of ¥ g (11.17 mmol approximately 117 add heated with re-vapour 001 ml) of ?a and/a©7 mg (11.11 mmol) of methyl hydrazine in mL toluene and heated with re-condensation of 100 ethanol. The mixture is concentrated and the residue is dissolved in

Cain' and washed twice with brine; (Ji h. The mixture was diluted with acetate VV steam for a period above 10880, and concentrated. The residue was purified by silica gel chromatography using separation © 01 to methanol 75 in methylene chloride to give 7.78 g of 7001 graded ethyl acetate as a white solid. ), 2.58(t,2H), 1.48(s,9H).hexahydro--pyrazolo;;6-7]pyridine-?-one hydrochloride —VeleoctalY—diue -7(b) 2-Methyl- 2.3a.4.5.6.7-hexahydro-pyrazolo[4,3-c]pyridin-3-one hydrochloride 10 milliliters 10 milliliters ethanol added Te in 11 milligrams (from Yond) 501 mg to a minute. The mixture is concentrated, the Yo concentrate crystallizes, and the thread is stirred at room temperature for about 11 mg HCI 11b as a yellow solid. £Y0 The residue is methanol/ethyl acetate to give 1111111 00(6:00) 4.27(s ,2H), 3.71(s,3H), 3.56(t,2H), 3.05(t,2H). hexa-17:304087:7:7-oscoa —¥=dine benzyl oxymethyl-7-(7--8(-1[1-1((c)0hydro-pyrazolo] ?;?-H]pyridine-*-yl)-7"-oxo-ethylcarbamoyl]-1-methyl-ethyl)-butyl ester tert carbamic acid {1-[1-(R)-Benzyloxymethyl -2-(2-methyl-3-0x0-2,3,3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl- ethyl } -carbamic acid tert- butyl ester Y. mg (010% mmol) of 001 according to the method described in general procedure (a); conjugate mmol) of 1e and the residue was purified by 0 OF analysis ) 17 and 0 mg silica gel chromatography (0:90 v/v methylene chloride: methanol) to give 08 mg of (01117.031 (CI, NH;) MS) as a white solid. C01 - 11:304:27:7:7-and ascoa-benzyloxymethyl-7-(7-methyl-?--8-1[-]-onema--Y (d) Ye pyridine-*- yl )-7-oxo-ethyl]-isobutyramide [eV ed] so om hexahydro-hydrochloride

7< 2-Amino-N-[1-R-benzyloxymethyl-2-(2-methyl-3-0x0-2.3.3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5) -yl)-2-oxo-ethyl]-isobutyramide hydrochloride To 0 mg (0 (0 lle mol) of 11g in 10 milliliters ethanol add 10 milliliters HCL concentrate and stir the mixture at room temperature for about 400 minutes. Mixture 0 was concentrated and a residue of methanol/ethyl acetate was precipitated to give 050 mg of #ED. (Cl, NH) MS £11 (0119. THNMR (CD;0D): (partial) 6 7.28(m,5H), 5.18(m, 1H), 4.69-4.38(m,4H), 3.88 (m,1H), 3.73 (m,2H), 3.68(s,2H), 3.61(m,1H), 2.67(m,1H), 1.57(s,6H). Example 11 0 *-amino-]-[7-(7-benzyl-3?-oxo-7:35:87:7:7-LuSa hydro-pyrazolo[??-m]pyridine-*-yl)-1 (06-(111-indole-”-ylmethyl)-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-(2-benzyl-3-0x0-2.3.3a.4.6.7) -hexahydro-pyrazolo[4.3-¢]pyridin-5- y1)-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide hydrochloride 0 (a) ? - –—Y=diyi oxo-7:647:7:7-hexahydro-pyrazolo[4;:?-]pyridine-e-carboxylic acid tert-butyl sind 2-Benzyl-3-0x0- 2.3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridine-5 -carboxylic acid tert-butyl ester heated with re-condensation for about 11 hours a mixture of 8060 mg (11 mL) mole:1 gram) of YAO, IF©,11 mg(mmol) of benzyl-hydrazine dihydrochloride in Ye mL ethanol.the suture concentrate and the residue was dissolved in 100 mL toluene and heated with recondensation steam for about 8; hour. The mixture was diluted with acetate “Jy” and washed twice with saline solution; dried over 1182807 and concentrated. The residue was purified by silica gel chromatography using a gradient separation of ethyl acetate 7001 to methanol 75 in methylene chloride to give oF vo mg of NT as a yellowish-brown solid. MS (F 1111 MH") 71 (Cl, (b) = benzyl-72543:7-hexahydro-[eT ef yy 3m pyridine-?-one hydrochloride

11 © 2-Benzyl-2.3a.4.5,6.7-hexahydro-pyrazolo[4,3-c]pyridin-3-one hydrochloride to (£9 mg (Ale, YE) mol) of 10a In Yoo milliliters ethanol add 10 milliliters HCI concentrate and stir the mixture at room temperature for about Yo minutes. The mixture was concentrated and the residue of methanol/ethyl acetate crystallized to give 057 mg of 11b as a yellow solid. .(MH") 001 (CLNH;) MS 0 ITHNMR(CD;0D): 6 7.26-7.40(m,5H), 5.22(s,2H), 4.12(s,2H), 3.53(t, 2H), 3.00 (t,2H). —d sd yl)-propionic acid (R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)- 01 propionic acid to solution stirred from 70.56 g (0010 mol) of 0-tryptophan; 70.4 g LY (mol) of N-methylmorpholine in £00 milliliters of (4:0) dioxane: cele added £0 g (110 mol) of ; 1E And stir the mixture for about 1 hour. Gd 1 Excess oxygen is removed by evaporation and water and ethyl acetate are added to the mixture. Adjust the pH of the solution to ? With 1101 centers and layers separated. Wash the organic layer with water and brine; dried over 1850 and concentrated. The ethyl acetate/hexane residue crystallizes to give TY g of an off-white solid. (d) (-[7-(?-benzyl-?-oxo-75:503:77-hexahydro-pyrazolo[?;?-]pyridine- AHIR)(dr -*|” indole-*-yl methyl)-"-oxo-ethylcarbamoyl]-1-methyl-ethyl)-carbamic acid tert-butyl ester {1-[2-(2-Benzyl-3-0x0-2,3.3a.4,6.7) -hexahydro-pyrazolo[4,3-c]pyridin-5-yD)-1-(R)- (1H-indole-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl } -carbamic acid tert-butyl ester Yo according to the method in general procedure (a); conjugate 100 mg TA (mmol) from b and 71 mg (1.0% mmol) from 1c and purify the substance Lagging parse

177

NT silica gel chromatography (0:90 vol/v methylene chloride: methanol) to give 0 mg of (MH*) 11 (Cl, NH;) MS 0 as a white solid benzyl-7-oxo- 7:765:87:7:71- hexahydro-pyrazolo —Y)-Y]-N- sil -7 (e)[?;6-7]pyridine-*-yl(-1-) 08-(111-indole-”-ylmethyl)-7?-oxo-ethyl]- isobutyramide hydrochloride 0 2-Amino-N-[2-(2-benzyl-3-0x0-2,3,32a) .4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5- yD-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide hydrochloride mL 010 mL Ethanol is added 01 mmol (from 10D at 10Y) to 0 mg min. The mixture was concentrated and the substance Yo concentrate was precipitated and the mixture was stirred at room temperature for a period of 17 mg HCI of 17 h. 1 residue of methanol / ethyl acetate to give 0 1117/1 (000): (partial) 8 7.4(m,4H) ), 7.25(m, 3H), 7.11(m,2H), 6.96(m,2H), 6.81(m,1H), 5.38-4.93(m,3H), 4.46(m,1H), 4.22 (m, 1H), 3.96(m, 1H), 3.9(m,1H), 3.18(m,1H), 2.28(m, 1H), 1.57(m,6H), 1.38(m,1H).7 Example ?-amino-[<-1[1-benzyl-oxy-methyl-7-(277-di_methyl-?-oxo-730567:7:7-, hexahydro-pyrazolo[;;©-8]pyridine-*-yl) -7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[1-benzyloxymethyl-2-(2,3a-dimethyl-3-0x0-2,3,3a,4,6,7- hexahydro- pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramide hydrochloride butyl ester ctert=) carboxylic acid ALD YO man methyl-;- oxo- - * (I)0 methyl ester -(R,S)-Y¥ 3-Methyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-(R,S)-methyl ester 318 DMF mL Yo g (7.77 mmol) of “Av1” was added to a solution of mg (0.77 mmol//) sodium hydride (dispersed oil 770) and stirred, etc. Light at milliliters (V,VY) in milliliters is 0.50 minutes. To the stirred solution add Yo at room temperature for about vo hr at room temperature 117 mol) of methyl iodide and stir the mixture for about once with water and four times with brine; Dry Jung dilute the mixture with ethyl acetate

Fed up ,4850 and focus. The residue was purified by silica gel chromatography (7: ?v/v hexane:ethyl acetate) to give 1,725 g of pure oil. (MH*)YYY (CI,NH;)MS (b)77p-(9yh)-_di_methyl-7-oxo-27:7:7; 4 - hexahydro- [oY] ols dom cpm —0— carboxylic acid -tert butyl ester 2.3a-(R.S)-Dimethyl-3-0x0-2,3.3a.4.6,7-hexahydro -pyrazolo[4,3-c]pyridine-5- ° carboxylic acid tert-butyl ester heated with re-vapor condensation for about § hours a mixture of 1.17 g (3.0 mmol) of IVY 5 lbs. 70 mg (9.50 mmol) of methyl hydrazine in 0?mL ethanol. The mixture was concentrated and the residue was dissolved in *0 milliliters of toluene and heated with [ale] 0 vapor condensation for about VE hours. The mixture was diluted with acetate “Ji” and washed twice with saline solution; dried over 118250 and concentrated. The residue was purified by silica gel chromatography iV (vol/vol hexane:ethyl acetate) to give 1 g of 711b as a white solid. 118 (Cl, NH3) MS (MH*)(C)270-(8,8)-di-VeTeocf caf Y= Jfe hexahydro-pyrazolo[;;7-]pyridine-Fe One hydrochloride 2.3a-(R.S)-Dimethyl-2,3a.,4.5,6,7-hexahydro-pyrazolo[4,3-c]pyridine-3-one hydrochloride to 1 g TIVE) of 711b in 50 milliliters ethanol lll A HCI concentrate was added and the mixture was stirred at room temperature for about 1 yo min. The mixture was concentrated and the 0 methanol/ethyl acetate residue crystallized to give 0 85 mg of 11g as a white solid. MS RET.(MH") Y1A (Cl, -8(-1[1-1(9) oxymethyl-7-(18,52-27:7- SD methyl-) ?-oxo-(Lua-7-7hydro-pyrazolo[?;”-8]pyridine-*-yl)-7-oxo-ethylcarbamoyl]-1-methyl-ethyl+-carbamic acid tert-butyl ester {1-[1-(R)-Benzyloxymethyl-2-(2,3a-(R.S)-dimethyl-3-0x0-2,3,3a,4.6,7-hexahydro- Yo pyrazolo[4,3] -c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl} -carbamic acid tert-butyl ester

