DE69534574T2 - Process for the preparation of substituted N- (indole-2-carbonyl) -glycine amides - Google Patents

Description

The The invention relates to a process for the preparation of glycogen phosphorylase inhibitors can be to diabetes, hyperglycemia, hypercholesterolemia, Hypertension or hypertension, hyperinsulinemia, hyperlipidemia, arteriosclerosis and myocardial ischemia in mammals to treat, and useful Intermediates.

Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes and the subsequent discovery and use of sulfonylureas (e.g., Chlorpropamide ^™ (Pfizer), Tolbutamide ^™ (Upjohn), Acetohexamid ^™ (EI Lilly), Tolazamid ^™ (Upjohn) ) and biguanides (for example, Phenformin ^™ (Ciba Geigy), Metformin ^™ (GD Searle)) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, which is necessary in about 10 of the diabetic patients in whom synthetic hypoglycemic agents are ineffective (type I diabetes, insulin-dependent diabetes mellitus), is required to require several daily dosages, usually by self-injection. The determination of the appropriate dosage of insulin requires frequent estimation of the level of sugar in the urine or in the blood. Administration of an overdose of insulin causes hypoglycemia with effects ranging from mild abnormalities in blood glucose levels to coma or even death. The treatment of non-insulin-dependent diabetes mellitus (Type II diabetes, NIDDM) is usually a combination of diet, exercise, oral agents, for example, sulfonylureas and, in more severe cases, insulin. However, the clinically available hypoglycemic agents may have other side effects that limit their use. Where one of these remedies can fail in one individual case, another can succeed. Therefore, there is a continuing need for hypoglycemic agents that have fewer side effects and succeed where others fail.

atherosclerosis, A disease of the arteries, is the main cause of death in the United States and Western Europe recognized. The pathological Consequence leading to atherosclerosis and heart disease is known. The earliest Stage in this episode is the formation of "fatty streaks" in the main artery, in the coronary and cerebral arteries and in the aorta. These lesions are colored yellow due to lipid deposits, which are mainly within of smooth muscle cells and in macrophages of the inner layer of Arteries and aorta finds. Furthermore It is postulated that most of it is found within the fatty streaks In turn, cholesterol gives rise to the development of "fibrous plaque," which consists of accumulated internal smooth muscle cells, loaded with lipid and wrapped with extracellular Lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous Cap, which has a deeper deposit of cell debris and extracellular lipid covered. The lipid is mainly free and esterified cholesterol. The fibrous plaque forms slowly and is likely to become calcified and necrotic over time and proceed to the "complicated Lesions ", which is used for arterial occlusion and tendencies to mural thrombosis and arterial muscular spasm, which characterize advanced atherosclerosis, are responsible.

epidemiological Studies have clearly hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) Atherosclerosis detected. In recent years, leading physicians again the lowering of plasma cholesterol levels and in particular low density lipoprotein cholesterol, as an essential step in the prevention of CVD highlighted. The upper bounds of "normal" are now considered significant less known than previously recognized. The result is now large sections of the population of the western world as having a particularly high risk recognized. Such independent Close risk factors Glucose intolerance, left ventricular hypertrophy, hypertension or hypertension and male Gender. cardiovascular Disease is especially prevalent among diabetics, at least partly due to the existence of several independent risk factors in this Population. Successful treatment of hyperlipidemia in the population in general and in diabetics in particular is therefore of special medical significance.

hypertension or hypertension (or hypertension) is a condition that is in of the human population as a secondary symptom of various others Diseases such as renal arteriostenosis, pheochromocytoma or endocrine Diseases, occurs. However, hypertension or hypertension also evident in many patients in whom the causative Pathogen or the disease is unknown. Although such "essential" hypertension or Hypertension often associated with disorders such as obesity, diabetes and hypertriglyceridemia is, the relationship between these diseases has not been clarified. In addition, show Many patients experience the symptoms of high blood pressure in complete absence any other hallmark of a disease or disorder.

It is known that hypertension or high blood pressure directly to heart failure, Kidney failure and stroke (brain hemorrhage) can result. These states are able to cause the death of the patient in a short time. Hypertension or hypertension can also contribute to the development of Arteriosclerosis and heart disease. These conditions weaken the situation Patients gradually and can in the longer term Lead death.

The exact cause of essential hypertension or hypertension is unknown although accepted by a variety of factors will make them contribute to the onset of the disease. Under such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin, aldosterone system), excessively salt and water, due of renal failure, wall thickening and hypertrophy of the vasculature the resulting, limited blood vessels and genetic factors.

The Treatment of essential hypertension or hypertension was considering the preceding factors. Thus, a broader Range of beta-blockers, vasoconstrictors, angiotensin-converting enzyme inhibitors and the like, and marketed as antihypertensives. The treatment of hypertension or hypertension while using These compounds have helped prevent immediate Death, such as heart failure, kidney failure and brain hemorrhage; proved helpful. However, the development of atherosclerosis or heart disease remains due to hypertension or hypertension over a long period of time Problem. This implies that although high blood pressure is diminished which is underlying essential hypertension or hypertension Cause does not respond to this treatment.

hypertension or hypertension is elevated with Blood insulin levels, a condition known as hyperinsulinemia is connected. Insulin, a peptide hormone whose primary effect glucose utilization, protein synthesis and formation and storage promotes neutral lipids, also works to increase vascular cell growth to promote and, among other things, to increase renal sodium retention. These latter functions can are performed without affecting glucose levels and are considered causes Hypertension or hypertension known. The peripheral vasculature growth may cause, for example, constriction of peripheral capillaries, while Sodium retention increases blood volume. Thus, lowering of Insulin levels in hyperinsulinemias abnormal vascular Growth and renal sodium retention, caused by high insulin levels, prevent hypertension or hypertension.

cardiac Hypertrophy is a major risk factor in development from sudden Death, heart attack and heart failure. These cardiac events are at least in part due to susceptibility to myocardial injury ischemia and reperfusion in outpatients and perioperative patients Intervene can occur due. It gives a hitherto unfulfilled medical need to address adverse myocardial perioperative events, especially perioperative myocardial infarction, to prevent or minimize. Both non-cardiac and cardiac surgery are essential Risks for Heart attack or death associated. To the 7 million patients, at those who have had a non-cardiac intervention are treated as having considered a risk, with the event of perioperative Death and severe cardiac complications is in some cases at a level of 20-25%. Furthermore is estimated, that of the 400,000 patients who had a coronary per annum Bypass surgery is performed at 5% perioperative myocardial infarction and 1-2% Death occurs. There is currently no drug therapy in this area, the damage of Cardiac tissue from perioperative myocardial ischemia diminished or resistance of the heart against ischemic Episodes increased. Such therapy is considered a life-saving and hospitalization decreasing the quality of life increasing and reducing the care costs of at-risk patients.

The hepatic glucose production is an important target in NIDDM therapy. The liver is the main regulator of plasma glucose levels in postabsorptive (fasting) condition, and the rate of hepatic glucose production in NIDDM patients is significantly increased, relative to the norma len Individuals. Similarly, in the postprandial (food recorded) Condition where the liver is a relatively lower Role in total plasma glucose supply plays the hepatic Glucose production abnormally high in NIDDM patients.

Glycogenolysis is an important target in interrupting hepatic glucose production. The liver produces glucose by glycogenolysis (degradation of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Various evidence suggests that glycogenolysis can provide a significant contribution to hepatic glucose output in NIDDM. First, in the normal postabsorptive patient, up to 75% of hepatic glucose production is Result of glycogenolysis estimated. Second, patients with liver glycogen storage disease, including Hers's disease (glycogen phosphorylase deficiency), have episodic hypoglycemia. These observations suggest that glycogenolysis may be a significant process for hepatic glucose production.

glycogenolysis gets into liver, muscle and brain through tissue-specific isoforms catalyzed by the enzyme glycogen phosphorylase. This enzyme splits the glycogen macromolecule, to release glucose-1-phosphate and a new truncated glycogen macromolecule. Two types of glycogen phosphorylase inhibitors have been reported so far: Glucose and glucose analogues [Martin, J.L. et al. Biochemistry 1991, 30, 10101] and caffeine and other purine analogues [Kasvinsky, P.J. et al. J. Biol. Chem. 1978, 253, 3343-3351 and 9102-9106]. Of these Compounds and glycogen phosphorylase inhibitors were generally postulated that they are used to treat NIDDM by lowering the hepatic Glucose production and lowering of glycemia are potentially useful. [Blundell, T.B. et al. Diabetologia 1992, 35, Suppl. 2, 569-576 and Martin et al., Biochemistry 1991, 30, 10101].

The / The for the myocardial injury responsible mechanism (s) after ischemia and Reperfusion is / are not fully understood. It has been reported (M. F. Allard, et al., Am. J. Physiol. 267, H66-H74, 1994) that "pre-ischemic glycogen reduction ... with improved post-ischemic, left ventricular, functional recovery associated with hypertrophied rat heart is ".

Even though Thus, there are a variety of therapies for hyperglycemia, hypercholesterolemia, hypertension or Hypertension, hyperinsulinemia, hyperlipidemia, Atherosclerosis and myocardial ischemia exist, there is a continued Need and continued search in this field for alternative Therapies.

BRIEF SUMMARY OF THE INVENTION

umfassend Umsetzen einer Verbindung der Formel II

mit einer Verbindung der Formel III

worin
die Punktlinie (---) eine mögliche Bindung darstellt;
A -C(H)=, -C((C₁-C₄)Alkyl)=, -C(Halogen)= oder -N= darstellt, wenn die Punktlinie (---) eine Bindung darstellt oder A Methylen oder -CH((C₁-C₄)Alkyl)- darstellt, wenn die Punktlinie (---) keine Bindung darstellt;
R₁, R₁₀ oder R₁₁ jeweils unabhängig voneinander H, Halogen, Cyano, 4-, 6- oder 7-Nitro, (C₁-C₄)Alkyl, (C₁-C₄)Alkoxy, Fluormethyl, Difluormethyl oder Trifluormethyl darstellen;
R² H darstellt;
R³ H oder (C₁-C₅)Alkyl darstellt;
R₄ H, Methyl, Ethyl, n-Propyl, Hydroxy(C₁-C₃)alkyl, (C₁-C₃)Alkoxy (C₁-C₃)alkyl, Phenyl(C₁-C₄)alkyl, Phenylhydroxy(C₁-C₄)-alkyl, (Phenyl)((C₁-C₄)alkoxy) (C₁-C₄)alkyl, Thien-2- oder -3-yl(C₁-C₄)alkyl oder Fur-2- oder -3-yl(C₁-C₄)alkyl darstellt, wobei die Ringe R₄ unabhängig voneinander am Kohlenstoffatom mit H, Halogen, (C₁-C₄)Alkyl, (C₁-C₄)Alkoxy, Trifluormethyl, Hydroxy, Amino, Cyano oder 4,5-Dihydro-1H-imidazol-2-yl mono-, di- oder trisubstituiert sind, oder
R₄ Pyrid-2-, -3- oder -4-yl(C₁-C₄)alkyl, Thiazol-2-, -4- oder -5-yl(C₁-C₄)alkyl, Imidazol-2-, -4- oder -5-yl(C₁-C₄)alkyl, Pyrrol-2- oder -3-yl(C₁-C₄)alkyl, Oxazol-2-, -4- oder -5-yl(C₁-C₄)alkyl, Pyrazol-3-, -4- oder -5-yl(C₁-C₄)alkyl, Isoxazol-3-, -4- oder -5-yl(C₁-C₄)alkyl, Isothiazol-3-, -4- oder -5-yl(C₁-C₄)alkyl, Pyridazin-3- oder -4-yl (C₁-C₄)alkyl, Pyrimidin-2-, -4-, -5- oder -6-yl(C₁-C₄)alkyl, Pyrazin-2- oder -3-yl (C₁-C₄)alkyl, 1,3,5-Triazin-2-yl(C₁-C₄)alkyl oder Indol-2-(C₁-C₄)alkyl darstellt, wobei die vorangehenden Heterocyclen R₄ gegebenenfalls unabhängig voneinander mit Halogen, Trifluormethyl, (C₁-C₄)Alkyl, (C₁-C₄)Alkoxy, Amino, Hydroxy oder Cyano mono- oder disubstituiert sind und die Substituenten an Kohlenstoff gebunden sind; oder
R₄ R₁₅-Carbonyloxymethyl darstellt, wobei R₁₅ Phenyl, Thiazolyl, Imidazolyl, 1H-Indolyl, Furyl, Pyrrolyl, Oxazolyl, Pyrazolyl, Isoxazolyl, Isothiazolyl, Pyridyl, Pyridazinyl, Pyrimidinyl, Pyrazinyl oder 1,3,5-Triazinyl darstellt und wobei die vorangehenden Ringe R₁₅ gegebenenfalls unabhängig voneinander mit Halogen, Amino, Hydroxy, (C₁-C₄)Alkyl, (C₁-C₄)Alkoxy oder Trifluormethyl mono- oder disubstituiert sind und die Mono- oder Disubstituenten an Kohlenstoff gebunden sind;
R₅ H darstellt;
R₆ Carboxy, (C₁-C₈)Alkoxycarbonyl, Benzyloxycarbonyl, C(O)NR₈R₉ oder C(O)R₁₂ darstellt,
worin
R₈ H, (C₁-C₆)Alkyl, Cyclo(C₃-C₆)alkyl, Cyclo(C₃-C₆)alkyl(C₁-C₅)alkyl, Hydroxy oder (C₁-C₈)Alkoxy darstellt und
R₉ H, Cyclo(C₃-C₈)alkyl, Cyclo(C₃-C₈)alkyl (C₁-C₅)alkyl, Cyclo(C₄-C₇)alkenyl, Cyclo(C₃-C₇)alkyl(C₁-C₅)alkoxy, Cyclo(C₃-C₇)alkyloxy, Hydroxy, Methylen-perfluoriertes (C₁-C₈)Alkyl, Phenyl oder einen Heterocyclus darstellt, wobei der Heterocyclus Pyridyl, Furyl, Pyrrolyl, Pyrrolidinyl, Oxazolyl, Thiazolyl, Imidazolyl, Pyrazolyl, Pyrazolinyl, Pyrazolidinyl, Isoxazolyl, Isothiazolyl, Pyranyl, Pyradinyl, Piperidinyl, Morpholinyl, Pyridazinyl, Pyrimidinyl, Pyrazinyl, Piperazinyl, 1,3,5-Triazinyl, Benzothiazolyl, Benzoxazolyl, Benzimidazolyl, Thiochromanyl oder Tetrahydrobenzothiazolyl darstellt, wobei die heterocyclischen Ringe Kohlenstoff-Stickstoff-gebunden sind, oder
R₉(C₁-C₆)Alkyl oder (C₁-C₈)Alkoxy darstellt, wobei das (C₁-C₆)Alkyl oder (C₁-C₈)Alkoxy gegebenenfalls mit Cyclo(C₄-C₇)alken-1-yl, Phenyl, Thienyl, Pyridyl, Furyl, Pyrrolyl, Pyrrolidinyl, Oxazolyl, Thiazolyl, Imidazolyl, Pyrazolyl, Pyrazolinyl, Pyrazolidinyl, Isoxazolyl, Isothiazolyl, Pyranyl, Piperidinyl, Morpholinyl, Thiomorpholinyl, 1-Oxothiomorpholinyl, 1,1-Dioxothiomorpholinyl, Pyridazinyl, Pyri midinyl, Pyrazinyl, Piperazinyl, 1,3,5-Triazinyl oder Indolyl monosubstituiert ist und wobei das (C₁-C₆)Alkyl oder (C₁-C₈)Alkoxy gegebenenfalls zusätzlich unabhängig voneinander mit Halogen, Hydroxy, (C₁-C₅)Alkoxy, Amino, Mono-N- oder Di-N,N-(C₁-C₅)alkylamino, Cyano, Carboxy oder (C₁-C₄)Alkoxycarbonyl mono- oder disubstituiert sind; und
wobei die Ringe R₉ gegebenenfalls unabhängig voneinander am Kohlenstoffatom mit Halogen, (C₁-C₄)Alkyl, (C₁-C₄)Alkoxy, Hydroxy, Hydroxy (C₁-C₄)alkyl, Amino(C₁-C₄)alkyl , Mono-N- oder Di-N,N-(C₁-C₄)alkylamino (C₁-C₄)alkyl, (C₁-C₄)Alkoxy (C₁-C₄)alkyl, Amino, Mono-N- oder Di-N,N- (C₁-C₄)alkylamino, Cyano, Carboxy, (C₁-C₅)Alkoxycarbonyl, Carbamoyl, Formyl oder Trifluormethyl mono- oder disubstituiert sind und die Ringe R₉ gegebenenfalls zusätzlich unabhängig voneinander mit (C₁-C₅)Alkyl oder Halogen mono- oder disubstituiert sein können;
mit der Maßgabe, dass an jedem Heterocyclus R₉ kein quaternisiertes Stickstoffatom eingeschlossen ist;
R₁₂ Morpholino, Thiomorpholino, 1-Oxothiomorpholino, 1,1-Dioxothiomorpholino, Thiazolidin-3-yl, 1-Oxothiazolidin-3-yl, 1,1-Dioxothiazolidin-3-yl, Pyrrolidin-1-yl, Piperidin-1-yl, Piperazin-1-yl, Piperazin-4-yl, Azetidin-1-yl, 1,2-Oxazinan-2-yl, Pyrazolidin-1-yl, Isoxazolidin-2-yl, Isothiazolidin-2-yl, 1,2-Oxazetidin-2-yl, Oxazolidin-3-yl, 3,4-Dihydroisochinolin-2-yl, 1,3-Dihydroisoindol-2-yl, 3,4-Dihydro-2H-chinol-1-yl, 2,3-Dihydro-benzo[1,4]oxazin-4-yl, 2,3-Dihydrobenzo[1,4]-thiazin-4-yl, 3,4-Dihydro-2H-chinoxalin-1-yl, 3,4-Dihydro-benzo[c][1,2]oxazin-1-yl, 1,4-Dihydrobenzo[d][1,2]-oxazin-3-yl, 3,4-Dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-Benzo[d]isoxazol-2-yl, 3H-Benzo[c]isoxazol-1-yl oder Azepan-1-yl darstellt;
wobei die Ringe R₁₂ gegebenenfalls unabhängig voneinander mit Halogen, (C₁-C₅)Alkyl, (C₁-C₅)Alkoxy, Hydroxy, Amino, Mono-N- oder Di-N,N-(C₁-C₅)alkylamino, Formyl, Carboxy, Carbamoyl, Mono-N- oder Di-N,N-(C₁-C₅)alkylcarbamoyl, (C₁-C₆)Alkoxy(C₁-C₃)alkoxy, (C₁-C₅)Alkoxycarbonyl, Benzyloxycarbonyl, (C₁-C₅)Alkoxycarbonyl(C₁-C₅)alkyl, (C₁-C₄)Alkoxycarbonylamino, Carboxy(C₁-C₅)alkyl, Carbamoyl(C₁-C₅)alkyl, Mono-N- oder Di-N,N-(C₁-C₅)alkylcarbamoyl(C₁-C₅)alkyl, Hydroxy(C₁-C₅)alkyl, (C₁-C₄)Alkoxy(C₁-C₄)alkyl, Amino(C₁-C₄)alkyl, Mono-N- oder Di-N,N-(C₁-C₄)-alkylamino(C₁-C₄)alkyl, Oxo, Hydroxyimino oder (C₁-C₆)Alkoxyimino mono-, di- oder trisubstituiert sind und wobei nicht mehr als zwei Substituenten aus Oxo, Hydroxyimino oder (C₁-C₆)Alkoxyimino ausgewählt sind und Oxo, Hydroxyimino oder (C₁-C₆)Alkoxyimino sich am nichtaromatischen Kohlenstoff befinden; und
wobei die Ringe R₁₂ gegebenenfalls zusätzlich unabhängig voneinander mit (C₁-C₅)Alkyl oder Halogen mono- oder disubstituiert sind;
mit der Maßgabe, dass wenn R₆ (C₁-C₅)Alkoxycarbonyl oder Benzyloxycarbonyl darstellt, R₁ dann 5-Halogen, 5-(C₁-C₄)Alkyl oder 5-Cyano darstellt und R₄ (Phenyl)(hydroxy)(C₁-C₄)alkyl, (Phenyl) ((C₁-C₄)alkoxy) (C₁-C₄)alkyl, Hydroxymethyl oder Ar(C₁-C₂)Alkyl darstellt, wobei Ar Thien-2- oder -3-yl, Fur-2- oder -3-yl oder Phenyl darstellt, wobei das Ar gegebenenfalls unabhängig voneinander mit Halogen mono- oder disubstituiert ist,
mit der Maßgabe, dass, wenn R₁ und R₁₀ und R₁₁ H darstellen, R₄ nicht Imidazol-4-ylmethyl, 2-Phenylethyl oder 2-Hydroxy-2-phenylethyl darstellt;
mit der Maßgabe, dass, wenn sowohl R₈ als auch R₉ n-Pentyl darstellen, R₁ 5-Chlor, 5-Brom, 5-Cyano, 5(C₁-C₅)Alkyl, 5(C₁-C₅)Alkoxy oder Trifluormethyl darstellt; mit der Maßgabe, dass, wenn R₁₂ 3,4-Dihydroisochinol-2-yl darstellt, das 3,4-Dihydroisochinol-2-yl nicht mit Carboxy(C₁-C₄)alkyl substituiert ist; mit der Maßgabe, dass, wenn R₈ H darstellt und R₉ (C₁-C₆)Alkyl darstellt, R₉ nicht mit Carboxy oder (C₁-Cq)Alkoxycarbonyl an dem Kohlenstoffatom, an das das Stickstoffatom N von NHR₉ gebunden ist, substituiert ist; und
mit der Maßgabe, dass, wenn R₆ Carboxy darstellt und R₁, R₁₀, R₁₁ und R₅ alle H darstellen, R₄ dann nicht Benzyl, H, (Phenyl)(hydroxy)methyl, Methyl, Ethyl oder n-Propyl darstellt.The invention relates to a process for preparing a compound of the formula I.

comprising reacting a compound of formula II

with a compound of formula III

wherein
the dotted line (---) represents a possible bond;
A is -C (H) =, -C ((C ₁ -C ₄ ) alkyl) =, -C (halo) = or -N = when the dotted line (---) is a bond or A is methylene or CH ((C ₁ -C ₄ ) alkyl) - when the dotted line (---) is not a bond;
R ₁ , R ₁₀ or R _{11 are} each independently H, halo, cyano, 4-, 6- or 7-nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl group;
R ^{2 represents} H;
R ^{3 is} H or (C ₁ -C ₅ ) alkyl;
R _{4 is} H, methyl, ethyl, n-propyl, hydroxy (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl, phenyl (C ₁ -C ₄ ) alkyl, phenylhydroxy (C ₁ -C ₄ ) -alkyl, (phenyl) ((C ₁ -C ₄ ) alkoxy) (C ₁ -C ₄ ) alkyl, thien-2 or 3-yl (C ₁ -C ₄ ) alkyl or Fur-2 or 3-yl (C ₁ -C ₄ ) alkyl, wherein the rings R ₄ independently of one another on the carbon atom with H, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy , Trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl mono-, di- or trisubstituted, or
R _{4 is} pyrid-2-, -3- or -4-yl (C ₁ -C ₄ ) -alkyl, thiazole-2-, -4- or -5-yl (C ₁ -C ₄ ) -alkyl, imidazole-2- , -4- or -5-yl (C ₁ -C ₄ ) alkyl, pyrrole-2 or 3-yl (C ₁ -C ₄ ) alkyl, oxazole-2, ₄ or 5-yl ( C ₁ -C ₄ ) alkyl, pyrazole-3, ₄ , or 5-yl (C ₁ -C ₄ ) alkyl, isoxazol-3, ₄ , or 5-yl (C ₁ -C ₄ ) alkyl, isothiazole-3, -4- or -5-yl (C ₁ -C ₄ ) -alkyl, pyridazine-3 or -4-yl (C ₁ -C ₄ ) -alkyl, pyrimidine-2, -4- , -5- or -6-yl (C ₁ -C ₄ ) alkyl, pyrazine-2 or 3-yl (C ₁ -C ₄ ) alkyl, 1,3,5-triazin-2-yl (C ₁ C ₄ ) represents alkyl or indole-2- (C ₁ -C ₄ ) -alkyl, where the preceding heterocycles R ₄ optionally independently of one another with halogen, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, amino, hydroxy or cyano mono- or disubstituted and the substituents are attached to carbon; or
R _{4 is} R ₁₅ -carbonyloxymethyl, wherein R _{15 is} phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl, and wherein the preceding rings R _{15 are} optionally independently of one another mono- or disubstituted by halogen, amino, hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or trifluoromethyl and the mono- or disubstituents are bonded to carbon ;
R _{5 represents} H;
R _{6 represents} carboxy, (C ₁ -C ₈ ) alkoxycarbonyl, benzyloxycarbonyl, C (O) NR ₈ R ₉ or C (O) R ₁₂ ,
wherein
R _{8 is} H, (C ₁ -C ₆ ) alkyl, cyclo (C ₃ -C ₆ ) alkyl, cyclo (C ₃ -C ₆ ) alkyl (C ₁ -C ₅ ) alkyl, hydroxy or (C ₁ -C ₈ ) Alkoxy represents and
R ₉ H, cyclo (C ₃ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl (C ₁ -C ₅ ) alkyl, cyclo (C ₄ -C ₇ ) alkenyl, cyclo (C ₃ -C ₇ ) alkyl (C ₁ -C ₅ ) alkoxy, cyclo (C ₃ -C ₇ ) alkyloxy, hydroxy, methylene perfluorinated (C ₁ -C ₈ ) alkyl, phenyl or a heterocycle, wherein the heterocycle is pyridyl, furyl, pyrrolyl, pyrrolidinyl , Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyradinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein the heterocyclic rings are carbon-nitrogen bonded, or
R _{9 is} (C ₁ -C ₆ ) alkyl or (C ₁ -C ₈ ) alkoxy, where the (C ₁ -C ₆ ) alkyl or (C ₁ -C ₈ ) alkoxy is optionally substituted by cyclo (C ₄ -C ₇ ) alken-1-yl, phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1- Dioxothiomorpholinyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl or indolyl monosubstituted and wherein the (C ₁ -C ₆ ) alkyl or (C ₁ -C ₈ ) alkoxy optionally additionally with independently halogen, hydroxy , (C ₁ -C ₅ ) alkoxy, amino, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylamino, cyano, carboxy or (C ₁ -C ₄ ) alkoxycarbonyl mono- or disubstituted; and
where the rings R ₉ optionally independently of one another on the carbon atom with halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, hydroxy, hydroxy (C ₁ -C ₄ ) alkyl, amino (C ₁ -C ₄ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) -alkylamino (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy (C ₁ -C ₄ ) -alkyl, amino, Mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino, cyano, carboxy, (C ₁ -C ₅ ) alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl mono- or disubstituted and the rings R ₉ optionally in addition independently of one another may be mono- or disubstituted by (C ₁ -C ₅ ) alkyl or halogen;
with the proviso that no quaternized nitrogen atom is included in each heterocycle R ₉ ;
R ₁₂ morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidine-1 yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1, 2-oxazetidin-2-yl, oxazoles din-3-yl, 3,4-dihydroisoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl, 2,3-dihydrobenzo [1, 4] oxazin-4-yl, 2,3-dihydrobenzo [1,4] thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo [c] [ 1,2] oxazin-1-yl, 1,4-dihydrobenzo [d] [1,2] oxazin-3-yl, 3,4-dihydro-benzo [e] [1,2] oxazine-2 yl, 3H-benzo [d] isoxazol-2-yl, 3H-benzo [c] isoxazol-1-yl or azepan-1-yl;
where the rings R _{12 are} optionally independently of each other halogen, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy, hydroxy, amino, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₅ ) -alkylcarbamoyl, (C ₁ -C ₆ ) -alkoxy (C ₁ -C ₃ ) -alkoxy, (C ₁ - C ₅ ) alkoxycarbonyl, benzyloxycarbonyl, (C ₁ -C ₅ ) alkoxycarbonyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonylamino, carboxy (C ₁ -C ₅ ) alkyl, carbamoyl (C ₁ -C ₅ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₅ ) -alkylcarbamoyl (C ₁ -C ₅ ) -alkyl, hydroxy (C ₁ -C ₅ ) -alkyl, (C ₁ -C ₄ ) -alkoxy ( C ₁ -C ₄ ) alkyl, amino (C ₁ -C ₄ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) -alkylamino (C ₁ -C ₄ ) alkyl, oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino are mono-, di- or trisubstituted and wherein not more than two substituents of oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino are selected and oxo, hydroxyimino or (C ₁ -C ₆ ) Alkoxyimino are on non-aromatic carbon; and
wherein the rings R _{12 are} optionally additionally mono- or disubstituted independently with (C ₁ -C ₅ ) alkyl or halogen;
with the proviso that when R _{6 is} (C ₁ -C ₅ ) alkoxycarbonyl or benzyloxycarbonyl then R ₁ is 5-halo, 5- (C ₁ -C ₄ ) alkyl or 5-cyano and R _{4 is} (phenyl) (hydroxy ) (C ₁ -C ₄ ) alkyl, (phenyl) ((C ₁ -C ₄ ) alkoxy) (C ₁ -C ₄ ) alkyl, hydroxymethyl or Ar (C ₁ -C ₂ ) alkyl, wherein Ar is thien-2 - or -3-yl, fur-2- or -3-yl or phenyl, wherein the Ar is optionally mono- or disubstituted independently of halogen,
with the proviso that when R ₁ and R ₁₀ and R _{11 are} H, R _{4 is} not imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl;
with the proviso that when both R ₈ and R _{9 are} n-pentyl, R _{1 is} 5-chloro, 5-bromo, 5-cyano, 5 (C ₁ -C ₅ ) alkyl, 5 (C ₁ -C ₅ ) Alkoxy or trifluoromethyl; with the proviso that when R _{12 is} 3,4-dihydroisoquinol-2-yl, the 3,4-dihydroisoquinol-2-yl is not substituted with carboxy (C ₁ -C ₄ ) alkyl; with the proviso that when R _{8 is} H and R _{9 is} (C ₁ -C ₆ ) alkyl, R ₉ does not bind with carboxy or (C ₁ -Cq) alkoxycarbonyl at the carbon atom to which N of NHR _{9 is} attached is, is substituted; and
with the proviso that when R _{6 is} carboxy and R ₁ , R ₁₀ , R ₁₁ and R _{5 are} all H, then R ₄ is not benzyl, H, (phenyl) (hydroxy) methyl, methyl, ethyl or n-propyl represents.

• a) Umsetzen einer Verbindung der Formel XXIII
  
  mit geeigneten Reagenzien, um eine geeignete Schutzgruppe P_t einzuführen, zur Gewinnung einer Verbindung der Formel XXIV
  
  dann
• b) Umsetzen von Verbindungen der Formel XXIV mit einer Verbindung der Formel R₁₂H, dann
• c) Entfernung von Schutzgruppe P_t, zur Gewinnung einer Verbindung der Formel III, worin R₃, R₄, R₅ und R₁₂ wie vorstehend definiert sind.

In particular, the invention relates to a process wherein
R _{4 is} H, phenylmethyl, thien-2 or 3-ylmethyl, fur-2 or 3-ylmethyl, said rings optionally mono- or disubstituted with fluorine; and
R _{6 represents} C (O) R ₁₂ ; wherein R _{12 is} thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl, 1,2-oxazinane 2-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl or oxazolidin-3-yl; where the rings R _{12 are} optionally independently of each other halogen, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy, hydroxy, amino, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₅ ) -alkylcarbamoyl, (C ₁ -C ₅ ) -alkoxycarbonyl, hydroxy (C ₁ -C ₅ ) -alkyl, amino- (C ₁ -C ₄ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl, oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino mono - or disubstituted, with the proviso that only the heterocycles R ₁₂ thiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidine 2-yl or oxazolidin-3-yl optionally mono- or disubstituted independently with oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino; and wherein the rings R _{12 are} optionally additionally mono- or disubstituted independently with (C ₁ -C ₅ ) alkyl; and with the proviso that R _{12 is} not 2-carboxy-4-hydroxy-pyrrolidin-1-yl, 2 - ((C ₁ -C ₅ ) alkoxycarbonyl) -4-hydroxypyrrolidin-1-yl, 2-carboxypiperidine 1-yl or 2 - ((C ₁ -C ₅ ) alkoxycarbonyl) -piperidin-1-yl,
and above all, a process that continues to include the steps of

• a) reacting a compound of formula XXIII
  
  with suitable reagents to introduce a suitable protecting group P _t to obtain a compound of formula XXIV
  
  then
• b) reacting compounds of formula XXIV with a compound of formula R ₁₂ H, then
• c) removal of protective group P _t to obtain a compound of formula III wherein R ₃ , R ₄ , R ₅ and R _{12 are} as defined above.

One Another aspect of this invention relates to intermediates which for the preparation of some of the compounds of formula I are useful.

worin
R₃ H darstellt; R₄ Phenylmethyl darstellt, wobei das Phenyl gegebenenfalls mit Fluor mono- oder disubstituiert ist;
R₅ H darstellt und
R₆ C(O)R₁₂ darstellt, worin R₁₂ 3-mono-substituiertes Azetidin-1-yl, 3-mono- oder 3,4-disubstituiertes Pyrrolidin-1-yl, 3-, 4- oder 5-mono- oder disubstituiertes Piperidin-1-yl, Thiazolidin-3-yl, 1-Oxo-thiazolidin-3-yl oder 1,1-Di-oxothiazolidin-3-yl darstellt, wobei das Pyrrolidin-1-yl oder Piperidin-1-yl unabhängig voneinander mit Hydroxy, Oxo, Hydroxyimino, Amino, Mono-N- oder Di-N,N-(C₁-C₄)alkylamino, (C₁-C₅)Alkoxycarbonyl oder Carboxy mono- oder disubstituiert sind, und die Ringe R₁₂ gegebenenfalls zusätzlich unabhängig voneinander mit (C₁-C₄)Alkyl mono- oder disubstituiert sind.Thus, the invention relates to a first group of intermediate compounds of formula III

wherein
R _{3 represents} H; R _{4 is} phenylmethyl, wherein the phenyl is optionally mono- or disubstituted with fluorine;
R _{5 represents} H and
R _{6 is} C (O) R ₁₂ in which R _{12 is} 3-mono-substituted azetidin-1-yl, 3-mono- or 3,4-disubstituted pyrrolidin-1-yl, 3, 4 or 5-mono- or disubstituted piperidin-1-yl, thiazolidin-3-yl, 1-oxothiazolidin-3-yl or 1,1-di-oxothiazolidin-3-yl, wherein the pyrrolidin-1-yl or piperidin-1-yl are independently mono- or disubstituted with hydroxy, oxo, hydroxyimino, amino, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonyl or carboxy, and the rings R ₁₂ optionally additionally mono- or disubstituted independently of each other with (C ₁ -C ₄ ) alkyl.

In the above-indicated group of intermediate compounds, preferred are those in which
R _{4 is} benzyl, R _{12 is} 3-hydroxypyrrolidin-3-yl and the stereochemistry of carbon is (a) (S);
R _{4 is} benzyl, R _{12 is} 3-hydroxyazetidin-1-yl and the stereochemistry of carbon is (a) (S);
R _{4 is} benzyl, R _{12 is} 3,4-dihydroxypyrrolidin-1-yl and the stereochemistry of carbon is (a) (S);
R _{4 is} benzyl, R _{12 is} 4-hydroxypiperidin-1-yl and the stereochemistry of carbon is (a) (S);
R _{4 is} 4-fluorophenylmethyl, R _{12 is} 4-hydroxypiperidin-1-yl and the stereochemistry of carbon is (a) (S) and
R _{4 is} benzyl, R _{12 is} 3-hydroxyiminoazetidin-1-yl and the stereochemistry of carbon is (a) (S).

In a further aspect, the invention relates to a second group of intermediate compounds of formula III given above, wherein
R _{3 represents} H;
R _{4 represents} H;
R _{5 represents} H and
R _{6 is} C (O) R ₁₂ wherein R _{12 is} thiazolidin-3-yl.

In a further aspect, the invention relates to a second group of intermediate compounds of formula III given above, wherein
R _{3 represents} H;
R _{4 represents} H;
R _{5 represents} H and
R _{6 is} C (O) R ₁₂ wherein R _{12 is} 1,1-dioxothiazolidin-3-yl.

In a further aspect, the invention relates to a second group of intermediate compounds of formula III given above, wherein
R _{3 represents} H;
R _{4 represents} H;
R _{5 represents} H and
R _{6 is} C (O) R ₁₂ wherein R _{12 is} 1-oxothiazolidin-3-yl.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of glycogen phosphorylase-dependent disease or condition in a mammal by administering to the glycogen phosphorylase dependent / m Disease or condition patients suffering from the glycogen phosphorylase-dependent disease or condition-treating amount of a compound of the formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of hyperglycemia in a mammal by administering to the patient suffering from a hyperglycemia treating amount of a compound of formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of diabetes in a mammal by administration the patient suffering from diabetes of a treating amount a compound of formula I. Included in the treatment Diabetes is prevention or alleviation of long-term complications, such as neuropathy, nephropathy, Retinopathy or cataract.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of hypercholesterolemia in a mammal Administering to patients suffering from hypercholesterolemia treating amount of a compound of formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of arteriosclerosis in a mammal by administration the patient suffering from arteriosclerosis Amount of a compound of formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of hyperinsulinemia in a mammal by administering to the patient suffering from hyperinsulinemia treating amount of a compound of formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of hypertension in a mammal by administration the patient suffering from hypertension of a treating Amount of a compound of formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of hyperlipidemia in a mammal by administering to the patient suffering from hyperlipidemia treating amount of a compound of formula I.

The Glycogenphosphorylase inhibitors of the formula I can be used for a process for the treatment of myocardial ischemia in a mammal Administer to a patient at risk for perioperative myocardial ischemia injury prevent perioperative myocardial ischemic injury Amount of a compound of formula I.

The Glycogen phosphorylase inhibitors of the formula I can be used for a process for the treatment of myocardial ischemia in a mammal Administer to a patient at risk for perioperative myocardial ischemia injury prevent perioperative myocardial ischemic injury Amount of a glycogen phosphorylase inhibitor.

These The invention also relates to pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier include.

preferred Compositions can pharmaceutical compositions for the treatment of glycogen phosphorylase-dependent disorders or states in mammals lock in, the one glycogen phosphorylase-dependent disease or condition treating amount of the compound of formula I and a pharmaceutically acceptable carrier include.

The glycogen phosphorylase inhibitors of the formula I can be used for the treatment of diabetes comprising a therapeutically effective amount of a glycogen phosphorylase inhibitor of the formula I,
one or more antidiabetic agents such as insulin and insulin analogues (for example LysPro insulin), GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) -NH ₂ , sulfonylureas and analogues: chlorpropamide, glibenclamide, tolbutamide, Tolazamide, acetohexamide, glypizide ^® , glimepiride, repaglinide, meglitinide; Biguanides: metformin, phenformin, buformin, α2-antagonists and imidazolines: midaglizole, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: Linoglirid, A-4166; Glitazones: ciglitazone, pioglitazone, englitazone, troglitazone, daglitazone, BRL49653; Fatty acid oxidation inhibitors: Clomoxir, Etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243; Phosphodiesterase inhibitors: L-386,398; Lipid-lowering agents: benfluorex; Anti-fogging agent: fenfluramine; Vanadate and vanadium complexes (e.g., Naglivan ^®) and Peroxovanadium complexes; Amylin antagonists; Glucagon antagonists; Gluconeogenesis inhibitors; Somatostatin analogues; Antilipolytic agents: nicotinic acid, Acipimox, WAG 994 and
optionally comprising a pharmaceutically acceptable carrier.

