RU2172742C2 - Stimulating agents of growth hormone secretion - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes novel compounds of the formula (I)

, racemic and diastereomeric mixtures and optical isomers of these compounds and their pharmaceutically acceptable salts and prodrugs where e = 0 or 1; n and w = 1; Y means oxygen atom; R¹ means hydrogen atom, -(CH₂)_t-A¹ where t = 0, 1 or 2; A¹ means phenyl or totally unsaturated 4-8-membered ring having optionally 1-2 hetero- -atoms taken independently among the group including sulfur and nitrogen atom, bicyclic system consisting of totally unsaturated 5- or 6-membered ring having optionally 1- 2 hetero- -atoms as nitrogen atom; in each case A¹ is substituted optionally and independently at one or optionally at both rings if A¹ means bicyclic ring system and has up to two substituents and each substituent is taken among the group including the following groups: F, Cl, Br, OCF₃, (C₁-C₆)-alkyl, phenyl; R² means hydrogen atom, (C₁-C₈)-alkyl where alkyl group is substituted optionally with CF₃; R³ means (C₁-C₅)-alkyl-X¹-(C₀-C₅)- -alkyl-A¹ where X¹ means -O-; values for A¹ are given above; R⁴ means hydrogen atom; X⁴ means hydrogen atom; R⁶ means a residue of the formula (II) X⁵ where a and b = 0; X^5a and (C₁-C₆) each means independently unsubstituted Z¹-alkyl; R⁷ means a bond; R⁸ and

Description

 The invention relates to dipeptide compounds that are growth hormone stimulants and can be used for the treatment and prevention of osteoporosis.

BACKGROUND OF THE INVENTION
Growth hormone (GH), which is secreted by the pituitary gland, stimulates the growth of all body tissues capable of growth. In addition, it is known that growth hormone has the following main effects on the metabolic process in the body:
1. Increases the rate of protein synthesis in essentially all cells of the body.

 2. Reduces the rate of use of carbohydrates in the cells of the body.

 3. Increases the mobilization of free fatty acids and the use of fatty acids as an energy source.

 Growth hormone deficiency leads to a variety of pathological disorders. In children, it causes dwarfism (dwarfism). In adults, the consequences of acquired GH deficiency include a profound decrease in lean body mass and a concomitant increase in total body fat, in particular in the trunk. Reduced skeletal and cardiac muscle mass and muscle strength lead to a significant decrease in the ability to tolerate physical activity. Bone density also decreases. The administration of exogenous growth hormone has been shown to reverse many of these metabolic changes. Additional benefits of this therapy include lowering LDL cholesterol and improving psychological health.

 In cases where elevated levels of growth hormone are desired, this problem was usually resolved by exogenous growth hormone or by the administration of an agent stimulating the formation and / or release of growth hormone. In any case, the peptidyl nature of such a compound required that it be administered by injection. Initially, growth hormone was obtained by extraction of pituitary bodies of corpses. This led to an expensive product and posed a danger that the disease associated with the pituitary source could be transmitted to the recipient of growth hormone (e.g., Creutzfeldt-Jakob disease). Recently, recombinant growth hormone has become available, which, although it does not already pose any danger of transmission of the disease, is still a very expensive product and must be administered by injection or in the form of a nasal spray.

 Most cases of GH deficiency are due to defects in the release of GH, rather than primary defects in the synthesis of GH in the pituitary gland. Therefore, an alternative strategy for normalizing serum GH levels is to stimulate its release from somatotrophic cells. An increase in GH secretion can be achieved by stimulation or inhibition of various neurotransmitter systems in the brain and hypothalamus. As a result, when developing synthetic growth hormone-releasing agents to stimulate the secretion of GH of the pituitary gland, some advantages of a relatively expensive and inconvenient GH replacement therapy could be achieved. Acting on physiological regulatory pathways, the most desirable agents could stimulate pulsating secretion of GH, and excessive levels of GH associated with undesirable side effects of administration of exogenous GH could be eliminated due to intact loops of negative feedback.

 Physiological and pharmacological stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin-induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause the release of growth hormone from the pituitary gland, acting in some way on the hypothalamus, possibly either by decreasing the secretion of somatostatin, or by increasing the secretion of a known growth hormone releasing factor-GHRF, or an unknown endogenous hormone Releasing growth hormone or all of these ways.

 Other compounds have been developed that stimulate the release of endogenous growth hormone, such as similar peptidyl compounds related to FGR, or US Patent 4411890 peptides. These peptides, although significantly smaller in size than growth hormones, are still sensitive to various proteases. As with most peptides, their potential for oral availability is low. WO 94/13696 describes some spiro piperidines and homologs that enhance the release of growth hormone. Preferred compounds have the general structure shown below.

В WO 94/11012 описаны некоторые дипептиды, которые усиливают высвобождение гормона роста. Эти дипептиды имеют общую структуру

где L представляет собой

В WO 94/11012 и WO 94/13696 сообщались соединения, применимые в лечении остеопороза в сочетании с паратиреоидным гормоном или бисфосфонатом.

WO 94/11012 describes certain dipeptides that enhance the release of growth hormone. These dipeptides have a common structure

where L is

Compounds useful in the treatment of osteoporosis in combination with parathyroid hormone or bisphosphonate have been reported in WO 94/11012 and WO 94/13696.

рацемически-диастереомерным смесям и оптическим изомерам этих соединений и их фармацевтически приемлемым солям и пролекарствам,
где e равно 0 или 1;
n и w, каждый независимо, равны 0, 1 или 2 при условии, что w и n не могут быть оба одновременно равны 0;
Y обозначает кислород или серу;
R¹ обозначает водород, -CN, -(CH₂)_qN(X⁶)C(O)X⁶, - (CH₂)_qN(X⁶)C(O) (CH₂)_t-A¹, -(CH₂)_qN(X⁶)SO₂(CH₂)_t-A¹ -(CH₂)_qN(X⁶)SO₂X⁶- (CH₂)_qN(X⁶)C(O)N(X⁶) (CH₂)_t -A¹, -(CH₂)_qN(X⁶)C(O)N(X⁶) (X⁶),
-(CH₂)_qC(O)N(X⁶) (X⁶), -(CH₂)_qC(O)N(X⁶) (CH₂)_t-A¹ -(CH₂)_qC(O)OX⁶,
-(CH₂)_qC(O)O(CH₂)_t-A¹, - (CH₂)_qOX⁶, -(CH₂)_qOC(O)X⁶, -(CH₂)_qOC(O)(CH₂)_t-A¹, - (CH₂)_qOC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qOC(O)N(X⁶)(X⁶), (CH₂)_qC(O)X⁶,
-(CH₂)_qC(O)(CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)OX⁶, -(CH₂)_qN(X⁶)SO₂N(X⁶) (X⁶), -(CH₂)_qS(O)_mX⁶, -(CH₂)_qS(O)_m(CH₂)_t-A¹, -(С₁-С₁₀)алкил, -(CH₂)_t-A¹, -(CH₂)_q-(C₃-C₇)циклоалкил, -(CH₂)_q-Y¹-(C₁-C₆)алкил,
-(CH₂)_q-Y¹-(CH₂)_t-A¹ или -(CH₂)_q-Y¹-(CH₂)_t- (C₃-C₇)циклоалкил; где группы алкил и циклоалкил в определении R¹ необязательно замещены (С₁-С₄) алкилом, гидроксилом, (C₁-С₄)алкокси, карбоксилом, -CONH₂, -S(O)_m(C₁-C₆) алкилом, CO₂(C₁- C₄)-алкиловым эфиром, 1Н-тетразол-5-илом или 1, 2, или 3 атомами фтора;
Y¹ обозначает О, S(O)_m, -C(O)NX⁶-, -CH= CH-, -C≡C-, - N(X⁶)C(O)-,-C(O)NX⁶-,-C(O)O-, -OC(O)N(X⁶)- или -ОС(O)-; q равно 0, 1, 2, 3 или 4;
t равно 0, 1, 2 или 3;
указанные группы (CH₂)_q и (CH₂)_t, каждая, могут быть необязательно замещены гидроксилом, (C₁-C₄) алкокси, карбоксилом, -CONH₂, -S(O)_m(С₁-C₆)алкилом, -CO₂ (C₁-C₄)-алкиловым эфиром, 1Н-тетразол-5-илом или 1, 2, или 3 атомами фтора или 1 или 2 (C₁-C₄)алкилами;
R² обозначает (С₁-С₈)алкил, -(С₀-С₃)алкил-(С₃-С₈)циклоалкил, -(C₁-C₄)алкил-A¹ или А¹;
где алкильные группы и циклоалкильные группы в определении R² необязательно замещены гидроксилом, - C(O)ОХ⁶, C(O)N(X⁶)(X⁶), -N(X⁶)(X⁶), -S(O)_m(C₁-C₆)алкилом, - C(O)А¹, -C(O)(X⁶), CF₃, CN или 1, 2 или тремя атомами галогена;
R³ обозначает А¹, (C₁-C₁₀)алкил, -(C₁-C₆)алкил-A¹, -(C₁-C₆)алкил- (C₃-C₇)циклоалкил,-(C₁-C₅)алкил-X¹-(C₁-C₅)алкил,(C₁-C₅)алкил-X¹-(C₀-C₅)алкил-A¹ или -(C₁-C₅)-X¹-(C₁-C₅)алкил- (C₃-C₇)циклоалкил;
где алкильные группы в определении R³ необязательно замещены
-S(O)_m(C₁-C₆)алкилом, -C(O)ОХ³, 1, 2, 3, 4 или 5 атомами галогена или 1, 2 или 3 ОХ³;
X¹ обозначает O, S(O)_m, -N(X²)C(O)- , -C(O)N(X²)-, -OC(O)-, -C(O)O-, -CX²=CX²-, -N(X²)C(O)O-, - OC(O)N(X²)- или -C≡C-;
R⁴ обозначает водород, (C₁-C₆)алкил или (C₃-C₇)циклоалкил или R⁴, взятый вместе с R³ и атомом углерода, с которым они соединены, образует (C₅-C₇) циклоалкил, (C₅-C₇)циклоалкенил, частично насыщенное или полностью насыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранных из группы, включающей кислород, серу и азот, или обозначает бициклическую кольцевую систему, состоящую из частично насыщенного или полностью насыщенного 5- или 6-членного кольца, конденсированного с частично насыщенным, полностью ненасыщенным или полностью насыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
X⁴ обозначает водород или (C₁-C₆)-алкил или X⁴, взятый вместе с R⁴ и атомом азота, с которым X⁴ соединен, и атомом углерода, с которым R⁴ соединен, образует 5-7-членное кольцо;
R⁶ обозначает связь или представляет собой

где а и b независимо равно 0, 1, 2 или 3;
X⁵ и X^5a, каждый независимо, выбраны из группы, включающей водород, трифторметил, А¹ и необязательно замещенный (C₁-C₆) алкил;
необязательно замещенный (C₁-C₆) алкил в определении X⁵ и X^5a необязательно замещен заместителем, выбранным из группы, включающей А¹, ОХ², - S(O)_m(C₁-C₆) алкил, -C(O)ОХ², (C₃-C₇)циклоалкил, -N(X²)(X²) и -C(O)N(X²)(X²);
или углерод, несущий X⁵ или X^5a, образует один или два алкиленовых мостика с атомом азота, несущим R⁷ и R⁸, причем каждый алкиленовый мостик содержит 1-5 атомов углерода при условии, что, когда образуется один алкиленовый мостик, X⁵ или X^5a, но не оба, могут быть на атоме углерода и R⁷ или R⁸, но не оба, могут быть на атоме азота, и, кроме того, при условии, что, когда образуются два алкиленовых мостика, X⁵ и X^5a не могут быть на атоме углерода и R⁷ и R⁸ не могут быть на атоме азота;
или X⁵, взятый вместе с X^5a и атомом углерода, с которым они соединены, образует частично насыщенное или полностью насыщенное 3-7-членное кольцо или частично насыщенное или полностью насыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранные из группы, включающей кислород, серу и азот;
или X⁵, взятый вместе с X^5a и атомом углерода, с которым они соединены, образует бициклическую кольцевую систему, состоящую из частично насыщенного или полностью насыщенного 5- или 6-членного кольца, необязательно имеющего 1 или 2 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород, конденсированного с частично насыщенным, полностью насыщенным или полностью ненасыщенным 5-или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
Z¹ обозначает связь, О или N-Х² при условии, что, когда а и b оба обозначают О, Z¹ не является N-X² или О;
R⁷ и R⁸ независимо обозначают водород или необязательно замещенный (С₁-С₆)алкил;
где необязательно замещенный (C₁-C₆) алкил в определении R⁷ и R⁸ необязательно независимо замещен А¹ -C(O)O-(C₁-С₆)алкилом, - S(O)_m(С₁-С₆)алкилом, 1-5 атомами галогена, 1-3 гидрокси, 1-3 -O-C(О)(С₁-С₁₀)алкилом или 1-3 (C₁- С₆)алкокси; или
R⁷ и R⁸, взятые вместе, могут образовать - (CH₂)_r-L-(CH₂)_r;
где L обозначает С(X²)(X²), S(O)_m или N(X²);
А¹ в каждом случае обозначает независимо (C₅-С₇)циклоалкенил, фенил или частично насыщенное или полностью насыщенное или полностью ненасыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранных из группы, включающей кислород, серу и азот, бициклическую кольцевую систему, состоящую из частично насыщенного, полностью ненасыщенного или полностью насыщенного 5- или 6-членного кольца, необязательно имеющего 1-4 гетероатома, выбранных из группы, включающей азот, серу и кислород, конденсированного с частично насыщенным, полностью насыщенным или полностью ненасыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
А¹ в каждом случае независимо необязательно замещен в одном или необязательно обоих кольцах, если А¹ является бициклической кольцевой системой, и имеет до 3 заместителей, каждый заместитель независимо выбран из группы, включающей F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, - ОХ⁶, -C(O)N(X⁶)(X⁶), -С(O)ОХ⁶, оксо, (С₁-С₆)алкил, нитро, циано, бензил, -S(O)_m(С₁-С₆)алкил, 1H-тетразол-5-ил, фенил, фенокси, фенилалкилокси, галогенфенил, метилендиокси, N(X⁶)(X⁶), - N(X⁶)C(O)(X⁶), -SO₂N(X⁶)(X⁶), -N(X⁶)SO₂-фенил, -N(X⁶)SO₂X⁶, -CONX¹¹X¹², -SO₂NX¹¹X¹², -NX⁶SO₂X¹², -NX⁶CONX¹¹X¹², -NX⁶SO₂NX¹¹X¹², -NX⁶C(O)X¹², имидазолил, тиазолил или тетразолил, при условии, что, если А¹ необязательно замещен метилендиокси, то он может быть замещен только одним метилендиокси;
где X¹¹ обозначает водород или необязательно замещенный (С₁-С₆)алкил;
необязательно замещенный (С₁-С₆)алкил, определенный для X¹², необязательно замещен фенилом, фенокси, (C₁-С₆)алкоксикарбонилом, -S(O)_m(С₁-С₆)алкилом, 1-5 атомами галогена, 1-3 гидрокси, 1-3 (С₁-С₁₀)алканоилокси или 1-3 (C₁-C₆) алкокси;
X¹² обозначает водород, (С₁-С₆)алкил, фенил, тиазолил, имидазолил, фурил или тиенил при условии, что, когда X¹² не является водородом, X¹² необязательно замещен одним-тремя заместителями, независимо выбранными из группы, включающей Cl, F, CH₃, OCH₃, OCF₃ и CF₃;
или X¹¹ и X¹², взятые вместе, образуют - (CH₂)_r-L-(CH₂)_r;
L¹ обозначает С(X²)(X²), О, S(O)_m или N(X²);
r для каждого случая независимо равно 1, 2 или 3;
X² для каждого случая обозначает независимо водород, необязательно замещенный (С₁-С₆)алкил или необязательно замещенный (C₃-C₇) циклоалкил, причем необязательно замещенный (С₁-С₆)алкил и необязательно замещенный (С₃-С₇) циклоалкил в определении X² необязательно независимо замещены S(O)_m(С₁-С₆)алкилом, -С(O)ОХ³, 1-5 атомами галогена или 1-3 ОХ³;
X³ для каждого случая обозначает независимо водород или (С₁-С₆)алкил;
X⁶ обозначает независимо водород, необязательно замещенный (С₁-С₆)алкил, (C₂-C₆) галогенированный алкил, необязательно замещенный (C₃-C₇) циклоалкил, (C₃-C₇)-галогенированный циклоалкил, причем необязательно замещенный (С₁-С₆)алкил и необязательно замещенный (С₃-C₇) циклоалкил в определении X⁶ необязательно независимо замещены 1-2 (C₁-C₄) алкилом, гидроксилом, (C₁-C₄) алкокси, карбоксилом, CONH₂, -S(O)_m(C₁-C₆) алкилом, карбоксилат-(С₁-С₄)алкиловым эфиром или 1H-тетразол-5- илом; или, когда на одном атоме имеются две группы X⁶ и оба X⁶ являются независимо (C₁-C₆)-алкилом, две (С₁-C₆)-алкильные группы могут быть необязательно соединены, вместе с атомом, с которым эти две группы X⁶ соединены, с образованием 4-9-членного кольца, необязательно имеющего кислород, серу или NX⁷;
X⁷ обозначает водород или (C₁-C₆)-алкил, необязательно замещенный гидроксилом; и m для каждого случая независимо равно 0, 1 или 2;
при условии, что
X⁶ и X¹² не могут быть водородом, когда они соединены с C(O) или SO₂ в форме С(O)X⁶, С(O)X¹², SO₂X⁶ или SO₂X¹²; и когда R⁶ обозначает связь, L обозначает N(X²), и каждый r в определении - (CH₂)_r-L-(CH₂)_r равно, независимо, 2 или 3.SUMMARY OF THE INVENTION
This invention relates to compounds of the formula

racemic-diastereomeric mixtures and optical isomers of these compounds and their pharmaceutically acceptable salts and prodrugs,
where e is 0 or 1;
n and w, each independently, are 0, 1 or 2, provided that w and n cannot both be equal to 0;
Y is oxygen or sulfur;
R ¹ is hydrogen, —CN, - (CH ₂ ) _q N (X ⁶ ) C (O) X ⁶ , - (CH ₂ ) _q N (X ⁶ ) C (O) (CH ₂ ) _t —A ¹ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ (CH ₂ ) _t -A ¹ - (CH ₂ ) _q N (X ⁶ ) SO ₂ X ⁶ - (CH ₂ ) _q N (X ⁶ ) C (O ) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ ) (X ⁶ ),
- (CH ₂ ) _q C (O) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ - (CH ₂ ) _q C (O) OX ⁶ ,
- (CH ₂ ) _q C (O) O (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OX ⁶ , - (CH ₂ ) _q OC (O) X ⁶ , - (CH ₂ ) _q OC ( O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (X ⁶ ), (CH ₂ ) _q C (O) X ⁶ ,
- (CH ₂ ) _q C (O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) OX ⁶ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q S (O) _m X ⁶ , - (CH ₂ ) _q S (O) _m (CH ₂ ) _t -A ¹ , - (C ₁ -C ₁₀ ) alkyl, - (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q - (C ₃ -C ₇ ) cycloalkyl, - (CH ₂ ) _q -Y ¹ - (C ₁ -C ₆ ) alkyl,
- (CH ₂ ) _q -Y ¹ - (CH ₂ ) _t -A ¹ or - (CH ₂ ) _q -Y ¹ - (CH ₂ ) _t - (C ₃ -C ₇ ) cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R ^{1 are} optionally substituted with (C ₁ -C ₄ ) alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ (C ₁ -C ₄ ) -alkyl ether, 1H-tetrazol-5-yl or 1, 2, or 3 fluorine atoms;
Y ¹ is O, S (O) _m , -C (O) NX ⁶ -, -CH = CH-, -C≡C-, - N (X ⁶ ) C (O) -, - C (O) NX ⁶ -, - C (O) O-, -OC (O) N (X ⁶ ) - or -OC (O) -; q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH ₂ ) _q and (CH ₂ ) _t groups each may optionally be substituted with hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, -CO ₂ (C ₁ -C ₄ ) -alkyl ether, 1H-tetrazol-5-yl or 1, 2, or 3 fluorine atoms or 1 or 2 (C ₁ -C ₄ ) alkyl;
R ² is (C ₁ -C ₈ ) alkyl, - (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl, - (C ₁ -C ₄ ) alkyl-A ¹ or A ¹ ;
where the alkyl groups and cycloalkyl groups in the definition of R ^{2 are} optionally substituted with hydroxyl, - C (O) OX ⁶ , C (O) N (X ⁶ ) (X ⁶ ), -N (X ⁶ ) (X ⁶ ), -S ( O) _m (C ₁ -C ₆ ) alkyl, - C (O) A ¹ , -C (O) (X ⁶ ), CF ₃ , CN or 1, 2 or three halogen atoms;
R ³ is A ¹ , (C ₁ -C ₁₀ ) alkyl, - (C ₁ -C ₆ ) alkyl-A ¹ , - (C ₁ -C ₆ ) alkyl- (C ₃ -C ₇ ) cycloalkyl, - (C ₁ -C ₅ ) alkyl-X ¹ - (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkyl-X ¹ - (C ₀ -C ₅ ) alkyl-A ¹ or - (C ₁ -C ₅ ) -X ¹ - (C ₁ -C ₅ ) alkyl- (C ₃ -C ₇ ) cycloalkyl;
where the alkyl groups in the definition of R ³ optionally substituted
—S (O) _m (C ₁ -C ₆ ) alkyl, —C (O) OX ³ , 1, 2, 3, 4 or 5 halogen atoms or 1, 2 or 3 OX ³ ;
X ¹ is O, S (O) _m , -N (X ² ) C (O) -, -C (O) N (X ² ) -, -OC (O) -, -C (O) O-, -CX ² = CX ² -, -N (X ² ) C (O) O-, - OC (O) N (X ² ) -, or -C≡C-;
R ⁴ is hydrogen, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl or R ⁴ taken together with R ³ and the carbon atom to which they are attached forms (C ₅ -C ₇ ) cycloalkyl, (C ₅ -C ₇ ) cycloalkenyl, a partially saturated or fully saturated 4-8 membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of partially saturated or fully saturated 5- or 6-membered ring fused to partially saturated, fully unsaturated, or fully saturated nnym 5- or 6-membered ring optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X ⁴ is hydrogen or (C ₁ -C ₆ ) -alkyl or X ⁴ taken together with R ⁴ and the nitrogen atom to which X ^{4 is} attached and the carbon atom to which R ⁴ is attached forms a 5-7 membered ring ;
R ⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3;
X ⁵ and X ^5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A ¹ and optionally substituted (C ₁ -C ₆ ) alkyl;
optionally substituted (C ₁ -C ₆ ) alkyl in the definition of X ⁵ and X ^{5a is} optionally substituted with a substituent selected from the group consisting of A ¹ , OX ² , - S (O) _m (C ₁ -C ₆ ) alkyl, -C ( O) OX ² , (C ₃ -C ₇ ) cycloalkyl, -N (X ² ) (X ² ) and -C (O) N (X ² ) (X ² );
or carbon bearing X ⁵ or X ^5a forms one or two alkylene bridges with a nitrogen atom carrying R ⁷ and R ⁸ , each alkylene bridge containing 1-5 carbon atoms, provided that when one alkylene bridge is formed, X ⁵ or X ^5a , but not both, can be on a carbon atom and R ⁷ or R ⁸ , but not both, can be on a nitrogen atom, and, moreover, provided that when two alkylene bridges form, X ⁵ and X ^5a cannot be on a carbon atom and R ⁷ and R ⁸ cannot be on a nitrogen atom;
or X ⁵ taken together with X ^5a and the carbon atom to which they are attached forms a partially saturated or fully saturated 3-7 membered ring or a partially saturated or fully saturated 4-8 membered ring having 1-4 heteroatoms, independently selected from the group consisting of oxygen, sulfur and nitrogen;
or X ⁵ taken together with X ^5a and the carbon atom to which they are attached forms a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group, including nitrogen, sulfur and oxygen, condensed with a partially saturated, fully saturated or completely unsaturated 5- or 6-membered ring, optionally having 1-4 heteroatoms, independently selected from the group comprising nitrogen, sulfur and oxygen;
Z ¹ is a bond, O or N-X ² , provided that when a and b are both O, Z ^{1 is} not NX ² or O;
R ⁷ and R ⁸ independently represent hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl;
where optionally substituted (C ₁ -C ₆ ) alkyl in the definition of R ⁷ and R ^{8 is} optionally independently substituted with A ¹ -C (O) O- (C ₁ -C ₆ ) alkyl, - S (O) _m (C ₁ -C ₆ ) alkyl, 1-5 halogen atoms, 1-3 hydroxy, 1-3 -OC (O) (C ₁ -C ₁₀ ) alkyl or 1-3 (C ₁ -C ₆ ) alkoxy; or
R ⁷ and R ⁸ taken together can form - (CH ₂ ) _r -L- (CH ₂ ) _r ;
where L is C (X ² ) (X ² ), S (O) _m or N (X ² );
And ¹ in each case denotes independently (C ₅ -C ₇ ) cycloalkenyl, phenyl or partially saturated or fully saturated or completely unsaturated 4-8 membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen , a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1-4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, condensed with partially saturated, completely on a saturated or fully unsaturated 5- or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A ¹ in each case is independently optionally substituted in one or optionally both rings, if A ¹ is a bicyclic ring system and has up to 3 substituents, each substituent is independently selected from the group consisting of F, Cl, Br, I, OCF ₃ , OCF ₂ H, CF ₃ , CH ₃ , OCH ₃ , - OX ⁶ , -C (O) N (X ⁶ ) (X ⁶ ), -C (O) OX ⁶ , oxo, (C ₁ -C ₆ ) alkyl, nitro , cyano, benzyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halogenophenyl, methylenedioxy, N (X ⁶ ) (X ⁶ ), - N (X ⁶ ) C (O) (X ⁶ ), -SO ₂ N (X ⁶ ) (X ⁶ ), -N (X ⁶ ) SO ₂ -phenyl, -N (X ⁶ ) SO ₂ X ⁶ , -CONX ¹¹ X ¹² , -SO ₂ NX ¹¹ X ¹² , -NX ⁶ SO ₂ X ¹² , -NX ⁶ CONX ¹¹ X ¹² , -NX ⁶ SO ₂ NX ¹¹ X ¹² , -NX ⁶ C (O) X ¹² , imidazo lil, thiazolyl or tetrazolyl, provided that, if A ^{1 is} optionally substituted with methylenedioxy, then it can be substituted with only one methylenedioxy;
where X ¹¹ is hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl;
optionally substituted (C ₁ -C ₆ ) alkyl defined for X ¹² , optionally substituted with phenyl, phenoxy, (C ₁ -C ₆ ) alkoxycarbonyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1-5 atoms halogen, 1-3 hydroxy, 1-3 (C ₁ -C ₁₀ ) alkanoyloxy or 1-3 (C ₁ -C ₆ ) alkoxy;
X ¹² is hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X ^{12 is} not hydrogen, X ^{12 is} optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH ₃ , OCH ₃ , OCF ₃ and CF ₃ ;
or X ¹¹ and X ¹² taken together form - (CH ₂ ) _r -L- (CH ₂ ) _r ;
L ¹ is C (X ² ) (X ² ), O, S (O) _m or N (X ² );
r for each case is independently 1, 2 or 3;
X ² for each case is independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₃ -C ₇ ) cycloalkyl, optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) the cycloalkyl in the definition of X ^{2 is} optionally independently substituted with S (O) _m (C ₁ -C ₆ ) alkyl, —C (O) OX ³ , 1-5 halogen atoms or 1-3 OX ³ ;
X ³ for each case is independently hydrogen or (C ₁ -C ₆ ) alkyl;
X ⁶ is independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) halogenated alkyl, optionally substituted (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) -halogenated cycloalkyl, wherein optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) cycloalkyl in the definition of X ^{6 are} optionally independently substituted with 1-2 (C ₁ -C ₄ ) alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy , carboxyl, CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, carboxylate- (C ₁ -C ₄ ) alkyl ether or 1H-tetrazol-5-yl; or, when one atom there are two X ⁶ groups and both X ⁶ are independently (C ₁ -C ₆₎ alkyl, the two (C ₁ -C ₆₎ alkyl groups may be optionally joined, together with the atom to which these two X ⁶ groups are connected to form a 4-9 membered ring, optionally having oxygen, sulfur, or NX ⁷ ;
X ⁷ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with hydroxyl; and m for each case is independently 0, 1 or 2;
provided that
X ⁶ and X ¹² cannot be hydrogen when they are combined with C (O) or SO ₂ in the form of C (O) X ⁶ , C (O) X ¹² , SO ₂ X ⁶ or SO ₂ X ¹² ; and when R ⁶ is a bond, L is N (X ² ), and each r in the definition of - (CH ₂ ) _r -L- (CH ₂ ) _r is, independently, 2 or 3.