YYA

mmol) of +E) 101 mg according to the method indicated in the general procedure (1) mmol) of 1 e is conjugated and the residue is purified by chromatographic analysis (0.5 mg) silica gel (10:40 vol/v hexane: ethyl acetate) to give 188 mg of a white solid. 7-(7?8,57-2)-di_methyl-?-oxo-© hexahydro-pyrazolo[?:?-e]pyridine-*-yl)-7-oxo-ethyl]-70427 isobutyramide 2-Amino-N-[1-(R)-benzyloxymethyl-2-(2.3a-(R.S)-dimethyl-3-0x0-2,3,3a,4.,6,7-hexahydro-pyrazolo[4, 3-c[pyridin-5-yl)-2-oxo-ethyl]-isobutyramide hydrochloride

Vo mL ethanol add 400 mmol) of 711b in TF) to 1177 mg v. Concentrate and stir the mixture at room temperature for about one hour. Concentrate the mixture in HCL in milliliters, the residue was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine; dried over 11021504, and the residue was purified by silica gel chromatography using separation in ethyl acetate. Residue 701 is dissolved into diethylamine 700 graded ethyl acetate [aqueous Jil Aue. The mixture was concentrated and the HCL residue was crystallized in ethanol and acidified with 0

MH") 017 (CI, NH;) MS ethyl to give 65 mg of 711H as a white solid.

ITHNMR(CD;0D): (partial) 8 7.32(m,5H), 5.14(m,1H), 4.53(m,3H), 3.71(m,3H), 2.97(m,1H), 2.83(m, 1H), 2.57 (m,1H), 1.98(m,2H), 1.61(m,6H), 1.38(s,3H). 18 Example benzyl-?-oxo-7a1:304:27071-hexahydro- —(R)=a¥)~Y]-N-5 ud -Y | © Pyrazolo[;6-7]pyridine-*-yl)-1-(08-benzyl oxymethyl-7-oxo-ethyl]-171:305:27:7:7-osco isobutyramide hydrochloride and 7-amino-7-[71-(27-57)-benzyl-”-hexahydro-pyrazolo[;;6-7]pyridine-*-yl)-1-(08-benzyl-oxymethyl-?- oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-(3a-(R)-benzyl-3-0x0-2.3.3a.4.6,7-hexahydro-pyrazolo[4,3-c] Yo pyridin -5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride

ARR and 2-Amino-N-[2-(3a-(S)-benzyl-3-0x0-2.3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1 -(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride Carboxylic acid methyl ester =F gu-benzyl-;-oxo-” (1) 3-Benzyl-4-oxo-piperidine-3- carboxylic acid methyl ester 0 mL At about 0*C add QF mmol) of 210A) 001 mg to 0° of cold trifluoroacetic acid and stir the mixture for about one hour. The mixture was concentrated and ¥ NaOH covalently evaporated the residue with ethyl acetate and hexane. To the residue is added to make it basic and the mixture is extracted with chloroform. The combined organic extracts were dried over SNA quantitative yield and concentrated to give MgSO, oxy-7-(08-(7-:-butoxycarbonylamino-?-[-1-lysene-R]-benzyl) ,S)-Y(b)0 methyl-propionylamino)-propionyl]-;-oxo-piperidine-"-carboxylic acid methyl ester 3-(R.S)-Benzyl-1-[3-benzyloxy-2 -(R)-(2-tert-butoxycarbonylamino-2-methyl- propionylamino)-propionyl]-4-oxo-piperidine-3-carboxylic acid methyl ester (mM)V1) g VL, VY according to For the method described in general procedure (a), conjugate to give a mixture of stereoisomer binary materials. Purify VE mmol (mg) from A) g TEs A. from 0 residue by silica gel chromatography (7). :?volume/volume of hexane: ethyl acetate) to give

VA) gm of an isomer? Most polar VV Eg (b18) Less polar 1 mg of isomer 0 of both isomers. -8,8(-2©(-[-1( (c) -1-]lyomabric [?©] pyridine-*-yl)-1-(8)-benzyl-oxymethyl-7- oxo-ethyl© butyl ester tert carbamic acid {JA methyl-{1-[2-(3a-(R.S)-benzyl-3-0x0-2.3.3a.4,6,7- hexahydro-pyrazolo[4.,3-c]pyridin-5-yl)- 1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl } -carbamic acid tert- butyl ester mL 1 (VA) 1 mg (,77 mmol) of the AY isomer to a solution of Yo (0,Y1) mM) of hydrazine sulfate and 17; mg (IY) mg VEY ethanol Add 117 mmol sodium acetate and heat the mixture with re-condensation of the vapor for about

hour. The mixture was concentrated, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and Gale's solution, dried over 148504 and concentrated. The residue was purified by silica gel chromatography using a gradient separation of ethyl acetate 775 in hexane to acetate 700 Gi −00 mg of isomer 1 of (210°) to a solution of 1.14 g VAT mmol) of isomer 1(81b) in 10 mL ethanol add 485 mg (0.77 mmol) of hydrazine sulfate and 11 mg (VEN) (mmol) of sodium acetate and the mixture is heated with re Steam condensation for about 117 hours. The mixture was concentrated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine; dried over 14850 and concentrated. The residue was purified by 0 silica gel chromatography (YoiVe) vol/vol ethyl acetate/hexane) to give 101 mg of the isomer ? From (=A)—Y (3)amino-7[1-7-(23-(08-benzyl-”-)—V lef @l eV e¥= gulf hexahydro-pyrazolo [ o-Ved]pyridine-*-yl)-1-(08-benzyl-oxymethyl-7-oxo-ethyl]-isobutyramide hydrochloride 2-Amino-N-[2-(3a-(R)-benzyl-) 3-0x0-2.3.3a.4.6.7-hexahydro-pyrazolo[4,3-c] Vo pyridin-5-y1)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride to 001 mg TE (milligram) of 1 isomer of (VA) in VY mL ethanol add 1 mL 1101 concentrate and stir the mixture at room temperature for about 2½ hours. The mixture was concentrated and evaporated three times with ethanol to give 71 mg of the 1 isomer of (A) 0 qa (CLNH; kcf MH") 8.42(br d,1H), 7, 35(m,5H), 7.18(m,5H), 5.23 (m,2H), E (partial): (0,00) 1111/1 4.91(m, 1H), 4.54(m,4H) ), 3.80(m,2H), 3.63(m,1H), 3.12(m,1H), 3.07(m, 3H), 2.61 (m,3H), 1.62(m,6H), 1.39(m, 1H). Pyridine-*-yl)-1-(08-benzyl oxymethyl-7-oxo-ethyl]-isobutyramide hydrochloride

1171 2-Amino-N-[2-(3a-(S)-benzyl-3-0x0-2.3.3a.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R (-benzyloxymethyl-2-oxo-ethyl]-isobutyramide hydrochloride mL ethanol Yo mM) of the ¥ isomer (801g) in (174) 001 mg to 1101 mL concentrate and stirred the mixture at a temperature room for about two hours 01 is added from 1 mg of isomer 71 1/2 The mixture is concentrated and covalently evaporated three times with ethanol to give 0

(1e). (MH*) £4Y (Cl, NH;) MS THNMR(CD;0D): (partial) 6 8.29(br d,1H), 7,30(m,5H), 7.11(m,4H) , 6.88(m,1H), 5.29(m,1H), 4.92(m,1H), 4.62(m,3H), 3.91-3.70(m,3H), 3.22-2.95(m,3H), 2.66 (m, 3H), 1.57(m,6H), 1.30(m,1H), 0.89(m,1H). 1 as 15"-amino-14-[1-(8)-benzyl oxymethyl-7-(17-methyl-?-oxo-27-(04,8-thiazole-;-butmethyl-76:5487202:70-hexahydro-pyrazolo[?;?-»]pyridine-*- yl)-1-oxo-ethyl]-1-isobutyramide hydrochloride 2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R.S)-thiazol- 4-ylmethyl-2.3,3a,4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-1-vo isobutyramide hydrochloride (i); - oxo-7-(08,5-thiazole-;-ylmethyl-piperidine-0;?- dicarboxylic acid-46-1-butyl ester*-ethyl ester 4-Ox0-3-(R.S)- thiazol-4-ylmethyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester Y. to a solution of 00 mg (0 VV mmol) of 1a in * milliliters of THF at approximately 0*C add TY mg (151 mmol) sodium hydride (oil dispersion A) The mixture is stirred for about 10 minutes. A solution of 704 mg, (71 mmol) of chloromethylthiazole (1990) 3507 M, 20 (Hsiao, C.N.; Synth.

Comm. in ve > milliliters of THE to the cold solution; Then AY mg (507+ mmol) of potassium iodide and the mixture was heated with vapor re-condensation for VY h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over 1182507, concentrated and purified (sald).