Glycogen phosphorylase-dependent diseases or states refer to diseases that are in whole or in part cleavage of the glycogen macromolecule by glycogen phosphorylase enzymes for the release of glucose-1-phosphate and a new shortened one glycogen molecule mediated, started or maintained. These diseases are alleviated by a decrease in glycogen phosphorylase activity or are by an increase the same. Examples include diabetes, hyperglycemia, hypercholesterolemia, hypertension or hypertension, hyperinsulinemia, hyperlipidemia, arteriosclerosis and myocardial ischemia one.

Of the Term glycogen phosphorylase inhibitor refers to any Substance or agent or any combination of substances and / or Agents that reduce the enzyme activity of glycogen phosphorylase, delay or pick up. The present known enzymatic action of glycogen phosphorylase is the Degradation of glycogen by catalysis of the reversible reaction of a glycogen macromolecule and inorganic phosphate to glucose-1-phosphate and a glycogen macromolecule containing a Glucosylrest shorter as the original one glycogen macromolecule (Forward direction glycogenolysis).

Of the The term "treatment" as used herein includes preventative (for example, prophylactic) and palliative treatment.

halogen means chlorine, bromine, iodine or fluorine.

alkyl means a straight-chain or branched saturated Hydrocarbon. examples for such alkyl groups (assuming the designated length comprises the respective example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, Pentyl, isopentyl, hexyl and isohexyl.

alkoxy represents a straight-chain or branched saturated alkyl group bound through an oxy group. Examples of such alkoxy groups (under the assumption, the designated length includes the respective example) are methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, tertiarybutoxy, Pentoxy, isopentoxy, hexoxy and isohexoxy.

Of the Term "pharmaceutical compatible anionic salt "refers refers to non-toxic anionic salts containing anions such as, but not limited to, chloride, bromide, iodide, sulfate, Bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, Citrate, gluconate, methanesulfonate and 4-toluenesulfonate.

Of the Term "pharmaceutical compatible cationic salt " non-toxic cationic salts such as (but not limited to sodium), potassium, calcium, magnesium, ammonium or protected benzathine (N, N'-di-benzylethylenediamine), Choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), Benethamine (N-benzylphenethylamine), Piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

The term "prodrug" refers to compounds which are prodrugs which, upon administration, release the drug in vivo via some chemical or physiological process (for example, a prodrug brought to physiological pH is converted to the desired drug form). Certain exemplary prodrugs release the corresponding free acid on cleavage, and such hydrolyzable ester-forming moieties of the compounds of the invention include, but are not limited to, carboxylic acid substituents (for example, R _{6 is} carboxy or R ₈ , R _9, or R ₁₂ Carboxy) in which the free hydrogen is replaced by (C ₁ -C ₄ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) - ethyl of 5 to 10 carbon atoms, alkoxycarbonyloxymethyl of 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl of 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl of 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl of 3 to 9 carbon atoms, 1- (N-alkoxycarbonyl) amino) ethyl of 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N, N- (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 ) alkylcarbamoyl (C ₁ -C ₂ ) alkyl and Piperidino, pyrrolidino or morpholino (C ₂ -C ₃ ) alkyl.

Other exemplary prodrugs release an alcohol of the formula I in which the free hydrogen of the hydroxy substituent (for example R ₈ , R ₉ or R ₁₂ contains hydroxy) is represented by (C ₁ -C ₆ ) alkanoyloxymethyl, 1 - ((C ₁ -C ₆ ) Alkanoyloxy) ethyl, 1-methyl-1 - ((C ₁ -C ₆ ) alkanoyloxyethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl , α-amino (C ₁ -C ₄ ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl wherein the α-aminoacyl moieties independently represent any of the naturally occurring L-amino acids found in proteins P (O) (OH) ₂ , -P (O) (O (C ₁ -C ₆ ) alkyl) ₂ or glycosyl (the remainder being due to the detachment of the hydroxyl of hemiacetal of a carbohydrate).

Other exemplary prodrugs include, but are not limited to, derivatives of formula I wherein R _{2 is} a free hydrogen atom substituted by R-carbonyl, RO-carbonyl, NRR'-carbonyl, wherein R and R 'are each independently ( C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl-natural-α-aminoacyl, -C (OH) C (O) OY, wherein (Y is H, (C ₁ -C ₆ ) alkyl or benzyl), -C (OY ₀ ) Y ₁ , wherein Y _{1 represents} (C ₁ -C ₄ ) alkyl and Y ₁ (C ₁ -C ₆ ) Alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl or mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoalkyl, -C (Y ₂ ) Y ₃ , wherein Y _{2 is} H or methyl and Y _{3 is} mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

Other exemplary prodrugs include, but are not limited to, derivatives of formula I carrying a hydrolyzable moiety on R ₃ which releases a compound of formula I wherein R _{3 is} a free hydrogen atom after hydrolysis. Such hydrolyzable moieties on R ₃ are / include 1-hydroxy (C ₁ -C ₆ ) alkyl or 1-hydroxy-1-phenylmethyl.

Other exemplary prodrugs include cyclic structures such as the compounds of formula I wherein R ₂ and R _{3 are} at a common carbon atom to form a five-membered ring. The linking carbon may be independently mono- or disubstituted with H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl or phenyl.

As As used herein, the terms "reaction inert solvent" and "inert Solvent "to a solvent, not with the starting materials, reagents, intermediates or Interacts with products in a way that increases the yield of the desired Product negatively affected.

Of the One of ordinary skill in the art will recognize that certain compounds of this invention contain one or more atoms in one particular stereochemical or geometric configuration can, which gives rise to stereoisomers and configuration isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of the invention are also included as an aspect of this invention.

Of the One of ordinary skill in the art will recognize that certain combinations heteroatom-containing substituents used in this invention listed are, define compounds that are under physiological conditions (for example, those containing acetal or aminal bonds) are less stable. Consequently, such compounds are less preferred.

The term "ring R _x " wherein x is an integer, for example, "ring R ₉ ", "ring R ₁₂ " or "ring R ₄ " as used herein means the exchange on the ring refers to units wherein the ring R _x and also wherein the ring is contained within R _x .

As used herein, the term mono-N- or di-N, N- (C ₁ -C _x ) alkyl refers to the moiety (C ₁ -C _x ) alkyl independently when they are di-N, Represents N- (C ₁ -C _x ) alkyl ... (x refers to integers).

Other Features and advantages will be apparent from the description and claims that describe the invention clearly.

DESCRIPTION OF THE INVENTION IN DETAIL

in the Generally can the compounds of the formula I by the process according to the invention getting produced. This procedure is explained by the following Reaction Schemes explained.

Reaction scheme I

Reaction scheme II

Reaction scheme III

Reaction scheme IV

Reaction scheme V

Reaction scheme VI

According to Reaction Scheme I, the compounds of formula I wherein R ₁ , R ₁₀ , R ₁₁ , A, R ₂ , R ₃ , R ₄ , R ₅ and R _{6 are} as defined above, can be prepared by one of the two general methods. In the first process of the invention, the desired compound of formula I may be prepared by coupling the appropriate indole-2-carboxylic acid, indoline-2-carboxylic acid or benzimidazole-2-carboxylic acid of formula II with the appropriate amine of formula III (ie, acylating the amine). getting produced. In the second process of the invention, the desired compound of formula I can be prepared by coupling the appropriate compound of formula IV (ie a compound of formula I wherein R _{6 is} carboxy) with the appropriate alcohol or amine or alcohol of formula R ₈ R ₉ NH or R ₁₂ H, wherein R ₈ , R ₉ and R _{12 are} as defined above (i.e. acylating the amine or alcohol). The first method (coupling of compounds of formula II with compounds of formula III) is generally preferred when R _{4 is} not H and R _{5 is} H.

In general, the compound of formula II is combined with the compound of formula III (or compound of formula IV) with the appropriate amine (e.g., R ₁₂ H or R ₈ R ₉ NH)) or alcohol, in the presence of a suitable coupling agent. A suitable coupling agent is that which converts a carboxylic acid to a reactive species which forms an amide or ester bond upon reaction with an amine or alcohol, respectively.

The Coupling agent may be a reagent that facilitates this condensation in one-pot process when combined with the carboxylic acid and Amine or alcohol is mixed. When the acid condenses with an alcohol it is preferable to have a large excess of the alcohol as the reaction solvent, with or without 1.0 to 1.5 equivalents added dimethylaminopyridine, apply. Exemplary coupling reagents are 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (DEC / HBT), Carbonyldiimidazole, dicyclohexylcarbodiimide / hydroxybenzotriazole (HBT), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole / HBT, Propanephosphonic anhydride (propanephosphonic anhydride, PPA) and diethylphosphoryl cyanide. The coupling is carried out in an inert solvent, preferably a aprotic solvents, at a temperature of about -20 ° C to about 50 ° C for about 1 until about 48 hours. Exemplary solvents shut down Acetonitrile, dichloromethane, ethyl acetate, dimethylformamide and chloroform and mixtures thereof. An example of a suitable one Coupling method is Method A, which is included herein (immediately before the examples).

The coupling agent may also be an agent that activates the carboxylic acid to an intermediate product which is isolated and / or formed in a first step and reacted with the amine or alcohol in a second step. Examples of such coupling agents and activated intermediates are thionyl chloride or oxalyl chloride to form the acid chloride, cyanuric fluoride to form the acid fluoride, or a alkyl chloroformate such as isobutyl or isopropenyl chloroformate (having a tertiary amine base) to form a mixed anhydride to form the carboxylic acid. When the coupling agent is oxalyl chloride, it is advantageous to use a small amount of dimethylformamide as a co-solvent with other solvent (such as dichloromethane) to catalyze the formation of the acid chloride. This acid chloride can be coupled by mixing with the intermediate of formula III in a suitable solvent together with a suitable base. Suitable solvent / base combinations are, for example, dichloromethane, dimethylformamide or acetonitrile or mixtures thereof in the presence of a tertiary amine base, for example triethylamine. Other suitable solvent / base combinations include water or a (C ₁ -C ₅ ) alcohol or mixture thereof, together with a co-solvent such as dichloromethane, tetrahydrofuran or dioxane, and a base such as sodium or potassium carbonate, sodium, potassium or lithium hydroxide or sodium bicarbonate in an amount sufficient to consume the acid liberated in the reaction. The use of a phase transfer catalyst (generally 1 to 10 mole percent) such as a quaternary ammonium halide (eg, tetrabutylammonium bromide or methyltrioctylammonium chloride) is advantageous when a mixture of only partially miscible cosolvents is used (for example, dichloromethane-water or dichloromethane-methanol). The use of these coupling agents and the appropriate choice of solvents and temperatures are known to those skilled in the art or can be readily determined from the literature. These and other exemplary conditions useful for coupling carboxylic acids are described in Houben-Weyl, Vol. XV, Part II, E. Wunsch, Ed. G. Thieme Verlag, 1974, Stuttgart, and M. Bodansky, Principles of Peptide Synthesis Springer-Verlag Berlin 1984, and The Pepti of Analysis, Synthesis and Biology (Ed. E. Gross and J. Meienhofer), Volumes 1-5 (Academic Press NY 1979-1983).

The compounds of formula IV, wherein R ₁ , R ₁₀ , R ₁₁ , A, R ₂ , R ₃ , R ₄ , and R _{5 are} as defined above, may be prepared from the corresponding ester of formula V (that is, compounds of formula I) wherein R _{6 represents} (C ₁ -C ₅ ) alkoxycarbonyl or benzyloxycarbonyl) by hydrolysis with aqueous alkali at a temperature from about -20 ° C to about 100 ° C, generally at about 20 ° C, for about 30 minutes to about Be prepared 24 hours.

Alternatively, the compounds of formula IV are prepared by activating an indolecarboxylic acid of formula II with a coupling agent (as described above) which produces an activated intermediate (such as an acid chloride, acid fluoride or mixed anhydride) which is then reacted with a compound of formula III wherein R is H ₃ , R ₄ and R _{5 are} as described above and R _{6 is} carboxy, reacted in a suitable solvent in the presence of a suitable base. Suitable solvents include water or methanol or a mixture thereof, together with a co-solvent such as dichloromethane, tetrahydrofuran or dioxane. Suitable bases include sodium, potassium or lithium hydroxides, sodium or potassium bicarbonate, sodium or potassium carbonate, or potassium carbonate, together with tetrabutylammonium bromide (1 equivalent), in an amount sufficient to consume acid released in the reaction (generally the sufficient amount to keep the pH of the reaction greater than 8). The base can be added incrementally, along with the activated intermediate, to effect proper pH control of the reaction. The reaction is generally carried out between -20 ° C and 50 ° C. The isolation procedures are adjusted by those skilled in the art to remove the contaminants, but generally consist of removing water-miscible cosolvents by evaporation, extraction of high pH contaminants with an organic solvent, acidification to low pH (1-5). 2) and filtration or extraction of the desired product with a suitable solvent such as ethyl acetate or dichloromethane.

The compound of formula V can be prepared by coupling the appropriate compound of formula III wherein R _{6 is} alkoxycarbonyl and the appropriate compound of formula II in an analogous procedure to that described above (for example, method A).

alternative can Compounds of formula I, the sulfur atoms in the sulfoxide or Sulfone oxidation state, from the corresponding compounds of the formula I with the sulfur atom in non-oxidized form Treatment with a suitable oxidizing agent, such as m-chloroperoxybenzoic acid in dichloromethane, at a temperature of about 0 ° C to about 25 ° C for about 1 hour to about 48 hours using about 1 to about 1.3 equivalents, for the Conversion to the sulfoxide oxidation state and greater than about 2 equivalents for the Conversion to the sulfone oxidation state.

Some the manufacturing process used for the preparation of the compounds described herein are (i.e. primary Amines, secondary Amines, carboxyl in precursors of compounds of formula I), the Require protection from removal of functionality. The need for such Protection becomes dependent vary by nature of the removed functionality and the conditions of the manufacturing processes. The need for such protection is readily determined by one skilled in the art. The usage Such protection / removal methods are also known to those skilled in the art. For one for a general description of protecting groups and their use see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1,991th

For example, compounds of formula I specified in Scheme I contain primary amine, secondary amine or carboxylic acid functionality in the portion of the molecule defined by R ₆ which may interfere with the intended coupling reaction of Scheme I when the intermediate of formula III or R ₁₂ H or R ₈ R ₉ NH-amine is left unprotected. Thus, during the coupling reaction of Scheme I, the primary or secondary amine functionality, when present in the R ₆ units of the intermediate of Formula III, R ₈ R ₉ NH or R ₁₂ H amine, may be protected by a suitable protecting group. The product of such a coupling reaction in this case is a compound of the formula I which contains the protective group. This protecting group is removed in a subsequent step to provide the compound of formula I. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as Nt-butoxycarbonyl, N-carbobenzyloxy and 9-fluorenylmethylene-oxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are not chemically reactive under the coupling conditions described above are reactive (and immediately precede the examples referred to herein as Process A) and can be removed without chemically altering the functionality in the compound of Formula I.

The in starting Scheme I used starting indole-2-carboxylic acids and indoline-2-carboxylic acids, when not commercially available or known in the art (such knowledge is widely publicized) by usual Synthetic method available. For example, according to the reaction scheme II of the indole ester of the formula VII from the compound of the formula VI (where Q is selected is to achieve the desired A as defined above) Fischer indole synthesis (see Fischer indole synthesis Robinson, B. (Wiley, New York, 1982)), followed by saponification of the resulting indole ester of formula VII to give the corresponding acid of formula VIII become. The starting arylhydrazone can be obtained by condensation of a readily available hydrazine with the suitable carbonyl derivative or over the Japp-Klingeman reaction (see Organic Reactions, Phillips, R. R., 1959, 10, 143).

alternative may be the indole-2-carboxylic acid of formula VIIIA by condensation of an orthomethyl nitro compound of formula IX with an oxalate ester to the indole ester of the formula X, followed by reduction of the nitro group and subsequent hydrolysis, getting produced.

This Three-step process is called Reissert's indole synthesis (Reissert, Chemical Reports 1897, 30, 1030). The conditions for To run this sequence and references to it are described in the literature (Kermack, et al., J.Chem.Soc. 1921, 119, 1602; Cannon, et al., J. Med. Chem. 1981, 24, 238; Julian, et al., In Heterocyclic Compounds, Volume 3 (Wiley, New York, NY, 1962, R.C. Elderfield, eds., P 18). An example for the special implementation of this sequence are examples 10A-10C here in.

3-halo-5-chloro-1H-indole-2-carboxylic acids can also produced by halogenation of 5-chloro-1H-indole-2-carboxylic acids become.

According to reaction scheme III can Benzimidazol-2-carboxylic acids intermediates of the formula XI by condensation of a Orthodiaminoverbindung the Formula XIII with glycolic acid, followed by oxidation of the obtained benzimidazole-2-methanol of the Formula XII (Bistrzycki, A. and Przeworski, G. Ber. 1912, 45, 3483) become.

alternative (to Reaction Scheme II) substituted indolines of the formula XIV by reduction of the corresponding Indoles of the formula XV with a reducing agent such as magnesium in Methanol, at a temperature of about 25 ° C to about 65 ° C for about 1 Hour to about 48 hours (Reaction Scheme III) are prepared.

The indoline-carboxylic acids of the formula XVI are prepared by saponification of the corresponding esters of the formula XVII (reaction scheme III). The ester of formula XVII is prepared by reduction of the corresponding indole ester of formula VII with a reducing agent, such as magnesium in methanol, as for the compounds ment of the compound of formula XV to the above-mentioned compound of formula XIV prepared.

The the following paragraphs describe how to prepare the various amines that used in the above reaction schemes.

According to Reaction Scheme IV, an α-amino acid of formula XXIII can be protected on nitrogen with a suitable protecting group (P _t ) (e.g., t-Boc) to give a compound of formula XXIV. One skilled in the art can readily identify a suitable protecting group and method for its introduction choose. For example, two common protecting groups are t-Boc (introduced by treating the amino acid with di-t-butyl dicarbonate in a suitably preferred protic solvent or solvent mixture at high pH) and CBZ (introduced by treating the amino acid with benzyl chloroformate in a suitable, preferably protic Solvent or solvent mixture and base). The compound of formula XXIV is coupled (in an analogous procedure to the described coupling procedures in Reaction Scheme XI) with a suitable amine R ₈ R ₉ NH or HR ₁₂ to give a compound of formula XXV, which is then purified to give the compound of formula IIIB ( ie compound of formula III wherein R _{6 is} C (O) R ₁₂ or C (O) NR ₈ R ₉ ) is deprotected. When the protecting group is t-Boc by treating the compound of formula XXV with an acid in a suitable, preferably aprotic solvent, acids for deprotection include HCl, MeSO ₃ H or trifluoroacetic acid.

According to Reaction Scheme V, a compound of formula XXXI (N-protected amine of formula III wherein R _{6 is} (C ₁ -C ₈ ) alkoxycarbonyl or benzyloxycarbonyl) can be prepared from the corresponding unprotected amino acid of formula XXX via N -protection (to give a protected Amino acid of formula XXXIII), followed by esterification. For example, the compound of formula XXXIII may be reacted with the appropriate alcohol and an acid catalyst such as hydrogen chloride or thionyl chloride or in the case of tert-butanol by treatment of the amino acid with isobutylene and an acid catalyst such as concentrated sulfuric acid or by treatment with an alkyl halide (e.g. Methyl iodide) and base (for example, potassium carbonate). Alternatively, the esterification may precede the protection step.

According to Reaction Scheme VI, compounds of formula XXX wherein R _{3 is} not H can be used in Reaction Scheme V, as prepared below. The amino acids of formula XLI can be prepared by N-alkylation of the protected (P _T ) amino acids of formula XL by treatment with a suitable base and an alkylating agent. Specific methods for this alkylation are described by Benoiton, Can. Chem. 1977, 55, 906-910, and Hansen, J. Org. Chem. 1985, 50 945-950. For example, when R ₃ is methyl and P _{T is} Boc, sodium hydride and methyl iodide in tetrahydrofuran are used. Deprotection of the compound of formula XLI gives the desired compound of formula XXX.

Alternatively, an amino acid of Formula XLII can be N-alkylated by a three-step series involving reductive benzylation (as with benzaldehyde, Pd / C-catalyzed hydrogenation) to the mono-N-benzyl derivative and reductive amination with the appropriate carbonyl compound ( for example, with formaldehyde and sodium cyanoborohydride to introduce R ₃ such as methyl) to the N-benzyl, NR ₃ -substituted amino acid. The N-benzyl protecting group is suitably removed (for example by hydrogenation with a suitable catalyst) to give the compound of formula XXX. Specific conditions for this three-step alkylation process are described by Reinhold et al., J. Med. Chem., 1968, 11, 258-260.

The immediately preceding preparation can also be used to introduce an R ₃ moiety into an intermediate of Formula IIIa (which is an intermediate of Formula III wherein R _{3 represents} H).

The amino acids used in the Schemes herein (e.g., XL, XLII), if not commercially available or reported in the literature, can be prepared by a variety of methods known to those skilled in the art. For example, the stretching synthesis or variations thereof may be used. Consequently, an aldehyde (R ₄ CHO), sodium or potassium cyanide and ammonium chloride react to form the corresponding aminonitrile. The aminonitrile is hydrolyzed with mineral acid to yield the desired amino acid of formula XLII R ₄ C (NH ₂ ) COOH. Alternatively, the Bucherer-Berg method can be used, wherein a hydantoin is obtained by heating an aldehyde (R ₄ CHO) with ammonium carbonate and potassium cyanide, followed by hydrolysis (e.g., barium hydroxide in refluxing dioxane) with acid or base to give the desired amino acid of formula XLII R ₄ C (NH ₂ ) COOH.

Other synthetic methods for α-amino acids are also cited in the literature, which would allow one skilled in the art to prepare the desired intermediate of the formula XLII R ₄ C (NH ₂ ) COOH necessary for the synthesis of compounds of formula I. ,

suitable Procedure for the synthesis and / or resolution of the compounds of formula XLII are in review articles by Duthaler (Tetrahedron 1994, 50, 1539-1650) or Williams (R.M. Williams, Synthesis of Optically Active Amino Acids. Oxford, GB, 1989).

A specific method for the synthesis of an intermediate of formula XLII in any enantiomeric form from the corresponding intermediate R ₄ X (X = Cl, Br or I) is the method of Pirrung and Krishnamurthy (J. Org. Chem. 1993, 58, 957 -958) or the method of O'Donnell et al. (J. Am. Chem. Soc. 1989, 111, 2353-2355). The requisite R ₄ X intermediates are readily prepared by many methods known to those skilled in the art. For example, compounds wherein R ₄ X represents ArCH ₂ X may be prepared by radical halogenation of the compound ArCH ₃ or by formulation of the arene Ar-H and conversion of the alcohol to the bromide.

Another specific method for the synthesis of intermediates of formula XLII in each enantiomeric form is that of Corey and Link (J. Am Chem. Soc. 1992, 114, 1906-1908). Thus, an intermediate of the formula R ₄ COCCl _{3 is} enantiospecifically reduced to intermediate R ₄ CH (OH) CCl ₃ , which upon treatment with azide or base, is converted to an intermediate R ₄ CH (N ₃ ) COOH, which by catalytic hydrogenation to the desired compound of formula XLII is reduced. The required trichloromethyl ketone R ₄ COCCl ₃ is obtained by reaction of the aldehyde R ₄ CHO with trichloromethane anion, followed by oxidation (Gallina and Giordano, Synthesis 1989, 466-468).

A compound of the formula R ₈ NH ₂ or R ₉ NH ₂ is monoalkylated with a carbonyl compound corresponding to R ₈ or R ₉ under suitable reductive amination conditions to give an amine of the formula R ₈ R ₉ NH. To avoid dialkylation, it may be preferable to protect the amines (R ₈ NH ₂ or R ₉ NH ₂ ) with a suitable protecting group (P _T ) to give R ₈ (P _T ) NH or R ₉ (P _T ) NH for example by reaction with benzaldehyde and a reducing agent. The protected amines are monoalkylated with a carbonyl compound corresponding to R ₉ or R ₈ under suitable reductive amination conditions to R ₈ R ₉ N (P _T ). The protecting group (P _T ) is removed (for example, by exhaustive catalytic hydrogenation when P _{T is} benzyl) to give a compound of the formula R ₈ R ₉ NH. Suitable reductive amination conditions are available from the literature to those skilled in the art. Conditions include those reported by Borch et al. (J. Am. Chem. Soc. 1971, 2897-2904) and those reviewed by Emerson (Organic Reactions, Wiley: New York, 1948 (14), 174), Hutchins et al. (Org. Prep. Proced. Int 1979 (11), 20) and Lane et al. (Synthesis 1975, 135). Reductive amination conditions that prefer N-monoalkylation include those reported by Morales et al. (Synthetic Communications 1984, 1213-1220) and Verardo et al. (Synthesis 1992 121-125). The amines R ₈ NH ₂ or R ₉ NH ₂ can also be monoalkylated with R ₉ X or R ₈ X, wherein X includes chloride, bromide, tosylate or mesylate. Alternatively, the intermediate of the formula R ₈ (P _T ) NH or R ₉ (P _T ) NH may be alkylated with R ₉ X or R ₈ X and the protecting group removed to yield a compound of the formula R ₈ R ₉ NH.

Other methods can be used to prepare amines of the formula R ₈ R ₉ NH wherein R ₈ -NH or R ₉ -NH are oxygen-nitrogen bonded. Thus, an easily available compound of the formula (C ₁ -C ₄ ) alkoxycarbonyl-NHOH or NH ₂ CONHOH is dialkylated on the nitrogen and oxygen by treatment with base and excess suitable alkylating agent (RX) to give the corresponding (C ₁ -C ₄ ) Alkoxycarbonyl-N (R) OR, which is subsequently hydrolyzed to give a compound of the formula R ₈ R ₉ NH (wherein R ₈ = R ₉ = R). Suitable conditions, base, and alkylating agents include those described by Goel and Krolls (Org., Prep., Proced., Int, 1987, 19, 75-78) and Major and Fleck (J. Am. Chem. Soc., 1928, 50, 1479). , one. Alternatively, N-hydroxyurea (NH ₂ CONH (OH)) can be alkylated stepwise, first on oxygen to NH ₂ CONH (OR '), then on nitrogen to NH ₂ CON (R'')(OR') followed by treatment with the Alkylating agents R'X or R''X in the presence of a suitable base. Suitable base and alkylating agents include those described by Kreutzkamp and Messfinger (Chem. Ber. 100, 3463-3465 (1967)) and Danen et al. (J. Am. Chem. Soc., 1973, 95, 5716-5724). Hydrolysis of these alkylated hydroxyurea derivatives gives amines R'ONH ₂ and R'ONHR '' corresponding to the particular amines of the formula R ₈ R ₉ NH. The skilled artisan may adapt the procedures described in this section to other alkylating agents R, R 'and R "-X to prepare other amines of the formula R ₈ R ₉ NH wherein R _{8 is} -N or R ₉ -N are oxygen-nitrogen bonded. Uno et al. (SynLett 1991, 559-560) describe the BF ₃ -catalyzed addition of an organometallic reagent R-Li to an O-alkyloxime of the formula R'CH = N-OR '' to give compounds of the formula R'RCH-NH (OR ''). This route can also be used to give compounds of the formula R ₈ R ₉ NH wherein one of R ₈ -NH or R ₉ -NH is oxygen-nitrogen bonded.

The Prodrugs of this invention wherein a carboxyl group in a carboxylic acid of the Formula I is replaced by an ester, may be by combining the carboxylic acid with the appropriate alkyl halide in the presence of a base such as potassium carbonate, in an inert solvent, such as dimethylformamide, at a temperature of about 0 to 100 ° C for about 1 until about 24 hours are produced. Alternatively, the acid with the appropriate alcohol as a solvent in the presence of a catalytic amount of acid, such as concentrated sulfuric acid a temperature of about 20 to 120 ° C, preferably at reflux for about 1 Hour to about 24 hours combined. Another method is the reaction of the acid with a stoichiometric Amount of alcohol in the presence of a catalytic amount of acid in one inert solvents, as tetrahydrofuran, with simultaneous removal of the generated Water by physical (for example Dean-Stark trap) or chemical (for example, molecular sieves) agents.

The Prodrugs of this invention wherein an alcohol function is an ether can be derivatized by Combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base, such as potassium carbonate, in an inert solvent, such as dimethylformamide, at a temperature of about 0 to 100 ° C for about 1 until about 24 hours are produced. Alkanoylaminomethyl ethers can by reaction of the alcohol with a bis (alkanoylamino) methane in the presence of a catalytic amount of acid in an inert.

Solvents, such as tetrahydrofuran, according to a method described in US 4997984 , to be obtained. Alternatively, these compounds may be prepared by methods described by Hoffman et al. in J. Org. Chem. 1994, 59, 3530.

The Dialkyl phosphate esters can by reaction of the alcohol with dialkyl chlorophosphate in the presence a base in an inert solvent, such as tetrahydrofuran. The dihydrogen phosphates can by reaction of the alcohol with one as described above Chlorphosphorsäurediaryl- or dibenzyl ester, followed by hydrolysis or hydrogenation in the presence of a noble metal catalyst.

glycosides be by reaction of the alcohol and a carbohydrate in one inert solvents, like toluene, in the presence of acid produced. In general, this is formed during the reaction Water, as it was formed, removed as described above. An alternative method is the reaction of the alcohol with a suitably protected Glycosyl halide in the presence of a base, followed by removal the protective groups.

N- (1-hydroxyalkyl) amides, N- (1-hydroxy-1- (alkoxycarbonyl) methyl) amides or compounds in which R _{2 has been} replaced by C (OH) C (O) OY can be obtained by the reaction of the parent amide or Indols with the appropriate aldehyde under neutral or basic conditions (for example, sodium ethoxide in ethanol) at temperatures between 25 to 70 ° C are prepared. N-alkoxymethylindoles or N-1- (alkoxy) alkylindoles can be obtained by reaction of the N-unsubstituted indole with the necessary alkyl halide in the presence of a base in an inert solvent. 1- (N, N-dialkylaminomethyl) indole, 1- (1- (N, N-dialkylamino) ethyl) indole, and N, N-dialkylaminomethylamides (e.g. R ₃ = CH ₂ N (CH ₃ ) ₂ ) may be converted by the reaction the parent NH compound with the appropriate aldehyde and amine in an alcoholic solvent at 25 to 70 ° C are prepared.

The prodrugs of this invention where R ₂ and R ₃ are a common carbon may be prepared by reaction of the parent compound (drug) with benzaldehyde or a ketone or its dimethyl acetal in an inert solvent in the presence of a catalytic amount of acid with concomitant water or methanol removal prepared ,

The starting materials and reagents for the above-described reaction schemes (for example, amines, substituted indolecarboxylic acids, substituted indoline carboxylic acids, and amino acids), although the preparation of most of them is described above, are readily available or readily synthesized by those skilled in the art using conventional methods of organic synthesis , For example, many of the intermediates used herein for the preparation of the compounds of formula I are derived from or related to amino acids found in nature for which it is There is great scientific and commercial interest, and consequently, many such intermediates are commercially available or cited in the literature, or are readily prepared from other commonly available substances by methods reported in the literature. Such intermediates include, for example, compounds of formula XXX, formula XLII, formula XXXII and formula XXXIII.

Some Compounds of formula I have asymmetric carbon atoms and are therefore enantiomers or diastereomers. diastereomer can into their individual diastereomers based on their physicochemical Differences by methods known per se, for example by chromatography and / or fractional crystallization. enantiomers (e.g., of Formula III, VIII or IX) may be prepared by converting the enantiomeric mixture into a mixture of diastereomers by reaction with a suitable optically active compound (for example, alcohol), separating the diastereomers and converting (for example, hydrolysis ren) the respective diastereomers to the correspondingly pure enantiomers be separated. All such isomers including diastereomers, enantiomers and mixtures thereof are considered part of this invention.

Even though many compounds of the invention are not ionizable under physiological conditions are some the compounds of the invention ionizable under physiological conditions. Thus, for example some of the compounds of the invention sour and they form a salt with a pharmaceutically acceptable Cation. All such salts are within the scope of this invention and you can by conventional Process are produced. For example, they can simply be brought into contact the acidic and basic units, usually in a stoichiometric Relationship, in either an aqueous, non-aqueous or partially aqueous Medium, if appropriate, are produced. The salts become either by filtration, by precipitation with a non-solvent, followed by filtration by evaporation of the solvent or in the case of aqueous solutions by lyophilization if appropriate.

In addition are some of the compounds of the invention basic and they form a salt with a pharmaceutically acceptable Anion. All such salts are within the scope of the invention and you can by conventional Process are produced. For example, they can simply be brought into contact the acidic and basic units, usually in a stoichiometric Relationship, in either an aqueous, non-aqueous or partially aqueous Medium, if appropriate, are produced. The salts become either by filtration, by precipitation with a non-solvent, followed by filtration, by evaporation of the solvent or in the case of aqueous solutions by lyophilization, if appropriate. If in addition the Compounds of the invention Hydrate or solvate form, these are also within the scope the invention.

Of the Use of the combinations according to the invention as drugs in the treatment of diseases, as herein in detail, in mammals (For example, humans) by the activity of the compounds of the invention in usual Assays and in the in vitro and in vivo assays described below shown. Such assays also provide a means whereby the activities the compounds of the invention with the activities from other known compounds can be compared. The Results of these comparisons are for determining dosage levels in mammals, including people, for the Treatment of such diseases usable.

The purified human liver glycogen phosphorylase a (HLGPa) is purified by obtained the following procedure.

Expression and fermentation

The HLGP cDNAa is expressed from plasmid pKK233-2 (Pharmacia Biotech Inc., Piscataway, New Jersey) in E. coli strain XL-1 Blue (Stratagene Cloning Systems, LaJolla, CA). The strain is inoculated into LB medium (consisting of 10 g tryptone, 5 g yeast extract, 5 g NaCl and 1 ml 1N NaOH per liter) plus 100 mg / l ampicillin, 100 mg / l pyridoxine and 600 mg / l MnCl ₂ and grow at 37 ° C to a cell density of OD ₅₅₀ = 1.0. At this point, the cells are induced with 1 mM isopropyl-1-thio-β-D-galactoside (IPTG). Three hours after induction, the cells are harvested by centrifugation and cell pellets are frozen at -70 ° C until necessary for purification.

cleaning of glycogen phosphorylase

The cells in pellets described above are resuspended in 25 mM β-glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl ₂ plus the following inhibitors: 0.7 μg / ml Pepstatin A 0.5 μg / ml leupeptin 0.2 mM Phenylmethylsulfonyl fluoride (PMSF) and 0.5 mM EDTA, lysed by pretreatment with 200 μg / ml lysozyme and 3 μg / ml DNAase, followed by sonication in 250 ml batches for 5 × 1.5 minutes on ice using a Branson Model 450 ultrasonic cell destroyer (Branson Sonic Power Co., Canbury, CT) , The cell lysates are then clarified by centrifugation at 35,000 x g for one hour, followed by filtration through 0.45 μm filters. HLGP in the soluble fraction of lysates (estimated at less than 1% of total protein) is purified by following the enzyme activity (as described in the HLGPa activity assay section below) from a series of chromatographic steps detailed below.

immobilized Metal Affinity Chromatography (IMAC):

This step is based on the method of Luong et al. (Luong et al., Journal of Chromatography (1992) 584, 77-84). 500 ml of the filtered soluble fraction of cell lysates (prepared from approximately 160 g of original cell pellet) are loaded onto a 130 ml column of IMAC Chelating-Sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey) containing 50 mM CuCl ₂ and 25 mM β-glycerophosphate, 250 mM NaCl and 1 mM imidazole at pH 7 equilibrium buffer was loaded. The column is washed with equilibrium buffer until the A ₂₈₀ returns to baseline. The sample is then eluted from the column with the same buffer containing 100 mM imidazole to remove the bound HLGP and other bound proteins. Fractions containing HLGP activity are collected (approximately 600 ml) and ethylenediaminetetraacetic acid (EDTA), DL-dithiothreitol (DTT), phenylmethylsulfonyl fluoride (PMSF), leupeptin and pepstatin A are added to give 0.3 mM, 0.2 mM, 0.2 mM, 0.5 μg / ml and 0.7 μg / ml concentrations, respectively. The collected HLGP is injected through a Sephadex G-25 column (Sigma Chemical Co., St. Louis, Missouri) injected with 25 mM Tris-HCl (pH 7.3), 3 mM DTT buffer (buffer A) Equilibrated, desalted to remove imidazole and kept on ice until the second chromatographic step.

5'-AMP-Sepharose chromatography:

The desalted, collected HLGP sample (approximately 600 ml) is then mixed with 70 ml of 5'-AMP-Sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey) equilibrated with Buffer A (see above). The mixture was gently stirred for one hour at 22 ° C, then poured into a column and washed with buffer A until the A _{280 returned} to baseline. HLGP and other proteins are eluted from the column with 25 mM Tris-HCl, 0.2 mM DTT and 10 mM adenosine 5'-monophosphate (AMP) at pH 7.3 (Buffer B). The HLGP-containing fractions are collected, followed by identification by determination of enzyme activity (described below) and visualization of the M, approximately 97 kDa HLGP protein band with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by silver staining (2D silver stain II "Daiichi Kit", Daiichi Pure Chemicals Co., LTD., Tokyo, Japan), and then collected The collected HLGP is dissolved in 25mM β-glycerophosphate, 0.2mM DTT, 0.3mM EDTA, 200mM NaCl , pH 7.0 buffer (Buffer C) dialyzed and stored on ice until use.

Determination of HLGP enzyme activity

A) Activation of HLGP: Conversion of HLGPb to HLGPa

In front In the determination of HLGP enzyme activity, the enzyme becomes the inactive Form as expressed in E. coli strain XL-1 Blue (designated HLGPb) (Stragene Cloning Systems, La Jolla, California), to the active Form (termed HLGPa) by phosphorylation of HLGP using of phosphorylase kinase as converted below.

HLGPb reaction with immobilized phosphorylase kinase

Phosphorylase kinase (Sigma Chemical Company, St. Louis, MO) is sold on Affi-Gel 10 (BioRad Corp., Melvile, NY) according to the manufacturer's instructions. The phosphorylase kinase enzyme (10 mg) is incubated with washed Affi gel beads (1 ml) in 2.5 ml of 100 mM HEPES and 80 mM CaCl ₂ at pH 7.4 for 4 hours at 4 ° C. The affi-gel beads are then washed once with the same buffer prior to blocking with 50 mM HEPES and 1 M glycine methyl ester at pH 8.0 for one hour at room temperature. Blocking buffer is removed and replaced with 50 mM HEPES (pH 7.4), 1 mM β-mercaptoethanol and 0.2% NaN ₃ for storage. Prior to use to convert HLGPb to HLGPa, the Affi-gel immobilized phosphorylase kinase beads are prepared by washing the buffer used to perform the kinase reaction consisting of 25mM β-glycerophosphate, 0.3mM DTT, and 0.3 mM EDTA at pH 7.8 (kinase assay buffer).