где Z¹ обозначает связь и а равно 0 или 1;
X⁵ и X^5a, каждый независимо, обозначают водород, трифторметил, фенил, необязательно замещенный (С₁-С₆)-алкилом;
где необязательно замещенный (C₁-C₆)-алкил необязательно замещен ОХ², имидазолилом, фенилом, индолилом, п-гидроксифенилом, (C₅-C₇) циклоалкилом, -S(O)_m(C₁-C₆)-алкилом, -N(X²)(X²) или - C(O)N(X²)(X²);
или X⁵ и R⁵, взятые вместе, образуют (C₁-C₅) алкиленовый мостик, а другие заместители, не определенные для соединений "Группы А", имеют значения, определенные для формулы (I) выше.A preferred group of compounds, designated as “Group A”, contains compounds of formula I shown above, wherein X ⁴ is hydrogen; R ⁴ is hydrogen or methyl; R ⁷ is hydrogen or (C ₁ -C ₆ ) -alkyl; R ⁸ is hydrogen or (C ₁ -C ₆ ) -alkyl optionally substituted with one or two hydroxyl groups;
R ⁶ is

where Z ¹ denotes a bond and a is 0 or 1;
X ⁵ and X ^5a , each independently, are hydrogen, trifluoromethyl, phenyl optionally substituted with (C ₁ -C ₆ ) -alkyl;
where optionally substituted (C ₁ -C ₆ ) -alkyl is optionally substituted with OX ² , imidazolyl, phenyl, indolyl, p-hydroxyphenyl, (C ₅ -C ₇ ) cycloalkyl, -S (O) _m (C ₁ -C ₆ ) - alkyl, —N (X ² ) (X ² ) or —C (O) N (X ² ) (X ² );
or X ⁵ and R ⁵ taken together form a (C ₁ -C ₅ ) alkylene bridge, and other substituents not defined for Group A compounds have the meanings defined for formula (I) above.

A group of compounds which is preferred among the “Group A” of compounds designated as “Group B” contains compounds of “Group A” having the formula I shown above, in which b is 0; and X ⁵ and X ^5a are each independently hydrogen, (C ₁ -C ₃ ) alkyl or hydroxy (C ₁ -C ₃ ) alkyl;
R ^{3 is} selected from the group consisting of 1-indolyl-CH ₂ -, 2-indolyl-CH ₂ -, 3-indolyl-CH ₂ -, 1-naphthyl-CH ₂ -, 2-naphthyl-CH ₂ -, 1-benzimidazolyl -CH ₂ -, 2-benzimidazolyl-CH ₂ -, phenyl- (C ₁ -C ₄ ) - alkyl-, 2-pyridyl- (C ₁ -C ₄ ) -alkyl-, 3-pyridyl- (C ₁ -C ₄ ) -alkyl-, 4-pyridyl- (C ₁ -C ₄ ) -alkyl-, phenyl-CH ₂ -S-CH ₂ -, thienyl- (C ₁ -C ₄ ) - alkyl-, phenyl- (C ₀ -C ₃ ) -alkyl-O-CH ₂ -, phenyl-CH ₂ -O-phenyl-CH ₂ - and 3-benzothienyl-CH ₂ -;
where the aryl part (s) of the groups defined for R ³ are optionally substituted with one to three substituents, each substituent independently selected from the group consisting of methylenedioxy, F, Cl, CH ₃ , OCH ₃ , OCF ₃ , OCF ₂ H and CF ₃ .

A group of compounds which is preferred among the “Group B” of compounds designated as “Group C” contains compounds of “Group B” having the formula I shown above in which R ⁴ is hydrogen; a is 0; n is 1 or 2; w is 0 or 1; X ⁵ and X ^5a , each independently, are hydrogen, methyl or hydroxymethyl, provided that when X ₅ is hydrogen, X ^{5a is} not hydrogen;
R ⁷ and R ⁸ are each hydrogen; and
R ³ is phenyl-CH ₂ —O — CH ₂ -, phenyl-CH ₂ -S-CH ₂ -, 1-naphthyl-CH ₂ -, 2-naphthyl-CH ₂ -, phenyl- (CH ₂ ) ₃ - or 3-indolyl-CH ₂ -;
where the aryl part of the groups defined for R ^{3 is} optionally substituted with one to three substituents, each substituent optionally selected from the group consisting of fluoro, chloro, methyl, OCH ₃ , OCF ₂ H, OCF ₃ and CF ₃ .

A group of compounds that is preferred among the “Group C” compounds, designated as “Group D”, contains compounds of “Group C” having the formula I shown above, in which R ¹ is - (CH ₂ ) _t -A ¹ , - ( CH ₂ ) _q - (C ₃ - C ₇ ) cycloalkyl or (C ₁ -C ₁₀ ) -alkyl;
where A ¹ in the definition of R ^{1 is} optionally substituted with one to three substituents, each substituent independently selected from the group consisting of fluoro, chloro, methyl, OCH ₃ , OCF ₂ H, OCF ₃ and CF ₃ ;
cycloalkyl and alkyl groups in the definition of R ^{1 are} optionally substituted with (C ₁ -C ₄ ) alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, CONH ₂ , -S (O) _m (C ₁ -C ₄ ) alkyl , CO ₂ (C ₁ -C ₄ ) alkyl ether, 1H-tetrazol-5-yl or 1-3 fluorine atoms;
Y is O; R ² is hydrogen, - (C ₀ -C ₃ ) -alkyl- (C ₃ -C ₈ ) cycloalkyl, phenyl or (C ₁ -C ₈ ) alkyl, where (C ₁ -C ₈ ) alkyl is optionally substituted with hydroxyl, - CF ₃ or 1-3 halogen atoms.

 A group of compounds that is preferred among the “Group D” compounds, designated as “F group”, contains compounds of Group D in which w is 0 and n is 1.

A group of compounds that is preferred among the “Group D” compounds, designated as “Group E”, contains compounds of Group D having the formula I shown above, in which e is 0; n and w are each equal to 1;
R ¹ is (CH ₂ ) _t —A ¹ ;
A ¹ in the definition of R ¹ is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H;
t is 0, 1 or 2;
and R ³ is phenyl-CH ₂ —O — CH ₂ , phenyl- (CH ₂ ) ₃ - or 3-indolyl-CH ₂ -, wherein the aryl moiety is optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H.

A group of compounds which is preferred among the “Group F” of compounds designated as “Group G” contains compounds of “Group F” having the formula I shown above, in which X ⁵ and X ^5a are each methyl; R ¹ is -CH ₂ -phenyl, -CH ₂ -4-fluorophenyl, -CH ₂ -pyridyl or -CH ₂ -thiazolyl and R ² is hydrogen, methyl, ethyl, tert-butyl or -CH ₂ CF ₃ .

рацемически-диастереомерные смеси и оптические изомеры этих соединений, в которых
R¹ обозначает -CH₂-фенил, R² обозначает метил и R³ обозначает -(CH₂)₃-фенил;
R¹ обозначает -CH₂-фенил, R² обозначает метил и R³ обозначает 3-индолил-СН₂-;
R¹ обозначает -CH₂-фенил, R² обозначает этил и R³ обозначает 3-индолил-СН₂-;
R¹ обозначает - CH₂-4-фторфенил, R² обозначает метил и R³ обозначает 3-индолил- CH₂-;
R¹ обозначает -CH₂-фенил, R² обозначает метил и R³ обозначает -CH₂-O-СН₂-фенил;
R¹ обозначает -CH₂-фенил, R² обозначает этил и R³ обозначает -CH₂-O-CH₂-фенил;
R¹ обозначает -CH₂-фенил, R² обозначает -CH₂-CF₃ и R³ обозначает -CH₂-O-СН₂-фенил;
R¹ обозначает -CH₂-4-фторфенил, R² обозначает метил и R³ обозначает -CH₂-O-СН₂-фенил;
R¹ обозначает -CH₂-фенил, R² обозначает трет-бутил и R³ обозначает -CH₂-O-СН₂-фенил; или
R¹ обозначает -CH₂-фенил, R² обозначает метил и R³ обозначает -CH₂-O-СН₂-3,4-дифторфенил.A group of compounds that is preferred among the “Group G” of compounds designated as “Group G ¹ ” contains Group G compounds of the formula

racemic-diastereomeric mixtures and optical isomers of these compounds in which
R ¹ is —CH ₂ phenyl, R ² is methyl, and R ³ is - (CH ₂ ) ₃ phenyl;
R ¹ is —CH ₂ phenyl, R ² is methyl, and R ³ is 3-indolyl-CH ₂ -;
R ¹ is —CH ₂ phenyl, R ² is ethyl, and R ³ is 3-indolyl — CH ₂ -;
R ¹ is —CH ₂ -4-fluorophenyl, R ² is methyl, and R ³ is 3-indolyl — CH ₂ -;
R ¹ is —CH ₂ phenyl, R ² is methyl, and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ phenyl, R ² is ethyl and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ phenyl, R ² is —CH ₂ —CF _3, and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ —4-fluorophenyl, R ² is methyl and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ phenyl, R ² is tert-butyl and R ³ is —CH ₂ —O — CH ₂ phenyl; or
R ¹ is —CH ₂ phenyl, R ² is methyl, and R ³ is —CH ₂ —O — CH ₂ —3,4-difluorophenyl.

Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydropyrazolo [4, 3-c] pyridin-5-yl) -1- (R) - (3,4-difluorobenzyloxymethyl) -2-oxoethyl] -2-methylpropionamide is preferred among the Group, G ¹ compounds and the separated isomers 3a- (R) and 3a- (S) diastereomeric mixtures are preferred.

A group of compounds which is preferred among the “Group G” of compounds designated as “Group H” contains compounds of “Group G” having the formula I shown above, in which R ¹ is —CH ₂ phenyl and R ³ is phenyl— ( CH ₂ ) ₃ -.

 Diastereomeric mixture of 2-amino-N- [1- (3- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-s] pyridine-5-carbonyl) -4-phenyl- (R) -butyl] -isobutyramide is preferred among the “Group H” compounds and the separated isomers of the 3a- (R) and 3a- (S) diastereomeric mixture are preferred.

A group of compounds that is preferred among the “Group G” of compounds designated as “Group I” contains compounds of “Group G” in which R ¹ is —CH ₂ phenyl or —CH ₂ —4-fluorophenyl and R ³ is 3- indolyl-CH ₂ -.

 Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazole [4, 3-s] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide is preferred among the “Group I” compounds and the separated isomers 3a- (R) and 3a- (S) diastereomeric mixtures are preferred.

 Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-s] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide is preferred among the “Group I” compounds and the separated isomers 3a- (R) and 3a- (S) diastereomeric mixtures are preferred.

 Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) - (4-fluorobenzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3 -c] pyridin-5-yl) -1- (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide is preferred among the “Group I” compounds and the separated isomers 3a- (R) and 3a- (S) diastereomeric mixtures are preferred.

A group of compounds that is preferred among the “Group G” of compounds designated as “Group J” contains compounds of “Group G” in which R ¹ is —CH ₂ phenyl or —CH ₂ -4-fluorophenyl and R ³ is phenyl CH ₂ —O — CH ₂ -. Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-s] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide is preferred among the “Group J” of compounds and the separated isomer 3a- (R) is preferred over the isomer 3a- (S) and the L- salt The tartaric acid of the 3- (R) -isomer is the preferred salt.

 Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-s] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide is also preferred among the “Group J” compounds and the separated isomers of the 3a- (R) and 3a- (S) diastereomeric mixture are preferred.

 Diastereomeric mixture 2-amino-N- [2- (3- (R, S) - benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7 - hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide is also preferred among the “Group J” compounds and the separated isomers 3a- (R) and 3a- (S a) diastereomeric mixtures are preferred and isomer 3a- (R) is preferred over isomer 3a- (S).

 Diastereomeric mixture of 2-amino-N- {1- (3- (R) -benzyloxymethyl-2- [3- (R, S) - (4-fluorobenzyl) -2-methyl-3-oxo-2,3,3a , 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl} -isobutyramide is also preferred among the “Group J” compounds and the separated isomers 3a- (R) and 3a- (S) diastereomeric mixtures are preferred.

 Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) - benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3- c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide is also preferred among the “Group J” compounds and the separated isomers of the 3a- (R) and 3a- (S) diastereomeric mixture are preferred.

A group of compounds that is preferred among the “Group D” compounds, designated as “Group K”, contains compounds of “Group D” in which e is 1; n is 1; w is 1; R ¹ is (CH ₂ ) _t —A ¹ ;
where A ¹ in the definition of R ¹ is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted with one to three substituents, each substituent selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H;
t is 0, 1 or 2;
and R ³ is phenyl-CH ₂ —O — CH ₂ -, phenyl- (CH ₂ ) ₃ - or 3-indolyl-CH ₂ -, wherein the aryl moiety is optionally substituted with one to three substituents, wherein the substituent is independently selected from the group consisting of F, Cl, Me, Ome, CF ₃ , OCF ₃ or OCF ₂ H.

A group of compounds which is preferred among the “Group K” of compounds designated as “Group L” contains compounds of “Group K” in which X ⁵ and X ^5a are each methyl; R ¹ is -CH ₂ -phenyl, -CH ₂ -4-fluorophenyl, -CH ₂ -pyridyl or -CH ₂ - and thiazolyl R ² is hydrogen, methyl, ethyl, t-butyl, or - CH ₂ CF _3.

A group of compounds which is preferred among the “Group L”, designated as “L ¹ ”, contains compounds of the “Group L” in which R ¹ is —CH ₂ phenyl; R ² is hydrogen or methyl; and R ³ is —CH ₂ —O — CH ₂ phenyl.

 Diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- il) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide is also preferred among the “Group J” compounds and the separated isomers of the 3- (R) and 3a- (S) diastereomeric mixture are preferred and the isomer 3- (R) preferred over isomer 3a- (S).

Another group of compounds, which is preferred among the “Group A” compounds, designated as “Group M”, contains compounds of “Group K” having the formula I shown above, where b is 0; X ⁵ and X ^5a , each independently, are hydrogen, (C ₁ -C ₃ ) alkyl or hydroxy (C ₁ -C ₃ ) alkyl; R ^{3 is} selected from the group consisting of 1-indolyl-CH ₂ -, 2-indolyl-CH ₂ -, 3-indolyl-CH ₂ -, 1-naphthyl-CH ₂ -, 2-naphthyl-CH ₂ -, 1-benzimidazolyl -CH ₂ -, 2-benzimidazolyl-CH ₂ -, phenyl- (C ₁ -C ₄ ) -alkyl-, 2-pyridyl- (C ₁ -C ₄ ) -alkyl-, 3-pyridyl- (C ₁ -C ₄ ) -alkyl-,
4-pyridyl- (C ₁ -C ₄ ) -alkyl-, phenyl-CH ₂ -S-CH ₂ -thienyl- (C ₁ -C ₄ ) -alkyl-, phenyl- (C ₀ -C ₃ ) alkyl-O -CH ₂ -, phenyl-CH ₂ -O-phenyl-CH ₂ -, 3-benzothienyl-CH ₂ -, thienyl-CH ₂ -O-CH ₂ -, thiazolyl-CH ₂ -O-CH ₂ -, pyridyl- CH ₂ —O — CH ₂ -, pyrimidyl-CH ₂ —O — CH ₂ - and phenyl-CH ₂ —O — CH ₂ -; where the aryl part (s) of the groups defined for R ³ are optionally substituted with one to three substituents, each substituent independently selected from the group consisting of methylenedioxy, F, Cl, CH ₃ , OCH ₃ , OCF ₃ , OCF ₂ H and CF ₃ .

A group of compounds which is preferred among the “Group M”, designated as “Group M ¹ ”, contains compounds of the “Group M” in which R ⁴ is hydrogen; a is 0; n is 1; w is 1; e is 0; X ⁵ and X ^5a , each independently, are hydrogen, methyl or hydroxymethyl, provided that when X ⁵ is hydrogen, X ^{5a is} not hydrogen; R ⁷ and R ⁸ are each hydrogen; Y is oxygen; R ² is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, —CH ₂ CF ₃ , CF ₃ or —CH ₂ - cyclopropyl; R ¹ is CH ₂ -A ¹ ; where A ¹ in the definition of R ¹ represents phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H; and R ³ is phenyl-CH ₂ -O-CH ₂ -, phenyl- (CH _{2) 3} -, 3-indolyl-CH ₂ -, _{thienyl-CH2-O-CH 2} -, thiazolyl-CH ₂ -O- CH ₂ -, pyridyl-CH ₂ -O-CH ₂ -, pyrimidyl-CH ₂ -O-CH ₂ - or phenyl-CH ₂ -O-CH ₂ -, where the aryl part is optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H.

A group of compounds which is preferred among the “Group M ¹ ”, designated as “Group N”, contains compounds of the “Group M ¹ ” having the formula I shown above, wherein X ⁵ and X ^5a are each methyl; R ² is methyl, ethyl or —CH ₂ CF ₃ ; A ¹ is phenyl optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H; and R ³ is phenyl-CH ₂ —O — CH ₂ -, phenyl- (CH ₂ ) ₃ - or thienyl-CH ₂ O — CH ₂ -, wherein the aryl moiety is optionally substituted with one to three substituents, each substituent independently selected from a group comprising F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H.

Another group of compounds, which is preferred among the “Group M ¹ ”, designated as “Group N”, contains compounds of the “Group M ¹ ” having the formula I shown above, wherein X ⁵ and X ^5a are each methyl; R ² is methyl, ethyl or —CH ₂ CF ₃ ; And ¹ is 2-pyridyl or 3-pyridyl optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H; R ³ is phenyl-CH ₂ —O — CH ₂ -, phenyl- (CH ₂ ) ₃ - or thienyl-CH ₂ O — CH ₂ -, wherein the aryl moiety is optionally substituted with one to three substituents, each substituent independently selected from the group including F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H.

Another group of compounds, which is preferred among the “Group M ¹ ”, designated as “Group P”, contains compounds of the “Group M ¹ ” having the formula I shown above, wherein X ⁵ and X ^5a are each methyl; R ² is methyl, ethyl or —CH ₂ CF ₃ ; A ¹ is phenyl optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H; R ³ is 2-pyridyl-CH ₂ -O-CH ₂ -or 3-pyridyl-CH ₂ -O-CH ₂ -, where the aryl moiety is optionally substituted with one to three substituents, each substituent independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₂ H.

рацемически-диастереомерные смеси и оптические изомеры этих соединений, где
R² обозначает метил; А¹ обозначает 2-пиридил и R³ обозначает -CH₂-O-CH₂-фенил;
R² обозначает CH₂CF₃; A¹ обозначает 2-пиридил и R³ обозначает -CH₂-O-CH₂-3-хлорфенил;
R² обозначает CH₂CF₃; A¹ обозначает 2-пиридил и R³ обозначает -CH₂-O-CH₂-4-хлорфенил;
R² обозначает CH₂CF₃; A¹ обозначает 2-пиридил и R³ обозначает -CH₂- O-CH₂-2,4-дихлорфенил;
R² обозначает CH₂CF₃; A¹ обозначает 2-пиридил и R³ обозначает -CH₂-O-CH₂-3-хлортиофен; или
R² обозначает CH₂CF₃; A¹ обозначает 2-пиридил и R³ обозначает -CH₂- O-CH₂-2,4-дифторфенил.A group of compounds that is preferred among Group O of compounds, designated as “Group Q”, contains compounds of “Group O” having the formula

racemic-diastereomeric mixtures and optical isomers of these compounds, where
R ² is methyl; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ —3-chlorophenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ —4-chlorophenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ -2,4-dichlorophenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ —3-chlorothiophene; or
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ -2,4-difluorophenyl.

 Diastereomeric mixture of 2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo- (3a- (R, S) -pyridin-2-ylmethyl-2,3,3a, 4 , 6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] -2-methylpropionamide is preferred among the "Group Q" compounds and the separated isomers of 3a- (R) and 3- (S) diastereomeric mixtures are preferred.

 Diastereomeric mixture of 2-amino-N- {1- (R) - (3-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo- (3- (R, S) -pyridin-2-ylmethyl-2- ( 2,2,2-trifluoroethyl) - 2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide is preferred among the “Group Q” compounds and separated isomers of 3a- (R) and 3a- (S) of the diastereomeric mixture are preferred.

 Diastereomeric mixture of 2-amino-N- {1- (R) - (4-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (R, S) -pyridin-2-ylmethyl-2- (2 , 2,2-trifluoroethyl) - 2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide is preferred among the “Group Q” compounds and separated isomers of 3a- (R) and 3a- (S) of the diastereomeric mixture are preferred.

 Diastereomeric mixture of 2-amino-N- {1- (R) - (2,4-dichlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R, S) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide is preferred among the “Group Q” compounds and the separated isomers of 3a- (R) and 3a- (S) of the diastereomeric mixture are preferred.

 Diastereomeric mixture of 2-amino-N- {1- (R) - (4-chlorothiophen-2-ylmethoxymethyl) -2-oxo-2- [3-oxo-3a- (R, S) -pyridin-2-ylmethyl- 2- (2,2,2-trifluoroethyl) -2,3, 3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] -2-ethyl} -2-methylpropionamide is preferred among " The Q "groups of the compounds and the separated isomers of the 3a- (R) and 3a- (S) diastereomeric mixture are preferred.

 Diastereomeric mixture of 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R, S) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide is preferred among the “Group Q” compounds and the separated isomers of 3a- (R) and 3a- (S) of the diastereomeric mixture are preferred.

рацемически-диастереомерные смеси и оптические изомеры этих соединений и их фармацевтически приемлемые соли, где e равно 0 или 1; n и w, каждый независимо, равно 0, 1 или 2, при условии, что w и n не могут быть оба одновременно равны 0;
R¹ обозначает водород, -CN, -(CH₂)_qN(X⁶)C(O)X⁶, -(CH₂)_qN(X⁶)C(O) (CH₂)_t-A¹, - (CH₂)_qN(X⁶)SO₂(CH₂)_t-A¹, -(CH₂)_qN(X⁶)SO₂X⁶,
-(CH₂)_qN(X⁶)C(O)N(X⁶) (CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)N(X⁶) (X⁶),
-(CH₂)_qC(O)N(X⁶) (X⁶), -(CH₂)_qC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qC(O)OX⁶,
-(CH₂)_qC(O)O(CH₂)_t-A¹, -(CH₂)_qOX⁶, -(CH₂)_qOC(O)X⁶, -(CH₂)_qOC(O)(CH₂)_t-A¹, - (CH₂)_qOC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qOC(O)N(X⁶)(X⁶), -(CH₂)_qC(O)X⁶,
-(CH₂)_qC(O)(CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)OX⁶, - (CH₂)_qN(X⁶)SO₂N(X⁶) (X⁶), -(CH₂)_qS(O)_mX⁶, -(CH₂)_qS(O)_m(CH₂)_t-A¹, -(С₁-С₁₀)алкил, -(CH₂)_t-A¹, -(CH₂)_q-(C₃-C₇)циклоалкил, (CH₂)_q-Y¹-(C₁-C₆)алкил,
-(CH₂)_q-Y¹-(CH₂)_t-A¹ или -(CH₂)_q-Y¹-(CH₂)_t-(С₃-С₇) циклоалкил; где группы алкил и циклоалкил в определении R¹ необязательно замещены (C₁-C₄) алкилом, гидроксилом, (C₁-C₄)алкокси, карбоксилом, -CONH₂, - S(O)_m(С₁-С₆)алкилом, CO₂(С₁-С₄)-алкилом, 1H-тетразол-5-илом или 1, 2, или 3 атомами фтора;
Y¹ обозначает О, S(O)_m, -C(O)NX⁶-, -CH=CH-, -C≡C-, - N(X⁶)C(O)-, -OC(O)NX⁶-, -С(O)O-, -OC(O)N(X⁶)- или -OC(O)-; q равно 0, 1, 2, 3 или 4;
t равно 0, 1, 2 или 3;
группы -(CH₂)_q и (CH₂)_t каждая, могут быть необязательно замещены 1-3 атомами фтора, 1 или 2 (C₁-C₄)-алкилом, гидроксилом, (C₁-C₄) алкокси, карбоксилом, -CONH₂, -S(O)_m(C₁-С₆)алкилом, -CO₂(C₁ -C₄)-алкиловым эфиром или 1H-тетразол-5-илом;
R² обозначает (С₁-C₈)алкил, -(С₀-С₃)алкил-(С₃-С₈)циклоалкил, -(C₁-C₄)алкил-A¹ или А¹;
где алкильные группы и циклоалкильные группы в определении R² необязательно замещены гидроксилом, -С(O)ОХ⁶, C(O)N(X⁶)(X⁶), -N(X⁶)(X⁶), -S(O)_m(С₁-С₆)алкилом, -С(O)А¹, - С(O)(X⁶), CF₃, ON или 1-3 атомами галогена;
А¹ в каждом случае обозначает независимо (C₅-С₇) циклоалкенил, фенил или частично насыщенное или полностью насыщенное или полностью ненасыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранных из группы, включающей кислород, серу и азот, или бициклическую кольцевую систему, состоящую из частично насыщенного, полностью ненасыщенного или полностью насыщенного 5- или 6-членного кольца, необязательно имеющего 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород, конденсированного с частично насыщенным, полностью насыщенным или полностью ненасыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
А¹ в каждом случае независимо необязательно замещен в одном или необязательно обоих кольцах, если А¹ является бициклической кольцевой системой, и имеет до 3 заместителей, причем каждый заместитель независимо выбран из группы, включающей F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, -ОХ⁶, -C(O)N(X⁶)(X⁶), -С(O)ОХ⁶, оксо, (С₁-С₆)алкил, нитро, циано, бензил, -S(O)_m(С₁-С₆)алкил, 1H-тетразол-5-ил, фенил, фенокси, фенилалкилокси, галогенфенил, метилендиокси, N(X⁶)(X⁶), -N(X⁶)C(O)(X⁶), -SO₂N(X⁶)(X⁶), N(X⁶)SO₂-фенил, -N(X⁶)SO₂X⁶, -CONX¹¹X¹², -SO₂NX¹¹X¹², - NX⁶SO₂X¹², -NX⁶CONX¹¹X¹², -NX⁶SO₂NX¹¹X¹², -NX⁶C(O)X¹², имидазолил, тиазолил или тетразолил, при условии, что, если А¹ необязательно замещен метилендиокси, то он может быть замещен только одним метилендиокси;
где X¹¹ обозначает водород или необязательно замещенный (C₁-С₆) алкил;
необязательно замещенный (С₁-С₆)алкил, определенный для X¹², необязательно замещен фенилом, фенокси, (C₁-С₆) алкоксикарбонилом, -S(O)_m(С₁-С₆)алкилом, 1-5 атомами галогена, 1-3 гидрокси, 1-3 (С₁-С₁₀)алканоилокси или 1-3 (C₁-С₆)алкокси;
X¹² обозначает водород, (С₁-С₆)алкил, фенил, тиазолил, имидазолил, фурил или тиенил при условии, что, когда X¹² не является водородом, X¹² необязательно замещен одним-тремя заместителями, независимо выбранными из группы, включающей Cl, F, CH₃, OCH₃, OCF₃ и CF₃;
или X¹¹ и X¹², взятые вместе, образуют -(CH₂)_r-L-(CH₂)_r;
L¹ обозначает С(X²) (X²), О, S(O)_m или N(X²);
r для каждого случая независимо равно 1, 2 или 3;
X² для каждого случая обозначает независимо водород, необязательно замещенный (С₁-С₆)алкил или необязательно замещенный (C₃-C₇) циклоалкил, причем необязательно замещенный (С₁-С₆)алкил и необязательно замещенный (С₃-C₇) циклоалкил в определении X² необязательно независимо замещены S(O)_m(С₁-С₆)алкилом, -С(O)ОХ³, 1-5 атомами галогена или 1-3 ОХ³;
X³ для каждого случая обозначает независимо водород или (C₁-С₆)алкил;
X⁶ для каждого случая обозначает независимо водород, необязательно замещенный (С₁-С₆)алкил, (C₂-С₆)галогенированный алкил, необязательно замещенный (С₃-C₇) циклоалкил, (С₃-С₇)-галогенированный циклоалкил, причем необязательно замещенный (C₁-С₆) алкил и необязательно замещенный (C₃-C₇) циклоалкил в определении X⁶ необязательно независимо замещены, гидроксилом, (С₁-С₄)алкокси, карбоксилом, CONH₂, -S (O)_m(C₁-C₆) алкилом, CO₂-(C₁-C₄) алкилом, 1H-тетразол-5-илом или 1-2 (C₁-C₄) алкилами; или
когда на одном атоме имеются две группы X⁶ и оба X⁶ являются независимо (C₁-C₆)-алкилом, две (C₁-C₆)-алкильные группы могут быть необязательно соединены, вместе с атомом, с которым эти две группы X⁶ соединены, с образованием
4-9-членного кольца, необязательно имеющего кислород, серу или NX⁷;
X⁷ обозначает водород или (С₁-С₆)-алкил, необязательно замещенный гидроксилом; и
m для каждого случая независимо равно 0, 1 или 2;
при условии, что
X⁶ и X¹² не могут быть водородом, когда они соединены с C(O) или SO₂ в форме С(O)X⁶, С(O)X¹², SO₂X⁶ или SO₂X¹²; и когда R⁶ является водородом, R¹ не является -C≡C- фенилом.A group of compounds containing intermediates useful in the synthesis of compounds of formula (I) has the formula