The residue was analyzed by silica gel chromatography (7:7 v/v hexane:ethyl acetate) to give 00 mg of the title compound. MS (F 1111 (Cl, 1448 (0111.b) 7-methyl-?-oxo-87-(08,5-thiazole-;-ylmethyl-702:5877:7-hexahydro-pyrazole] ;;6-7]pyridine--carboxylic acid tert-butyl ester 2-Methyl-3-0x0-3a-(R.S)-thiazol-4-ylmethyl-2,3.3a,4,6,7-hexahydro- pyrazolo [4,3-©c]pyridin-5-carboxylic acid tert-butyl ester to 90 mg TE (milligram) from 51a in 1 milliliter ethanol added 0.11 mg YE ) milligrams) of methyl hydrazine and the mixture was heated with vapor re-condensation for about 11 hours. An additional 37.7 mg (177 mmol) of 0-methyl hydrazine was added and the mixture was heated with re-condensation for 1 hour. The mixture was concentrated and the residue was dissolved in “ml toluene” and heated with vapor re-condensation for VY hours. The mixture was concentrated and the residue was purified by silica gel chromatography (7: ; v/v hexane: ethyl acetate) to give 6 lbs mg of pollen. MH") 1¢A (CL, NH;) MS (c) ?-methyl-27-(8,5)-thiazole-;-ylmethyl-7755077-hexahydro-Sym0[6] -7:4]pyridine-7-one-dihydrochloride 2-Methyl-3a-(R.S)-thiazol-4-ylmethyl-2,32.4.5.6.7-hexahydro-pyrazolo[4,3-c | pyridin-3 -one dihydrochloride was stirred at room temperature for about 2 hours a mixture of £1 mg (1+ lle mol) of 91b in 1 milliliter of 1101 mol in dioxane The mixture was concentrated and covalently vaporized with methylene chloride to give 50 mg of 4 H. (MH*)Yo) (CL NH;) MS (d)-08(-1[1-1)benzyl oxymethyl-7-(7-methyl-” *- oxo-27-(158,8)-thiazole-;- ylmethyl 77: La 17056462707 hydro-pyrazolo[?;6-7]pyridine-*-yl)-7-oxo-ethylcarbamoyl]-1- Methyl-ethyl-carbamic acid tert-butyl ester {1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-ox0-3a-(R.S)-thiazol-4-ylmethyl- 2.3.32.4.6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1- Yo ‎methyl-ethyl}-carbamic acid tert-butyl ester

According to the method described in the general procedure of ©0 mg Y (+ mM) of 4 g YA mg VY (mM) of VE was conjugated and the residue was purified by gel chromatography Silica (1:19 vol/v ethyl acetate/hexane) to give 0 mg of 19H. (MH*)11 (Cl, NH;) MS (a) ?-amino-]-[1-(-So-methyl-7-(7?--V—fe-oxo-benzyl) ~(R,S)=a¥~ thiazole-;-ylmethyl-705664687:727-hexahydro-pyrazolo[;;6-7]pyridine-*-yl)-?-oxo-ethyl]-1- Isobutyramide hydrochloride 2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-0x0-3a-(R.S)-thiazol-4- ylmethyl-2,3,3a, 4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-1- isobutyramide hydrochloride Ve was stirred at room temperature for about © hours mixture of 560 mg ) 101+ milligrams) from 51d in 1 milliliter of HCL ; Grammolecular in dioxane. The mixture was concentrated and covalently vaporized with methylene chloride to give 401 mg of 159 H. MS (F-111 MH") 01 (CL, Ex 01-Y 10 Amino--[7-(©2-(08-benzyl-7-methyl-?-oxo-7:60508777- Hexahydro-pyrazolo[;6-7]pyridine-*-yl)-1-(08-oxymethyl-benzyl-?-oxo-ethyl]-isobutyramide salt of A-Tartric acid 2-Amino-N-[ 2-(3a-(R)-benzyl-2-methyl-3-0x0-2.3,32.4,6,7-hexahydro-pyrazolo [4,3-c]pyridin-5-yl)-1-(R)- benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartaric acid salt Y. to .7 g of compound example title 164 in 10 milliliters methanol; added at about 0*C a solution of 1, 77 g of 1.a- tertric acid in 10 mL methanol.ay the mixture brought to room temperature stirred for about 0 min and concentrated by vacuum the residue was diluted with 100 mL ethyl acetate reheated The vapor condensed for about an hour and a half, then fluctuated at Yo at about 77*C for about VA an hour. The mixture was cooled to room temperature and filtered to give 5.4 g of the title compound as a colorless crystalline solid. Mal 1?

?- “Yd methoxycarbonyl methyl-;- oxo-piperidine-1-carboxylic acid” tert butyl ester 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester 0(a)*-benzyl-?-oxo-piperidine-1-carboxylic acid tert-butyl ester 3-Benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester A mixture of m-keto ester (44860 mg; 17.9 mmol) and 1101 (0+ VY ana 159.8 mmol) in DMF (Y) mL) is heated at about Yo) ga for about 117 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (V+ + XY) in milliliters). The combined extracts were dried and concentrated by vacuum. The crude product was chromatographically decomposed at 5:0 with 7710 ethyl acetate/hexanes to give 1771 mg of the desired product as yellow oil. d: 7.4 (m,5H), 4.2(m,1H), 3.4(m,1H), 3.3(dd,1H), 3.05 (bl:000, 11111/12501112 (dd,1H), 2.7(m) ,1H), 2.55(m 4H), 1.5(s,9H); Piperidine-1-carboxylic acid tert-butyl ester 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidine-1 -carboxylic acid tert-butyl ester Y. The vapor of a solution of the product is re-condensed from step (a) of example 11 above is 1171(mg 01,01 milligram ); pyrrolidine (AVY) mg; VY milligrams) and p-toluene sulfonic acid (YY mg) in Yo benzene (mL) through “Angstrom” molecular sieves for about VY hours. The reaction mixture was cooled to room temperature and concentrated by vacuum. The residue was dissolved in benzene (bile 01) and cooled to about 0°C. Methyl bromoacetate VOY (mg; 01 mmol Ye) was added dropwise. The reaction mixture, liad, was slowly brought to room temperature. Then heated with vapor re-condensation for about 11 hours at which point 0:11 (0 milliliters) was added. After vapor-re-condensing for about another 2 hours the reaction mixture was cooled to room temperature and extracted with 100% BtOAC

ARN

United organic extract and concentrate by suction. Substance chromatography analyzes (of gall in milliliters). mg of the crude YA residue was dried on a 5107 gel using 716 ethyl acetate/hexanes to give the product. TH NMR(250MHz,CDCl,): d: 7.35(m,5H), 4.5(m,1H) , 3.8(s,3H), 3.4(dd,1H), 3.1(m,1H), 2.85(m,4H), 2.6(m,1H), 2.4(m,1H), 1.5(s,9H); MS: (APCI) ° (M+1) ¥1Y

YY eg -1-butyl ester tertY cyclohexane-701- dicarboxylic acid —d -1-osco -> methyl-ester 6-Oxo-1-phenyl-cyclohexane-1,3- dicarboxylic acid 3-tert-butyl ester 1-methyl-ester 00 mg; 0,¥ mM AGL) a solution of diphenylmercury siete heated to about

Y.0 mg 1111 (lead tetraacetate Np add milliliter) under £) CHCl gram) in git edie mol) in small batches and stir the greenish-yellow solution lle about half hour. Then a 3-keto ester (700 mg; ¥ millimol) and then pyridine (mM). After about ½ hours at about 6 µC; the mixture was concentrated (0 mL Yio lle Yio) and filtered. The filtrate was washed with reaction 001 (vacuuming and the residue was dissolved in standard ether (¥ times); dried and concentrated. to yield 1176 mg of a yellow solid.N* 1150+ using 770 ethyl acetate/hexanes provides SiO;stain chromatography over a mg gel of desired product. FIA

IH NMR (400MHz,CDCly): d: 7.15(m,5H), 4.4(s,2H), 3.7(s,SH), 2.6(s,2H), 1.5 A (s,9H). (M+1) 3: (APCl) MS

YY Example (©0-?-amino-7-(7;-dichloro-benzyloxy)-propionic acid hydrochloride (D)-2-Amino-3-(2,4-dichloro-benzyloxy)-propionic acid hydrochloride Yo butoxycarbonylamino-7-("?-dichloro-benzyl oxy)-~tert=Y=(D)(a)propionic acid

(D)-2-tert-Butoxycarbonylamino-3-(2,4-dichloro-benzyloxy)-propionic acid to a stirred solution of -D-Boc serine AY) g; 560 mmol) in DMF (Vo milliliters) at about 0*C. NaH (dispersion 7250 7.7 g; Av mmol) is added over about 10 minutes. The reaction mixture was stirred for about 1.75 hours at about 0"C; then 0 about 1.70 hours at room temperature. After cooling to about 0*C; AUS-chlorotoluene (AUS) was added dropwise 0.07 milliliters; 460 milligrams) in DMF (© milliliters). The reaction mixture was left to warm to about 77”C and stirred for about 117 hours; then divided between di-isopropyl ether (J) + HCly, extracted Aqueous solution with di-isopropyl ether (twice) The combined extracts were washed with saturated aqueous brine, dried and concentrated to give 16.78 g Ga 0 crude product which is used without further purification IH NMR (400MHz,CDCl,): d 7.6-7.2(m, 3H), 5.4(d,1H), 4.6(s,2H), 4.0(d,1H), 3.8(dd,2H), 1.1(s,9H); ranatm): M+1, M+2) Y11 (Y1¢ (b) (©-?-EY) Y= sind — dichloro-benzyl oxy)-(D)-2propionic acid hydrochloride -Amino-3-(2.,4-dichloro-benzyloxy)-propionic acid hydrochloride Vo Stir the product from Step A of Example YY above VE,Y (g; £0 mmol) in HCL ;momolecular/dioxane 001(mL) for about 117 hours.The reaction mixture is concentrated by suction to give 11 g of a pale yellow solid (M+1) 731 ((APCI) MS (7100). Ph RN 1 INE 0 * STEAL H 0 where RY is phenyl-112©- -CH-phenyl and 18 is cmethyl in a manner similar to the procedures described in examples a to “and using the title compound of Example 71 as a prefix. Both stereoisomers isolate SR RR (* denotes the center of the other stereoisomer at carbon C-3 lll ve above). Mass spectrum (oY = 0 + 1) MS method = particle ejection.

yyy and 77 Yo Examples 77 and yy have the form shown below: Yo Examples 2

PEA 0 0

LN NH; 1 N 0 R 0 H 0

Yo where the example is “methyl and 12 is methyl phenyl is RI phenyl and 77 is Yo where for both examples

A Blas by YT Yo The two examples create SR and Example 77 is the RR isomer RR is the © isomer as a precursor then YY to “and using the example title compound oF for the actions described in Examples 497; Method = (M+]) Each example AES Chromatographic separation of the two separated isomers. The ejection spectrum of a particle. = MS 10-717 Examples According to the program shown below by NED noted in Table Ved Examples are brought to 1 by the appropriate substituent of formula 1 (in the program pyrazalone-piperidine Conjugate the pyrazalone-biperidine derivative [1] (in the program below) in a manner similar to the procedures described in (D)-OBnSer below) with . SY Example 1 e and example