The partially purified inactive HLGPb obtained from the above 5'-AMP Sepharose chromatography is diluted 1:10 with kinase assay buffer, then mixed with the above-mentioned phosphorylase kinase enzyme immobilized on the Affi gel beads. NaATP is added to 5 mM and MgCl ₂ to 6 mM. The resulting mixture is gently mixed at 25 ° C for 30 to 60 minutes. The sample is removed from the beads and the percent activation of HLGPb by conversion to HLGPa is estimated by determining the HLGP enzyme activity in the presence and absence of 3.3 mM AMP. The percentage of total HLGP enzyme activity due to HLGPa enzyme activity (AMP independent) is then calculated as follows:

B) HLGPa activity assay

The hypoglycemic activity (also the other disease / condition treatment / prevention activities described here) Compounds of this invention can indirectly by evaluating the effect of the compounds of the invention on the activity activated form of glycogen phosphorylase (GPa) by a the two methods are determined. Glycogen phosphorylase α activity is in the forward direction by following the production of glucose-1-phosphate from glycogen or by following the reverse reaction, measuring glycogen synthesis from glucose-1-phosphate by release of inorganic phosphate. All reactions run in triplicate into 96-well microtiter plates, and the change The absorption due to the formation of the reaction product is at which is described below in an MCC / 340 MKII Elisa Reader (Lab Systems, Finland) connected to a Titertech Microplate Stacker (ICN Biomedical Co, Huntsville, Alabama).

To measure forward HLGPa enzyme activity, the production of glucose-1-phosphate from glycogen by the multienzyme-coupled general method of Pesce et al. [Pesce, MA, Bodourian, SH, Harris, RC and Nicholson, JF (1977) Clinical Chemistry 23, 1711-1717] modified as follows 1 to 100 μg of phosphorylase, 10 units of phosphoglucomutase and 15 units of glucose-6-phosphate dehydrogenase ( Boehringer Mannheim Biochemicals, Indianapolis, IN) are diluted to 1 ml in Buffer A (described below), followed. Buffer A is at pH 7.2 and contains 50 mM HEPES, 100 mM KCl, 2.5 mM ethylene glycol tetraacetic acid (EGTA), 2.5 mM MgCl ₂ , 3.5 mM KH ₂ PO _4, and 0.5 mM dithiothreitol. 20 μl of this stock solution is added to 80 μl of Buffer A containing 0.47 mg / ml of glycogen, 9.4 mM of glucose, 0.63 mM of the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP +). The compounds to be tested are added as a 5 μl solution in 14% dimethyl sulfoxide (DMSO) prior to addition of the enzymes. The basal rate of HLGPa enzyme activity in the absence of inhibitors is determined by adding 5 μM 14% DMSO and a fully inhibited rate of HLGPa enzyme activity is obtained by adding 20 μL of 50 mM positive control test substance caffeine. The reaction is monitored at room temperature by measuring the conversion of oxidized NADP + to reduced NADPH at 340 nm.

In order to measure the HLGPa enzyme activity in the reverse direction, the conversion of glucose 1-phosphate to glycogen plus inorganic phosphate by the general procedure described by Engers et al. [Engers, HD, Shechosky, S. and Madsen, NB (1970) Can. J. Biochem. 48, 746-754], modified as follows: 1 to 100 μg of HLGPa are diluted in 1 ml of Buffer B (described below). Buffer B is at pH 7.2 and contains 50mM HEPES, 100mM KCl, 2.5mM EGTA, 2.5mM MgCl ₂ and 0.5mM dithiothreitol. 20 μl of this stock solution is added to 80 μl of Buffer B with 1.25 mg / ml glycogen, 9.4 mM glucose and 0.63 mM glucose-1-phosphate. The compounds to be tested are added as a 5 μl solution in 14% DMSO prior to addition of the enzyme. The basal rate of GPa enzyme activity in the absence of added inhibitors is determined by adding 5 μl of 14% DMSO and the fully inhibited rate of HLGPa enzyme activity is obtained by adding 20 μl of 50 mM caffeine. This mixture is incubated at room temperature for one hour and that released from the glucose-1-phosphate inorganic phosphate is prepared by the general method of Lanzetta et al. [Lanzetta, PA, Alvarez, LJ, Reinach, PS, and Candia, O.A. (1979) Anal. Biochem. 100, 95-97] modified as follows: 150 μl of 10 mg / ml ammonium molybdate, 0.38 mg / ml malachite green in 1N HCl is added to 100 μl of the enzyme mixture, measured. After incubation for 20 minutes at room temperature for 20 minutes, absorbance at 620 nm is measured.

The Compounds of the invention Become readily available to clinical use as hypoglycemic agents customized. The hypoglycemic activity the compounds of the invention can be determined by the amount of the test compound, the glucose levels, based on a carrier without test compound, in males ob / ob mice reduced. The test allows also the provision of an approximate, minimal effective dose level (MED) for the in vivo reduction of the plasma glucose concentration in such mice for such Test compounds.

There the concentration of glucose in the blood with the development of diabetic Illnesses are closely related, prevent, inhibit these Compounds due to their hypoglycemic effect diabetic Diseases and / or develop them back.

Five to eight week old male C57BL / 6J ob / ob mice (obtained from Jackson Laboratory, Bar Harbor, ME) are housed five per cage under standard animal husbandry conditions. After one week acclimation period, the animals are weighed and 25 microliters of blood are collected from the retro-orbital sinus prior to each treatment. The blood sample is immediately diluted 1: 5 with saline containing 0.025% sodium heparin and kept on ice until metabolite analysis. Animals are assigned to treatment groups so that each group has a similar average plasma glucose concentration. After the labeling group animals are orally dosed each day for four days with the vehicle consisting of either: 1) 0.25% w / v methylcellulose in water without pH adjustment or 2) 0.1% Pluronic ^® P105 Block Copolymer Surfactant (BASF Corporation, Parsippany, NJ) in 0.1% saline, without pH adjustment. On day 5, the animals are weighed again and then dosed orally with the test compound or vehicle alone. All drugs were in vehicle consisting of either: 1) 0.25 weight / volume methylcellulose in water, without pH adjustment; or 2) 10% DMSO / 0.1% Pluronic ^® P105 (BASF Corporation, Parsippany, NJ) in 0.1% saline without pH adjustment, is administered. The animals were then bled from the retro-orbital sinus three hours later for the determination of blood metabolite levels. The freshly collected samples are centrifuged for two minutes at 10,000 x g at room temperature. The supernatant was applied to glucose, for example, by the Abbott VP ^™ (Abbott Laboratories, Diagnostics Division, Irving, TX) and VP Super System ^® Autoanalyzer (Abbott Laboratories, Irving, TX) using the A-Gent ^TM Glucose-UV Testreagenzsystems ( Abbott Laboratories, Irving, TX) (a modification of the method of Richterich and Dauwalder, Swiss Medical Weekly, 101, 860 (1971)) (hexokinase method), using a 100 mg / dl standard. Plasma glucose is then calculated by the equation:
Plasma glucose (mg / dl) = sample value × 5 × 1,784 = 8.92 × sample value, where 5 is the dilution factor and 1.774 is the plasma hematocrit setting (assuming the hematocrit is 44%).

The with carrier dosed animals retain essentially unchanged hyperglycemic glucose levels (for example, greater than or equal to 250 mg / dl); with the test compounds at appropriate Canned animals have significantly depressed levels of glucose. hypoglycemic activity The test compounds are analyzed by statistical analysis (unpaired T-test) of the mean plasma glucose concentration between the test compound group and vehicle-treated Group determined on day 5. The above assay, carried out with a dosage range of test compounds, allows the determination an approximate minimally effective dose level (MED) for in vivo reduction the plasma glucose concentration.

The Compounds of the invention be easily adapted to clinical use as hyperinsulinemia-reversing Agents, triglyceride lowering agents and hypercholesterolemic agents customized. Such activity can be determined by the amount of the test compound, the insulin, Triglyceride or Cholesterol level, relative to a control vehicle, without test compound, in male ob / ob mouse reduced.

There the concentration of cholesterol in the blood in close relation to the development of cardiovascular, cerebrovascular or peripheral-vascular Disorders, prevent inhibit the compounds of the invention because of their hypocholesterolemic Effect arteriosclerosis and / or develop this back.

Since the concentration of insulin in the blood is related to the promotion of vascular cell growth and increased renal sodium retention (in addition to other effects, e.g. Glucose consumption) and these functions are known to cause hypertension or hypertension, the compounds according to the invention inhibit hypertension or hypertension and / or develop them due to their hypoinsulinemic action.

There the concentration of triglycerides in the blood to the total levels contributes to blood lipids, prevent inhibit the compounds of the invention due to their Triglyceride-lowering activity hyperlipidemia and / or develop these back.

Five to eight week old male C57BL / 6J ob / ob mice (obtained from Jackson Laboratory, Bar Harbor, ME) are housed five per cage under standard animal husbandry conditions and fed casually with standard rodent diets. After one week acclimation period, the animals are weighed and 25 microliters of blood are collected from the retro-orbital sinus prior to each treatment. The blood sample is immediately diluted 1: 5 with saline containing 0.025% sodium heparin and kept on ice until plasma glucose analysis. Animals are assigned to treatment groups so that each group has a similar plasma glucose concentration agent. The compound to be tested is administered by oral gavage as an about 0.02% strength by weight to 2.0% solution (weight / volume (wt./vol.)) In either 1) 10% DMSO / 0.1% Pluronic ^® P105 Block copolymer surfactant (BASF Corporation, Parsippany, NJ) in 0.1% saline, without pH adjustment, or 2) 0.25% w / v of methyl cellulose in water, without pH adjustment. Single daily dosing (sid) or double daily dosing (bid) is maintained for 1 to 15 days. Control mice receive the 10% DMSO / 0.1% Pluronic ^® P105 in 0.1% saline without pH adjustment or the 0.25 w / v methylcellulose in water without pH adjustment only.

Three hours later If the last dose is administered, the animals will be decapitated sacrificed and the fuselage blood is added to 0.5 ml serum separation tubes, the 3.6 mg of a 1: 1 w / w sodium fluoride: potassium oxalate mixture included, collected. The freshly collected samples become two Minutes at 10 000 × g centrifuged at room temperature and the serum supernatant is transferred and 1: 1 volume / volume with a 1TIU / ml rprotinin solution in 0.1% saline, without pH adjustment, diluted.

The diluted serum samples are then stored at -80 ° C until analysis. The thawed, diluted serum samples are analyzed for insulin, triglyceride and cholesterol levels. Serum insulin concentration is determined using Equate ^® RIA INSULIN kits (double antibody method as specified by the manufacturer) available from Binax, South Portland, ME, determined. The interassay coefficient of variation is <10%. Serum triglycerides of the Abbott VP ^TM and VP Super System ^® Autoanalyzer be using (Abbott Laboratories, Irving, TX) using the A-Gent ^TM Triglycerides Test reagent system (Abbott Laboratories, Diagnostics Division, Irving, TX) (lipase-coupled enzyme A modification of the method of Sampson, et al., Clinical Chemistry 21, 1983 (1975)). Serum total cholesterol levels are determined using the Abbott VP ^TM and VP Super System ^® Autoanalyzer (Abbott Laboratories, Irving, TX) and A-Gent ^TM Cholesterol Test reagent system (cholesterol esterase-coupled enzyme method; a modification of the method of Allain, et al Clinical Chemistry 20, 470 (1974)) using a 100 and 300 mg / dl standard. Serum insulin, triglyceride and total cholesterol levels are then calculated by the equations:
Serum insulin (μU / ml) = sample value × 2
Serum triglycerides (mg / dl) = sample value × 2
Total serum cholesterol (mg / dl) = sample value × 2,
where 2 is the dilution factor.

The with carrier dosed animals maintain essentially unchanged elevated serum insulin (e.g. 225 μU / ml), Serum triglyceride (eg, 225 mg / dl) and serum total cholesterol levels (for example, 160 mg / dl) while Animals with the test compounds of the invention treated, decreased serum insulin, triglyceride and total cholesterol levels demonstrate. Serum insulin, triglyceride and total cholesterol lowering activity of the test compounds are determined by statistical analysis (unpaired T-test) of medium Serum insulin, triglyceride and total cholesterol concentration between the test compound group and the vehicle-treated control group certainly.

The activity in providing protection from cardiac tissue damage to the compounds of the invention may be determined in vitro according to the methods described in Butwell et al., Am. J. Physiol., 264, H1884-H1889, 1993, and Allard et al., Am. J. Physio., 1994, 267, H66-H74. The experiments were carried out using a uniform volume, isolated rat heart preparation as essentially described in the above-referenced article. Normal Male Sprague-Dawley Rats, Male Sprague-Dawley Rats Treated by Aortic Bandage Surgery to Give Heart Ver acute diabetic male BB / W rats or non-diabetic BB / W, age matched control rats are pretreated with heparin (1000 U, ip) followed by pentobarbital (65 mg / kg ip). After deep anesthesia, determined by the absence of a foot reflex, the heart is quickly removed and placed in ice-salt solution. The heart is perfused retrogradially through the aorta within 2 minutes. Heart rate and ventricular pressure are determined using a latex balloon in the left ventricle with high pressure tubes connected to a pressure transducer. The heart is perfused with a perfusate solution consisting of (mM) NaCl 118, KCl 4.7, CaCl ₂ 1.2, MgCl ₂ 1.2, NaHCO ₃ 25, glucose 11. The perfusion apparatus is tightly temperature controlled with hot baths used for perfusate and water jacketing around the perfusion tube to maintain cardiac temperature at 37 ° C. Oxygenation of the perfusate is provided by a pediatric hollow fiber oxygenator (Capiax, Terumo Corp., Tokyo, Japan) immediately proximal to the heart. The hearts are exposed to perfusion solution ± test compound for about 10 minutes or more, followed by 20 minutes of global ischemia and 60 minutes of reperfusion, in the absence of the test compound. The heartbeats of the control and the test compound-treated hearts are compared during the period following ischemia. The left ventricular pressure of the control and test compound-treated hearts is compared in the period following ischemia. At the end of the experiment, the hearts are perfused and stained to determine the infarct area ratio based on the area of risk (% IA / AAR), as described below.

The therapeutic effects of the compounds of this invention in preventing cardiac tissue damage that otherwise result from ischemic injury may also be reported in vivo together according to Liu et al., Circulation, Vol. 84, No. 1 (July 1991), as specifically described herein to be shown. The in vivo assay tests the protection of the heart by the test compound relative to the control group receiving saline carriers. As background information, brief periods of myocardial ischemia followed by coronary artery reperfusion protect the heart from subsequent severe cardiac ischemia (Murry et al., Circulation 74: 1124-1136, 1986). Cardiac protection, as evidenced by a reduction in myocardial infarction, can be induced pharmacologically, using intravenously administered adenosine receptor agonists, to intact, anesthetized rabbits that are being studied as an in situ model of myocardial ischemic preconditioning (Liu et al., Circulation 84: 350-356, 1991). The in vivo assay tests whether compounds can pharmacologically induce cardiac protection; that is, decreased myocardial infarct size when administered parenterally to intact, anesthetized rabbits. The effects of the compounds of the present invention can be demonstrated with ischemic preconditioning using the Al adenosine agonist N ⁶ -1- (phenyl-2R-isopropyl) adenosine (PIA) which has been shown to pharmacologically protect the heart in intact anesthetized in situ tested rabbits , (Liu et al., Circulation 84: 350-356, 1991). The exact methodology will be described below.

Surgery: male Rabbit white New Zealander (3-4 kg) anesthetized with sodium pentobarbital (30 mg / kg i.v.). A tracheostomy will over performed a ventral midline cervical incision and the rabbits are fed with 100 oxygen using a positive pressure ventilator ventilated. Catheters are placed in the left jugular vein for drug administration and arranged in the left carotid artery for blood pressure measurements. The hearts are then punctured by a left thoracotomy and a sling (00 Silk), arranged around a known branch of the left coronary artery, exposed. ischemia is induced by tightening the sling and tightening. The Release the loop allows it, the affected area to flow through again. Myocardial ischemia is evident by regional cyanosis; Reperfusion was through reactive hyperemia clarified.

Course: Are at least once arterial pressure and heart rate Stable for 30 minutes, the trial is started. ischemic Preconditioning is achieved by closing the Coronary artery for 5 minutes, followed by reperfusion for 10 minutes. pharmacological Preconditioning is accomplished by infusing the test compound twice within for example 5 minutes and leave for 10 minutes before further intervention or by infusing the adenosine agonist, PIA (0.25 mg / kg). Following ischemic preconditioning pharmacological preconditioning or no conditioning (unconditioned Vehicle inspection), the artery is closed for 30 minutes and then for two hours flows through is used to induce myocardial infarction. The test compound and PIA will be in saline or other suitable carrier solved or 1 to 5 ml / kg released.

Staining (Liu et al., Circulation 84: 350-356, 1991): At the end of the 2 hour reperfusion period, the hearts are rapidly removed, attached to a Langendorff apparatus, and exposed to normal saline, heated to body temperature (38 ° C ), rinsed. The silk cord that is used as a sling becomes then tightened to reseal the artery and a 0.5% suspension of fluorescent particles (1-10 μm) is infused through the perfusate to stain the entire myocardium, except for the risk area (nonfluorescent support). The hearts are then quickly frozen and stored overnight at -20 ° C. The following day, the hearts are cut into 2 mm slices and stained with 1% triphenyltetrazolium chloride (TTC). Since TTC reacts with living tissue, staining differs between living (red-stained) tissue and dead tissue (unstained infarcted tissue). The infarct area (no staining) and the area of risk (no fluorescent particles) are calculated for each slice of the left ventricle using a pre-calibrated image analyzer. To normalize ischemic damage to differences in heart risk area, data are expressed as the ratio of infarct area to risk area (% IA / AAR). All data are expressed as mean ± SEM and compared statistically using one-factor ANOVA or non-paired t-test. The significance is considered as p <0.05.

The Administration of the compounds of the invention can over Any method that makes a connection of this invention preferably to the desired tissue (e.g. Liver and / or heart tissue). These methods include the oral route, parenteral, intraduodenal routes, etc. In general be the compounds of the invention in simple (eg once a day) or multiple doses administered.

however are the amount and timing of compound (s) administered be, of course the particular condition / condition to be treated the patient to be treated, the severity of the attack, the type depend on the administration and the attitude of the attending physician. Consequently be due to the variability from patient to patient the dosages given below are a guideline and the doctor can adjust the doses of the drug, about the activity (For example, glucose-lowering activity) to reach the doctor for the Patients considered suitable. Taking into consideration the desired activity level the doctor needs a variety of factors, such as the initial level, other risk (cardiovascular) - Factors, presence of previous disease and age of Align patients and patient motivation.

in the Generally, there is an effective dosage for the activities of these Invention, for example, the blood glucose, triglycerides and cholesterol lowering activities and hyperinsulinemia reversing activities of the compounds of this invention in the range of 0.005 to 50 mg / kg / day, preferably 0.01 to 25 mg / kg / day and more preferably 0.1 to 15 mg / kg / day.

in the In general, the compounds according to the invention are administered orally, however, parenteral administration (for example, intravenous, intramuscular, subcutaneous or intramedullary) when applied, for example, oral administration for the present Target is inappropriate or if the patient is unable to to swallow the medicine. Local administration may also be displayed, for example, if the patient is under gastrointestinal Illness suffers or whenever the medication works best the surface a tissue or organ as determined by the attending physician, is applied.

The Compounds of the invention are generally in the form of a pharmaceutical composition, comprising at least one of the compounds according to the invention, together with a pharmaceutically acceptable carrier or diluents, administered. Thus, you can the compounds of the invention individually or together in any usual oral, parenteral or transdermal dosage form.

For oral administration, a pharmaceutical composition may take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used together with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates together with excipients such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often applicable for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules, preferred materials in this context also including lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs for oral administration are desired, the compounds of the invention may be treated with various sweetening, flavoring, coloring, emulsifying and / or suspended agents as well as diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations.

For purposes parenteral administration solutions in sesame or peanut oil or in watery Propylene glycol and sterile aqueous solutions the corresponding water-soluble Salts are applied. Such aqueous solutions may suitably, if required, buffered and the liquid diluent first with sufficient saline solution or glucose is made isotonic. These aqueous solutions are especially for intravenous, intramuscular, subcutaneous and intraperitoneal injections. In this context are the sterile aqueous applied media all by standard techniques familiar to those skilled in the art well known, available.

For purposes transdermal (for example, local administration) diluted sterile aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions produced.

method for the preparation of various pharmaceutical compositions with a certain amount of active ingredient are known or are in the This disclosure will be apparent to those skilled in the art. Examples of procedures for the preparation of pharmaceutical compositions see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The pharmaceutical according to the invention Compositions can 0.1% -95% the compound (s) according to the invention, preferably 1% to 70%. In any case, the too administering compound or formulation for treatment the disease / condition of the patient to be treated, i. one Glycogen phosphorylase dependent Disease / condition effective amount of the compounds of the invention) contain.

General experimental Procedure for Examples 1 - 99 and 166-172

NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto, California) or Bruker AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) at about 23 ° C at 300 MHz for protons and 75, 4 MHz recorded for carbon nuclei. The chemical shifts are expressed in parts per million downfield from trimethylsilane. The exchangeable resonances do not appear in a separate NMR experiment in which the sample was shaken with a few drops of D ₂ O in the same solvent. FAB-MS spectra were obtained on a VG70-2505 spectrometer (V4 analytical LTD., Wythanshaw, Manchester, UK) using a liquid matrix consisting of 3: 1 dithiothreitol / dithioerythritol. Thermospray MS (TSPMS) was obtained on a Fisons Trio-1000 spectrometer (Fisons Co., Valencia, California) using ammonia ionization. The chemical ionization mass spectra were obtained on a Hewlett Packard 5989 instrument (Hewlett Packard Co., Palo Alto, California) (ammonia ionization, PBMS). When describing the intensity of ions containing chlorine or bromine, the expected intensity ratio was observed (approximately 3: 1 for ions containing ³⁵ Cl / ³⁷ Cl and 1: 1 for ⁷⁹ Br / ⁸¹ Br containing ions) and only the intensity of the ion the smaller mass is given.

HPLC was performed with 214 nM detection on a 250 x 4.6 mm Rainin Microsorb C-18 column (Rainin Co., Woburn, Massachusetts) isocratically eluted through a two pump / mixer system by feeding the designated mixture of acetonitrile and aqueous respectively pH 2.1 (with H ₃ PO ₄ ) 0.1M KH ₂ PO ₄ at 1.5 ml / min. The samples were injected in a 1: 1 mixture of acetonitrile and pH 7.0 phosphate buffer (0.025M in each of Na ₂ HPO ₄ and KH ₂ PO ₄ ). Percent purities are percent of total integrated area, usually within a 10 to 15 minute run. Melting points are uncorrected and were determined on a Buchi 510 melting point apparatus (Buchi Laboratoriums-Technik Ag., Flawil, Switzerland) using melting points of 120.5 to 122 ° C for benzoic acid and 237.5 to 240.5 ° C for p -Chlorobenzoic acid (Aldrich 99 +% grades) were obtained. Column chromatography was performed with Amicon silica gel (30 μM, 60A pore size) (Amicon D Vision, WR Grace% Co., Beverly, Mass.) In glass columns under low nitrogen pressure. Unless otherwise indicated, reagents were obtained as obtained from commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran and dichloromethane used as reaction solvents were available in the anhydrous state from Aldrich Chemical Company (Milwaukee, Wisconsin). The microanalyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrated" and coevaporated refer to removal of solvent at water jet pressure on a rotary evaporator having a bath temperature of less than 45 ° C. The reactions carried out at "0 to 20 ° C" or "0 to 25 ° C" were carried out with initial cooling of the vessel in an insulated ice bath, which within a few hours to room temperature was allowed to warm. The abbreviations "min" and "h" stand for "minutes" or "hours".

• Anmerkung 1: Bei einem größeren Kopplungsausmaß (> 50 ml Lösungsmittel) wurde das Gemisch an diesem Punkt aufkonzentriert und der Rückstand in Essigsäureethylester gelöst.
• Anmerkung 2: Wenn das Produkt ionisierbare Aminfunktionalität enthielt, wurde das Säurewaschen weggelassen. Ausnahmen bei der Verwendung von Verfahren A sind einzeln angeführt (falls nachstehend geeignet), gewöhnlich in Klammern, unmittelbar nach der Erwähnung von Verfahren A.

Method A (Peptide Coupling Using DEC) A 0.1 to 0.7 M solution of the primary amine (1.0 equiv or a primary amine hydrochloride and 1.0 to 1.3 equivalents of triethylamine per equivalent of HCl) in dichloromethane ( unless otherwise stated solvent) is added successively at 25 ° C with 0.95 to 1.2 equivalents of the indicated carboxylic acid, 1.2 to 1.8 equivalents of hydroxybenzotriazole hydrate (usually 1.5 equivalents based on the carboxylic acid) and 0.95 to 1.2 equivalents (corresponding to the molar ratio of the carboxylic acid) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC) and the mixture is stirred for 14 to 20 hours (see note 1 below). The mixture is diluted with ethyl acetate, washed two to three times with 1 or 2N NaOH, two to three times with 1 or 2N HCl (Note 2), the organic layer dried over MgSO ₄ and concentrated to give crude product which is purified by chromatography on silica gel, trituration or recrystallization as indicated using the indicated solvents. Purified products were analyzed by RP-HPLC and found to be greater than 95% pure unless otherwise stated. The reactions, carried out at 0 to 25 ° C, were carried out with initial cooling of the vessel in an insulated ice bath which was allowed to warm to room temperature within a few hours.

• Note 1: For a larger coupling level (> 50 ml of solvent), the mixture was concentrated at this point and the residue was dissolved in ethyl acetate.
• Note 2: If the product contained ionizable amine functionality, acid wash was omitted. Exceptions to the use of Method A are given individually (if appropriate below), usually in parentheses, immediately after the mention of Method A.

example 1

(2S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid methyl ester

L-phenylalanine methyl ester hydrochloride (77.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (77 mmol) were coupled according to Method A (0-25 ° C) and the product was chromatographed on silica gel in 10% and 20% ethyl acetate Hexanes to give the title substance as an off-white solid (22.12 g, 81%): mp 156-157 ° C; HPLC (60/40) 9.5 minutes (98%); PBMS 357/359 (MH +, 100%).
¹ H NMR (CDCl ₃ ) δ 9.40 (br, 1H), 7.60 (d, 1H, J = ca. 1 Hz), 7.35 (d, 1H, J = 8.9 Hz), 7 , 3-7.2 (m, 4H), 7.13 (m, 2H), 6.74 (d, 1H, J = 1.7 Hz), 6.62 (d, 1H, J = 7.5 Hz), 5.11 (m, 1H), 3.77 (s, 3H), 3.26 (m, 2H);
Anal. calculated for C ₉ H _{17 1} ClN ₂ O _3: C, 63.96; H, 4.80; N, 7,85.
Found: C, 64, 24; H, 4,84; N, 8.02.

Example 2

2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid

Aqueous 2M LiOH (33.10 mL) was added to a solution of (2S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid, methyl ester (21.47 g, 60 mmol). in THF (140 ml) at 0-5 ° C. After 0.5 h, the mixture was partially concentrated, acidified to pH 1-2 with 6N HCl, concentrated to dryness and the solids washed with water and then ether to give a colorless solid (18.78 g, 91%): mp. 248-255 ° C; HPLC (60/40) 5.21 minutes (98%); TSPMS 343/345 (MH +, 100%).
¹ H NMR (DMSO-d ₆ ) δ 12.85 (br, 1H), 11.75 (d, 1H, J = <1 Hz), 8.84 (d, 1H, J = 8.4 Hz), 7.35-7.14 (m, 7H), 4.65 (m, 1H), 3.20 (A of AB, 1H, J = 4.5, 13.9 Hz), 3.07 (B of AB, 1H, J = 10.8, 13.8 Hz);
Anal. Calcd for C ₁₈ H ₁₅ ClN ₂ O _3: C, 63.07; H, 4:41; N, 8,17.
Found: C, 62.90; H, 4.60; N, 8.04.

Example 3

[(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid methyl ester

Glycine methyl ester hydrochloride (50 mmol) and 5-chloro-1H-indole-2-carboxylic acid (50 mmol) were coupled according to Procedure A, replacing the following: The reaction mixture was washed with ethyl acetate (250 ml), hexanes (50 ml) and 1N NaOH (50 ml) and the suspension was filtered. The solid was washed with 1N NaOH, 1N HCl, with water, ethyl acetate and dried: yield 11.5 g, 86%, m.p. 252-254 ° C with decomposition;
¹ H NMR (DMSO-d ₆ ) δ 11.87 (br, 1H), 9.05 (t, 1H, J = 6.0 Hz), 7.72 (d, 1H, J = 2.0 Hz) , 7.45 (d, 1H, J = 8.7 Hz), 7.19 (dd, 1H, J = 2.0, 8.7 Hz), 4.05 (d, 2H, J = 6.0 Hz), 3.91 (s, 3H);
Anal. calculated for C _{1 2} H ₁₁ ClN ₂ O _3: C, 54.05; H, 4,16; N, 10.50.
Found: C, 54.11; H, 4,23; N, 10.56.

Example 4

[(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid

1 N NaOH (35 mL) was added to a suspension of [(5-chloro-1H-indol-2-carbonyl) -amino] -acetic acid, methyl ester (8.0 g, 30 mmol) in THF (100 mL) and the resulting mixture Stirred for 18 hours at 25 ° C. The solution was acidified with 6N HCl (7 mL), the mixture concentrated, the solids suspended in water, filtered and washed with water (7.42 g, 98%): HPLC (60/40) 2.89 minutes (100 %);
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.86 (br, 1H), 11.85 (br, 1H), 8.95 (t, 1H, J = 5.9 Hz), 7.72 (d, 1H, J = 2.0 Hz), 7.44 (d, 1H, J = 8.7 Hz), 7.19 (dd, 1H, J = 2.0, 8.7 Hz), 7 , 14 (d, 1H, J = <2 Hz), 3.96 (d, 2H, J = 5.9 Hz)
Anal. calculated for C ₁₁ H ₉ N ₂ O ₃ Cl: C, 52.29; H, 3.59; N, 11.09.
Found: C, 52.26; H, 3.73; N, 11,20.

Example 5

5-chloro-1H-indole-2-carboxylic acid [2 - ((3RS) -hydroxy-pyrrolidin-1-yl) 2-oxo-ethyl] -amide

3-Pyrrolidinol (1.25 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid (1.19 mmol) were coupled according to Method A with the following work-up: The reaction mixture was washed with ethyl acetate and 2N HCl, stirred for 1 hour, the mixture filtered and the resulting solids washed sequentially with 2N HCl, 2N NaOH, 2N HCl, dried, triturated with 1: 1 ether / hexanes and dried to give an off-white solid: yield 280 mg , 73%; HPLC (60/40), 4.66 minutes (96%); PBMS 322/324 (MH +, 100%).
¹ H NMR (DMSO-d ₆ ) δ 11.87 (br, 1H), 8.71 (q, 1H), 7.71 (d, 1H, J = 2.1 Hz), 7.45 (d, 1H, J = 8.8Hz), 7.19 (dd, 1H, J = 3.1, 8.8Hz), 7.16 (s, 1H), 5.07 (d, 0.5H, J = 3.6 Hz), 4.97 (d, 0.5H, J = 3.1 Hz), 4.35 (m, 1H), 4.27 (m, 1H), 4.10 (t, 1H ), 4.03 (d, 1H), 3.59 (m, 1H); 3.49-3.27 (m, 2H), 2.04-1.79 (m, 2H).

Example 6

5-chloro-1H-indole-2-carboxylic acid [2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) 2-oxo-ethyl] -amide

(3R, 4S) -3,4-dihydroxypyrrolidine hydrochloride (the cis or meso isomer, 1.79 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid (0.85 mmol) according to Method A (1: 1 CH ₂ Cl ₂ / DMF reaction solvent) coupled with the following work-up: The reaction mixture was concentrated, the residue suspended in 10 mL EtOAc and 10 mL 2N NaOH, the solids filtered and washed sequentially with aqueous 1 N NaOH, EtOAc , aqueous 1N HCl, H ₂ O and ether. This wash was repeated and the resulting solids were suspended in EtOAc, stirred for one hour, filtered and dried: yield 252 mg, 88%; HPLC (60/40), 2.33 minutes (93%); TSPMS 338/340 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.82 (s, 1H), 8.72 (t, 1H), 7.73 (d, 1H), 7.45 (d, 1H), 7.20 ( dd, 1H), 7.15 (s, 1H), 5.05 (d, 1H), 4.98 (d, 1H), 4.10 (m, 1H), 4.03 (m, 3H), 3.68 (dd, 1H), 3.42 (dd, 1H), 3.33 (dd, 1H), 3.23 (dd, 1H).

Example 7

5-chloro-1H-indole-2-carboxylic acid [2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

4-Hydroxypiperidine (0.83 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid (0.8 mmol) were coupled according to Method A (dimethylformamide-dichloromethane reaction solvent), with the following Workup: The reaction mixture was stirred with ethyl acetate and aqueous 2N HCl, the resulting suspension filtered and the collected solid washed successively with aqueous 2N HCl, aqueous 2N NaOH, ether and dried: Yield 180 mg, 68%; TSPMS 336/338 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.84 (br, 1H), 8.68 (br, 1H), 7.71 (d, 1H), 7.43 (d, 1H), 7.17 ( dd, 1H), 7.14 (s, 1H), 4.80 (br, 1H), 4.15 (m, 2H), 3.91 (m, 1H), 3.72 (m, 2H), 3.20 (m, 1H), 3.05 (m, 1H), 1.75 (m, 2H), 1.48 (m, 1H), 1.38 (m, 1H).

Example 8

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2- (3-hydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide

Racemic 3-pyrrolidinol (2.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (1 mmol) was prepared according to Method A (0-25 ° C Reaction temperature, washing first with acid then base) and the product purified by column chromatography on silica gel eluted with 0.5 to 16% ethanol in dichloromethane to give a colorless foam: yield 260 mg, 63%; HPLC (60/40) 100%, 3.86 minutes; PBMS 412/414 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₃ + 0.2 H ₂ O: C, 63.60; H, 5:43; N, 10.11.
Found: C, 63.90; H, 5.93; N, 10.11.

Example 9

5-chloro-1H-indole-2-carboxylic acid (1-diethylcarbamoyl-2-phenyl-ethyl) -amide

Diethylamine (1.2 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (0.6 mmol) were prepared according to Method A (0-25 ° C for The crude product was suspended in 1: 1 chloroform-dichloromethane, sonicated, filtered to remove the solids, concentrated and the residue purified by column chromatography on silica gel eluted with 10, 20 and 30% ethyl acetate in water Hexanes, purified: yield 14 mg, 6%; HPLC (60/40) 8.88 minutes (98%); PBMS 398/400 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.31 (br, 1H), 7.61 (d, 1H), 7.32 (d, 1H, J = 8.7 Hz), 7.28 to 7.18 ( m, 7H), 6.87 (d, 1H, J = 1.4Hz), 5.26 (m, 1H), 3.6 (m, 1-1.5H), 3.2-2.9 (m, 4.5-5H), 1.07 (t, 3H, J = 7.2Hz), 1.02 (t, 3H, J = 7.2Hz).
Analysis calculated for C ₂₂ H ₂₄ ClN ₃ O ₂ + 0.25 H ₂ O: C, 65.66; H, 6,14; N, 10.44.
Found: C, 65.61; H, 6.20; N, 10.11.

Example 10

4- {2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -piperazine-1-carboxylic acid tert-butyl ester

1-piperazinecarboxylic acid t-butyl ester (1.2 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenylpropionic acid (0.6 mmol) were prepared according to method A (0- 25 ° C reaction temperature, reaction time 4 days, extraction first with acid then base) and the crude product purified by column chromatography on silica gel eluted with 30% ethyl acetate in hexanes to give a colorless foam: yield 290 mg, 95%; HPLC (70/30) 6.23 minutes (99%); PBMS 512/514 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.32 (br, 1H), 7.60 (d, 1H, J = 1.9 Hz), 7.32 (d, 1H, J = 8.7 Hz), 7 , 3-7.15 (m, ca. 7H), 6.87 (d, 1H, J = 1.5 Hz), 5.33 (m, 1H), 3.65-2.9 (overlapping m, 9H), 2.70 (m, 1H), 1.43 (s, 9H).
Anal. Calcd. For C ₂₇ H ₃₁ ClN ₄ O ₄ : C, 63.46, H, 6.11; N, 10.96.
Found: C, 63.33; H, 5.97; N, 10.97.

Example 11

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2- (4-methylamino-piperidin-1-yl) -2-oxo-ethyl] -amide

Dimethylamine hydrochloride (1.1 mmol), sodium acetate (2.1 mmol), activated 3A molecular sieves and sodium cyanoborohydride (0.25 mmol) were added in this order to 5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2 -oxo-2- (4-oxopiperidin-1-yl) -ethyl] -amide (0.21 mmol) in methanol (2 ml) at 0 ° C. After 18 hours the mixture was concentrated, the residue taken up in ethyl acetate, the resulting solution washed with 2N NaOH and brine, dried with Na ₂ SO ₄ and concentrated. The product was purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane containing 0.5% NH ₄ OH, followed by trituration with ether: Yield 82%; HPLC (60/40) 2.79 minutes (98%); PBMS 439/441 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 8.94 (d, 0.5H, J = 8.8 Hz), 8.90 (d, 0.5H), 7, 71 (d, 1H, J = 1.8 Hz), 7.40 (d, 1H, J = 8.7 Hz), 7.31-7.20 (m, 6-7H), 7.17 (dd , 1H, J = 2.1, 8.7 Hz), 5.15 (m, 1H), 4.22 (m, 0.5H), 4.08 (m, 0.5H), 3.96 ( m, 0.5H), 3.85 (m, 0.5H), 3.2-2.9 (m, 4H), 2.78 (m, 0.5H), 2.72 (m, 0, 5H), 2.25 (s, 1.5H), 2.24 (s, 1.5H), 1.75 (m, 2H), 1.3-0.8 (m, 2H).
Analysis calculated for C ₂₉ H ₂₇ ClNgO ₂ + 1.0 H ₂ O: C, 63.08; H, 6, 40; N, 12, 26.
Found: C, 63.18; H, 6,16; N, 12,46.

Example 12

5-chloro-1H-indole-2-carboxylic acid (1-benzyl-2-morpholin-4-yl-2-oxo-ethyl) -amide

Morpholine (0.33 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (0.30 mmol) were prepared according to Method A (0-25 ° C reaction temperature , 48 hours reaction time) coupled. The crude product was chromatographed on silica gel eluted with 1: 1 acetic acid / hexanes, the desired fractions concentrated, the residue dissolved in chloroform and methanol, and the resulting solution stirred with about 128 mg of dimethylaminopyridine-polystyrene resin (Fluka Chemical Co.) , The solution was filtered, concentrated and the residue triturated with ether: yield 51%, HPLC (60/40), 5.92 minutes (98%);
PBMS 412/414 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 8.95 (d, 1H), 7.72 (d, 1H), 7.39 (d, 1H, J = 8.7 Hz), 7.35-7.15 (m, 7H), 5.13 (m, 1H), 3.65-3.10 (m, 8H), 3.05 (m, 2H).
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₃ + 0.33 H ₂ O: C, 63 23; H, 5, 47; N, 10, 06.
Found: C, 63.28; H, 5.32; N, 10,10.