racemic-diastereomeric mixtures and optical isomers of these compounds and their pharmaceutically acceptable salts, where e is 0 or 1; n and w, each independently, are 0, 1 or 2, provided that w and n cannot both be equal to 0;
R ¹ is hydrogen, —CN, - (CH ₂ ) _q N (X ⁶ ) C (O) X ⁶ , - (CH ₂ ) _q N (X ⁶ ) C (O) (CH ₂ ) _t —A ¹ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ X ⁶ ,
- (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ ) ( X ⁶ )
- (CH ₂ ) _q C (O) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q C (O) OX ⁶ ,
- (CH ₂ ) _q C (O) O (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OX ⁶ , - (CH ₂ ) _q OC (O) X ⁶ , - (CH ₂ ) _q OC ( O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O) X ⁶ ,
- (CH ₂ ) _q C (O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) OX ⁶ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q S (O) _m X ⁶ , - (CH ₂ ) _q S (O) _m (CH ₂ ) _t -A ¹ , - (C ₁ -C ₁₀ ) alkyl, - (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q - (C ₃ -C ₇ ) cycloalkyl, (CH ₂ ) _q -Y ¹ - (C ₁ -C ₆ ) alkyl,
- (CH ₂ ) _q -Y ¹ - (CH ₂ ) _t -A ¹ or - (CH ₂ ) _q -Y ¹ - (CH ₂ ) _t - (C ₃ -C ₇ ) cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R ^{1 are} optionally substituted with (C ₁ -C ₄ ) alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ (C ₁ -C ₄ ) -alkyl, 1H-tetrazol-5-yl or 1, 2, or 3 fluorine atoms;
Y ¹ is O, S (O) _m , -C (O) NX ⁶ -, -CH = CH-, -C≡C-, - N (X ⁶ ) C (O) -, -OC (O) NX ⁶ -, -C (O) O-, -OC (O) N (X ⁶ ) - or -OC (O) -; q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
groups - (CH ₂ ) _q and (CH ₂ ) _t each, may optionally be substituted with 1-3 fluorine atoms, 1 or 2 (C ₁ -C ₄ ) -alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl , -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, -CO ₂ (C ₁ -C ₄ ) -alkyl ether or 1H-tetrazol-5-yl;
R ² is (C ₁ -C ₈ ) alkyl, - (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl, - (C ₁ -C ₄ ) alkyl-A ¹ or A ¹ ;
where the alkyl groups and cycloalkyl groups in the definition of R ^{2 are} optionally substituted with hydroxyl, -C (O) OX ⁶ , C (O) N (X ⁶ ) (X ⁶ ), -N (X ⁶ ) (X ⁶ ), -S ( O) _m (C ₁ -C ₆ ) alkyl, -C (O) A ¹ , -C (O) (X ⁶ ), CF ₃ , ON or 1-3 halogen atoms;
And ¹ in each case denotes independently (C ₅ -C ₇ ) cycloalkenyl, phenyl or partially saturated or fully saturated or completely unsaturated 4-8 membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen or a bicyclic ring system consisting of a partially saturated, completely unsaturated or fully saturated 5- or 6-membered ring, optionally having 1-4 heteroatoms, independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with partially saturated a fifth, completely saturated or completely unsaturated 5- or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A ¹ in each case is independently optionally substituted in one or optionally both rings if A ¹ is a bicyclic ring system and has up to 3 substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF ₃ , OCF ₂ H, CF ₃ , CH ₃ , OCH ₃ , —OX ⁶ , —C (O) N (X ⁶ ) (X ⁶ ), —C (O) OX ⁶ , oxo, (C ₁ -C ₆ ) alkyl, nitro, cyano, benzyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halogenophenyl, methylenedioxy, N (X ⁶ ) (X ⁶ ), - N (X ⁶ ) C (O) (X ⁶ ), -SO ₂ N (X ⁶ ) (X ⁶ ), N (X ⁶ ) SO ₂ -phenyl, -N (X ⁶ ) SO ₂ X ⁶ , -CONX ¹¹ X ^12, -SO ₂ NX ¹¹ X ^12, - NX ⁶ SO ₂ X ^12, -NX ⁶ CONX ¹¹ X ^12, -NX ⁶ SO ₂ NX ¹¹ X ^12, -NX ⁶ C (O) X ^12, and idazolil, thiazolyl or tetrazolyl, provided that if A ¹ is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X ¹¹ is hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl;
optionally substituted (C ₁ -C ₆ ) alkyl defined for X ¹² , optionally substituted with phenyl, phenoxy, (C ₁ -C ₆ ) alkoxycarbonyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1-5 atoms halogen, 1-3 hydroxy, 1-3 (C ₁ -C ₁₀ ) alkanoyloxy or 1-3 (C ₁ -C ₆ ) alkoxy;
X ¹² is hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X ^{12 is} not hydrogen, X ^{12 is} optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH ₃ , OCH ₃ , OCF ₃ and CF ₃ ;
or X ¹¹ and X ¹² taken together form - (CH ₂ ) _r -L- (CH ₂ ) _r ;
L ¹ is C (X ² ) (X ² ), O, S (O) _m or N (X ² );
r for each case is independently 1, 2 or 3;
X ² for each case means independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₃ -C ₇ ) cycloalkyl, optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) the cycloalkyl in the definition of X ^{2 is} optionally independently substituted with S (O) _m (C ₁ -C ₆ ) alkyl, —C (O) OX ³ , 1-5 halogen atoms or 1-3 OX ³ ;
X ³ for each case is independently hydrogen or (C ₁ -C ₆ ) alkyl;
X ⁶ for each case means independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) halogenated alkyl, optionally substituted (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) -halogenated cycloalkyl, wherein optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) cycloalkyl in the definition of X ^{6 are} optionally independently substituted with hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ - (C ₁ -C ₄ ) alkyl, 1H-tetrazol-5-yl or 1-2 (C ₁ -C ₄ ) alkyl; or
when there are two X ⁶ groups on one atom and both X ⁶ are independently (C ₁ -C ₆ ) -alkyl, two (C ₁ -C ₆ ) -alkyl groups may optionally be joined together with the atom with which these two groups X ⁶ connected to form
A 4-9 membered ring optionally having oxygen, sulfur, or NX ⁷ ;
X ⁷ is hydrogen or (C ₁ -C ₆ ) -alkyl optionally substituted with hydroxyl; and
m for each case is independently 0, 1 or 2;
provided that
X ⁶ and X ¹² cannot be hydrogen when they are combined with C (O) or SO ₂ in the form of C (O) X ⁶ , C (O) X ¹² , SO ₂ X ⁶ or SO ₂ X ¹² ; and when R ⁶ is hydrogen, R ^{1 is} not -C≡C- phenyl.

A group of intermediates preferred among the preceding group of formula (II), designated as “Group AA”, contains compounds in which w is 0 or 1; n is 1; R ¹ is hydrogen, - (CH ₂ ) _q - (C ₃ -C ₇ ) cycloalkyl, (CH ₂ ) _t -A ¹ or (C ₁ -C ₁₀ ) alkyl, where (C ₁ -C ₁₀ ) is alkyl and ( C ₃ -C ₇ ) cycloalkyl groups are substituted with 1-3 fluorine atoms and A ¹ in the definition of R ^{1 is} optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Me, methoxy, CF ₃ , OCF ₃ and OCF ₂ H; R ² is hydrogen, (C ₁ -C ₈ ) alkyl, (C ₀ -C ₃ ) alkyl- (C ₃ -C ₇ ) cycloalkyl, phenyl or (C ₁ -C ₃ ) alkyl phenyl, where the alkyl and phenyl groups are optionally substituted one to three substituents independently selected from the group consisting of F, CF ₃ , OH and methoxy.

A group of compounds preferred among the “Group AA” compounds, designated as “Group BB”, contains compounds of Group AA in which w is 1; e is 0; R ¹ is —CH ₂ pyridyl, —CH ₂ thiazolyl or —CH ₂ phenyl optionally substituted with one to three substituents independently selected from the group consisting of fluoro and chloro; and R ² is hydrogen, (C ₁ -C ₄ ) alkyl or phenyl, where (C ₁ -C ₄ ) alkyl or phenyl groups in the definition of R ^{2 are} optionally substituted with one to three substituents independently selected from the group consisting of fluoro, hydroxy or methoxy.

Compounds that are preferred among the “BB Group” of compounds are a diastereomeric mixture of a compound in which R ¹ is —CH ₂ phenyl and R ² is methyl or hydrogen; and preferred are the separated isomers of 3a- (R) and 3a- (S) of the diastereomeric mixture.

и содержит также рацемически-диастереомерные смеси и оптические изомеры этих соединений, где Z¹⁰⁰ обозначает метил, BOC, CBZ, CF₃C(О)-, FMOC, TROC, тритил, тозил, CH₃С(О)- или необязательно замещенный бензил, необязательно замещенный метокси, диметокси или нитро; e равно 0 или 1; n и w, каждый равен независимо, 0, 1 или 2 при условии, что w и n оба одновременно не могут быть равны 0;
R¹ обозначает водород, -CN, -(CH₂)_qN(X⁶)C(O)X⁶, -(CH₂)_qN(X⁶)C(O)(CH₂)_t-A¹, -(CH₂)_qN(X⁶)SO₂(CH₂)_t-A¹, -(CH₂)_qN(X⁶)SO₂X⁶, -(CH₂)_qN(X⁶)C(O)N(X⁶(CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)N(X⁶)(X⁶), -(CH₂)_qC(O)N(X⁶)(X⁶), -(CH₂)_qC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qC(O)OX⁶, -(CH₂)_qC(O)O(CH₂)_t-A¹, -(CH₂)_qOX⁶-(CH₂)_qOC(O)X⁶,
-(CH₂)_qOC(O)(CH₂)_t-A¹, -(CH₂)_qOC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qOC(O)N(X⁶)(X⁶),
-(CH₂)_qC(O)X⁶, -(CH₂)_qC(O)(CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)OX⁶, -(CH₂)_qN(X⁶)SO₂N(X⁶)(X⁶), -(CH₂)_qS(O)_mX⁶, -(CH₂)_qS(O)_m(CH₂)_t-A¹,
-(C₁-C₁₀)алкил, -(CH₂)_t-A¹, -(CH₂)_q-(C₃-C₇)циклоалкил, -(CH₂)_q-Y¹(C₁-C₆)алкил, -(CH₂)_q-Y¹-(CH₂)_t-A¹ или -(CH₂)_q-Y¹-(CH₂)_t(C₃-C₇) циклоалкил;
где группы алкил и циклоалкил в определении R¹ необязательно замещены (C₁-C₄) алкилом, гидроксилом, (C₁-C₄)алкокси, карбоксилом, -CONH₂, - S(O)_m(C₁-C₆)алкилом, CO₂(C₁-C₄)-алкилом, 1Н-тетразол-5-илом или 1-3 атомами фтора;
Y¹ обозначает О, S(O)_m, -C(O)NX⁶-, -CH= CH-, -C≡C-, -N(X⁶)C(O)-, -C(O)NX⁶, -C(O)O-, -OC(O)N(X⁶)- или -OC(O)-;
q равно 0, 1, 2, 3 или 4;
t равно 0, 1, 2 или 3;
группы -(CH₂)_q и (CH₂)_t каждая, могут быть необязательно замещены гидроксилом, (C₁-C₄)алкокси, карбоксилом, -CONH₂, -S(O)_m(C₁-C₆)алкилом, - CO₂(C₁-C₄)-алкилом, 1Н-тетразол-5-илом, 1-3 атомами фтора или 1 или 2 (C₁-C₄) алкилами;
R² обозначает водород, (C₁-C₈)алкил, - (C₀-C₃)алкил-(C₃- C₈)циклоалкил,
-(C₁-C₄)алкил-A¹ или А¹;
где алкильные группы и циклоалкильные группы в определении R² необязательно замещены гидроксилом, -C(O)OX⁶, C(O)N(X⁶)(X⁶), -N(X⁶)(X⁶), -S(O)_m(C₁-C₆)алкилом, -C(O)А¹ -C(O)(X⁶), CF₃, CN или 1-3 атомами галогена;
А¹ в каждом случае обозначает независимо (C₅- C₇) циклоалкенил, фенил или частично насыщенное или полностью насыщенное или полностью ненасыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранных из группы, включающей кислород, серу и азот, или бициклическую кольцевую систему, состоящую из частично насыщенного, полностью ненасыщенного или полностью насыщенного 5- или 6-членного кольца, необязательно имеющего 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород, конденсированного с частично насыщенным, полностью насыщенным или полностью ненасыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
А¹ в каждом случае независимо необязательно замещен в одном или необязательно обоих кольцах, если А¹ является бициклической кольцевой системой, и имеет до 3 заместителей, причем каждый заместитель независимо выбран из группы, включающей F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, -OX⁶, -C(O)N(X⁶)(X⁶), -C(O)OX⁶, оксо, (C₁-C₆)алкил, нитро, циано, бензил, -S(O)_m(C₁-C₆)алкил, 1H-тетразол-5-ил, фенил, фенокси, фенилалкилокси, галогенфенил, метилендиокси, N(X⁶)(X⁶), -N(X⁶)C(O)(X⁶), -SO₂N(X⁶)(X⁶), -N(X⁶)SO₂-фенил, -N(X⁶)SO₂X⁶, -CONX¹¹X¹², -SO₂NX¹¹X¹², -NX⁶SO₂X¹², -NX⁶CONX¹¹X¹², -NX⁶SO₂NX¹¹X¹², -NX⁶C(O)X¹², имидазолил, тиазолил или тетразолил при условии, что, если А¹ необязательно замещен метилендиокси, то он может быть замещен только одним метилендиокси;
где X¹¹ обозначает водород или необязательно замещенный (C₁-C₆)алкил;
необязательно замещенный (C₁-C₆)алкил, определенный для X¹², необязательно замещен фенилом, фенокси, (C₁-C₆)алкоксикарбонилом, -S(O)_m(C₁-C₆)алкилом, 1-5 атомами галогена, 1-3 гидрокси, 1-3 (C₁-C₁₀)алканоилокси или 1-3 (C₁-C₆) алкокси;
X¹² обозначает водород, (C₁-C₆)алкил, фенил, тиазолил, имидазолил, фурил или тиенил при условии, что, когда X¹² не является водородом, X¹² необязательно замещен одним-тремя заместителями, независимо выбранными из группы, включающей Cl, F, CH₃, OCH₃, OCF₃ и CF₃;
или X¹¹ и X¹², взятые вместе, образуют -(CH₂)_r-L¹-(CH₂)_r;
L¹ обозначает C(X²)(X²), О, S(O)_m или N(X²);
r для каждого случая независимо равно 1, 2 или 3;
X² для каждого случая обозначает независимо водород, необязательно замещенный (C₁-C₆)алкил или необязательно замещенный (C₃-C₇)циклоалкил, причем необязательно замещенный (C₁-C₆)алкил и необязательно замещенный (C₃-C₇)циклоалкил в определении X² необязательно независимо замещены S(O)_m(C₁-C₆)алкилом, -C(O)ОХ³, 1-5 атомами галогена или 1-3 OX³;
X³ для каждого случая обозначает независимо водород или (C₁-C₆)алкил;
X⁶ для каждого случая обозначает независимо водород, необязательно замещенный (C₁-C₆)алкил, (C₂-C₆)галогенированный алкил, необязательно замещенный (C₃-C₇)циклоалкил, (C₃-C₇)-галогенированный циклоалкил, причем необязательно замещенный (C₁-C₆) алкил и необязательно замещенный (C₃-C₇) циклоалкил в определении X⁶ необязательно независимо замещены, гидроксилом, (C₁-C₄)алкокси, карбоксилом, CONH₂, -S(O)_m(C₁-C₆)алкилом, CO₂-(C₁-C₄)алкилом, 1H-тетразол-5-илом или 1-2 (C₁-C₄) алкилами; или, когда на одном атоме имеются две группы X⁶ и оба X⁶ являются независимо (C₁-C₆)-алкилом, две (C₁-C₆)-алкильные группы могут быть необязательно соединены, вместе с атомом, с которым эти две группы X⁶ соединены, с образованием 4-9-членного кольца, необязательно имеющего кислород, серу или NX⁷;
X⁷ обозначает водород или (C₁-C₆)-алкил, необязательно замещенный гидроксилом; и
m для каждого случая независимо равно 0, 1 или 2;
при условии, что
X⁶ и X¹² не могут быть водородом, когда они соединены с C(O) или SO₂ в форме C(O)X⁶, C(O)X¹², SO₂X⁶ или SO₂X¹²; и когда R⁶ является водородом, R¹ не является -C≡C- фенилом;
когда R² является H и R¹ является -CH₂-CH=CH-Ph, Z¹⁰⁰ не является BOC;
когда R² является H и R¹ является H, Z¹⁰⁰ не является BOC;
когда R² является H и R¹ является -CH₂-С(CH₃)=CH₂, Z¹⁰⁰ не является BOC; и
когда R² является фенилом и R¹ является -CH₃, Z¹⁰⁰ не является CH₃С(О)-.Another group of intermediates useful in the synthesis of compounds of formula (I) has the formula

and also contains racemic-diastereomeric mixtures and optical isomers of these compounds, where Z ¹⁰⁰ is methyl, BOC, CBZ, CF ₃ C (O) -, FMOC, TROC, trityl, tosyl, CH ₃ C (O) - or optionally substituted benzyl optionally substituted methoxy, dimethoxy or nitro; e is 0 or 1; n and w, each equal independently, 0, 1 or 2, provided that w and n both cannot be equal to 0 at the same time;
R ¹ is hydrogen, —CN, - (CH ₂ ) _q N (X ⁶ ) C (O) X ⁶ , - (CH ₂ ) _q N (X ⁶ ) C (O) (CH ₂ ) _t —A ¹ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ X ⁶ , - (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O ) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q C (O) OX ⁶ , - ( CH ₂ ) _q C (O) O (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OX ⁶ - (CH ₂ ) _q OC (O) X ⁶ ,
- (CH ₂ ) _q OC (O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (X ⁶ ),
- (CH ₂ ) _q C (O) X ⁶ , - (CH ₂ ) _q C (O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) OX ⁶ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q S (O) _m X ⁶ , - (CH ₂ ) _q S (O) _m (CH ₂ ) _t -A ¹ ,
- (C ₁ -C ₁₀ ) alkyl, - (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q - (C ₃ -C ₇ ) cycloalkyl, - (CH ₂ ) _q -Y ¹ (C ₁ -C ₆ ) alkyl, - (CH ₂ ) _q -Y ¹ - (CH ₂ ) _t -A ¹ or - (CH ₂ ) _q -Y ¹ - (CH ₂ ) _t (C ₃ -C ₇ ) cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R ^{1 are} optionally substituted with (C ₁ -C ₄ ) alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ (C ₁ -C ₄ ) -alkyl, 1H-tetrazol-5-yl or 1-3 fluorine atoms;
Y ¹ is O, S (O) _m , -C (O) NX ⁶ -, -CH = CH-, -C≡C-, -N (X ⁶ ) C (O) -, -C (O) NX ⁶ , -C (O) O-, -OC (O) N (X ⁶ ) - or -OC (O) -;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
the groups - (CH ₂ ) _q and (CH ₂ ) _t each, may optionally be substituted with hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl , - CO ₂ (C ₁ -C ₄ ) -alkyl, 1H-tetrazol-5-yl, 1-3 fluorine atoms or 1 or 2 (C ₁ -C ₄ ) alkyl;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, - (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl,
- (C ₁ -C ₄ ) alkyl-A ¹ or A ¹ ;
where the alkyl groups and cycloalkyl groups in the definition of R ^{2 are} optionally substituted with hydroxyl, -C (O) OX ⁶ , C (O) N (X ⁶ ) (X ⁶ ), -N (X ⁶ ) (X ⁶ ), -S ( O) _m (C ₁ -C ₆ ) alkyl, -C (O) A ¹ -C (O) (X ⁶ ), CF ₃ , CN or 1-3 halogen atoms;
And ¹ in each case means independently (C ₅ - C ₇ ) cycloalkenyl, phenyl or partially saturated or fully saturated or fully unsaturated 4-8 membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen or a bicyclic ring system consisting of a partially saturated, completely unsaturated or fully saturated 5- or 6-membered ring, optionally having 1-4 heteroatoms, independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with partially saturated a fifth, completely saturated or completely unsaturated 5- or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A ¹ in each case is independently optionally substituted in one or optionally both rings if A ¹ is a bicyclic ring system and has up to 3 substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF ₃ , OCF ₂ H, CF ₃ , CH ₃ , OCH ₃ , -OX ⁶ , -C (O) N (X ⁶ ) (X ⁶ ), -C (O) OX ⁶ , oxo, (C ₁ -C ₆ ) alkyl, nitro, cyano, benzyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halogenophenyl, methylenedioxy, N (X ⁶ ) (X ⁶ ), - N (X ⁶ ) C (O) (X ⁶ ), -SO ₂ N (X ⁶ ) (X ⁶ ), -N (X ⁶ ) SO ₂ -phenyl, -N (X ⁶ ) SO ₂ X ⁶ , - CONX ¹¹ X ¹² , -SO ₂ NX ¹¹ X ¹² , -NX ⁶ SO ₂ X ¹² , -NX ⁶ CONX ¹¹ X ¹² , -NX ⁶ SO ₂ NX ¹¹ X ¹² , -NX ⁶ C (O) X ¹² , imidaz olyl, thiazolyl or tetrazolyl with the proviso that, if A ^{1 is} optionally substituted with methylenedioxy, then it may be substituted with only one methylenedioxy;
where X ¹¹ is hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl;
optionally substituted (C ₁ -C ₆ ) alkyl defined for X ¹² , optionally substituted with phenyl, phenoxy, (C ₁ -C ₆ ) alkoxycarbonyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1-5 atoms halogen, 1-3 hydroxy, 1-3 (C ₁ -C ₁₀ ) alkanoyloxy or 1-3 (C ₁ -C ₆ ) alkoxy;
X ¹² is hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X ^{12 is} not hydrogen, X ^{12 is} optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH ₃ , OCH ₃ , OCF ₃ and CF ₃ ;
or X ¹¹ and X ¹² taken together form - (CH ₂ ) _r -L ¹ - (CH ₂ ) _r ;
L ¹ is C (X ² ) (X ² ), O, S (O) _m or N (X ² );
r for each case is independently 1, 2 or 3;
X ² for each case means independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₃ -C ₇ ) cycloalkyl, optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) cycloalkyl in the definition of X ^{2 is} optionally independently substituted with S (O) _m (C ₁ -C ₆ ) alkyl, —C (O) OX ³ , 1-5 halogen atoms or 1-3 OX ³ ;
X ³ for each case is independently hydrogen or (C ₁ -C ₆ ) alkyl;
X ⁶ for each case means independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) halogenated alkyl, optionally substituted (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) -halogenated cycloalkyl, wherein optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) cycloalkyl in the definition of X ^{6 are} optionally independently substituted with hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ - (C ₁ -C ₄ ) alkyl, 1H-tetrazol-5-yl or 1-2 (C ₁ -C ₄ ) alkyl; or, when there are two X ⁶ groups on one atom and both X ⁶ are independently (C ₁ -C ₆ ) -alkyl, two (C ₁ -C ₆ ) -alkyl groups may optionally be joined together with the atom with which these two X ⁶ groups are connected to form a 4-9 membered ring, optionally having oxygen, sulfur, or NX ⁷ ;
X ⁷ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with hydroxyl; and
m for each case is independently 0, 1 or 2;
provided that
X ⁶ and X ¹² cannot be hydrogen when they are combined with C (O) or SO ₂ in the form of C (O) X ⁶ , C (O) X ¹² , SO ₂ X ⁶ or SO ₂ X ¹² ; and when R ⁶ is hydrogen, R ^{1 is} not -C≡C- phenyl;
when R ² is H and R ¹ is —CH ₂ —CH = CH — Ph, Z ^{100 is} not BOC;
when R ² is H and R ¹ is H, Z ^{100 is} not BOC;
when R ² is H and R ¹ is —CH ₂ —C (CH ₃ ) = CH ₂ , Z ^{100 is} not BOC; and
when R ² is phenyl and R ¹ is —CH ₃ , Z ^{100 is} not CH ₃ C (O) -.

A group of compounds preferred among the preceding group of compounds of formula (III), designated as “Group CC”, contains compounds in which w is 0 or 1; n is 1;
Z ¹⁰⁰ is BOC, methyl, benzyl or CBZ;
R ¹ is hydrogen, - (CH ₂ ) _q - (C ₃ -C ₇ ) cycloalkyl, (CH ₂ ) _t -A ¹ or (C ₁ -C ₁₀ ) -alkyl, where (C ₁ -C ₁₀ ) are alkyl and (C ₃ -C ₇ ) - cycloalkyl groups optionally substituted with 1-3 fluorine atoms and A ¹ in the definition of R ¹ optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Me, OMe, CF ₃ , OCF ₃ and OCF ₃ ;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, - (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl, phenyl or - (C ₁ -C ₃ ) alkyl phenyl, where the alkyl and phenyl groups optionally substituted with one to three substituents independently selected from the group consisting of F, CF ₃ , OH and OMe.

A group of compounds preferred among the “CC Group” of compounds designated as “DD Group” contains compounds in which Z ¹⁰⁰ is BOC, w is 1; e is 0; R ¹ is —CH ₂ —pyridyl, —CH ₂ thiazolyl or —CH ₂ phenyl optionally substituted with one to three substituents independently selected from the group consisting of fluoro and chloro; and R ² is hydrogen, (C ₁ -C ₄ ) alkyl or phenyl, where (C ₁ -C ₄ ) alkyl or phenyl groups in the definition of R ^{2 are} optionally substituted with one to three substituents independently selected from the group consisting of fluoro, hydroxy and methoxy.

Compounds preferred among the “DD Group” of compounds are a diastereomeric mixture of a compound in which R ¹ is —CH ₂ phenyl and R ² is methyl or hydrogen; and preferred are the separated isomers of 3a- (R) and 3a- (S) of the diastereomeric mixture.