R2

A

NN Ar 18 r 0 0 N 1. EDC, HOAT NS 0

R + A 2. HCI LLL:

H o 1 OR § HK 0) 0 According to Jab I of the formula pyrazalone-piperidines, prepare the pyrazalone-piperidines ve for the procedures described in Example B and Example C by starting with the appropriate alkylating agent and alkyl hydrazine in three steps in a manner Similar IT (D)-OBnSer talkylhydrazine derivatives Ex. 77b and Ex. #f.YY are prepared for the procedures described in Ex. 2

Na0

RN0

LN NH; 1 N 0 R on

CHAR | 8 | Like | isomer

YYA

Say EE EE A = v

Rl 2-pyridyl £44 phenyl thiazolyl phenyl —¢ H 01 YA MSS 7 L I I 4-thiazolyl EN 5-thiazolyl 4 L T PB | Unhappy Alt

ERE | ala "2-pyridyl

PS

PB [NY | 35diChip

APCI | 1 3-Cl-thiophene phenyl Me 01 3 fl I tall Uh I A PB | ov

PB[Se| 4CIPh | phenyl

PLL Ge[ELT 4-Pyridyl

ER a a a d 4-thiazolyl APCI| E0 thiazolyl —o phenyl Me dl ¢EA

RT Bal Ba Moaning EEE ah benzisoxazolyl

R= a 7 a 4-pyrimidinyl ) 4-thiazolyl NB 2-Pyridyl

FB [TE| phenyl ds | 4FPR | Me

PB

7B [eon| Ch | 4FPh | El

PB [een| Tate | 420 | Me | © |] Layth | 0f | 420 2-pyridyl 3-pyridyl oA Phenyl?*-pyridyl = Me di 1¢

I I = I~ I 0q¢ phenyl quinolinylphenyl —Y Me 01 10

El A FS —Y Me d2 17 quinolinyl phenyl 0d¢ phenyl msn ss a mainly —Y Me dl pyridyl phenyl J N N A SL qan 0 a 0000 U SAS Me d1 ,2 | 4” - Pyridyl 3-F-4-CI-Ph Non | APCI i I= = Me dl 2 "- pyridyl 3-Cl-thiophene km | APCI din n b lakhad ovo 3-CF3-Ph pyridyl -” Me ll i i HL oe tL Ee

API| E0 phenyl thiazolyl phenyl —¢ Me 01 l rh ss yen lsals PB ony phenyl?; Pyridyl Phenyl - Et 01 vy Alance S + Ea a Sed A Al + I

PB et | 54 0

PB [eet| Sh. 34

A A A Nancy Nil Bal Et d2 | AA "- Peredil Tay 3,4-di-F-Ph ahma © | 8 - ~= i 8 PB | ev. | 34diFPh | 4CLPh | © | di | av | PB | en. | 34dibPh | 4CKPh | © | @ | av] PB | WY | 35dClph | 4CKPh | Bt | dl | aA 2e | © | PB | WY | 35.4iClPh_ | 4CLPh (PB | ohn | 3CiPh | 4CKPh | © | 0 01 | PB | oat | 3.CLPh | 4CPh | © | © [Vo PB | ove | 34diPPh | A4FPh | © | dl 011 0.tl | © | PB | ove |3AdiFPh |4FPh CFsCH, |21,2 108 phenyl ¢—thiazolyl 5 APCI|i n EE al hl

APC) or 4-thiazolyl

API| 1¢v pyridyl —Y 2,4-di-Cl-Ph 1 CF3CH, | d1,2 00 tooth AA that we forget i that

011 4-thiazolyl EN

I I i i] i 4-thiazolyl 2-pyridyl 2-pyridyl

RE a lisn C 2-pyridyl

Bl I = il I sn 2-pyridyl 2-pyridyl n I == ad sn 2-pyridyl

Ea 2-pyridyl

I i I + 11 3,4-di-F-Ph pyridyl -"

ER 2-pyridyl 2-pyridyl

BA I «= a +

API| We 3-Cl-thiophene pyridyl —Y CF;CH, | dl 08 fl The cornerstone of the corner + id I na APCI | YY 3-F-4-CI-Ph Pyridyl -" CF;CH, | 2 74

EEA 2-pyridyl

API| 4 3-OCF3-Ph Pyridyl - "Assan OER for EE the L I Shak God 2-1 WIM C for Sales 2-pyridyl re ons

VEY

APCI 4-C1-Ph Yatooq? - Peredel | d1,2 1 856 3-pyridyl

APCI 3-Cl-Ph 4-CH3-Ph | CF;CH,

APCI 3-Cl-Ph 4-CH3-Ph | CF;CH, (PB | NEE | 34 402 | 0

PB | nit | 34 4-CLPh | CRsCH,

PB | Wve | 3,5-di-Cl-Ph 4-Cl-Ph CF;CH, [PB| ve | 35-diCLPh 4-CLPh__| CRiCH,

PB | WY | 5-Clph 46 | CRCH,

PB | iv | 3-ClPh 4-CLPh__| crCl,

PB | Ya | 34-diF-Ph 4200 | CRiCH,

PB | Ya | 34-4 420 | CRiCH

PB | Yt | 03-00 420 | CRC (PB | WT | 3-00 G4 | CRiCH

APCI 2-CF;-Ph 4-Me-Ph CF3CH,

APCI 3,4-di-F-Ph 4-Me-Ph CF;CH, note in the above table; The isomer refers to the stereochemistry at position 0–3 (delimited by “pyrazalone-piperidine by the symbol “*” in the construction) of the pyrazalone-piperidine group and 22 to chromatographically separated isomers; 01,2 refers to a mixture of isomers 1 is a particle ejection; 17 Example IH NMR(400MHz,d4-MeOH): d 7.2(m,5H), 5.2(t,1H), 4.6(m,3H), 3.8 (d,2H), 3.1(d, 1H) , 3.0(s,3H), 2.6(dd,2H), 1.6(s,6H).

TA and eg TY eg IH NMR(300MHz,d4-MeOH): d 8.85(s,1H), 8.6(t,1H), 8.1(d,1H), 8.0(t,1H), 7.35 1 (s,5H), 5.15(s,1H), 4.6(bs,3H), 3.85(m,2H), 3.65(m,2H), 3.2(s,3H), 2.75(m,2H), 1.65( s,6H).

YA Example IH NMR(400MHz,d4-MeOH): d 8.8(s,1H), 8.6(s,1H), 8.5(t,1H), 7.96 (t,1H), 7.9(d, 1H) , 7.45(d,1H), 7.33(d,1H), 5.2(s,1H), 4.6(s,3H), 4.4(m,1H), 4.2 (m,2H), vo 3.9(m,4H) , 3.5(m), 3.2(m,2H), 2.8(dd,2H), 1.6(s,6H).

Ye and example of 16 examples

VEY

IH NMR (400MHz,d4-MeOH): d 8.76(s,1H), 8.50(t,1H), 7.92(dt,2H), 7.43(q,1H), 6.90(t,1H), 5.20(m, 1H), 4.90(m), 4.30(m, 1H), 4.20(m,1H), 3.7-3.4(m), 3.30(s,2H), 3.20(m, 1H), 2.80(dd,2H), 1.60(s,6H).

TY Example IH NMR (300MHz,d4-MeOH): d 8.7(1,1H), 8.45(t,1H), 7.9(t,2H), 7.25 (m,4H), > 5.2(m, 1H) ), 4.95(d, 1H), 4.6(s,2H), 4.3(m,1H), 3.8(t,2H), 3.5(dd,2H), 2.8 (m,1H), 2.8(dd,2H) , 1.6(s,6H).

SAYA Example 1H NMR (400MHz,d4-MeOH): d 8.8(dd, 1H), 8.6(s,1H), 8.5(t,1H), 7.95 (t,1H), 7.9(s,1H) , 7.3(s, 1H), 7.0(s,1H), 5.2(s,1H), 4.85(s,3H), 4.4(m,1H), 4.18(m, 1H), 1 3.8(m,2H) , 3.5(dd,2H), 3.2(d,2H), 2.8(dd,2H), 1.6(s,6H).

VEY and example VE) example 1H NMR(300MHz,d4-MeOH): d 8.75(m, 1H), 8.5(m, 1H), 7.9(m, 2H), 7.3(s,2H), 5.2 (m, 1H), 4.65(m, 1H), 4.55(s,2H), 4.35(m, 1H), 4.20(m, 1H), 3.8 (t,1H), 3.5(dd, 2H), 3.15( d, 1H), 2.8(dd,2H), 1.6(s,2H). vo 171-1560 The examples shown in the table below are according to the program shown below by 1749 to 060 The appropriate examples are prepared (in the program) with (I) substituted pyrazalone-piperidine Conjugation of pyrazalone-piperidine (See Example C) in a manner similar to the procedures described in Hammel's example (ID) derivative 0(-770) and Example O. 00 a ha 75 y 0 - 0 1. EDC, HOAT

A + HO oe 2. HCI JR N > ND 8 9 B OH

NH

= I 2 dw Tuy

m [ as No. | visit | 8 | CAR APC +-CF Ph APCI 4-CF; Ph PB | evr | arn PB | ovr | ak APC] +P Ph APCI 24-di-CLPh APCI 24F-Ph APCI CF, Ph APCI CFP P| ev | scien ‎PB | ew | 4Cirh [APC] ED) except APC] APCI 24-0 | CRiCH;APCI 24-diFPh | CR.OH;TPB | Ww | 4CiPh | CECH PB | Uv | 4CPh | CRCH d | K 0 m CROHL | ke APC] 4MePh | 0 0 Note: In the above table; The isomer refers to the stereochemistry at position C-3 (identified by the symbol “*” in the construction) of the pyrazalone-piperidine group. 1 and 22 refer to isomers that have separated chromatographically; 01,2 indicates a mixture of isomers. EXAMPLES 187-186° Examples 088 to VAY shown in the table below are prepared according to the program shown below by conjugating the appropriate pyrazalone-piperidine substituent 1 with the acidic intermediate Iv in a manner similar to the procedures described in Example E The example "and .

