MXPA00002325A - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase - Google Patents

Abstract

There are provided according to the invention compounds of formula (I) wherein R1, R2 and R3 are as defined in the specification. Compounds of formula (I) are useful, i(inter alia), in the treatment of inflammatory disorders of the respiratory tract.

Description

DERIVATIVES OF PIRROLOPROROLLONE AS INHIBITORS OF ELASTASE NEUTROFILA FIELD OF THE INVENTION The present invention relates to therapeutically active bicyclic compounds, to processes for their manufacture, to pharmaceutical formulations containing them and to their use in chemotherapy. In particular, a group of new bicyclic compounds have been found that are effective in the treatment of inflammatory diseases.

BACKGROUND OF THE INVENTION Inflammation is a primary response to tissue damage or microbial invasion and is characterized by circulating leukocytes that bind or bind to and extravasate through the vascular endothelium. Circulating leukocytes include neutrophils, eosinophilic cells, basophils, monocytes, and lymphocytes. Different forms of inflammation, which involve different types of infiltration leukocytes. Ref .: 32989 The inflammatory process can be caused in a number of ways, including by infection, tissue damage and autoimmunity reactions. As part of the inflammatory process, neutrophils move from the bloodstream in the tissue at the site of tissue injury. Neutrophils contain large numbers of different intracellular granules and when they are activated at the site of inflammation, the contents of these granules are secreted into the tissue. Different granules contain a variety of enzymes and other proteins, many of which have antibacterial properties. One of the enzymes found in azurophilic granules is neutrophil elastase. Neutrophil elastase has a broad spectrum of activities in the body. For example, within the lung the enzyme increases the production of mucus and changes the cellular composition of the epithelium. The enzyme also causes vascular permeability changes within the icrocirculation of many tissues and is a potent destructive agent against a number of connective tissue components. Although endogenous elastase inhibitors exist in the body, including anti-trypsin and the leukocyte protease inhibitor, elastase activity has been implicated in the pathogenesis of a number of disease states including inflammatory respiratory diseases, joints and the skin. The enzyme is also responsible for one or more of the symptoms of acute respiratory distress syndrome (ARDS) and other acute inflammatory conditions caused by trauma and / or sepsis. We have now found a group of new compounds which inhibit neutrophil elastase. Therefore, these compounds are of potential therapeutic benefit in the treatment and amelioration of disease symptoms where elastase activity is involved.

DESCRIPTION OF THE INVENTION Thus, in accordance with one aspect of this invention, a compound of the formula is provided (I) O) (indicated relative stereochemistry) wherein: R 1 represents alkyl of 1 to 6 carbon atoms; R2 represents alkyl of 2 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; X represents CO or S02; Het represents an optionally substituted monocyclic or bicyclic aromatic ring system of 5 to 10 elements, containing 1 to 4 heteroatoms selected from O, N and S; n represents an integer from 0 to 4; R3 and R4 independently represent hydrogen, alkyl of 1 to 8 carbon atoms, - (CH2)? _4CONR5R6, COC? _alkyl or (CH2) or-2EN in which Fen represents phenyl optionally substituted by one or more alkyl groups of 1 to 4 carbon or halogen atoms or NR3R4 together represent azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl optionally N-substituted by alkyl of 1 to 6 carbon atoms, phenyl (optionally substituted by halogen or alkyl of 1 to 4 carbon atoms ) or benzyl (optionally substituted on the benzene ring by halogen or alkyl of 1 to 4 carbon atoms) or NR3R4 together represent a ring as described heretofore unless it is substituted at the carbon by one or more alkyl groups of 1 to 4 carbon atoms, CONR5R6 or COOR6. R5 and R6 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and salts and solvates thereof (later referred to as "compounds of the invention"). Formula (I) shows the relative stereochemistry of the chiral centers. The invention includes compounds of the invention in racemic form as well as in a form in which an enantiomer predominates or is present exclusively. Generally, it is preferred to provide a compound of the formula (I) in the enantiomerically pure form, more particularly the enantiomer has the absolute stereochemistry illustrated in the formula (I).

The present invention also covers the physiologically acceptable salts of the compounds of the formula (I). Suitable physiologically acceptable salts of the compounds of the formula (I) include salts of inorganic and organic acid such as hydrochloride and tartrate. When used herein "alkyl" includes branched chain alkyl as well as straight or linear and may also include cycloalkyl when 3 or more carbon atoms are present.

Suitable Ri alkyl groups include methyl, ethyl and propyl. Examples of Het groups include furanyl, imidazolyl, thiophenyl, pyrrolyl, thiazolyl, isoxazolyl, pyrazolyl, pyridinyl and pyrazinyl. Het can be connected to the pyrrolidine ring via X in any position. Examples of connectivities include furan-2-yl, furan-3-yl, imidazol-2-yl, imidazol-4-yl, thiophen-2-yl, pyrrol-2-yl, thiazol-4-yl, isoxazole-3 -yl,? irazol-3-yl, pyrazol-5-yl, pyridin-3-yl, l-methyl-pyrrol-2-yl, 1-methyl-pyrazol-3-yl, l-methyl-pyrazole-5- ilo and pyrazin-2-yl. Examples of substituents for Het include alkyl of 1 to 6 carbon atoms (for example, methyl, ethyl), alkoxy of 1 to 6 carbon atoms (for example, methoxy), nitro and halogen (for example, chlorine, bromine, fluorine). , iodo). The substituent (s) may be carbon or nitrogen. Examples of substituted Het include 1-methyl pyrrolyl, 1-methyl pyrazolyl. Examples of positions for the side chain shown in formula (I) include for furan-2-yl the 5-position, for furan-3-yl the 2-position, for thiophen-2-yl the 5-position, for pyrrole-2- ilo position 4 6 5, for 1-methyl pyrrol-2-yl position 5, for thiazol-4-yl position 2, for isoxazol-3-yl position 5, for l-methyl-pyrazol-3-yl position 5, for l-methyl-pyrazol-5-yl the 3-position, for pyridin-3-yl the 6-position and for pyrazin-2-yl the position 5. When R3 and R4 independently represent alkyl of 1 to 8 atoms of carbon, examples include methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, CH (iPr) 2 and cyclohexyl. When R3 and R4 independently represent (CH2) 0-2fen, examples include phenyl, benzyl and (4-F-phenyl) methyl. When NR3R4 together represent N-substituted piperazinyl, examples include N-phenyl-piperazinyl and N-methyl-piperazinyl. When NR3R4 together represent a carbon-substituted ring, examples of substituents include methyl, C0NH2 and COOMe. Examples of such NR3R4 include 4-methyl piperidin-1-yl. It is preferred that R1 represents methyl or ethyl, especially methyl. It is preferred that R2 represents isopropyl or propyl, especially isopropyl. It is preferred that X represents CO.

It is preferred that Het represents a 5- or 6-membered monocyclic aromatic ring containing 1 or 2 heteroatoms selected from O, N and S which is more preferably thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl, especially thiazolyl (particularly thiazol-4-yl) ) or pyrazinyl. It is also preferred that Het represents pyridinyl, especially 3-pyridinyl. More particularly, it is preferred that Het represents pyrazinyl. Ideally Het represents pyrazin-2-yl in which the side chain is in the 5-position. It is also preferred that Het represents oxazolyl, particularly oxazol-4-yl. It is preferred that n represents 1 to 3, particularly 1 or 2, especially 1. It is preferred that R 3 and R 4 independently represent hydrogen or alkyl of 1 to 8 carbon atoms or for NR 3 R 4 representing pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally N- substituted by alkyl of 1 to 8 carbon atoms or phenyl (optionally substituted by halogen or alkyl of 1 to 4 carbon atoms). When R3 and R4 independently represent hydrogen or alkyl of 1 to 8 carbon atoms, the preferred NR3R4 groups are NMe2, N (n-butyl) 2, NHMe NH (cyclopropyl), NHCH (iPr) 2 and N (cyclohexyl) 2. A group of compounds of the formula (I) of particular interest are the compounds of the formula (IA) in which Het represents oxazol-4-yl with the side chain in the 2-position: (Relative stereochemistry indicated) wherein R4, R3, n, X, R2 and R1 are as defined above. It is preferred that X represents CO. It is preferred that R2 represents isopropyl or propyl, especially isopropyl. It is preferred that R1 represents methyl or ethyl, especially methyl. It is preferred that n represents 1 to 3, particularly 1 6 2, especially 1. It is preferred that R 3 and R 4 independently represent hydrogen or alkyl of 1 to 8 carbon atoms or for NR 3 R 4 representing pyrrolidinyl, piperidinyl, orpholinyl or piperazinyl optionally N- substituted by alkyl of 1 to 8 carbon atoms or phenyl (optionally substituted by halogen or alkyl of 1 to 4 carbon atoms). It is particularly preferred that -NR3R4 represent pyrrolidinyl, piperidinyl, N-phenylpiperazinyl, N (butyl) 2, NMe (cyclopropyl) or N (cyclohexyl) 2, more particularly pyrrolidinyl. The potential for the compounds of the invention to inhibit the activity of neutrophil elastase can be demonstrated, for example, by using the following assays vi n and vi vi: Tests on the human neutrophil elastase Essay contents: 50mM Tris / HCl (pH 8.6) 150mM NaCl ll.dnM purified human neutrophil elastase The appropriate concentrations of the compound under the test diluted with water from a lOmM base solution in dimethylsulfoxide. The above values are final concentrations after the addition of substrate solution (see below). The above mixture was incubated for fifteen minutes at 30 ° C at this time the remaining or residual elastase activity was measured for 10 minutes on a BioTek 340i plate reader, after the addition of O.ßmM of MeO-succinyl-alanyl- alanyl-prolyl-valyl-p-nitroanilide. The ratio of the increase in absorbency to 405nm is proportional to the elastase activity. The activity of the enzyme is delineated for the inhibitor concentration and an IC50 determined using a programming system or curve fitting software.

M ivo activity of human neutrophil elastase inhibitors: An oral in vivo model using the induced lung of infiltrated IL-8 for the valuation of intracellular elastase inhibition.

Adult Hamsters (100-150g) are randomly selected into groups (n = 4) and fed throughout the night. Under gas anesthesia (3% isoflurane) the animals are dosed orally with lmL / lOOg of water as a vehicle or containing pre-dissolved compounds. Either at the same time, or subsequently under anesthesia, the animals are dosed intratracheally with lug of recombinant human IL-8 in 100uL of sterile saline. Six hours later animals dosed with IL-8 are sacrificed using intraperitoneal pentobarbitone. The lungs were washed with 2 x 2.5 mL of sterile saline and the femurs were removed by dissection. Intracellular elastase is prepared from neutrophils collected by washing and from the bone marrow of the femoral bone. This is achieved by sonication of neutrophils and centrifugation to produce intracellular granules. These are separated by freezing / thawing and sonication. The elastase and myeloperoxidase assays were then performed on these samples to verify the efficacy of the compounds and to normalize by neutrophil recovery.