рацемически-диастереомерные смеси и оптические изомеры этих соединений, в которых Z²⁰⁰ обозначает трет-BOC, CBZ, CF₃C(О)-, FMOC, TROC, тритил, тозил или необязательно замещенный бензил, который необязательно замещен метокси, диметокси или нитро;
e равно 0 или 1;
n и w, каждый равен, независимо, 0, 1 или 2 при условии, что w и n не могут быть оба одновременно равны 0;
Y обозначает кислород или серу;
R¹ обозначает водород, -CN, - (CH₂)_qN(X⁶)C(O)X⁶, -(CH₂)_qN(X⁶)C(O) (CH₂)_t-A¹, -(CH₂)_qN(X⁶)SO₂(CH₂)_t-A¹ -(CH₂)_qN(X⁶)SO₂X⁶,
-(CH₂)_qN(X⁶)C(O)N(X⁶) (CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)N(X⁶)(X⁶),
-(CH₂)_qC(O)N(X⁶)(X⁶), -(CH₂)_qC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qC(O)OX⁶ -(CH₂)_qC(O)O(CH₂)_t-A¹, -(CH₂)_qOX⁶, -(CH₂)_qOC(O)X⁶, -(CH₂)_qOC(O)(CH₂)_t-A¹,
-(CH₂)_qOC(O)N(X⁶)(CH₂)_t-A¹, -(CH₂)_qOC(O)N(X⁶)(X⁶), -(CH₂)_qC(O)X⁶,
-(CH₂)_qC(O)(CH₂)_t-A¹, -(CH₂)_qN(X⁶)C(O)OX⁶, -(CH₂)_qN(X⁶)SO₂N(X⁶)(X⁶),
-(CH₂)_qS(O)_mX⁶, -(CH₂)_qS(O)_m(CH₂)_t-A¹, -(С₁-С₁₀)алкил, -(CH₂)_t-A¹, -(CH₂)_q-(C₃-C₇)циклоалкил, -(CH₂)_q-Y¹-(C₁-C₆)алкил, -(CH₂)_q-Y¹-(CH₂)_t-A¹ или -(CH₂)_q-Y¹-(CH₂)_t-(C₃-C₇) циклоалкил;
где группы алкил и циклоалкил в определении R¹ необязательно замещены (C₁-C₄) алкилом, гидроксилом, (C₁-С₄)алкокси, карбоксилом, -CONH₂, - S(O)_m(С₁-С₆)алкилом, CO₂(C₁-C₄)-алкиловым эфиром, 1H-тетразол-5- илом или 1-3 атомами фтора;
Y¹ обозначает О, S(O)_m, -C(O)NX⁶-, -CH= CH-, -C≡C-, -N(X⁶)C(O)-, -C(O)NX⁶, -С(O)O-, -OC(O)N(X⁶)- или -OC(O)-;
q равно 0, 1, 2, 3 или 4;
t равно 0, 1, 2 или 3;
группы -(CH₂)_q и (CH₂)_t каждая, могут быть необязательно замещены гидроксилом, (C₁-C₄) алкокси, карбоксилом, -CONH₂, - S(O)_m(C₁-C₆)алкилом, -CO₂(C₁-C₄)-алкилом, 1H-тетразол-5-илом, 1-3 атомами фтора или 1 или 2 (С₁-С₄)алкилами;
R² обозначает водород, (C₁-C₈)алкил, -(C₀-C₃)алкил-(C₃-C₈)циклоалкил, -(C₁-C₄)алкил-A¹ или A¹;
где алкильные группы и циклоалкильные группы в определении R² необязательно замещены гидроксилом, -C(O)ОХ⁶, C(O)N(X⁶)(X⁶), -N(X⁶)(X⁶), -S(O)_m(C₁-C₆)алкилом, -C(O)A¹, -C(O)(X⁶), CF₃, CN или 1-3 атомами галогена;
R³ обозначает A¹, (C₁-C₁₀)алкил, -(C₁-C₆)алкил-A¹, -(C₁-C₆)алкил-(C₃-C₇)циклоалкил, -(C₁-C₅)алкил-X¹-(C₁-C₅)алкил, -(C₁-C₅)алкил-X¹-(С₀-С₅)алкил-A¹ или -(С₁-С₅)-Х¹-(С₁-С₅) алкил- (С₃-С₇)циклоалкил;
где алкильные группы в определении R³ необязательно замещены -S(O)_m(C₁-C₆)алкилом, -C(O)ОХ³, 1, 2, 3, 4 или 5 атомами галогена или 1, 2 или 3 ОХ³;
Х¹ обозначает O, S(O)_m, -N(X²)C(O)-, -C(O)N(X²)-, -OC(O)-, -C(O)O-, -CX²= CX²-, -N(X²)C(O)O-, -OC(O)N(X²)- или -C≡C-; R⁴ обозначает водород, (C₁-C₆) алкил или (C₃-C₇) циклоалкил или R⁴, взятый вместе с R³ и атомом углерода, с которым они соединены, образует (C₅-C₇)циклоалкил, (C₅-C₇)циклоалкенил, частично насыщенное или полностью насыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранных из группы, включающей кислород, серу и азот, или обозначает бициклическую кольцевую систему, состоящую из частично насыщенного или полностью насыщенного 5- или 6-членного кольца, конденсированного с частично насыщенным, полностью ненасыщенным или полностью насыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
X⁴ обозначает водород или (C₁-C₆)-алкил или X⁴, взятый вместе с R⁴ и атомом азота, с которым X⁴ соединен, и атомом углерода, с которым R⁴ соединен, образует 5-7-членное кольцо;
R⁶ обозначает связь или представляет собой

где а и b независимо равны 0, 1, 2 или 3;
X⁵ и X^5a, каждый независимо, выбраны из группы, включающей водород, трифторметил, А¹ и необязательно замещенный (C₁-C₆) алкил;
необязательно замещенный (C₁-C₆) алкил в определении X⁵ и X^5a необязательно замещен заместителем, выбранным из группы, включающей А¹, OX², -S(O)_m(C₁-C₆) алкил, -C(O)OX², (C₃-C₇) циклоалкил, -N(X²)(X²) и -C(O)N(X²)(X²); или углерод, несущий X⁵ или X^5a образует один или два алкиленовых мостика с атомом азота, несущим Z²⁰⁰ и R⁸, причем каждый алкиленовый мостик содержит 1-5 атомов углерода при условии, что, когда образуется один алкиленовый мостик, X⁵ или X^5a, но не оба, могут быть на атоме углерода и Z²⁰⁰ или R⁸, но не оба, могут быть на атоме азота;
или X⁵, взятый вместе с X^5a и атомом углерода, с которым они соединены, образует частично насыщенное или полностью насыщенное 3-7-членное кольцо или частично насыщенное или полностью насыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранные из группы, состоящей из кислорода, серы и азота;
или X⁵, взятый вместе с X^5a и атомом углерода, с которым они соединены, образует бициклическую кольцевую систему, состоящую из частично насыщенного или полностью насыщенного 5- или 6-членного кольца, необязательно имеющего 1 или 2 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород, конденсированного с частично насыщенным, полностью насыщенным или полностью ненасыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
Z¹ обозначает связь, О или N-X² при условии, что, когда а и b оба равны 0, Z¹ не является N-X² или О;
R⁸ обозначает водород или необязательно замещенный (C₁-C₆) алкил;
где необязательно замещенный (C₁-C₆)алкил в определении R⁸ необязательно независимо замещен А¹, -C(O)O-(C₁-C₆)алкилом, -S(O)_m(C₁-C₆)алкилом, 1-5 атомами галогена, 1-3 гидрокси, 1-3-O-C(O)(C₁-C₁₀)алкилом или 1-3 (C₁-C₆)алкокси;
А¹ в каждом случае обозначает независимо (C₅-C₇)циклоалкенил, фенил или частично насыщенное, полностью насыщенное или полностью ненасыщенное 4-8-членное кольцо, имеющее 1-4 гетероатома, независимо выбранных из группы, включающей кислород, серу и азот, или бициклическую кольцевую систему, состоящую из частично насыщенного, полностью ненасыщенного или полностью насыщенного 5- или 6-членного кольца, необязательно имеющего 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород, конденсированного с частично насыщенным, полностью насыщенным или полностью ненасыщенным 5- или 6-членным кольцом, необязательно имеющим 1-4 гетероатома, независимо выбранных из группы, включающей азот, серу и кислород;
А¹ в каждом случае независимо необязательно замещен в одном или необязательно обоих кольцах, если А¹ является бициклической кольцевой системой, и имеет до 3 заместителей, причем каждый заместитель независимо выбран из группы, включающей F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, -ОХ⁶, -C(O)N(X⁶)(X⁶), - С(O)ОХ⁶, оксо, (C₁-C₆)алкил, нитро, циано, бензил, -S(O)_m(С₁-С₆)алкил, 1H-тетразол-5-ил, фенил, фенокси, фенилалкилокси, галогенфенил, метилендиокси, N(X⁶)(X⁶), -N(X⁶)C(O)(X⁶), - SO₂N(X⁶)(X⁶), N(X⁶)SO₂-фенил, -N(X⁶)SO₂X⁶, -CONX¹¹X¹², - SO₂NX¹¹X¹², -NX⁶SO₂X¹², -NX⁶CONX¹¹X¹², -NX⁶SO₂NX¹¹X¹², - NX⁶C(O)X¹², имидазолил, тиазолил или тетразолил, при условии, что, если А¹ необязательно замещен метилендиокси, то он может быть замещен только одним метилендиокси;
где X¹¹ обозначает водород или необязательно замещенный (C₁-C₆)алкил;
необязательно замещенный (С₁-С₆)алкил, определенный для X¹², необязательно замещен фенилом, фенокси, (C₁- C₆)алкоксикарбонилом, -S(O)_m(C₁-C₆)алкилом, 1-5 атомами галогена, 1-3 гидрокси, 1-3 (C₁-C₁₀)алканоилокси или 1-3 (C₁-C₆) алкокси;
X¹² обозначает водород, (C₁-C₆)алкил, фенил, тиазолил, имидазолил, фурил или тиенил при условии, что, когда X¹² не является водородом, X¹² необязательно замещен одним-тремя заместителями, независимо выбранными из группы, включающей Cl, F, CH₃, OCH₃, OCF₃ и CF₃;
или X¹¹ и X¹², взятые вместе, образуют - (CH₂)_r-L¹-(CH₂)_r;
L¹ обозначает C(X²)(X²), О, S(O)_m или N(X²);
r для каждого случая обозначает независимо 1, 2 или 3;
X² для каждого случая обозначает независимо водород, необязательно замещенный (C₁-C₆)алкил или необязательно замещенный (C₃-C₇)циклоалкил, причем необязательно замещенный (C₁-C₆)алкил и необязательно замещенный (C₃-C₇) циклоалкил в определении X² необязательно независимо замещены S(O)_m (C₁-C₆)алкилом, -C(O)ОX³, 1-5 атомами галогена или 1-3 ОX³;
X³ для каждого случая обозначает независимо водород или (C₁-C₆)алкил;
X⁶ для каждого случая обозначает независимо водород, необязательно замещенный (C₁-C₆)алкил, (C₂-C₆)галогенированный алкил, необязательно замещенный (C₃-C₇)циклоалкил, (C₃-C₇)-галогенированный циклоалкил, причем необязательно замещенный (C₁-C₆)алкил и необязательно замещенный (C₃-C₇) циклоалкил в определении X⁶ необязательно независимо замещены, гидроксилом, (C₁-C₄) алкокси, карбоксилом, CONH₂, -S(O)_m(C₁-C₆)алкилом, CO₂-(C₁-C₄)алкилом, 1H-тетразол-5-илом или 1-2 (C₁-C₄) алкилами; или когда на одном атоме имеются две группы X⁶ и оба X⁶ являются независимо (C₁- C₆)-алкилом, две (C₁-C₆)-алкильные группы могут быть необязательно соединены, вместе с атомом, с которым эти две группы X⁶ соединены, с образованием 4-9-членного кольца, необязательно имеющего кислород, серу или NX⁷;
X⁷ обозначает водород или (C₁-C₆)-алкил, необязательно замещенный гидроксилом; и
m для каждого случая независимо равно 0, 1 или 2;
при условии, что
X⁶ и X¹² не могут быть водородом, когда они соединены с C(O) или SO₂ в форме C(O)X⁶, C(O)X¹², SO₂X⁶ или SO₂X¹²; и когда R⁶ является связью, L является N(X²), и каждый r в определении
-(CH₂)_r-L-(CH₂)_r - представляет собой 2 или 3.Another group of compounds useful in the synthesis of compounds of formula (I) contains compounds of formula IV

racemic-diastereomeric mixtures and optical isomers of these compounds in which Z ²⁰⁰ is tert-BOC, CBZ, CF ₃ C (O) -, FMOC, TROC, trityl, tosyl or optionally substituted benzyl, which is optionally substituted with methoxy, dimethoxy or nitro;
e is 0 or 1;
n and w, each is independently 0, 1 or 2, provided that w and n cannot both be equal to 0;
Y is oxygen or sulfur;
R ¹ is hydrogen, —CN, - (CH ₂ ) _q N (X ⁶ ) C (O) X ⁶ , - (CH ₂ ) _q N (X ⁶ ) C (O) (CH ₂ ) _t —A ¹ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ (CH ₂ ) _t -A ¹ - (CH ₂ ) _q N (X ⁶ ) SO ₂ X ⁶ ,
- (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) N (X ⁶ ) ( X ⁶ )
- (CH ₂ ) _q C (O) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q C (O) OX ⁶ - (CH ₂ ) _q C (O) O (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OX ⁶ , - (CH ₂ ) _q OC (O) X ⁶ , - ( CH ₂ ) _q OC (O) (CH ₂ ) _t -A ¹ ,
- (CH ₂ ) _q OC (O) N (X ⁶ ) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q OC (O) N (X ⁶ ) (X ⁶ ), - (CH ₂ ) _q C (O) X ⁶ ,
- (CH ₂ ) _q C (O) (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q N (X ⁶ ) C (O) OX ⁶ , - (CH ₂ ) _q N (X ⁶ ) SO ₂ N (X ⁶ ) (X ⁶ ),
- (CH ₂ ) _q S (O) _m X ⁶ , - (CH ₂ ) _q S (O) _m (CH ₂ ) _t -A ¹ , - (C ₁ -C ₁₀ ) alkyl, - (CH ₂ ) _t -A ¹ , - (CH ₂ ) _q - (C ₃ -C ₇ ) cycloalkyl, - (CH ₂ ) _q -Y ¹ - (C ₁ -C ₆ ) alkyl, - (CH ₂ ) _q -Y ¹ - ( CH ₂ ) _t —A ¹ or - (CH ₂ ) _q —Y ¹ - (CH ₂ ) _t - (C ₃ -C ₇ ) cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R ^{1 are} optionally substituted with (C ₁ -C ₄ ) alkyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ (C ₁ -C ₄ ) -alkyl ether, 1H-tetrazol-5-yl or 1-3 fluorine atoms;
Y ¹ is O, S (O) _m , -C (O) NX ⁶ -, -CH = CH-, -C≡C-, -N (X ⁶ ) C (O) -, -C (O) NX ⁶ , -C (O) O-, -OC (O) N (X ⁶ ) - or -OC (O) -;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
the groups - (CH ₂ ) _q and (CH ₂ ) _t each, may optionally be substituted with hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, -CONH ₂ , - S (O) _m (C ₁ -C ₆ ) alkyl , -CO ₂ (C ₁ -C ₄ ) -alkyl, 1H-tetrazol-5-yl, 1-3 fluorine atoms or 1 or 2 (C ₁ -C ₄ ) alkyl;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, - (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl, - (C ₁ -C ₄ ) alkyl-A ¹ or A ¹ ;
where the alkyl groups and cycloalkyl groups in the definition of R ^{2 are} optionally substituted with hydroxyl, -C (O) OX ⁶ , C (O) N (X ⁶ ) (X ⁶ ), -N (X ⁶ ) (X ⁶ ), -S ( O) _m (C ₁ -C ₆ ) alkyl, -C (O) A ¹ , -C (O) (X ⁶ ), CF ₃ , CN or 1-3 halogen atoms;
R ³ is A ¹ , (C ₁ -C ₁₀ ) alkyl, - (C ₁ -C ₆ ) alkyl-A ¹ , - (C ₁ -C ₆ ) alkyl- (C ₃ -C ₇ ) cycloalkyl, - (C ₁ -C ₅ ) alkyl-X ¹ - (C ₁ -C ₅ ) alkyl, - (C ₁ -C ₅ ) alkyl-X ¹ - (C ₀ -C ₅ ) alkyl-A ¹ or - (C ₁ -C ₅ ) -X ¹ - (C ₁ -C ₅ ) alkyl- (C ₃ -C ₇ ) cycloalkyl;
where the alkyl groups in the definition of R ^{3 are} optionally substituted with —S (O) _m (C ₁ -C ₆ ) alkyl, —C (O) OX ³ , 1, 2, 3, 4 or 5 with halogen atoms or 1, 2 or 3 OX ³ ;
X ¹ is O, S (O) _m , -N (X ² ) C (O) -, -C (O) N (X ² ) -, -OC (O) -, -C (O) O-, -CX ² = CX ² -, -N (X ² ) C (O) O-, -OC (O) N (X ² ) - or -C≡C-; R ⁴ is hydrogen, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl or R ⁴ taken together with R ³ and the carbon atom to which they are attached forms (C ₅ -C ₇ ) cycloalkyl, (C ₅ -C ₇ ) cycloalkenyl, a partially saturated or fully saturated 4-8 membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or denotes a bicyclic ring system consisting of partially saturated or fully saturated 5- or 6-membered ring fused to partially saturated, fully unsaturated, or fully saturated a 5- or 6-membered ring optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X ⁴ is hydrogen or (C ₁ -C ₆ ) -alkyl or X ⁴ taken together with R ⁴ and the nitrogen atom to which X ^{4 is} attached and the carbon atom to which R ⁴ is attached forms a 5-7 membered ring ;
R ⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3;
X ⁵ and X ^5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A ¹ and optionally substituted (C ₁ -C ₆ ) alkyl;
optionally substituted (C ₁ -C ₆ ) alkyl in the definition of X ⁵ and X ^{5a is} optionally substituted with a substituent selected from the group consisting of A ¹ , OX ² , -S (O) _m (C ₁ -C ₆ ) alkyl, -C ( O) OX ² , (C ₃ -C ₇ ) cycloalkyl, -N (X ² ) (X ² ) and -C (O) N (X ² ) (X ² ); or carbon bearing X ⁵ or X ^5a forms one or two alkylene bridges with a nitrogen atom carrying Z ²⁰⁰ and R ⁸ , each alkylene bridge containing 1-5 carbon atoms, provided that when one alkylene bridge is formed, X ⁵ or X ^5a , but not both, may be on a carbon atom and Z ²⁰⁰ or R ⁸ , but not both, may be on a nitrogen atom;
or X ⁵ taken together with X ^5a and the carbon atom to which they are attached forms a partially saturated or fully saturated 3-7 membered ring or a partially saturated or fully saturated 4-8 membered ring having 1-4 heteroatoms, independently selected from the group consisting of oxygen, sulfur and nitrogen;
or X ⁵ taken together with X ^5a and the carbon atom to which they are attached forms a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group, including nitrogen, sulfur and oxygen, condensed with a partially saturated, fully saturated or completely unsaturated 5- or 6-membered ring, optionally having 1-4 heteroatoms, independently selected from the group comprising nitrogen, sulfur and oxygen;
Z ¹ is a bond, O or NX ² , provided that when a and b are both 0, Z ^{1 is} not NX ² or O;
R ⁸ is hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl;
where optionally substituted (C ₁ -C ₆ ) alkyl in the definition of R ^{8 is} optionally independently substituted with A ¹ , -C (O) O- (C ₁ -C ₆ ) alkyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1-5 halogen atoms, 1-3 hydroxy, 1-3-OC (O) (C ₁ -C ₁₀ ) alkyl or 1-3 (C ₁ -C ₆ ) alkoxy;
And ¹ in each case means independently (C ₅ -C ₇ ) cycloalkenyl, phenyl or partially saturated, fully saturated or completely unsaturated 4-8 membered ring having 1-4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1-4 heteroatoms, independently selected from the group consisting of nitrogen, sulfur and oxygen, condensed with partially saturated, p a fully saturated or completely unsaturated 5- or 6-membered ring, optionally having 1-4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A ¹ in each case is independently optionally substituted in one or optionally both rings if A ¹ is a bicyclic ring system and has up to 3 substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF ₃ , OCF ₂ H, CF ₃ , CH ₃ , OCH ₃ , —OX ⁶ , —C (O) N (X ⁶ ) (X ⁶ ), —C (O) OX ⁶ , oxo, (C ₁ -C ₆ ) alkyl, nitro, cyano, benzyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halogenophenyl, methylenedioxy, N (X ⁶ ) (X ⁶ ), - N (X ⁶ ) C (O) (X ⁶ ), - SO ₂ N (X ⁶ ) (X ⁶ ), N (X ⁶ ) SO ₂ phenyl, -N (X ⁶ ) SO ₂ X ⁶ , -CONX ¹¹ X ¹² , - SO ₂ NX ¹¹ X ¹² , -NX ⁶ SO ₂ X ¹² , -NX ⁶ CONX ¹¹ X ¹² , -NX ⁶ SO ₂ NX ¹¹ X ¹² , - NX ⁶ C (O) X ¹² , and midazolyl, thiazolyl or tetrazolyl, provided that if A ^{1 is} optionally substituted with methylenedioxy, then it can be substituted with only one methylenedioxy;
where X ¹¹ is hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl;
optionally substituted (C ₁ -C ₆ ) alkyl defined for X ¹² , optionally substituted with phenyl, phenoxy, (C ₁ -C ₆ ) alkoxycarbonyl, -S (O) _m (C ₁ -C ₆ ) alkyl, 1-5 atoms halogen, 1-3 hydroxy, 1-3 (C ₁ -C ₁₀ ) alkanoyloxy or 1-3 (C ₁ -C ₆ ) alkoxy;
X ¹² is hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X ^{12 is} not hydrogen, X ^{12 is} optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH ₃ , OCH ₃ , OCF ₃ and CF ₃ ;
or X ¹¹ and X ¹² taken together form - (CH ₂ ) _r -L ¹ - (CH ₂ ) _r ;
L ¹ is C (X ² ) (X ² ), O, S (O) _m or N (X ² );
r for each case is independently 1, 2 or 3;
X ² for each case means independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₃ -C ₇ ) cycloalkyl, optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) the cycloalkyl in the definition of X ^{2 is} optionally independently substituted with S (O) _m (C ₁ -C ₆ ) alkyl, —C (O) OX ³ , 1-5 halogen atoms or 1-3 OX ³ ;
X ³ for each case is independently hydrogen or (C ₁ -C ₆ ) alkyl;
X ⁶ for each case means independently hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) halogenated alkyl, optionally substituted (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) -halogenated cycloalkyl, wherein optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₃ -C ₇ ) cycloalkyl in the definition of X ^{6 are} optionally independently substituted with hydroxyl, (C ₁ -C ₄ ) alkoxy, carboxyl, CONH ₂ , -S (O) _m (C ₁ -C ₆ ) alkyl, CO ₂ - (C ₁ -C ₄ ) alkyl, 1H-tetrazol-5-yl or 1-2 (C ₁ -C ₄ ) alkyl; or when there are two X ⁶ groups on one atom and both X ⁶ are independently (C ₁ - C ₆ ) -alkyl, two (C ₁ -C ₆ ) -alkyl groups may optionally be joined together with the atom with which these two X ⁶ groups are joined to form a 4-9 membered ring, optionally having oxygen, sulfur, or NX ⁷ ;
X ⁷ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with hydroxyl; and
m for each case is independently 0, 1 or 2;
provided that
X ⁶ and X ¹² cannot be hydrogen when they are combined with C (O) or SO ₂ in the form of C (O) X ⁶ , C (O) X ¹² , SO ₂ X ⁶ or SO ₂ X ¹² ; and when R ⁶ is a bond, L is N (X ² ) and each r in the definition
- (CH ₂ ) _r -L- (CH ₂ ) _r - represents 2 or 3.

A compound that is preferred among the previous compounds of formula (IV) is a compound in which e is O; Y represents O; R ¹ represents —CH ₂ phenyl; R ² represents methyl or hydrogen; n is 1; w is 1; R ³ represents —CH ₂ —O — CH ₂ phenyl; R ⁴ represents hydrogen; X ⁴ represents hydrogen; R ⁶ represents - C (CH ₃ ) ₂ -; Z ²⁰⁰ represents BOC and R ⁸ represents hydrogen.

This invention also provides:
a method for increasing levels of endogenous growth hormone in a human or other animal, which comprises administering to such a human or animal an effective amount of a compound of formula I;
a pharmaceutical composition useful for enhancing the endogenous formation or release of growth hormone in a human or other animal, comprising an inert carrier and an effective amount of a compound of formula I;
a pharmaceutical composition useful for enhancing the endogenous production or release of growth hormone in a human or other animal, containing an inert carrier, an effective amount of a compound of formula I and another growth hormone secretion stimulator, such as GHRP-6, Hexarelin, GHRP-1, IGF-1, IGF-2, B-HT920 or growth hormone release factor (GHF);
a method of treating or preventing osteoporosis, which comprises administering to a person or other animal in need of such treatment or prevention, an amount of a compound of formula I effective in treating or preventing osteoporosis;
a method for treating or preventing osteoporosis, which comprises administering to a person or other animal suffering from osteoporosis a combination of a bisphosphonate compound such as alendronate, and particularly preferably a bisphosphonate compound ibandronate, and a compound of formula I;
a method of treating or preventing osteoporosis, which comprises administering to a human or other animal with osteoporosis a combination of estrogen or Premarin ^® and a compound of formula I and, optionally, progesterone;
a method of increasing IGF-1 levels in a person or other animal with an IGF-1 deficiency, which method comprises administering to a person or other animal with an IGF-1 deficiency a compound of formula I;
a method for treating osteoporosis, which comprises administering to a human or other animal with osteoporosis a combination of an estrogen agonist or antagonist such as tamoxifen, droloxifene, raloxifene and idoxifene, and a compound of formula I;
a particularly preferred method for treating osteoporosis involves administering to a human or other animal with osteoporosis a combination of an estrogen agonist or antagonist such as cis-6- (4-fluorophenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5 6,7,8-tetrahydronaphthalen-2-ol;
(-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy] -5,6,7,8-tetrahydronaphthalen-2-ol,
cis-1- [6'-pyrrolidinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1- (4-pyrrolidinoethoxyphenyl) -2- (4 '' fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-ylethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol; or
1- (4-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline, and the compounds of formula I;
a method for treating osteoporosis, which comprises administering to a human or other animal with osteoporosis a combination of calcitonin and a compound of formula I;
a method of increasing muscle mass, which comprises administering to a human or other animal in need of such treatment an amount of a compound of formula I that is effective in enhancing the release of endogenous growth hormone; and
a method of enhancing the growth of growth hormone deficient children, which comprises administering to a child with a growth hormone deficiency an amount of a compound of formula I effective in enhancing the release of endogenous growth hormone.

 The invention further provides a method of treating or preventing diseases or conditions that can be treated or prevented by growth hormone, which comprises administering to a human or other animal in need of such treatment or prevention, an amount of a compound of formula I that is effective in enhancing the release of endogenous growth hormone.

 In another aspect, the invention provides methods of treating or preventing congestive heart failure, aging-related weakness, and obesity, comprising administering to a human or other animal in need of such treatment or prevention an amount of a compound of formula I that is effective in enhancing the release of endogenous growth hormone ; in the case of this method, it is preferable that the disease or condition being treated or prevented is congestive heart failure or weakness associated with aging.

 In another aspect, the present invention provides methods for accelerating the healing of bone fractures, attenuating the protein catabolic response after extensive surgery, reducing cachexia and protein loss caused by a chronic disease such as AIDS and cancer, accelerating wound healing and accelerating recovery of burn patients or patients who have undergone extensive surgical intervention, providing for the introduction to a person or other animal in need of such treatment, an amount of a compound of formula I, ffektivnogo to enhance release of endogenous growth hormone; in the case of this method, it is preferable to use it to accelerate the healing of bone fractures or to accelerate the healing of patients after extensive surgery.

 In yet another aspect, the invention provides methods for improving muscle strength, mobility, maintaining skin thickness, metabolic homeostasis, and renal homeostasis, which comprises administering to a human or other animal in need of such treatment an amount of a compound of claim 1 that is effective in enhancing release endogenous growth hormone.

 The described compounds accelerate the release of growth hormone, are stable under various physiological conditions, and can be administered parenterally, nasally or orally.

DETAILED DESCRIPTION OF THE INVENTION
One skilled in the art will recognize that certain substituents listed in this invention may have reduced chemical stability when combined with each other or with heteroatoms in these compounds. Such compounds with reduced chemical stability are not preferred.

 In General, the compounds of formula I can be obtained by methods that include methods known in the fields of chemistry involving the preparation of compounds. Some processes for the preparation of compounds of formula I are provided here as additional features of the present invention and are illustrated by the following reaction schemes.

 In the above structural formulas and throughout this application, the following terms have the indicated meanings, unless otherwise indicated.

 Alkyl groups include alkyl groups of a specified length of a straight or branched configuration, which may optionally contain double or triple bonds. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl, butanedienyl, hexenyl and the like.

When the definition contains C ₀ -alkyl, this means an ordinary covalent bond.

 Alkoxy groups mentioned above include alkoxy groups of a specified length of a straight or branched configuration, which may optionally contain double or triple bonds. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxy, etc.

 The term “halogen” or “halo” includes halogen atoms, fluorine, chlorine, bromine and iodine.

 The term “halogenated alkyl” includes an alkyl group as defined above substituted with one or more halogen atoms as defined above.

 The term “halogenated cycloalkyl” includes a cycloalkyl group substituted with one or more halogen atoms as defined above.

 The term “aryl” includes phenyl and naphthyl and aromatic 5-6 membered rings with 1-4 heteroatoms or fused 5- or 6-membered bicyclic rings with 1-4 heteroatoms of nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene (also known as thienyl), furan, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine and thiadiazole.

 A chemist with ordinary skill will appreciate that certain combinations of the heteroatom-containing substituents listed in this invention define compounds that will be less stable under physiological conditions (e.g., compounds containing acetal or aminal bonds). Therefore, such compounds are less preferred.

The term “prodrug” refers to compounds that are drug precursors that, after administration, release the drug in vivo through a chemical or physiological process (for example, a prodrug, when it enters a physiological pH environment, is converted to the desired form of the drug). Exemplary prodrugs release the corresponding free acid and such hydrolyzable ester-forming radicals of the compounds of this invention include, but are not limited to, carboxylic acid derivatives (e.g., R ¹ is (CH ₂ ) _q C (O) ₂ X ⁶ , where X ⁶ is hydrogen, or R ² or A ¹ contains carboxylic acid) in which free hydrogen is substituted with (C ₁ -C ₄ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, (C ₄ -C ₉ ) -1- (alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy) ethyl having 5-10 carbon atoms, al hydroxycarbonyloxymethyl having 3-6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4-7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5-8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3-9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4-10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (C ₁ -C ₂ ) alkylamino (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (such as β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C ₁ -C ₂₎ -alkilkarbamoil- (C ₁ -C ₂₎ alkyl and piperidino-, pyrrolidino Whether morpholino (C ₂ -C ₃₎ alkyl.

Other exemplary prodrugs release an alcohol of formula I in which the free hydrogen of a hydroxyl substituent (e.g., R ¹ contains hydroxyl) is substituted with (C ₁ -C ₆ ) alkanoyloxymethyl, 1 - ((C ₁ -C ₆ ) alkanoyloxy) ethyl, 1 -methyl-1 - ((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α- amino (C ₁ -C ₄ ) alkanoyl, aryl acetyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, where these α-aminoacyl moieties are any naturally occurring L-amino acids found in proteins are P (O) (OH) ₂ -P (O) (O) (C ₁ -C ₆ ) alkyl) ₂ or glycosyl (a radical resulting from the separation of the hydroxyl of the hemiacetal carbohydrate).

Prodrugs of the present invention in which the carboxy group in the carboxylic acid of formula (I) is replaced by ether can be prepared by combining the carboxylic acid with a suitable alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as DMF at a temperature of ~ 0 ^° C - 100 ^o C for ~ 1 - ~ 24 hours. Alternatively, 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 ~ 20 ^° C to 120 ^° C, preferably when heated under reflux, for ~ 1 to ~ 24 hours. Another method is the reaction of this acid in an inert solvent, such as THF, while removing water by physical (e.g. Dean-Stark trap) or chemical (e.g. molecular sieves) means.