Example 13

5-chloro-1H-indole-2-carboxylic acid (1-butylcarbamoyl-2-phenyl-ethyl) -amide

n-Butylamine (0.66 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) -amino) -3-phenyl-propionic acid (0.60 mmol) were prepared according to Method A (0-25 ° C reaction temperature) coupled. The crude product was dissolved in chloroform and methanol and the resulting solution stirred with 50 mg dimethylaminopyridine polystyrene resin (Fluka Chemical Co.) for 18 hours, the solution filtered, concentrated and the solids triturated with ether: Yield 83%, HPLC (60%). 40), 8.88 minutes (92%), mp 192-193 ° C, TSPMS 398/400 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.71 (br, 1H), 8.70 (d, 1H, J = 8.3 Hz), 8.10 (t, 1H), 7.72 (d, 1H, J = 2.0 Hz), 7.39 (d, 1H, J = 8.7 Hz), 7.35-7.15 (m, 7H), 4.70 (m, 1H), 3, 13-2.93 (m, 4H), 1.38 (m, 2H), 1.25 (m, 2H), 0.86 (t, 3H, J = 7.2 Hz);
Analysis calculated for C ₂₂ H ₂₀ ClN ₃ O _2: C, 66.41; H, 6.08; N, 10.56.
Found: C, 66.15; H, 6.05; N, 10.52.

Example 14

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2-oxo-2- (4-oxo-piperidin-1-yl) -ethyl] -amide

4-piperidone monohydrate (2.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (1.0 mmol) were prepared according to Method A (0-25 ° C The reaction mixture was diluted with ethyl acetate, the resulting solution washed with 2N NaOH and 2N HCl, the suspension filtered, and the solids dried: Yield 111 mg, 26%, HPLC (60/40), 8.88 minutes (92%), PBMS 424/426 (MH +, 100%); M.p. 258-261 ° C, PBMS 424/426 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 9.03 (d, 1H, J = 8.1 Hz), 7.72 (d, 1H, J = 1.9 Hz) , 7.39 (d, 1H, J = 8.7 Hz), 7.4-7.15 (m, 7H), 5.20 (m, 1H, J = 8.2 Hz), 3.88 ( m, 1H), 3.73 (m, 3H), 3.1 (m, 3H), 2.5-2.22 (m, 3H), 2.05 (m, 1H).
Analysis calculated for C ₂₃ H ₂₂ ClN ₃ O ₃ + 0.75 H ₂ O: C, 63.16; H, 5:42; N, 9,61.
Found: C, 63.11, H, 5, 15; N, 9.53.

Example 15

5-chloro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-pyrrolidin-1-yl-ethyl) -amide

Pyrrolidine (0.35 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (0.31 mmol) were prepared according to Method A (0-25 ° C reaction temperature , 140 hours reaction time) coupled and triturated the crude product with ether: Yield 89 mg, 71%; HPLC (70/30), 7.57 minutes (98%), PBMS 396/398 (MH +, 100/80%);
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₂ + 0.33 H ₂ O: C, 65.75; H, 5.68; N, 10.48.
Found: C, 65.56; H, 5.81; N, 10.44.

Example 16

5-chloro-1H-indole-2-carboxylic acid {1 - [(3-dimethylamino-propyl) -methyl-carbamoyl] -2-phenyl-ethyl} -amide

N, N, N'-trimethyl-1,3-diaminopropane (0.31 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (0.28 mmol) were coupled according to Method A (0-25 ° C reaction temperature, 120 hours reaction time) and the product purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane containing 0.5% ammonium hydroxide: Yield 86 mg , 69%; HPLC (40/60), 7.57 minutes (>99%); M.p. 187-190.5 ° C, TSPMS 441/443 (MH +, 100%);
Analysis calculated for C ₂₄ H ₂₉ ClN ₄ O ₂ + 0.25 H ₂ O: C, 64.71; H, 6.68; N, 12.58.
Found: C, 64.73; H, 6.94; N, 12,86.

Example 17

5-chloro-1H-indole-2-carboxylic acid [1- (3-morpholin-4-yl-propylcarbamoyl) -2-phenyl-ethyl] -amide

4- (3-Aminopropyl) morpholine (0.34 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (0.30 mmol) were prepared according to method A The reaction mixture was diluted with ethyl acetate, the resulting solution washed three times with 2N NaOH and once with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was stirred under ether for 1 h, the solid filtered and dried. Yield 125 mg, 87%, HPLC (60/40), 2.85 minutes (98%); PBMS 469/471 (MH +, 100/90%).
Analysis calculated for C ₂₅ H ₂₉ ClNgO ₃ + 0.25 H ₂ O: C, 63.42; H, 6.28; N, 11,83.
Found: C, 63.31; H, 6.57; N, 12.04.

Example 18

5-chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide

Dimethylamine hydrochloride (0.96 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (0.90 mmol) were prepared according to Method A (0-25 ° C reaction temperature , 60 hours reaction time, first washed with acid, then base) coupled and the resulting solid triturated with ether:
Yield 320 mg, 99%; HPLC (60/40), 5.87 minutes (100%);
Mp 224-225 ° C; PBMS 370/372 (MH +, 100%).
A sample was recrystallized from hot ethyl acetate for analysis (mp 224-225 ° C).
Analysis calculated for C ₂₀ H ₂₀ ClN ₃ O ₂ + 0.5 C ₄ H ₈ O ₂ : C, 63.80; H, 5.84, N, 10.15.
Found: C, 63.81; H, 5.80; N, 10.21.

Example 19

5-chloro-1H-indole-2-carboxylic acid [2 - ((3R, 4R) -dihydroxypyrrolidin-1-yl) -2-oxo-ethyl] -amide

(3R, 4R) -3,4-Dihydroxypyrrolidine (from unnatural tartaric acid by the method described in U.S. Patent No. 4,634,775, 1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino ] acetic acid (1.1 mmol) was coupled according to Method A (dimethylformamide reaction solvent), replacing the following work-up: The reaction mixture was concentrated, diluted with 20 ml ethyl acetate and 20 ml 2N NaOH, the suspension was stirred for 0.5 h, filtered and the resulting solids were washed successively with 2N NaOH, water, 1N HCl and ethyl acetate: yield 77%; HPLC (40/60), 10, 7 minutes (99%); TSPMS 338/340 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.84 (br, 1H, exchanged), 8.72 (t, 1H, exchanged), 7.72 (d, 1H, J = 1.9 Hz), 7, 44 (d, 1H, J = 8.7 Hz), 7.19 (dd, 1H, J = 2.1, 8.8 Hz), 7.16 (s, 1H), 5.26 (d, 1H , J = 4.4 Hz, exchanged), 5.17 (d, 1H, J = 3.2 Hz, exchanged), 4.04 (m, 3H), 3.92 (m, 1H), 3.66 (dd, 1H, J = 4.0, 10.8 Hz), 3.42-3.28 (m, 3H);
Analysis calculated for C ₁₅ H ₁₆ ClN ₃ O ₄ + 0.25 H ₂ O: C, 52.64; H, 4,86; N, 12:28.
Found: C, 52.61; H, 4.85; N, 12,23.

Example 20

5-chloro-1H-indole-2-carboxylic acid [2 - ((3S, 4S) -dihydroxypyrrolidin-1-yl) -2-oxo-ethyl] -amide

(3S, 4S) -3,4-Dihydroxypyrrolidine (from naturally occurring tartaric acid by the method, be in U.S. Patent No. 4,634,775, 1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid (1.0 mmol) were coupled under Method A (dimethylformamide reaction solvent) Exchanging the following procedure: The reaction mixture was diluted with ethyl acetate and 2N NaOH, the resulting suspension filtered, the solids washed with ethyl acetate, water and dried: Yield 135 mg, 40%; HPLC (40/60), 7.29 minutes (98%); TSPMS 338/340 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 12.1 (br, 1H), 8.86 (br, 1H), 7.71 (d, 1H, J = 2 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.17 (dd, 1H, J = 2.8.8 Hz), 7.13 (s, 1H), 5.35 (br, 1H, exchanged with D ₂ O), 5, 28 (br, 1H, exchanged with D ₂ O), 4.03 (m, 3H), 3, 92 (s, 1H), 3, 66 (dd, 1H, J = 4.11 Hz), 3 , 4 - 3.2 (m, 3H).
Analysis calculated for C ₁₅ H ₁₆ ClN ₃ O ₄ + 1.5 H ₂ O: C, 49.39; H, 5:25; N, 11.52.
Found: C, 49.50; H, 5.04; N, 11,27.

Example 21

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2- (4-methoxymethoxy-piperidin-1-yl) -2-oxo-ethyl] -amide

4-Methoxymethoxy-piperidine (1.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (1.0 mmol) were coupled according to method A and the Product by chromatography on silica gel, eluted with 1: 1 ethyl acetate-ethyl acetate-hexanes, purified: Yield 241 mg, 50%; HPLC (60/40), 7.67 minutes (94%);
PBMS 470/472 (MH +, 100%);
Analysis calculated for C ₂₅ H ₂₈ ClN ₃ O ₄ : C, 63.89; H, 6.01; N, 8.94.
Found: C, 63.91; H, 6.00; N, 8.95.

Example 22

5-chloro-1H-indole-2-carboxylic acid [2-phenyl-1- (2,2,6,6-tetramethyl-piperidin-4-ylcarbamoyl) -ethyl] -amide

2,2,6,6-tetramethyl-piperidine (1.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (1.0 mmol) coupled according to method A. The resulting yellow foam was triturated with ether, 1: 5 dichloromethane-ether. The resulting solid was dissolved in dichloromethane and the resulting solution treated with 0.20 ml of 4N HCl in dioxane. A precipitate formed, which was filtered, washed with dichloromethane and dried: Yield 220 mg, 42%; HPLC (60/40), 3.19 minutes (96%); PBMS 481/483 (MH +, 100%);
Analysis calculated for C ₂₇ H ₃₃ ClN ₄ O ₂ + HCl + 1.5 H ₂ O: C, 59.56; H, 6.85; N, 10.29.
Found: C, 59.30; H, 6.90; N, 10.22.

Example 23

(1- {2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine- (3RS) -yl) -carbamic acid tert-butyl ester

Racemic tert-butyl pyrrolidine-3-carbamate (1.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (1.0 mmol) were prepared according to Procedure A coupled and the product purified by chromatography on silica gel eluted with 1: 1 ethyl acetate-hexanes: Yield 302 mg, 59%; PBMS 511/513 (MH +, 100%);
Analysis calculated for C ₂₇ H ₃₁ ClN ₄ O ₄ ; C, 63, 46; H, 6,11, N, 10,96.
Found: C, 63.32; H, 6.26; N, 10,89.

Example 24

5-chloro-1H-indole-2-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl) -amide

Morpholine (1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid (1.0 mmol) were coupled according to Method A. The resulting solid was suspended in ether, filtered and dried to give a beige solid: Yield 264 mg, 71%; HPLC (60/40), 3.28 minutes (100%); TSPMS 322/324 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.85 (s, 1H), 8.68 (t, 1H), 7.72 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.19 (dd, 1H, J = 2.1, 8.8 Hz), 7.16 (s, 1H), 4.17 (d, 2H, J = 5 , 7 Hz), 3.65-3.45 (m, 8H).
Analysis calculated for C ₁₅ H ₁₆ ClN ₃ O ₃ + 0.25 H ₂ O: C, 55.22; H, 5.10; N, 12,88.
Found: C, 55.22; H, 5.08; N, 12,82.

Example 25

5-chloro-1H-indole-2-carboxylic acid - [(methoxy-methyl-carbamoyl) -methyl] -amide

Methoxymethylamine hydrochloride (1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino) -acetic acid (1.0 mmol) were coupled according to Method A. The resulting solid was suspended in ether, filtered and dried: yield 158 mg, 53%; PBMS 296/298 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.82 (s, 1H), 8.77 (t, 1H, J = 6 Hz), 7.73 (d, 1H, J = 2.0 Hz), 7 , 43 (d, 1H, J = 8.7 Hz), 7.19 (dd, 1H, J = 2.0, 8.7 Hz), 7.16 (s, 1H), 4.22 (d, 2H, J = 5.7 Hz), 3.76 (s, 3H), 3.14 (s, 3H).
Analysis calculated for C ₁₃ H ₁₄ ClN ₃ O _3: C, 52.80; H, 4,77; N, 14.21.
Found: C, 52.51; H, 4,82; N; 14.01.

Example 26

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2-dimethylaminopiperidine-1-yl) -2-oxo-ethyl] -amide

4-Dimethylaminopiperidine (1.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (1.0 mmol) were coupled according to Method A. The residue was purified by chromatography on silica gel eluted with 5-30% ethanol in dichloromethane containing 0.5% ammonium hydroxide, followed by trituration with ether: Yield 21 mg, 5%; PBMS 453/455 (MH +, 100%);
¹ H NMR (DMSO-d ₆ , partial) δ 11.75 (br, 1H), 8.94 (m, 1H), 7.72 (d, 1H, J = 2 Hz), 7.45-7, 10 (m, 8H), 5.17 (m, 1H), 4.63 (m), 4.38 (m), 4.03 (m), 3.50 (m), 3.15-2, 8 (m), 2.51 (s, 3H), 2.50 (s, 3H).

Example 27

5-chloro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-piperazin-1-yl-ethyl) -amide

Trifluoroacetic acid (4 ml) was added to 4- {2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -piperazine-1-carboxylic acid tert -butyl ester (0.6 mmol) at 0 ° C and the resulting solution was stirred for 0.3 hours and concentrated. The residue was partitioned between ethyl acetate and 2N NaOH, the organic layer separated and washed with brine, dried over Na ₂ SO ₄ , concentrated and the resulting solid triturated with ether: Yield 189 mg, 77%; HPLC (60/40), 2.63 minutes (99%); Mp 166.5-168 ° C; TSPMS 411/413 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₃ ClN ₄ O ₂ + 0.5 H ₂ O: C, 62.93; H, 5.76; N, 13.34.
Found: C, 62.64; H, 5.52; N, 13.34.

Example 28

5-chloro-1H-indole-2-carboxylic acid [2 - ((3RS) -amino-pyrrolidin-1-yl) -1-benzyl-2-oxo-ethyl] -amide

4N HCl in 1,4-dioxane (5 ml) was added to (1- {2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine (3RS-yl The resulting solution was stirred at 25 ° C for 0.5 h, concentrated and the residue triturated with ether: Yield 190 mg, 85%; HPLC (60%). 40), 2.62 minutes (98%); PBMS 411/413 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₃ ClN ₄ O ₂ + HCl + 1.7 H ₂ O: C, 55.28; H, 5.78; N, 11,72.
Found: C, 55.14; H, 5.86; N, 11,45.

Example 29

1 - {(2RS) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine- (2S) -carboxylic acid

Trifluoroacetic acid became tert-butyl 1- [2 (RS) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine (2S) -carboxylate (1, 0 mmol) at 25 ° C. After 1.5 hours, the reaction mixture was concentrated and the residue was triturated first with ether, then with a mixture of ether and hexanes. Yield 360 mg, 82%; HPLC (60/40), 4.84 minutes (99%); PBMS 440/442 (MH +, 40%), 396/398 (MH-44, 100%).
Analysis calculated for C ₂₃ H ₂₂ ClN ₃ O ₄ + 0.8 H ₂ O: C, 60.81; H, 5:24; N, 9,25.
Found: C, 60.74; H, 5:42; N, 8.96.

Example 29a

1- {2 (R, S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine- (2S) -carboxylic acid tert-butyl ester

L-proline t-butyl ester (2.0 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (2.0 mmol) were prepared according to procedures A coupled and the crude product by chromatography on silica gel through Elution with 1: 2 ethyl acetate-ethyl acetate-hexanes purified: yield 611 mg, 62%; HPLC (60/40), 13.45 minutes (57 %) and 14.46 minutes (41%).

Example 30

5-chloro-1H-indole-2-carboxylic acid - ((1S) -methylcarbamoyl-2-thiazol-4-yl-ethyl) -amide

(S) -2-Amino-N-methyl-3-thiazol-4-yl-propionamide hydrochloride (0.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.51 mmol) were prepared according to method A ( 0-25 ° C reaction temperature, reaction solvent dimethylformamide) coupled. The crude product was stirred in ether for 0.5 h, then filtered to give a beige solid: 182 mg, 98%; HPLC (60/40), 3.41 minutes (98%), mp> 260 ° C (decomp.); TSPMS 363/365 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.82 (br, 1H), 9.0 (d, 1H), 8.82 (br, 1H), 8.10 (br, 1H), 7.70 ( m, 1H), 7.44-7.38 (m, 2H), 7.21-7.15 (m, 2H), 4.80 (m, 1H), 3.24 (m, 1H), 3 , 05 (m, 1H), 2.60 (d, 3H).

Example 30a

(S) -2-amino-N-methyl-3-thiazol-4-yl-propionamide hydrochloride

(S) - (1-Methylcarbamoyl-2-thiazol-4-yl-ethyl) -carbamic acid tert-butyl ester (248 mg, 0.87 mmol) was dissolved in 4M HCl-dioxane at 0 ° C. The resulting mixture was one hour at 25 ° C touched, focused on and the residue triturated with ether. Yield 202 g, 102%; HPLC (70/30) for 2.41 minutes (96%).

Example 30b

(S) -2- (N-t-butoxycarbonylamino) -N-methyl-3-thiazol-4-yl-propionamide

Methylamine hydrochloride (1.2 mmol) and Boc-L-3- (4-thiazolyl) alanine (1.0 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, acid wash was omitted) coupled and the product without further purification used. Yield 250 mg, 88%.

Example 31

(±) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-hydroxy-propionic acid methyl ester

D, L-Serine methyl ester hydrochloride (2.1 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.0 mmol) were washed according to Method A (0-25 ° C reaction temperature, first with acid then saturated NaHCO ₃ ) and the product purified by chromatography on silica gel eluted with 10, 20, 40 and 60 ethyl acetate on hexanes: Yield 565 mg, 95%; HPLC (60/40) 3.46 minutes (98%); Mp 153-155 ° C, TSPMS 297/299 (MH +, 100/40%);
Analysis calculated for C ₁₃ H ₁₃ ClN ₂ O _4: C, 52.62; H, 4:42; N, 9,44.
Found: C, 52.62; H, 4.54; N, 9.53.

Example 32

5-chloro-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-thiazol-4-yl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-thiazol-4-yl-propionamide hydrochloride (0.43 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.40 mmol) were prepared according to procedures A (0-25 ° C reaction temperature) coupled and the crude product was triturated first with 1: 1 ether-hexanes, then with hexanes. Yield 115 mg, 75%; HPLC (60/40) 3.72 minutes (99%); Mp 198-202 ° C (contracts on reaching 192 ° C); PBMS 377/379 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.75 (s, 1H), 9.02 (d, 1H, J = 2 Hz), 8.9 (d, 1H, J = 8.2 Hz), 7 , 7 (d, 1H, J = 1.8 Hz), 7.41 (d, 1H, J = 6.7 Hz), 7.39 (s, 1H), 7.22 (s, 1H), 7.17 (dd, 1H, J = 2.2, 8.7 Hz) , 5.30 (m, 1H), 3.24 (dd, A of AB, 1H, J = 7.13 Hz), 3.16 (dd, B of AB, 1H, J = 8.5, 16 Hz ), 3.07 (s, 3H), 2.84 (s, 3H).
Analysis calculated for C ₁₇ H ₁₇ ClN ₄ O ₂ S + 0.125 H ₂ O: C, 53.86; H, 4.59; N, 14.78.
Found: C, 53.92; H, 4:47; N, 14.42.

Example 32a

(S) -2-amino-N, N-dimethyl-3-thiazol-4-yl-propionamide hydrochloride

(S) - (1-Dimethylcarbamoyl-2-thiazol-4-yl-ethyl) -carbamic acid tert-butyl ester was in 4M HCl dioxanes at 0 ° C solved and at 25 ° C Stirred for 2 hours. The mixture was concentrated and the residue triturated with ether. Yield 3.06 g, 105%; HPLC (70/30), 2.12 minutes (97%), PBMS 200 (MH +, 100%).

Example 32b

(S) - (1-Dimethylcarbamoyl-2-thiazol-4-yl-ethyl) -carbamic acid tert-butyl ester

dimethylamine (1.2 mmol) and Boc-L-3- (4-thiazolyl) alanine (1.0 mmol) were prepared according to procedures A (0-25 ° C reaction temperature) coupled and the product by chromatography on silica gel, eluted with 1 to 16% ethanol in dichloromethane containing 0.5% ammonium hydroxide, cleaned. Yield 124 mg, 41%.

Example 33

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2 - ((3R, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide

(3R, 4S) -Dihydroxypyrrolidine hydrochloride (0.5 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.5 mmol) were coupled according to method A and the product was purified by chromatography on silica gel eluted with 2-10%. Ethanol in dichloromethane, purified. Yield 180 mg, 86%; HPLC (60/40), 3.14 minutes (98%); TSPMS 428/430 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 8.94 (d, 1H, J = 8 Hz), 7.72 (s, 1H), 7.4-7.1 ( m, 8H), 5.03 (d, 0.5H, J = 5 Hz), 4.95 (d, 0.5H, J = 5 Hz), 4.90 (d, 1H, J = 5 Hz) , 4.87 (m, 1H), 4.08 (m, 0.5H), 4.00 (m, 0.5H), 3.88 (m, 1.5H), 3.5-3 , 3 (m, 2.5H), 3.2 (m, 0.5H), 3.0 (m, 2H).
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₄ + 0.25 H ₂ O: C, 61.11; H, 5:25; N, 9,72.
Found: C, 60.91; H, 5:46; N, 9,43.

Example 33a

(Cis-3,4 -) - Dihydroxypyrrolidinhydrochlorid

cis-3,4-dihydroxy-pyrrolidin-1-carboxylic acid tert-butyl ester (1.99 g, 9.8 mmol) was dissolved in 4M HCl-dioxane at 5 ° C and the resulting suspension at 25 ° C stirred for an hour. The mixture was concentrated and the residue triturated with ether yielding a light red powder (1.30 g, 95%).

Example 33b

cis-3,4-dihydroxy-pyrrolidin-1-carboxylic acid tert-butyl ester

A solution of crude 2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (10.5 g, 62.1 mmol) in tetrahydrofuran (300 ml) was added successively with osmium tetroxide (2.5% in t-butanol, 6 ml) and N-methylmorpholine-N-oxide at 25 ° C. After 48 hours became watery 10% sodium thiosulfate solution added and the mixture stirred for 30 minutes, partially concentrated with removal of tetrahydrofuran and the resulting aqueous mixture extracted twice with ether. The ether extracts were 10% sodium thiosulfate, 0.1N HCl, dried and concentrated to yield a dark orange oil, on silica gel eluted with 1%, 2%, 4%, 8% and 10% ethanol-dichloromethane, was chromatographed, yielding an amber colored Syrups (4.09 g).

Example 33c

2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester

Di-t-butyl dicarbonate (83 g, 380 mmol) was added to a solution of 3-pyrroline (containing 35% pyrrolidine, 25 g, 362 mmol) in tetrahydrofuran (500 mL) 0 ° C given. The mixture was stirred for one hour at 25 ° C and concentrated under Recovery of 76.2 g of a yellow oil, without further purification has been used.

Example 34

(3S) - [(5-chloro-1H-indol-1-carbonyl) -amino] -4- (4-hydroxy-piperidin-1-yl) -4-oxo-butyric acid tert-butyl ester

(S) -3-amino-4- (4-hydroxy-piperidin-1-yl) -4-oxo-butyric acid tert-butyl ester (0.8 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.8 mmol) were prepared according to procedures A coupled and the product by chromatography on silica gel, eluted with 25, 40, 50, 75 and 100% ethyl acetate in hexanes, purified. Yield 330 mg, 94%; HPLC (60/40), 4.18 minutes (97%); TSPMS 450/452 (MH +, 100%).

Example 34a

(S) -3-amino-4- (4-hydroxy-piperidin-1-yl) -4-oxo-butyric acid tert-butyl ester

diethylamine (1.0 mmol) became (S) -3- (9H-fluoren-9-ylmethoxycarbonylamino) -4- (4-hydroxy-piperidin-1-yl) -4-oxo-butyric acid tert-butyl ester in dimethylformamide (5 ml) at 25 ° C given. After 1 hour, the reaction mixture was concentrated, the residue suspended in 1: 1 ether / dichloromethane, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 1 to 50% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 217 mg, 80%.

Example 34b

(S) -3- (9H-fluoren-9-ylmethoxycarbonylamino) -4- (4-hydroxy-piperidin-1-yl) -4-oxo-butyric acid

4-hydroxypiperidine (2.1 mmol) and N-FMOC-L-aspartic acid β-t-butyl ester (2.0 mmol) according to procedure A (96 hours reaction time, washed only with acid) coupled and the product is purified by chromatography on silica gel eluted with 1 to 4% ethanol in dichloromethane, purified. Yield 516 mg, 52%; HPLC (60/40), 5.33 minutes (93%).

Example 35

5-chloro-1H-indole-2-carboxylic acid - [(1R) -benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(R) -2-Amino-1- (4-hydroxy-piperidin-1-yl) -3-phenylene-propan-1-one hydrochloride (3.1 mmol) and 5-chloro-1H-indole-2-ol carboxylic acid (3.4 mmoles) were coupled according to Method A (0-25 ° C reaction temperature, 60 hours reaction time) and the product was purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes, followed by trituration with 1: 1 ether-hexanes, purified. Yield 1.1 g, 84%; HPLC (60/40), 4.06 minutes (99%); PBMS 426/428 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₄ ClN ₃ O ₃ + 0.25 H ₂ O: C, 64.18, H, 5.74; N, 9,76.
Found: C, 64.28; H, 5.94; N, 9,41.

Example 35a

(R) -2-amino-1- (4-hydroxy-piperidin-1-yl) -3-phenyl-propan-1-one hydrochloride

(R) -2- (N-t-butoxycarbonylamino) -1- (4-hydroxy-piperidin-1-yl) -3-phenyl-propan-1-one (12.5 mmol) was dissolved in 4M HCl-dioxane at 0 ° C solved and the resulting suspension is stirred for one hour at 25 ° C. The mixture was on concentrated and the residue triturated with ether. Yield 3.44 g, 97%.

Example 35b

(R) -2- (N-t-butoxycarbonylamino) -1- (4-hydroxy-piperidin-1-yl) -3-phenyl-propan-1-one

(R) -2- (N-t-butoxycarbonylamino) -3-phenyl-propan-1-one (14 mmol) and 4-hydroxypiperidine (21.5 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, first with acid, then washed base) and the product without further purification used. Yield 4.7 g, 94%; HPLC (60/40) 3.52 minutes (98%).

Example 36

1H-indole-2-carboxylic acid [2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -ethanone hydrochloride (1.0 mmol) and 1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to Method A (0- The reaction mixture was diluted with ethyl acetate and 2N NaOH, the resulting precipitate was collected and washed with 2N NaOH, 1N HCl and water. Yield 135 mg, 42%; HPLC (60/40) 2.97 minutes (97%); PBMS 322 (MH +, 100%),
Analysis calculated for C ₁₄ H ₁₅ N ₃ O ₄ S + 0.25 H ₂ O: C, 51.60; H, 4.79; N, 12,90.
Found: C, 51.31; H, 4.66; N, 12,88.

Example 36a

2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -ethanone hydrochloride

[2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (11 mmol) was dissolved in 4M HCl-dioxane at 0 ° C and the resulting suspension one hour at 25 ° C touched. The mixture was concentrated and the residue triturated with ether. Yield 2.3 g, 100%.

Example 36b

[2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

M-chloroperoxybenzoic acid (35 mmoles) was added slowly to (2-oxo-2-thiazolidin-3-yl-ethyl) -carbamic acid tert -butyl ester (14 mmoles) in dichloromethane (35 ml) at 0 ° C. After the foaming was completed, the mixture was stirred for an additional 2.5 hours at 25 ° C. The mixture was diluted with ethyl acetate, the resulting solution washed three times with a 1: 1 mixture of saturated aqueous NaHCO ₃ and 10% aqueous NaS ₂ O ₃ solution, once with saturated NaHCO ₃ solution, dried, concentrated, and Residue triturated with 1: 1 ether / hexanes. Yield 3.6 g, 92%.

Example 36c

(2-oxo-2-thiazolidin-3-yl-ethyl) -carbamic acid tert-butyl ester

thiazolidine (85 mmol) and Boc-glycine (57 mmol) were prepared according to method A (0-25 ° C reaction temperature, 60 hours reaction time) and the product without purification used. Yield 12.7 g, 90%.

Example 37

5-fluoro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (4-hydroxy-piperidin-1-yl) -3-phenylpropan-1-one hydrochloride (0.65 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (0, 73 mmol) were coupled according to Method A (0-25 ° C reaction temperature) and the product purified by chromatography on silica gel eluted with 20, 30, 40, 50, 75 and 100% ethyl acetate in hexanes. Yield 228 mg, 84%; HPLC (60/40), 3.57 minutes (98%), PBMS 410 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₄ FN ₃ O ₃ + 0.25 H ₂ O: C, 66.73; H, 5.97; N, 10.15.
Found: C, 66.68; H, 6,19; N, 9,94.

Example 38

1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (4-hydroxy = piperidin-1-yl) -3-phenylpropan-1-one hydrochloride (3.4 mmol) and 1H-indole-2-carboxylic acid (3.7 mmol) according to method A (0-25 ° C reaction temperature, 48 hours reaction time) coupled. The product was purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes, followed by trituration with 1: 1 ether-hexanes. Yield 1.14 g, 86%; HPLC (60/40) 3.52 minutes (98%); PBMS 392 (MH +, 100%); Analysis calculated for C ₂₃ H ₂₅ N ₃ O ₃ + 0.25 H ₂ O: C, 69.77; H, 6:49; N, 10.61.
Found: C, 69.99, H, 6.72; N, 10,47.

Example 39

5-fluoro-1H-indole-2-carboxylic acid - [(1S) - (4-fluoro-benzyl) -2-morpholin-4-yl-2-oxo-ethyl] -amide

(S) -2-Amino-3- (4-fluoro-phenyl) -1-morpholin-4-yl-propan-1-one hydrochloride (0.48 mmol) and 5-fluoro-1H-indole-2-ol carboxylic acid (0.48 mmol) were coupled according to Method A (0-25 ° C reaction temperature, 48 hours reaction time, first with acid, then base) and the product was purified by chromatography on silica gel eluted with 20, 30, 40, 50 and 75% ethyl acetate in hexanes, purified. Yield 189 mg, 95%; HPLC (60/40) 4.76 minutes (97%); PBMS 414 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.23 (br, 1H), 7.4-7.1 (m, 5H), 7.1 to 6.94 (m, 3H), 6.9 (d, 1H , J = 2 Hz), 5.30 (m, 1H), 3.72-3.48 (m, 5H), 3.42 (m, 1H), 3.03 (m, 4H).
Analysis calculated for C ₂₂ H ₂₁ F ₂ N ₃ O _3: C, 63.92; H, 5,12, N, 10,16.
Found: C, 64.30; H, 5.34; N, 9,82.

Example 39a

(S) -2-amino-3- (4-fluoro-phenyl) -1-morpholin-4-yl-propan-1-one hydrochloride

(S) -2- (N-t-butoxycarbonylamino) -3- (4-fluoro-phenyl) -1-morpholin-4-yl-propan-1-one (3.1 mmol) was dissolved in 4M HCl-dioxane at 0 ° C and the resulting suspension one hour at 25 ° C touched. The mixture was concentrated and the residue triturated with ether. Yield 776 mg, 88%; HPLC (60/40) 2.31 minutes (99%).

Example 39b

(S) - (2) - (N-t-butoxycarbonylamino) -3- (4-fluoro-phenyl) -1-morpholin-4-yl-propan-1-one

morpholine (3.7 mmol) and (S) -Boc-4-fluoro-phenylalanine (3.5 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 60 hours reaction time, first with acid, then base washed) coupled and the product by chromatography on silica gel eluted with 20, 30 and 40% ethyl acetate in hexanes, cleaned. Yield 1.08 g of oil, 87%.

Example 40

5-fluoro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one hydrochloride (1.0 mmol) and 5-fluoro-1H-indole 2-Carboxylic acid (1.0 mmol) was coupled according to Method A (0-25 ° C reaction temperature, reaction time 48 hours, first acid, then base) and the product was purified by chromatography on silica gel eluted with 20, 30, 40 and 50% ethyl acetate in hexanes, purified. Yield 404 mg, 94%; HPLC (60/40) 4.74 minutes (98%), PBMS 430 (MH +, 100%)
¹ H NMR (CDCl ₃ ) δ 9.53 (br, 0.5H), 9.44 (br, 0.5H), 7.44 (d, 0.5H, J = 9 Hz), 7.4- 7.1 (m, 7H), 7.02 (m, 1H), 6.84 (s, 0.5H), 6.81 (s, 0.5H), 5.20 (m, 0.5H) , 4.96 (m, 0.5H), 4.68 (d, 0.5H, J = 11 Hz), 4.52 (d, A of AB, 0.5H, J = 11.5 Hz), 4.37 (d, B of AB, 0.5H, J = 11.5Hz), 4.20 (m, 0.5H), 4.03 (m, 0.5H), 3.80 (m, 0.5H), 3.50 (d, 0.5H, J = 11Hz), 3.3-3.0 (m, 4H), 2.69 (m, 0.5H).

Example 40a

(S) -2-amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one hydrochloride

(S) -2- (N-t-butoxycarbonylamino) -1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one was in 4M HCl dioxanes at 0 ° C solved. The solution was at 25 ° C stirred for an hour, focused on and the residue triturated with ether. Yield 866 mg, 84%.

Example 40b

(S) -2- (N-t-butoxycarbonylamino) -1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one

A solution of m-chloroperoxybenzoic acid (9 mmol) and tert-butyl (S) - (1-benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -carbamate (3 mmol) in dichloromethane (9 ml) became 6 Heated under reflux for hours. The mixture was diluted with ethyl acetate, the resulting solution washed three times with a 1: 1 mixture of 10% aqueous Na ₂ SO ₃ and saturated aqueous NaHCO ₃ , dried and concentrated. The resulting foam was purified by chromatography on silica gel eluted with 20, 30 and 40% ethyl acetate in hexanes to give a colorless foam (979 mg, 89% yield).

Example 40c

(S) - (1-3enzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -carbamic acid tert-butyl ester

thiazolidine (38 mmol) and Boc-L-phenylalanine (19 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, with acid, then washed base) and the product without further purification used. Yield 5.5 g, 86%.

Example 41

5-fluoro-1H-indole-2-carbamic acid, [2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -ethanone hydrochloride (1.0 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 48 hours reaction time) coupled with the following work-up. The reaction mixture was diluted with ethyl acetate and 1N HCl, the resulting suspension was filtered and the collected solid washed with 2N HCl, 2N NaOH and water. The filtered solid was boiled in acetone, filtered and dried. Yield 134 mg, 40%; HPLC (60/40) 3.06 minutes (97%); Mp 239-241 ° C (with decolorization); PBMS 340 (MH +, 70%); 357 (100%)
¹ H NMR (DMSO-d ₆ ) δ 11.74 (s, 1H), 8.82 (m, 1H), 7.43 (m, 2H), 7.17 (s, 1H), 7.05 ( dt, 1H, J = 3.9 Hz), 4.86 (s, 1.2H), 4.52 (s, 0.8H), 4.27 (d, 0, 8H, J = 5.5 Hz ), 4.13 (d, 1.2H, J = 6 Hz, m over it, 1.2H), 3.86 (t, 1.2H, J = 7.4 Hz), 3.58 (t, 0.8H, J = 7Hz), 3.46 (t, 1.2H, J = 7, 2Hz).
Analysis calculated for C ₁₄ H ₁₄ FN ₃ O ₄ S + 0.6 H ₂ O: C, 48.02; H, 4:38; N, 12.00.
Found: C, 47.99; H, 4.04; N, 12.00.

Example 42

5-cyano-1H-indole-2-carboxylic acid - ((1S) -benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -amide

(S) -2-Amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride (4.0 mmol) and 5-cyano-1H-indole-2-carboxylic acid (4.0 mmol The reaction mixture was diluted with ethyl acetate and 2N HCl, the resulting precipitate collected by filtration, washed with 2N HCl and 2N NaOH. The crude product was purified by chromatography on silica gel eluted with 30, 40 and 50% ethyl acetate in hexanes. Yield 1.22 g, 75%; HPLC (60/40), 4.74 minutes (97%); PBMS 405 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₀ N ₄ O ₂ S + 0.5 H ₂ O: C, 63.90; H, 5:12; N, 13.55.
Found: C, 64.18; H, 5.04; N, 13.47.

Example 42a

(S) -2-amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride

(S) - (1-benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -carbamic acid tert-butyl ester (16 mmol) was dissolved in 4M HCl dioxanes at 0 ° C, the solution stirred at 25 ° C for one hour, the Concentrated reaction mixture and the residue triturated with ether. Yield 4.2 g, 95%.

Example 42b

5-cyano-1H-indole-2-carboxylic acid

5-cyano-1H-indole-2-carboxylate (1.71 g, 8.0 mmol) was added to a solution of ethanol (10 mL) and Potassium hydroxide (2 g) was added and the resulting mixture for one hour under reflux heated. Water became dissolving of the precipitate and 6N HCl was added to bring the pH to 1. A precipitate formed. The mixture was in an ice bath cooled, filtered and the resulting colorless solid with cold water washed and dried (1.51 g). One part (1.4 g) was dissolved in hot acetic acid (40 ml) and cooled to give a solid which is filtered with cold ethyl acetate washed and dried: yield 980 mg (70%); HPLC (60/40), 3.09 minutes (97%).

Example 43

1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one hydrochloride (0.56 mmol) and 1H-indole-2-carboxylic acid ( 0.56 mmol) were coupled according to Method A (0-25 ° C reaction temperature) and the product was triturated with 1: 1 ether-hexanes. Yield 213 mg, 92%; HPLC (60/40), 4.15 minutes (99%); PBMS 412 (MH +, 100%);
Analysis calculated for C ₂₁ H ₂₁ N ₃ O ₄ S + 0.5 H ₂ O: 59.99; H, 5:27; N, 9.99.
Found: C, 60.25; H, 5:27; N, 9,98.

Example 44

5-chloro-1H-indole-2-carboxylic acid [2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -ethanone hydrochloride (0.6mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.6mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 120 hours reaction time) coupled with the following work-up: The reaction mixture was diluted with ethyl acetate and 2N HCl, the resulting precipitate was collected by filtration, followed by washing with 2N HCl, 2N NaOH, water and ether , Yield 110 mg, 52%; HPLC (60/40), 3.37 minutes (99%); Mp 236-239 ° C (decomp.); PBMS 356/358 (MH +, 100%);
¹ H NMR (acetone-d ₆ ) δ 11.0 (br, 1H), 8.0 (br, 1H), 7.66 (d, 1H, J = 2 Hz), 7.55 (d, 1H, J = 8.7 Hz), 7.21 (dd, 1H, J = 2.0, 8.7 Hz), 7.15 (d, 1H, J = 2 Hz), 4.77 (s, 1, 1 H), 4.49 (s, 0.9H), 4, 37 (d, 0.9H, J = 5.3 Hz), 4, 27 (d, approx. 1H, J = 5, 3 Hz, 1H), 4, 04 (t, 1, 1H, J = 7 Hz), 3.54 (t, 0.9H, J = 7 Hz), 3.40 (t, 1.1H , J = 7 Hz).
Analysis calculated for C ₁₄ H ₁₄ ClN ₃ O ₄ S + 1.6 H ₂ O: C, 43.72; H, 4.51; N, 10,93.
Found: C, 44.05; H, 3.88; N, 10.99.