Test of elastase inhibition in human whole blood The triplicate aliquots of freshly heparinized (200 μl) whole human blood were added to appropriately diluted samples (10 μl) of compounds under test. The control samples (6 duplicates) contain water instead of the compound. The samples are completely mixed by pipette, and then incubated for 30 minutes at 37 ° C. The cold red cell lysis buffer (750μl of 155mM ammonium chloride, 0.12mM EDTA, 10M potassium bicarbonate, pH 7.4) is then added. The tubes are covered or closed with a lid, inverted several times, and kept at 4 ° C for 15 minutes, reversing every 5 minutes. After centrifugation at 250g for 10 minutes, at 4 ° C, the cells are washed in the form of resulting pellets. The washing is with saline solution (300μl), followed by centrifugation at 100g for 10 minutes at 4 ° C. The pellets or pills are washed two or more times, before resuspending the final cell pill in the buffer (200μl of 100mM Tris, 300mM of NaCl, 1% (w / v) of H , pH 8.6). Samples were stored at -20 ° C. After freezing-thawing the samples four times, the elastase activity was determined by a colorimetric assay in 50mM Tris, 150mM NaCl, 0.6mM MeO-Succ-Ala-Ala-Ala-Pro-Val-pNA at pH 8.6, measuring the speed of increase in absorbency at 405nm.

Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and amelioration of disease symptoms where elastase activity is involved. Such diseases include particularly bronchitis, including chronic bronchitis. Also any chronic obstructive pulmonary disease (COPD). Examples of disease states in which the compounds of the invention have potentially beneficial effects include inflammatory diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma and conditions of lung hyperreactivity, acute respiratory distress syndrome and shock septic, inflammatory or destructive conditions of the lung such as emphysema and cystic fibrosis and inflammatory or destructive conditions of external tissue such as skin diseases (for example lupus and psoriasis) and periodontal disease including gingivitis. Additional examples of disease states and conditions in which the compounds of the invention have potentially beneficial effects include wound healing and treatment of burns, cardiovascular diseases such as myocardial infarction and stroke, peripheral vascular disease including intermittent claudication, atherosclerosis, reperfusion damage, cardiovascular changes that occur during cardiopulmonary bypass surgery and septicemia. The compounds of the invention may also be useful in the treatment of connective tissue disorders such as rheumatoid arthritis, osteoarthritis and spondylitis and inflammatory conditions of the kidney such as glomerulonephritis. They may also be useful in the treatment of certain leukemias including acute myelogenous leukemia, acute myelomonocytic leukemia and chronic monocytic leukemias and in the prevention or inhibition of metastases of solid tumors for example, melanomas and cancers of the lung, chest, the prostate and the stomach. A particular aspect of the present invention is the use of compounds of the formula (I) in the treatment of chronic bronchitis. Chronic bronchitis is a condition that results from exposure of the airway surface to chemicals or noxious agents or is second to another disease. The symptoms of the condition are caused by the excessive secretion of mucus on the surface of the respiratory tract. This excess mucus can not be clearly effective and the result is reduced gas exchange within the lungs resulting in labored breathing and hypoxemia, recurrent microbial infections and persistent cough associated with expectoration of mucoidal material. The proposed mechanism for excessive secretion of mucus involves the recruitment of neutrophils into the respiratory tract following exposure of the epithelium to irritating materials; neutrophils secrete elastase on the surface of the airways and the enzyme binds approximately both an increase in the amount of mucus secreted on the surfaces of the airway and a dramatic change in the cellular composition of the airway epithelium. The inhibition of elastase activity by the administration of compounds of this invention is, therefore, an approach to the treatment of chronic bronchitis. Lung function reduced in COPD (for example in chronic bronchitis with airflow obstruction) is also due to elastase-mediated lung damage that leads to reduction and inflammation of the airway. Thus an elastase inhibitor will improve lung function. As stated above, the compounds of the invention are useful in human or veterinary medicine, in particular as inhibitors of the neutrophil elastase of the enzyme. Thus, a compound of the formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine is provided as a further aspect of the present invention, particularly in the treatment of conditions wherein the elastase activity is involved such as chronic bronchitis. It will be appreciated that references here to treatment extend to prophylaxis as well as to the treatment of established conditions. According to another aspect of the invention, there is provided the use of a compound of the formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture or production of a medicament for the treatment of conditions wherein the elastase activity is involved, particularly in chronic bronchitis. In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with a condition caused or mediated by elastase activity, this method comprises administering to the human or animal subject an effective amount of a compound of the formula (I). ) or a physiologically acceptable salt or solvate thereof. The compounds according to the invention can be formulated by administration in any convenient way, and the invention, therefore, also includes within their scope pharmaceutical compositions for use in therapy, which comprises a compound of the formula (I) or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers. Also provided according to the invention is a process for the preparation of a pharmaceutical composition comprising mixing the ingredients. The compounds according to the invention can be formulated, for example, for oral, buccal, parenteral, topical or rectal administration. Tablets and capsules for oral administration may contain conventional excipients such as binding or binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage or polyvinyl pyrrolidone.; fillers, for example, lactose, microcrystalline cellulose, sugar, corn starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffers, flavors, colorants and / or sweetening agents (for example mannitol) where appropriate. For oral administration the compositions may take the form of tablets or lozenges formulated in a conventional manner. The compounds can also be formulated as suppositories, for example, containing conventional suppository bases such as cocoa butter or other glycerides. The compounds according to the invention can also be formulated by parenteral administration by injection of large pills or boluses or continuous infusion and can be presented in unit dose form, for example as ampoules, vials or knobs, small volume infusions or syringes prefilled, or in multiple dose containers with an added condom. The compositions may take such forms as solutions, suspensions or emulsions in aqueous or non-aqueous vehicles, and may contain formulating agents such as antioxidants, buffers, antimicrobial agents and / or toxicity adjusting agents. Alternatively, the activity ingredient may be in the powder form to be constituted with a suitable vehicle, eg, pyrogen-free, sterile water, before use. The presentation of dry solid can be prepared by filling a sterile powder aseptically in individual sterile containers or by filling a sterile solution aseptically in each container and drying by freezing. By topical administration as used herein, administration by insufflation and inhalation is included. Examples of various types of preparation by topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g., eye or nasal drops). The ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of thickening agents and / or gelling agents and / or solvents. Thus, such bases may include, for example, water and / or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil or a solvent such as polyethylene glycol. Thickening agents that can be used include soft or soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax. Lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspension agents or thickening agents. Powders for external application can be formed with the aid of any suitable powder base, for example, talc, lactose or starch. The drops can be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspension-forming agents. Spray compositions can be formulated, for example, as aqueous solutions or suspensions or as aerosols supplied from pressurized packages, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3, 3-heptafluoropropane, 1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.

Capsules and cartridges for use in an inhaler or insufflator, or for example gelatin, can be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The pharmaceutical compositions according to the invention can also be used in combination with other therapeutic agents, for example anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 and xanthine adrenergic agonists (for example theophylline), mucolytic agents, antimuscarinics, antileukotrienes, cell adhesion inhibitors (for example, ICAM antagonists), antioxidants (for example N-acetylcysteine), lung surfactants and / or antimicrobial and antiviral agents. The compositions according to the invention can also be used in combination with gene replacement therapy. The invention, therefore, provides in a further aspect, a combination comprising a compound of the formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent.

The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represents a further aspect of the invention. The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. The appropriate dose of known therapeutic agents will be readily appreciated by those skilled in the art. The compound of the invention can be conveniently administered in amounts of, for example, 0.01 to 50 mg / kg of body weight, conveniently 0.05 to 25 mg / kg of body weight orally, one or more times per day. The precise dose will of course depend on the age and condition of the patient, the particular route of administration chosen, and the disease to be treated. The compound is preferably administered orally for the treatment of bronchitis. Other routes of administration may be necessary for other indications, for example, v.i. for ARDS.

The compounds of the invention have useful duration of action. The compounds of the formula (I) and salts and solvates thereof can be prepared by the methodology described below, constituting a further aspect of this invention. A process according to the invention for preparing a compound of the formula (I) comprises (i) the condensation of a compound of the formula (II): (indicated relative stereochemistry) with a compound R4R3N (CH2) nHetC00H or an acid derivative thereof such as an acid chloride, activated ester, acid anhydride, or a mixed anhydride or with a compound R4R3N (CH2) nHetXY, where y is a reactive group such as halogen, for example, chlorine, or a protected derivative thereof; or (ii) sulfonylation of a compound of the formula (III): (Relative stereochemistry indicated) or a protected derivative thereof with a compound Y02SR1 wherein Y is a reactive group such as halogen, for example, chloro; or (iii) cyclizing a compound of the formula (IV): (relative stereochemistry indicated) or a carboxylic acid ester thereof; or (iv) oxidation of a corresponding compound of the formula (V) R1 (Relative stereochemistry indicated) where Xa is sulfur or SO; or (v) reaction of a corresponding compound of the formula (VI) (Relative stereochemistry indicated) wherein L is a separation group with a compound of the formula R 4 R 3 NH; or (vi) preparation of a compound of the formula I in which n represents an integer from 1 to 4 by reduction of the reaction product of a corresponding compound of the formula (VII) (Relative stereochemistry indicated) with a compound of the formula R 4 R 3 NH; or (vii) preparation of a compound of the. Formula I in which n represents 1 by reaction of a corresponding compound of the formula (VIII) (indicated relative stereochemistry) with formaldehyde or paraformaldehyde together with a compound of the formula R4R3NH under acidic conditions; or (viii) deprotection of a compound of the formula (I) which is protected; or (ix) purifying an enantiomer of the compound of the formula (I) from a mixture of enantiomers; and wherein it is desired or necessary to convert a resulting free base compound of formula I into a physiologically acceptable salt form or vice versa or to convert one salt form into another physiologically acceptable salt form.