R2 /

N-N A =O ‘0 1. EDC, HOAT po (fs Ao m + HO mil 2.00 N NA

H o Hf OR n 8 0 av) with the product of amino acid by treating an amino acid (IV) the acid intermediate compound is prepared. §© Example 20 using the known process described in Example 01

Vio

Ns Ar

Sg A my oR 5 A s way | 5 Ar -CH,-A' = R Example | isomer

ms i,

PB | of | (CH Phenyl Js

PB | een | SCHR Phenyl So it was said i Yr is 2-Naphthalenyl [PB | ove | CHbO-(4-F-Ph) | Phenyl Tel Note: In the table above; isomer denotes stereochemistry at position 0-3 (identified by the symbol “*” in construction) of the pyrazalone-biperidine group ©0778281006-010©:1010» 0778281006-010©:1010» denotes chromatographically separated isomers; 01,2 denotes a mixture of isomers.‎ 1

Claims (1)

VET protection elements qt-1 method 1 to treat or prevent a disease or Als that may be treated or prevented by growth hormone It includes the consumption of a human or other animal in need of such treatment or prevention of a quantity of a compound of 1 Formula: Rl i R3 ¥ SUG ENR Ne, # ! | I RS We forgot right 0) ¢ Racemic-diastereomeric mixtures and isomers 1 18010618 ophthalmic of the aforementioned compounds, salts, and prodrugs accepted Pharmacologically, gia where: 4 6 is zero; san | zero, nor is it 7; or © is 1 saws) or © is 1 and is zero; Y 0 is oxygen or sulfur RI 1 Maru ~(CHy)N(X6)SO,(CH,)-A! ¢-(CHp)N(XS)C(O)(CHy)A! (CH), C(OIN(X6)(CH,)-A! (CH) N(XE)C(OIN(XSCH) Al 0 «(CH,),0C(0)(CH,) A! (CH) C(O)O(CHpA! 0 ~(CH;)S(0)n(CHy)-A! (CH) C(O) CHy)-A!(CHp),OC(ONXO(CHy)-A!0 d -(CH,),-Y!-(CHy)-A!4 -(CHp) -A!8 where optionally substitutes the alkyl and cycloalkyl groups in the definition of “0 for an alkyl (C1-Cy) oli-,0); alkoxy hydroxyl (CLC) M “(C;-Cy)alkoxy carbox_yl “-CONH, “carboxyl keql and -2). - ester or oleyl-0)0-1H-7tetrazole-#-yl 1H-tetrazol-5-yl or 1 ? or? fluoro (¢fluoro Y) rmo 0. ,;)0(§ -ksarma). -N(X6)C(0)- «-C=C- «-CH=CH- ¢-0C(0)- 4 -OC(O)N(X6)- «-C(0O)O - ¢-C(O)NX6- YY Yr is yellow J YY);; at Ye yellow 1 »1 or ?; 01 mentioned with (CH), and the (CHy)q group may optionally substitute a vo “carboxyl group” (C-Cylalkoxy (C;-Cy) chydroxyl hydroxyl 1 -COy (C-Cy) alkyl (m0-2)m(5)0-alyl (m-5)0(.)0-; alkyl ester -CONH, Yv or *fluoro-YY (1H-tetrazol-5) -yl tetrazole-#-yl-1H “-CO,(C;-Cy)alkyl ester YA ¢(C;-Cyalkyl (C1-C4) Alkyl Y 4 1 see “fluoro Ya alkyl) (C3-Cg) cyclic alkyl “(Cy-Cylalkyl (C-Cg) alkyl chydrogen is hydrogen 12 7 y-abolly-)- (C1-C4) because chyla -(Co -C3)alkyl-(C3-Cg)cycloalkyl -(Co-C3) 1 Al or vy in cycloalkyl and cycloalkyl where optionally substituted by alkyl groups ry -N(X6)(X6) «- C(O)N(X6)(X0) «-C(0)OX® hydroxyl with hydracamyl R?definition 7 d J CN «CF; «-C(O)(X®) -C (0)A!(b0-2)rf)q-S(0)(C;-Cq) alkyl Yo ¢ halogen or * halogen “a” - (C1-Cg)alkyl-A ' -(C1-Cg) the alkyl «(C;-Cypalkyl (C,-C;o) alkyl (Al sa R3 Yv -X'-(C1-Cs) alkyl ¢ ~(C- Cg)alkyl-(C3-Cr)eycloalkyl -(C1-Ce) alkyl -(C3-Cr) cycloalkyl va (C1-Cs) alkyl -X'-(Co -Cs) Alkyl -A! «-(C-Cs)alkyl-X'-(Ci-Cs)alkyl -(C1-Cs) alkyl v3 X'«(C}-Cs) alkyl + (C3-C7) or dary alkyl ‎ -(Ci-Cs)alkyl-X'-(Co-Cs)alkyl-A' ¢. ¢-(C,-Cs)alkyl-X'-(C;-Cs)alkyl-(C3-C7)cycloalkyl -(C1-Cs) alkyl oy in definition 183 with alkyl (M6-:5)0 (,,)0- alkyl where alkyl groups are optionally substituted 6 10 or halogens or © halogen atoms € oF T 1 OL-0 (0(0)s-03rt) 31 OX3 or ? “ 2 “-C(0)0- “-OC(0)- “-C(O)N(X?2)- “-N(X2)C(0)- “S(0),, <O bitter XI go -C=C- 4 -OC(O)N(X2)- «-N(X2)C(0)O- ”-CX2=CX2- £1 (C3-Cy) or Cycloalkyl (C|-Cglalkyl (C|-C¢) Alkyl chydrogen is hydrogen 4 3 ¢ (C5-C;)cycloalkyl ¢ together RY Ar 164 is taken with (C;-Cgalkyl (C;-Cq) an alkyl of hydrogen is hydrogen 4£4 bonded to a carbon atom bonded to 14, a nitrogen atom and a nitrogen atom oo to form a five- to seven-membered ring p110; 84 oy YEA ANZ _ AQ ANS 21 6 is (CH2)a (CH2)b 1 ov where 8 and 0 separately are 1 ha or ?; 65D and 1458 are selected separately from the group consisting of 00 fluoromethyl covalent hydrogen Al «trifluoromethyl and the alkyl (and ©-©) (optionally substituted C1-Cglalkyl; 01 optionally substituted for the alkyl (C- Colalkyl (C1-Co) optionally substituted in definition of X5a and 1458 with a substituent chosen from the group consisting of the alkyl OX?Al-S(0)(C-Cq)oA and for bucket5(0). ) 0-0- SSI -C(O)OX2 dre baee) «(C3-C;)eyeloalkyl ¢-C(OIN(X2)(X2) 5 -N(X2)(X?) od 1 1 is bond © or (N-X2) provided that Laie is bya both are zeros then 71 11 is not N-X2 or 0; 27 7 each separately is hydrogen or the optionally substituted alkyl (C1-Cgalkyl (C-Cg) ay; 1 where each optionally replaces the optionally substituted alkyl (m©-,©) 01l8m©-,0) in Te definitions 167 and 1854 with (Al alkyl (m©-:,6)-0(0)©- or Al(0-0)-0)0(0-; 1 alkyl ¢8(0)y(Ci-Coalkyl -S) 0)y(C-C) ~~ ™ to © halogen atoms 1 chalogens to 3 1 hydroxy 1 cihydroxy to ¥ alkyl (f:©-:0-6)0()6-tola(j,©- ,©)(0-0)0- or 1m1 to the koxy (CC) and «and above (and -©); or 14 can be taken y R7 and 1285 come together to form ¢-(CH,),-L-(CH,),- q where L is “C(XH(X?) E(5)20 or - NX?) 1 because uh in the definition of R! To A members saturated (Wa saturated LIS or unsaturated (LS) a ring system vy a bicyclic ring consisting of a ring p0 with 0 or > fully saturated members (La ve unsaturated or saturated (LS welded to a © ring or 6-membered partly saturated fully saturated or not fully saturated; Al 7 in the definition of at least RPS 187 RC separately the alkyl is circular (C5-Cy ) “(Cs-Co)cycloalkenyl vv phenyl or ring having ¢ to A members partially saturated; saturated 4<" va completely or completely unsaturated optionally has 1 to; heteroatoms selected separately va 0 the group consisting of oxygen coxygen sulfur and nitrogen cnitrogen ring system system A. A circular binary consisting of a 0 or 7-membered p0 ring saturated (Wa 0 completely unsaturated or optionally saturated (WS) having 1 to 1 individually selected heteroatoms from AY The group consisting of nitrogen «©010088» sulfur & oxygen fused to ar liming ring © or + partially saturated members US or optionally totally unsaturated having 1 to AS 0 ? Heteroatoms selected separately from the group consisting of nitrogen Ae sulfur sulfur and oxygen 860-: e; AT AY in each Ala separately is substituted (Lobia) in one p0 ring or both AY rings if Al is a bicyclic ring system; with up to three (Jia AA) each alternative being separately selected from the set formed by l «OCF,H (OCF; d Br «Cl «OCH; «CH; «CF; AS ClDM -C(0)OX6 « -C(OIN(X6)(X6) OXO Jl (0 x0 «(Cj-Celalkyl (C4-Ce) a nitrite cyano situs «nitro alkyl benzyl -S(0),,(C1-Cg) -1H «-S(0) ,,(C-Cg)alkyl 91 tetrazol -*- yl “1H-tetrazol-5-yl phenyl cphenoxy 9 phenylalkyloxy halophenyl chalophenyl methylene ar dioxy -SO,N(X6)(X6) «-N(X6)C(0)(X6) -N(X6)(X6) cmethylenedioxy (CONX!1X12 -N(X6)SO,X6 « -N(X6)SO,-phenyl -N(X6)SOp-d— yi 0 «-NX6SO,NX11X12 ~NX6CONX11X12 »~-NX650,X12 «-SO,NX 11X12 qo -NX6C(0)X12 11 cimidazolyl thiazolyl or dtetrazolyl ay provided that if A is optionally substituted with a methylenedioxy then aA can only be substituted with one methylenedioxy; 14 where !151 is hydrogen or (C)-Cglalkyl (C;-Cq) optionally substituted for Veo; 11 Each optionally substituted for an alkyl (Cy-Collalkyl (C-Cg) optionally substituted x in definition X11 with phenoxyphenyl 1601:0600 alkoxy carbonyl 00-,©) ¢(C;-Cg )alkoxycarbonyl Vor 1 alkyl -§(0),,(C;-Cpalkyl -S(0),(C-Cg) to You alkanoyl oxy YW hydroxy to “1 hydroxy chalogens” halogen atoms © Vet ¢(C;-Cglalkoxy (C;-Cg) to alkoxy 1 or (C-Cjg)alkanoyloxy (C1-Cyg) ) Veo thiazolyl phenyl