Example 45

5-chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl) -amide

2-Amino-1-thiazolidin-3-yl-ethanone hydrochloride (3.1mmol) and 5-chloro-1H-indole-2-carboxylic acid (3.4mmol) were prepared according to Method A (0-25 ° C, 120h The reaction mixture was stirred with ethyl acetate and 2N HCl, filtered and the filtered solid washed with 2N HCl, 2N NaOH and ether. Yield 988 mg, 98%; HPLC (70/30), 3.25 minutes (99%); Mp 253-255 ° C (decomposition, darkening at 243 ° C); PBMS 324/326 (MH +, 100%);
¹ H NMR (acetone-d ₆ ) δ 11.03 (br, 1H), 7.88 (br, 1H), 7.66 (d, 1H, J = 2 Hz), 7.54 (d, 1H, J = 8.3 Hz), 7.21 (dd, 1H, J = 2.0, 8.3 Hz), 4.67 (s, 0.8H), 4.53 (s, 1, 2H), 4.24 (m, 2H), 3.87 ( t, 1, 2H, J = 7Hz), 3.78 (t, 0.8H, J = 7Hz), 3.18 (t, 1.2H, J = 7Hz), 3.05 (t, 0.8H, J = 7 Hz).
A sample was recrystallized from acetic acid for analysis (mp 262-264 ° C):
Analysis calculated for C ₁₄ H ₁₄ ClN ₃ O ₂ S: C, 51.93; H, 4:36; N, 12,98.
Found: C, 51, 78; H, 4, 38; N, 12, 95.

Example 45a

2-Amino-1-thiazolidin-3-yl-ethanone hydrochloride

(2-Oxo-2-thiazolidin-3-yl-ethyl) -carbamic acid tert-butyl ester (5,41 g, 22 mmol) was dissolved in 4M HCl-dioxane (80 ml) at 0 ° C. The resulting solution was 2 hours at 25 ° C touched, focused on and the residue triturated with ether. Yield 3.9 g, 97%.

Example 46

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (4-hydroxy-piperidin-1-yl) -3-phenylpropan-1-one hydrochloride (0.8 mmol) and 5-chloro-1H-indole-2-carboxylic acid ( 0.9 mmoles) were coupled according to Method A (0-25 ° C reaction temperature, 48 hours reaction time) and the product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes, followed by trituration from 1: 1 ether hexanes. Yield 266 mg, 76%; HPLC (60/40), 4.09 minutes (99%), PBMS 426/428 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₄ ClN ₃ O ₃ + 0.33 H ₂ O: C, 63.96; H, 5.76; N, 9,73.
Found: C, 63.90; H, 5.74; N, 9.58.

Example 46a

(S) -2-amino-1- (4-hydroxy-piperidin-1-yl) -3-phenyl-propan-1-one hydrochloride

(S) - [1-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (3.66 g, 10.5 mmol) was dissolved in 4M HCl-dioxane (39 mL) at 0 ° C. The Mixture was at 25 ° C for one hour touched, focused on and the residue triturated with ether. Yield 3.06 g, 102%.

Example 46b

(S) - [1-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

4-hydroxypiperidine (75 mmol) and Boc-L-phenylalanine (38 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 144 hours reaction time) coupled and the product without further Cleaning used. Yield 12.2 g, 96%; HPLC (60/40) 3.45 minutes (97%).

Example 47

5-bromo-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one hydrochloride (0.3 mmol) and 5-bromo-1H-indole 2-carboxylic acid (0.3 mmol) was coupled according to method A (0-25 ° C reaction temperature, first with acid, then base) and the product was purified by chromatography on silica gel eluted with 30, 40 and 50% ethyl acetate in hexanes, cleaned. The product was collected as a whitish foam and triturated with 1: 1 ether-hexanes to give 107 mg, 73%; HPLC (60/40), 6.21 minutes (99%), PBMS 490/492 (MH +, 100%);
¹ H NMR (CDCl ₃ ) δ 9.53 (br, 0.5H), 9.44 (br, 0.5H), 7.78 (d, 0.5H, J = 2 Hz), 7.76 ( d, 0.5H, J = 2Hz), 7.4-7.2 (m, 7H), 7.10 (d, 0.5H, J = 9Hz), 7.02 (d, 0.5H , J = 9 Hz), 6, 86 (s, 0.5H), 6.81 (s, 0.5H), 5.21 (m, 0.5H), 4.95 (m, 0.5H) , 4.62 (d, 0.5H, J = 11 Hz), 4.47 (d, A of AB, 0.5H, J = 13 Hz), 4.38 (d, B of AB, 0.5H , J = 13 Hz), 4.20 (m, 0.5H), 4.03 (m, 0.5H), 3.82 (m, 0.5H), 3.44 (d, 0.5H, J = 11 Hz), 3.33-3.0 (m, 4H), 2.70 (m, 0.5H).
Analysis calculated for C ₂₁ H ₂₀ BrN ₃ O ₄ S + 0.2 H ₂ O: C, 51.06; H, 4,16; N, 8.51.
Found: C, 51.44; H, 4:36; N, 7,93.

Example 48

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2-oxo-2- (3-oxo-pyrrolidin-1-yl) -ethyl] -amide

(S) -1- (2-Amino-3-phenyl-propionyl) -pyrrolidin-3-one hydrochloride (0.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmol) according to method A (0-25 ° C reaction temperature, first washed with acid, then base) and the product purified by chromatography on silica gel eluted with 40% and 50% ethyl acetate in hexanes followed by trituration of the resulting foam with ether. Yield 112 mg, 45%; HPLC (60/40), 5.13 minutes (> 99%), PBMS 410/412 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.19 (m, 1H), 7.60 (m, 1H), 7.3 to 7.15 (m, 8H), 6.86 (m, 1H), 4, 23 (m, 0.5H), 4.95 (m, 0.5H), 4.0-3.7 (m, 3H), 3.27 (m, 1H), 3.15 (m, 1H) , 3.05 (m, 0.5H), 2.85 (d, 0.5H, J = 28Hz), 2.45 (m, 1.5H), 2.15 (m, 0.5H).
Analysis calculated for C ₂₂ H ₂₀ ClN ₃ O ₃ + 0.55 H ₂ O: C, 62.95; H, 5.07; N, 10.01.
Found: C, 63.31; H, 5.09; N, 9,61.

Example 48a

(S) -1- (2-amino-3-phenyl-propionyl) -pyrrolidin-3-one hydrochloride

(S) - [1-Benzyl-2-oxo-2- (3-oxo-pyrrolidin-1-yl) -ethyl] -carbamic acid tert-butyl ester (552 mg, 1.7 mmol) was dissolved in 4M HCl-dioxane (6.2 mL) at 0 ° C. The Mixture was at 25 ° C for one hour touched, focused on and the residue with Ether triturated to give a bright brown solid. Yield 482 mg, 108%.

Example 48b

(S) - [1-Benzyl-2-oxo-2- (3-oxo-pyrrolidin-1-yl) -ethyl] -carbamic acid tert-butyl ester

A solution of dimethyl sulfoxide (4.07 g, 52 mmol) and oxalyl chloride (3.61 g, 28 mmol) was added slowly in order to dichloromethane (50 mL) at -78 ° C. (S) - [1-Benzyl-2- (3-hydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (24 mmol) in dichloromethane (30 ml) became the above solution via cannula, the reaction temperature was brought to -30 ° C for 0.5 h, then lowered to -78 ° C, followed by the addition of triethylamine (118 mmol). The reaction mixture was then warmed to 25 ° C, diluted with ethyl acetate, washed three times with 1: 1 saturated NaHCO ₃ / brine, the organics dried over MgSO ₄ and concentrated. The resulting foam was purified by chromatography on silica gel eluted with 30, 40 and 50% ethyl acetate in hexanes to give a light yellow foam (7.5 g, 95% yield).

Example 48c

(S) - [1-Benzyl-2- (3RS) -hydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

(±) -3-pyrrolidinol (75 mmol) and Boc-L-phenylalanine (38 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, first with acid, then washed base) and the product without further purification used. Yield 12.2 g, 96%; HPLC (60/40), 3.45 minutes (96 %).

Example 49

5-chloro-1H-indole-2-carboxylic acid - ((1S) -benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -amide

(S) -2-Amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol ) were coupled according to Method A (0-25 ° C reaction temperature, 96 hour reaction time, first washed with acid, then base). The crude product was triturated with 1: 1 ether-hexanes and dried. Yield 966 mg, 91%; HPLC (60/40), 7.99 minutes (97%); PBMS 414/416 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.26 (br, 1H), 7.59 (m, 1H), 7.35-7.20 (m, 8H), 6.84 (m, 1H), 5, 14 (m, 1H), 4.61 (d, A of AB, 0.6H, J = 10.3 Hz), 4.52 (d, 0.4H, J = 11.6 Hz), 4.42 (d, B of AB, 0.6H, J = 10.3Hz), 3.88 (m, 0.4H), 3.80-3.65 (m, about 1.5H), 3.2 (m, ca. 2, 5H), 3.04 (m, 0, 4H), 2.95-2.8 (m, 1, 2H), 2.63 (m, 0.6H).
Analysis calculated for C ₂₁ H ₂₀ ClN ₃ O ₂ S + 0.6 H ₂ O: C, 59.39; H, 5.03; N, 9,89.
Found: C, 59.39; H, 4.96; N, 9,52.

Example 50

5-chloro-1H-indole-2-carboxylic acid - ((1S) -benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl) -amide

(S) -2-Amino-3-phenyl-1-thiomorpholin-4-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol) according to method A (0-25 ° C reaction temperature, first washed with acid, then base). The crude product was then triturated with 1: 1 ether-hexanes and dried. Yield 1.03 g, 94%; HPLC (60/40), 8.74 minutes (99%); PBMS 428/430 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₂ S: C, 61.75; H, 5:18; N, 9,82.
Found: C, 62.04; H, 5.58; N, 9,72.

Example 50a

(S) -2-amino-3-phenyl-1-thiomorpholin-4-yl-propan-1-one hydrochloride

(S) - (1-benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl) -carbamic acid tert-butyl ester (17.8 mmol) was dissolved in 4M HCl-dioxane (67 ml) at 0 ° C, the solution stirred for one hour at 25 ° C, the Concentrated reaction mixture and the residue triturated with ether. Yield 5.0 g, 98%; PBMS 251 (MH +, 100%).

Example 50b

(S) - (1-benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl) -carbamic acid tert-butyl ester

Thiomorpholine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to Method A (0-25 ° C reaction temperature) with the following work-up: The reaction mixture was concentrated, diluted with ethyl acetate, then washed three times with 1N HCl, then washed with 2N NaOH, the organic layer dried over MgSO ₄ and concentrated. The resulting foam was used without further purification. Yield 6.3 g, 95%.

Example 51

5-chloro-1H-indole-2-carboxylic acid - [(15) -benzyl-2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one hydrochloride (0.8 mmol) and 5-chloro-1H-indole 2-carboxylic acid (0.8 mmol) was coupled according to Method A (0-25 ° C reaction temperature, washed first with acid, then base). The product was purified by chromatography on silica gel eluted with 30, 40 and 50% ethyl acetate in hexanes, followed by trituration with 1: 1 ether-hexanes. Yield 266 mg, 75%; HPLC (60/40), 5.52 minutes (> 99%), PBMS 446/448 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.21 (br, 0.5H), 9.15 (br, 0, 5H), 7.62 (br, 0.5H, J = 2 Hz), 7.60 ( d, 0.5H, J = 2Hz), 7.35-7.20 (m, 7H), 7.10 (d, 0.5H, J = 8.5Hz), 7.02 (d, 0 , 5H, J = 8.5 Hz), 6.84 (d, 0.5H, J = 2 Hz), 6.81 (d, 0.5H, J = 2 Hz), 5.21 (m, 0 , 5H), 4.93 (m, 0.5H), 4.62 (d, 0.5H, J = 11 Hz), 4.47 (d, A of AB, 0.5H, J = 13 Hz) , 4.39 (d, B of AB, 0.5H, J = 13 Hz), 4.22 (m, 0.5H), 4.03 (m, 0.5H), 3.83 (m, 0 , 5H), 3.44 (d, 0.5H, J = 11 Hz), 3.33-3.0 (m, 4H), 2.67 (m, 0.5H).

Example 52

5-chloro-1H-indole-2-carboxylic acid - [(1S) - (4-chloro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-3- (4-chlorophenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.98 mmol) and 5-chloro-1H- Indole-2-carboxylic acid (0.92 mmol) was coupled according to Method A and the product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes. Yield 362 mg, 86%; HPLC (60/40), 5.06 minutes (97%), m.p. 227-229 ° C, TSPMS 460/462 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₃ Cl ₂ N ₃ O _3: C, 60.01; H, 5.04; N, 9,13.
Found: C, 59.83; H, 5:18; N, 9,16.

Example 52a

(S) -2-amino-3- (4-chloro-phenyl) -1- (4-hydroxy-piperidin-1-yl) propan-1-one hydrochloride

(S) - [1- (4-Chloro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert -butyl ester (475 mg, 1.2 mmol) were dissolved in 4M HCl-dioxane (5 ml) at 0 ° C. The mixture was stirred at 25 ° C for 1.5 hours, concentrated and the residue triturated with ether. Yield 422 mg, 105%; TSPMS 283 (MH +, 100%).

Example 52b

(S) - [1- (4-Chloro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

4-hydroxypiperidine (2.6 mmol) and Boc-L-p-chlorophenylalanine (2.5 mmol) were prepared according to procedures A coupled and the product by chromatography on silica gel, eluted with 1: 1 and 3: 1 ethyl acetate / hexanes, cleaned. Yield 662 mg, 69%.

Example 53

5-chloro-1H-indole-2-carboxylic acid [2- (4-hydroxy-piperidin-1-yl) - (1S) - (1H-imidazol-4-ylmethyl) -2-oxo-ethyl] -amide

(S) -2-Amino-1- (4-hydroxy-piperidin-1-yl) -3- (1H-imidazol-4-yl) -propan-1-one hydrochloride (0.7 mmol) and 5-chloro 1H-indole-2-carboxylic acid (0.7 mmol) was coupled according to Method A (120 hours reaction time, acid wash was omitted). The crude product was triturated twice with ether, with 1: 1 ether-hexanes, and the residue was purified by chromatography on silica gel eluted with 5-20% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 232 mg, 81%; HPLC (40/60) 2.57 minutes (98%); PBMS 416/418 (MH +, 100%);
Anal. Calcd. For C ₂₀ H ₂₂ ClN ₅ O ₃ + 0.55 H ₂ O: C, 56.42; H, 5:47; N, 16,45.
Found: C, 6.07; H, 5.65; N, 16.08.

Example 53a

(S) -2-amino-1- (4-hydroxy-piperidin-1-yl) -3- (1H-imidazol-4-yl) -propan-1-one hydrochloride

(S) - {2- (4-hydroxy-piperidin-1-yl) -2-oxo-1- [1- (toluene-4-sulfonyl) -1H-imidazol-4-ylmethyl] -ethyl} -carbaminsäuretert- butyl ester (512mg, 1.0mmol) were dissolved in 4M HCl-dioxane (3ml) at 0 ° C. The Mixture was 1.5 hours at 25 ° C touched, focused on and the residue triturated with ether. Yield 422 mg, 105%; TSPMS 283 (MH +, 100 %).

Example 53b

(S) - {2- (4-hydroxy-piperidin-1-yl) -2-oxo-1- [1- (toluene-4-sulfonyl) -1H-imidazol-4-ylmethyl] -ethyl} carbamic acid tert-butyl ester

4-hydroxypiperidine (303 mg, 3.0 mmol), triethylamine (394 mg, 3.9 mmol) and diethyl cyanophosphonate (636 mg, 3.9 mmol) were added in order to Boc-N _in tosyl-L-histidine ( J. Med. Chem. 30 536 (1987); 1.32 g, 3.9 mmol) in dichloromethane (10 ml) at 25 ° C. After 120 hours, the solution was diluted with ethyl acetate, washed twice with saturated NaHCO ₃ , dried and concentrated. The residue was purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane. Yield 517 mg, 35%; HPLC (50/50), 4.75 minutes (97%).

Example 54

5-chloro-1H-indole-2-carboxylic acid, (2S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3- (4-hydroxy-piperidin-1-yl) -3- oxo-propyl

(S) -2-Amino-3-hydroxy-1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.89 mmol) and 5-chloro-1H-indole-2-carboxylic acid ( 0.85 mmol) were coupled according to Method A and the product isolated by chromatography, together with the more polar serine analog (40%) on silica gel eluted with 1-16 ethanol in dichloromethane. Yield 51 mg, 16%; HPLC (60/40) 7.06 minutes (96%); PBMS 348/350 (100%), 543/545 (MH +, <5%).
Analysis calculated for C ₂₆ H ₂₄ Cl ₂ N ₄ O ₅ + 0.57 H ₂ O: C, 56.40; H, 4.58, N, 10.12.
Found: C, 56.79; H, 4.90; N, 9,65.

Example 54a

(S) -2-amino-3-hydroxy-1- (4-hydroxy-piperidin-1-yl) propan-1-one hydrochloride

(S) - [1-Hydroxymethyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (595 mg, 2.0 mmol) was dissolved in 4M HCl dioxane (2 mL) at 0 ° C. The Mixture was stirred for one hour at 25 ° C, on concentrated and the residue triturated with ether. Yield 506 mg, 105%; MS 189 (MH +, 100%).

Example 54b

(S) - [1-Hydroxymethyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

4-hydroxypiperidine (6.7 mmol) and Boc-L-Serine (6.4 mmol) were prepared according to Method A (60 hours reaction time). coupled with the following workup: The reaction mixture was focused on the backlog dissolved in chloroform and 1N NaOH (6 ml) and the resulting solution repeated (ten or more times) extracted with chloroform. The chloroform extracts were concentrated and the residue was purified by chromatography on silica gel, eluted with 1-16 % Ethanol in dichloromethane, purified. Yield 751 mg, 41%; HPLC (60/40) 2.72 minutes (96%).

Example 55

5-chloro-1H-indole-2-carboxylic acid - [(1S) - (4-hydroxy-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-3- (4-hydroxy-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.68 mmol) and 5-chloro-1H- indole-2-carboxylic acid (0.65 mmol) was coupled according to Method A (0-25 ° C reaction temperature) with the following workup: The reaction mixture was diluted with ethyl acetate, the resulting solution washed with 1N NaOH (2 mL), the aqueous Extracted layer three times with ethyl acetate, washed the combined organic extracts with 1N HCl, dried and concentrated. The residue was purified by chromatography on silica gel eluted with 1-16 ethanol in dichloromethane. Yield 150 mg, 52%; HPLC (60/40) 3.53 minutes (99%); PBMS 442/444 (100%) (MH +, 100%).
Analysis calculated for C ₂₃ H ₂₄ ClN ₃ O ₄ + 0.5 H ₂ O: C, 61.26; H, 5.59; N, 9,32.
Found: C, 61.52; H, 5.89; N, 8,98.

Example 55a

(S) -2-amino-3- (4-hydroxy-phenyl) -1- (4-hydroxy-piperidin-1-yl) propan-1-one hydrochloride

(S) - [1- (4-Hydroxy-benzyl) -2- (4-hydroxy-1-piperidin-1-yl) -2-oxo-ethyl] -carbamate tert-butyl ester (450 mg, 1.2 mmol) was dissolved in 4M HCl-dioxane (2 ml) at 0 ° C. The Mixture was stirred for one hour at 25 ° C, on concentrated and the residue triturated with ether. Yield 400 mg, 107%; MS 265 (MH +, 100%).

Example 55b

(S) - [1- (4-hydroxy-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

4-Hydroxypiperidine (3.9 mmol) and Boc-L-tyrosine (3.7 mmol) were coupled according to Method A (0-25 ° C reaction temperature, 60 hour reaction time) with the following work-up: The reaction mixture was diluted with ethyl acetate and washed once with base, the base layer was acidified with 2N HCl and extracted three times with chloroform and the chloroform extracts were concentrated. The resulting foam was purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane containing 0.5% NH ₄ OH. Yield 550 mg, 41%; HPLC (40/60) for 5.02 minutes (87%).

Example 56

5-chloro-1H-indole-2-carboxylic acid [2- (4-hydroxy-piperidin-1-yl) -2-oxo- (1S) -pyridin-3-ylmethyl-ethyl] -amide

(S) -2-Amino-1- (4-hydroxy-piperidin-1-yl) -3-pyridin-3-yl-propan-1-one dihydrochloride (0.8 mmol) and 5-chloro-1H-indole 2-carboxylic acid (0.7 mmol) was gekup according to method A (0-25 ° C reaction temperature) pelt and the product purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield 26 mg, 8%; HPLC (50/50), 5.02 minutes (99%); PBMS 427/429 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₃ ClN ₄ O ₃ + 0.5 H ₂ O: C, 60.62; H, 5.55; N, 12,85.
Found: C, 60.57; H, 5.74; N, 12.53.

Example 56a

(S) -2-amino-1- (4-hydroxy-piperidin-1-yl) -3-pyridin-3-yl-propan-1-one dihydrochloride

(S) - [2- (4-hydroxy-piperidin-1-yl) -2-oxo-1-pyridin-3-ylmethyl-ethyl] -carbamic acid tert-butyl ester (367mg, 1.05mmol) was dissolved in 4M HCl-dioxane at 0 ° C. The suspension obtained was stirred for 1.5 hours at 25 ° C, concentrated and the residue triturated with ether. Yield 450 mg, 100%.

Example 56b

(S) - [2- (4-hydroxy-piperidin-1-yl) -2-oxo-1-pyridin-3-yl-methyl-ethyl] -carbamic acid tert-butyl ester

4-hydroxypiperidine (2.9 mmol) and N-t-Boc-L-3- (3-pyridyl) alanine (2.8 mmol) were prepared according to method A (0-25 ° C reaction temperature, 96 hours reaction time, acid washing was omitted) coupled and the product by chromatography on silica gel, eluted with 1-8 % Ethanol in dichloromethane, purified. Yield 454 mg, 46%; MS 350 (MH +, 100%).

Example 57

1 H-indole-2-carboxylic acid - [(1R) - (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(R) -2-Amino-3- (4-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.5 mmol) and 1H-indole-2-one carboxylic acid (0.5 mmol) was coupled according to Method A (0-25 ° C reaction temperature) and the product purified by chromatography on silica gel eluted with 25, 30, 50, 75 and 80 ethyl acetate in hexanes. Yield 150 mg, 60%; HPLC (60/40) 3.66 minutes (97%), m.p. 204-207 ° C, PBMS 410 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₄ FN ₃ O _3: C, 67.47; H, 5.91; N, 10.26.
Found: C, 67.18; H, 6.03; N, 10.21.

Example 57a

(R) -2-amino-3- (4-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) propan-1-one hydrochloride

(R) - [1- (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (2.6 mmol) was dissolved in 4M HCl-dioxane (2 ml) at 0 ° C. The solution was stirred at 25 ° C for 2 hours concentrated and the residue triturated with ether. Yield 920 mg, 124%; HPLC (60/40), 2.23 Minutes (98%).

Example 57b

(R) - [1- (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

4-hydroxypiperidine (3.7 mmol) and (R) -N-t-Boc-p-fluoro-phenylalanine (3.5 mmol) were prepared according to procedures A coupled to give a foam, which without further purification has been used. Yield 940 mg, 73%; HPLC (60/40) 3.64 minutes (95%), MS 367 (MH +, 100%).

Example 58

5-chloro-1H-indole-2-carboxylic acid - [(1R) - (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl) -amide

(R) -2-amino-3- (4-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.6 mmol) and 5-chloro-1H- Indole-2-carboxylic acid (0.6 mmol) was coupled according to Method A and the crude product was purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes. Yield 171 mg, 765%; HPLC (60/40), 4.23 minutes (97%); MS 444/446 (MH +, 100%), TSPMS 444/446 (MH +, 100%).
¹ H NMR _(CDCl3) δ 9.20 (br, 1H), 7.57 (d, 1H, J = 2 Hz), 7.33 (d, 1H, J = 8 Hz), 7.3 to 7 , 2 (m, 2H), 7.14 (m, 2H), 6.97 (m, 2H), 6.85 (m, 1H), 5.34 (m, 1H), 4.05-3.80 (m, 2H), 3.7-3.3 (m, 1.5H), 3.25 (m, 1H), 3.10 (m, 2H), 2.93 (m, 0.5H), 1.9-1.7 (m, 2.5H), 1 , 45 (m, 2H), 1.15 (m, 0.5H).
Analysis calculated for C ₂₃ H ₂₃ ClFN ₃ O ₃ + 0.05 H ₂ O: C, 62.11; H, 5:23; N, 9,45.
Found: C, 62, 51; H, 5, 66; N, 9, 19.

Example 59

5-fluoro-1H-indole-2-carboxylic acid - [(1S) - (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

(S) -2-Amino-3- (4-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.5 mmol) and 5-fluoro-1H- indole-2-carboxylic acid (0.5 mmol) was coupled according to Method A. The crude product was triturated once with 1: 1 ether-hexanes and once with hexanes. The resulting solid was boiled in ethyl acetate, the resulting suspension filtered and the collected solid dried. Yield 103 mg, 48%; HPLC (60/40) 3.69 minutes (95%); PBMS 428 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₃ F ₂ N ₃ O ₃ + 0.25 H ₂ O: C, 63 95; H, 5:48; N, 9,73.
Found: C, 63, 93; H, 5, 66; N, 9, 87.

Example 59a

(S) -2-amino-3- (4-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) propan-1-one hydrochloride

[(S) -1- (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (20.2 g, 55 mmol) was dissolved in 4M HCl-dioxane (25 mL) at 25 ° C. To A thick syrup had precipitated for 3 hours and additional 4M HCl dioxane (10 ml) was added added. The mixture was stirred for 2 hours, concentrated and the solid residue in 4M HCl dioxanes suspended. After 2 hours at 25 ° C, the mixture was concentrated and the residue evaporated twice with ether. The resulting solid became in a mixture of ether (75 ml) and hexanes (10 ml) at 25 ° C for 18 hours touched, the mixture filtered and the filtered solid with 1: 1 ether-hexanes washed and dried to yield a hygroscopic solid (16.3 g, 97%).

Example 59b

[(S) -1- (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

4-hydroxypiperidine (0.29 mol) and (S) -N-t-Boc-p-fluoro-phenylalanine (0.28 mol) were prepared according to procedures A coupled to give crude product as a foam in 84% Yield. A portion of this material (81.6 g) was dissolved in hot ethyl acetate (400 ml) dissolved and hexanes (25 ° C) were the solution obtained, to slight cloudiness occurred, added. The mixture was heated to boiling and the obtained clear solution at 25 ° C overnight cooling down to let. The resulting suspension was filtered and the collected solid with ethyl acetate-hexanes washed and dried (68.1 g, 67%).

Example 60

1 - {(2S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} - (4R) -hydroxy-pyrrolidine- (2S) -carboxylic acid

1 - ((2S) -Amino-3-phenyl-propionyl) - (4R) -hydroxy-pyrrolidine (2S) -carboxylic acid benzyl ester hydrochloride (0.56 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0, 53 mmol) were coupled according to Method A (0-25 ° C reaction temperature, 60 hours reaction time) and the product purified by chromatography on silica gel eluted with 20, 30 and 50% ethyl acetate in hexanes. Yield 26 mg, 8%; HPLC (60/40) 8.14 minutes (98%); PBMS 546/548 (MH +, 100%);
Analysis calculated for C ₃₀ H ₂₈ ClN ₃ O ₅ : C, 65.99; H, 5:17; N, 7,70.
Found: C, 66.14; H, 5:37; N, 7,60.

Example 60a

1 - ((2S) -Amino-3-phenyl-propionyl) - (4R) -hydroxy-pyrrolidine- (2S) -carbonsäurebenzylesterhydrochlorid

1 - ((2S) -tert-butoxycarbonylamino-3-phenyl-propionyl) - (4R) -hydroxy-pyrrolidine (2S) -carboxylic acid benzyl ester (3.0 mmol) was dissolved in 4M HCl-dioxane at 0 ° C. The mixture was stirred at 25 ° C for 1 hour concentrated and the residue triturated with ether. Yield 1.16 g, 96%.

Example 60b

1 - ((2S) -tert-butoxycarbonylamino-3-phenyl-propionyl) - (4R) -hydroxy-pyrrolidine- (2S) -carboxylic acid

trans-L-Hydroxyprolinbenzylester (3.15 mmol) and L-Boc-phenylalanine (3.0 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 1: 1 dichloromethane / dimethylformamide) coupled and the product without used more cleaning. Yield 1.31 g, 99%; HPLC (60/40), 6.1 minutes (95%).

Example 61

5-chloro-1H-indole-2-carboxylic acid - [(1S) - (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl) -amide

(S) -2-Amino-3- (4-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride (0.051 mol) and 5-chloro-1H-indole 2-carboxylic acid (0.051 mol) was coupled according to Method A and the product was purified by chromatography on silica gel eluted with 50%, 75%, 80% and 100% ethyl acetate-hexanes to give a foam (78% yield), HPLC ( 60/40), 4.21 minutes (99%). A portion of this material was recrystallized by dissolving in hot ethyl acetate (about 5 to 7 ml / g) and adding an approximately equal volume of hexanes under reflux, followed by slowly cooling the solution to 25 ° C. The solid was filtered and washed with 1: 4 ethyl acetate-hexanes and dried (70-90% recovery): mp 175-177 ° C;
¹ H NMR (CDCl ₃ ) δ 9, 41 (m, 0.5H), 9.36 (m, 0.5H), 7.59 (d, 1H, J = 2 Hz), 7.37 (d, 1H, J = 8 Hz), 7.29 (dd, 1H, J = 2.9 Hz), 7.20 (dd, 1H, J = 2.0, 8.9 Hz), 7, 14 (m, 2H), 6.95 (m, 2H), 6.86 (m, 1H), 5.34 (m, 1H), 4.05 (m, 0.5H), 3.90 (m, 1.5H ), 3.65 (m, 0.5H), 3.45 (m, 1H), 3.25 (m, 1H), 3.10 (m, 2H), 2.93 (m, 0.5H) , 1.88 (br, 1H, exchanged with D ₂ O), 1.80 (m, 1.5H), 1.45 (m, 2H), 1.12 (m, 0.5H).
PBMS 444/446 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₃ ClFN ₃ O ₃ + 0.2 H ₂ O: C, 61.73; H, 5:27; N, 9,39.
Found: C, 61.40; H, 5:37; N, 9.11.

Example 62

5-chloro-1H-indole-2-carboxylic acid - [(1S) - (methoxy-methyl-carbamoyl) -2-pyridin-3-yl-ethyl] -amide

(2S) -Amino-N-methoxy-N-methyl-3-pyridin-3-yl-propionamide dihydrochloride (1.3 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.25 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 1: 1 dichloromethane / DMF reaction solvent) coupled and the product purified by chromatography on silica gel, eluted with ethyl acetate. Yield 313 mg, 65%; HPLC (60/40), 2, 84 minutes (99%); TSPMS 387/389 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.1 (br, 1H), 8.48 (dd, 1H), 8.43 (m, 1H), 7.60 (d, 1H), 7.50 (m, 1H, J = about 8 Hz), 7.37 (d, 1H, J = about 8 Hz), 7.23 (d, 1H), 7.18 (dd, 1H, J = about 8 Hz) , 7.10 (d, 1H, J = about 8 Hz), 6.82 (d, 1H), 5.42 (m, 1H), 3.78 (s, 3H), 3.25 (s, 3H), 3, 32 (dd, A of AB, 1H, J = about 7.14 Hz), 3.10 (dd, B of AB, 1H, J = about 7.14 Hz).
Anal. Calcd. For C ₁₉ H ₁₉ ClN ₄ O ₃ + 0.4 H ₂ O: C, 57.91; H, 5.07; N, 14:22.
Found: C, 58.19; H, 5:23; N, 13,82.

Example 62a

(2S) -Amino-N-methoxy-N-methyl-3-pyridin-3-yl-propionamiddihydrochlorid

[(1S) - (Methoxy-methyl-carbamoyl) -2-pyridin-3-yl-ethyl] -carbamic acid tert-butyl ester (1.5 mmol) was dissolved in 4M HCl-dioxane at 0 ° C. The resulting solution was 2 hours at 25 ° C touched, focused on and the residue triturated with ether. Yield 390 mg, 95%.

Example 62b

(S) - [1- (Methoxy-methyl-carbamoyl) -2-pyridin-3-yl-ethyl] -carbamic acid tert-butyl ester

N, O-Dimethylhydroxylamine hydrochloride (1.7mmol) and Boc-3-pyridyl-L-alanine (1.6mmol) were added according to method A (0-25 ° C reaction temperature, 2: 1 dichloromethane / dimethylformamide reaction solution tel, acid wash was omitted, Na ₂ SO ₄ was used for drying) coupled. The residue was triturated with ether to give 428 mg (86% yield) of a yellow solid.

Example 63

(R, S) -2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3- (3-fluoro-phenyl) -propionic acid methyl ester

(R, S) -2-Amino-3- (3-fluoro-phenyl) -propionic acid methyl ester (2.05 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.03 mmol) were prepared according to method A ( 0-25 ° C reaction temperature, 1: 1 dichloromethane / DMF reaction solvent) and the product purified by chromatography on silica gel eluted with 10.20 and 40% ethyl acetate in hexanes. The residue was triturated with 1: 1 ether-hexanes and hexanes to give an off-white solid (484 mg, 63%): HPLC (60/40), 8.13 minutes (95%); TSPMS 375/377 (MH +, 100%).
¹ H NMR (CDCl ₃ ) δ 9.26 (br, 1H) 7.60 (d, 1H, J = ca. 1 Hz), 7.35 (d, 1H, J = 8.7 Hz), 7, 25 (m, 2H), 6.95 (m, 1H), 6, 91 (m, 1H), 6.84 (m, 1H), 6, 77 (d, 1H, J = 1.5 Hz), 6, 63 (d, 1H, J = 7.7 Hz), 5.08 (m, 1H), 3.78 (s, 3H), 3.28 (dd, 1H, A of AB, J = 5, 7.14 Hz), 3.21 (dd, 1H, B of AB, J = 5, 5.14 Hz).
Anal. Calcd. For C ₁₉ H ₁₆ ClFN ₂ O ₃ : C, 60.89; H, 4.30; N, 7,47.
Found: C, 60.79; H, 4.58; N, 7,18.

Example 63a

(R, S) -2-Amino-3- (3-fluoro-phenyl) -propionic acid, methyl ester hydrochloride

trimethylsilylchloride (1.07 g, 9.9 mmol) was added to a suspension of m-fluoro-DL-phenylalanine (0.404 g, 2.2 mmol) in methanol (4 ml) at 25 ° C. The resulting solution was 1 hour under reflux brought, cooled and focused on. The residue was triturated with ether. Yield 515 mg, 100%; HPLC (60/40), 2.31 minutes (95%).

Example 64

5-chloro-1H-indole-2-carboxylic acid - [(1S) - (methoxy-methyl-carbamoyl) -2-thiophen-2-yl-ethyl] -amide

(S) -2-Amino-N-methoxy-N-methyl-3-thiophen-2-yl-propionamide hydrochloride (1.2 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.2 mmol) according to method A (0-25 ° C reaction temperature, 2: 1 dichloromethane / dimethylformamide reaction solvent) coupled. The crude product was purified by chromatography on silica gel eluted with 10.20, 30 and 40% ethyl acetate in hexanes. Yield 375 mg, 80%; HPLC (60/40) 6.36 minutes (99%); PBMS 392/394 (MH +, 100%);
¹ H NMR (CDCl ₃ ) δ 9.33 (br, 1H), 7.60 (d, 1H, J = ca. 1 Hz), 7.30 (d, 1H, J = 8.8 Hz), 7 , 20 (dd, 1H, J = 2.0, 8.7 Hz), 7.15 (dd, 1H, J = 1.5, 0 Hz), 6.91 (dd, 1H, J = 3.4 , 5.1 Hz), 6.86 (d, 1H, J = 1.6 Hz), 6.84 (d, 1H, J = about 2 Hz), 5.40 (m, 1H), 3, 77 (s, 3H), 3.46 (dd, 1H, A of AB, J = 6.2, approx. 14 Hz), 3.37 (dd, 1H, B of AB, J = 6.2, approx 14.2 Hz), 3.25 (s, 3H).
Analysis calculated for C ₁₈ H ₁₈ ClN ₃ O ₃ S + 0.25 C ₄ H ₈ O _2: C, 55.15; H, 4,87; N, 10.15.
Found: C, 55.41; H, 4.79; N, 10,17.

Example 64a

(S) 2-Amino-N-methoxy-N-methyl-3-thiophen-2-yl-propionamide hydrochloride

(S) - [1- (Methoxy-methyl-carbamoyl) -2-thiophen-2-yl-ethyl] -carbamic acid tert-butyl ester (1.3 mmol) was dissolved in 4M HCl-dioxane (1 ml) at 0 ° C and the resulting solution two Hours at 25 ° C touched. The mixture was concentrated and the residue triturated with ether to give a yellow solid (321 mg, 96%); HPLC (60/40) 2.24 minutes (98%); MS 215 (MH +, 100%).

Example 64b

(S) - [1- (Methoxy-methyl-carbamoyl) -2-thiophen-2-yl-ethyl] -carbamic acid tert-butyl ester

N, O-dimethylhydroxylamine hydrochloride (1.4 mmol) and Boc- (2-thienyl) -L-alanine (1.3 mmol) was prepared according to procedures A (0-25 ° C reaction temperature) coupled with recovery of the product without further purification has been used. Yield 426 mg, 104%.

Example 65

(RS) -2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3- (4-fluoro-phenyl) -propionic acid methyl ester

(R, S) -2-Amino-3- (3-fluoro-phenyl) -propionic acid methyl ester (3.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.9 mmol) were prepared according to method A ( 0-25 ° C reaction temperature, 3: 2 dichloromethane / dimethylformamide reaction solvent) coupled and the resulting crude product triturated with 1: 1 ether-hexanes. Yield 1.03 g, 92%; HPLC (60/40), 7.95 minutes (96%); PBMS 375/377 (MH +, 100%);
¹ H NMR (CDCl ₃ ) δ 9.30 (br, 1H), 7.60 (d, 1H, J = ca. 1 Hz), 7.35 (d, 1H, J = 8.8 Hz), 7 , 25 (dd, 1H, J = 2.0, 8.7 Hz), 7.10 (m, 2H), 6.97 (m, 2H), 6.77 (d, 1H, J = 2 Hz) , 6.62 (d, 1H, J = 7.8 Hz), 5.06 (m, 1H), 3.78 (s, 3H), 3.27 (dd, 1H, A of AB, J = 7 , 14 Hz), 3, 19 (dd, 1H, B of AB, J = 7, 14 Hz).
Anal. Calcd. For C ₁₉ H ₁₆ ClFN ₂ O ₃ : C, 60.89; H, 4.30; N, 7,47.
Found: C, 60.74; H, 4:36; N, 7.55.