Process (i; This condensation reaction with R .4RT-.3N »(CH2) pHetC00H is suitably carried out in the presence of a coupling agent such as l- (3-N, N-dimethylaminopropyl) -3-ethylcarbodiimide, preferably also in the presence of HOBT, and a solvent such as dichloromethane, DMF, MeCN or tetrahydrofuran at a temperature conveniently between 0 ° C and ambient. When an acid derivative such as the acid chloride, activated ester, acid anhydride, or a mixed anhydride is used, the reaction conditions will be modified accordingly, for example by inclusion of a base. If one of both of R3, R4 represents hydrogen, it will generally be preferred to protect the nitrogen, for example with BOC.

With R4R3N (CH2) nHetS02Y, the reaction is suitably performed in the presence of a base such as triethylamine and a solvent such as DCM, conveniently at 0 ° C-ambient.

Process (ii) The sulfonylation reaction is suitably performed in the presence of LHMDS or NaH, in a solvent such as tetrahydrofuran at a temperature conveniently between -78 ° C to 0 ° C. When one of both of R3 and R4 represents hydrogen, it may be necessary to protect the nitrogen, for example with BOC.

Process (iii) The cyclization reaction is conveniently carried out in the presence of 2-chloro-1-methylpyridinium iodide, or EDC, in a solvent such as dichloromethane, at a temperature of suitably 0 ° C-reflux. This reaction can also be carried out using a carboxylic acid thioester derivative of the compound of the formula (IV). Alternatively, another acid derivative such as an acid halide (for example acid chloride) can be used.

Process (iv) This oxidation reaction can be carried out in a conventional manner such as by permeation oxidation.

Process (v) Preferred separation groups include halogen (such as chlorine, bromine, or iodine), mesylate, or tosylate. The reaction can be carried out by combining the reactants optionally in the presence of a base such as triethylamine or potassium carbonate in an inert solvent such as DMF or MeCN.

Process (vi) This reaction is carried out by combining the reactants in an inert solvent, for example, DCM at room or elevated temperature.

The reduction can be effected in situ using a conventional mild reducing agent such as NaBH3CN or NaBH (OAc) 3.

Process (vii) The reaction of the heterocyclic compound of the formula (viii) with formaldehyde or paraformaldehyde and the amine will be carried out under standard Mannich conditions, for example, reflux under acidic conditions, typically in acetic acid / ethanol. If the amine is used as an acid salt (for example, the hydrochloride) the acetic acid can be omitted.

Process (viii) Protective groups, especially nitrogen protection groups, and means for deprotection are described in T W Greene "Protective Groups in Organic Synthesis", 2nd Ed. (1991) J Wiley & Sons.

Process (ix) The purification of a single or single enantiomer can be achieved by conventional methods such as chiral chromatography (for example chiral HPLC) and crystallization with a homochiral acid (for example tartaric acid).

The physiologically acceptable acid salts of the compound of the formula (I) such as the hydrochloride or tartrate can be prepared by treating a base compound of the formula (I) with the desired acid. The intermediates of the formula (II) can be conveniently prepared in accordance with the methodology in Scheme I below.

SCHEME 1 metiphopypa (IX) (X) (c) (XIII) (XII) (XI) (fl (XIV) () rel-. { 2S, 3R) 0) Step (a) This is a conventional protection reaction which, in the case when P2 represents BOC, can be effected by reacting with (BOC) 20 in the presence of base (for example NaOH) in a polar solvent system such as dioxane / water Step (b) This conversion can be carried out in the treatment with ammonium bicarbonate in the presence of a suitable solvent such as pyridine / DMF and in the presence of (B0C) 20 or suitable equivalent.

Step (c) This is a conventional protection reaction which, in the case when Pi represents CBZ, can be effected by the reaction with nBuLi followed by CBZ-C1 in the presence of an inert solvent such as THF less than -50 °. C.

Step (d) This reaction can be carried out by treatment with RX wherein RX is a compound (for example, Mel, benzyl iodide or Me2S04) capable of converting the sulfur in the SMe portion to sulfonium in a suitable solvent, for example, propanone or acetonitrile. Generally R will represent alkyl or aralkyl and X will represent halide, especially iodide, or sulfate. The protection of the amide is convenient, although not essential, for this reaction.

Step (e) This ring closure reaction can be effected by treatment with Dowex 2 x 8 400 mesh OH resin in a suitable solvent, for example, MeCN Alternatively, ring closure can be effected by treatment with sodium carbonate. potassium in a suitable solvent, for example, MeCN.

Step (f) The deprotection can be carried out in a conventional manner, for example, a BOC protection group can be removed by treatment with HCl, for example, in dioxane.

Step (g) This reaction can be carried out by treatment with an alkyl ester of trifluoroacetic acid (for example, the methyl ester) or trifluoroacetic anhydride in the presence of a suitable base for example N-methylmorpholine.

Step (h) This conversion will be carried out by treating the compound of the formula (XV) with a reducing agent, for example, lithium borohydride, followed by the treatment with concentrated sulfuric acid in the presence of an alkyl alcohol, for example , ethanol solvent.

Step (i) The reaction of the compounds of the formula (XV) and (XVII) is carried out in the presence of a Lewis acid, for example, boron trifluoride diethrate and an inert solvent, for example, dichloromethane or MeCN . The group "alkyl" in Oalkyl and OS (alkyl) 3 generally represents alkyl with 1 to 6 carbon atoms. In the compound of the formula (XVII), suitable alkyl groups in the silyl alkyl moiety include methyl, isopropyl and t-butyl. The preferred Oalkyl is OEt and the preferred Osi (alkyl) 3 is OSi (i-Pr) 3 or Osi (Me) z (t-Bu). The use of variants of the compounds of the formula (XVII) in which Oalkyl is replaced by OSi (alkyl) 3 is also contemplated.

The compounds of the formula (XVII) can be prepared by treatment of the corresponding carboxylic acid ester (R2CH2COOEt or any alkyl ester, these compounds are either known or can be prepared by known methods) with a strong base (e.g., LHMDS) ) followed by a trialkylsilylchloride (such as trimethylsilylchloride) or a trialkylsilyltriflate. Typically the reaction will be carried out at low temperature (less than 0 ° C) in an inert solvent (such as THF) in the presence of DMPU.

Step (j) This deprotection reaction will be carried out in the base treatment, such as potassium carbonate.

Step (k) This ring closure reaction can be performed in the treatment with an alkyl Grignard reagent (eg, t-butylmagnesium chloride) in an inert solvent such as THF in the presence of tetramethylethylenediamine at a temperature of -20. ° C at 25 ° C.

Step (1) This is a reaction of lactam sulfonylation. Conveniently it is carried out by the reaction with R1S02-Y, wherein Y is a reactive group, preferably chlorine, in the presence of LHMDS, NaH or KH, in a solvent such as THF, at a temperature of conveniently -78 ° C to 0 ° C.

Step (m) This is an N-deprotection reaction, which can be conveniently carried out in a conventional manner. Thus, when Pi is CBZ, it is suitably carried out by hydrogenation over Pd (OH) 2 catalyst in solvents such as ethyl acetate or THF.

The compounds of the formula (XV) can also be prepared following a route described in Scheme 2: Scheme 2 (XXIII) (d) Step (a) This reaction will proceed under standard conditions to form alkyl esters, for example, by treatment with an alcohol, for example, methanol in the presence of S0C12. R 3 is suitably an alkyl group of 1 to 6 carbon atoms, preferably methyl.

Step (b) The cyclization reaction will be carried out by stirring in water with Dowex 2X8 (preferably 400 esh).

Step (c) The TFA protected amine is formed by treating the compound of the formula (XXIV) with methyl trifluoroacetate in a polar protic solvent, for example MeOH.

Step (d) The appropriate protection groups Pi include CBZ. In this case, the compound of the formula (XXV) can be treated with a strong base such as LHMDS or nBuLi in an inert solvent such as THF, followed by treatment with CBZ-C1.

An alternative route for the preparation of the compounds of the formula (XX) from Scheme 1 is given in Scheme 3: Scheme 3 I) Scheme 3 (continued) (XX) Step (a) The compounds of the formula (XXVI) are either known compounds or can be made analogously to known compounds. Pi is a group of N-protection, preferably CBZ. Step (a) is an additional N-protection reaction. P2 in the formula (XXVII) is a different N-protection group, preferably BOC. When P2 is BOC, the reaction is conveniently performed using BOC20. Conveniently the reaction is carried out in the presence of a base such as triethylamine or 4-dimethylaminopyridine in a solvent such as ethyl acetate, at a temperature of suitably 0-25 ° C.

Step (b) This conversion is suitably carried out with pyridinium p-toluenesulfonate, in a solvent such as acetone / water, at a temperature suitably between 25 ° -75 ° C.

Step (c) This is a condensation rearrangement reaction conveniently performed using an ester of 2-phenylsulfinyl acetic acid (FenS0CH2C02R? 3) and piperidine, in a solvent such as acetonitrile, conveniently at room temperature. R13 is suitably an alkyl group of 1 to 6 carbon atoms, preferably methyl.

Step (d) This is a substitution reaction of Mitsunobu, using phthalimide, PFen3 and a dialkylazodicarboxylate such as DEAD, in the presence of a solvent such as THF, at a temperature of conveniently 0 ° -40 ° C.

Step (e) This is a deprotection reaction, preferably using a strong acid such as TFA in such a solvent or DCM, at a temperature of suitably 0 ° -40 ° C.

R13 is suitably alkyl of 1 to 6 carbon atoms, preferably ethyl.

Step (f) This is a cyclization reaction, suitably performed as an intramolecular Michael reaction. Suitably NaH is used, in a solvent such as THF, at a temperature such as 0 ° -25 ° C.

Step (q) In this step two reactions occur: N-deprotection and reprotection. The phthalimido group is conveniently removed with hydrazine hydrate in a solvent such as ethanol at a temperature between 0 ° C and reflux temperature. The protection group P3 is incorporated in a conventional manner. When P3 is BOC, this is adequately achieved with BOC20.

Step (h) The side chain of R2 can be introduced by alkylation, using as reagent R2-Y, where Y is a reactive group such as bromine or iodine. Thus, the reaction is carried out using a base, preferably a strong base such as LHMDS. With LHMDS a DMPU cosolvent in THF is suitably used. Suitable reaction temperatures are -78 ° C to 50 ° C. Under these conditions the reaction is usually carried out with good stereochemical control.

Step (i) This is an ester hydrolysis reaction, followed by an N-deprotection reaction. The former is made in a conventional manner, for example using KOH in an aqueous ethanol, at a temperature of suitably 25 ° -80 ° C. The latter is carried out in a conventional manner, for example using HCl in dioxane, at a temperature of suitably 0o-50 ° C or, if the protection group is trifluoroacetate, by treatment with base.