phenyl “(Cy-Coalkyl (C1-Cg) Alkyl hydrogen is hydrogen 2 0 provided that when cthienyl furyl cimidazolyl imidazolyl ctiazolyl no optionally substituted with one to three X12 the chydrogen is hydrogen X12 not being 0 OCF; “OCH; “CH; L” Cl substituents selected separately from the group consisting of 4 (- (CH,),-L1-(CH,),- and 3612 come together to form X11 or take ¢CFy "" N(X2) Ar (SO), m 202 m LI Cua 11? or 10 in each case is "1" (C,-Coalkyl alkyl (and ©-)) hydrogen in each case is Optionally substituted X2 ny hydrogen where optionally substituted (C3-Cyleyeloalkyl (C3-Cy) or optionally substituted Mie cyclic alkyl and cyclic alkyl (C-Cglalkyl) optionally substituted alkyl (m©-,©) JS 5 -S(0)(C1- Cg) optionally substituted in definition 162 with an alkyl (C3-Co)eyceloalkyl (C5-C7) 75 «0X3 ¥ to 1 or halogens to © halogen atoms 1 -C(0)OX3 lollo-,5)0(.,)0-; 0 or alkyl (and©-:©) children (and-0); hydrogen separately Alla hydrogen is 53 in each oleate (0-,0) inferred (C;-Cq) alkyl hydrogen separately is hydrogen 6 14 (C3-C) alkyl Circular ¢(Cy-Co)halogenated alkyl (C,-Cq) Selectively alkyl halogenated 0 (C3-C)- sim a Selectively alkyl daric Vague (C3-Cy)eycloalkyl 1 (C1-Ce) where The optionally substituted (C3-Co)-halogenatedeycloalkyl 0 (C3-C)eycloalkyl optionally substituted (C3-Co)eycloalkyl (m©-,©) and the cyclic (b©-r©) vr (anolelidean hydroxyl) are each separately substituted ©-,©) hydroxyl (C=C) or ? Alkyl 1 by X6 optionally in definition of 1s -S(0),,(C-C¢) alkyl «CONH, «carboxyl carboxylate «(Cy-Cylalkoxy (J6-0)0 » carboxylate (C,-Cy)alkyl ester carboxylate (C1-Cy) -8(0),(C,-Cglalkyl rv atom) on an X6 atom or when there are two ¢1H-tetrazol groups -5-yl tetrazole-*- yl -1H or xv so the two alkyl groups ((C-Cglalkyl (C1-Cg)) are separated by one alkyl X6 and both 08 form a Lagan ring Associated atom Alleles (J©-,©) optionally and together with the atom (C-Cq) 4 (NX? or sulfur sulfur oxygen of the same; to 4 members that optionally have an oxygen atom | 0 Yo optionally substituted with C-Celalkyl (C-Cg) or the alkyl hydrogen is hydrogen 7 71 or ?; that: ry in SO; or C(O) when bonded with hydrogen cannot be hydrogen X12 5 X6 "7 and ¢S0,X12 R SO,X6 in the form Term definition of dr is bond 150001 then, a is (11042) and each RS when it is 171 oF separately is ? or -(CHy)-L-(CH,)- rv which is influential in Stimulation of endogenous growth hormone secretion; and where the other human or animal is an adult with growth hormone deficiency. [7-(27-(018)-benzyl-7-methyl-7-oxo-765427:707-hexahydro-"Ypyridine-*-yl)-1-(08-benzyl-oxymethyl-1-oxo) - ethyl]- feet] sev isobutyramide. 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-0x0-2,3,3a,4,6,7 -hexahydro-pyrazolo ° [4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide.1 where the compound is: 1 of the claimant method -Y 01 - Hydro Lua Amino-1-[7-( 27-(8)-benzyl-7-methyl-?-oxo-7:566587677-"Y-pyrazolo[?;"-8]pyridine-*-yl)-1-(8)-benzyl-oxymethyl- ?- oxo-ethyl]- v ; Isobutyramide is a .1-tartaric acid salt. 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-0x0-2,3,3a,4,6,7-hexahydro-pyrazolo) Eh [4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartaric 1 acid salt. L For the treatment or prevention of a disease or condition that may be treated or prevented by growth hormone method 01 method for the treatment or prevention of a human or other animal in need of such treatment or prevention, an amount of a compound of:] and the formula , 001 R! i R3 ¥ 7 a "84 EAN a c— RO » with other | | “RS R27 TN (CH2)w RA 0 0) Racemic-diastereomeric mixtures and isomers Optical isomers of the aforementioned compounds, salts, and prodrugs that are accepted pharmacologically, where: A € is zero; 4 8 is zero wy is Y ang) saws) san oY l is zero; sulfur or sulfur oxygen is oxygen 7 Ye «(CH,)N(X6)SOo(CHy)-A! «(CH N(X)C(O)CH)rA! hurro R! "1 (CH), C(O)N(X6)(CHp)-A! (CH,)N(XOC(ON(XO)(CH)-Al 0 -(CHy)OC(O)(CHy)- A!-(CH,)C(O)O(CHy)-Al 00 (CH), S(0)u(CHy)-A! (CH)C(O)CHy)-A! (CH), OC(ON(XE)(CH)-Al 0 {(CHy) Y!-(CHy)-A!J (CHA! d) In the definition of cycloalkyl and cycloalkyl groups optionally substituted Alkyl Cus 8 (C1-Cy) alkoxy chydroxyl hydroxyl “(C-Cylalkyl) i.e. with alkyl (J-©) VY -8(0),,(C4-C¢) chyle -CONH , «carboxyl Jus <5 S ¢(C;-Cy)alkoxy VA -111 «-CO,(C;-Cylalkyl ester -COH(C-Cq) -8(0),(C;-Co) ) alkyl a ¢fluoro or ¥ fluoro ¥ 0 or 1H-tetrazol-5-yl tetrazol-5#-yl Ye “-N(X6)C(0)- C “-CH=CH- “-C(O)NX$- S(O), © s—— a Y! 1 ar -(00)0; 1 1 yellow at 7 mentioned with (CHy) and the (CHy)q group may optionally substitute a carboxyl Yo «carboxyl group» (C-Cylalkoxy (C;-Cy) hydroxyl 71-hydroxyl alkyl (F©-:5)0(,)0-1, ole(F-0-R5)0(0-); alkyl ester (R00)0-0-CONH, Yv yor —o=J sl si -1H “-CO,(C,-Cyalkyl ester YA 1 yl (1H-tetrazol-5-yl) or ?fluoro Ye 1 er 1 alkyl ¢(C-Cpalkyl (C{-Cy) R2 re is an alkyl chydrogen (Cy-Cyalkyl (C1-Cg) cyclic alkyl (and 0-:0)- alkyl (C1-Cyalkyl- A! -(C1-Cy) J—— SI -A! “(Co-Cy)alkyl-(C3-Cs)cycloalkyl (Co-C3)© ry or Al rr groups are optionally substituted The JS alkyl cycloalkyl in ve identifies R2 with -N(X6)(X6) «-C(OIN(X6)(X6) «-C(O)OXE hydroxyl re Alkyl CN (CF; “-C(0)(X®) “-C(O)A! ¢-8(0)y(C;-Cyalkyl -S(0),(C-Cq)r 1 Yo Y 1 halogen R3 ry alkyl-A' “(C}-Cypalkyl (C,-Cyg) alkyl -(C1-Co)alkyl-A' {( C)-C) ra cycloalkyl -(C3-C7) alkyl ~(Cy-Ce)alkyl-(C3-Cr)cycloalkyl -(Ci-Co) alkyl X'-(C1-) Cs) va alkyl -A" +(C)-Cs)alkyl-X'-(Ci-Cs)alkyl -(Ci-Cs) alkyl -X'(C-Cs) alkyl { (C1-Cs) §f (Ci-Cs)alkyl-X'-(Co-Cs)alkyl-A' "- dary alkyl ~(C3-Cy) alkyl X'A(C1-Cs) ) ¢-(C1-Cs)alkyl-X'-(C,-Cs)alkyl-(C3-C7)cycloalkyl -(Ci-Cs) JV £Y where test Optionally substitute the alkyl groups in the definition of R3 with the alkyl -8(0)n(C1-Cq) Ff) -C(O)OX3 ¢-S(0)(C1-Co)alkyl ey 4 or 30 <i halogens or 10 3 or ? OX3 to hand 0< only “-C(0)O- “-OC(0)- “-C(OIN(X2)- “-N(X2)C(0)- ¢- C=C- 4 -OC(ON(X2)- «-N(X2)C(0)0- ¢-CX2=CX?2- 5 RY £v is an alkyl chydrogen (m©- ,©) anole(m©-,©) or cycloalkyl (bit-y) ¢(C;-Cq)cycloalkyl ¢a 4 4 is hydrogen or alkyl (C)-Cqlalkyl (C;- Cq) or X4 taken together with 164 0 and a nitrogen atom bonded to X4 and a carbon atom bonded to 0 164 form a five to seven membered ring; aa', 6 is cH 7-0 and dua or 8 and 5 each individually is 1 11 ha or ?; A8 XO and 7650 are selected separately from the group consisting of chydrogen Al trifluoromethyl and an alkyl (and ©-©) (optionally substituted C-Cglalkyl; 1 optionally substituted for the alkyl (Cp-) Optionally substituted Celalkyl (C1-Co) in the definition of XS X32 ov with a substituent chosen from the group consisting of (Al 0162 Alkyl (and 2-:5)0(,)0- “-C(0) 0X?2 «-S(0),,(C;-Cg)alkyl oA alkymsil dari «((C5-Co)cycloalkyl (C3-C7) -C(OINXD(X?) 5 -N) X2)(X2) 4 1 . 