Prodrugs of the present invention in which an alcohol group was used to form an ether derivative can be prepared by combining the alcohol with a suitable alkyl bromide or iodide in the presence of a base such as potassium carbonate in an inert solvent such as DMF at a temperature of ~ 0 - 100 ^o C for ~ 1 - ~ 24 hours. Alkanoylaminomethyl ethers can be prepared by reacting an alcohol with bis- (alkanoylamino) methane in the presence of a catalytic amount of an acid in an inert solvent such as THF according to the method described in US 4997984. Alternatively, these compounds can be obtained by the methods described by Hoffman et al. in J. Org. Chem. 1994, 59, p. 3530.

 Some of the terms defined above may occur more than once in the above formula, and in such cases, each term should be defined independently of the others.

Throughout the description and the attached claims, the following abbreviations are used with the following meanings:
BOC - tert-butyloxycarbonyl
BOP - Benzotriazol-1-yloxytris (dimethylamino) -phosphonium-hexafluorophosphate
CBZ - benzyloxycarbonyl,
CDI - N, N'-carbonyldiimidazole,
CH ₂ Cl ₂ - methylene chloride,
CHCl ₂ - chloroform,
DCC - dicyclohexylcarbodiimide,
DMF - dimethylformamide,
EDC - 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,
EtOAc - ethyl acetate
FMOC - 9-fluorenylmethoxycarbonyl,
h is the clock
Hex - hexane
HOAT - 1-hydroxy-7-azabenzotriazole,
HOBT - Hydroxybenzotriazole Hydrate,
HPLC - high pressure liquid chromatography,
MHz - megahertz,
MS - mass spectrum,
NMR - nuclear magnetic resonance,
PTH - parathyroid hormone
TFA - trifluoroacetic acid,
THF - tetrahydrofuran,
TLC - thin layer chromatography,
TRH - thyrotropin releasing hormone,
TROC - 2,2,2-trichloroethoxycarbonyl.

 All compounds of this invention have at least one asymmetric center marked with an asterisk in structural formula I above. Additional asymmetric centers may be present on the molecule depending on the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers, and it is understood that all such optical isomers, separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures are included in the scope of this invention. In the case of the asymmetric center represented by an asterisk, it was found that the absolute stereochemistry of the more active and therefore more preferred isomer is shown in formula IA. This preferred absolute configuration is also applicable to formula I.

С водородом в качестве заместителя R⁴ пространственная конфигурация асимметричного центра соответствует конфигурации в D-аминокислоте. В большинстве случаев она также обозначается как R-конфигурация, хотя она будет изменяться в соответствии со значениями R³ и R⁴, используемыми в получении R- или S-стереохимических структур.

With hydrogen as the substituent R ^{4, the} spatial configuration of the asymmetric center corresponds to the configuration in the D-amino acid. In most cases, it is also referred to as the R-configuration, although it will change in accordance with the values of R ³ and R ⁴ used in the preparation of R- or S-stereochemical structures.

 These compounds are usually isolated in the form of their pharmaceutically acceptable acid addition salts, such as salts prepared using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, proionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methanesulfonic, etc. In addition, some compounds containing an acid group, such as a carboxy group, can be isolated in the form of their inorganic salt, in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium, etc., as well as from organic bases.

 Pharmaceutically acceptable salts are prepared by taking ~ 1 equivalent of a compound of formula I and contacting it with ~ 1 equivalent of a suitable acid salt, which is desired. The processing and isolation of the resulting salt is well known to those of ordinary skill in the art.

 The hormone-releasing compounds of formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the level of the pituitary gland. Clarification of this includes the use in the evaluation of many factors for which it is assumed or known that they affect the secretion of growth hormone, such as age, gender, nutrition factors, glucose, amino acids, fatty acids, as well as states of abstinence from food or non-abstinence. In addition, the compounds of this invention can be used to evaluate how other hormones modify growth hormone releasing activity. For example, it has already been found that somatostatin inhibits the release of growth hormone.

 The compounds of formula I can be administered to animals, including humans, to release growth hormone in vivo. These compounds are useful for treating symptoms associated with GH deficiency; to stimulate growth or increase the efficiency of feed use in animals reared for meat production, to improve the quality of carcasses; to increase milk yield in dairy cattle; to improve the healing of bones or wounds and improve the function of vital organs. The compounds of this invention, by inducing the secretion of endogenous GH, will alter body composition and modify other metabolic, immunological or developmental processes dependent on GH. For example, the compounds of this invention can be given to chickens, turkeys, livestock (such as sheep, pigs, horses, cattle, etc.), domestic animals (e.g. dogs), or they can be used in agriculture to accelerate growth and improve protein / fat ratios. In addition, these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary gland releases growth hormone. For example, compounds of formula I can be administered in vivo to children. Serum samples taken before and after such administration can be evaluated for growth hormone. Comparing the amounts of growth hormone in each of these samples would be a means of directly determining the ability of the patient's pituitary to release growth hormone.

 Thus, this invention includes within its scope pharmaceutical compositions containing, as an active ingredient, at least one of the compounds of formula I together with a pharmaceutically acceptable carrier. Optionally, the pharmaceutical compositions may further comprise an anabolic agent, in addition to at least one of the compounds of formula I, or another compound that exhibits different activity, such as an antibiotic growth factor, or an agent for the treatment of osteoporosis, or other pharmaceutically active materials, when such a combination increases efficacy and reduces side effects.

 Growth-promoting and anabolic agents include, but are not limited to, TRH, PTH, diethylstilbesterol, estrogens, β-agonists, theophylline, anabolic steroids, enkephalins, series E prostaglandins, compounds described in US Patent N 3239345, the description of which is included here as links, for example zeranol; compounds described in US Patent N 4411890, the description of which is incorporated herein by reference.

 The growth hormone secretion stimulants of the present invention in combination with other growth hormone secretion stimulants, such as the growth hormone releasing peptides GHRP-6 and GHRP-1 described in US Patent N 4411890, the disclosure of which is incorporated herein by reference, and WO 89/07110 , WO 89/07111, and B-HT920, as well as hexarelin and the recently discovered GHRP-2, described in WO / 93/04081, or releasing growth hormone hormone (GHRH, also referred to as FGR) and its analogs or growth hormone and its analogues or somatomedins, including IGF-1 and IGF-2 or μ-adrenergic agonists, such ak clonidine or serotonin 5HTID agonists such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine, are useful for increasing the endogenous levels of GH in mammals. The combination of GH secretion stimulators of the present invention with FGR results in synergistic increases in endogenous growth hormone levels.

As well known to those skilled in the art, the known and potential uses of growth hormone are diverse and numerous [See "Human Growth Hormone", Strobel and Thomas, Pharmacological Reviews, 46, p. 1-34 (1994); T. Rosen et al., Horm Res, 1995; 43: pp. 93-99; M. Degerblad et al. , European Journal of Endocrinology, 1995, 133: pp. 180-188; JO Jorgenson, European Journal of Endocrinology, 1994, 130: pp. 224-228; K. C. Copeland et al. Journal of Clinical Endocrinology and Metabolism, Vol. 78, No. 5, pp. 1040-1047; Ja aloi
et al. , Journal of Clinical Endocrinology and Metabolism, Vol. 79, No. 4, pp. 943-949; F. Corido et al., Metab. Clin. Exp., (1995), 44 (6), pp. 745-748; K. M. Fairhall et al., J. Endocrinol., (1995), 145 (3), pp. 417-426; RM. Frieboes et al., Neuroendocrinology, (1995), 61 (5), pp. 584-589; and M. Llovera et al. Int. J. Cancer, (1995), 61 (1), pp. 138-141]. Thus, the administration of the compounds of this invention for the purpose of stimulating the release of endogenous growth hormone can have the same effects or uses as the administration of the hormone itself. These various uses of growth hormone can be summarized as follows: stimulation of the release of growth hormone in old people; treatment of adults with growth hormone deficiency; prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, acceleration of bone restoration during fractures, treatment of growth retardation, treatment of congestive heart failure described in PCT publications WO 95/281173 and WO 95/281174 (example of a method for analyzing stimulants growth hormone secretion for efficacy in treating 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 decompensation Treatment of physiological short stature, including children with growth hormone deficiency, treatment of short stature associated with chronic illness, treatment of obesity, treatment of growth retardation associated with Prader-Willi syndrome and Turner's syndrome; accelerating recovery and shortening the hospitalization period of burn patients or after extensive surgery, such as gastrointestinal surgery; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisonism and Cushing's syndrome; displacement of growth hormone in stressed patients; treatment of osteochondrodysplasias, Noonan syndrome, sleep disorders, Alzheimer's disease, delayed wound healing and psychosocial deprivation; treatment of pulmonary dysfunction and dependence on mechanical ventilation apparatus; attenuation of the protein catabolic response after extensive surgery; treating poor absorption syndromes, reducing cachexia, and protein loss caused by a chronic disease such as cancer or AIDS; acceleration of weight gain and protein accumulation in patients on general parenteral nutrition (TPN); treatment of hyperinsulinemia, including pancreatic islet hyperplasia; complementary treatment to induce ovulation and to prevent and treat gastric and duodenal ulcers; stimulation of the development of the thymus and prevention of aging-related decline in the function of the thymus; adjunctive therapy for patients with chronic hemodialysis; treatment of patients with a weakened immune system and increased antibody production after vaccination; improving muscle strength, increasing muscle mass, mobility, maintaining skin thickness, metabolic homeostasis, renal homeostasis in weak old people; stimulation of osteoblasts, correction of bones and cartilage growth; the treatment of neurological diseases such as peripheral and drug-induced neuropathy, Guillain-Barré syndrome, amyotrophic lateral sclerosis, multiple sclerosis, strokes and dimyelinating diseases; stimulation of the immune system in pets and treatment of aging-related disorders in pets; acceleration of growth in livestock and stimulation of growth of wool in sheep.

 Specialists in this field know that there are numerous compounds that are currently used in attempts to treat diseases or therapeutic indications described above. Combinations of these therapeutic agents, some of which are also mentioned above, with a growth promoter exhibit the anabolic and desirable properties of these various therapeutic agents. In these combinations, therapeutic agents and growth hormone secretion stimulants of the present invention can be administered independently and sequentially or co-administered in dose ranges from 1/100 to 1 dose of those levels that are effective in the separate use of these compounds and secretion stimulants. Combination therapy for inhibiting bone resorption, preventing osteoporosis, healing skeletal fracture, accelerating healing of bone fractures, stimulating bone formation and increasing bone mineral density can be performed using combinations of bisphosphonates and growth hormone secretion stimulants of the present invention, see PCT publication WO 95/11029 for discussion of combination therapy using bisphosphonates and stimulators of secretion of GH. A review of the use of bisphosphonates for these applications is provided, for example, by Hambdy, N. A. T., Role of Bisphosphonates in Metabolic Bone Disease, Trends in Endocrinol. Metab. , 1993, 4, pp. 19-25. Used bisphosphonates include, but are not limited to, alendronate, tiludronate, dimethyl-APD, risedronate, ethidronate, YM-175, clodronate, pamidronate and BM-210995 (ibandronate). In accordance with their activity, oral levels of daily doses of 0.1 mg - 5 g bisphosphonate and levels of daily doses of growth hormone secretion stimulators 0.01 mg / kg - 20 mg / kg of the patient’s body weight are administered to patients to achieve effective treatment of osteoporosis.

 The compounds of this invention may be combined with a mammalian estrogen agonist / antagonist. Any estrogen agonist / antagonist can be used as the second compound of the present invention. The term estrogen agonist / antagonist refers to compounds that bind to an estrogen receptor, inhibit bone renewal, and prevent bone loss. In particular, estrogen agonists are defined herein as chemical compounds capable of binding to estrogen receptor sites in mammalian tissue and mimicking the effects of estrogen in one or more tissues. Estrogen antagonists are defined herein as chemical compounds capable of binding to estrogen receptor sites in mammalian tissue and blocking the effects of estrogen in one or more tissues. Such activities are readily determined by those skilled in the art using standard methods, including estrogen receptor binding methods, standard histomorphometric and densitometric methods for bones (see Eriksen EF et al. Bone Histomorphometry, Raven Press, New York, 1994, pp. 1- 74; Grier SJ et al. The Use of Dual-Energy X-Ray Absorptiometry in Animals, Inv. Radiol., 1996, 31 (l): 50-62; Wahner HW and Fogelman I., The Evalution of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pp. 1-296). A variety of these compounds are described and referenced below, however, other estrogen agonists / antagonists may be known to those skilled in the art. A preferred estrogen agonist / antagonist is droloxifene (phenol, 3- [4- [2-dimethylamino) ethoxy] phenyl] - 2-phenyl-1-butenyl] -, (E) -) and the related compounds described in US patent 5047431 (the description of which is incorporated herein by reference).

 Another preferred estrogen agonist / antagonist is tamoxifen (ethanamine, 2- [4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethyl, (Z) -2-, 2-hydroxy-1,2 , 3-propanetricarboxylate (1: 1)) and related compounds described in US patent 4536516 (the description of which is incorporated herein by reference). Another related compound is 4-hydroxy tamoxifen, which is described in US Pat. No. 4,623,660 (the disclosure of which is incorporated herein by reference).

 Another preferred estrogen agonist / antagonist is raloxifene (methanone, [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] - [4- [2- (1-piperidinyl) ethoxy] phenyl] - hydrochloride) and related compounds described in US patent 4418068 (the description of which is incorporated herein by reference).

 Another preferred estrogen agonist / antagonist is idoxifene (pyrrolidone, 1- [4 - [[1- (4-iodophenyl) -2-phenyl-1-butenyl] phenoxy] ethyl] and related compounds described in US patent 4839155 (the description of which included here by reference).

Other preferred estrogen agonists / antagonists include the compounds described in US patent N 5552412, the description of which is incorporated herein by reference. Particularly preferred compounds that are described therein are given below:
cis-6- (4-fluorophenyl) -5- [4- (2-piperidin-1-ylethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
(-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - 5,6,7,8-tetrahydronaphthalen-2-ol;
cis-6-phenyl-5- [4- (2-pyrrolidin -1-ylethoxy] -5,6,7,8-tetrahydronaphthalene -2-ol;
cis-1- [6'-pyrrolidinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1- (4'-pyrrolidinoethoxyphenyl) -2- (4 '' fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-ylethoxy) phenyl] -5,6,7, 8-tetrahydronaphthalen-2-ol; and
1- (4'-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

 Other estrogen agonists / antagonists are described in US patent 4133814 (the description of which is incorporated herein by reference). US Pat. No. 4,133,814 describes derivatives of 2-phenyl-3-aroylbenzothiophene and 2-phenyl-3-aroylbenzothiophen-1-oxide.

 The following paragraphs give preferred dose ranges for various antiresorptive agents.

 The amount of antiresorptive agent to be used is determined by its activity as an inhibitor of bone rarefaction (osteoporosis). This activity is determined by determining the pharmacokinetics of an individual compound and its minimum maximum effective dose in inhibiting bone re-classification using the protocol mentioned above.

 Typically, an effective dose for the activities of this invention, for example, for the treatment of osteoporosis, for estrogen agonists / antagonists (when used with a compound of formula I of the present invention) is in the range of 0.01 to 200 mg / kg / day, preferably 0.5 to 100 mg / kg / day.

 In particular, the effective dose for droloxifene is in the range of 0.1-40 mg / kg / day, preferably 0.1-5 mg / kg / day.

 In particular, the effective dose for raloxifene is in the range of 0.1-100 mg / kg / day, preferably 0.1-10 mg / kg / day.

 In particular, the effective dose for tamoxifen is in the range of 0.1-100 mg / kg / day, preferably 0.1-5 mg / kg / day.

In particular, an effective dose for the compounds:
cis-6- (4-fluorophenyl) -5- [4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
(-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy] -5,6,7,8-tetrahydronaphthalen-2-ol;
cis-1- [6'-pyrrolidinoethoxy-3 '-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1- (4'-pyrrolidinoethoxyphenyl) -2- (4 '' fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol; or
1- (4'-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline is in the range of 0.0001-100 mg / kg / day, preferably 0.001-10 mg / kg / day.

 In particular, the effective dose for 4-hydroxy tamoxifen is in the range of 0.0001-100 mg / kg / day, preferably 0.001-10 mg / kg / day.

Compounds with the ability to stimulate the secretion of GH from cultured pituitary cells are identified using the following protocol. This test is also used to compare with standards to determine dose levels. Cells are isolated from the pituitary glands of 6-week-old male Wistar rats. After decapitation, the anterior pituitary gland is removed into a cold, sterile Hanks balanced salt solution without calcium or magnesium (HBSS). The tissues are finely ground, then subjected to two cycles of mechanical dispersion with the enzyme using 10 E / ml bacterial protease (EC 3.4.24.4, Sigma P-6141) in HBSS. The tissue-enzyme mixture was stirred in a rotary flask at 30 rpm in an atmosphere of 5% CO ₂ at ~ 37 ^° C for approximately 30 minutes, manually triturated after ~ 15 minutes using a 10 ml pipette. This mixture is centrifuged at 200 x g for approximately 5 minutes. Horse serum is added to the supernatant to neutralize excess protease. The pellet was resuspended in fresh protease, stirred for another approximately 30 minutes under the previous conditions and manually triturated very finely through a 23 G needle. Horse serum was added again, then the cells from both digest products were combined, centrifuged (200 x g for ~ 15 minutes ), washed, resuspended in culture medium and counted. Cells are seeded at 6.0-6.5 x 10 ⁴ cells per cm ² in 48-well Costar plates and cultured for 3-4 days in Dulbecco's modified Eagle medium (D-MEM) supplemented with 4.5 g / l glucose, 10% horse serum, 2.5% fetal calf serum, 1% non-essential amino acids, 100 E / ml nystatin and 50 mg / ml gentamicin sulfate, before determining the secretion of GR.

Immediately before the test, the culture wells are washed twice, then balanced for ~ 30 minutes in a release medium (D-MEM, buffered with 25 mM HEPES, pH 7.4, and containing 0.5% bovine serum albumin, at 37 ^° C.). Test compounds are dissolved in DMSO, then diluted in a pre-heated medium to release. Tests are performed in four replicates. The test is initiated by adding 0.5 ml of release medium (with vehicle or with test compound) to each culture well. Incubation is carried out at ~ 37 ^o C for -15 minutes, then stopped by removing the culture medium, which is centrifuged at 2000 x g for ~ 15 minutes to remove cellular material. Rat growth hormone concentrations in supernatants are determined according to the standard radioimmunoassay protocol using the rat growth hormone reference preparation (NIDDK-rGH-RP-2) and anti-rat growth hormone obtained in monkeys (NIDDK-anti-rGH-S-5) from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, CA). Additional rat growth hormone (1.5 E / mg, N G2414, Scripps Labs, San Diego, CA) was iodinated to a specific activity of approximately 30 μCi / μg according to the method with chloramine T for use as an indicator. Immune complexes are obtained by adding goat antiserum against monkey IgG (Organon Teknika, Durham, NC) plus polyethylene glycol, MM 10000-20000 to a final concentration of 4.3%; extraction is performed by centrifugation. This test has an operating range of 0.08-2.5 μg of rat growth hormone per tube above background levels. Active compounds usually stimulate the release of growth hormone by more than 1.4 times. Reference: Cheng, K., Chan, W.-S., Barreto, Jr., A., Convey, EM, Smith, RG 1989.

Test for determining exogenously stimulated release of growth hormone in rats after intravenous administration of test compounds
Female 21-day old Sprague-Dawley rats (Charles River Laboratory, Wilmington, MA) were allowed to acclimatize to local vivarium conditions (24 ^° C., 12 hours light cycle, 12 hours dark) for approximately 1 week before testing the compounds. All rats were given access to water and commercial granular food (Agway County Food, Syracuse NY) ad libitum. The experiments are carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals.

On the day of the experiment, test compounds are dissolved in a vehicle containing 1% ethanol, 1 mM acetic acid, and 0.1% bovine serum albumin in saline. Each compound is tested with n = 3. Rats were weighed and anesthetized with an intraperitoneal injection of sodium pentobarbital (Nembutol, 50 mg / kg body weight). 14 minutes after the administration of the anesthetic solution, a blood sample was taken by rupture of the tip of the tail, allowing the blood to drip into a microcentrifuge tube (background - blood sample, approximately 100 μl). 15 minutes after the administration of the anesthetic solution, the test compound is administered by intravenous injection into the tail vein, with a total injection volume of 1 ml / kg body weight. Additional blood samples are taken from the tail at 5, 10 and 15 minutes after administration of the compound. Blood samples are stored on ice until the serum is separated by centrifugation (1430 x q for 10 minutes at 10 ^o C). Serum was stored at -80 ^° C until serum growth hormone was determined by radioimmunoassay, as described above and below.

Assessment of exogenously stimulated release of growth hormone in dogs after oral administration
On the day of the experiment, the test compound is weighed to obtain a suitable dose and dissolved in water. Doses are administered in a volume of 0.5 ml / kg by feeding through a gastric tube to 4 dogs for each dosing regimen. Blood samples (2 ml) are collected from the cervical vein by a direct puncture of the vein before the dose at 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours after the dose using 2 ml containers (vacutainer) containing lithium heparin. The resulting plasma was stored at -20 ^o C until analysis.

Dog Growth Hormone Measurement
Dog growth hormone concentrations are determined according to a standard radioimmunoassay protocol using dog growth hormone (iodination antigen and reference preparation AFP-1983B) and monkey growth hormone antiserum (AFP-21452578) obtained from Dr. A. Parlow (Harbor- UCLA Medical Center, Torrence, CA). The indicator is obtained by iodination according to the method with chloramine T of dog growth hormone to a specific activity of 20-40 μCi / μg. Immune complexes are obtained by adding goat antiserum against monkey IgG (Organon Teknika, Durham, NC) plus polyethylene glycol, MM 10000-20000 to a final concentration of 4.3%; extraction is performed by centrifugation. This test has an operating range of 0.08-2.5 μg of canine GH per tube.

 The compounds of this invention can be administered orally, parenterally (for example, by intramuscular, intraperitoneal, intravenous or subcutaneous injection or as an implant), nasally, vaginally, rectally, sublingually or topically, and they can be prepared with pharmaceutically acceptable carriers to provide dosage forms suitable for each method of administration.

 Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such a solid dosage form, the active compound is mixed with at least one pharmaceutically acceptable carrier, such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than similar inert diluents, for example wetting agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. Tablets and pills may also be prepared with enteric coatings.

 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in the art, such as water. In addition to such inert diluents, the compositions may also include adjuvants, such as gumming agents, emulsifying and suspending agents, and sweetening, taste and odor improving and flavoring agents.

 Formulations for parenteral administration of the invention include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants, such as preservatives, macerators, emulsifiers and dispersants. They can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the composition, by irradiating the compositions, or by heating the compositions. They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or in some other sterile injectable medium just before use.

 Compositions for rectal or vaginal administration are preferably suppositories, which may contain, in addition to the active substance, excipients, such as cocoa butter or suppository wax.

 Compositions for nasal and sublingual administration are also prepared with standard excipients well known in the art.

 The dose of the active ingredient in the compositions of this invention may vary; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The dose chosen depends on the desired therapeutic effect, on the route of administration and on the duration of treatment. Typically, dose levels of 0.0001 and 100 mg / kg body weight per day are administered to humans and other animals, such as mammals, to obtain effective release of growth hormone.

 The preferred dose range is from 0.01 to 5.0 mg / kg body weight per day, and such a dose can be entered in a single dose or can be divided into multiple doses.

 The preparation of compounds of formula I of the present invention can be carried out by sequential or convergent synthetic routes. Syntheses that detail the preparation of compounds of formula I in a sequential manner are presented in the reaction schemes set forth below.

Many protected amino acid derivatives are commercially available in which the protective groups Prt, Z ¹⁰⁰ and Z ²⁰⁰ are, for example, BOC, CBZ, benzyl, ethoxycarbonyl groups, CF ₃ C (O) -, FMOC, TROC, trityl or tosyl. Other protected amino acid derivatives may be prepared by methods described in the literature. Some 3-oxo-2-carboxylpyrrolidines and 4-oxo-3-carboxylpiperidines are commercially available and many other related pyrrolidines and 4-substituted piperidines are known in the literature.

Many schemes (schemes 1 - 27 with comments are given at the end of the description) describe compounds that contain Prt, Z ¹⁰⁰ or Z ²⁰⁰ protecting groups. Benzyloxycarbonyl groups can be removed by a variety of methods, including catalytic hydrogenation with hydrogen in the presence of a palladium or platinum catalyst in a protic solvent, such as methanol. Preferred catalysts are palladium-carbon hydroxide or palladium-carbon. Hydrogen pressures of 1-1000 psi (6894.757-6894757 Pa) can be used; pressures of 10-70 psi are preferred (68947.57-482632.99 Pa).

BOC protecting groups can be removed using a strong acid, such as trifluoroacetic acid or hydrochloric acid in the presence (or absence) of a co-solvent, such as dichloromethane, ethyl acetate, ether or methanol, at a temperature of ~ 30 - 70 ^° C, preferably ~ 5 - ~ 35 ^o C.

 Amine benzyl esters can be removed by a variety of methods, including hydrogenation with hydrogen in the presence of a palladium catalyst in a protic solvent, such as methanol. Hydrogen pressures of 1-1000 psi (6894.757-6894757 Pa) can be used; pressures of 10-70 psi are preferred (68947.57-482632.99 Pa). The addition and removal of these and other protective groups are discussed by T. Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981.

 The following examples are provided for the purpose of further illustration only and are not intended to limit the described invention.

Basic experimental procedures
Amicon 30 μM silica, pore size 60 angstroms, was used for column chromatography. Melting points were determined on a Buchi 510 and they are uncorrected. Proton and carbon NMR spectra were recorded on a Varian XL-300, Bruker AC-300, Varian Unity 400 or Bruker AC-250 at 25 ^° C. Chemical shifts were expressed in parts per million by field from trimethylsilane. Mass spectra of particle beams were obtained on a Hewlett-Packard 5989A spectrometer using ammonia as a source of chemical ionization. Chloroform or methanol was used to initially dissolve the sample. LSIMS mass spectra (liquid secondary ion) were obtained on a high resolution spectrometer
Kratos Concept-1S using cesium ion bombardment on a sample dissolved in a 1: 5 mixture of dithioerythritol and dithiothreitol, or in a thioglycerol matrix. Chloroform or methanol was used to initially dissolve the sample. Reported data are the sums of 3-20 scans calibrated against cesium iodide. TLC analyzes were performed using E. Merck Kieselgel 60 F254 silica plates, visualized (after elution with the indicated solvent (s)) by staining with 15% phosphomolybdic acid in ethanol and heating on a hot plate. Basic Procedure A (peptide binding using EDC): a 0.2-0.5 M solution of primary amine (1.0 equivalent) in dichloromethane (or primary amine hydrochloride and 1.0-1.3 equivalents of triethylamine) is treated sequentially 1, 0-1.2 equivalents of carboxylic acid as a binding partner, 1.5-1.8 equivalents of hydroxybenzotriazole hydrate (HOBT) or HOAT, and 1.0-1.2 equivalents (stoichiometrically equivalent to the amount of carboxylic acid) of 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide (EDC) and the mixture was stirred overnight in a bath ice (ice bath is allowed to warm, thus the reaction mixture is usually maintained at a temperature of about 0-20 ^o C for about 4-6 hours and at about 20-25 ^o C for the remaining period). The mixture was diluted with ethyl acetate or another solvent, as indicated, and the resulting mixture was washed twice with 1 N. NaOH, twice 1 N. HCl (if the product is not basic), once with brine, dried over Na ₂ SO ₄ and concentrated to give a crude product, which is purified as indicated. The carboxylic acid component can be used in the form of a dicyclohexylamine salt in the binding of a primary amine or its hydrochloride; in this case, triethylamine is used.

Example 1
2-amino-N- {1 (R) - benzyloxymethyl-2- [3- (R) - (4-fluorobenzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] - 2-oxoethyl} -isobutyramide, a hydrochloride salt, and
2-amino-N- {1 (R) -benzyloxymethyl -2- [3a- (S) - (4-fluorobenzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] -2-oxoethyl} -isobutyramide, hydrochloride salt
A. 4-Oxo piperidine-1,3-dicarboxylic acid, 1-tert-butyl ether, 3-ethyl ether
A mixture of 8.00 g (38.5 mmol) of 4-oxopiperidine-3-carboxylic acid ethyl ester hydrochloride, 9.23 g (42.4 mmol) of di-tert-butyl carbonate and 3.89 g (38.5 mmol) of triethylamine in 150 ml of THF was stirred at room temperature for approximately 72 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed three times (with each solution) with 10% aqueous HCl, saturated aqueous sodium bicarbonate and brine, dried over MgSO _4, and concentrated to give 10.0 g of 1A as a white solid. MS (Cl, NH ₃ ) 272 (MH ⁺ ).

B. 3- (R, S) - (4-Fluorobenzyl) -4-oxopiperidin-1, 3-dicarboxylic acid, 1-tert-butyl ether, 3-ethyl ether
To a solution of 2.00 g (7.4 mmol) in 10 ml of DMF was added 282 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for ~ 15 minutes. To the stirred solution was added a solution of 1.39 g (7.4 mmol) of 4-fluorobenzyl bromide in 7 ml of DMF, and the mixture was stirred for approximately 72 hours at room temperature. The mixture was diluted with ethyl acetate and washed once with water and four times with brine, dried over MgSO ₄ and concentrated to obtain 2.8 g of 1B. MS (Cl, NH ₃ ) 380 (MH ⁺ ).