Step (j) This is a cyclocondensation reaction, conveniently performed in the presence of 2-chloro-1-methylpyridinium iodide and a suitable base such as N, N-diisopropyl ethylamine in a solvent such as dichloromethane, at a temperature of suitably 0 ° C-reflux. It has also been found that it is possible to use the compound of the formula (XXXV) as an ester of the carboxylic acid in this case the ester hydrolysis of step (i) is not necessary. In this case the preferred conditions for the cyclocondensation reaction involve the use of an alkyl Grignard reagent for example t-BuMgCl in THF at a temperature between -20 ° C and 25 ° C. An alternative process for the preparation of compounds of the formula (XXXIII) is shown in Scheme 4: Scheme 4 diamindbutyric acid c) Step (a) The compounds of the formula (XXXVI) are either known compounds or can be prepared analogously to the known compounds. P3 is a protection group as described above, and is appropriately BOC. The reaction is performed properly using PIFA (phenyl ylsilobis (trifluoroacetate)) and a base such as pyridine in an aqueous solvent, such as aqueous THF, dioxane or acetonitrile. This is the method of Stansfield, C.F. Organic Preparations and Procedures Int., 1990, 22 (5), 593-603.

Step (b) Pi is a protection group for example CBZ. This protection reaction can be carried out in a conventional manner. For example, it is suitably carried out in a water-miscible solvent such as THF, DMF or dioxane using N- (benzyloxycarbonyloxy) succinamide, benzyloxycarbonyl chloride, or any suitable source of the benzyloxycarbonyl group, with pH to alkaline adjustment with sodium carbonate.

As an alternative step (b), the compounds of the formula (XXXVIII) can be prepared in a conventional manner from diaminobutyric acid.

Step (c) This reaction is conveniently carried out in two stages. The first step involves the reaction of the compound of the formula (XXXVIII) at reduced temperature with N-methylmorpholino and then an alkyl chloroformate such as ethyl chloroformate, in an organic solvent such as DCM, dioxane or THF. In the second stage the product is reduced, suitably with sodium borohydride at reduced temperature, such as -20 ° to 10 ° C, in a solvent such as THF.

Step (d) This oxidation reaction can be carried out in any suitable manner, for example using oxalyl chloride in DMSO and methylene dichloride under nitrogen at reduced temperature, such as -30 ° C to -70 ° C, followed by triethylamine. The intermediary (XXXX) is not isolated or separated properly.

Step (e) This reaction is conveniently carried out using a Wittig reagent such as a triphenylphosphorane R? 302CCH = PFen3, or it can also be carried out using a phosphonate in a Wadsworth-Emmons reaction.

Step (f) This Michael addition reaction is suitably performed using LHMDS or another strong base in an organic solvent such as THF, ether or toluene, and preferably a complexing agent such as TMEDA is also present. Intermediate compounds of the formula (III) can be prepared by reacting a deprotected compound of the formula (XX) of Scheme 1 with R4R3N (CH2) nHetCOOH or R4R3N (CH2) nHetXY in the manner described above in relation to the main process (I ) previous. (The initial N-deprotection can be performed as described above under Scheme 1 Step (m). Formula (IV) can be prepared from a compound of formula (XIX) (with the suitably protected primary amine) in a manner analogous to that described above to prepare a compound of formula (III) from a compound of the formula (XX) together with the main process (ii) above. The compounds of the formula (V) wherein Xa represents S can be prepared by the reaction of a corresponding compound of the formula (III) with a compound of the formula R1SSR1 under standard conditions by nucleophilic displacement. The compounds of the formula (V) wherein Xa represents SO can be prepared by the oxidation of peracid of a corresponding compound wherein Xa represents S.

The compounds of the formula (VI), (VII) and (VIII) can be prepared from the compounds of the formula (II) following the conventional methods known per se. The mesylate and tosylate derivatives can be prepared from the corresponding alcohol following the treatment with MeS02Cl or paramethylbenzenesulfonylchloride. The compounds of the formula R4R3N (CH2) nHetCOOH or an acid derivative thereof, and RR3N (CH2) nHetXY are either known or can be prepared by conventional methods known per se. It will be apparent that Schemes 1, 2, 3 and 4 can be modified to produce homochiral products using homochiral starting materials (e.g., S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4) or by performing a step of additional chiral resolution. If the compounds of the formula (XIV) in the racemic form are prepared following Scheme 1 from racemic methionine, it has been found that the isomers of the compounds of the formula (XIV) can be resolved by a dynamic resolution procedure. Thus, a racemic compound of the formula (XIV) can be treated with homoquiral di-p-toluoyl tartaric acid in the presence of 3,5-dichloro-2-hydroxybenzaldehyde as a catalyst in an inert solvent, for example, THF. A homochiral salt of the compound of the formula (XIV) results. A compound of the formula (XV) can then be produced by subsequent treatment with trifluoroacetic acid methyl ether in the presence of N-methylmorpholine. Both enantiomers of the compound of the formula (XIV) can also be produced from a synthesis based on S-methionine or R-methionine followed by similar procedures. It will be apparent to a person skilled in the art that the above synthetic processes for the preparation of the compounds of the formula (I) can be modified so that they include or omit protecting groups or so that they use alternative protecting groups (for example those described in TW Greene "Protective Groups in Organic Synthesis", 2nd Ed (1991) J Wiley &Sons) in the course of routine optimization of experimental conditions. New chiral intermediates in the resolution and chiral sections described above also form an important aspect of this invention. Processes for the preparation of intermediates are also provided as an aspect of this invention. The compounds of the invention have the advantage that they can be more effective, show greater selectivity, have few side effects, have a longer duration of action, be more bioavailable by the preferred route, have more attractive pharmacodynamic or pharmacokinetic properties or have other more desirable properties than similar known compounds. The following non-limiting Examples illustrate the present invention.

ABBREVIATIONS BOC t-but i loxy carbonyl CBZ Benzyloxycarbonyl (BOC) 20 Di-tert-butyldicarbonate THF Tetrahydrofuran LHMDS Bis (trimethylsilyl) lithium amide DMPU 1,3-dimethyl-3, 4,5,6-tetrahydro 2 (1H) -pyrimidinone DMAP 4-dimethylaminopyridine DMF Dimethylformamide EDC l- (3-N, N-dimethylaneopropyl) -3-ethylcarbodiimide DEAD Diethylazodicarboxylate DCM Dichloromethane TMEDA Tetramethylethylenediamine DMSO Dimethylsulfoxide HOBT 1-hydroxybenzotriazole NaBH (OAc) 3 Sodium triacetoxyborohydride In the previous Intermediaries and Examples, all the experiments by C.c.d. They were made on silica plates.

Intermediates Intermediate 1 2,4-diamino-butyric acid methyl ester dihydrochloride For the D, L-diaminobutyric acid dihydrochloride (350 g) in methanol (1.61) at 0 ° C, thionyl chloride (200 ml) was added during the hour. . After refluxing for 3 h, the solvent was removed in vacuo and the residue was triturated with toluene (650 ml) to give the title compound as a white solid (385 g). Mass spectrum of free base MH + (found) 133 MH + (calculated) 133 Intermediate 2 3-amino-pyrrolidin-2-one Intermediate 1 (lg), water (70ml) and Dowex 2x8-400 mesh (16.4ml) were stirred by lh. The resin was then filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.40g), C.c.d. (6: 1 ethyl acetate: methanol) Rf 0.07.

Intermediate 3 2,2, 2-Trifluoro-N- (2-oxo-pyrrolidin-3-yl) -acetamide A suspension of intermediate 2 (181g), methyl trifluoroacetate (218ml) and methanol (2.6 1) were suspended for 2h . The solvent was then stirred in vacuo to yield the title compound as a cream solid (355g). Spectrum of mass MNH4 + (found) 214 MNH4 + (calculated) 214 Intermediate 4 Benzyl ester of 2-oxo-3- (2,2,2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic acid To intermediate 3 (3.5g) and tetrahydrofuran (100 ml) at -70 ° C was added LHMDS (20ml). After l / 4h, the benzyl chloroformate (2.8 ml) was added. The mixture was warmed to room temperature by Ih and IH hydrochloric acid (25ml) was added. After extraction with ethyl acetate (3x25ml), the combined extracts were washed with 2% ammonia solution, 2M hydrochloric acid and brine then dried (MgSO4). After removal of the solvent, the white solid was recrystallized from 5: 1 ethyl acetate: hexane to give the title compound as white crystals (4.2g), C.c.d. (9: 1 ethyl acetate: methanol) Rf 0.7.

Intermediary 5 2-Ethoxy-3- (2,2,2-trifluoro-acetylamino) -pyrrolidine-l-carboxylic acid benzyl ester Intermediary 4 (34g) in ethanol (1070ml) at -5 ° C was added borohydride of sodium (9.86g). A 4M solution of hydrogen chloride in 1,4-dioxane (20ml) was then added by drip. Periodically additional 4M portions of hydrogen chloride were added in 1,4-dioxane (2x5ml, lxlOml) and sodium borohydride (2g). After 3 h, the concentrated sulfuric acid (llml) was added and the mixture was heated at room temperature for 2 h. Aqueous, saturated sodium bicarbonate (300ml) was then added and the ethanol and dioxane were removed in vacuo. The residue was diluted with water (500ml) and extracted with ethyl acetate (3x500ml). The combined extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel 9385 eluting with ether to give the title compound as a solid (21g). Spectrum of mass MNH4 + (found) 378 MNH4 + (calculated) 378.

Intermediate 6 Trans-2- (l-ethoxycarbonyl-2-methyl-propyl) -3- (2,2,2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic acid benzyl ester Intermediate 5 (lOg), ethyl trimethylsilyl isopropylkene acetal (llml) and dichloromethane (250ml) were cooled to 5 ° C and the boron trifluoride dieterate (17ml) was added during l / 4h. After lh, additional boron trifluoride dieterate (3.4ml) and acetal (llml) were added. After an additional lh, the hydrochloric acid was added to IM (200 ml) and the organic layer was separated and washed with brine and dried (MgSO4). The solvent removed in vacuo gave the title compound as an oil (16.7g), C.c.d. (2: 1 ether: cyclohexane) Rf 0.18 and 0.27.