21 is an O bond or (N-X2) provided that Laie is bya both zeros then 71 41 is not N-X2 or 0; "0 87 and 83 Each of them separately is hydrogen i.e. the alkyl (C1-Cg) 1 and lm©-:©) "+ optionally substituted; Optionally in » define 187 and 1648 with A!alkyl (m©6-2)-0(0)©- or 0-,0)-0)0(0-; 1 alkyl S(0)(C-Coalkyl) -S(0)(C,-Co) 5 to © 1 halogen atoms chalogens to +1 hydroxy ben chydroxy to ?alkyl (f-0-0)0()0-0-alloy(f,©- ,©)(0)©-0- or 1 A to ?alkoxy (0-0) 4(Cy-Cg)alkoxy or 1 4 R83 R7 can be taken together to form ¢-(CH,),-L-(CH,),- Vv. Hay Amar 202, (5)0- 3 N(X2) Al 2 in the definition of R' is a circular alkenyl “(Cs-C,)cycloalkenyl (C5-Cq) fil phenyl vy ring or “and” ring with 4 to A partially saturated members LIS or wholly unsaturated A ring system vy ring system is bicyclic consisting of a 0” ring with 0 or > partially saturated unsaturated members ve completely or saturated (LIS welded to a © ring or 1-membered partly saturated; fully saturated or not vo fully saturated; b-p) “(Cs-Cq)cycloalkenyl vv phenyl or p-ring” having to A partially saturated members completely saturated or unsaturated va optionally having 1 to hetero-atoms Heteroatoms selected separately VA. From the group consisting of sulfur oxygen Cy xS “oxygen” and nitrogen cnitrogen ring system A. A double circular ring consisting of a p0 ring with © or 1 saturated members (Wa unsaturated Yoo selected separately from heteroatoms to ; hetero atoms 1 optionally having (LIS wholly or saturated AY) fused with oxygen and oxygen sulfur sulfur nitrogen the group consisting of nitrogen AY to 1 optionally having (LS or unsaturated LIS p0 ring with © or 1 partially saturated saturated member ar selected separately from the group consisting of nitrogen heteroatoms 4 oxygen and sulfur oxygen nitrogen Ae both ssa alyring in Each case is optionally substituted in a two-cycled Al A (Jay) ring; with up to three ring system it is an AT ring system if the two rings AY “OCF,H”OCF; I Br “Cl Each substitution is selected separately from the set consisting of AA J <I «0x0 OXS » -C(0)OXS -C(O)N(XE)(XE) shoulder «OCH; «CH; CF, 84 alkyl (2-R5)0(,0-benzyl) cyano nitro (and-0) nitro a. phenyl «1H-tetrazol-5-yl tetrazole-*-yl -1H «-S(0),(C,-Cg)alkyl 91 methylene chalophenyl halophenyl «phenylalkyloxy phenylalkyl oxy phenoxy KY -SO,N(X6)(X6) Hormwool «-N(X6)(X6) di-cmethylenedioxy Oxy en ("CONXIIX12 (-N(X6)SO,X6 "-N(X6)SO,-phenyl 210408 0. PAL 0 -NX6SO,NX11X12 "-NX6CONX11X12 "-NX6S0,X12 "-SO,NX 11X12 0 ctetrazolyl or thiazolyl imidazoyl 01062011 thiazolyl “-NX6C(0)X!2 y: then methylenedioxy optionally substituted with methylenedioxy Al provided that if av is one; methylenedioxy It can only be substituted with dioxymethylene 18 or an alkyl (m©-,6) oleate (m-0,0) substituted hydrogen is hydrogen XI where 44 is optionally; the optionally substituted Ve ( Cp-Collalkyl optionally substitutes for each alkyl (m©-,©) 0 (C1-Cg) alkoxy carbonyl cphenoxy phenyl with phenyl XI in Vox definition to (1 80) C;-Collalkyl -S(0),(C-Cq) Alkyl «(C;-Cg)alkoxycarbonyl Vor Alcanoyl oxy TY hydroxy to 2 hydroxy 1 chalogens halogen atoms 0 3 {(C1- Celalkoxy (C1-Cg) To? Crixy 1R (C,-Cyplalkanoyloxy (C;-Cio)-alkyl ephenyl thiazolyl (m©-,©) anolhelm©-,©); phenyl hydrogen is hydrogen 2 » provided that when cthienyl or thienyl furyl furyl cimidazolyl imidazolyl ctiazolyl Vey you is optionally substituted with one to three X12 then the cthienyl is hydrogen X12 not 1 OCF; «OCH; «CH; © «Cl Substituents selected separately from the group consisting of Ved (CHLI-(CHy)y together to form X12, X11 and ©; or take 1. N(X2)Ar (SO), 0 202 mr LI where 11 OF ? or 1 each case is br NY (C-Cyalkyl (C-Cg) alkyl hydrogen each case is hydrogen 8X2 nr substituted Optionally, where (C3-Co)eyeloalkyl (C3-C7) is optionally substituted or the cyclic alkyl he separately optionally substitutes the (m©-,©) 1 nal (m©-,©) alkyl (m0-,6) optionally and the cyclic alkyl JS 1 with the optionally substituted alkyl (C3-Co)(C5-C7) 0 (C3-Co)(C5-C7) 1 «0X3 to ?1 or halogens to ©1 halogen atoms -C(O)OX3 1 and for ZO-5)0©(..)0-” D0 ¢(C,-Cgalkyl (C-Cq) or alkyl hydrogen in each case is hydrogen 3 VIA Substituting the C-Cyalkyl (C-Cg) alkyl <hydrogen separately is 6'4 (C-Cg)halogenated alkyl halogen (m-0): 0) JS optionally 0 optionally substituted for an alkyl darihalogen-(0-t©) (C5-Coeycloalkyl 1) Optionally the alkyl (and,0©-) saa replaces each with Cua (C3-Cy) -halogenate optionally substituted dcycloalkyl 0(m0-,0) and cycloalkyl (b©-f6) 1-1l0,(0:010-f0) substituted #0 hydroxyl alkyl (j-©) 1 and cycloalkyl(j-,©) ; hydroxyl Y or 1 by optionally X6 in definition of 4 -S(0),,(C1-C¢)alkyl «CONH, «carboxyl carboxylate» (C-Cyalkoxy (Ci-Cy ) alkoxy 0 “carboxylate (C,-C,)alkyl ester carboxylate (C1-Cy) alkyl ester -8(0),(C1-Cglalkyl 001) on an X6 atom or when there are two groups ¢1H-tetrazol-S-yl Jy tetrazole-*- -1H or svv so the two alkyl groups ((C-Collalkyl) can be separately alkyl (m©-,©) X6 one and both atom 174 associated with them form a ring atom (m©-©) Allah©-,©) to optionally connect and together with atom 0 NX or sulfur sulfur oxygen above itself to 9 optionally members An oxygen atom | In a separate case, it is “” ry, provided that: re 10 in SO, when bonded with (0)0 or hydrogen C6 and 1012 cannot be hydrogen and ¢50,X12 4 SO,X6 «C(0)X!12 «C(O) X6 Figure vx In the definition of “J SyNX?) L is bond 5001, then RO when it is 17 H (0) SAM (J©)- separately is ? or vA counts that are effective in stimulating endogenous growth hormone secretion; and .glucocorticoid where the disease or condition is to treat the side effects of glucocorticoids Vi. of the protective element; Where the disease or condition is to treat side effects method *- Method 1. glucocorticoid catabolism of glucocorticoid Y from the protective component; where the compound is: method +“-method 1-benzyl-7-methyl-7-oxo-7036587:7:71-hexahydro -(8)-27)-7[-17-sual — ¥ oxo-ethyl]-Yd ie pyridine-*-yl)-1-(8)-benzyl oxy [Tet] den .* ; isobutyramide. 2-Amino-N-[2-(3a-) (R)-benzyl-2-methyl-3-o0x0-2,3,3a,4,6,7-hexahydro-pyrazolo °[4,3-c]pyridin-5-y1)-1-(R)- benzyloxymethyl-2-oxo-ethyl]-isobutyramide .1 of the claimant where the compound is: Methyl--oxo-73665687677-hexahydro-"Y pyrazolo[;;7?-6]pyridine-*-yl)-1-(8-benzyl-oxymethyl-?-oxo-ethyl]-x ;- Isobutyramide salt.1-Tartrate. -pyrazolo ° [4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartaric ~~ + acid salt.v For the treatment or prevention of a disease or condition that may be treated or prevented by growth hormone method “- method 1 l and includes the consumption of a human or other animal in need of such treatment or prevention an amount of a compound of:] and the formula R! i R3 X ol wt "8 '~ LN Ng NP b | SRS .Bahai REO YoA and isomers of racemic-diastereomeric mixtures, mixtures of racemic-diastereomeric mixtures of accepted prodrugs and prodrugs, optical salts of the aforementioned compounds and salts 1900068 0 pharmacologically terminated where: v is zero; © A is zero; -A! -(CHp)N(XO)C(O)CH,)-Al Ag Mo "1 «-(CHy){C(O)N(X6)(CH,),-A! «(CH N( XO)C(OIN(XO)(CH)-Al 00 «-(CH,);0C(0)(CHy)-A' «-(CH,),C(O)O(CH,)-A! 0“ -(CH)S(O)n(CHY-A! -(CH,) C(O)(CHy)-A! -(CHy) OC(OIN(X6)(CH,)-A! 0 ( CH) Y'-(CHp)-A!a «(CHp)-A!d in the definition of a cycloalkyl and a cycloalkyl in which 1 (C1-Cy) alkyl groups optionally substituted for alkoxy chydroxyl “(C-Cylalkyl (C-Cy) alkyl RI 17, 0011 alkyl, 0-R5)0(.)0- “carboxyl carboxyl (C,-C,)alkoxy VA -1H” -CO,(C4-Cylalkyl ester -CO,(C;-Cy) alkyl ester -5(0),,(C;-Cg)alkyl "4 ¢fluoro? or ¥1 fluoro or 1H -tetrazol-5-yl —o—( 3 Ye -N(X6)C(0)- -C=C- -CH=CH- -C(O)NXS- S(O), <0 Yr Y!¢-0C(0)- Ar -OC(O)N(X6)- ¢-C(0)O- kyram vy YY) is yellow Yr ?; JY) is yellow; 1 Ye mentioned with (CHy); and the (CHy)g group may optionally substitute a Yo «carboxyl group ¢ (C-Cylalkoxy (Ci-Cy) chydroxyl 71 Alkyl (m©0-:0)n(0)5-allola(f-0:r5)0(,)0-; alkyl ester (J-,002)0-CONH, vv fluoro Y or YO) (IH-tet razol-5-yl tetrazole-*-yl -1H -CO,(C,-C alkyl ester YA {(Ci-Cylalkyl (C-Cy) alkyl Y 4) alkyl ester va 1014 7 2 is the chydrogen the alkyl (and ©-©) and the alyl (and ©-,©); Circular alkyl (and-0:0)- alkyl -(Co-C3)-1 alkyl(C1-Ca)-1 alkyl (-and 0)- A' alkyl (Co-:)- (C1-Ca)alkyl -A'm or (Al ry) where the alkyl and cycloalkyl groups in 2 definition 182 are optionally substituted with a hydroxyl -C(O)N(X8)(X6)¢-C( or 1 rt ¥ or ¥ halogen «-(C1-Ce)alkyl-A' -(C1-Cg) alkyl -A' «(C}-C}g)alkyl (C;-C g) alkyl (Al mr 3 rv X'-(C1-Cs) alkyl «-(C1-Ce)alkyl-(C3-Cr)eycloalkyl -(C1-Cs) alkyl -(C3-C7) cycloalkyl va -(C1-Cs ) Alkyl -X'-(Co-Cs) Alkyl -A' +(C1-Cs)alkyl-X'-(Ci-Cs)alkyl -(C1-Cs) Alkyl vs -X'- (C1-Cs) alkyl «(C3-C7) dari SI or «(C}-Cs)alkyl-X'«(Co-Cs)alkyl-A!