Example 66

5-chloro-1H-indole-2-carboxylic acid [2- (4-amino-phenyl) - (1S) -dimethylcarbamoyl-ethyl] -amidh hydrochloride

(S) -2-Amino-3- (4-amino-phenyl) -N, N-dimethyl-propionamide dihydrochloride (0.7 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmol) according to method A (0-25 ° C reaction temperature, 3: 1 dichloromethane / DMF reaction solvent, washed with base only) and the product purified by chromatography on silica gel eluting with 1-16% ethanol in dichloromethane with 0.5% NH ₄ 0H , cleaned. The combined fractions were concentrated, dissolved in methanol at 0 ° C, and the resulting solution treated with 1.0 1N HCl (1.05 eq.). After 5 minutes, the reaction mixture was concentrated and the residue triturated with ether to give an orange solid (79 mg, 29% yield): TSPMS 385/387 (MH +, 100%);
Analysis calculated for C ₂₀ H ₂₁ ClN ₄ O ₂ + 1.5 HCl: C, 54.65; H, 5:16; N, 12,75.
Found: C, 54, 96; H, 5, 53; N, 12, 53.

Example 66a

(S) -2-amino-3- (4-amino-phenyl) -N, N-dimethyl-propionamiddihydrochlorid

(S) - [2- (4-Amino-phenyl) -1-dimethylcarbamoyl-ethyl] -carbamic acid tert-butyl ester (214 mg, 0.7 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0 ° C and the solution 2 hours at 25 ° C touched. The mixture was concentrated and the residue triturated with ether. Yield 294 mg, 102%; PBMS 208 (MH +, 100%).

Example 66b

(S) - [2- (4-Amino-phenyl) -1-dimethylcarbamoyl-ethyl] -carbamic acid tert-butyl ester

dimethylamine (2.04 mmol) and Boc-p-amino-L-phenylalanine (1.7 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 4: 1 dichloromethane / dimethylformamide reaction solvent, washed with base only) coupled. The product was purified by chromatography on silica gel, eluted with 50, 60, 70 and 100% ethyl acetate in hexanes. Yield 226 mg, 42%; HPLC (70/30) 2.45 minutes (100%).

Example 67

5-chloro-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-3-phenylpropyl) -amide

(S) -2-Amino-N, N-dimethyl-4-phenylbutyramide hydrochloride (0.76 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.76 mmol) were prepared according to Method A (0- 25 ° C reaction temperature, 3: 1 dichloromethane / DMF reaction solvent) and the product purified by chromatography on silica gel eluted with 10, 20, 30, 40, 50 and 60% ethyl acetate in hexanes. Yield 263 mg, 90%; HPLC (60/40) 7.12 minutes (99%); TSPMS 384/386 (MH +, 100%);
Analysis calculated for C ₂₁ H ₂₂ ClN ₃ O _2: C, 65.71; H, 5.78; N, 10.95.
Found: C, 65, 34; H, 5, 93; N, 10, 91.

Example 67a

(S) -2-amino-N, N-dimethyl-4-phenyl-butyramide hydrochloride

(S) - (1-dimethylcarbamoyl-3-phenyl-propyl) -carbamic acid tert-butyl ester (235 mg, 0.8 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0 ° C. The mixture was 1.5 hours at 25 ° C touched, focused on and the residue triturated with ether. Yield 187 mg, 100%; HPLC (60/40), 2.31 Minutes (99%).

Example 67b

(S) - (1-dimethylcarbamoyl-3-phenyl-propyl) -carbamic acid tert-butyl ester

dimethylamine (1.0 mmol) and (S) -N-t-butoxycarbonyl-2-amino-4-phenylbutyric acid (0.84 mmol). were according to procedures A (0-25 ° C reaction temperature, 3: 1 dichloromethane / DMF reaction solvent) coupled with recovery of the product without further purification has been used. Yield 283 mg, 93%; HPLC (60/40) 5.98 minutes (97%).

Example 68

5-chloro-1H-indole-2-carboxylic acid - ((1S) -dimethyl-carbamoyl-2- (4-hydroxy-phenyl) ethyl] -amide

(S) -2-Amino-3- (4-hydroxy-phenyl) -N, N-dimethyl-propionamide hydrochloride (1.05 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.0 mmol) according to method A (0-25 ° C reaction temperature, 2: 1 dichloromethane / DMF reaction solvent, washed with acid only) and the product purified by chromatography on silica gel eluted with 20, 40, 50 and 75% ethyl acetate in hexanes, followed by Trituration with ether. Yield 400 mg, 104%; HPLC (60/40) 3.93 minutes (98%); Mp 228-231 ° C (decomposition, yellowed at 210 ° C); TSPMS 386/388 (MH +, 100%);
Analysis calculated for C ₂₀ H ₂₀ ClN ₃ O ₃ + 0.9 H ₂ O: C, 59.75; H, 5:47; N, 10.45.
Found: C, 61.05; H, 5.79; N, 10.08.

Example 68a

(S) -2-amino-3- (4-hydroxy-phenyl) -N, N-dimethyl-propionamide hydrochloride

(S) - [1 -Dimethylcarbamoyl-2- (4-hydroxy-phenyl) -ethyl] -carbamic acid tert-butyl ester (5.7 g, 18.5 mmol) was dissolved in 4M HCl-dioxane (7 mL) at 0 ° C. The Mixture was 3 hours at 25 ° C touched, focused on and the residue triturated with ether. Yield 5.23 g, HPLC (60/40), 3.32 minutes (98%).

Example 68b

(S) - [1 -Dimethylcarbamoyl-2- (4-hydroxy-phenyl) -ethyl] -carbamic acid tert-butyl ester

dimethylamine (79 mmol) and Boc-L-tyrosine (66 mmol) were prepared according to method A (0-25 ° C reaction temperature, 12: 1 dichloromethane / DMF reaction solvent, 60 hours reaction time) and the product by chromatography on silica gel, eluted with 10.20, 30.50 and 70 ethyl acetate in hexanes, cleaned. Yield 20.6 g, 102%; HPLC (60/40) 3.21 Minutes (96%).

Example 69

5-chloro-1H-indole-2-carboxylic acid - ((1S) -methoxycarbamoyl-2-phenyl-ethyl) -amide

(2S) -Amino-N-methoxy-3-phenyl-propionamide hydrochloride (1.02 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.02 mmol) were coupled according to Method A. The residue was triturated with ether to give a light yellow solid. Yield 160 mg, 36%; Mp 210-213 ° C (decomposition); PBMS 372/374 (MH +, 100%);
Analysis calculated for C ₁₉ H ₁₈ ClN ₃ O ₃ + 1.75 H ₂ O: C, 56.58; H, 5:37; N, 10.42.
Found: C, 56.88; H, 5.09; N, 10.03.

Example 69a

(2S) -Amino-N-methoxy-3-phenyl-propionamide hydrochloride

[(1S) - (Methoxy-carbamoyl) -2-phenyl-ethyl] -carbamic acid tert-butyl ester (200mg, 0.68mmol) was dissolved in 4M HCl-dioxane at 0 ° C and the mixture stirred at 25 ° C. To 0.5 hours, the mixture was concentrated and the residue triturated with ether.

Example 69b

[(1S) - (Methoxy-carbamoyl) -2-phenyl-ethyl] -carbamic acid tert-butyl ester

methoxyamine (83.5 mmol) and Boc-L-phenyl-alanine (20 mmol) were prepared according to method A coupled and the product by chromatography on silica gel, eluted with 1: 1 and 2: 1 ethyl acetate / hexanes, followed by trituration with ether, purified. Yield 1.80 g, 31 %.

Example 70

5-chloro-1H-indole-2-carboxylic acid - ((1 R) -methyl-2-phenyl-ethyl) -amide

(R) -2-Amino-N-methyl-3-phenyl-propionamide hydrochloride (0.84 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.84 mmol) were prepared according to Method A (0-25 ° C reaction temperature) coupled. The crude product was triturated with dichloromethane and then ether and dried. Yield 236 mg, 79%; HPLC (60/40), 4.63 minutes (97%); PBMS 356/358 (MH +, 100%);
Analysis calculated for C ₁₉ H ₁₈ ClN ₃ O ₂ + 0.25 H ₂ O: C, 63.33; H, 5:18; N, 11,66.
Found: C, 63.37; H, 5.50; N, 12.06.

Example 70a

(R) -2-Amino-N-methyl-3-phenyl-propionamide hydrochloride

(R) - (1-Methylcarbamoyl-2-phenyl-ethyl) -carbamic acid tert -butyl ester (722 mg, 2.6 mmol) was dissolved in 4M HCl-dioxane (10 ml) at 0 ° C. The Mixture was at 25 ° C for one hour touched, focused on and the residue triturated with ether. Yield 517 mg, 93%.

Example 70b

(R) - (1-methylcarbamoyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester

Methylamine hydrochloride (3.1 mmol) and Boc-D-phenyl-alanine (2.8 mmol) were prepared according to procedures A (0-25 ° C reaction temperature, 144 hours reaction time, first washed with acid, then base) recovering the product used without further purification has been. Yield 760 mg, 96%.

Example 71

5,6-dichloro-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (0.06 mmol) and 5,6-dichloro-1H-indole-2-carboxylic acid (0.06 mmol) were prepared according to method A ( 0-25 ° C reaction temperature, 96 hours reaction time). The crude product was triturated with 1: 1 ether-hexanes and dried. Yield 24 mg, 96%; HPLC (60/40) 8.05 minutes (97%); PBMS 405/407 (MH +, 100%);
Analysis calculated for C ₂₀ H ₁₉ Cl ₂ N ₃ O ₂ + 0.25 H ₂ O: C, 58.76; H, 4.81; N, 10.28.
Found: C, 58, 95; H, 4, 89; N, 9, 90.

Example 71a

(S) -2-amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride

Tert-Butyl (1-dimethylcarbamoyl-2-phenyl-ethyl) -carbamate (8.6 g, 29 mmol) was dissolved in 4M HCl-dioxane (110 ml) at 0 ° C and the mixture was stirred at 25 ° C for one hour. The mixture was on concentrated and triturated the solids with ether. Yield 6.2 g, 92%; PBMS 193 (MH +, 100%).

Example 71b

5,6-dichloro-1H-indole-2-carboxylic acid

zinc dust (3.52 g, 54 mmol) slowly became a warm solution of 3,4-Dichloro-5-nitrophenylpyruvic acid (1.5 g, 5.4 mmol) in acetic acid (15 ml). After a few minutes, a violent reaction occurred (Exotherm). The resulting solution was at 80 ° C heated and the reaction appeared complete (TLC). The mixture was filtered, the filtered solids washed with acetic acid and the filtrate focused on. The residue was dissolved in 2N NaOH, the solution obtained washed with ether (3x), dichloromethane (2x) and with 6N HCl acidified to pH 1 and with ethyl acetate extracted. The extracts were dried and concentrated to give a tan solid (458 mg, 34%); HPLC (60/40) 5, 31 (93%).

Example 71c

3,4-dichloro-5-nitrophenylpyruvic acid

absolute Ethanol (25 ml) became at 3-15 ° C stirred A mixture of potassium metal (2.67 g, 68 mmol) in ether (100 ml) was added. The resulting solution was at 3 ° C with a solution of diethyl oxalate (10.0 g, 62 mmol) within 5-10 Minutes treated and the resulting solution for 30 minutes at 3 ° C and 18 Hours at 25 ° C touched. The mixture was filtered and the resulting solid with ether washed and dried (13.7 g). This material (12.7 g) was in 400 ml of hot Solved water, the solution cooled and extracted with ether. The resulting aqueous layer was washed with conc. HCl acidified to pH 2 and the ether layer separated, dried and concentrated to give 7.5 g of a solid which was triturated with hexanes to give the title substance as a yellow solid (1.07 g, 41%).

Example 72

5-bromo-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (1.0 mmol) and 5-bromo-1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to Method A (0- 25 ° C reaction temperature) coupled and the resulting foam triturated with 1: 1 ether-hexanes and dried. Yield 374 mg, 90%; HPLC (60/90) 6.17 minutes (98%); Mp 199-201 ° C, PBMS 414/416 (MH +, 100%);
Analysis calculated for C ₂₀ H ₂₀ BrN ₃ O ₂ - C, 57.98; H, 4,82; N, 10,14.
Found: C, 58.07; H, 5:12; N, 10.08.

Example 73

5-methyl-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (1.0 mmol) and 5-methyl-1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to method A (0- 25 ° C reaction temperature) coupled. The crude product was triturated with 1: 1 ether-hexanes and dried. Yield 302 mg, 87%; HPLC (60/40) 5, 46 minutes (99%); Mp 198.5-200 ° C, PBMS 350 (MH +, 100%);
Analysis calculated Ha _{21 3} N ₃ O ₂ C: C, 72.18; H, 6.63; N, 12.04.
Found: C, 72.14; H, 6.90; N, 12.11.

Example 74

5-methoxy-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (1.0 mmol) and 5-methoxy-1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to Method A (0- 25 ° C reaction temperature, 60 hours reaction time) coupled and triturated the resulting foam with ether. Yield 329 mg, 90%; HPLC (60/40) 4.27 minutes (99%); PBMS 366 (MH +, 100%);
Analysis calculated for C ₂₁ H ₂₃ N ₃ O ₃ + 0.125 H ₂ O: C, 68.60; H, 6:37; N, 11,43.
Found: C, 68.50; H, 6, 34; N, 11, 45.

Example 75

5-fluoro-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (1.0 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to Method A (0- 25 ° C reaction temperature, 60 hours reaction time) and the resulting solid triturated with ether. Yield 320 mg, 91%; HPLC (60/40) 4.74 minutes (100%); Mp 229.5-232 ° C; PBMS 354 (MH +, 100%);
Analysis calculated for C ₂₀ H ₂₀ FN ₃ O ₂ : C, 67, 97; H, 5, 70; N, 11,89.
Found: C, 67.88; H, 5.74; N, 11,71.

Example 76

5-cyano-1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (0.16 mmol) and 5-cyano-1H-indole-2-carboxylic acid (0.16 mmol) were prepared according to Method A (0- 25 ° C reaction temperature) and the product was purified by chromatography on silica gel, eluted with 1: 1 ethyl acetate / hexanes. Yield 38 mg, 66%; HPLC (60/40) 4.08 minutes (97%); PBMS 361 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 12.1 (br, 1H), 9.04 (d, 1H, J = 8.1 Hz), 8.27 (s, 1H), 7.52 (m, 2H), 7.43 (m, 1H), 7.33 (m, 2H), 7.25 (m, 2H), 7.18 (m, 1H), 5.10 (m, 1H), 3, 03 (m, 2H), 3.00 (s, 3H), 2.83 (s, 3H).
Analysis calculated for C ₂₁ H ₂₀ N ₄ O ₂ + 0.5 H ₂ O: C, 68.28; H, 5.73; N, 15:17.
Found: C, 68.51; H, 5.66; N, 14,85.

Example 76a

5-cyano-1H-indole-2-carboxylic acid

5-cyano-1H-indole-2-carboxylate (1.71 g, 8.0 mmol) was added to a solution of ethanol (10 mL) and Potassium hydroxide (2 g) was added and the resulting mixture for 1 hour under reflux heated. Water became dissolving the precipitate was added and 6N HCl was added to the pH to bring to 1. The mixture was cooled in an ice bath, filtered and the resulting colorless solid washed with cold water and dried (1.51 g). A portion (1.4 g) was dissolved in hot acetic acid (40 ml) and cooled to give a solid which is filtered with cold ethyl acetate washed and dried: Yield 980 mg, 70%, HPLC (60/40), 3.09 minutes (97%).

Example 76b

5-cyano-1H-indole-2-carboxylate

zinc dust (57.8 g, 887 mmol) became a hot suspension of ethyl 3-cyano-5-nitrophenylpyruvate (23.2 g, 88 mmol) in acetic acid (225 ml) and water (225 ml, careful !, vigorous initial Exothermic) at a rate added to the reflux and the reaction was refluxed for 0.5 hours held. The mixture was filtered, the filtered salts with hot Acetic acid (150 ml) and the filtrate over Night cooled yielding crystals which were filtered with cold 1: 1 acetic acid-water, Water and dried (10.11 g, 53%). The filtrate was concentrated, the residue in ethyl acetate solved and the resulting solution with saturated, aqueous sodium bicarbonate, saline solution washed, dried and concentrated to give a second Batch (5.05 g). The main amount was in subsequent conversions used.

Example 76c

Ethyl 3-cyano-5-nitro-henylpyruvate

A solution of sodium ethoxide in ethanol (from 2.2 g, 400 mmol sodium metal in 400 mL ethanol) was added at 0 ° C to a mixture of distilled diethyl oxalate (120 g, 821 mmol) and 3-methyl-4-nitrobenzonitrile (32 g , 197 mmol). The resulting red solution was heated to 40 ° C for 18 hours. The cooled mixture was diluted with water (600 ml) and conc. HCl acidified to pH 2.1. The precipitate formed was collected by filtration of the mixture at 13 ° C, dried and purified by chromatography on silica gel eluted with 15, 30 and 50% acetone-hexanes to give an orange solid which was used without purification (23.6 g, 31%). A sample was recrystallized from ethyl acetate for characterization.

Example 77

1H-indole-2-carboxylic acid - ((1S) -dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-Amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (1.0 mmol) and 1H-indole-2-carboxylic acid (1.0 mmol) were prepared according to Method A (0-25 ° C reaction temperature ) coupled. The resulting solid was triturated with hexanes, then with ether. Yield 272 mg, 81%; HPLC (70/30), 3.49 minutes (99%); Mp 199-200 ° C; PBMS 336 (MH +, 100%);
Analysis calculated for C ₂₀ H ₂₁ N ₃ O ₂ : C, 71.62; H, 6.31; N, 12.53.
Found: C, 71.45; H, 6:39; H, 12.50.

Example 78

5-chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2 - ((3S, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide

(3S, 4S) -2-Amino-1- (3,4-dihydroxypyrrolidin-1-yl) -3-phenyl-propan-1-one hydrochloride (0.94 mmol) and 5-chloro-1H- Indole-2-carboxylic acid (1.03 mmol) was coupled according to Method A (170 hours reaction time) and the crude product purified by column chromatography on silica gel eluted with ethyl acetate. Yield 150 mg, 37%; HPLC (60/40), 3.08 minutes (96%);
¹ H NMR (DMSO-d ₆ ) δ 11.73 (s, 1H), 8.90 (d, 1H, J = 8.5 Hz), 7.72 (d, 1H, J = 1.5 Hz) , 7.39 (d, 1H, J = 8.7 Hz), 7.30 (m, 2H), 7.30-7.1 (m, 5H), 5.22 (m, 1H), 5, 13 (m, 1H), 4.91 (m, 1H), 3.97 (m, 1H), 3.91 (m, 1H), 3.60 (m, 2H), 3.5-3.2 (m, 2H), 3.00 (m, 2H).
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O _4: C, 61.75; H, 5:18; N, 9,82.
Found: C, 61.65; H, 5.45; N, 9,17.

Example 78a

(3S, 4S) -2-Amino-1- (3,4-dihydrox-pyrrolidin-1-yl) -3-phenyl-propan-1-one hydrochloride

(3S, 4S) - [1-Benzyl-2- (3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (360mg, 1.00mmol) was dissolved in 4M HCl-dioxane (4ml) at 25 ° C for 3 hours solved. The mixture was concentrated and the resulting yellow solid triturated with ether and dried. Yield 304 mg, 103%.

Example 78b

[-1-benzyl-2- (3,4-dihydroxy-pyrrolidin-1-yl-2-oxo-ethyl] -carbamic acid tert-butyl ester

Boc-L-phenylalanine (2.2 mmol) and (3S, 4S) -dihydroxypyrrolidine (U.S. Patent No. 4,634,775, Example 1C, 206 mg, 2.0 mmol) were prepared according to Method A (0-25 ° C reaction temperature). coupled to give a colorless solid which without further Cleaning was used. Yield 431 mg, 61%.

Example 79

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2 - ((3RS) -hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

2 (S) -Amino-1 - ((3RS) -hydroxy-piperidin-1-yl) -3-phenylpropan-1-one hydrochloride (570 mg, 2.0 mmol) and 5-chloro-1H-indole-2-one carboxylic acid (429 mg, 2.2 mmol) were coupled according to Method A (5: 2 dichloromethane - dimethylformamide solvent) and the crude product was triturated with 1: 1 ether - hexanes. The resulting solid was purified by column chromatography on silica gel eluted with 3: 2 and 2: 1 ethyl acetate / hexanes, followed by trituration with 1: 1 ether / hexanes. Yield 430 mg, 51%; HPLC (60/40) 3.45 minutes (95%);
Analysis calculated for C ₂₃ H ₂₄ ClN ₃ O ₃ + 0.125 C ₆ H _14: C, 65.32; H, 5.94; N, 9,62.
Found: C, 65.01; H, 6,19; N, 9,22.

Example 79a

(2S) -amino-1- (3-hydroxy-piperidin-1-yl) -3-phenyl-propan-1-one hydrochloride

[(1S) -benzyl-2 - ((3RS) -hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (7.13g, 20mmol) was dissolved in 4M HCl-dioxane (40ml) at 25 ° C for 3 hours. The Mixture was concentrated and the resulting oil was added Ether stirred for 72 hours. The resulting suspension was filtered and the solid was treated with ether washed and dried. Yield 5, 64 g, 99%.

Example 79b

[(1S) -benzyl-2 - ((3RS) -hydroxy-piperidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

Boc-L-phenylalanine (8.17 mg, 30.8 mmol) and 3-hydroxypiperidine hydrochloride (4.24 g, 30.8 mmol) were prepared according to procedures A coupled to give the title compound as an oil without further cleaning was used. Yield 7.79 g, 73%.

Example 80

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2-oxo-2- (3-oxo-piperazin-1-yl) -ethyl] -amide

4 - ((2S) -Amino-3-phenyl-propionyl) -piperazin-2-one hydrochloride (140 mg, 0.5 mmol) and 5-chloro-1H-indole-2-carboxylic acid (98 mg, 0.5 mmol ) were coupled according to Method A and the crude product purified by column chromatography on silica gel, eluting with ethyl acetate and 2% ethanol in ethyl acetate, followed by trituration with ether. Yield 71 mg, 33%: HPLC (60/40), 3.53 minutes (100%); PBMS 425/427 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.78 (br, 0.5H), 11.76 (br, 0.5H), 9.03 (m, 0.5H), 9.02 (m, 0 , 5H), 8.06 (m, 0.5H), 8.04 (m, 0.5H), 7.73 (d, 1H, J = 2 Hz), 7.38 (d, 1H, J = 8.7 Hz), 7.32 (m, 2H), 7.20 (m, 2H), 7.2-7.1 (m, 2H), 5.15 (m, 0.5H), 5, 05 (m, 0.5H), 4.20 (d, 0.5H, J = 17Hz), 4.08 (d, 0.5H, J = 17Hz), 3.85 (d, 0.5H , J = 17 Hz), 3.9 (m, 0.5H), 3.6 (m, 2H), 3.2-2.9 (m, 4H).

Example 80a

4 - ((2S) -Amino-3-phenyl-propionyl) -piperazine-2-one hydrochloride

[(1S) -benzyl-2-oxo-2- (3-oxo-piperazin-1-yl) -ethyl) -carbamic acid tert-butyl ester (400mg, 1.2mmol) in 4M HCl-dioxane (10ml) at 25 ° C for 0.5h solved. The mixture was concentrated and the residue was combined with dichloromethane evaporated, triturated with ether and dried. Yield 340 mg, 103 %.

Example 80b

[(1S) -benzyl-2-oxo-2- (3-oxo-piperazin-1-yl) -ethyl] -carbamic acid tert-butyl ester

Boc-L-phenylalanine (530mg, 2mmol) and piperazin-2-one (J. Am. Chem. Soc., 62, 1202 (1940), 200 mg, 2 mmol) were prepared according to procedures A (2: 1 dichloromethane / dimethylformamide reaction solvent, washed with 1N NaOH after acid washings) coupled and the product used without further purification. yield 404 mg, 58%.

Example 81

5-chloro-1H-indole-2-carboxylic acid - ((1S) -methyl-2-morpholin-4-yl-2-oxo-ethyl) -amide

(2S) -Amino-1-morpholin-4-yl-propan-1-one hydrochloride (195 mg, 1.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (195 mg, 1.0 mmol) according to Method A (washed with 1N NaOH after acid washings) to give crude product which was triturated with ether and dried. Yield 150 mg, 45%: HPLC (60/40) 3.51 minutes (100%); PBMS 336/338 (MH +, 100%);
Analysis calculated for C ₁₆ H ₁₈ ClN ₃ O _3: C, 57.23; H, 5.40; N, 12.51.
Found, 57.01; H, 5:49; N, 12,24.

Example 81a

s (2S) -Amino-1-morpholin-4-yl-propan-1-one hydrochloride

((1S) -Methyl-2-morpholin-4-yl-2-oxo-ethyl) -carbamic acid tert-butyl ester (3.88 g, 15 mmol) was dissolved in 4M HCl-dioxane (20 mL) at 25 ° C for 1.25 hours. The Mixture was concentrated and the residue triturated with ether and dried: yield 2.51 g, 86%.

Example 81b

((1S) -Methyl-2-morpholin-4-yl-2-oxo-ethyl) -carbamic acid tert-butyl ester

Boc-L-alanine (3.50 mg, 20 mmol) and morpholine (1.74 g, 20 mmol) were prepared according to procedures A (washed with 1N NaOH after acid washings) coupled to give a colorless oil, which without further purification has been used. Yield 3, 94 g, 76%.

Example 82

5-chloro-1H-indole-2-carboxylic acid - ((1S) -methyl-2-phenyl-ethyl) -amide

(2S) -Amino-N-methyl-3-phenyl-propionamide hydrochloride (214 mg, 1.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (195 mg, 1.0 mmol) were coupled according to Method A. and the crude product triturated with ether and dried. Yield 160 mg, 45%: HPLC (60/40), 4.60 minutes (100%);
¹ H NMR (DMSO-d ₆ ) δ 11.70 (br, 1H), 8.73 (d, 1H, J = 8.5 Hz), 8.08 (q, 1H, J = 4.6 Hz) , 7.72 (d, 1H, J = 1.9 Hz), 7.39 (d, 1H, J = 8.8 Hz), 7.32 (m, 2H), 7.25-7.10 ( m, 5H), 4.68 (m, 1H), 3.10 (dd, A of AB, 1H, J = 4.2, 13 Hz), 2.96 (dd, 1H, J = 10.7, 13 Hz), 2.62 (d, 3H, J = 4.6 Hz).

Example 82a

(2S) -Amino-N-methyl-3-phenyl-propionamide hydrochloride

[((1S) -1-methylcarbamoyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester (2.35 g, 8.45 mmol) was dissolved in 4M HCl-dioxane (20 mL) at 25 ° C for 2 hours. The Mixture was concentrated and the residue triturated with ether and dried. Yield 1.70 g, 94%.

Example 82b

((1 S) -1-methylcarbamoyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester

Boc-L-phenylalanine (2.65 g, 10 mmol) and methylamine hydrochloride (675 mg, 10 mmol) according to procedure A (washed with 1N NaOH after acid washings) coupled to give the title compound as a colorless solid, which was used without further purification. Yield 2.41 g, 87 %; HPLC (60/40) 3.83 minutes (100%).

Example 83

5-chloro-1H-indole-2-carboxylic acid - [(1S) - (methoxy-methyl-carbamoyl) -ethyl] -amide

(2S) -Amino-N-methoxy-N-methyl-propionamide hydrochloride (169 mg, 1.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (195 mg, 1.0 mmol) were prepared according to method A ( washed with 1N NaOH after acid washings) coupled to give the product (290 mg, 94%): HPLC (60/40) 4.03 minutes (94%); PBMS 310/312 (MH +, 100%);
Analysis calculated for C ₁₄ H ₁₆ ClN ₃ O _3: C, 54.29; H, 5.21; N, 13.57.
Found: C, 54.17; H, 5:26; N, 13.31.

Example 83a

(2S) -Amino-N-methoxy-N-methyl-propionamide hydrochloride

[(1S) - (methoxy-methyl-carbamoyl) -ethyl] -carbamic acid tert -butyl ester (3.55 g, 15.3 mmol) was dissolved in Dissolve 4M HCl-dioxane (20 mL) at 25 ° C for 0.75 hours. The mixture was concentrated and the residue was coevaporated with ether and dichloromethane and dried. Yield 2.2 g (86%).

Example 83b

[1- (Methoxy-methyl-carbamoyl) -ethyl] -carbamic acid tert-butyl ester

L-Boc-alanine (3.50 g, 20 mmol) and O, N-dimethylhydroxylamine hydrochloride (1.94 g, 20 mmol) were prepared according to procedures A (washed with 1N NaOH after acid washings) coupled and the resulting colorless solid was without further Cleaning used. Yield 3.71 g (80%).

Example 84

5-bromo-1H-indole-2-carboxylic acid - ((1S) -carbamoyl-2-phenyl-ethyl) -amide

L-Phenylalanine amide hydrochloride (835mg, 4.17mmol) and 5-bromo-1H-indole-2-carboxylic acid (1.0g, 4.17mmol) were coupled according to Method A to replace the following work-up Ethyl acetate and 2N NaOH. The resulting suspension was filtered and the collected solid washed with ethyl acetate, 2N NaOH, 2N HCl, ether and dried. Yield 890 mg; PBMS 386/388 (MH +, 100%);
Analysis calculated for C ₁₈ H ₁₆ BrN ₃ O _2: C, 55 97; H, 4:18; N, 10,88.
Found: C, 55.69; H, 4:48; N, 10.48.

Example 85

5-chloro-1H-indole-2-carboxylic acid - ((1S) - (methoxy-methyl-carbamoyl) -2-phenyl-ethyl) -amide

(2S) -Amino-N-methoxy-N-methyl-3-phenyl-propionamide hydrochloride (317mg, 1.3mmol) and 5-chloro-1H-indole-2-carboxylic acid (253mg, 1.3mmol) according to method A (0-25 ° C, washed first with acid, then base). The crude product was purified by column chromatography on silica gel eluted with 30% and 40% ethyl acetate in hexanes. The resulting foam was triturated with isopropyl ether to give an off-white solid (356 mg, 71%): HPLC (60/40) 8.28 minutes (98%);
Analysis calculated for C ₂₀ H ₂₀ ClN ₃ O ₃ : C, 62.26; H, 5:22; N, 10,89.
Found: C, 62.22; H, 5.60; N, 10,73.

Example 85a

(2S) -Amino-N-methoxy-N-methyl-3-phenyl-propionamide hydrochloride

[(1S) - (Methoxy-methyl-carbamoyl) -2-phenyl-ethyl] -carbamic acid tert-butyl ester (2.97 g, 9.6 mmol) was dissolved in 4M HCl-dioxane (35 mL) at 0 ° C. The The resulting mixture was stirred for one hour at 25 ° C, concentrated and the Residue triturated with ether and dried. Yield 2.27 g, 96%.

Example 85b

[(1S) - (Methoxy-methyl-carbamoyl) -2-phenyl-ethyl] -carbamic acid tert-butyl ester

Boc-L-phenylalanine (4.0 g, 15.1 mmol) and O, N-dimethylhydroxylamine hydrochloride (3.82 g, 15.1 mmol) were prepared according to procedures A (0-25 ° C, first with acid, then washed base) coupled. The resulting colorless oil was used without purification (3.22 g, 69%).

Example 86

(2RS) - [(5-chloro-1H-indole-2-carbonyl) -amino] -2-methyl-3-phenyl-propionic acid methyl ester

Racemic methyl 2-amino-2-methyl-3-phenylpropionate (200mg, 0.87mmol) and 5-chloro-1H-indole-2-carboxylic acid (170mg, 0.87mmol) were prepared according to Method A (2 : 1 dichloromethane / dimethylformamide solvent) and the product purified by chromatography on silica gel eluted with 10% ethyl acetate in hexanes. Yield 286 mg, 89%; HPLC (60/40) 9.63 minutes (85%); TSPMS 371/373 (MH +, 100%);
¹ H NMR _(CDCl3) δ 9.31 (s, 1H), 7.57 (d, 1H, J = <1 Hz), 7.37 (d, 1H, J = 8.8 Hz), 7, 20 (m, 4H), 7.04 (m, 2H), 6.84 (s, 1H), 6.66 (s, 1H), 3.81 (s, 3H), 3, 67 (A of AB , 1H, J = 13.5 Hz), 3.28 (B of AB, 1H, J = 13.5 Hz), 1.80 (s, 3H).

Example 87

(2RS) - [(5-chloro-1H-indole-2-carbonyl) -amino] -2-methyl-3-phenyl-propionic acid

Aqueous 2N LiOH (0.10 mL, 0.50 mmol) became a solution of (2RS) - [(5-chloro-1H-indole-2-carbonyl) -amino] -2-methyl-3-phenyl-propionic acid, methyl ester (132mg, 0.36mmol) in tetrahydrofuran (8ml) at 25 ° C. The resulting solution was stirred for one hour, concentrated, and the residue was dissolved in ethyl acetate and water (15 ml). The pH was adjusted to 1 with 2N HCl at 0 ° C. The organic layer was separated, washed with water, brine and dried to give a foam which was used without further purification (129 mg, 102%): HPLC (60/40) 4.42 minutes (99%); TSPMS 357/359 (MH +, 100%);
¹ H NMR (CDCl ₃ ) δ 9.88 (s, 1H), 7.57 (s, 1H), 7.35 (d, 1H, J = 8.8 Hz), 7.3-7.2 ( m, 5H), 7.16 (m, 2H), 6.75 (m, 1H), 6.67 (m, 1H), 3.57 (A of AB, 1H, J = 13.7 Hz), 3.42 (B of AB, 1H, J = 13.7 Hz), 1.80 (s, 3H).
Analysis calculated for C ₁₉ H ₁₇ ClN ₂ O ₃ + 0.3 H ₂ O: C, 63.00; H, 4, 90; N, 7,73.
Found: C, 63.38; H, 5.31; N, 7,42.

Example 88

5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2-oxo-2- (1-oxo-1-thiomorpholin-4-yl) -ethyl] -amide

m-chloroperoxybenzoic acid (80 mg of 50%, 0.23 mmol) was converted at 25 ° C to a solution of 5-chloro-1H-indole-2-carboxylic acid - ((1S) -benzyl-2-oxo-2-thiomorpholine -4-yl-ethyl) -amide (100mg, 0.23mmol) in dichloromethane (2ml). After 1 hour, the mixture was diluted with ethyl acetate and washed three times with a 50:50 mixture of saturated aqueous sodium bicarbonate solution and 10% aqueous sodium thiosulfate solution, once with saturated aqueous sodium bicarbonate solution, brine, and dried. The crude product was purified by column chromatography on silica gel eluted with 0.5-8% ethanol in dichloromethane to give the title compound. Yield 76%; HPLC (60/40) 3.97 minutes (97%); Mp 230-234 ° C; TSPMS 444/446 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₃ S + 0.5 H ₂ O: C, 58.34; H, 5:12; N, 9:28.
Found: C, 58.41; H, 5, 37; N, 8, 90.

Example 89

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (1,1-dioxo-1-thiomorpholin-4-yl) -2-oxo-ethyl) -amide

m-chloroperoxybenzoic acid (202 mg of 50%, 0.58 mmol) was converted at 25 ° C to a solution of 5-chloro-1H-indole-2-carboxylic acid - ((1S) -benzyl-2-oxo-2-thiomorpholine -4-yl-ethyl) -amide (100mg, 0.23mmol) in dichloromethane (2ml). After 1 hour, the mixture was diluted with ethyl acetate and the resulting solution was washed three times with a 50:50 mixture of saturated aqueous sodium bicarbonate solution and 10% aqueous sodium thiosulfate solution, once with saturated aqueous sodium bicarbonate solution, brine, and dried. The crude product was purified by column chromatography on silica gel eluted with 30%, 40% and 50% ethyl acetate in hexanes to give the title compound. Yield 60%; HPLC (60/40) 5.69 minutes (98%); PBMS 460/462 (MH +, 100%);
Analysis calculated for C ₂₂ H ₂₂ ClN ₃ O ₄ S + 0.4 H ₂ O: C, 55.56; H, 4.92; N, 8.99.
Found: C, 56.77; H, 5, 15; N, 8.60.

Example 90

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2-oxo-2- (1-oxo-1-thiozolidin-3-yl) -ethyl] -amide

m-chloroperoxybenzoic acid (167 mg of 50%, 0.48 mmol) was added at 25 ° C to a solution of 5-chloro-1H-indole-2-carboxylic acid ((1S) -benzyl-2-oxo-2-one thiozolidin-3-yl-ethyl) -amide (200mg, 0.48mmol) in dichloromethane (4ml). After 0.5 h, the mixture was diluted with ethyl acetate and washed three times with a 50:50 mixture of saturated aqueous sodium bicarbonate solution and 10% aqueous sodium thiosulfate solution, once with saturated aqueous sodium bicarbonate solution, brine and dried. The crude product was concentrated to a yellow solid and then purified by column chromatography on silica gel eluted with 1-8% ethanol in dichloromethane and then triturated with ether to give the title compound. Yield 151 mg (73%); HPLC (60/40) 3, 64 minutes (98%); PBMS 430/432 (MH +, 100%);
Analysis calculated for C ₂₁ H ₂₀ ClN ₃ O ₃ S + 0.6 H ₂ O: C, 57.23; H, 4.85; N, 9.53.
Found: C, 57.00; H, 4.85; N, 9,25.

Example 91

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (3-hydroxyimino-pyrrolidin-1-yl) -2-oxo-ethyl] -amide

Hydroxylamine hydrochloride (68 mg, 0.82 mmol) and potassium carbonate (136 mg, 0.98 mmol) were added to a solution of 5-chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2-oxo-2-one. (3-oxo-pyrrolidin-1-yl) -ethyl] -amide in ethanol (5 ml) and water (1 ml) at 25 ° C. After 48 hours, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The resulting solution was washed twice with water and once with brine, dried over Na ₂ SO ₄ and concentrated. Two substances, which appear as syn / anti-oxime isomers, separated by chromatography on silica gel, eluting with 2.5%, 5%, and 10% ethanol in dichloromethane.

Example 91 (i)

For the less polar isomer:

Yield 48 mg (14%); HPLC (60/40), 4.69 minutes (97%); Mp 216-220 ° C (darkened at 210 ° C); PBMS 425/427 (MH +, 100 °).
¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 10.87 (s, 0.5H), 10.86 (s, 0.5H), 9.02 (m, 1H), 7.72 (d, 1H, J = 2, 0 Hz), 7.4-7.1 (m, 8H), 4.95 (m, 0.5H), 4.85 (m, 0.5H ), 4.40 (d, 0.5H, J = 15 Hz), 4.0 (m, 1.5H), 3.9 (m, 0.5H), 3.61 (m, 1H), 3 , 5 (m, 0.5H), 3.10 (m, 2H), 2.8-2.5 (m, 2H);
Analysis calculated for C ₂₂ H ₂₁ ClN ₄ O _3: C, 62.19; H, 4.98; N, 13:19.
Found: C, 61.82; H, 5.07; N, 12.95.