Intermediate 7 Trans-3-amino-2- (1-ethoxycarbonyl-2-methyl-propyl) -pyrrolidine-1-carboxylic acid benzyl ester Intermediate 6 (31g), potassium carbonate (71g), water (930ml) and ethanol (930ml) were heated at 60 ° C for 3h. The ethanol was removed in vacuo and the aqueous residue was extracted with ethyl acetate (3x300ml). The combined extracts were washed with brine and dried (MgSO) and concentrated in vacuo to give the title compound as a brown oil (17.5g). Mass spectrum: MH + (found) 349 MH + (calculated) 349 Intermediate 8 Benzyl ester of (3R, 3aR, 6aS) -6-isopropyl-5-oxo-hexahydro-pyrrolo [3, 2-b] pyrrole-1-carboxylic acid benzyl acid Intermediate 7 (17.5g) in tetrahydrofuran , 800ml) was cooled to -5 ° C and IM of t-butylmagnesium chloride in tetrahydrofuran (204ml) was added during l / 2h. After 2 h, ÍM hydrochloric acid (250ml) and brine (300ml) were added and the mixture was extracted with ethyl acetate (250ml). After concentration, the extracts left the volume in vacuo, the extracts were washed with brine and dried (MgSO4). Removal of the solvent in vacuo followed by trituration with diethyl ether (60ml) gave a white solid. This was recrystallized from ethyl acetate to give the title compound (3.4g). Mass spectrum MH + (found) 303 MH + (calculated) 303 Intermediate 9 Benzyl ester of (3R, 3aR, 6aS) -6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3, 2-b] pyrrole-1-carboxylic acid benzyl acid To a stirred solution of Intermediate 8 (15.01g) in anhydrous tetrahydrofuran (950ml) at -74 ° C under nitrogen, 1.0M of LHMDS in tetrahydrofuran (69.5ml) was added dropwise. After stirring at -74 ° C for 10 min, the mixture was allowed to warm to 0 ° C for 45 min, then left at this temperature for 20 min. It was then cooled to -76 ° C, treated by dripping with methanesulfonyl chloride (9.61 ml) and allowed to stir at this temperature for 1.5 h. Then it was warmed to -50 ° C, cooled rapidly with saturated ammonium chloride solution (480ml) and allowed to warm to room temperature. The mixture was partitioned between water (300ml) and ethyl acetate (750ml), the aqueous layer was extracted with additional ethyl acetate (750ml), then the combined organic extracts were washed with brine (450ml), dried (Na2SO) and they were concentrated in vacuo to a solid cream. Purification by flash column chromatography on silica (Merck 9385) eluting with ethyl acetate: cyclohexane (1: 3, 1: 2, 1: 1 then 3: 1) gave the title compound as a white crystalline solid (13.65g ). C.c.d. (dichloromethane) Rf 0.22 Mass spectrum MNH4 + (found) = 398 MNH4 + (calculated) = 398 Intermediate 10 (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one A suspension of Intermediate 9 (13.63g) in ethyl acetate (900ml ) was added to 20% (wet) palladium hydroxide on carbon (3.16g) and the resulting black suspension was stirred vigorously under hydrogen at room temperature for 90 min. The mixture was then filtered through Harborlite J2 and concentrated in vacuo to give the title compound as a fine white powder (8.63g). C.c.d. (Methanol: dichloromethane 1: 9) Rf 0.50 Mass spectrum MH + (found) = 247 MH + (calculated) = 247 Intermediate 11 re-5- (6R-Isopropyl-4-methanesulfonyl-5-oxo-hexahydro- (3aS, 6aR) -pyrrolo [3,2- b] pyrrol-1-carbonyl) -furan-2-carbaldehyde To one solution hectic of Intermediary 10 (lOOmg) in acetonitrile (5ml) was added 5-formyl-2-furoic acid (74mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (156 mg). The reaction mixture was stirred for 3 days. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried (MgSO 4) and concentrated in vacuo. The residue was purified by flash column chromatography (silica Merck 9385; eluant dichloromethane: acetonitrile 9: 1) to give the title compound (80mg) as a white solid. Mass spectrum MH + (found) 369 MH + (calculated) 369.

Intermediate 12 (3R, 3aR, 6aS) -3- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3,2- b] pyrrole-1-carbonyl) -furan-2-carbaldehyde A a stirred solution of Intermediate 10 (540mg) in acetonitrile (40ml) was added 2-formyl-3-furoic acid (400mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (841mg). The reaction mixture was stirred for 16 h. The acetonitrile was stirred in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined organic products were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (silica Merck 9385; eluent: dichloromethane: acetonitrile 9: 1) to give the title compound (626mg) as a cream solid. Mass spectrum MH + (found) 369 MH + (calculated) 369.

Intermediary 13 (3R, 3aR, 6aS) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3,2- b] pyrrole-1-carbonyl) -thiophen-2-carbaldehyde A a stirred solution of Intermediate 10 (250mg) in acetonitrile (10 mL) is added 5-formylthiophene-2-carboxylic acid (206mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (389mg). The reaction mixture was stirred for 3 h. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined organic products were washed with brine, dried (MgSO4) and concentrated in vacuo to leave a foam. The foam was purified by flash column chromatography (silica Merck 9385; eluent dichloromethane: acetonitrile 9: 1) to give the title compound (280 mg) as a cream solid.

Mass spectrum MH + (found) 385 MH + (calculated) 385.

Intermediary 14 (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrol-2-one A solution of pyrrole-2-carboxylic acid (60mg), 1-hydroxybenzotriazole (81mg), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (115mg) and triethylamine (10mg) in dimethylformamide (3ml) was stirred for 5 minutes then treated with Intermediate 10 (lOOmg). The reaction mixture was stirred for 6 h. then it was divided between 8% solution of sodium bicarbonate (25ml) and ethyl acetate (50ml). The organic phase was separated, washed with water (2x50ml) and the solvent was stirred in vacuo to leave a solid. A suspension of the solid in diethyl ether (25ml) was stirred for 10 minutes then filtered under suction. The residue was dried to give the title compound (123mg) as a white powder. Melting point 200-203 ° C. Mass spectrum MH + (found) 340 MH + (calculated) 340.

Intermediate 15 (3R, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (1-methyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrole-2-intermediary A solution of 1-methylpyrrole-2-carboxylic acid (150mg), 1-hydroxybenzotriazole (180mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250mg) and triethylamine (240mg) in dimethylformamide (5ml) were added. stirred for 15 min. then he was treated with Intermediary 10 (246mg). The reaction mixture was stirred for 18 h, then it was partitioned between 2% sodium bicarbonate solution (135 ml) and ethyl acetate (150 ml). The organic phase was separated, washed with water (2xl20ml), dried (Na2SO4) and the solvent was removed in vacuo to leave a semi-solid. The semi-solid was suspended in diethyl ether (20 ml) and the suspension was stirred for 10 min. The ether decanted and replaced by more ether (lOml) The resulting suspension was stirred for 10 min.

The ether was decanted again and the residue was dried to give the title compound (227mg) as a pale brown solid. Melting point 176-178 ° C. Mass spectrum MH + (found) 354 MH + (calculated) 354.

Intermediate 16 2- (2, 2-Dimethyl-propionyloxymethyl) -thiazole-4-carboxylic acid A mixture of a-bromopyruvic acid (1.85g), 1- (tert-butylcarbonyloxy) thioacetamide (1.75g) and 4 Angstrom molecular sieves activated (lOg) in ethanol (100ml) was stirred for 24 hours. The solvent was removed in vacuo and replaced with dichloromethane (100 ml). The resulting suspension was stirred for 5 min. then it was filtered through Harborlite J2. The filtrate was evaporated to leave a solid, which was dissolved in ethyl acetate, dried (Na2SO) and the solvent was removed in vacuo to give the title compound (1.83g) as a waxy solid, pale yellow. Melting point 155-158 ° C. Mass spectrum MH + (found) 244 MH + (calculated) 244.

Intermediary 17 2-Hydroxymethyl-thiazole-4-carboxylic acid A solution of Intermediate 16 (1.78g) and potassium carbonate (1.80g) in methanol (90ml) and water (30ml) was stirred and heated to reflux for 4.5h. , cooled, concentrated to 30 mL, acidified with 2M hydrochloric acid and extracted with dichloromethane (5x60ml), then concentrated in vacuo to leave a solid which was extracted with a hot (2: 1) mixture of alcohols. industrial methylated and ethyl acetate (2xl50ml). These extracts were combined with the dichloromethane extracts and the solvents were removed in vacuo. The residual gum was crystallized from diethyl ether to give the title compound (834mg) as a brown powder. Melting point 121-127 ° C Mass spectrum MH + (found) 160 MH + (calculated) 160.

Intermediate 18 (3S, 3aS, 6aR) -4- (2-hydroxymethyl-thiazole-4-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one solution of Intermediate 17 (787mg), Intermediate 10 (l.OOg), triethylamine (655mg), 1-hydroxybenzotriazole (718mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (997mg) in dimethylformamide (5ml) It stirred for 17h. then it was divided between 8% sodium bicarbonate solution (250ml) and ethyl acetate (250ml). The aqueous phase was separated and extracted with ethyl acetate (250ml). The combined organic products were washed with 0.5M hydrochloric acid (2x200ml) and water (2x200ml), dried (Na2SO4) and the solvent was removed in vacuo to give a foam. The foam was suspended in diethyl ether (100 ml), with stirring, for 5 min. The suspension of the resulting solid was filtered under suction. The residue was dried to leave the title compound (1.23g) as a brown powder. Melting point 197-201 ° C. Mass spectrum MH + (found) 388 MH + (calculated) 388.

Intermediate 19 2-Dimethylaminomethyl-thiazole-carboxylic acid A mixture of a-bromopyruvic acid (370mg), 1- (dimethylamino) thioacetamide hydrochloride (300mg) and sodium bicarbonate (200mg) in ethanol (25ml) was stirred and heated at reflux for 1.5h. Potassium carbonate (213mg) was added and reflux was maintained for 0.75h. The reaction mixture was cooled and the solvent was stirred in vacuo. The residue was stirred in ethyl acetate (30ml) for 0.5h. The solvent was decanted. The residual solid was partitioned between 0.5M hydrochloric acid (16ml) and ethyl acetate (20ml). The aqueous phase was separated and concentrated in vacuo to leave a gum. The gum was treated with methanol (20ml) and filtered. The filtrate was concentrated in vacuo and the residue was dried to leave the title compound (430mg) as a dark brown powder. Mass spectrum MH + (found) 187 MH + (calculated) 187.

Intermediate 20 5-formyl-isoxazole-3-carboxylic acid A solution of ethyl-5-formylisoxazole-3-carboxylate (25mg) in 1,4-dioxane (3ml) and 2M hydrochloric acid (lml) was stirred and heated to reflux for 5 h .; it was cooled and the solvents were removed in vacuo. The residue was triturated in diethyl ether. The solvent was removed and the residue was dried to leave the title compound (ldmg) as an orange / brown solid. C.c.d. (dichloromethane: methanol 9: 1) Rf = 0.32.