C. 3a- (R, S) - (4-Fluorobenzyl) -2-methyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ether
A mixture of 2.54 g (6.7 mmol) of 1B and 309 mg (6.7 mmol) of methylhydrazine in 100 ml of ethanol was heated under reflux for ~ 8 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for ~ 17 hours. The mixture was concentrated and the residue was purified by silica gel chromatography with an elution gradient of (18:82 (v / v) ethyl acetate: hexane) - (75: 25 (v / v) ethyl acetate: hexane) to give 1.0 g of 1C as a clear colorless oil . MS (Cl, NH ₃ ) 362 (MH ⁺ ).

D. 3a- (R, S) - (4-Fluorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one, trifluoroacetate
To 1.00 g (2.8 mmol) of 1C was added 10 ml of trifluoroacetic acid at ~ 0 ^° C and the mixture was stirred for ~ 1 hour. Ethyl acetate was added and the mixture was concentrated to obtain 1.0 g of 1D. MS (Cl, NH ₃ ) 263 (MH ⁺ ).

E. (R) -3-Benzyloxy-2- (2-tert-butoxycarbonylamino-2-methylpropionylamino) propionic acid
To 1.83 g (6.2 mmol) of N-tert-BOC-O-benzyl-D-serine in 35 ml of DMF was added 1.02 g (7.4 mmol) of potassium carbonate and then 0.92 g (6, 5 mmol) of iodomethane. The mixture was stirred overnight at ~ 24 ^° C. under nitrogen. The reaction mixture was diluted with 200 ml of water and extracted with ethyl acetate three times. The combined organic extracts were washed five times with water and once with brine, dried over MgSO ₄ and concentrated. The crude methyl ester of (R) -3-benzyloxy-2-tert-butoxycarbonylaminopropionic acid was dissolved in 15 ml of cold trifluoroacetic acid at ~ 0 ^° C and the mixture was stirred for ~ 1 hour. The mixture was concentrated and the residue was diluted with 1 N. NaOH and extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ to give 0.84 g (4.02 mmol) of (R) -2-amino-3-benzyloxypropionic acid methyl ester, which was bound to 0.81 g (4, 02 mmol) of N-tBOC-α-methylamine to give 1.80 g of (R) -3-benzyloxy-2- (2-tert-butoxycarbonylamino-2-methylpropionylamino) propionic acid methyl ester. The crude product was dissolved in 20 ml of a 4: 1 THF: water mixture, and a solution of 335 mg (7.98 mmol) of lithium hydroxide hydrate in 1 ml of water was added to the solution, and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was diluted with ethyl acetate and acidified with an aqueous HCl solution and extracted with ethyl acetate three times. The organic extracts were combined and washed once with brine, dried over Na ₂ SO ₄ and concentrated to give 1.60 g of 1E as an oil which solidified upon standing.

¹ H NMR (CDCl ₃ 300 MHz): δ 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).

F. (1- {1 (R, S) -Benzyloxymethyl-2- [3- (R, S) - (4-fluorobenzyl) -2-methyl-3-oxo -2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridin-5-yl] -2-oxoethylcarbamoyl} -1-methylethyl) - carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 193 mg (0.51 mmol) of 1D and 196 mg (0.51 mmol) of 1E were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography with an elution gradient (1: 1 v / v ethyl acetate: hexane) - 100% ethyl acetate to give 60 mg less than the polar 1F isomer 1 and 100 mg more than the polar 1F isomer 2. MS (Cl, NH ₃ ) 624 ( MH ⁺ ) for both isomers.

G. 2-amino-N- {1 (R) -benzyloxymethyl-2- [3- (R) - (4-fluorobenzyl) -2-methyl-3-oxo -2,3,3a, 4,6,7 -hexahydropyrazolo [4, 3-c] pyridin-5-yl] -2-oxoethyl} - isobutyramide, hydrochloride
To 60 mg (0.10 mmol) of 1F isomer 1 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 2 hours. The mixture was concentrated and the residue was precipitated from ethanol / hexane to give 50 mg of 1G isomer 1 as a white powder. MS (Cl, NH ₃ ) 524 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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. 2-amino-N- {1 (R) -benzyloxymethyl-2- [3- (R) - (4-fluorobenzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7 -hexahydropyrazolo [4,3-c] pyridin-5-yl] -2-oxoethyl} -isobutyramide, hydrochloride
To 100 mg (0.16 mmol) of 1F isomer 2 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated and the residue was precipitated from ethanol / hexane to give 1H isomer 2 as a white powder. MS (Cl, NH ₃ ) 524 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

Example 2
2-amino-N-2- [3a- (R, S) - (4-fluorobenzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c ] pyridin-5-yl] -1 (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] -isobutyramide, hydrochloride
A. (R) -2-amino-3 - [(1H-indol-3-yl) -propionic acid, methyl ester
To 4.92 g (16.2 mmol) of N-α-tert-BOC-D-tryptophan in 100 ml of DMF was added 2.46 g (17.8 mmol) of potassium carbonate and then 2.41 g (17.0 mmol) ) iodomethane and the mixture was stirred overnight at 24 ^o C in nitrogen atmosphere. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were washed five times with 500 ml of water and once with brine, dried over MgSO ₄ and concentrated to give 4.67 g of a white solid. To the crude methyl ester of (R) -2-tert-butoxycarbonylamino-3- (1H-indol-3-yl) -propionic acid was added 15 ml of cold trifluoroacetic acid at ~ 0 ^° C and the mixture was stirred for ~ 2 hours. The mixture was concentrated and the residue was diluted with 1 N. NaOH and extracted with ethyl acetate three times. The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ to give (R) -2-amino-3- (1H-indol-3-yl) -propionic acid methyl ester as an orange oil in quantitative yield.

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

C. (R) -2- (2-tert-Butoxycarbonylamino -2-methylpropionylamino) -3- (1H-indol-3-yl) propionic acid
To a solution of 1.03 g (2.64 mmol) of 2B in 10 ml of THF was added 381 g (9.1 mmol) of lithium hydroxide hydrate in 2 ml of water, and the mixture was stirred overnight at room temperature. The excess THF was removed by evaporation and the alkaline aqueous mixture was extracted with ethyl acetate three times and then acidified to pH 4 with diluted acetic or hydrochloric acid. The product was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO ₄ and evaporated to give 1.03 g of 2C as an orange foam. MS (Cl, NH ₃ ) 390 (MH ⁺ ).

¹ H NMR (CDCl ₃ 300 MHz): δ 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).

D. {1- [2- [3a- (R, S) - (4-Fluorobenzyl) -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-s ] pyridin-5-yl] -1- (R) - (1H-indol-3-ylmethyl) -2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 193 mg (0.51 mmol) 1D and 200 mg (0.51 mmol) 2C were combined and the residue was purified by silica gel chromatography with an elution gradient (1: 1 v / v ethyl acetate: hexane) - 100% ethyl acetate to give 230 mg 2D. MS (Cl, NH ₂ ) 633 (MH ⁺ ).

E. 2-amino-N-2- [3- (R, S) - (4-fluorobenzyl) -2-methyl-3-oxo-2, 3, 3a, 4,6,7-hexahydropyrazolo [4,3 -c] pyridin-5-yl] -1 (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide, hydrochloride
To 230 mg (0.36 mmol) of 2D in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated and the residue was precipitated from ethanol / hexane to give 130 mg of 2E as a white powder. MS (Cl, NH ₃ ) 533 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 7.79 (d, 1H), 7.48 (m, 1H), 7.33 (m, 2H), 7.19 - 6.77 (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 3
2-amino-N-2- [3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -yl] -1 (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide
A. 4-Oxopiperidin-1,3-dicarboxylic acid, 1-tert-butyl ether, 3-methyl ether
To a mixture of 7.00 g (36.2 mmol) of 4-oxopiperidin-3-carboxylic acid methyl ester and 8.82 g (72.3 mmol) of 4,4-dimethylaminopyridine in 200 ml of methylene chloride at ~ 0 ^° C was added a solution of 7 88 g (36.2 mmol) of di-tert-butyl dicarbonate in 150 ml of methylene chloride for ~ 30 minutes. The mixture was heated at room temperature and then stirred for ~ 17 hours. The mixture was concentrated and the residue was diluted with chloroform and washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO ₄ and concentrated to give 9.18 g of a clear yellow oil.

B. 3- (R, S) -Benzyl-4-oxopiperidine -1,3-dicarboxylic acid, 1-tert-butyl ether, 3-methyl ether
To a solution of 5.00 g (19.4 mmol) of 3A in 10 ml of DMF was added 745 mg (7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for ~ 15 minutes. A solution of 3.32 g (19.4 mmol) of benzylamide in 15 ml of DMF was added to the stirred solution through a cannula and the mixture was stirred for ~ 42 hours at room temperature. The mixture was diluted with ethyl acetate and washed once with water and 4 times with brine, dried over MgSO ₄ and concentrated to obtain 6.0 g of 3B as a yellow oil. MS (Cl, NH ₃ ) 348 (MH ⁺ ).

C. 3a- (R, S) -Benzyl-2-methyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid, tert- butyl ether
A mixture of 4.00 g (11.5 mmol) of 3B and 530 mg (11.5 mmol) of methylhydrazine in 100 ml of ethanol was heated under reflux for approximately 8 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for approximately 17 hours.

The mixture was concentrated and the residue was purified by silica gel chromatography with an elution gradient. (15:85 v / v ethyl acetate: hexane) - (75:25 v / v ethyl acetate: hexane) to give 2.6 g of 3C as a clear, colorless oil. MS (Cl, NH ₃ ) 344 (MH ⁺ ).

D. 3- (R, S) -Benzyl-2-methyl-2,3, 3a, 4,5,6, 7-hexapyrazolo [4,3-c] pyridin-3-one
To 2.60 g (7.6 mmol) was added 20 ml of trifluoroacetic acid at ~ 0 ^° C and the mixture was stirred for ~ 2.5 hours. Ethyl acetate was added and the solution was washed with 6 N. NaOH, dried over MgCO ₄ and concentrated to obtain 1.8 g of 3D. MS (Cl, NH ₃ ) 244 (MH ⁺ ).

E. {1- [2- [3a- (R, S) -Benzyl-2-methyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -yl] -1- (R) - (1 H-indol-3-ylmethyl) -2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 125 mg (4.6 mmol) 3C and 1.75 g (0.51 mmol) 2C were combined and the residue was purified by silica gel chromatography with an elution gradient (6: 4 v / v ethyl acetate: hexane ) - 7% methanol in ethyl acetate to give 150 mg 3E.

F. 2-amino-N-2 [3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl] -1 (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] -isobutyramide, hydrochloride
~ 150 ml of concentrated HCl was added to 150 mg (0.24 mmol) of 3E in 15 ml of ethanol and stirred at room temperature for approximately 3 hours. The mixture was concentrated and the residue was crystallized from ethanol / hexane to give 100 mg of 3F. MS (Cl, NH ₃ ) 515 (MH ⁺ ).

¹ H NMR (CD ₃ OD): δ 7.20 - 6.91 (m, 9H), 6.56 (m, 1), 5.17 (m, 1H), 4.05 (m, 1H), 2.96 (s, 3H), 2.62 (m , 1H), 2.38 (m, 1H), 2.06 (m, 2H), 1.61 (m, 8H).

Example 4
2-amino-N-2- [3- (R) -benzyl-2-methyl-3-oxo-2,3, 3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl ] -1 (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride and 2-amino-N-2- [3- (S) -benzyl-2-methyl-3-oxo-2,3,3a, 4 , 6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] -1 (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
A. {1- [2- [3a- (R, S) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -yl] -1- (R) -benzyloxymethyl-2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 1.12 g (4.6 mmol) of 3C and 1.75 g (0.51 mmol) of 1E were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography with an elution gradient (1: 1 v / v ethyl acetate: hexane) - 100% ethyl acetate to give 350 mg less polar 4A isomer 1 and 250 mg more polar 4A isomer 2. MS (Cl, NH ₃ ) 606 ( MH ⁺ ) for both isomers.

C. 2-amino-N- [2- (3- (R) -benzyl -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
To 250 mg (0.41 mmol) of 4A isomer 1 in 15 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 5 hours. The mixture was concentrated and the residue was precipitated from ethanol / hexane and dried in vacuo to give 130 mg of 4B isomer 1. MS (Cl, NH ₃ ) 506 (MH ⁺ ).

¹ H NMR (CD ₃ OD): δ 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, 2H), 1.63 (m, 7H).

C. 2-amino-N- [2- (3- (S) -benzyl -2-methyl-3-oxo-2,3,3a, 4, 6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
To 250 mg (0.41 mmol) of 4A isomer 2 in 15 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 5 hours. The mixture was concentrated and the residue was precipitated from ethanol / hexane and dried in vacuo to give 120 mg of 4C isomer 1. MS (Cl, NH ₃ ) 506 (MH ⁺ ).

¹ H NMR (CD ₃ OD): δ 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).

D. 2-amino-N- [2- (3- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, methanesulfonate
A saturated aqueous sodium bicarbonate solution was added to 3.60 g (6.6 mmol) of 4B of isomer 1, and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated. The residue was dissolved in ethyl acetate, cooled to ~ 0 ^° C and 0.43 ml (6.6 mmol) of methanesulfonic acid was added and the mixture was stirred for ~ 0.5 hours. Hexane (200 ml) was added to the solution, and the mixture was stirred for ~ 1 hour and filtered to obtain 3.40 g of a white solid. The solid was recrystallized from a 3% aqueous solution of ethyl acetate to give 2.55 g of 4D isomer 1 as a white crystalline solid. MS (Cl, NH ₃ ) 506 (MH ⁺ ).

Example 5
2-amino-N- [1- (3- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- carbonyl) -4-phenyl- (R) -butyl] - isobutyramide, hydrochloride and
2-amino-N- [1- (3- (S) -benzyl-2-methyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- carbonyl) -4-phenyl- (R) -butyl] -isobutyramide, hydrochloride
A. 2-Oxo-5,6-diphenyl-3- (3-phenylallyl) -morpholine-4-carboxylic acid, tert-butyl ether
To a solution of 13.8 g (70.0 mmol) of cinnamyl bromide and 4.94 g (14.0 mmol) of tert-butyl- (2S, 3R) - (+) - 6-oxo-2 cooled to ~ -78 ^° C , 3-diphenyl-4-morpholinocarboxylate in 350 ml of anhydrous THF was added 28 ml (28 mmol) of 1 M sodium bistrimethylsilylamide in THF. The mixture was stirred at ~ -78 ^° C for ~ 1.5 hours and then poured into 750 ml of ethyl acetate. The mixture was washed twice with brine, dried over MgSO ₄ and concentrated to give a yellow oil. The oil was stirred in 150 ml of hexane overnight and the precipitated solid was collected by filtration to obtain 3.2 g of 5A as a white solid.

B. 5 (S), 6 (R) -Diphenyl-3 (R) - (3-phenylallyl) -morpholin-2-one
To 2.97 g (6.33 mmol) of 5A was added 20 ml of trifluoroacetic acid at ~ 0 ^° C and the mixture was stirred for ~ 2 hours and then concentrated. The residue was dissolved in water and made basic with an aqueous NaOH solution to a stable pH of 10. The mixture was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated to give an orange oil, which was purified by silica gel chromatography (10: 90 v / v) ethyl acetate: hexane) to give 880 mg of 5B as a white solid.

C. 2- (R) -Amino-5-phenylpentanoic acid
A mixture of 440 mg (1.19 mmol) of 5B and 120 mg of palladium chloride in 20 ml of ethanol and 10 ml of THF was hydrogenated at 45 psi (310,264.06 Pa) for approximately 16 hours. The mixture was filtered through diatomaceous earth and concentrated, and the residue was triturated with ether to give 240 mg of 5C as a white solid.

D. 2-tert-Butoxycarbonylamino -2-methylpropionic acid, 2,5-dioxopyrrolidin-1-yl ester
To a suspension of 5.0 g (24.6 mmol) of N-tert-BOC-α-methylalanine in 13.5 ml of methylene chloride was added 3.40 g (29.6 mmol) of N-hydroxysuccinamide and 5.65 g (29.6 mmol) EDC. The suspension was stirred for approximately 17 hours at room temperature. The mixture was diluted with ethyl acetate and washed twice with water, saturated aqueous sodium bicarbonate and brine (each of them). Dried over MgSO ₄ and concentrated. The product was purified by silica gel chromatography (1: 1 v / v ethyl acetate: hexane) to give 5.2 g of the title compound of this part D as a white solid.

E. (R) -2- (2-tert-Butoxycarbonylamino-2-methylpropionylamino) -5-phenylpentanoic acid
A mixture of 203 mg (1.05 mmol) of 5D, 378 mg (1.26 mmol) of 5C and 434 mg (3.36 mmol) of diisopropylethylamine in 2 ml of DMF was stirred overnight. The mixture was dissolved with ethyl acetate and was extracted twice with 1 N. HCl. The aqueous phase was extracted 1 time with ethyl acetate. The combined organic extracts were washed three times with water and 1 time with brine. The mixture was dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 80% chloroform in hexane and then with 100% chloroform and 10% methanol in chloroform to obtain 127 mg of 5E.

F. {1- [2- [3a- (R, S) -Benzyl-2-methyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -carbonyl] -4-phenyl- (R) -butylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 130 mg (0.53 mmol) of 3C and 200 mg (0.53 mmol) of 5E were combined to form a mixture of diastereomers. The residue was purified by silica gel chromatography with an elution gradient (1: 1 v / v ethyl acetate: hexane) - 100% ethyl acetate to give 40 mg less than the polar 5F isomer 1 and 40 mg more than the polar 5F isomer 2. MS (Cl, NH ₃ ) 604 ( MH ⁺ ) for both isomers.

G. 2-amino-N- [1- (3- (R) -benzyl -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-carbonyl) -4-phenyl- (R) -butyl] -isobutyramide, hydrochloride
To 40 mg (0.07 mmol) of 5F isomer 1 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 4 hours. The mixture was concentrated and the residue was precipitated from methylene chloride / hexane and dried in vacuo to give 30 mg of 5G isomer 1. MS (Cl, NH ₃ ) 504 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

H. 2-amino-N- [1- (3- (S) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-carbonyl) -4-phenyl- (R) -butyl] -isobutyramide, hydrochloride
To 40 mg (0.07 mmol) of 5F isomer 2 in 10 ml of ethanol was added 4 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 4 hours. The mixture was concentrated and the residue was precipitated from methylene chloride / hexane and dried under vacuum to give 30 mg of 5H isomer 1. MS (Cl, NH ₃ ) 504 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (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).

Example 6
2-amino-N-2- [3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -yl] -1 (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
A. {1- [2- [3a- (R, S) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -yl] -1- (R) - benzyloxymethyl-2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 200 mg (0.82 mmol) of 3C and 320 mg (0.82 mmol) of 1E were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography with an elution gradient (1: 1 v / v ethyl acetate: hexane) - 10% methanol in ethyl acetate to give 170 mg of 6A.

C. 2-amino-N-2- [3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridine -5-yl] -1 (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
To 170 mg (0.28 mmol) of 6A in 20 ml of ethanol was added 5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2.5 hours. The mixture was concentrated and the residue was precipitated from ethanol / hexane to give 70 mg of 6B. MS (Cl, NH ₃ ) 506 (MH ⁺ ).

¹ H NMR (CD ₃ OD): δ 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).

Example 7
2-amino-N- [2- (3a-benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1 - (1H-indol-3-ylmethyl) -2-oxoethyl] -isobutyramide, hydrochloride
A. 3- (R, S) -Benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid, tert-butyl ether
To 555 mg (1.60 mmol) of 3B in 27 ml of ethanol was added 240 mg (1.60 mmol) of ethyl hydrazinoxalate and the mixture was heated under reflux for ~ 4 hours. The mixture was concentrated and the residue was purified by silica gel chromatography with an elution gradient (10: 1 v / v hexane: ethyl acetate) - (3: 7 v / v hexane: ethyl acetate) to give 357 mg 7A. MS (Cl, NH ₃ ) 358 (MH ⁺ ).

B. 3a- (R, S) -Benzyl-2-ethyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one
To 350 mg (0.98 mmol) of 7A in 3 ml of ethanol was added 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated to give 257 mg of 7B. MS (Cl, NH ₃ ) 258 (MH ⁺ ).

C. {1- [2- [3a- (R, S) -Benzyl -2-ethyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5 -yl] -1- (R) - (1H-indol-3-ylmethyl) -2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 82 mg (0.28 mmol) of 7B and 100 mg (0.26 mmol) of 2C were combined and the residue was purified by silica gel chromatography with an elution gradient of 100% methylene chloride - 2% methanol in methylene chloride to give 110 mg 7C. MS (Cl, NH ₃ ) 629 (MH ⁺ ).

D. 2-amino-N- [2- (3a-benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide, hydrochloride
To 100 mg (0.15 mmol) of 7C in 2 ml of ethanol was added 1 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated to give 72 mg of 7D as a colorless foam. MS (Cl, NH ₃ ) 529 (MH ⁺ ).

Example 8
2-amino-N- [2- (3- (R) -benzyl -2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine -5- il) -1- (R) - benzyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride and 2-amino-N- [2- (3a- (S) -benzyl-2-ethyl-3-oxo-2,3,3a , 4,6,7-hexahydropyrazolo [4, 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride
A. {1- [2- [3a-Benzyl-2-ethyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] -1- (R) - (benzyloxymethyl) -2-oxoethylcarbamoyl] -1-methylethyl} - carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 85 mg (0.29 mmol) of 7B and 100 mg (0.26 mmol) of 1E were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography with an elution gradient of 100% methylene chloride - 2% methanol in methylene chloride to give 6 mg less polar 8A isomer 1 and 11 mg more polar 8A isomer 2. MS (Cl, NH ₃ ) 620 (MH ⁺ ) for both isomers .

B. 2-amino-N- [2- (3- (R) -benzyl -2-ethyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride
To 5.7 mg (0.009 mmol) of 8A isomer 1 in 1 ml of ethanol was added 0.4 ml of concentrated HCl and the mixture was stirred at room temperature for about 3 hours. The mixture was concentrated to obtain 4.7 mg of 8B isomer 1. MS (Cl, NH ₃ ) 520 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

C. 2-amino-N- [2- (3- (S) -benzyl -2-ethyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) - benzyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride
To 10 mg (0.016 mmol) of 8A isomer 2 in 1 ml of ethanol was added 0.4 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 3 hours. The mixture was concentrated to give 8 mg of 8C isomer 2. MS (Cl, NH ₃ ) 520 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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 9
2-amino-N- [2- (2-benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
A. 2-Benzyl-3-hydroxy-2,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-carboxylic acid, tert-butyl ether
A mixture of 800 mg (3.11 mmol) of 3B and 495 mg (3.11 mmol) of benzylhydrazine dihydrochloride and 423 mg (3.11 mmol) of sodium acetate trihydrate in 15 ml of ethanol was heated under reflux for ~ 17 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for approximately 48 hours. The mixture was diluted with ethyl acetate and washed with brine, dried over MgSO ₄ and concentrated, and the residue was purified by silica gel chromatography eluting with 100% ethyl acetate and then 5% methanol in methylene chloride to give 530 mg 9A as a light brown solid. MS (Cl, NH ₃ ) 330 (MH ⁺ ).

B. 2-Benzyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c] pyridin-3-ol
To 411 mg (1.24 mmol) of 3E in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 30 minutes. The mixture was concentrated and the residue was crystallized from methanol / acetate to give 353 mg of 9B. MS (Cl, NH ₃ ) 230 (MH ⁺ ).

C. {1- [2- [2-Benzyl-3-hydroxy-2,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] -1-R-benzyloxymethyl-2-oxoethylcarbamoyl] -1-methylethyl} carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 100 mg (0.38 mmol) 9B and 145 mg (0.38 mmol) 1E were combined and the residue was purified by silica gel chromatography (95: 5 v / v methanol: methylene chloride) to obtain 42 mg 9C as a white solid. MS (Cl, NH ₃ ) 592 (MH ⁺ ).

D. 2-amino-N- [2- (2-benzyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- ( R) -benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
To 42 mg (0.07 mmol) of 9D in 20 ml of ethanol was added 6 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 30 minutes. The mixture was diluted with ethanol, concentrated and the residue was precipitated from methanol / ethyl acetate to give 35 mg of 9D as a white solid. MS (Cl, NH ₃ ) 492 (MH ⁺ ).

¹ H NMR (CD ₃ 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).

Example 10
2-amino-N- {2- [3- (R) -benzyl-3-oxo-2- (2,2,2-trifluoroethyl) - 2,3,3a, 4,6, 7-hexahydropyrazolo [4, 3-c] pyridin-5-yl] -1- (R) -benzyloxymethyl-2-oxoethyl} -isobutyramide, hydrochloride and 2-amino-N- {2- [3- (S) -benzyl-3-oxo- 2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] -1- (R) -benzyloxymethyl-2-oxoethyl} -isobutyramide hydrochloride
A. 3- (R, S) -Benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3, 3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-carboxylic acid, tert-butyl ether
A mixture of 840 mg (2.42 mmol) of 3B and 276 mg (2.42 mmol) of 2,2,2-trifluoroethylhydrazine (70% in water) in 20 ml of ethanol was heated under reflux for ~ 5 hours and then concentrated. The residue was dissolved in 40 ml of toluene and heated under reflux for ~ 17 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (9: 1 v / v hexane: ethyl acetate) to obtain 703 mg of 10A as a yellow oil. MS (Cl, NH ₃ ) 412 (MH ⁺ ).

B. 3- (R, S) -Benzyl-3- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one
To 600 mg (1.46 mmol) of 10A at ~ 0 ^° C, 3 ml of cold trifluoroacetic acid was added and the mixture was stirred for ~ 3 hours while allowing the solution to reach room temperature. The mixture was concentrated and the residue was dissolved in water and the solution was alkalinized to pH 11 5 N. NaOH and then saturated with potassium carbonate. The solution was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated to give 345 mg of 10B as an opaque oil. MS (Cl, NH ₃ ) 312 (MH ⁺ ).

C. {1- [2- [3a- (R, S) -Benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4 , 3-c] pyridin-5-yl] -1- (R) -benzyloxymethyl-2-oxoethylcarbamoyl} -1-methylethyl) -carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 137 mg (0.44 mmol) of 10B and 167 mg (0.44 mmol) of 1E were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography with an elution gradient of 100% methylene chloride - 5% methanol in methylene chloride to give 128 mg of less polar 10C isomer 1 and 63 mg of more polar 10C isomer 2. MS (Cl, NH ₃ ) 674 (MH ⁺ ) for both isomers .

D. 2-amino-N- {2- [3a- (R) -benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [ 4,3-c] pyridin-5-yl] -1- (R) -benzyloxymethyl-2-oxoethyl} -isobutyramide, hydrochloride
To 120 mg (0.18 mmol) of 10C isomer 1 in 3.5 ml of ethanol was added 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated to obtain 94 mg of 10D isomer 1 as an off-white powder. MS (Cl, NH ₃ ) 574 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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. 2-amino-N- {2- [3- (S) - benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [ 4,3-c] pyridin-5-yl] -1- (R) -benzyloxymethyl -2-oxoethyl} - isobutyramide, hydrochloride
To 53 mg (0.079 mmol) of 10C isomer 2 in 3.5 ml of ethanol was added 1.5 ml of concentrated HCl and the mixture was stirred at room temperature for ~ 2 hours. The mixture was concentrated to obtain 41 mg of 10E isomer 2 as a pale yellow solid. MS (Cl, NH ₃ ) 574 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 7.33 (m, 5H), 7.15 (m, 4H), 6.81 (m, 1H), 5.30 (m, 1H), 4.67 (m, 4H), 4.15 ( m, 2H), 3.77 (m, 2H), 3.09 (m, 3H), 2.64 (m, 3H), 1.58 (m, 6H).

Example 11
2-amino-N- [2- (3- (R) -benzyl-2-tert-butyl-3-oxo-2,2,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) benzyloxymethyl -2-oxoethyl] isobutyrate, methanesulfonate and 2-amino-N- [2- (3- (S) -benzyl-2-tert-butyl-3-oxo- 2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyrate, methanesulfonate
A. 3a- (R, S) -Benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid, tert butyl ether
To 2.07 g (5.95 mmol) of 14B in 40 ml of ethanol was added 0.97 g (7.7 mmol) of tert-butylhydrazine hydrochloride and 0.63 g (7.7 mmol) of sodium acetate and the mixture was heated at ~ 70 ^o C for ~ 17 hours. The mixture was cooled and the solution was decanted from the precipitate and concentrated. The residue was dissolved in 80 ml of toluene and heated under reflux for ~ 6 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (9: 1 v / v hexane: ethyl acetate) to obtain 1.7 g, 11A. MS (Cl, NH ₃ ) 386 (MH ⁺ ).