Example 91 (ii)

For the more polar isomer:

Yield 69 mg (20%); HPLC (60/40), 6.78 minutes (>99%); Mp 223-224 ° C (decomposition, tar); PBMS 425/427 (MH +, 100%).
¹ H NMR (DMSO-d ₆ ) δ 11.74 (br, 1H), 10.87 (s, 1H), 10, 84 (s, 1H), 9, 05 (d, 0.5H, J = 8 , 1 Hz), 8, 99 (d, 1H, J = 8.0 Hz), 7.73 (d, 1H, J = 2 Hz), 7.4-7.1 (m, 8H), 4, 97 (m, 1H), 4.85 (m, 1H), 4, 47 (d, 0.5H, J = 17 Hz), 3.95 (m, 1.5H), 3.87 (m, 0 , 5H), 3.65-3.4 (m, 1.5H), 3, 10 (m, 2H), 2.7-2.5 (m, 2H).
Analysis calculated for C ₂₂ H ₂₁ ClNyO _3: C, 62.19; H, 4.98; N, 13:19.
Found: C, 61.85; H, 5:17; N, 13,16.

Example 92

5-chloro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-piperidin-1-yl-ethyl) -amide

Piperidine hydrochloride (0.34 mmol) and 2 - [(5-chloro-1H-indole-2-carbonyl) amino] -3-phenyl-propionic acid (0.30 mmol) were prepared according to Method A (0-25 ° C reaction temperature ) coupled. The crude product was chromatographed on silica gel eluting with 20%, 30%, 40%, 50%, 75% and 100% ethyl acetate in hexane to give a partial separation. The pure fractions were pooled to give 31 mg (25%) of the title substance: HPLC (60/40) 9.38 minutes (94%); PBMS 410/412 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₄ N ₃ O ₂ Cl + 0.5 H ₂ O: C, 65.94; H, 6.02; N, 10.03.
Found: 65.70; H, 6,19; N, 9,66.

Example 93

5-chloro-1H-indole-2-carbonsäurecarbamoylmethylamid

[(5-chloro-1H-indole-2-carbonyl) -amine] -acetic acid methyl ester (100 mg, 0.40 mmol) was added to a saturated solution of ammonia in methanol (about 3 mL) at 25 ° C. The suspension was sonicated for 1 hour and the resulting solution was concentrated. The residue was triturated with ether / hexanes and dried. Yield 77 mg, 77%; HPLC (60/40), 2.78 minutes (98%); PBMS 252/254 (MH +, 100%);
¹ H NMR (DMSO-d ₆ ) δ 11.82 (br, 1H), 8.80 (t, 1H), 7.71 (d, 1H, J = ca. 1 Hz), 7.43 (d, 1H, J = 7-8 Hz), 7.42 (br, 1H), 7.18 (dd, 1H, J = 7-8, ca. 2 Hz), 7.14 (s, 1H), 7, 08 (br, 1H), 3.82 (m, 2H).
Analysis calculated for C ₁₁ H ₁₀ ClN ₃ O ₂ + 0.125 H ₂ O: C, 52.03; H, 4.07; N, 16.55.
Found: C, 52.05; H, 4.08; N, 16.63.

Example 94

1 - {(2S) - [(5-bromo-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine- (2S) -carboxylic acid

Trifluoroacetic acid was added to a solution of tert-butyl 1 - {(2S) - [(5-bromo-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine (2S) -carboxylate ( 345 mg, 0.64 mmol) in dichloromethane (2 ml) at 0 ° C. After 1 h at 25 ° C, the reaction mixture was concentrated, triturated with ether and dried to give a yellow solid. Yield 273 mg, 88%; HPLC (70/30) 4.75 minutes (98%); TSPMS 484/486 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₂ BrN ₃ O ₄ + 0.25 H ₂ O: C, 56.51; H, 4.64; N, 8.60.
Found: C, 56.28; H, 4.78; N, 8,26.

Example 94a

1 - {(2S) - [(5-bromo-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} -pyrrolidine- (2S) -carboxylic acid tert-butyl ester

L-phenylalanine-L-proline tert-butyl ester (333 mg, 1.0 mmol) and 5-bromo-1H-indole-2-carboxylic acid were prepared according to procedures A (72 hours reaction time) coupled. The product was through column on silica gel eluted with 15%, 20% and 30% ethyl acetate, purified to give a pale yellow foam. yield 428 mg (79%); HPLC (70/30) 5.84 minutes (81%).

Example 95

5-chloro-1H-indole-2-carboxylic acid [2-oxo-2- (1RS) -oxo-1-thiazolidin-3-yl) -ethyl] -amide

m-chloroperoxybenzoic acid (426 mg of 50%, 1.2 mmol) was added at 25 ° C to a solution of 5-chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl ) -amide (400 mg, 1.2 mmol) in dichloromethane (8 mL) at 25 ° C. After 1 hour, the mixture was diluted with ethyl acetate (ca 80 ml) and the resulting solution was washed three times with a 1: 1 mixture of saturated aqueous NaHCO ₃ /10% aqueous Na ₂ S ₂ O ₃ , saturated aqueous NaHCO ₃ and brine washed. The resulting suspension was filtered and the filtered solid washed with water and dried to give a crystalline solid. HPLC (60/40) 2.52 minutes (98.5%; TSPMS 340/342 (MH +, 70%), 357 (100%);
¹ H NMR (DMSO-d ₆ ) δ 11.82 (br, 1H), 8.84 (m, 1H), 7.73 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 8.7 Hz), 7.19 (dd, 1H, J = 2..0, 8.7 Hz), 7.18 (s, 1H), 4.92 (dd, 0.5H, J = 12.1 Hz), 4.71 (dd, 0.5H, J = 2.2.13 Hz), 4.47 (d, 1H, J = 12.1 Hz), 4.4-3.9 (m, 4, 5H), 3.3 (m, 0.5H), 3.13 (m, 1H), 3.0 (m, 0.5H).
Analysis calculated for C ₁₄ H ₁₄ ClN ₃ O ₃ S + 0.8 H ₂ O: C, 47.47; H, 4:44; N, 11,86.
Found: C, 47.46; H, 4.07; N, 11,83.

Example 96

1 - {(2S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} - (4R) -hydroxy-pyrrolidine- (2S) -carboxylic acid

Excess aqueous 2M LiOH was added to a solution of 1 - {(2S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionyl} - (4R) -hydroxy-pyrrolidine ( 2S) -benzyl benzoate (215 mg, 0.40 mmol) in tetrahydrofuran at 25 ° C. After 2 hours the mixture was diluted with ethyl acetate and ice and the mixture acidified to pH 1-2 with 6N HCl. The acid layer was extracted three times with ethyl acetate and the organic layers were combined and dried. The residue was washed with ether triturated and dried to give a colorless solid (190 mg, 106%): HPLC (60/40) 3.43 minutes (94%); TSPMS 456/458 (MH +, 100%);
Analysis calculated for C ₂₃ H ₂₂ ClN ₃ O ₅ + 0.5 C ₄ H ₈ O _2: C, 60.06; H, 5:24; N, 8,40.
Found: C, 60.27; H, 5.33; N, 8:13.

Example 97

(S) -2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3- (1H-indol-3-yl) -propionic acid methyl ester

L-tryptophan methyl ester hydrochloride (1.05 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to method A (0-25 ° C, dimethylformamide reaction solvent) and the product was purified by chromatography on silica gel, eluted with 10%, 20%, 30%, 40%, 50% and 60% ethyl acetate-hexanes, purified to give a yellow foam. Yield 79%; HPLC (60/40); 7.43 minutes (96%);
¹ H NMR (DMSO-d ₆ ) δ 11.78 (br, 1H), 10.85 (br, 1H), 8.93 (d, 1H, J = 7.7 Hz), 7.73 (d, 1H, J = 1.9 Hz), 7.57 (d, 1H, J = 7.7 Hz), 7.41 (d, 1H, J = 8.7 Hz), 7.32 (d, 1H, J = 8.0 Hz), 7.22 (m, 2H), 7.18 (dd, 1H, J = 2.1, 8.8 Hz), 7.06 (m, 1H), 6.99 ( m, 1H), 4.74 (m, 1H), 3.65 (s, 3H), 3.35-3.2 (m, 2H).

Example 98

(±) -3 - {[(5-chloro-1H-indole-2-carbonyl) -amino] -acetyl} -thiazolidine-2-carbonsäuremethylester

(±) -Thiazolidine-2-carboxylic acid, methyl ester hydrochloride (1.02 mmol) and [(5-chloro-1H-indole-2-carbonyl) -amino] -acetic acid (1.02 mmol) were prepared according to Method A (1: 1 dichloromethane Dimethylformamide solvent) and the crude product triturated with 1: 1 ether-hexanes to give a light yellow solid. Yield 79%; HPLC (60/40) 4.47 minutes (95%); TSPMS 382/384 (MH +, 100%):
¹ H NMR (DMSO-d ₆ ) δ 11.82 (s, 1H), 8.85 (t, 1H, J = 7 Hz), 7.73 (d, 1H, J = 2 Hz), 7, 43 (d, 1H, J = 8.8 Hz), 7.18 (dd, 1H, J = 8.8, 2 Hz), 7.17 (s, 1H), 5.44 (s, 1H), 4 , 25 (m, 1H), 4, 1 (m, 1H), 3, 95 (m, 1H), 3, 34 (s, 3H), 3, 3 (m, 2H)
Analysis calculated for C ₁₆ H ₁₆ ClN ₃ O ₄ S: C, 50.33; H, 4:22; N, 11.00.
Found: C, 50.56; H, 4, 46; N, 10,89.

Example 99

(±) -3 - {[(5-chloro-1H-indole-2-carbonyl) -amino] -acetyl} -thiazolidine-2-carboxylic acid

A solution of 3 - {[(5-chloro-1H-indole-2-carbonyl) -amino] -acetyl} -thiazolidine-2-carboxylic acid, methyl ester (196 mg, 0.5 mmol) in methanol (10 mL) was washed with aqueous Treated 1N NaOH (0.5 ml) at 25 ° C. After 3 hours, additional 1N NaOH (0.25 ml) was added. The mixture was stirred overnight at 25 ° C, concentrated, the residue stirred with ethyl acetate (30 mL) and 1N NaOH (5 mL) and the resulting mixture acidified to pH 1.8 with aqueous 6N HCl. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried and concentrated to give a solid which was triturated with 1: 1 ether-hexane and dried. Yield 186 mg, 99%; HPLC (60/40) 3, 13 minutes (98%); TSPMS 368/370 (MH +, 70%), 339 (100%).
¹ H NMR (DMSO-d ₆ ) δ 11.80 (s, 1H), 8.84 (br, 1H), 7.23 (s, 1H), 7.44 (d, 1H, J = 8.8 Hz), 7.18 (dd, 1H), 7.17 (s, 1H), 4.32 (s, 1H), 4.25 (m, 2H), 4.0 (m, 2H), 3, 3 (m, 2H).

Example 99a

(±) -thiazolidine-2-carbonsäuremethylester

One Mixture of (±) -thiazolidine-2-carboxylic acid (1.58 g, 11.9 mmol) and chlorotrimethylsilane (5.1 g, 47 mmol) in methanol (22 ml) was refluxed for 5 hours heated, cooled and concentrated to give a solid (2.19 g, 100 %).

Example 100

2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid S-tert-butyl ester

Method B

To a solution of 5-chloro-1H-indole-2-carboxylic acid (0.50 g, 2.6 mmol), L-phenylalanine tert -butyl ester hydrochloride (0.66 g, 2.6 mmol), triethylamine (0, 36 ml, 2.6 mmol) and 4-dimethylaminopyridine (0.16 g, 1.3 mmol) in dichloromethane (20 ml) was added 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide (0.73 g, 3 , 8 mmol). The mixture was stirred at room temperature overnight, diluted with chloroform, washed with 2N HCl, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (30% acetone in hexanes) and obtained as a pale yellow foam (0.86 g, 85%).
Analysis calculated: C, 66.25, H, 5.81, N, 7.03;
Found: C 66.57, H 6.11, N 6.86.

The The following Examples (101 to 122) were prepared by methods to method B are analogous.

Example 101

2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid-methylester-R

From 5-fluoro-1H-indole-2-carboxylic acid and D-phenyl-alanine methyl ester.
¹ H NMR (300 MHz, CDCl ₃₎ δ 3.22 (m, 2H), 3.80 (s, 3H), 5.10 (m, 1H), 6.62 (d, 6 Hz, 1H), 6.75 (d, 2Hz, 1H), 7.05 (dt, 2Hz, 8Hz, 1H), 7.10-7.15 (m, 2H), 7.25-7.40 (m, 4H), 7.73 (d, 2.1Hz, 1H), 9, 50 (br, 1H).

Example 102

2 - [(5,7-dichloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid-methylester-R

From 5,7-dichloro-1H-indole-2-carboxylic acid and D-phenylalanine methyl ester.
¹ H NMR (300 MHz, CDCl ₃₎ δ 3.25 (m, 2H), 3.80 / 3.95 (s, 3H), 5.10 (m, 1H), 6.62 (d, 6 Hz , 1H), 6.69 (d, 2Hz, 1H), 7.10-7.15 (m, 2H), 7.25-7.35 (m, 3H), 7.50-7.56 ( s, 1H), 9.35 (br, 1H).

Example 102a

5,7-dichloro-1H-indole-2-carboxylic acid

A. 2-Oxopropionic acid ethyl ester-2,4-dichlorophenyl hydrazone

One Mixture of 2,4-dichlorophenylhydrazine (1.0 g, 4.7 mmol), pyruvic acid ethyl ester (0.53 ml, 4.7 mmol), triethylamine (0.65 ml, 4.7 mmol) and ethanol (5 ml) was over Night under reflux heated. The solvent was evaporated and the residue taken up in chloroform. The solution was with water and brine washed and over Dried magnesium sulfate and concentrated to leave an oil (1.1 g, 98%).

B. 5,7-dichloro-1H-indole-2-carboxylic acid ethyl ester

A solution of 2-Oxopropionsäureethylester-2,4-dichlorophenylhydrazone (1.1 g, 4.6 mmol) and anhydrous zinc chloride (10 g, 74 mmol) in Glacial acetic acid (12 ml) was refluxed for half an hour. The reaction mixture was poured into water and extracted twice with ether. The United organic layers were washed with water and brine, over magnesium sulfate dried and concentrated. The product was purified by flash chromatography (30% ethyl acetate in hexanes) and obtained as an oil (0.80 g, 67%).

C. 5,7-dichloro-1H-indole-2-carboxylic acid

A solution of ethyl 5,7-dichloro-1H-indole-2-carboxylate (0.80 g, 3.1 mmol) in 1N NaOH (40 mL) and methanol (50 mL) was heated at reflux for 3 hours. The methanol was removed in vacuo and the aqueous residue was acidified with 1N HCl and extracted twice with chloroform. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to a solid (0.58 g, 76%).

The the following indole carboxylic acids were prepared by the same sequence: 4-chloro-5-fluoro-1H-indole-2-carboxylic acid and 6-Chloro-5-fluoro-1H-indole-2-carboxylic acid (as a mixture) of 3-chloro-4-fluorophenylhydrazine. 5,7-Difluoro-1H-indole-2-carboxylic acid 2,4-difluorophenylhydrazine

Example 103

2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (±) ethyl

From 5-chloro-1H-indole-2-carboxylic acid and DL-phenyl-alanine ethyl ester. Mp 146-147 ° C.
Analysis calculated: C, 64.61, H, 5.42, N, 7.54;
Found: C 64.73, H 5.26, N 7.57.

Example 104

S-3-bromo-5-chloro-1H-indole-2-carboxylic acid (1-dimethyl-carbamoyl-2-phenyl-ethyl) -amide

From 3-bromo-S-chloro-1H-indole-2-carboxylic acid and S-2-amino-N, N-dimethyl-3-phenyl-propionamide.
Analysis calculated: C, 53.53, H, 4.27, N, 9.36;
Found: C 53.51, H 4.46, N 9.38.

Example 104a

3-bromo-5-chloro-1H-indole-2-carboxylic acid

To a solution of 5-chloro-1H-indole-2-carboxylic acid (2.0 g, 10.2 mmol) in acetic acid (24 ml) became a solution of bromine (0.53 ml, 10.2 mmol) in acetic acid (16 ml). After 20 Minutes, the mixture was poured into water and washed twice with chloroform extracted. The combined extracts were washed twice with water and saline solution washed over Dried magnesium sulfate and concentrated. The product was as a solid (2.5 g, 89%).

Example 104b

(S) -2-amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride

A. (S) - (1-Dimethylcarbamoyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester

To a solution of tert-Boc-phenylalanine (10g, 38mmol), dimethylamine hydrochloride (3.4 g, 41 mmol), triethylamine (5.8 mL, 42 mmol) and hydroxybenzotriazole (6.6 g, 49 mmol) in dichloromethane (300 mL) became 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (9.4 g, 49 mmol). The mixture was stirred overnight, then stopped with 2N HCl and concentrated on. The residue was taken up in ethyl acetate and this solution was with water and brine washed over Dried magnesium sulfate and concentrated. The residue was triturated with chloroform, the solid was filtered and the Filtrate to an oil concentrated (11 g, 100%).

B. (S) -2-amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride

(S) - (1-dimethylcarbamoyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester (11.0 g, 38 mmol) was dissolved in ethyl acetate (125 mL) and HCl into the solution 10 minutes initiated. The solution was stirred for one hour at room temperature, then concentrated. The residue was triturated with ether, the solid was filtered and in Dried under high vacuum (8.6 g, 100%).

Example 105

S-5-Chloro-4-nitro-1H-indole-2-carboxylic acid (1-dimethyl-carbamoyl-2-phenyl-ethyl) -amide

From 4-nitro-5-chloro-1H-indole-2-carboxylic acid and S-2-amino-N, N-dimethyl-3-phenyl-propionamide.
¹ H NMR (300 MHz, CDCl ₃₎ δ 2.75 (s, 3H), 2.97 (s, 3H), 3.20 (m, 2H), 5.30 (m, 1H), 7.07 (d, 2Hz, 1H), 7.24-7.32 (m, 5H), 7.40 (d, 7Hz, 1H), 8.12 (br d, 7Hz, 1H), 9.85 (br, 1H).

Example 105a

4-nitro-5-chloro-1H-indole-2-carboxylic acid

A. 2 - [(4-Chloro-3-nitro-phenyl) -hydrazono] -propionic acid ethyl ester

To a solution of sodium nitrite (2.17 g, 31 mmol) in water (60 ml) and conc. HCl (12 ml) at 0 ° C 4-chloro-3-nitroaniline (5.0 g, 29 mmol). After 5 minutes, a solution of Methylacetoessigsäureethylester (4.5 ml, 29 mmol) in water (60 ml), ethanol (30 ml) and 50% strength Potassium hydroxide (10 ml) was added and the reaction mixture became overnight touched. The precipitate was collected (7.0 g, 91%).

B. 5-chloro-4-nitro-1H-indole-2-carboxylic acid ethyl ester

One Mixture of ethyl 2 - [(4-chloro-3-nitro-phenyl) -hydrazono] -propionate (2.0 g, 6.7 mmol) and Polyphos phorsäure (7 g) was 2 hours on 90 to 110 ° C heated. The mixture was cooled, poured into an ice / water mixture and the solid was collected. Flash chromatography (1% methanol in chloroform) provided the title compound (0.58 g, 32%) and 5-chloro-6-nitro-1H-indole-2-carboxylate (0.31 g, 17%).

C. 4-nitro-5-chloro-1H-indole-2-carboxylic acid

The Title compound was prepared by hydrolysis of 5-chloro-4-nitro-1H-indole-2-carboxylic acid ethyl ester, as for describe the preparation of 5,7-dichloro-1H-indole-2-carboxylic acid, produced.

Example 106

S-7-Nitro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide

From 7-nitro-1H-indole-2-carboxylic acid and S-2-amino-N, N-dimethyl-3-phenyl-propionamide.
¹ H NMR δ 2.8 (s, 3H), 3.0 (s, 3H), 3.1-3.3 (m, 2H), 5.35 (q, 7 Hz, 1H), 6.95 (s, 1H), 7.15-7.3 (m, 6H), 7.9 (d, 8Hz, 1H), 8.2 (d, 8Hz, 1H), 10.3 (br, 1H ).

Example 107

2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-butyric acid (±) methylester

From 5-chloro-1H-indole-2-carboxylic acid and DL-β-methyl-phenylalanine methyl ester.
Mp 135-136 ° C.
Analysis calculated: C, 64.78, H, 5.17, N, 7.56;
Found: C 64, 76, H, 5.26, N 7.64.

Example 108

(±) - (5-chloro-1H-indole-2-carboxylic acid [1- (2-fluoro-benzyl) -2-oxo-2-thiazolidin-3-yl-ethyl) -amide

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-3- (2-fluoro-phenyl) -1-thiazolidin-3-yl-propan-1-one.
Mp 216-217 ° C.
Analysis calculated: C, 58.40, H, 4.43, N, 9.73;
Found: C 58.45, H, 4.53, N 9.71.

Example 108a

(±) -2-amino-3- (2-fluorophenyl) -1-thiazolidin-3-yl-propan-1-one hydrochloride

A. (±) -2-tert-Butoxycarbonylamino-3- (2-fluoro-phenyl) -propionic acid

To a mixture of DL-3-fluoro-phenylalanine (1.0 g, 5.5 mmol) and Triethylamine (1.14 mL, 8.2 mmol) in dichloromethane (20 mL) Added di-tert-butyl dicarbonate (1.4 g, 6.55 mmol). The mixture was over Stirred at room temperature overnight, then poured into water, acidified with 1N HCl and extracted with chloroform. The combined extracts were washed with water and brine, over magnesium sulfate dried and concentrated. The product was purified by flash chromatography (Chloroform / methanol / acetic acid, 89:10: 1) and obtained as a solid (1.28 g, 83%, m.p. 118-119 ° C).

B. (±) - [1- (2-fluorobenzyl) -2-oxo-2-thiazolidin-3-yl-ethyl) -carbamic acid tert-butyl ester

To a mixture of 2-tert-butoxycarbonylamino-3- (2-fluoro-phenyl) -propionic acid (0.50 g, 1.77 mmol), thiazolidine (0.15 ml, 1.94 mmol) and 4-dimethylaminopyridine (0.21 g, 1.77 mmol) in dichloromethane (15 mL) was added EDC (0.44 g, 2.31 mmol). The reaction mixture was stirred at room temperature overnight, with Diluted in chloroform, with 2N HCl, water and brine washed over Dried magnesium sulfate and concentrated. The product was purified by flash chromatography (30% acetone in hexanes) and as a colorless solid (0.39 g, 62%, mp 133-134 ° C).

C. (±) -2-Amino-3- (2-fluorophenyl) -1-thiazolidin-3-yl-propan-1-one hydrochloride

HCl was in a solution [1- (2-Fluoro-benzyl) -2-oxo-2-thiazolidin-3-yl-ethyl] -carbamic acid tert-butyl ester (0.39 g, 1.1 mmol) in ethyl acetate (15 ml). The solution was focused on the backlog was triturated with ether, the solid was filtered and dried (0.27 g, 84%, mp 217-218 ° C).

The following amines were prepared analogously to procedures in the same sequence:
(±) -2-Amino-3- (2-chlorophenyl) -1-thiazolidin-3-yl-propan-1-one from DL-2-chloro-phenylalanine
(±) -2-amino-3- (3-cyano-phenyl) -1-thiazolidin-3-yl-propan-1-one from DL-3-cyano-phenylalanine
(±) -2-Amino-3- (3-chloro-phenyl) -1-thiazolidin-3-yl-propan-1-one from DL-3-chloro-phenylalanine
(±) -2-Amino-3- (3-trifluoromethylphenyl) -1-thiazolidin-3-yl-propan-1-one from DL-3-trifluoromethylphenylalanine
(S) -2-Amino-1- (4-hydroxy-piperidin-1-yl) -3- (4-methoxy-phenyl) -propan-1-one from L-4-methoxy-phenylalanine

Example 109

(±) -5-chloro-1H-indole-2-carboxylic acid [1- (2-chloro-benzyl) -2-oxo-2-thiazolidin-3-yl-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-3- (2-chloro-phenyl) -1-thiazolidin-3-yl-propan-1-one.
Mp 214-216 ° C.
Analysis calculated: C, 56.26, H, 4.58, N, 9.37;
Found: C 56.27, H, 4.54, N 9.36.

Example 110

(±) -5-chloro-1H-indole-2-carboxylic acid [2- (3-cyano-phenyl) -1- (thiazolidine-3-carbonyl) -ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-3- (3-cyano-phenyl) -1-thiazolidin-3-yl-propan-1-one.
Mp 183-184 ° C.
Analysis calculated: C, 60.20, H, 4.36, N, 12.77;
Found: C 60.11, H, 4.84, N 12.43.

Example 111

(±) -5-chloro-1H-indole-2-carboxylic acid [1- (3-chloro-benzyl) -2-oxo-2-thiazolidin-3-yl-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-3- (3-chloro-phenyl) -1-thiazolidin-3-yl-propan-1-one.
Mp 188-190 ° C.
Analysis calculated: C, 56.26, H, 4.27, N, 9.37;
Found: C, 56.38, H, 5.04, N, 9.04.

Example 112

(±) -5-chloro-1H-indole-2-carboxylic acid [2-oxo-2-thiazolidin-3-yl-1- (3-trifluoromethyl-benzyl) -ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-3- (3-trifluoromethyl-phenyl) -1-thiazolidin-3-yl-propan-1-one.
Mp 205-207 ° C.
Analysis calculated: C, 54.83, H, 3.97, N, 8.72;
Found: C 54.44, H, 4.14, N 8.88.

Example 113

S-5-chloro-1H-indole-2-carboxylic acid [1- (4-methoxy-benzyl) -2-oxo-2-thiazolidin-3-yl-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and S-2-amino-3- (4-methoxyphenyl) -1-thiazolidin-3-yl-propan-1-one.
Analysis calculated: C 59.52, H 5.00, N 9.47;
Found: C 60, 00, H, 5, 55, N 8, 90.
Mass spectrum m / e 444 (M + +1).

Example 114

(±) -5-chloro-1H-indole-2-carboxylic acid [1- (3-chloro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-1- (4-hydroxy-piperidin-1-yl) -3- (3-chloro-phenyl) -propan-1-one ,
Mp. 98 ° C decomposition.

Example 115

S-5-chloro-4-fluoro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -amide and S-6-chloro-4-fluoro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -amide

From a mixture of 5-chloro-4-fluoro-1H-indole-2-carboxylic acid and 6-chloro-4-fluoro-1H-indole-2-carboxylic acid and S-2-amino-3-phenyl-1-thiazolidine 3-yl-propan-1-one.
Mp 105-125 ° C decomposition.
Analysis calculated: C, 58.40, H, 4.43, N, 9.73;
Found: C 58.54, H, 4.59, N 9.58.

Example 116

(+) - 2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -propionic acid methyl ester

From 5-chloro-1H-indole-2-carboxylic acid and DL-alanine methyl ester hydrochloride.
Mp 199-201 ° C.
Analysis calculated: C, 55.63, H, 4.67, N, 9.98;
Found: C 55.70, H 4.75, N 10.06.

Example 117

(±) -2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3- [4- (4,5-dihydro-1H-imidazol-2-yl) -phenyl] -propionic acid methyl ester

From 5-chloro-1H-indole-2-carboxylic acid and (±) -2-amino-3- [4- (4,5-dihydro-1H-imidazol-2-yl) -phenyl] -propionic acid methyl ester.
¹ H NMR (300 MHz, CDCl ₃₎ δ 3.1-3.3 (m, 2H), 3.70 (s, 3H), 3.95 (s, 4H), 4.85 (m, 1H) , 7.15 (s, 1H), 7.17 (d, 8Hz, 1H), 7.40 (d, 8Hz, 1H), 7.65 (d, 7Hz, 1H), 7.75 ( s, 1H), 7, 88 (d, 8Hz, 1H), 9.10 (br d, 9Hz, 1H), 10.5 (s, 1H), 11.8 (br s, 1H).

Example 117a

(±) -2-amino-2- [4- [4,5-dihydro-1H-imidazol-2-yl) -phenyl] -propionic acid methyl ester

A. diethyl 2-acetylamino-2- [9- (4,5-dihydro-1H-imidazol-2-yl) benzyl] malonate

A solution of diethyl 2-acetylamino-2 - [(4-methoxycarbonimidoyl) benzyl] malonate (Wagner, G. et al., Pharm. 1974, 29, 12) (5.3 g, 13 mmol) and ethylenediamine (4.8g, 80mmol) in ethanol (100ml) was stirred at 60 ° C for 5 hours. To Cool became the solvent evaporated, water became the residue and the solid was filtered and heated in hot 1N HCl solved. After cooling the precipitate was filtered and dried (3.1 g).

B. (±) -2-amino-3- [4- [4,5-dihydro-1H-imidazol-2-yl) -phenyl] -propionic acid dihydrochloride

To 2-acetylamino-2- [4- (4,5-dihydro-1H-imidzaol-2-yl) benzyl) malonate (3.0 g, 7.3 mmol) was added glacial acetic acid (50 ml) and 3N HCl (100 ml). The solution was refluxed for 3 hours, chilled and concentrated to a white solid made from methanol / ether was recrystallized (2.0 g, mp 270-272 ° C decomposition).

C. (±) -2-Amino-3- [4- (4,5-dihydro-1H-imidazol-2-yl) -phenyl] -propionic acid methyl ester

(±) -2-amino-3- [4- (4,5-dihydro-1H-imidazol-2-yl) phenyl] -propionsäuredihydrochlorid (0.50 g, 1.6 mmol) was dissolved in thionyl chloride (1 mL) and methanol (25 ml). The mixture was refluxed for 30 minutes heated, followed by a large amount of thionyl chloride (3 ml) and methanol (75 ml) were added. After a further 3 hours under reflux became the solution concentrated, the residue was dissolved in a small amount of methanol and ethyl acetate became the initiation of precipitation added. The solid was collected and dried (0.40 g, Mp 230 ° C Decomposition).

Example 118

(S) -5,7-difluoro-1H-indole-2-carboxylic acid [1-benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

From 5,7-Difluoro-1H-indole-2-carboxylic acid and (S) -2-amino-1- (4-hydroxy-piperidin-1-yl) -3-phenyl-propan-1-one.
Mp 95-110 ° C.

Example 119

S-4-chloro-5-fluoro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide and S-6-chloro-5-fluoro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide

From a mixture of 5-chloro-4-fluoro-1H-indole-2-carboxylic acid and 6-chloro-4-fluoro-1H-indole-2-carboxylic acid and (S) -2-amino-N, N-dimethyl 3-phenyl-propionamide.
Mp 200-210 ° C.
Analysis calculated: C, 61.94, H, 4.94, N, 10.83;
Found C 62.21, H 4.99, N 10.84.

Example 120

(S) -5,7-difluoro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-thiazolidin-3-yl-ethyl) -amide

From 5,7-Difluoro-1H-indole-2-carboxylic acid and (S) -2-amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one.
Mp 175-185 ° C.
Analysis calculated: C, 60.71, H, 4.61, N, 10.11;
Found C 60, 79, H 4,66, N 9,93.

Example 121

(S) -5,7-difluoro-1H-indole-2-carboxylic acid [1-benzyl-2- (1,1-dioxo-thiazolidin-3-yl) -2-oxo-ethyl] -amide

From 5,7-difluoro-1H-indole-2-carboxylic acid and (S) -2-amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3-phenyl-propan-1-one hydrochloride ,
Mp 95-110 ° C.
MS 448 (MH +).

Example 122

S-5-chloro-1H-indole-2-carboxylic acid [1- (2-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

Method C

To a solution of 5-chloro-1H-indole-2-carboxylic acid (0.49 g, 2.5 mmol), S-2-amino-3- (2-fluoro-phenyl) -1- (4-hydroxy) piperidin-1-yl) -propan-1-one (0.76g, 2.5mmol), triethylamine (0.35ml, 2.5mmol) and hydroxybenzotriazole (0.34g, 2.5mmol) in Dichloromethane (6 mL) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.53 g, 2.8 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with water, 1N HCl and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (chloroform / methanol, 8: 1) and obtained as an off-white solid (0.82 g, 73%).
Mp 120-122 ° C.

Example 122a

(S) -2-Amino-3- (2-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) propan-1-one hydrochloride

A. (S) -2-tert-Butoxycarbonylamino-3- (2-fluorophenyl) -1-thiazolidin-3-yl-propan-1-one

Out L-Boc-2-fluorophenylalanine and 4-hydroxypiperidine by a process analogous to method C.

B. (S) -2-amino-3- (2-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one hydrochloride

The Title compound was prepared by reaction of L-2-tert-butoxycarbonylamino-3- (2-fluorophenyl) -1-thiazolidin-3-yl-propan-1-one with HCl according to the analog Method, described in Example 108a, step C, prepared.

The following amines were prepared by analogous procedures in the same sequence:
S-2-amino-3- (4-methoxy-phenyl) -1-thiazolidin-3-yl-propan-1-one
S-2-Amino-3- (2-fluoro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one
S-2-amino-1- (4-hydroxy-piperidin-1-yl) -3- (4-methoxyphenyl) propan-1-one
S-2-Amino-3- (2-chloro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one
S-2-Amino-3- (4-methoxy-phenyl) -1-morpholin-4-yl-propan-1-one
S-2-amino-3- (4-methoxy-phenyl) -1- (4-acetyl-piperazinyl) -propan-1-one

By an analogous procedure to that of (Method C) were the following Examples (122-138) produced.

Example 123

(2SR), (3RS) -2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-hydroxy-3-phenyl-propionic acid methyl ester

From 5-chloro-1H-indole-2-carboxylic acid and (±) -thhreo-bphenylserine methyl ester.
Mp 196-197 ° C.

Example 129

S-5-fluoro-1H-indole-2-carboxylic acid [1- (4-methoxy-benzyl) -2-oxo-2-thiazolidin-3-yl-ethyl] -amide

From 5-fluoro-1H-indole-2-carboxylic acid and S-2-amino-3- (4-methoxyphenyl) -1-thiazolidin-3-yl-propan-1-one.
Mp 90-115 ° C.
Analysis calculated: C, 61.81, H, 5.19, N, 9.83;
Found: C, 60.94, H, 5.33, N, 10.01.

Example 125

S-S-Chloro-1H-indole-2-carboxylic acid [1- (2-chloro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and S-2-amino-3- (2-chloro-phenyl) -1- (4-hydroxy-piperidin-1-yl) -propan-1-one.
Mp 127-129 ° C.

Example 126

5-5-Chloro-1H-indole-2-carboxylic acid [1- (4-methoxy-benzyl) -2-morpholin-4-yl-2-oxo-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid, S-2-amino-3- (4-methoxyphenyl) -1-morpholin-4-yl-propan-1-one.
Mp 95-105 ° C.
Analysis calculated: C, 62.51, H, 5.47, N, 9.51;
Found: C 61.82, H 6.05, N 8.97.

Example 127

S-5-chloro-1H-indole-2-carboxylic acid [2- (4-acetyl-piperazin-1-yl) -1- (4-methoxy-benzyl) -2-oxo-ethyl] -amide

From 5-chloro-1H-indole-2-carboxylic acid and S-2-amino-3- (4-methoxyphenyl) -1- (4-acetyl-piperazinyl) -propan-1-one.
Mp 120-135 ° C.
Analysis calculated: C, 62.17, H, 5.64, N, 11.60;
Found: C 62.76, H 6.20, N 10.44.

Example 128

S-5-fluoro-1H-indole-2-carboxylic acid [1- (benzothiazol-2-ylcarbamoyl) -2-phenyl-ethyl] -amide

From 5-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid and 2-amino-1,3-benzothiazole.
Mp 139-141 ° C.

Example 129

S-5-fluoro-1H-indole-2-carboxylic acid (1-benzyl-2-morpholin-4-yl-2-oxo-ethyl) -amide

From 5-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid and morpholine.
Mp 234-236 ° C.

Example 130

5-fluoro-1H-indole-2-carboxylic acid [1S-benzyl-2-oxo-2- (3,3,5RS-trimethyl-azepan-1-yl) -ethyl] -amide

From 2 - [(5-fluoro-1H-indole-2-carbonyl) amino] -3-phenylpropionic acid and (±) -3,3,5-trimethylazepan.
Mp 125-127 ° C.
Analysis calculated: C, 72.14, H, 7.18, N, 9.35;
Found: C 72.00, H 7.58, N 9.10.

Example 131

5-fluoro-1H-indole-2-carboxylic acid [1S-benzyl-2- (3RS-carbamoyl-piperidin-1-yl) -2-oxo-ethyl] -amide

From 5-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid and 3-carbamoyl-piperidine.
Mp 234-236 ° C.

Example 132

5-fluoro-1H-indole-2-carboxylic acid [2-phenyl-1S- (thiochroman-4RS-ylcarbamoyl) -ethyl] -amide

From S-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid and (±) thiochroman-4-ylamine.
Mp 225-226 ° C.
Analysis calculated: C, 68.48, H, 5.11, N, 8.88;
Found: C 68.40, H 5.64, N 8.61.

Example 133

S-5-fluoro-1H-indole-2-carboxylic acid [1- (5-methyl-isoxazol-3-ylcarbamoyl) -2-phenyl-ethyl] -amide

From 5-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid and 5-methyl-isoxazol-3-ylamine.
Mp 219-221 ° C.

Example 134

S-S-fluoro-1H-indole-2-carboxylic acid [2-phenyl-1- (4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl) -ethyl] -amide

From 5-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenylpropionic acid and 4,5,6,7-tetrahydro-benzothiazol-2-yl-amine.
Mp 162-165 ° C.

Example 135

S-5-fluoro-1H-indole-2-carboxylic acid [1- (5-methyl-thiazol-2-ylcarbamoyl) -2-phenyl-ethyl] -amide

From 5-2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenylpropionic acid and 4-methyl-thiazol-2-ylamine.
Mp 211-213 ° C.

Example 136

S-5-methyl-1H-indole-2-carboxylic acid [1- (5-methyl-isoxazol-3-ylcarbamoyl) -2-phenyl-ethyl] -amide

From S-2 - [(5-methyl-1H-indole-2-carbonyl) -amino] -3-phenylpropionic acid and 5-methyl-isoxazol-3-ylamine.
Mp 243-245 ° C.
Analysis calculated: C, 68.64, H, 5.51, N, 13.93;
Found: C 68.29, H 5.81, N 14.05.

Example 137

S-5-methyl-1H-indole-2-carboxylic acid [2- (4-acetyl-piperazin-1-yl) -1-benzyl-2-oxo-ethyl] -amide

From 5-2 - [(5-methyl-1H-indole-2-carbonyl) -amino] -3-phenylpropionic acid and 1-piperazin-1-yl-ethanone.
Mp 221-223 ° C.

Example 138

S-5-Chloro-1H-indole-2-carboxylic acid (1-carbamoyl-2-phenyl-ethyl) -amide

From 5-chloro-1H-indolecarboxylic acid and S-2-amino-3-phenyl-propionamide.
Mp 257-258 ° C.

Examples 139 and 140

(2RS) -2,3-dihydro-1H-indole-2-carboxylic acid (R-1-dimethylcarbamoyl-2-phenyl-ethyl) -amide

To a mixture of DL-indoline-2-carboxylic acid (0.38 g, 2.3 mmol), (R) -2-amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (0.53 g, 2.3 mmol), hydroxybenzotriazole (0.66 g, 4.2 mmol) and triethylamine (0.32 ml, 2.3 mmol) in dichloromethane (5 ml) was added EDC (0.64 g, 2.7 mmol). The solution was over Night stirred, diluted with dichloromethane, with water and saline washed over Dried magnesium sulfate and concentrated. The two isomers Products were purified by flash chromatography (EtOAc, then EtOAc / MeOH, 20: 1) separately.