Intermediary 21 rel- (3R, 3aR, 6aS) -3- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3,2- b] pyrrole-l-carbonyl) -isoxazole-5-carbaldehyde A a stirred solution of Intermediate 10 (670mg) in acetonitrile (50ml) was added Intermediate 20 (500mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.04g). The reaction mixture was stirred for 4 h. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was separated and passed through elution silica elution cartridge Varied SPE, eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give the title compound (660mg) as a white solid. C.c.d. (dichloromethane: acetonitrile 9: 1) Rf = 0.33.

Intermediary 22 L-Methyl-5-styryl-lH-pyrazole-3-carboxylic acid ethyl ester A solution of (E) -ethyl-2,4-dioxo-6-phenylhex-5-enoate (40g) and methylhydrazine (9g) ) in ethanol (250ml) was heated to reflux for 2h. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica, using a mixture (1: 1) of diethyl ether and cyclohexane as the eluent.

Fractions containing the more polar of the two new major components were combined and the solvent was evaporated to leave the title compound (25.4g) as yellow crystals. C.c.d. (diethyl ether: cyclohexane 1: 1) Rf = 0.14. Intermediary 23 was also isolated from this reaction.

Intermediate 23 2-Methyl-5-styryl-2H-pyrazole-3-carboxylic acid ethyl ester The fractions containing the less polar of the two new major components obtained from the chromatographic purification of Intermediary 22 were combined and the solvent was evaporated to leave the title compound (11.4g) as a yellow oil. C.c.d. (diethyl ether: cyclohexane 1: 1) Rf = 0.62.

Intermediate 24 5-Formyl-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester The bubble was bubbled through a stirred solution of Intermediate 22 (156mg) in ethyl acetate (lOml) at -78 ° C. 2h The nitrogen was then bubbled through the solution, the triphenylphosphine (500 mg) was added, the solution was warmed to room temperature and the solvent was removed in vacuo. The product was passed through a silica elution linker cartridge Varied SPE, eluting sequentially with dichloromethane, chloroform and diethyl ether. The fractions containing the required product were combined and evaporated to give the title compound (127 mg) as white crystals C.c.d. (diethyl ether: cyclohexane 1: 1) Rf = 0.5d.

Intermediate 25 5-formy1-1-methyl-1H-pyrazole-3-carboxylic acid A solution of Intermediate 24 (1.02g) in 1,4-dioxane (lOml) and 2M hydrochloric acid (lOml) was stirred and heated to reflux for 24 h. The reaction mixture was cooled and the solvent was stirred in vacuo to leave the title compound as a pale yellow solid (0.d5g). C.c.d. (dichloromethane: methanol 9: 1) Rf = 0.19 (altered or scored).

Intermediary 26 (3R, 3aR, 6aS) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3,2- b] pyrrol-1-carbonyl) -2-methyl-2H- pyrazole-3-carbaldehyde To a stirred solution of Intermediate 10 (783mg) in acetonitrile (60ml) was added Intermediary 25 (645mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.22g). The reaction mixture was stirred overnight. The acetonitrile was stirred in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was separated and passed through a elution silica elution cartridge Varian SPE, eluting sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate. The fractions containing the required product were combined and evaporated to give the title compound (315mg) as a white solid. C.c.d. (dichloromethane: acetonitrile 9: 1) Rf = 0.24.

Intermediate 27 (3R, 3aR, 6aS) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3,2- b] pyrrol-1-carbonyl) -2-methyl-2H- pyrazole-3-carbaldehyde Ozone was bubbled through a stirred solution of Intermediate 23 (124mg) in ethyl acetate (15ml) at -78 ° C for 3h. The nitrogen was then bubbled through the solution, the triphenylphosphine (500 mg) was added, the solution was warmed to room temperature and the solvent was removed in vacuo. The product was passed through a silica elution linker cartridge Varied SPE, eluting sequentially with dichloromethane, chloroform and diethyl ether. The fractions containing the required product were combined and evaporated to give the title compound (62 mg) as white crystals. C.c.d. (diethyl ether: cyclohexane 1: 1) Rf = 0.70.

Intermediate 28 5-formyl-2-methyl-2H-pyrazo-3-carboxylic acid A solution of Intermediate 27 (l.Og) in 1,4-dioxane (10 L) and 2M hydrochloric acid (10 L) was stirred and it heated to reflux all night. The reaction mixture was cooled and the solvent was stirred in vacuo to leave the title compound as a pale yellow solid (O.dg). C.c.d. (dichloromethane: methanol 9: 1) Rf = 0.54 (marked with stripes).

Intermediary 29- (3R, 3aR, 6aS) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-pyrrolo [3,2- b] pyrrol-1-carbonyl) -1-methyl-1H- pyrazole-3-carbaldehyde To a stirred solution of Intermediate 10 (612mg) in acetonitrile (45ml) was added Intermediary 28 (660mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.26g). The reaction mixture was stirred for 22 h. The acetonitrile was stirred in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was separated and passed through a elution silica elution cartridge Varian SPE, eluting sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate. Fractions containing the required product were combined and evaporated to give the title compound (955mg) as a white solid. C.c.d. (dichloromethane: acetonitrile 9: 1) Rf = 0.22.

Intermediary 30 6-Bromomethyl-nicotinic acid A mixture of methyl 2- (bromomethyl) pyridine-5-carboxylate (3.8 g) and bis (tri-n-butyl tin) oxide (16.5 ml) in toluene (80 ml) was stirred and heated to 80 ° C for 24h. The reaction mixture was cooled and extracted with 2M-hydrochloric acid (2x50ml). The combined aqueous extracts were washed with toluene (40ml) and concentrated in vacuo to leave the title compound (3.0g) as a yellow / brown solid. Mass spectrum MH + (found) 216.218 MH + (calculated) 216.218.

Intermediary 31 rel- (3R, 3aR, 6aS) -4- (6-Chloromethyl-pyridine-3-carbonyl) isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2- b] pyrrole-2 -one To a stirred suspension of Intermediate 30 (177mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (236mg) in acetonitrile (5ml) was added Intermediate 10 (100g). The reaction mixture was stirred for 2 h. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane (40ml) and 2M sodium carbonate solution (40ml). The organic phase was separated, washed with 2M sodium carbonate solution (20ml) and water (20ml), dried (MgSO) and concentrated to leave an oil. The oil was purified using flash column chromatography on silica, with dichloromethane: acetonitrile (7: 3) as the eluent, to give the title compound (76mg) as a white foam. C.c.d. (dichloromethane: acetonitrile 7: 3) Rf = 0.45.

Intermediary 32 Methyl 5-bromomethyl-pyrazine-2-carboxylic acid ester A mixture of methyl (5-methyl) pyrazine-2-carboxylate (5.3 g), N-bromosuccinimide (6.3 g) and dibenzoyl peroxide (0.33 g) in tetrachloride of carbon (125ml) was stirred and heated to reflux, with irradiation using a 200W tungsten lamp, for 5h. The reaction mixture was cooled, washed with 10% sodium sulfite solution (2x20ml), water (20ml) and saturated brine (15ml), dried (MgSO4) and concentrated to leave an oil. The oil was purified using flash column chromatography on silica, with cyclohexane: ethyl acetate (3: 2) as the eluent, to give the title compound (3.dg) as a brown solid. C.c.d. (cyclohexane: ethyl acetate 3: 2) Rf = 0.28.

Intermediate 33 5-Bromomethyl-pyrazine-2-carboxylic acid hydrochloride A mixture of Intermediary 32 (3.48 g) and sodium hydroxide (6.00 g) in water (40 ml) was stirred for 2 h .; it was acidified with 2M hydrochloric acid and extracted with ethyl acetate (4x30ml). The combined extracts were washed with saturated brine (15ml), dried (MgSO4) and the solvent removed in vacuo to leave the title compound (2.5dg) as a pale yellow solid. Mass spectrum MH + (found) 217.219 MH + (calculated) 217.219.

Intermediate 34- (3R, 3aR, 6aS) -4- (5-chloromethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one A a stirred solution of Intermediate 10 (800mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (934mg) in acetonitrile (10ml) was added Intermediary 33 (1.23g). The reaction mixture was stirred for 18 h. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane (20ml) and 2M sodium carbonate solution (25ml). The aqueous phase was separated and extracted with dichloromethane (2x20ml). The combined organics were washed with water (15ml) and saturated with brine (15ml), dried (MgSO 4) and concentrated to leave an oil. The oil was purified using flash column chromatography on silica, with dichloromethane: acetonitrile (7: 3) as the eluent, to give the title compound (562mg) as a white foam. C.c.d. (dichloromethane: acetonitrile 7: 3) Rf = 0.42.

Intermediate 35 2R- (2,2,2-trifluoroacetylamino) -succinnamic acid To a stirring suspension of D-Asparagine (37.9g, powder and dried at 110 ° C for 48hrs) in methanol (144ml, dried over 3A sieves for 5 hours) under a nitrogen atmosphere was added triethylamine (40.2ml) followed by methyl trifluoroacetate (36ml). The resulting mixture was allowed to stir for 4 d hours. To the reaction mixture was added dry methanol (145ml) then Dowex 50 form H + resin (115g, dried at 56 ° C for 24 hours). The resulting mixture was stirred for 10 minutes, filtered and the solvent was removed in vacuo to give a crude white solid containing the title compound. This crude product was combined with the crude product from a similar experiment and recrystallized from hot water to yield the title compound as a white crystalline solid (106g). Spectrum of mass MNH4 + (found) 246 MNH + (calculated) 246.

Intermediary 36 2R- (2,2,2-trifluoroacetylamino) succinamic acid methyl ester A stirring solution of Intermediate 35 (95.14g) in methanol (1150ml, dried over 3A molecular sieves) was cooled to -70 ° C. The acetyl chloride (162ml) was added slowly while the reaction temperature was maintained below -60 ° C. The reaction mixture was allowed to warm to -20 ° C and left for 48 hours at this temperature. The solvent was removed in vacuo to give a clear, colorless oil containing the title compound.This was triturated with diethyl ether and the resulting white solid was recrystallized from boiling water to yield the title compound as a white crystalline solid (42g). ) Mass spectrum MH + (found) 243 MH + (calculated) 243.