B. 3a- (R, S) -Benzyl-2-tert-butyl -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one
To 535 mg (1.39 mmol) of 11A in 20 ml of methylene chloride, 225 μl of methanesulfonic acid was added and the mixture was stirred for ~ 1.5 hours at room temperature. The mixture was diluted with ethyl acetate and washed twice with 1 N. NaOH and 1 time with brine, dried over Na ₂ SO ₄ and concentrated to obtain 246 mg of 11B. MS (Cl, NH ₃ ) 286 (MH ⁺ ).

C. {1- [2- [3a- (R, S) -Benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine -5-yl] -1- (R) -benzyloxymethyl-2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 246 mg (0.86 mmol) of 11B and 328 mg of 14F were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography (6: 4 v / v hexane / ethyl acetate) to give 250 mg less than the polar 11C isomer 1 and 90 mg more than the polar 11C isomer 2. MS (Cl, NH ₃ ) 648 (MH ⁺ ) for both isomers.

D. 2-amino-N- [2- (3- (R) -benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-s] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyrate, methanesulfonate
To 210 mg (0.32 mmol) of 11C isomer 1 in 15 ml of methylene chloride at ~ 0 ^° C was added 28 μl (0.44 mmol) of methanesulfonic acid. The ice bath was removed and the mixture was stirred for ~ 3 hours, diluted with 15 ml of diethyl ether and the precipitated solid was collected by filtration to obtain 100 mg of 11D isomer 1. MS (Cl, NH ₃ ) 548 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 7.33 (m, 5 H), 7.27 - 7.07 (m, 5H), 5.21 (m, 1H), 4.54 (m, 3H), 3.86 (m, 3H) 3.10 (m, 4H), 2.61 (s, 3H), 1.62 (m, 6H), 1.18 (s, 9H).

E. 2-amino-N- [2- (3- (S) -benzyl-2- tert-butyl-3-oxo-2,3, 3a, 4,6,7-hexahydropyrazolo [4,3-s] pyridin-5-yl) -1- (R) - benzyloxymethyl -2-oxoethyl] isobutyrate, methanesulfonate
To 85 mg (0.13 mmol) of the 11C isomer 2 in 10 ml of methylene chloride at ~ 0 ^° C was added 21 μl (0.32 mmol) of methanesulfonic acid. The ice bath was removed and the mixture was stirred for ~ 3 hours, diluted with 20 ml of diethyl ether and the precipitated solid was collected by filtration to obtain 46 mg of 11E isomer 2. MS (Cl, NH ₃ ) 548 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

Example 12
2-amino-N- [1- (R) - (1H-indol-3-ylmethyl) -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-oxoethyl] - isobutyramide, dihydrochloride
A. 4-Oxo-3- (R, S) -pyridin-2-methylmethylpiperidine-1,3-dicarboxylic acid, 1-tert-butyl ether, 3-methyl ether
To a solution of 2.00 g (7.8 mmol) of 3A in 32 ml of THF was added 468 mg (11.7 mmol) of sodium hydride (60% oil dispersion) at ~ 0 ^° C and the mixture was stirred for ~ 30 minutes. To the stirred solution was added a solution of 762 mg (6.0 mmol) of 2-picolyl chloride in 5 ml of THF over ~ 5 minutes, followed by 432 mg (2.6 mmol) of potassium iodide. The ice bath was removed and the mixture was heated for approximately 17 hours under reflux. The mixture was diluted with ethyl acetate and washed once with brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography, eluting with 6: 4 v / v ether: hexane and then 6: 4 v / v ethyl acetate: hexane to give 1.2 g 12A. MS (Cl, NH ₃ ) 349 (MH ⁺ ).

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

C. 2-Methyl-3a- (R, S) -pyridin -2-ylmethyl-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one, dihydrochloride
A mixture of 450 mg (1.30 mmol) of 12B in 2 ml of a mixture of 4 M HCl / dioxane was stirred at room temperature for approximately 4.5 hours. The mixture was concentrated to give 450 mg of 12C. MS (Cl, NH ₃ ) 245 (MH ⁺ ).

D. {1- [1- (1- (R) -H-indol-3-ylmethyl-2- (2-methyl-3-oxo-3- (R, S) -pyridin-2-ylmethyl-2, 3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-oxoethylcarbamoyl] -1-methylethyl) carbamic acid, tert-butyl ether
According to the main procedure A, 108 mg (0.31 mmol) of 12C and 122 mg (0.31 mmol) of 2C were combined and the residue was purified by silica gel chromatography (95: 5 v / v ethyl acetate: methanol) to obtain 118 mg of 12D. MS (Cl, NH ₃ ) 616 (MH ⁺ ).

E. 2-Amino-N- [1- (R) - (1H-indole-3-ylmethyl) -2- (2-methyl-3-oxo-3- (R, S) - pyridin-2-ylmethyl- 2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] isobutyramide, dihydrochloride
A mixture of 110 mg (0.18 mmol) of 12D in 1 ml of a mixture of 4 M HCl / dioxane was stirred at room temperature for 17 hours. The mixture was concentrated to give 51 mg of 12E. MS (Cl, NH ₃ ) 516 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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, 6 H).

Example 13
2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3- (R, S) -pyridin-2-ylmethyl-2,3,3a, 4,6, 7- hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] - isobutyramide, dihydrochloride
A. {1- [1- (R) -Benzyloxymethyl-2- (2-methyl-3-oxo-3- (R, S) - pyridin-2-ylmethyl-2,3,3a, 4,6,7 -hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethylcarbamoyl] -1-methylethyl} - carbamic acid, tert-butyl ether
According to the main procedure A, 86 mg (0.27 mmol) of 12C and 103 mg (0.27 mmol) of 1E were combined and the residue was purified by silica gel chromatography (95: 5 v / v ethyl acetate: hexane) to give 82 mg of 13A.

C. 2-amino-N- [1- (R) -benzyloxymethyl -2- (2-methyl-3-oxo-3a- (R, S) - pyridin-2-ylmethyl-2,3,3a, 4, 6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] isobutyramide, dihydrochloride
A mixture of 75 mg (0.12 mmol) of 13A in 1 ml of a mixture of 4 M HCl / dioxane was stirred at room temperature for ~ 17 hours. The mixture was concentrated to give 80 mg of 13B. MS (Cl, NH ₃ ) 507 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 8.78 (m, 1H), 8.46 (m, 1H), 8.13-7.82 (m, 2H), 7.32 (m, 5H), 4.57 (m, 3H), 3.96 (m, 1H), 3.82 (m, 2H), 1.63 (m, 6H).

Example 14
2-amino-N- [2- (3- (R) - benzyl-2-methyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- il) -1- (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] isobutyramide
A. 4-Oxopiperidin-1,3-dicarboxylic acid, 1-tert-butyl ether, 3-methyl ether
To a mixture of 100.0 g (516.4 mmol) of 4-oxopiperidin-3-carboxylic acid methyl ester and 63 g (516.4 mmol)
A solution of 113.0 g (516.4 mmol) of di-tert-butyl carbonate in 100 ml of methylene chloride was added over about 90 minutes to 4,4-dimethylaminopyridine in 1 L of methylene chloride at ~ 0 ^° C. The mixture was slowly warmed to room temperature and then stirred for approximately 19 hours. The mixture was washed three times with 10% aqueous HCl, saturated aqueous sodium bicarbonate and brine (each), dried over MgSO ₄ and concentrated to give 130.5 g of 14A as an amorphous solid.

¹ H NMR (CDCl ₃ ): δ 4.03 (br, 2H), 3.74 (s, 3H), 3.56 (t, 2H), 2.36 (t, 2H), 1.42 (s, 9H).

B. 3- (R) -Benzyl-4-oxopiperidin-1,3-dicarboxylic acid, 1-tert-butyl ether, 3-methyl ether
To a stirred suspension of 11.7 g (293 mmol) of sodium hydride (60% oil suspension washed twice with 100 ml of hexane) in 100 ml of DMF was added a solution of 65.4 g (254 mmol) of 14A and in 150 ml of DMF at about 0 ^° C for about 45 minutes. The ice bath was removed and the mixture was stirred at room temperature for approximately 45 minutes. The mixture was re-cooled to 0 ^° C. and 35.2 ml (296 mmol) of benzyl bromide in 200 ml of DMF was added dropwise to the stirred solution, and the mixture was stirred for approximately 23 hours at room temperature. 550 ml of water was carefully added to the solution, and the mixture was stirred for approximately 30 minutes. The mixture was extracted 3 times with ethyl acetate and the combined organic extracts were washed five times with water, once with brine, dried over MgSO ₄ and concentrated to give 98 g of a yellow oil. The oil was crystallized from hexane to give 71 g of 14B as a white solid. MS (Cl, NH ₃ ) 348 (MH ⁺ ).

¹ H NMR (CDCl ₃ ): (partial) δ 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).

C. 3- (R) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid, tert-butyl ether
A mixture of 47.0 g (135 mmol) of 14B, 38.9 g (270 mmol) of methylhydrazine sulfate and 44.3 g (540 mmol) of sodium acetate in 900 ml of ethanol was heated under reflux for approximately 17 hours under nitrogen atmosphere. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed three times with water and once with brine, dried over MgSO ₄ and concentrated to obtain 41.17 g of 14C as a white solid. MS (Cl, NH ₃ ) 344 (MH ⁺ ).

¹ H NMR (CDCl ₃ ): (partial) δ 7.19 (m, 3H), 7.05 (m, 2H), 4.61 (br m, 2H), 3.24 (m, 1H), 3.09 (s, 3H), 3.01 ( m, 1H), 2.62 (m, 4H), 1.52 (s, 9H).

D. 3a- (R, S) -Benzyl-2-methyl-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one, hydrochloride
Anhydrous hydrogen chloride was bubbled through a solution of 24.55 g (71.5 mmol) of 14C in 800 ml of diethyl ether at about 0 ^° C for about 12 minutes. The mixture was stirred for approximately 3 hours and a white precipitate formed during this period. The precipitated solid was collected by filtration to obtain 19.2 g of 14D. MS (Cl, NH ₃ ) 244 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

E. 2-tert-Butoxycarbonylamino -2-methyl propionic acid, 2,5-dioxopyrrolidin-1-yl ester
To a stirred solution of 100.0 g (492 mmol) of Boc-α-methylalanine and 94.0 g (492 mmol) of EDC in 1 L of methylene chloride at ~ 0 ^° C was added 56.63 g (492 mmol) of N-hydroxysuccinimide in portions and then the reaction was allowed to warm to room temperature. The mixture was stirred for approximately 24 hours and washed twice with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to give 124.0 g of 14E as a white solid.

¹ H NMR (CDCl ₃ ): δ 4.96 (br, 1H), 2.82 (s, 4H), 1.66 (s, 6H), 1.48 (s, 9H).

F. 3- (R) -Benzyloxy-2- (2-tert-butoxycarbonylamino-2-methylpropionylamino) propionic acid
A mixture of 50.5 g (168 mmol) of 14E, 33.5 g (168 mmol) of N-tert-BOC-O-benzyl-D-serine and 51.05 g (505 mmol) of triethylamine in 400 ml of dioxane and 100 ml of water heated at approximately 45 ^{° C.} for approximately 16 hours. The mixture was diluted with ethyl acetate and acidified to pH 2 with acetic acid. The layers were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated to give 650 g of 14F as a white solid.

¹ H NMR (CD ₃ OD): (partial) δ 7.55 (d, 1H), 7.29 (m, 5H), 4.52 (m, 1H), 4.48 (s, 2H), 3.84 (d of d, 1H), 3.69 (d of d, 1H), 1.42 (s, 6H), 1.38 (s, 9H).

G. 3- (R) -Benzyl-2-methyl-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one L-tartrate
To a mixture of 5.00 g (20.6 mmol) of the free base 14D and 3.09 g (20.6 mmol) of L-tartaric acid in 80 ml of acetone and 3.2 ml of water was heated under nitrogen at approximately 70 ^° C. for about 70 hours, during which time the reaction mixture became a thick suspension and another 20 ml of acetone was added. The reaction mixture was slowly cooled to room temperature and then filtered. Then, the solid was collected by filtration, washed with acetone and dried in vacuo to give 7.03 g of 14G as a white solid.

N. 3- (R) -Benzyl-2-methyl -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one
To a suspension of 5.00 g (12.7 mmol) of 14G in 80 ml of methylene chloride at about 0 ^° C. was added 1.72 ml (25.4 mmol) of ammonium hydroxide and the mixture was stirred for approximately 15 minutes. A cold solution was filtered and used immediately in the next step.

I. {1- [2- (3a- (R) -Benzyl -2-methyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl ) -1- (R) - (1H-indol-3-ylmethyl-2-oxoethylcarbamoyl] -1-methylethyl} - carbamic acid, tert-butyl ether
A mixture of 4.83 g (12.7 mmol) of 14F, a solution of 14H, 2.60 g (19.1 mmol) of HOAT and 2.45 g (12.8 mmol) of EDC was stirred at about 0 ^{° C.} under nitrogen in for about 1 hour and then warmed to room temperature and stirred for about 16 hours. The mixture was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate and water, dried over MgSO ₄ and concentrated to obtain 7.35 g of 14I as a white solid.

J. 2-amino-N- [2- (3- (R) -benzyl -2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -1- (R) - (1H-indol-3-ylmethyl -2-oxoethyl] isobutyramide
To 755 mg (1.25 mmol) of 14I in 7 ml of methylene chloride at approximately 0 ^° C., 3.5 ml of cold trifluoroacetic acid was added and the mixture was stirred for approximately 1 hour at approximately 0 ^° C. The mixture was allowed to warm to room temperature and was stirred at for about 2 hours. The mixture was concentrated and 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 MgSO ₄ and concentrated to give 594 mg of 14J as an oil.

Example 15
2-amino-N- [1- (R) -benzyloxymethyl -2- (2-methyl-3-oxo-2,3, 3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- sludge) -2-oxoethyl] -isobutyramide, hydrochloride
A. 2-Methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid, tert-butyl ether
A mixture of 3.00 g (11.66 mmol) of 3A and 537 mg (11.66 mmol) of methylhydrazine in 100 ml of ethanol was heated under reflux for approximately 17 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and washed twice with brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography with an elution gradient of 100% ethyl acetate - 5% methanol in methylene chloride to give 2.28 g of 15A as a white solid.

¹ H NMR (CD ₃ OD): δ 4.20 (s, 2H), 3.67 (t, 2H), 3.43 (s, 3H), 2.58 (t, 2H), 1.48 (s, 9H).

B. Hydrochloride 2-methyl-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one
To 510 mg (2.01 mmol) of 15A in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 35 minutes. The mixture was concentrated and the residue was crystallized from methanol / ethyl acetate to give 425 mg of 15B as a yellow solid.

¹ H NMR (CD ₃ OD): δ 4.27 (s, 2H), 3.71 (s, 3H), 3.56 (t, 2H), 3.05 (t, 2H).

C. {1- [1- (R) -Benzyloxymethyl -2- (2-methyl-3-oxo-2,3, 3a, 4,6,7-hexahydropyrazolo [4,3c] pyridin-5-yl) - 2- oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
According to the method described in Basic Procedure A, 100 mg (0.53 mmol) 15B and 202 mg (0.53 mmol) 1E were combined and the residue was purified by silica gel chromatography (95: 5 v / v methylene chloride: methanol) to obtain 54 mg 15C as a white solid. MS (Cl, NH ₃ ) 516 (MH ⁺ ).

D. 2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine- 5-yl) -2-oxoethyl] isobutyramide, hydrochloride
To 54 mg (0.10 mmol) of 15C in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 40 minutes. The mixture was concentrated and the residue was precipitated from methanol / ethyl acetate to give 50 mg of 15D. MS (Cl, NH ₃ ) 416 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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 16
2-amino-N- [2- (2-benzyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin -5-yl) -1 (R) - (1H-indol-3-ylmethyl) -2-oxoethyl] -isobutyramide, hydrochloride
A. 2-Benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid, tert-butyl ether
A mixture of 800 mg (3.11 mmol) of 3A and 495 mg (3.11 mmol) of benzyl hydrazindichloride in 15 ml of ethanol was heated under reflux for approximately 17 hours. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated under reflux for approximately 48 hours. The mixture was diluted with ethyl acetate and washed twice with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 100% ethyl acetate - 5% methanol in methylene chloride to give 530 mg 16A as a tan solid. MS (Cl, NH ₃ ) 330 (MH ⁺ ).

B. Hydrochloride 2-benzyl-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one
To 411 mg (1.24 mmol) of 16A in 30 ml of ethanol was added 10 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 30 minutes. The mixture was concentrated and the residue was crystallized from methanol / ethyl acetate to give 353 mg 16B as a yellow solid. MS (Cl, NH ₃ ) 230 (MH ⁺ ).

¹ H NMR (CD ₃ OD): δ 7.26-7.40 (m, 5H), 5.22 (s, 2H), 4.12 (s, 2H), 3.53 (t, 2H), 3.00 (t, 2H).

C. (R) -2- (2-tert-Butoxycarbonylamino-2-methylpropionylamino) -3- (1H-indol-3-yl) -propionic acid
To a stirred solution of 30.6 g (0.15 mol) of D-tryptophan, 30.4 g (0.30 mol) of N-methylmorpholine in 450 ml (4: 1) dioxane: water was added 45.0 g (0.15 mol) mol) 14E and the mixture was stirred for approximately 72 hours. Excess dioxane was removed by evaporation and water and ethyl acetate were added to the mixture. The pH of the solution was adjusted to 3 with concentrated HCl and the layers were separated. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was crystallized from ethyl acetate / hexane to give 37.0 g of a custom white solid.

D. {1- [2- (2-Benzyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) - (1 H-indol-3-ylmethyl) -2-oxoethylcarbamoyl] -1-methylethyl} carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 100 mg (0.38 mmol) 16B and 202 mg (0.53 mmol) 16C were combined and the residue was purified by silica gel chromatography (95: 5 v / v methylene chloride: methanol) to obtain 45 mg 16D as a white solid. MS (Cl, NH ₃ ) 601 (MH ⁺ ).

E. 2-amino-N- [2- (2-benzyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1 (R ) - (1H-indol-3-ylmethyl) -2-oxoethyl] -isobutyramide, hydrochloride
To 45 mg (0.07 mmol) of 16D in 60 ml of ethanol was added 20 ml of concentrated HCl and the mixture was stirred at room temperature for 35 minutes. The mixture was concentrated and the residue: precipitated from methanol / ethyl acetate to obtain 30 mg of 16E.

¹ H NMR (CD ₃ OD): (partial) δ 7.40 (m, 4H), 7.25 (m, 3H), 7.11 (m, 2H), 6.96 (m, 2 H), 6.81 (m, 1H), 5.38 - 4.93 (m, 3H), 4.46 (m, 1H), 4.22 (m, 1H), 3.96 (m, 1H), 3.69 (m, 1H), 3.18 (m, 1H), 2.28 (m, 1H), 1.57 (m, 6H), 1.38 (m, 1H).

Example 17
2-amino-N- [1-benzyloxymethyl-2- (2,3a-dimethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) - 2-oxoethyl] -isobutyramide, hydrochloride
A. 3-Methyl-4-oxopiperidine -1,3-dicarboxylic acid, 1-tert-butyl ether, 3- (R, S) -methyl ether
To a solution of 2.00 g (7.77 mmol) of 3A in 30 ml of DMF was added 308 mg (7.77 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred at room temperature for approximately 25 minutes. 0.50 ml (7.77 mmol) of methyl iodide was added to the stirred solution, and the mixture was stirred for approximately 17 hours at room temperature. The mixture was diluted with ethyl acetate and washed once with water and 4 times with brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography (7: 3 v / v hexane: ethyl acetate) to obtain 1.75 g of 17A as a clear oil. MS (Cl, NH ₃ ) 272 (MH ⁺ ).

B. 2, 3a- (R, S) -Dimethyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridine -5-carboxylic acid, tert-butyl ether
A mixture of 1.62 g (9.50 mmol) of 17A and 435 mg (9.50 mmol) of methylhydrazine in 30 ml of ethanol was heated under reflux for approximately 4 hours. The mixture was concentrated and the residue was dissolved in 50 ml of toluene and heated under reflux for approximately 14 hours. The mixture was diluted with ethyl acetate and washed twice with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (7: 3 v / v hexane: ethyl acetate to obtain 1.00 g of 17B as a white solid. MS (Cl, NH ₃ ) 268 (MH ⁺ ).

C. Hydrochloride 2,3- (R, S) -dimethyl-3-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one
To 1.00 g (3.74 mmol) of 17B in 40 ml of ethanol was added 8 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 35 minutes. The mixture was concentrated and the residue was crystallized from methanol / ethyl acetate to give 850 mg of 17C as a white solid. MS (Cl, NH ₃ ) 168 (MH ⁺ ).

D. {1- [1- (R) -Benzyloxymethyl-2- (2,3a- (R, S) -dimethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3 -c] pyridin-5-yl) -2-oxoethylcarbamoyl] -1-methylethyl} carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 150 mg (0.74 mmol) of 17C and 514 mg (1.35 mmol) of 1E were combined and the residue was purified by column chromatography (85:15 v / v hexane: ethyl acetate) to obtain 185 mg of 17D in the form of a white solid.

E. 2-amino-N- [1-benzyloxymethyl -2- (2,3a-dimethyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- sludge) -2- oxoethyl] -isobutyramide, hydrochloride
To 173 mg (0.33 mmol) of 17B in 40 ml of ethanol was added 15 ml of concentrated HCl and the mixture was concentrated at room temperature for approximately 1 hour. The mixture was concentrated and the residue was diluted with chloroform and washed with saturated aqueous sodium bicarbonate and brine, dried over Na ₂ SO ₄ and the residue was purified by silica gel chromatography with an elution gradient of 100% ethyl acetate - 10% diethylamine in ethyl acetate. The residue was dissolved in ethanol and acidified with aqueous HCl. The mixture was concentrated and the residue was crystallized from methanol / ethyl acetate to give 65 mg of 17E as a white solid. MS (Cl, NH ₃ ) 502 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

Example 18
2-amino-N- [2- (3- (R) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1 - (R) - benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride and 2-amino-N- [2- (3a- (S) -benzyl-3-oxo-2,3,3a, 4,6,7- hexahydrapyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] - isobutyramide, hydrochloride
A. 3-Benzyl-4-oxopiperidin-3-carboxylic acid, methyl ester
To 200 mg (0.58 mmol) of 3B at ~ 0 ^° C, 5 ml of cold trifluoroacetic acid was added and the mixture was stirred for approximately 1 hour. The mixture was concentrated and the residue was coevaporated with ethyl acetate and hexane. To the residue was added 2 N. Alkaline NaOH and the mixture was extracted with chloroform. The combined organic extracts were dried over MgSO ₄ and concentrated to give 18A in quantitative yield.

B. 3- (R, S) -Benzyl-1- [3-benzyloxy -2- (R) - (2-tert-butoxycarbonylamino -2-methylpropionylamino) propionyl] -4- oxopiperidin-3-carboxylic acid, methyl ether
According to the method described in Basic Procedure A, 1.77 g (7.16 mmol) of 18A and 3.04 g (8.0 mmol) of 14F were combined to give a mixture of diastereomers. The residue was purified by silica gel chromatography (7: 3 v / v hexane: ethyl acetate) to give 820 mg of the less polar 18B isomer 1 and 1.14 g of the more polar 18B isomer 2. MS (Cl, NH ₃ ) 611 (MH ⁺ ) for both isomers.

C. {- [2- (3a- (R, S) -Benzyl-3-oxo-2, 3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1 - (R) - benzyloxymethyl-2-oxoethylcarbamoyl] -1-methylethyl} -carbamic acid, tert-butyl ether
To a solution of 820 mg (1.32 mmol) of 18B isomer 1 in 13 ml of ethanol was added 342 mg (2.63 mmol) of hydrazine sulfate and 431 mg (5.26 mmol) of sodium acetate, and the mixture was heated under reflux for approximately 17 hours. The mixture was concentrated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 75% ethyl acetate in hexane - 100% ethyl acetate to give 550 mg of 18C isomer 1.

To a solution of 1.14 g (1.86 mmol) of 18B isomer 2 in 20 ml of ethanol was added 485 mg (3.73 mmol) of hydrazine sulfate and 613 mg (7.48 mmol) of sodium acetate and the mixture was heated under reflux for approximately 17 hours. The mixture was concentrated and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography (75:25 v / v ethyl acetate: hexane) to give 710 mg of 18C isomer 2.

D. 2-amino-N- [2- (3- (R) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) - benzyloxymethyl-2-oxoethyl] isobutyramide, hydrochloride
To 200 mg (0.34 mmol) of 18C isomer 1 in 12 ml of ethanol was added 6 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 2.5 hours. The mixture was concentrated and coevaporated three times with ethanol to give 20 mg of the 18D isomer 1. MS (Cl, NH ₃ ) 492 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 8.42 (br d, 1H), 7.35 (m, 5H), 7.18 (m, 5H), 5.23 (m, 2H), 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).

E. 2-amino-N- [2- (3a- (S) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] -isobutyramide, hydrochloride
To 200 mg (0.34 mmol) of 18C isomer 2 in 20 ml of ethanol was added 1 ml of concentrated HCl and the mixture was stirred at room temperature for approximately 2.5 hours. The mixture was concentrated and coevaporated three times with ethanol to give 30 mg of the 18E isomer 2. MS (Cl, NH ₃ ) 492 (MH ⁺ ).

¹ H NMR (CD ₃ OD): (partial) δ 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).

Example 19
2-amino-N- [1- (R) -benzyloxymethyl -2- (2-methyl-3-oxo-3- (R, S) -thiazole-4-methylmethyl-2,3,3a, 4,6, 7- hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] - isobutyramide, dihydrochloride
A. 4-Oxo-3- (R, S) -thiazol-4-ylmethylpiperidin-1,3-dicarboxylic acid, 1-tert-butyl ether, 3-ethyl ether
To a solution of 300 mg (1.10 mmol) of 1A in 5 ml of THF at ~ 0 ^° C was added 67 mg (1.66 mmol) of sodium hydride (60% oil dispersion) and the mixture was stirred for 30 minutes. To a cold solution was added a solution of 204 mg (1.21 mmol) of 4-chloromethylthiazole (Hsiao, C. N .; Synth. Comm. 20, p. 3507 (1990)) in 5 ml of THF and then 87 mg (0.53 mmol) ) potassium iodide and the mixture was heated under reflux for approximately 17 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and the residue was purified by silica gel chromatography (7: 3 v / v hexane: ethyl acetate) to obtain 90 mg of the title compound. MS (Cl, NH ₃ ) 648 (MH ⁺ ).

B. 2-Methyl-3-oxo-3- (R, S) -thiazol-4-ylmethyl-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ether
To 90 mg (0.24 mmol) of 19A in 2 ml of ethanol was added 11.2 mg (0.24 mmol) of methyl hydrazine and the mixture was heated under reflux for approximately 17 hours. An additional 33.6 mg (0.72 mmol) of methylhydrazine was added and the mixture was heated under reflux for approximately 7 hours. The mixture was concentrated and the residue was dissolved in 3 ml of toluene and heated under reflux for approximately 17 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (6: 4 v / v hexane: ethyl acetate) to obtain 44 mg 19B. MS (Cl, NH ₃ ) 648 (MH ⁺ ).

C. 2-Methyl-3-3- (R, S) -thiazol-4-ylmethyl-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-3-one dihydrochloride
A mixture of 44 mg (0.10 mmol) of 19B in 1 ml of 4 M HCl in dioxane was stirred at room temperature for approximately 4 hours. The mixture was concentrated and evaporated together with methylene chloride to give 40 mg 19C. MS (Cl, NH ₃ ) 251 (MH ⁺ ).

D. {1- [1- (R) -Benzyloxymethyl-2- (2-methyl-3-oxo-3- (R, S) -thiazol-4-ylmethyl-2,3,3a, 4,6,7 -hexahydropyrazolo [4, 3-c] pyridin-5-yl) - 2-oxoethylcarbamoyl] -1-methylethyl] -carbamic acid, tert-butyl ether
According to the method described in the main procedure A, 40 mg (0.12 mmol) of 19C and 39 mg (0.12 mmol) of 14F were combined and the residue was purified by silica gel chromatography (9: 1 v / v ethyl acetate: hexane) to give 40 mg 19D. MS (Cl, NH ₃ ) 613 (MH ⁺ ).

E. 2-amino-N- [1- (R) -benzyloxymethyl -2- (2-methyl-3-oxo-3a- (R, S) -thiazol-4-ylmethyl-2,3,3a, 4, 6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] isobutyramide, dihydrochloride
A mixture of 40 mg (0.06 mmol) of 19D in 1 ml of 4 M HCl in dioxane was stirred at room temperature for approximately 5 hours. The mixture was concentrated and evaporated with methylene chloride to give 40 mg 19E. MS (Cl, NH ₃ ) 513 (MH ⁺ ).

Example 20
2-amino-N- [2- (3- (R) -benzyl-2-methyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5- il) -1- (R) - (1H-indol-3-ylmethyl-2-oxoethyl] -isobutyramide, salt of L-tartaric acid
To 4.6 g of the title compound of Example 14 in 20 ml of methanol was added a solution of 1.36 g of L-tartaric acid in 20 ml of methanol at ~ 0 ^° C. The mixture was warmed to room temperature, stirred for approximately 40 minutes and concentrated in vacuo. The residue was diluted with 220 ml of ethyl acetate, heated under reflux for approximately 1.5 hours, then stirred at approximately 72 ^° C. for approximately 18 hours. The mixture was cooled to room temperature and filtered to give 5.78 g of the title compound as a colorless crystalline solid.