Example 139

Less polar isomer (oil, 0.23 g, 30%):
¹ H NMR (300 MHz, CDCl ₃₎ δ 2.68 (s, 3H), 2.87 (s, 3H), 3.02 to 3.09 (m, 3H), 3.55 (dd, J = 10 Hz, 6 Hz, 1H), 4.61 (m, 1H), 5.10 (q, J = 8 Hz, 1H), 6, 95 (d, J = 8 Hz, 1H), 7,11- 7.30 (m, 8H), 8.12 (br, 1H).
MS (Cl, NH ₃ ) 394 (M + + 17)

Example 140

More polar Isomer (0.11 g, 14%): mp 136-140 ° C.

Examples 141 and 142

(2 RS) -S-chloro-2,3-dihydro-1H-indole-2-carboxylic acid (1-5-dimethylcarbamoyl-2-phenyl-ethyl) -amide

To a solution of S-5-chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide (2.60 g, 7.0 mmol) in THF (20 ml) and methanol (20 ml) became magnesium (1.75 g, 73 mmol) in portions at such a rate given that the reaction proceeds without excess heating. After this When the reaction was over, the reaction mixture became low Volume on concentrated, the residue was between 1N HCl and ethyl acetate distributed, the combined ethyl acetate layers were with water and brine washed over Dried magnesium sulfate and concentrated. The products were separated by flash chromatography (1% methanol in chloroform).

Example 141

Less polar isomer:
¹ H NMR (300 MHz, CDCl ₃₎ δ 2.61 (s, 3H), 2.83 (s, 3H), 3.00 to 3.02 (m, 3H), 3.47 (dd, J = 9.9 Hz, 6.4 Hz, 1H), 4.43 (m, 1H), 5, 10 (q, J = 7.5 Hz, 1H), 6.64 (d, J = 8.8 Hz , 1H), 7, 00 (s, 1H), 7.16-7.29 (m, 7H), 7.70 (br, 1H).
MS (Cl, NH ₃₎ 372 (M + +1)

Example 142

More polar Isomer: mp 125 ° C Decomposition.

Examples 143 and 144

2RS 5-chloro-2,3-dihydro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenyl-ethyl) -amide

By an analogous procedure to that of Example 141 and 142 using of R-5-chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide the two diastereomers were prepared.

Example 143

Fewer polar isomer: mp 122-124 ° C decomposition.

Example 144

Polar isomer:
¹ H NMR (300 MHz, CDCl ₃₎ δ 2.70 (s, 3H), 2.83 (s, 3H), 2.77 to 2.97 (m, 3H), 3.40 (dd, J = 16.6 Hz, 10.8 Hz, 1H), 4.28 (m, 1H), 4.40 (d, J = 5.2 Hz, 1H), 5.12 (q, J = 7.8 Hz , 1H), 6, 56 (d, J = 9, 0Hz, 1H), 6, 96 (d, J = 7, 8Hz, 1H), 6, 99 (s, 1H), 7,03-7 , 07 (m, 2H), 7,11-7,18 (m, 3H), 7,74 (d, J = 8,8 Hz, 1H).

Example 145

3-chloro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenyl-ethyl) -amide

To a solution of 2,3-dihydro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenyl-ethyl) -amide (less polar isomer, 0.50 g, 1.42 mmol) in DMF (7 , 5 ml) was added N-chlorosuccinimide (0.55 g, 1.42 mmol). After stirring overnight, the solvent was evaporated and the product purified by flash chromatography (hexanes / ethyl acetate, 1: 1).
¹ H NMR (300 MHz, CDCl ₃₎ δ 2.55 (s, 3H), 2.80 (s, 3H), 3.05-3.20 (m, 3H), 5.32 (m, 1H) , 7.10-7.25 (m, 6H), 7.30 (d, 7Hz, 1H), 7.58 (d, 7Hz, 1H), 8.11 (br d, 7Hz, 1H) , 10.20 (br, 1H). MS m / e 370 (M ⁺ +1).

Example 146

3-chloro-1H-indole-2-carboxylic acid (1S-dimethylcarbamoyl-2-phenyl-ethyl) -amide

The title compound was prepared by an analogous procedure to that of Example 145 from the more polar isomer of 2,3-dihydro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenyl-ethyl) -amide.
¹ H NMR (300 MHz, CDCl ₃ ) δ 2, 55 (s, 3H), 2, 85 (s, 3H), 3.05-3.20 (m, 2H), 5.32 (m, 1H) , 7.10-7.25 (m, 6H), 7.35 (d, 7Hz, 1H), 7.58 (d, 7Hz, 1H), 8, 11 (br, d, 7Hz, 1H ), 10, 30 (br, 1H). MS m / e 370 (M + +1).

HPLC conditions for examples 147-165: Detector wavelength 215 nm.

HPLC retention time (in minutes) from a Waters Novapac C18 3.9 x 150 mm column. Eluent A = 50 mM KH ₂ PO ₃ , pH 3; Eluent B = acetonitrile; Flow rate 1.5 ml / minute; Gradient 90% A / 10% B (5 minutes) to 40% A / 60% B (held for 5 minutes). HPLC retention times (room temperature) are in minutes. The reported percentage is the percentage of the total integration due to the reported peak.

Loud HPLC was the starting acid in an amount of less than 5% of the total integration, provided that not stated otherwise.

Example 147

(S) -2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid

To a solution of 5-fluoroindole-2-carboxylic acid (5.0 g, 28 mmol) and methylene chloride (250 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.53 g, 27.9 mmol). Add L-phenylalanine t-butyl ester hydrochloride (6.54 g, 27.9 mmol) and triethylamine (7.1 mL, 5.13 g, 51 mmol). After stirring for 40 hours at room temperature, the reaction mixture was washed with an equal volume of water followed by an equal volume of 1N HCl. The aqueous acid was extracted with methylene chloride and the combined organic layers were washed successively with equal volumes of water (twice) and brine washed. The organic solution was dried (MgSO ₄ ), filtered, and concentrated to give 2 - [(5-fluoro-1H-indole-2-carbonyl) -amino) -3-phenyl-propionic acid, st-butyl ester (2.97 g, 31%). This was then diluted with methylene chloride (75 ml) and cooled to 0 ° C. Trifluoroacetic acid (8 ml) was added and the reaction mixture was then stirred for 2 days at room temperature and then refluxed for 6.5 hours. Upon reaching room temperature overnight, the solution was concentrated to dryness to give a brown solid. This was then dissolved in a small amount of ether and pentanes, filtered to remove particulates, and concentrated to give the title compound as a brown foam (2.65 g, quantitative yield): mp 125-127 ° C; HPLC RT 5.72; TSPMS ion (expected) 327 (326);
¹ H NMR (CDCl ₃ ) δ 9.0 (br s, 2H), 7.4-7.2 (m, 6H), 7.02 (dt, J = 2.4, 9.1 Hz, 1H) , 6.80 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 5, 09 (q, J = 7.6 Hz, 1H), 3 , 35 (dd, J = 5, 8, 7.6 Hz, 1H), 3, 26 (dd, J = 5, 8.7.6 Hz, 1H).

Example 148

(S) -2 - [(5-methyl-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid

A repeat of the above procedure with 5-methylindole-2-carboxylic acid (3.0 g, 17 mmol), methylene chloride (185 mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.28 g, 17.1 mmol ), L-phenylalanine t-butyl ester hydrochloride (4.01 g, 15.6 mmol) and triethylamine (4.5 mL, 3.31 g, 32.7 mmol) afforded the analogous t-butyl ester (2.42, 41 %). After dilution with methylene chloride (60 ml) and trifluoroacetic acid (6.6 ml), the reaction mixture was refluxed for 3 hours, allowed to reach room temperature overnight and concentrated. The crude product was slurried in ethyl acetate, filtered to remove insoluble material, and concentrated (twice) to give the title compound as a brown foam (2.54 g, quantitative yield).
HPLC RT 5.98; TSPMS ion (expected) 323 (322);
¹ H NMR _(CDCl3) δ 9.9 (br s, 1H), 8.5 (br s, 2H), 7.38 (s, 1H), 7.3-7.1 (m, 6H), 6.77 (m, 2H), 5.09 (q, J = 7.6Hz, 1H), 3.35 (dd, J = 5.6, 7.6Hz, 1H), 3.26 (d , J = 5.6, 7.6 Hz, 1H), 2.43 (s, 3H).

Example 149

5-fluoro-1H-indole-2-carboxylic acid {1- [2- (5-methoxy-1H-indol-3-yl) -ethylcarbamoyl] -2-phenyl-ethyl} -amide

To 5.0 μmol 2 - [(5-Fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid (50 μl of a 0.1 mM solution in Dimethylformamide) became 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50 μl of a 0.11 mM solution in DM F, 5.5 μmol), followed by 5-methoxytryptamine (50 μl of a 0.11 mM solution in DM F, 5.5 μmol) given. The reaction mixture was stirred for 3 days and then brought to dryness concentrated. The crude product was partitioned between chloroform (0.5 ml) and water (0.25 ml) and the organic layer then became concentrated on obtaining the title compound. TSPMS ion (expected) 499 (499); HPLC RT 6.78 (25%).

For the following Examples which were prepared analogously to Example 149 apply Examples 150-156 2 - [(5-fluoro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid and Example 157-163 2 - [(5-methyl-1H-indole-2-carbonyl) amino] -3-phenylpropionic acid.

Example 150

5-fluoro-1H-indole-2-carboxylic acid {1- [2- (1H-indol-3-yl) -1-methyl-ethylcarbamoyl] -2-phenyl-ethyl} -amide

TSPMS ion (expected) 482 (483); HPLC RT unknown, several small peaks noticed, estimated Purity <10%; % SM (HPLC) not determined.

Example 151

5-fluoro-1H-indole-2-carboxylic acid [1-benzyl-2- (2-ethyl-piperidin-1-yl) -2-oxo-ethyl] -amide

TSPMS ion (expected) 420 (421); HPLC RT 6.61 (40%).

Example 152

5-fluoro-1H-indole-2-carboxylic acid (1-cyclohexylcarbamoyl-2-phenyl) -amide

TSPMS ion (expected) 408 (407); HPLC RT 6.60 / 7.11 (The two largest peaks are roughly of the same concentration); estimated purity (25%).

Example 153

5-fluoro-1H-indole-2-carboxylic acid {2-phenyl-1 - [(thiophen-2-ylmethyl) -carbamoyl] -ethyl} -amide

TSPMS ion (expected) 422 (421); HPLC RT 7.50 (50%).

Example 154

5-fluoro-1H-indole-2-carboxylic acid [1-benzyl-2- (3,4-dihydro-1H-isoquinolin-2-yl) -2-oxo-ethyl] -amide

TSPMS ion (expected) 442 (441); HPLC RT 6.78 (35%), 5% SM.

Example 155

5-fluoro-1H-indole-2-carboxylic acid [1- (2-cyclohexen-1-yl-ethylcarbamoyl) -2-phenyl-ethyl] -amide

TSPMS ion (expected) 434 (433); HPLC RT 6.27 / 6.60 (the two largest peaks are roughly of the same concentration); estimated purity (35%), 5% SM.

Example 156

5-fluoro-1H-indole-2-carboxylic acid [1- (5-cyano-pentyl-carbamoyl) -2-phenyl-ethyl] -amide

TSPMS ion (expected) 421 (420); HPLC RT 6.61 / 7.71 (The two largest peaks are roughly of the same concentration) (40%).

Example 157

5-methyl-1H-indole-2-carboxylic acid [2-phenyl-1- (thiochroman-4-ylcarbamoyl) -ethyl] -amide

TSPMS ion (expected) 470 (470).

Example 158

5-methyl-1H-indole-2-carboxylic acid (1-cyclohexylcarbamoyl-2-phenyl-ethyl) -amide

TSPMS ion (expected) 404 (404); HPLC RT 6.21 (70%).

Example 159

5-methyl-1H-indole-2-carboxylic acid (1-benzyl-2-morpholin-4-yl-2-oxo-ethyl) -amide

TSPMS ion (expected) 392 (391); HPLC RT 6.86 (50%).

Example 160

5-Methyl-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-pyrrolidin-1-yl-ethyl) -amide

TSPMS ion (expected) 376 (375); HPLC RT 6.50 (40%).

Example 161

5-methyl-1H-indole-2-carboxylic acid {2-phenyl-1 - [(thiophen-2-ylmethyl) -carbamoyl] -ethyl} -amide

TSPMS ion (expected) 418 (417); HPLC RT 7.89 (70%).

Example 162

5-methyl-1H-indole-2-carboxylic acid [1- (5-cyano-pentylcarbamoyl) -2-phenyl-ethyl] -amide

TSPMS ion (expected) 417 (417); HPLC RT 6.49 / 6.88 (the two largest peaks are roughly of the same concentration) (40%).

Example 163

5-methyl-1H-indole-2-carboxylic acid (1-cyclopentylcarbamoyl-2-phenyl-ethyl) -amide

TSPMS ion (expected) 390 (389); HPLC RT 6.96 (55%).

Example 164

{2 - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionylamino} -acetic acid methyl ester

To 5.0 mmol of 5-chloro-1H-indole-2-carboxylic acid (50 ml of a 0.1M solution in Acetonitrile) were 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50 ml of a 0.10M solution in Acetonitrile, 5.0 mmol), 1-hydroxybenzotriazole (50 ml of a 0.10M solution in Acetonitrile, 5.0 mmol), followed by (2-amino-3-phenylpropionylamino) -acetic acid methyl ester (50 ml of a 0.10M solution in acetonitrile, 5.0 mmol). The reaction mixture was over night at 80 ° C touched and then concentrated to dryness to give the title compound. HPLC RT 8.15 (65%).

Example 165

2- (S) - [(5-chloro-1H-indole-2-carbonyl) -amino] -3-phenyl-propionic acid benzyl ester

The title compound was prepared by dipping L-phenylalanine benzyl ester into (2-amino-3-phenyl-propionylamino) -acetic acid methyl ester in a procedure analogous to that of Example 164.
HPLC RT 8.13 (40%).

Example 166

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (3-hydroxyazetidin-1-yl) -2-oxo-ethyl] -amide

2-Amino-1- (3-hydroxy-azetidin-1-yl) -3-phenyl-propan-1-one hydrochloride (1.18 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.18 mmol) were prepared according to procedures A (4: 1 dichloromethane-dimethylformamide reaction solvent) coupled and the product was purified by chromatography on silica gel eluted with 25%, 50%, 75% and 100% ethyl acetate-hexanes purified yielding the title substance as a colorless foam (104 mg, 22%). A mixture (180 mg) of the less polar products was also added isolated. Title substance: HPLC (60/40) 4.18 minutes (97%); TSPMS 398/400 (MH +, 100%).

Example 166a

(2S) -amino-1- (3-hydroxy-azetidin-1-yl) -3-phenyl-propan-1-one hydrochloride

[(1S) -benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (515mg, 1.6mmol) were dissolved in cold 4N HCl-dioxane, the Mixture was 2 hours at 25 ° C touched, focused on and the residue Evaporated with ether to give a colorless solid (415mg, 100%).

Example 167

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (3-hydroxyimino-azetidin-1-yl) -2-oxo-ethyl] -amide

A solution of 5-chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (3-oxo-azetidin-1-yl) -2-oxo-ethyl] -amide (product of Example 170, 50 mg, 0.13 mmol), sodium acetate trihydrate (43 mg, 0.32 mmol) and hydroxylamine hydrochloride (18 mg, 0.25 mmol) in methanol (2 mL) was refluxed for 8 hours and concentrated. The residue was partitioned between dichloromethane and saturated aqueous NaHCO ₃ solution. The organic layer was separated and dried to give a colorless solid which was triturated with ether-hexanes and dried (yield 36 mg, 69%): HPLC (50/50) 6.74 minutes (99%); TSPMS 411/413 (MH +, 10%), 180 (100%); ¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 11.10 (s, 0.5H), 11, 08 (s, 0.5H), 8.99 (d, 1H, J = 9 Hz), 7.73 (d, 1H, J = 2 Hz), 7.4-7.1 (m, 8H), 5.0 (m, 1H), 4.8-4.5 (m , 4H), 3.1 (m, 2H).

Example 168

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (4-hydroxy-imino-piperidin-1-yl) -2-oxo-ethyl] -amide

A mixture of 5-chloro-1H-indole-2-carboxylic acid [1 (S) -benzyl-2-oxo-2- (4-oxopiperidin-1-yl) -ethyl] -amide (406 mg, 0 , 96 mmol), hydroxylamine hydrochloride (80 mg, 1.15 mmol) and potassium carbonate (159 mg, 1.15 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25 ° C for 18 hours and concentrated. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (411 mg, 98%): HPLC (60/40) 5.13 minutes (97%); TSPMS 439/441 (MH +, 100%); ¹ H NMR (DMSO-d ₆ ) δ 11.75 (br, 1H), 10.45 (s, 0.5H), 10.44 (s, 0.5H), 9.00 (m, 1H), 7.72 (d, 1H, J = 2Hz), 7.40 (d, 1H, J = 8.8Hz), 7.35-7.15 (m, 7H), 5.17 (m, 1H ), 3.8-3.5 (m, 4H), 3.1 (m, 2H), 2.45 (m, 2H), 2.25 (m, 2H).

Example 168a

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2-oxo-2- (4-oxo-piperidin-1-yl) -ethyl] -amide

5-Chloro-1H-indole-2-carboxylic acid [(1S) -benzyl-2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -amide (Example 46,669 mg) was added in one portion at 0 ° C to a mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC, 1.80 g, 9.4 mmol) and dichloroacetic acid (307 mg, 1.5 mmol) in anhydrous toluene (e ml). and anhydrous dimethyl sulfoxide (e ml). The mixture was stirred at 0-20 ° C for 2 hours, diluted with ethyl acetate, the resulting solution washed twice with 1N HCl, twice with saturated aqueous NaHCO ₃ , dried, concentrated, and the residue chromatographed on silica gel eluted with 25 %, 50% and 75% ethyl acetate-hexanes, purified to give a foam (424 mg, 64%).

Example 169

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (1,3-dihydro-isoindol-2-yl) -2-oxo-ethyl] -amide

2-Amino-1- (1,3-dihydro-isoindol-2-yl) -3-phenyl-propan-1-one hydrochloride (0.20 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0, 20 mmol) were coupled according to Method A and the product was purified by chromatography on silica gel eluted with 5%, 10%, 20% and 50% ethyl acetate-hexanes (55 mg, 62% yield): HPLC (70/30) 6 , 58 minutes (90%)% TSPMS 444/446 (MH +, 50%), 180 (100%).
¹ HNMR (CDCl ₃₎ δ 9.25 (br, 1H), 7.60 (s, 1H), 7.45 (m, ca. 1H), 7.3-7.1 (m, ca. 11H ), 6.90 (5.25 (m, 1H), 5.0 (d, 1H, ca. 16 Hz), 4.85 (d, 1H, J = ca. 16 Hz), 4.70 (i.e. , 1H, J = about 16 Hz), 4.20 (d, 1H, J = 16 Hz).

Example 169a

(2S) -amino-1- (1,3-dihydro-isoindol-2-yl) -3-phenyl-propan-1-one hydrochloride

[(1S) -benzyl-2- (1,3-dihydro-isoindol-2-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester (88 mg) was dissolved in cold 4N HCl-dioxane (1.5 ml), 2 hours at 25 ° C touched and the mixture is concentrated. The residue was triturated with ether and dried (65 mg, 91%). TSPMS 267 (MH +, 100%).

Example 169b

[(1S) -benzyl-2- (1,3-dihydro-isoindol-2-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

N-t-Boc-L-phenylalanine (1 mmol) and isoindoline (J. Org. Chem. 1988, 53, p. 5382, 70-80% Purity, 1 mmol) were prepared according to procedures A and the product by chromatography on silica gel, eluted with 20% and 50% ethyl acetate-hexanes, purified to give an amber oil (88 mg, 23%): TSPMS 367 (MH +, 100%).

Example 170

5-chloro-1H-indole-2-carboxylic acid - [(1S) -benzyl-2- (3-oxo-azetidin-1-yl) -2-oxo-ethyl] -amide

1 - ((2S) -Amino-3-phenyl-propionyl) -azetidin-3-one hydrochloride (3.2 mmol) and 5-chloro-1H-indole-2-carboxylic acid (3.2 mmol) were prepared according to method A ( 0-25 ° C reaction temperature) and the resulting yellow foam was purified by chromatography on silica gel eluted with 20%, 30%, 40% and 50% ethyl acetate in hexane to give the title substance as a colorless foam (600 mg, 47%): HPLC (60/40) 5.09 minutes (98%); TSP-MS 396 (MH +, 100%); ¹ H NMR (CDCl ₃ ) δ 9, 14 (br, 1H), 7.62 (d, 1H, J = 3 Hz), 7.4-7.2 (m, 7H), 7.11 (d, 1H, J = 8.0 Hz), 6.85 (m, 1H), 4.90 (m, 1H), 4.78 (m, 2H), 4.63 (m, 1H), 3.65 ( m, 1H), 3, 25 (dd, 1H, A of AB, J = 5.1, 12.9 Hz), 3, 10 (dd, 1H, B of AB, J = 10, 12.9 Hz) ,

Example 170A

1 - ((2S) -Amino-3-phenyl-propionyl) azetidin-3-one hydrochloride

[(1S) -benzyl-2-oxo-2- (3-oxo-azetidin-1-yl) -ethyl] -carbamic acid tert-butyl ester (297mg, 0.9mmol) was dissolved in 4N HCl-dioxane (3ml). The solution obtained was at 25 ° C Stirred for 2 hours, focused on and the residue triturated with ether and dried (196 mg, 82%).

Example 170B

[(1S) -benzyl-2-oxo-2- (3-oxo-azetidin-1-yl) -ethyl] -carbamic acid tert-butyl ester

[(1S) -benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxo-ethyl] -carbamic acid tert -butyl ester (320 mg, 1 mmol) was added in one portion to a mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC, 575 mg, 3 mmol) and dichloroacetic acid (192 mg, 1.5 mmol) in anhydrous toluene (2 mL) and anhydrous dimethylsulfoxide (2 mL). The mixture was stirred for one hour at 0-20 ° C, diluted with ethyl acetate, the resulting solution washed twice with 1N HCl, twice with saturated aqueous NaHCO ₃ solution, dried and concentrated to give a colorless solid (304 mg, 96%). ).

Example 170C

[(1S) -benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester

3-hydroxyazetidine hydrochloride (J. Chem. Soc., Chem. Commun. 1968, p. 93, 27 mmol) and N-t-Boc-L-phenylalanine (27 mmol) were prepared according to procedures A coupled to give the title substance as a colorless foam (8.15 g, 93%).

Example 171

5-chloro-1H-benzimidazol-2-carboxylic acid (1-dimethylcarbamoyl-2-phenyl-ethyl) -amide

(S) -2-amino-N, N-dimethyl-3-phenyl-propionamide hydrochloride (2.0 mmol) and 5-chloro-1H-benzoimidazole-2-carboxylic acid (Crowther et al., J. Chem. Soc. 1949 , P. 1268, 2.0 mmol) were coupled according to Method A and the product was purified by chromatography on silica gel eluted with 1: 1 ethyl acetate-hexanes (235 mg, 63%): HPLC (60/40) 4.92 Minutes (91%); PBMS 371/373 (MH +, 100%); ¹ H NMR (CDCl ₃ ) δ 11.25 (br, 0.6H), 10.9 (br, 0.4H), 8.36 (m, 1H), 7.78 (d, 0.4H, J = 7.72 (d, 0, 6H, J = 8.8 Hz), 7.52 (d, 0, 6H, J = 2 Hz), 7.41 (d, 0.4H, J = 8.4 Hz), 7.35-7.1 (m, 6H), 7.35 (m, 1H), 3.16 (m, 2H), 2.90 (s, 3H), 2.68 (s, ca 2H), 2.67 (s, about 1H).

Example 172

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2-oxo-2- (2-oxo-oxazolidin-3-yl) -ethyl] -amide

3 - ((2S) -Amino-3-phenyl-propionyl) -oxazolidin-2-one hydrochloride (0.50 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.50 mmol) were prepared according to method A ( 3: 1 dimethylformamide-dichloromethane reaction solvent) and the product was triturated with 2: 1 ether-hexanes and dried (130 mg, 63%): HPLC (60/40) 6.22 minutes (95%); TSPMS 429/431 (45%, MH + NH ₃ ), 412/414 (30%, MH +), 325/327 (100%). ¹ H NMR (DMSO-d ₆ ) δ 11.68 (br, 1H), 8, 92 (d, 1H, J = 8.5 Hz), 7.75 (s, 1H), 7.42 (m, 3H), 7.26 (m, 3H), 7.18 (m, 2H), 5.83 (m, 1H), 4.50 (m, 2H), 4.0 (m, 1H), 3, 25 (m, 1H), 2, 95 (m, 1H).

Example 172a

3 - ((2S) -Amino-3-phenyl-propionyl) -oxazolidin-2-one hydrochloride

(1S) -benzyl-2-oxo-2- (2-oxo-oxzaolidin-3-yl) -ethyl] -carbamic acid tert-butyl ester (2.29 g, 6.68 mmol) was dissolved in 4N HCl-dioxane (10 mL) at 0 ° C. The solution obtained was 2 hours at 25 ° C touched, focused on and the residue triturated with ether and dried (1.98 g, 107%).

Example 172b

[(1S) -benzyl-2-oxo-2- (2-oxo-oxazolidin-3-yl) -ethyl] -carbamic acid tert-butyl ester

N-butyl lithium (2.35M in hexanes, 11.5ml) was added at -78 ° C to a solution of 2-oxazolidinone (2, 04 g, 23.4 mmol) in tetrahydrofuran (25 ml). After 30 minutes at -78 ° C was the solution with N-t-Boc-L-phenylalanine N-hydroxysuccinimide ester (9, 31 g, 25, 7 mmol) in tetrahydrofuran (10 ml) and the stirred mixture was over Night at 25 ° C heat to let. Water (10 ml) was added and the resulting mixture concentrated, the residue in ethyl acetate solved and the resulting solution twice with 1N NaOH, once with water, once with brine, dried and concentrated. The residue was chromatographed on silica gel, eluted with 25% and 50% ethyl acetate in hexanes, chromatographed to give a colorless solid (3.42 g, 44%).

It should of course that the invention is not limited by the individual embodiments described herein is limited, but that different changes and modifications be executed can, without departing from the spirit and scope of this new concept, as in the following claims defined, depart.

Claims (13)

Process for preparing a compound of formula I

comprising reacting a compound of formula II

with a compound of formula III

wherein the dotted line (---) represents a possible bond; A is -C (H) =, -C ((C ₁ -C ₄ ) alkyl) =, -C (halo) = or -N = when the dotted line (---) is a bond or A is methylene or CH ((C ₁ -C ₄ ) alkyl) - when the dotted line (---) is not a bond; R ₁ , R ₁₀ or R _{11 are} each independently H, halo, cyano, 4-, 6- or 7-nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl group; R _{2 represents} H; R _{3 is} H or (C ₁ -C ₅ ) alkyl; R _{4 is} H, methyl, ethyl, n-propyl, hydroxy (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl, phenyl (C ₁ -C ₄ ) alkyl, phenylhydroxy (C ₁ -C ₄ ) -alkyl, (phenyl) ((C ₁ -C ₄ ) alkoxy) (C ₁ -C ₄ ) alkyl, thien-2 or 3-yl (C ₁ -C ₄ ) alkyl or Fur-2 or 3-yl (C ₁ -C ₄ ) alkyl, wherein the rings R ₄ independently of one another on the carbon atom with H, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy , Trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl mono-, di- or tri-substituted, or R _{4 is} pyrid-2-, -3- or -4-yl (C ₁ C ₄ ) alkyl, thiazole-2, ₄ or 5-yl (C ₁ -C ₄ ) -alkyl, imidazol-2, ₄ or 5-yl (C ₁ -C ₄ ) -alkyl, Pyrrole-2 or 3-yl (C ₁ -C ₄ ) alkyl, oxazole-2, ₄ or 5-yl (C ₁ -C ₄ ) alkyl, pyrazole-3, ₄ or 5-yl (C ₁ -C ₄₎ alkyl, isoxazol-3-, -4- or -5-yl (C ₁ -C ₄₎ alkyl, isothiazol-3-, -4- or -5-yl (C ₁ C ₄ ) alkyl, pyridazine-3 or 4-yl (C ₁ -C ₄ ) alkyl, pyrimidine-2, ₄ , 5 or 6-yl (C ₁ -C ₄ ) alkyl, Pyrazine-2 or 3-yl (C ₁ -C ₄ ) alkyl, 1 Represents 3,5-triazin-2-yl (C ₁ -C ₄₎ alkyl or indol-2- (C ₁ -C ₄₎ alkyl, wherein said preceding heterocycles R ₄ is optionally substituted independently with halo, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, amino, hydroxy or cyano mono- or disubstituted and the substituents are bonded to carbon; or R _{4 is} R ₁₅ -carbonyloxymethyl, wherein R _{15 is} phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein the preceding rings R _{15 are} optionally independently of one another mono- or disubstituted by halogen, amino, hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or trifluoromethyl and the mono- or disubstituents bonded to carbon are; R _{5 represents} H; R _{6 is} carboxy, (C ₁ -C ₈ ) alkoxycarbonyl, benzyloxycarbonyl, C (O) NR ₈ R ₉ or C (O) R ₁₂ , wherein R _{8 is} H, (C ₁ -C ₆ ) alkyl, cyclo (C ₃ C ₆ ) alkyl, cyclo (C ₃ -C ₆ ) alkyl (C ₁ -C ₅ ) alkyl, hydroxy or (C ₁ -C ₈ ) alkoxy and R _{9 is} H, cyclo (C ₃ -C ₈ ) alkyl, Cyclo (C ₃ -C ₈ ) alkyl (C ₁ -C ₅ ) alkyl, cyclo (C ₄ -C ₇ ) alkenyl, cyclo (C ₃ -C ₇ ) alkyl (C ₁ -C ₅ ) alkoxy, cyclo (C ₃ -C ₇ ) alkyloxy, hydroxy, methylene perfluorinated (C ₁ -C ₈ ) alkyl, phenyl or a heterocycle, wherein the heterocycle is pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl , Isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl, wherein the heterocyclic rings are carbon-nitrogen bonded, or R _{9 is} (C ₁ -C ₆ ) alkyl or (C ₁ -C ₈ ) alkoxy, wherein the (C ₁ -C ₆ ) alkyl or (C ₁ -C ₈ ) alkoxy optionally with cyclo (C ₄ -C ₇ ) alken-1-yl, phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, Imidazolyl, pyra zolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl or indolyl, and wherein the (C ₁ -C ₆ ) alkyl or (C ₁ -C ₈ ) alkoxy optionally additionally with halogen, hydroxy, (C ₁ -C ₅ ) alkoxy, amino, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylamino, cyano, carboxy or (C ₁ -C ₄ ) alkoxycarbonyl mono- or disubstituted; and wherein the rings R ₉ optionally independently of one another on the carbon atom with halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, hydroxy, hydroxy (C ₁ -C ₄ ) alkyl, amino (C ₁ -C ₄ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl, amino , Mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino, cyano, carboxy, (C ₁ -C ₅ ) alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl mono- or disubstituted and the rings R ₉ optionally may additionally be mono- or disubstituted independently with (C ₁ -C ₅ ) alkyl or halogen; with the proviso that no quaternized nitrogen atom is included in each heterocycle R ₉ ; R ₁₂ morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidine-1 yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1, 2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl, 2, 3-dihydro-benzo [1,4] oxazin-4-yl, 2,3-dihydro-benzo [1,4] thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1-yl, 3 , 4-Dihydrobenzo [c] [1,2] oxazin-1-yl, 1,4-dihydrobenzo [d] [1,2] oxazin-3-yl, 3,4-dihydrobenzo [e] [1,2] oxazin-2-yl, 3H-benzo [d] isoxazol-2-yl, 3H-benzo [c] isoxazol-1-yl or azepan-1-yl; where the rings R _{12 are} optionally independently of each other halogen, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy, hydroxy, amino, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylcarbamoyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₅ ) alkoxycarbonyl, benzyloxycarbonyl, (C ₁ -C ₅ ) alkoxycarbonyl (C ₁ -C ₅ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonylamino, carboxy (C ₁ -C ₅ ) alkyl, carbamoyl (C ₁ -C ₅ ) alkyl, mono-N or di-N, N- (C ₁ -C ₅ ) alkylcarbamoyl (C ₁ -C ₅ ) alkyl, hydroxy (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl, amino (C ₁ -C ₄ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) -alkylamino (C ₁ -C ₄ ) alkyl, oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino mono-, di- or trisubstituted and wherein not more than two substituents of oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino are selected and oxo, hydroxyimino or (C ₁ -C ₆ ) Alkoxyimino are on non-aromatic carbon; and wherein the rings R _{12 are} optionally additionally mono- or disubstituted independently with (C ₁ -C ₅ ) alkyl or halogen; with the proviso that when R _{6 is} (C ₁ -C ₅ ) alkoxycarbonyl or benzyloxycarbonyl then R ₁ is 5-halo, 5- (C ₁ -C ₄ ) alkyl or 5-cyano and R _{4 is} (phenyl) (hydroxy ) (C ₁ -C ₄ ) alkyl, (phenyl) ((C ₁ -C ₄ ) alkoxy) (C ₁ -C ₄ ) alkyl, hydroxymethyl or Ar (C ₁ -C ₂ ) alkyl, wherein Ar is thien-2 - or -3-yl, fur-2- or -3-yl or phenyl, wherein the Ar is optionally mono- or disubstituted independently with halogen, with the proviso that when R ₁ and R ₁₀ and R _{11 is} H represent, R ₄ is not, 2-phenylethyl or 2-hydroxy-2-phenylethyl represents imidazol-4-ylmethyl; with the proviso that when both R ₈ and R _{9 are} n-pentyl, R _{1 is} 5-chloro, 5-bromo, 5-cyano, 5 (C ₁ -C ₅ ) alkyl, 5 (C ₁ -C ₅ ) Alkoxy or trifluoromethyl; with the proviso that when R _{12 is} 3,4-dihydroisoquinol-2-yl, the 3,4-dihydroisoquinol-2-yl is not substituted with carboxy (C ₁ -C ₄ ) alkyl; with the proviso that when R _{8 is} H and R _{9 is} (C ₁ -C ₆ ) alkyl, R ₉ does not react with carboxy or (C ₁ -C ₄ ) alkoxycarbonyl on the carbon atom to which the nitrogen atom N of NHR ₉ is bound, is substituted; and with the proviso that when R _{6 is} carboxy and R ₁ , R ₁₀ , R ₁₁ , and R _{5 are} all H, then R ₄ is not benzyl, H, (phenyl) (hydroxy) methyl, methyl, ethyl, or n -Propyl represents. The process of claim 1 wherein R _{4 is} H, phenylmethyl, thien-2 or 3-ylmethyl, fur-2 or 3-ylmethyl, said rings optionally mono- or disubstituted with fluorine; and R _{6 is} C (O) R ₁₂ ; wherein R _{12 is} thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl, 1,2-oxazinane 2-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl or oxazolidin-3-yl; where the rings R _{12 are} optionally independently of each other halogen, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy, hydroxy, amino, mono-N- or di-N, N- (C ₁ -C ₅ ) alkylamino, formyl, carboxy, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₅ ) -alkylcarbamoyl, (C ₁ -C ₅ ) -alkoxycarbonyl, hydroxy (C ₁ -C ₅ ) -alkyl, amino- (C ₁ -C ₄ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl, oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino mono - or disubstituted, with the proviso that only the heterocycles R ₁₂ thiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidine 2-yl or oxazolidin-3-yl optionally mono- or disubstituted independently with oxo, hydroxyimino or (C ₁ -C ₆ ) alkoxyimino; and wherein the rings R _{12 are} optionally additionally mono- or disubstituted independently with (C ₁ -C ₅ ) alkyl; and with the proviso that R _{12 is} not 2-carboxy-4-hydroxy-pyrrolidin-1-yl, 2 - ((C ₁ -C ₅ ) alkoxycarbonyl) -4-hydroxy-pyrrolidin-1-yl, 2-carboxy piperidin-1-yl or 2 - ((C ₁ -C ₅ ) alkoxycarbonyl) -piperidin-1-yl. The method of claim 2, further comprising the steps of a) reacting a compound of formula XXIII

with suitable reagents to introduce a suitable protecting group P _t to obtain a compound of formula XXIV

then b) reacting compounds of formula XXIV with a compound of formula R ₁₂ H, then c) removing protecting group P _t to obtain a compound of formula III wherein R ₃ , R ₄ , R ₅ and R _{12 are} as in claim 2 are defined. An intermediate compound of formula III as defined in claim 1 wherein R _{3 is} H; R _{4 is} phenylmethyl, wherein the phenyl is optionally mono- or disubstituted with fluorine; R _{5 is} H and R _{6 is} C (O) R ₁₂ , wherein R _{12 is} 3-mono-substituted azetidin-1-yl, 3-mono- or 3,4-disubstituted pyrrolidin-1-yl, 3, 4 or 5-mono- or disubstituted piperidin-1-yl, thiazolidin-3-yl, 1-oxothiazolidin-3-yl or 1,1-dioxothiazolidin-3-yl, wherein the pyrrolidin-1-yl or piperidine 1-yl are independently mono- or disubstituted by hydroxy, oxo, hydroxyimino, amino, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonyl or carboxy, and the rings R ₁₂ optionally additionally mono- or disubstituted independently of each other with (C ₁ -C ₄ ) alkyl. An intermediate compound of formula III as defined in claim 1 wherein R _{3 is} H; R _{4 represents} H; R _{5 is} H and R _{6 is} C (O) R ₁₂ wherein R _{12 is} thiazolidin-3-yl. An intermediate compound of formula III as defined in claim 1 wherein R _{3 is} H; R _{4 represents} H; R _{5 is} H and R _{6 is} C (O) R ₁₂ wherein R _{12 is} 1,1-dioxothiazolidin-3-yl. An intermediate compound of formula III as defined in claim 1, wherein R 3 represents H; R _{4 represents} H; R _{5 is} H and R _{6 is} C (O) R ₁₂ wherein R _{12 is} 1-oxothiazolidin-3-yl. An intermediate compound according to claim 4 wherein R _{4 is} benzyl, R _{12 is} 3-hydroxypyrrolidin-3-yl and the stereochemistry of carbon is (a) (S). An intermediate compound according to claim 4 wherein R _{4 is} benzyl, R _{12 is} 3-hydroxyazetidin-1-yl and the stereochemistry of carbon is (a) (S). An intermediate compound according to claim 4 wherein R _{4 is} benzyl, R _{12 is} 3,4-dihydroxypyrrolidin-1-yl and the stereochemistry of carbon is (a) (S). An intermediate compound according to claim 4 wherein R _{4 is} benzyl, R _{12 is} 4-hydroxypiperidin-1-yl and the stereochemistry of carbon is (a) (S). An intermediate compound according to claim 4, wherein R _{4 is} 4-fluorophenylmethyl, R _{12 is} 4-hydroxypiperidin-1-yl and the stereochemistry of carbon is (a) (S). An intermediate compound according to claim 4 wherein R _{4 is} benzyl, R _{12 is} 3-hydroxyiminoazetidin-1-yl and the stereochemistry of carbon is (a) (S).