Intermediary 37 3-Cyano-2R- (2,2,2-trifluoro-acetylamino) -propionic acid methyl ester To a stirring suspension of Intermediary 36 (3.0g) in dichloromethane (20ml) was added pyridine (4.92ml) and p-toluene sulphonyl chloride (4.92g). More dichloromethane (15ml) was added and the brown solution was allowed to stir at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (25ml), washed with 1M aqueous H3P04 (74ml), dried (Na2SO4) was filtered and the solvent was removed in vacuo to give a crude brown solid (3.57g) containing the title compound. The crude mixture was purified by flash chromatography (Si02, Merck, 9385) eluting with 1: 3 then 1: 2 ^ ethyl acetate: cyclohexane. The eluent was evaporated in vacuo to give the dl compound title as a white crystalline solid (1.62g).

C.c.d. (1: 1 ethyl acetate: cyclohexane) Rf 0.5 Spectrum of mass MNH4 + (found) 242 MNH4 + (calculated) 242.

Intermediate 36 2, 2, 2-trifluoro-N- (2-oxo-pyrrolidin-3R-yl) -acetamide A solution of Intermediate 37 (200 mg) in ethanol (10 ml) was stirred under an atmosphere of hydrogen gas with 5% of Rhodium in alumina (l.OOg) for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield a crude gum containing the title compound. The mixture was purified by flash chromatography (Si02, merck, 9365) eluting with acetonitrile. The eluent was evaporated in vacuo to yield the title compound as a white solid (40mg). C.c.d. (Acetonitrile) Rf 0.63 Mass spectrum MNH4 + (found) 214 MNH4 + (calculated) 214.

Intermediate 39 2-Oxo-3R- (2,2,2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic acid benzyl ester For a stirring solution of Intermediate 3d (1.04g) in tetrahydrofuran cooled to -70 ° C, d2 added n-butyl lithium (1.6M in hexanes, 3.31ml). After 5 minutes the benzylchloroformate (633 μl) was added and the reaction mixture allowed to warm to room temperature. After 2 hours the reaction mixture was diluted with ethyl acetate (100ml) and washed with 1M hydrochloric acid (2x50ml). The combined organic extracts were dried (MgSO), filtered and concentrated in vacuo to give a crude orange / white solid which was purified by trituration with diethyl ether to yield the title compound as a white solid (1.25g). Spectrum of mass MNH4 + (found) 346 MNH4 + (calculated) 348 Chiral HPLC (Chiracel AD, ethanol eluent system: 15:65 eptane, flow rate = lml / min.). The retention time of the R enantiomer = 10.08 min (71.8%). The retention time of the enantiomer S = 12.50 min (28.2%).

Intermediary 40 2-Ethoxy-3R- (2,2,2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic acid benzyl ester Intermediate 39 (100mg) was dissolved in dry tetrahydrofuran (lml), cooled to -20 ° C and lithium borohydride (2.0M in THF, 0.15ml) was added. After that time ethanol (lml) was added followed by concentrated H2SO4 (33μl) and the resulting stirring solution was left at room temperature for 3 hours. The reaction mixture was adjusted to pH 8-9 by the addition of saturated aqueous sodium bicarbonate and the organic solvents were removed in vacuo. The resulting residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the aqueous phase was extracted with additional ethyl acetate (10 ml). The combined organic layers were dried (Na2S0)were filtered and concentrated in vacuo to yield the title compound as a clear oil (lOlmg) which was used without further purification. Spectrum of mass MNH4 + (found) 378 MNH4 + (calculated) 378.

Intermediary 40 (Alternative synthesis) Benzyl ester of 2-ethoxy-3R- (2,2,2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic acid A solution of Intermediate 39 (214. dg) in dry THF (1200 ml) is stirred and cooled to -30 ° C. Lithium borohydride (2.0M in THF, 336ml) was added (after an initial temperature rose to -12 ° C, the temperature remained below -17 ° C throughout the entire addition). The mixture was stirred at -20 ° C for 90 minutes before the ethanol (760ml) was added to the mixture while the temperature was maintained. lower than -19 ° C. A cooled mixture of concentrated sulfuric acid (75ml) in ethanol (215ml) was slowly added to the mixture while maintaining the initial temperature below -d ° C. The cooling bath was removed and the reaction allowed to stir for 90 minutes, after which the internal temperature had to rise to + 15 ° C. A saturated solution of sodium bicarbonate (1600ml) was carefully added to the mixture for 35 min before the removal of volatile substances in vacuo. The residual aqueous phase was extracted with ethyl acetate (lOOOml + 2x800ml) the combined extracts were washed with brine (800ml), dried (Na2SO4) overnight and the solvent was removed in vacuo to give the title compound (211.6g). ) as an orange oil. C.c.d. (4: 1; CH2Cl2: Et20) Rf = 0.64 and 0.43.

Intermediate 41 Benzyl ester of (2S, 3R) -2- (rel-lS-ethoxycarbonyl-2-methyl-propyl) -3- (2,2,2-trifluoroacetylamino) -pyrrolidine-1-carboxylic acid Intermediary 40 (90mg) ), (l-ethoxy-3-methyl-but-1-1-enyloxy) -triisopropylsilane (Intermediary 95 of International Patent Application No. WO97 / 36903) d5 (0.22g) and dichloromethane (1ml) were cooled to 5 ° C and boron trifluoride dieterate (0.15ml) was added. After 55 min, the reaction was quenched with 2M aqueous sodium bicarbonate (15ml) and diluted with dichloromethane (10ml). The aqueous layer was separated and the organic layer was washed with a saturated aqueous solution of sodium chloride (10 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a colorless oil (106mg). Mass spectrum MH + (found) 445 MH + (calculated) 445 Intermediary 41 (Alternative Synthesis) Benzyl ester of (2S, 3R) -2- (rel-lS-ethoxycarbonyl-2-methyl-propyl) -3- (2,2,2-trifluoroacetylamino) -pyrrolidine-1-carboxylic acid Intermediate 40 (97.9g), (Z) - (l-ethoxy-3-methyl-but-1-enyloxyl-triisopropyl-silane) (233g) and dichloromethane (600ml) were cooled to 5 ° C under nitrogen and diethyl ether of boron trifluoride (200ml) was added for 15 minutes. After about 15 additional minutes, 2M sodium carbonate (750ml) was added, keeping the temperature below 20 ° C. The reaction mixture was filtered through Hyflo and the solid material was washed with dichloromethane d6 (2x200ml). After adding the washed products to the mixture of phase 2 the aqueous layer was separated and extracted with dichloromethane (2x400ml). The combined extracts were washed with brine (2x250ml), dried (MgSO) and concentrated in vacuo to give the title compound (154g). C.c.d. Si02 (1: 3; ethyl acetate: cyclohexane) Rf = 0.49 (ß-anomer), 0.42 (a-anomer). Mass spectrum (found) MH + = 445 (calculated) MH + = 445.

Intermediary 42 (2S, 3R) -3-amino-2- (1-ethoxycarbonyl-2-methyl-propyl) -pyrrolidine-1-carboxylic acid benzyl ester Intermediary 41 (97mg), potassium carbonate (300mg), ethanol (2ml) and water (2ml) were heated to reflux for 21/4 hours. The ethanol and water were evaporated in vacuo and the residue was partitioned between ethyl acetate (lOml) and water (10L). The aqueous extract was recovered to pH 9-10 by the addition of 2M aqueous sodium hydroxide solution and extracted with diethyl ether (3x20ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a clear oil (56mg).

Intermediary 42 (Alternative Synthesis) (2S, 3R) -3-Amino-2- (1-ethoxycarbonyl-2-methyl-propyl) -pyrrolidine-l-carboxylic acid benzyl ester Intermediate 41 (153g), potassium carbonate ( 183.3 g), ethanol (100%) and water (100%) were refluxed together for 5 h. The organic layer was then separated and concentrated in vacuo. The residue, the aqueous layer and brine (200ml) were extracted with ether (2x500ml, + 250ml) and the combined extracts were extracted with ÍM hydrochloric acid (3x500ml). The combined acid extracts were recovered to pH8 with solid sodium acid carbonate (150g) and extracted with dichloromethane (600ml, + 3x300ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to yield the title compound (87.9g). C.c.d. SiO 2 (100: 8: 1 dichloromethane: ethanol: ammonia) Rf = 0.55 Mass spectrum (found) MH + = 349 (calculated) MH + = 349.

Intermediary 43 (3aR, 6S, 6aS) -6-isopropyl-5-oxo-hexahydro-pyrrolo [3, 2-b] pyrrole-1-carboxylic acid benzyl ester Intermediate 42 (50mg) was dissolved in tetrahydrofuran (lml) and tetramethylethylenediamine (Iml) 86 Then, ÍM of t-butylmagnesium chloride in tetrahydrofuran (0.4ml) was added. After stirring for 3 hours the reaction was quenched with saturated ammonium chloride solution (lml). The aqueous layer was separated and extracted with ethyl acetate (4 ml). The combined organic extracts were evaporated in vacuo. The residue was partitioned between dichloromethane (lOml) and 2M hydrochloric acid (lOml). The aqueous phase was separated and extracted with dichloromethane (3x5ml). The combined organic extracts were dried (MgSO), filtered and concentrated in vacuo to give a crude white solid containing the title compound. Purification by flash chromatography (Si02, Merck, 9385) eluting with 1: 1 ethyl acetate: cyclohexane afforded the title compound as a white solid (16mg). C.c.d. (2: 1 ethyl acetate: cyclohexane) Rf 0.38 CLAR Chiral (Column Chiracel AD, ethanol eluent system: heptane 10:90, flow rate lml / min.). Retention time of RRS lactama = 9.92min (73.6%). Retention time of lactam SSR = 13.12 min. (26.4%).

Intermediary 44 Benzyl acid ester (3aR, 6S, 6aS) -6-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-? Irrolo [3, 2-b]? Irrol-1-carboxylic Intermediary 43 (0.46g) in dry tetrahydrofuran (30ml) at -70 ° C under nitrogen was added iM of lithium hexamethyldisilazide in tetrahydrofuran (2.0ml). The solution was heated to 0 ° C for 15 minutes and then cooled to -70 ° C when the methanesulfonyl chloride (0.30 ml) was added. After 1.5 hours, saturated aqueous ammonium chloride (30ml) was added and the mixture was extracted with ethyl acetate (3x5ml). The combined extracts were washed with brine (2x25ml), dried (MgSO4) and the solvent was removed in vacuo. Flash chromatography of the residue on silica with 1: 1 ethyl acetate: cyclohexane gave the title compound as a white solid (0.34g). C.c.d. Si02 (1: 1 ethyl acetate: cyclohexane) Rf 0.4 Mass spectrum MNH4 + (found) = 398 MNH4 + (calculated) = 398.