Example 21
3-Benzyl-3-methoxycarbonylmethyl-4-oxopiperidin-1-carboxylic acid, tert-butyl ether
A. 3-Benzyl-4-oxopiperidin-1-carboxylic acid, tert-butyl ether
A mixture of β-ketoester (4480 mg, 12.9 mmol) and LiCl (1100 mg, 25.8 mmol) was heated in DMF (2.0 ml) at about 120 ^° C. for about 17 hours. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried and concentrated in vacuo. The crude product on SiO ₂ eluted with 20% ethyl acetate / hexane to give 1320 mg of the desired product as a yellow oil.

¹ H NMR (250 MHz, CDCl ₃ ): d: 7.4 (m, 5H), 4.2 (m, 1H), 3.4 (m, 1H), 3.3 (dd, 1H), 3.05 (dd, 1H), 2.7 ( m. 1H), 2.55 (m, 4H), 1.5 (s, 9H); MS (APCl): 190 (M + 1-BOC).

B. 3-Benzyl-3-methoxycarbonylmethyl-4-oxopiperidin-1-carboxylic acid, tert-butyl ether
A solution of the product from Step A of Example 21 above (1320 mg, 4.56 mmol), pyrrolidine (972 mg, 13 mmol) and p-toluenesulfonic acid (33 mg) in benzene (30 ml) was heated under reflux with molecular sieves for about 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in benzene (10 ml) and cooled to ~ 0 ^° C. Methyl bromoacetate (1530 mg, 10 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and then it was heated under reflux for approximately 17 hours and then H ₂ O (5 ml) was added. After heating under reflux for another ~ 2 hours, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried and concentrated in vacuo. The crude residue was chromatographed on SiO ₂ gel, eluting with 15% ethyl acetate / hexane to give 280 mg of product.

¹ H NMR (250 MHz, CDCl ₃ ): 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 (APCl): 362 (M + 1).

Example 22
6-oxo-1-phenylcyclohexane-1,3-dicarboxylic acid, 3-tert-butyl ether, 1-methyl ether
A solution of diphenyl-mercury (890 mg, 2.5 mmol) of CHCl ₃ (4 ml) is heated to about 40 ^o C in a stream of nitrogen.

Lead tetraacetate (1110 mg, 2.5 mmol) is added in small portions the resulting greenish-yellow solution is stirred at a temperature of about 40 ^o C for about 0.5 hours. Β-Ketoester (520 mg, 2.0 mmol) is added, followed by pyridine (0.2 ml, 2.5 mmol). After 5 hours at 40 ^° C., the reaction mixture was concentrated in vacuo, the residue was dissolved in ether (100 ml) and filtered. The filtrate is washed three times with 3 N. H ₂ SO ₄ , dried and evaporated to give 616 mg of a yellow solid. Flash chromatography on silica gel using 25% ethyl acetate / hexane as eluent gives 368 mg of the expected product.

¹ H NMR (400 MHz, CDCl ₃ ): d 7.15 (m, 5H), 4.4 (s, 2H), 3.7 (s, 5H), 2.6 (s, 2H), 1.5 (s, 9H); MS (APCl): 334 (M + 1).

Example 23
(D) -2-amino-3- (2,4-dichlorobenzyloxy) -propionic acid hydrochloride
A. (D) -2-tert-Butoxycarbonylamino-3- (2,4-dichlorobenzyloxy) propionic acid
To a stirred solution of Boc-D-serine (8.2 g, 40 mmol) in DMF (75 ml) at ~ 0 ^° C was added NaH (60% dispersion, 3.2 g, 80 mmol) over a 10-minute period. The reaction mixture was stirred for approximately 1.75 hours at approximately 0 ^° C, then approximately 0.25 hours at room temperature. After cooling to approximately 0 ^° C., a solution of 2,4-dichlorotoluene (5.56 ml, 40 mmol) in DMF (5 ml) was added dropwise. The reaction mixture was allowed to warm to approximately 23 ^° C. and was stirred for approximately 17 hours, then partitioned between diisopropyl ether and 10% HCl. The aqueous solution was extracted with diisopropyl ether (2 x). The combined organic extracts were washed with brine, dried and concentrated to give 14.75 g of a crude product, which was used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ): 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); MS (APCl): 264.266 (M + 1, M + 2).

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

где R¹ обозначает -CH₂-фенил и R² обозначает метил, синтезировали аналогично процедурам, описанным в Примерах 3C - 3F с использованием соединения заголовка Примера 21 в качестве исходного материала. Выделяли как диастереомеры R,R, так и S,R (^* указывает другой центр стереоизомера при углероде C-3 показанной выше структуры). Масс-спектр (М+1)=520. Способ МС - бомбардировка частицами.Example 24
Example 24 having the formula shown below

where R ¹ is —CH ₂ phenyl and R ² is methyl, was synthesized in a manner analogous to the procedures described in Examples 3C to 3F using the title compound of Example 21 as a starting material. Both diastereomers R, R and S, R were isolated ( ^* indicates a different center of the stereoisomer at carbon C-3 of the structure shown above). Mass spectrum (M + 1) = 520. MS method - particle bombardment.

где для обоих примеров 25 и 26 R¹ обозначает фенил и R² обозначает метил, причем пример 25 представляет собой R,R- изомер, а пример 26 представляет собой S, R-изомер. Примеры 25 и 26 синтезировали аналогично процедурам, описанным в Примерах 3C-3F с использованием соединения заголовка Примера 22 в качестве исходного материала с последующим хроматографическим разделением двух отдельных изомеров. Масс-спектр каждого примера (М+1)=493. Способ МС - бомбардировка частицами.Examples 25 and 26
Examples 25 and 26 have the formula shown below

where for both examples 25 and 26, R ¹ is phenyl and R ² is methyl, wherein example 25 is an R, R isomer, and example 26 is an S, R isomer. Examples 25 and 26 were synthesized in a manner analogous to the procedures described in Examples 3C-3F using the title compound of Example 22 as starting material, followed by chromatographic separation of two separate isomers. The mass spectrum of each example (M + 1) = 493. MS method - particle bombardment.

 Examples 27 to 183 are given at the end of the description.

Claims (94)

1. The compound of formula I

racemic-diastereomeric mixtures, optical isomers of these compounds and their pharmaceutically acceptable salts and prodrugs,
where e is 0 or 1;
n and w are 1;
Y is oxygen;
R ¹ is hydrogen, - (CH ₂ ) _t —A ¹ , where t is 0, 1 or 2;
And ¹ is a phenyl or fully unsaturated 4-8 membered ring, optionally having 1 to 2 heteroatoms independently selected from the group consisting of sulfur and nitrogen, a bicyclic ring system consisting of a fully unsaturated 5- or 6-membered ring, optionally having 1 - 2 heteroatoms represented by nitrogen;
A ¹ in each case, independently, is optionally substituted in one or optionally both rings, if A ¹ is a bicyclic ring system and has up to 2 substituents, each substituent is independently selected from the group consisting of F, Cl, Br, OCF ₃ , (C ₁ -C ₆ ) alkyl, phenyl;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, wherein the alkyl group is optionally substituted with CF ₃ ;
R ³ is (C ₁ -C ₅ ) alkyl-X ¹ - (C ₀ -C ₅ ) alkyl-A ¹ , where X ¹ is —O—; the values of A ¹ are indicated above;
R ⁴ is hydrogen;
X ⁴ is hydrogen;
R ⁶ represents

where a and b are 0;
X ⁵ and X ^5a each independently represent unsubstituted (C ₁ -C ₆ ) alkyl;
Z ¹ is a bond;
R ⁷ and R ⁸ each represents hydrogen. 2. The compound of claim 1, wherein X ⁵ and X ^5a are each independently (C ₁ -C ₃ ) alkyl; R ³ represents phenyl (C ₀ -C ₃ ) alkyl-O — CH ₂ -, where the phenyl defined for R ³ is optionally substituted with one to two substituents selected from the group consisting of F, Cl, OCF ₃ , methyl. 3. The compound of claim 2, wherein X ⁵ and X ^{5a are} each methyl; R ³ is phenyl-CH ₂ —O — CH ₂ , where the phenyl defined for R ³ is optionally substituted with one to two substituents selected from the group consisting of fluoro, chloro, methyl, OCF ₃ . 4. The compound according to claim 3, where R ¹ is - (CH ₂ ) _t -A ¹ , where A ¹ in the definition of R ^{1 is} optionally substituted with one to two substituents selected from the group consisting of fluoro, chloro, methyl and OCF ₃ . 5. The compound according to claim 4, where e is 0; R ¹ is - (CH ₂ ) _t -A ¹ , where A ¹ in the definition of R ¹ is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which is optionally substituted with one to two substituents, each Deputy is independently selected from the group consisting of F, Cl , Me and OSF ₃ ; t is 0, 1 or 2 and R ³ is phenyl-CH ₂ —O — CH ₂ -, where the phenyl moiety is optionally substituted with one to two substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ . 6. The compound according to claim 5, where X ⁵ and X ^{5a are} each methyl; R ¹ is —CH ₂ phenyl, —CH ₂ -4-fluorophenyl, —CH ₂ pyridyl or —CH ₂ thiazolyl and R ² is hydrogen, methyl, ethyl, tert-butyl or —CH ₂ CF ₃ . 7. The compound of claim 6, wherein R ¹ is —CH ₂ phenyl or —CH ₂ —4-fluorophenyl and R ³ is phenyl — CH ₂ —O — CH ₂ -.  8. The compound according to claim 7, which is a diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  9. The compound of claim 8, where the compound is 2-amino-N- [2- (3- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  10. The compound according to claim 9, where the compound is a salt of L-tartaric acid 2-amino-N- [2- (3- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4 , 6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  11. The compound of claim 8, where the compound is 2-amino-N- [2- (3- (S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydropyrazolo- [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  12. The compound according to claim 7, which is a diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-ethyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  13. The compound of claim 12, wherein the compound is 2-amino [2- (3- (R) -benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [ 4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  14. The compound of claim 12, wherein the compound is 2-amino-N- [2- (3- (S) -benzyl-2-ethyl-3-oxo-2,3,3a, 4,6,7- hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  15. The compound according to claim 7, which is a diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2, 3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  16. The compound according to clause 15, where the compound is 2-amino-N- [2- (3- (R) -benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3, 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  17. The compound according to clause 15, where the compound is 2-amino-N- [2- (3- (S) -benzyl-3-oxo-2- (2,2,2-trifluoroethyl) -2,3, 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  18. The compound according to claim 7, which is a diastereomeric mixture of 2-amino-N- {1- (R) -benzyloxymethyl-2- [3- (R, S) - (4-fluorobenzyl) -2-methyl-3- oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl] -2-oxoethyl} isobutyramide.  19. The compound of claim 18, wherein the compound is 2-amino-T- {1- (R) -benzyloxymethyl-2- [3- (R) - (4-fluorobenzyl) -2-methyl-3-oxo- 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl] -2-oxoethyl} -isobutyramide.  20. The compound of claim 18, wherein the compound is 2-amino-N- {1- (R) -benzyloxymethyl-2- [3- (S) - (4-fluorobenzyl) -2-methyl-3-oxo- 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl] -2-oxoethyl} -isobutyramide.  21. The compound according to claim 7, which is a diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-2-tert-butyl-3-oxo-2,3,3a, 4, 6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide.  22. The compound according to item 21, where the compound is 2-amino-N- [2- (3- (R) -benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo- [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxoethyl] isobutyramide.  23. The compound according to item 21, where the compound is 2-amino-N- [2- (3- (3) -benzyl-2-tert-butyl-3-oxo-2,3,3a, 4,6, 7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) benzyloxymethyl-2-oxoethyl] isobutyramide. 24. The compound according to claim 4, where e is 1; R ¹ is - (CH ₂ ) _t -A ¹ , where A ¹ in the definition of R ¹ is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl, which are optionally substituted with one to two substituents, each substituent selected from the group consisting of F, Cl, Me and OSF ₃ ; t is 0, 1 or 2 and R ³ is phenyl-CH ₂ —O — CH ₂ -, where the phenyl moiety is optionally substituted with one to two substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ . 25. The compound of claim 24, wherein X ³ and X ^{5a are} each methyl; R ¹ is -CH ₂ -phenyl, -CH ₂ -4-fluorophenyl, -CH ₂ -pyridyl or CH ₂ -thiazolyl and R ² is hydrogen, methyl, ethyl, t-butyl or -CH ₂ CF _3.  26. The compound according to claim 7, which is a diastereomeric mixture of 2-amino-N- [2- (3- (R, S) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [ 4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-hydroxyethyl] isobutyramide.  27. The compound of claim 26, wherein the compound is 2-amino-N- [2- (3- (R) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4, 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-hydroxyethyl] isobutyramide.  28. The compound according to p. 26, where the compound is 2-amino-N- [2- (3- (8) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4, 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-hydroxyethyl] isobutyramide. 29. The compound of claim 1, wherein X ⁵ and X ^5a each independently are (C ₁ -C ₃ ) alkyl; R ^{3 is} selected from the group consisting of phenyl (C ₀ -C ₃ ) alkyl-O-CH ₂ -, 3-benzothienyl-CH ₂ -, thienyl-CH ₂ -O-CH ₂ -, thiazolyl-CH ₂ -O-CH ₂ -, pyridyl-CH ₂ -O-CH ₂ -, pyrimidyl-CH ₂ -O-CH ₂ - and phenyl-CH ₂ -O-CH ₂ , where the aryl part (s) of the groups defined for R ³ are optionally substituted one to two substituents, each substituent is independently selected from the group consisting of F, Cl, CH ₃ and OCF ₃ . 30. The compound according to clause 29, where X ⁵ and X ^5a each independently represent methyl; R ² is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl or —CH ₂ OCF ₃ , R ¹ is —CH ₂ —A ¹ , where A ¹ in the definition of R ¹ is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl which is optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ ; R ³ is phenyl-O-CH ₂ , thienyl-CH ₂ -O-CH ₂ -, thiazolyl-CH ₂ -O-CH ₂ -, pyridyl-CH ₂ -O-CH ₂ -, pyrimidyl-CH ₂ -O- CH ₂ - or phenyl-CH ₂ -O-CH ₂ -, where the aryl moiety is optionally substituted with one to two substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ . 31. The compound of claim 29, wherein R ² is methyl, ethyl or —CH ₂ CF ₃ ; A ¹ is phenyl optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ ; R ³ is phenyl-CH ₂ —O — CH ₂ - or thienyl-CH ₂ —O — CH ₂ -, wherein the aryl moiety is optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ . 32. The compound of claim 30, wherein R ² is methyl, ethyl or —CH ₂ CF ₃ ; A ¹ is 2-pyridyl or 3-pyridyl optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ ; R ³ is phenyl-CH ₂ —O — CH ₂ - or thienyl-CH ₂ —O — CH ₂ -, wherein the aryl moiety is optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ . 33. The compound of claim 30, wherein X ⁵ and X ^{5a are} each methyl; R ² is methyl, ethyl or —CH ₂ CF ₃ ; A ¹ is phenyl optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl, Me and OCF ₃ ; R ³ is 2-pyridyl-CH ₂ O-CH ₂ - or 3-pyridyl-CH ₂ -O-CH ₂ -, where the aryl moiety is optionally substituted with 1-2 substituents, each substituent independently selected from the group consisting of F, Cl , Me and OCF ₃ . 34. The compound according to p, having the formula

racemic-diastereomeric mixtures and optical isomers of these compounds,
where R ² is methyl; And ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ phenyl. R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ —3-chlorophenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ —4-chlorophenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl and R ³ is —CH ₂ —O — CH ₂ -2,4-dichlorophenyl;
R ² is CH ₂ CF ₃ ; A ¹ is 2-pyridyl; R ³ is —CH ₂ —O — CH ₂ -2,4-difluorophenyl.  35. The compound according to clause 34, representing a diastereomeric mixture of 2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3- (R, S) -pyridin-2-ylmethyl -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] -2-methylpropionamide.  36. The compound according to clause 35, where the compound is 2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3- (R) -pyridin-2-ylmethyl- 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] -2-methylpropionamide.  37. The compound of claim 35, wherein the compound is 2-amino-N- [1- (R) -benzyloxymethyl-2- (2-methyl-3-oxo-3- (S) -pyridin-2-ylmethyl- 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-oxoethyl] -2-methylpropionamide.  38. The compound according to clause 34, representing a diastereomeric mixture of 2-amino-N {1 (R) - (3-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (R, S) -pyridin-2 -ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo- [4,3-c] pyridyl-5-yl] ethyl} -2-methylpropionamide.  39. The compound of claim 38, wherein the compound is 2-amino-N {1- (R) - (3-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (R) -pyridin-2 -ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide.  40. The compound of claim 38, wherein the compound is 2-amino-N {1- (R) - (3-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (S) -pyridin-2 -ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide.  41. The compound according to clause 34, which is a diastereomeric mixture of 2-amino-N {1- (R) - (4-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (R, S) -pyridine -2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide.  42. The compound according to paragraph 41, where the compound is 2-amino-N {1- (R) - (4-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (R) -pyridin-2 -ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide.  43. The compound according to paragraph 41, where the compound is 2-amino-N {1- (R) - (4-chlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3- (S) -pyridin-2 -ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide.  44. The compound according to clause 34, which is a diastereomeric mixture of 2-amino-N- {1- (R) - (2,4-dichlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R, S ) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2 methyl propionamide.  45. The compound of claim 44, wherein the compound is 2-amino-N- {1- (R) - (2,4-dichlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R) - pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide .  46. The compound of claim 44, wherein the compound is 2-amino-N- {1- (R) - (2,4-dichlorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (S) - pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide .  47. The compound according to clause 34, which is a diastereomeric mixture of 2-amino-N- {1- (R) - (4-chlorothiophen-2-ylmethoxymethyl) -2-oxo-2- [3-oxo-3- (R , S) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7) -hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl } -2-methylpropionamide.  48. The compound of claim 47, wherein the compound is 2-amino-N- {1- (R) - (4-chlorothiophen-2-ylmethoxymethyl) -2-oxo-2- [3-oxo-3a- (R ) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2 methyl propionamide.  49. The compound of claim 47, wherein the compound is 2-amino-N- {1- (R) - (4-chlorothiophen-2-ylmethoxymethyl) -2-oxo-2- [3-oxo-3- (S ) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo- [4,3-c] pyridin-5-yl] ethyl} - 2-methylpropionamide.  50. The compound according to clause 34, which is a diastereomeric mixture of 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R, S ) -pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2 methyl propionamide.  51. The compound of claim 50, wherein the compound is 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (R) - pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide .  52. The compound of claim 50, wherein the compound is 2-amino-N- {1- (R) - (2,4-difluorobenzyloxymethyl) -2-oxo-2- [3-oxo-3a- (S) - pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl] ethyl} -2-methylpropionamide . 53. The compound according to claim 6, having the formula

racemic-diastereomeric mixtures and optical isomers of these compounds,
where R ¹ is —CH ₂ phenyl, R ² is methyl and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ phenyl, R ² is ethyl and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ phenyl; R ² is —CH ₂ —CF _3; and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ -4-fluorophenyl, R ² is methyl and R ³ is —CH ₂ —O — CH ₂ phenyl;
R ¹ is —CH ₂ phenyl, R ² is tert-butyl, and R ³ is —CH ₂ —O — CH ₂ phenyl or
R ¹ is —CH ₂ phenyl, R ² is methyl, and R ³ is —CH ₂ —O — CH ₂ —3,4-difluorophenyl.  54. The compound according to item 53, which is a diastereomeric mixture of 2-amino-N- [2-3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7 -hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) - (3,4-difluorobenzyloxymethyl) -2-oxoethyl] -2-methylpropionamide.  55. The compound of claim 54, wherein the compound is 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) - (3,4-difluorobenzyloxymethyl) -2-oxoethyl] -2-methylpropionamide.  56. The compound of claim 54, wherein the compound is 2-amino-N- [2- (3- (S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (R) - (3,4-difluorobenzyloxymethyl) -2-oxoethyl] -2-methyl-propionamide. 57. The compound of claim 25, wherein R ¹ is —CH ₂ phenyl; R ² represents hydrogen or methyl and R ³ represents —CH ₂ —O — CH ₂ phenyl.  58. The pharmaceutical composition used to enhance the endogenous formation or release of growth hormone in humans or animals, containing an inert carrier and an effective amount of a compound according to claim 1.  59. A method of increasing levels of endogenous growth hormone in a human or animal, which comprises administering to such a human or animal an effective amount of a compound according to claim 1.  60. The method according to § 59, where the growth hormone is IGF-1.  61. A method of treating or preventing diseases or conditions associated with growth hormone deficiency, comprising administering to a person or animal in need of such treatment or prevention, the compound of claim 1 in an effective amount, in free form or in combination with additives.  62. The method of claim 61, wherein the disease is osteoporosis.  63. The method of claim 61, wherein the disease or condition is chronic heart failure, weakness associated with aging or obesity.  64. The method according to 61, where the disease or condition is a protein catabolic reaction after extensive surgery, cachexia and protein loss caused by a chronic disease, wounds and burns in patients or patients who underwent extensive surgery.  65. The method of claim 61, wherein the disease or condition is a weakening of muscle strength, mobility, change in skin thickness, metabolic homeostasis, or renal homeostasis.  66. The method of claim 62, wherein the compound of claim 1 is administered in combination with a bisphosphonate compound.  67. The method of claim 66, wherein the bisphosphonate compound is alendronate. 68. The method of claim 62, wherein the compound of claim 1 is administered in combination with estrogen or Premarin ^® and, optionally, progesterone.  69. A method of treating osteoporosis according to claim 62, wherein the compound of claim 1 is administered in combination with calcitonin.  70. A method of treating osteoporosis according to claim 62, wherein the compound of claim 1 is administered in combination with an estrogen agonist or antagonist.  71. The method according to item 70, where the estrogen agonist or antagonist is tamoxifen, droloxifene, raloxifene or idoxifen.  72. The method of claim 63, wherein the disease or condition is chronic heart failure.  73. The method of claim 63, wherein the disease or condition is a weakness associated with aging.  74. The method of claim 64, wherein the disease or condition requires accelerated recovery of patients undergoing extensive surgery.  75. The method according to item 64, where the disease or condition requires accelerating the healing of bone fractures.  76. The method of claim 64, wherein the disease or condition requires an increase in muscle mass.  77. A method for treating osteoporosis according to claim 66, wherein the bisphosphonate compound is ibandronate. 78. The method of claim 70, wherein the estrogen agonist or antagonist is
cis-6- (4-fluorophenyl) -5- [4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
(-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
cis-6-phenyl-5- [4- (2-pyrrolidi-1-ylethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;
cis-1- [6-pyrrolidinoethoxy-3-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1- (4-pyrrolidinoethoxyphenyl) -2- (4-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol or
1- (4-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.  79. The method of claim 61, wherein the disease or condition is stunted growth of children with growth hormone deficiency.  80. The method of claim 61, wherein the disease or condition is sleep disturbance. 81. The compound of the formula

racemic-diastereomeric mixtures, optical isomers of these compounds and their pharmaceutically acceptable salts,
where e is 0 or 1;
n and w are each equal to 1;
R ¹ is hydrogen, (CH ₂ ) _t —A ¹ , where t is 0, 1 or 2;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, wherein the alkyl group in the definition of R ^{2 is} optionally substituted with CF ₃ ;
And ¹ in each case denotes a phenyl or completely unsaturated 4 to 8 membered ring, optionally having 1 to 2 heteroatoms independently selected from the group consisting of sulfur and nitrogen, or a bicyclic ring system consisting of a fully unsaturated 5 or 6 membered ring optionally having 1 to 2 heteroatoms represented by nitrogen;
A ¹ in each case is independently, optionally substituted in one or optionally both rings, if A ¹ is a bicyclic ring system and has up to two substituents, each substituent is independently selected from the group consisting of F, Cl, Br, OCF ₃ , (C ₁ - C ₆ ) alkyl, phenyl. 82. The compound of claim 81, wherein R ¹ is hydrogen, (CH ₂ ) _t A ¹ , and A ¹ in the definition of R ^{1 is} optionally substituted with 1 to 2 substituents independently selected from the group consisting of F, Cl, Me, and OCF ₃ . 83. The compound of claim 82, wherein e is 0; R ¹ is —CH ₂ —pyridyl, —CH ₂ thiazolyl or —CH ₂ phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of fluoro and chloro; and R ² is hydrogen, (C ₁ -C ₄ ) alkyl, where (C ₁ -C ₄ ) alkyl is optionally substituted with CF ₃ . 84. The compound of claim 83, wherein R ¹ is —CH ₂ phenyl and R ² is methyl or hydrogen.  85. The compound of claim 84, wherein the compound is a 3- (R) enantiomer.  86. The compound of claim 84, wherein the compound is a 3- (S) enantiomer. 87. The compound of formula III

racemic-diastereomeric mixtures and optical isomers of these compounds,
where Z ¹⁰⁰ is methyl, BOC, CBZ, CF ₃ C (O) -, FMOC, TROC, trityl, tosyl, CH ₃ C (O) - or optionally substituted benzyl, which is optionally substituted with methoxy, dimethoxy or nitro;
e is 0 or 1;
n and w are 1;
R ¹ is hydrogen, (CH ₃ ) _t —A ¹ , t is 0, 1 or 2;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, wherein the alkyl portion is optionally substituted with CF ₃ ;
And ¹ in each case denotes an independently phenyl or completely unsaturated 4-8 membered ring, optionally having 1 to 2 heteroatoms independently selected from the group consisting of sulfur and nitrogen, or a bicyclic ring system consisting of a fully unsaturated 5- or 6-membered a ring optionally having 1 to 2 heteroatoms represented by nitrogen,
A ¹ in each case is independently optionally substituted in one or optionally both rings, if A ¹ is a bicyclic ring system and has up to two substituents, each substituent is independently selected from the group consisting of F, Cl, Br, OCF ₃ , (C ₁ -C ₆ ) alkyl, phenyl, provided that when R ² is H and R ¹ is H, then Z ^{100 is} not BOC. 88. The compound of claim 87, wherein Z ¹⁰⁰ is BOC, methyl, benzyl, or CBZ; R ¹ is hydrogen, (CH ₂ ) _t -A ¹ in the definition of R ^{1 is} optionally substituted with 1 to 2 substituents independently selected from the group consisting of F, Cl and OCF ₃ ; R ² is hydrogen, (C ₁ -C ₄ ) alkyl, where the alkyl portion is optionally substituted with CF ₃ . 89. The compound of claim 88, wherein Z ¹⁰⁰ is BOC; w is 1; e is 0; R ¹ is —CH ₂ —pyridyl, —CH ₂ thiazolyl or —CH ₂ phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of fluoro and chloro; and R ² is hydrogen, (C ₁ -C ₄ ) alkyl, where (C ₁ -C ₄ ) alkyl in the definition of R ^{2 is} optionally substituted with CF ₃ . 90. The compound of claim 89, wherein R ¹ is —CH ₂ phenyl and R ² is methyl or hydrogen.  91. The compound of claim 90, wherein the compound is a 3- (R) enantiomer.  92. The compound of claim 90, wherein the compound is a 3- (S) enantiomer. 93. The compound of formula IV

racemic-diastereomeric mixtures and optical isomers of these compounds,
where Z ²⁰⁰ is tert-BOC, CBZ, CF ₃ C (O) -, FMOC, TROC, trityl, tosyl or optionally substituted benzyl, which is optionally substituted with methoxy, dimethoxy or nitro;
e is 0 or 1;
n and w are 1;
Y is oxygen;
R ¹ is hydrogen, (CH ₂ ) _t —A ¹ , t is 0, 1 or 2; And ¹ in each case denotes a phenyl or completely unsaturated 4 to 8 membered ring, optionally having 1 to 2 heteroatoms independently selected from the group consisting of sulfur and nitrogen, or a bicyclic ring system consisting of a fully unsaturated 5 or 6 membered ring optionally having 1 to 2 heteroatoms represented by nitrogen;
A ¹ in each case is independently, optionally substituted in one or optionally both rings, if A ¹ is a bicyclic ring system, has up to 2 substituents, each substituent is independently selected from the group consisting of F, Cl, Br, OCF ₃ , (C ₁ - C ₆ ) alkyl, phenyl;
R ² is hydrogen, (C ₁ -C ₈ ) alkyl, where the alkyl groups in the definition of R ^{2 are} optionally substituted with CF ₃ ,
R ³ is - (C ₁ -C ₅ ) alkyl-X ¹ - (C ₀ -C ₅ ) alkyl-A ¹ , where X ¹ is O, the values of A ¹ are indicated above,
R ⁴ is hydrogen;
X ⁴ is hydrogen;
R ⁶ represents

where a and b are 0;
X ⁵ and X ^5a each independently mean unsubstituted (C ₁ -C ₄ ) alkyl;
Z ¹ is a bond;
R ^{8 is} independently hydrogen. 94. The compound of claim 93, wherein e is 0; R ¹ represents —CH ₂ phenyl; R ² represents methyl or hydrogen; R ³ represents —CH ₂ —O — CH ₂ phenyl; R ⁶ represents —C (CH ₃ ) ₂ -; Z ²⁰⁰ is a BOC.

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