¢-(C1-Cs)alkyl -X'-(C}-Cs)alkyl-(C3-C7)cycloalkyl -(C1-Cs) alkyl 4 Cua 3 optionally replaces the alkyl groups in the definition of RI with the alkyl -S(0)n(C-Cq) 31 aldro0- 5)0(..)2-? Qaduru) n-; 1 - 7 oF ; or © halogen atoms bowl 8m1f or 0 £4 "or «0X3 v -C(0)0- -0C(0)- «-C(O)N(X2)- -N(X2)C(0)- S(O), 0 imo XI go ¢-C= C- A -OC(O)N(X2)- «-N(X2)C(0)O- -CX2=CX2- £1 B4 is an alkyl hydrogen (Cy-Cgalkyl (C;-Cg) or cycloalkyl (C3-C7) ¢(C5-Cy)cycloalkyl <A X4 4 is hydrogen or an alkyl (Ci-Cglalkyl (C1-Cy) or X* is taken with R* together 0 and the nitrogen atom bonded to 4 and the carbon atom atom associated with 0 84 and form a five to seven membered a0 ring; No | z FENCED CHD a OF YO) watts of each are zero; 8 Cua or − X5 and 1658 are selected separately from the group consisting of an Al trifluoromethyl chydrogen and an optionally substituted C-Cglalkyl (C1-Cg); 10 2 Optionally substitute the alkyl (m©-,0) (C-Calkyl optionally substituted in definition 5 No X52 with a substituent chosen from the group consisting of 0X2 Al alkyl “S(O)m(C1-Co) J— ll «-C(0)OX2 -8(0),(C;-Cg)alkyl oA dary «(C3-Cq)cycloalkyl (C5-Cy) -C(ON(X2) (X2) 5 -NXH)(X?) od ZI 1 is an O bond or (N-X2) provided that Laie is bya both zeros then 721 1 + is not N-X2 or 0; > 87 and 88 each separately hydrogen or alkyl (C-Collalkyl (C1-Cq) Value vr optional? Cua it separately optionally substituted Alkyl (C1-Colalkyl (C1-Co) optionally substituted in + definition R85 RT with Al Alkyl -C(0)0-(C;-Cglalkyl -C) (O)O-(C1-Cq) 0.0 alkyl (80- oldm-5)0(,)0- 1 to © halogens to © Tv 1 hydroxy to ¥ alkyl ( n0-,0-0)0()6- enola(f.©-,©)(0-0)0- or 1 A to 3 alkoxy 4(C1-Collalkoxy (C;-Cg) Or 14 R83 R7 can be taken together to form ¢-(CH,),-L-(CH,),- NX?) 5 y(5)0- «CXD(X?) is L where ve 2 Uh in the definition of R! TO A Partially saturated members LIS saturated or completely unsaturated Ring system vr bicyclic consisting of a 108-membered ring with © or 7 saturated Lida members unsaturated vs completely or completely saturated fused to a ring ring with © or 1 member saturated (Ui ja fully saturated or unsaturated vo eI Al 71 in definition 8 RP at 187 and 1853 separately is Jal a (Cs-C) phenyl Jui “(C5-Cy)cycloalkenyl vv or p” ring with ; to A saturated members olf ja totally saturated va or unsaturated WS having optionally 1 to ; Selected heteroatoms JS separately from the group consisting of oxygen sulfur sulfur and nitrogen “ring system A. A double circular ring consisting of a ring 108 with 0 or > partially unsaturated members fully saturated a or saturated (US optionally has 1 to; heteroatoms selected separately from the AY group consisting of nitrogen sulfur sulfur and oxygen coxygen fused with 011 to 1 optionally having LS partially saturated members wholly saturated or unsaturated 1 p0 ring with © or ar separately selected from the group consisting of nitrogen heteroatoms as 4 heteroatoms oxygen and oxygen Sulfur nitrogen in one or both rings separately is optionally substituted in the Ala ring in every 1 dicyclic; With up to three substituents; 0X0 OXO-C(0)OXS6 -C(OIN(X6)(XS) Clamp «OCH; «CH, «CF, 84 alkyl (M0-RN)(5)0-cbenzylbenzyl) cyano 1-(m©-,©); 8(0),,(C,-Cy)alkyl 1 methylene chalophenyl halophenyl «phenylalkyloxy alkyl oxy J »phenoxy 9 -SO,N(X6)(X6) -N(X6)C(0 )(X6) «-N(X6)(X6) «methylenedioxy oxy Jp qv «CONX'X12 -N(X6)S0,X6 -N(X6)SO,-phenyl -N(X6)SOp-J_ 0 Y 2 y 2 “-NX6S0,X12 “-SO,NX 1X12 de tetrazolyl or tetrazoyl thiazolyl dmidazolyl Jd 5 ame “-NX6C(0)X12 av then methylenedioxy optionally substituted with dioxymethylene AT provided that if qy is one; Optionally? Ve substitute my sister aria (C1-Collalkyl optionally substituted for each alkyl (0,0-M) 0 alkoxy carbonyl (and 0-,0)) phenoxy phenyl in definition !61 with phenyl 001" to 1 Alkyl (and ©-0)m(5)0- oleh (and 8)0(,)-0-”” “(C,-Calkoxycarbonyl Vor) to ? cannoyl oxy chydroxy to? 1-hydroxy halogens © Vat halogen atoms “(Cy-Colalkoxy (C;-Cg) to 1-alkoxy ¥ or (C;-Cjp)alkanoyloxy (C;-C,p) Veo phenyl thiazolyl Phenyl (C1-Colalkyl (C1-Cg) Alkyl hydrogen is hydrogen X12 » provided that when cthienyl or thienyl furyl cimidazolyl imidazolyl dtiazolyl Voy is optionally substituted with one to three X12 hydrogen is hydrogen X12 not being 001 yy OCF; “OCH;” CHj ¢F “Cl substituents selected separately from the group consisting of 4 ¢CF;3 VY -(CHp),- L1-(CH,),- together to form X12 4 1611 or take 111 NX?) 4 (60) 0 0202 where we pass NY or ?; 1 1 in each case is # nr (C-Coleyeloalkyl (C-Cg) alkyl <hydrogen) in each case the 2 Ve hydrogen is optionally substituted where (C3-Coleyeloalkyl (C3-Cy) ._ is optionally substituted or circular alkyl 5 Optionally substituted alkyl (m©-,0) 811971(m0-,©) and the cyclic alkyl saa each on with the alkyl (0-r5)0()0- X2 anole H07©1(,© -.f©) optionally substituted in the definition of (C3-C;) iv '0X3 ¥ to 1 or halogens to © atoms Login 1 - dd a1old(and0(.)0-0)- 0.03 )a or alkyl (and-0)weldzem 0-0)) hydrogen in each individual case being hydrogen 3 14 substituted (C-Celalkyl (C1-Cq) Alkyl hydrogen separately is hydrogen 6 VY. (C3-Cy) cycloalkyl (C,-Cy)halogenated alkyl (Cy-Co) optionally substituted 1 cycloalkyl halogen-(6-:6-)J optionally substituted (C5-Crloycloalkyl 0 ( C1-Co) are individually substituted for the optionally substituted alkyl Cua «(C3-Cy)-halogenatedcycloalkyl 00 oldomen-0) and the cyclic (©-F0) 1,1L0(07010-R0) substituted 004 hydroxyl or ? Kale (b©-,6) 1 wala (m-0,©); 1 hydroxyl optionally in definition 755 by 0 alkyl (Wm0-R5)0(0)- «CONH, «carboxyl carboxylate «(C-Cypalkoxy (C;-Cy) - « carboxylate ( or When there are two groups 166 on a yva atom that are separately alkyl (m©-,©) and aryl (m©-,©), then the two alkyl groups X6 MS, one atom 4 bonded with them may form an atom ring To optionally connect and; together with the atom (Cy-Cgalkyl)-(0” INX7 or sulfur sulfur oxygen except for those with 4 to 4 members that optionally have an oxygen atom 01 lm 0-0) optionally substituted with ( CC) alkyl hydrogen is hydrogen XT© and thydroxyl is hydroxyl ¢Y of in each case to be yellow “ 7 provided that: bar 11 6 12 they cannot be hydrogen when bonded with C(O) or SO, in rv of the form SO,X6 «C(0)XI2 «C(0)X6 or ¢ S0,X12 and Lea ic 1 be RE is bond 5000 then ,1 is (140642 and each: in the definition of 0.h(and 01)-1m(J01)- separately it is ? or oF VE, which are effective in stimulating endogenous growth hormone secretion; and 1, where humans or other animals need to activate the immune system. “-amino-7-[7-(27-(8)-benzyl-7-methyl-7-oxo-7056568707:71-hexahydro-[e-Yet]odin x pyridine-*-yl)- 1-(8)-benzyl-oxymethyl-7-oxo-ethyl]-isobutyramide. 3,3a,4,6,7-hexahydro-pyrazolo ° [4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide.1 -01-1 method of claim A where the compound is: –(R)=a¥)~Y]-N-sid -" Y benzyl-7-methyl-7-oxo-7 :566587:7:71-hexahydro-xpyrazolo[;;?-8]pyridine-*-yl)-1-(8)-benzyl oxymethyl-7-oxo-ethyl]- ; Isobutyramide is the salt of L tertiary acid. 2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-0x0-2,3,3a,4,6,7-hexahydro-pyrazolo ° [4,3- c[pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide L-tartaric 1 acid salt. 7