Intermediate 45 (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole-2 -one Intermediate 44 (0 .31g), 10% palladium hydroxide on carbon (0.24g) 1,4-dioxane (25ml) and ethyl acetate (25ml) were mixed under hydrogen for 3 hours. The catalyst was then removed by filtration through hyflo and the filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (0.20g). C.c.d. Si02 (9: 1 chloroform: methanol) Rf = 0.36 Mass spectrum MH + (found) = 247 MH + (calculated) = 247.

Intermediary 46 (3S, 3aS, 6aR) -4- (5-Chloromethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one To one solution of Intermediary 45 (900mg) and 1- (3-dimethylamino-ropil) -3-ethylcarbodiimide hydrochloride (1.25g) in acetonitrile (25ml) was added Intermediary 1 (1.16g). The reaction mixture was stirred by Ih and additional acetonitrile (25ml) was added. The mixture was stirred for 19 hours before the acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane (30ml) and 2M sodium carbonate solution (30ml). The aqueous phase was separated and extracted with dichloromethane (2x30ml). The combined organics were dried (MgSO4), filtered and concentrated to leave a brown foam. The foam was purified using flash column chromatography on silica (Merck 9385), with 20% acetonitrile / dichloromethane as the eluent. The required fractions were evaporated to dryness in vacuo to give the title compound (1.095g) as a white foam. C.c.d. (20% acetonitrile: dichloromethane) Rf = 0.52. Mass spectrum MH + (found) 401,403, MH + (calculated) 401,403 Intermediate 47 5- [(tert-Butoxycarbonyl-cyclopropyl-amino) -methi] -pyrazine-2-carboxylic acid Bromine was added to a stirred suspension of 2-methylpyrazine-5-carboxylic acid (60g) in acetic acid (300ml). The reaction mixture was then heated at 80 ° C for one hour. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (250ml) and 2M aqueous HCl (250ml). The aqueous phase was extracted with additional ethyl acetate (5x250ml), the combined organics were washed with 2M HCl (100 l) and saturated brine solution (100ml), dried (MgSO4), filtered and the solvent was evaporated in vacuo to leave a brown solid. The solid was stirred in acetonitrile (900ml) and triethylamine (60ml) and cyclopropylamine (300ml) were added. After stirring for 20 hours at room temperature, additional cyclopropylamine (30ml) was added and the mixture was stirred for an additional 15 minutes. The volatiles were evaporated in vacuo, and the residue was partitioned between ethyl acetate (200ml) and 2M aqueous HCl (300ml). The organic phase was extracted with 2M additional HCl (4x200ml), the combined aqueous extracts were washed with ethyl acetate (50ml), cooled in an ice bath and basified with 10M aqueous sodium hydroxide (120ml). The solution was washed with ethyl acetate (3x200ml) and diethyl ether (200ml), and the remaining volatile organic substances were removed in vacuo to give a brown aqueous solution. To the solution was added 1,4-dioxane (500ml) and di-tert-butyldicarbonate (71g) and the mixture was stirred at room temperature for 20 hours. In addition, di-tert-butyldicarbonate (lOg) was added and the stirring continued for an additional 24 hours. The citric acid (85g) was added to the stirred mixture before extracting it with ethyl acetate (2x200ml + 3xl50ml + 2xl00ml). The combined extracts were dried (MgSO 4), filtered and the solvent was stirred in vacuo to give a brown oil which was purified by flash column chromatography on silica (Merck 9385), with 100: 8: 1 dichloromethane / methane / acetic acid as the eluent.

The required fractions were evaporated to dryness in va cuo to give a tan solid which was vigorously stirred in 5: 1 cyclohexane / diethyl ether until finally it was divided. The solid was removed by filtration and dried in vacuo to give the title compound as an orange / brown solid (16.65g). C.c.d. (100: 8: 1 dichloromethane / methanol / acetic acid) Rf = 0.31. Mass spectrum MH + (found) 294, MH + (calculated) 294.

Intermediate 48 Cyclopropyl- [5- (6S-isopropyl-4-methanesulfonyl-5-oxo-hexahydro- (3aR, 6aS) -pyrrolo [3, 2-b] pyrrole-1-carbonyl) -pyrazine tert-butyl ester -2-ylmethyl] -carbamic Intermediate 45 (11.36g), Intermediate 47 (13.53g) and O- (7-azabenzotriazol-1-yl) -N, N, NAN'-tetramethyluronium hexafluorophosphate (19.3g) were stirred in acetonitrile (260ml) at room temperature and N, N-diisopropylethylamine (16ml) was added. After stirring for two hours, the solvent was removed in vacuo, the residue was diluted with dichloromethane (250ml) and washed with 1M sodium carbonate solution (250ml). The aqueous phase was extracted with dichloromethane (3xl50ml). The combined organics were washed with IMM of sodium carbonate solution (50ml), dried (MgSO 4), filtered and the solvent evaporated in vacuo to leave a yellow-brown solid. The solid was purified by flash column chromatography (Merck 9385 silica) and eluted with 50% ethyl acetate / cyclohexane, and the required fractions were evaporated to dryness in vacuo to give the title compound as a white foam (21.55). g). Mass spectrum MH + (found) 522, MH + (calculated) 522. [a] D20 +69.5 (c = 0.8, MeCN) Intermediate 49: 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid ethyl ester To a stirred solution of 2- (bromomethyl) -oxazole-4-carboxylic acid ethyl ester (43.9g) in acetonitrile (300ml) was added pyrrolidine (15.7ml). After the agitation for 10 more minutes, pyrrolidine (7.8ml) was added. After about 30 additional minutes the solvent was stirred in va cuo to leave an orange oil. The oil was partitioned between sodium carbonate (400 ml) and dichloromethane (500 ml) and the phases were separated. The organic phase was washed with water (100 ml), dried (MgSO 4), filtered and the solvent removed in vacuo to give the title compound as an orange oil (24. Og). Mass spectrum MH + (found) = 225. MH (calculated) = 225.

Intermediary 50 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid methyl ester Pyrrolidine (14mg) was added to a suspension of potassium carbonate (25mg) and 2- (bromomethyl) oxazole-4-methyl ester carboxylic acid (27.5mg) in acetonitrile (2.5ml). The reaction mixture was stirred for 6 h. The solvent was removed in va cuo. The residue was partitioned between ethyl acetate (15ml) and water (5ml). The organic phase was dried (Na2SO) and the solvent was removed in vacuo to give the title compound. (23mg) as a pale brown oil. Mass spectrum MH + (found) = 211. MH + (calculated) = 211.

The following intermediates 51-55 were prepared in a manner similar to Intermediate 2 from 2- (bromomethyl) oxazole-4-carboxylic acid methyl ester: Intermediary 51 2- [(Cyclopropyl-methyl-amino) -methyl] -oxazole-4-carboxylic acid methyl ester hydrochloride Isolated as the hydrochloride: a pale brown gum. Mass spectrum MH + (found) = 211. MH + (calculated) = 211.

Intermediary 52 2- [(Dicyclohexylamino) -methyl] -oxazole-4-carboxylic acid methyl ester Waxy, pale yellow solid. Mass spectrum MH + (found) = 321. MH + (calculated) = 321.

Intermediate 53: 2-piperidin-l-ylmethyl-oxazole-4-carboxylic acid methyl ester Waxy solid, pale brown. Mass spectrum MH + (found) = 225. MH + (calculated) = 225.

Intermediary 54 2- (4-Phenyl-piperazin-1-ylmethyl) -oxazole-4-carboxylic acid methyl ester Pale yellow waxy solid. Mass spectrum MH + (found) = 302. MH + (calculated) = 302.

Intermediary 55: 2-dibutylaminomethyl-oxazole-4-carboxylic acid methyl ester Pale yellow, viscous oil. Mass spectrum MH + (found) = 269. MH + (calculated) = 269.

Intermediary 56: Potassium salt of 2-pyrrolidin-l-ylmethyl-oxazole-4-carboxylic acid / 2-pyrrolidin-l-ylmethyl-oxazole-4-carboxylic acid First Preparation: Potassium carbonate (14. dg) was added to a solution of Intermediary 49 (24. Og) in ethanol (150ml) and water (150ml). The reaction mixture was refluxed with stirring for 4 h. The solvent was removed in va cuo. The orange / brown residue was azeotroped with toluene (x3) and then dried in vacuo. The solid obtained was vigorously stirred with ether (100 ml) and filtered off before being dried in vacuo to give a mixture of the title compound and potassium bicarbonate as a brown solid (34.5 g). This material was used without further purification. 96 Second Preparation: A solution of Intermediary 50 (22mg) in dioxane (1.5ml) and 1.0M. of sodium hydroxide (0.3ml) was stirred by 5. Oh. The solution was neutralized (pH ca 7) by drip addition of 2. OM hydrochloric acid. The solvents were removed in vacuo and the solid residue was further dried in vacuo to give a mixture of the title compound and sodium chloride as a pale yellow solid (40mg). Mass spectrum MH + (found) = 19. MH + (calculated) = 197.

The following Intermediaries 57-59 were prepared in a manner similar to Intermediary 56 (second preparation) of Intermediaries 53-55 respectively.

Intermediary 57: 2-piperidin-l-ylmethyl-oxazole-4-carboxylic acid Creamy solid. Mass spectrum MH + (found) = 211 MH + (calculated) = 211.

Intermediate 56 2- (4-Phenyl-piperazin-1-ylmethyl) -oxazole-4-carboxylic acid White solid. Mass spectrum MH + (found) = 28d MH + (calculated) = 288.

Intermediate 59: 2-dibutylaminomethyl-oxazole-4-carboxylic acid Pale yellow semi-solid. Mass spectrum MH + (found) = 255. MH + (calculated) = 255.

Examples In the preceding dihydrochloride salts, they were indicated by the qualification "(2: 1)" after the chemical name.

Example 1 Rel- (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-furan-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one A mixture of Intermediate 11 (80mg) and pyrrolidine (17mg) in dichloromethane (6ml) was stirred for 2h. Sodium triacetoxyborohydride (69mg) was added and stirring was continued overnight. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution and water. The organic phase was passed through a silica eluting link cartridge Varian SPE (which had been preconditioned by eluting a column volume of dichloromethane), eluting sequentially with dichloromethane, chloroform, diethyl ether, a mixture (1: 1) of diethyl ether and ethyl acetate, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give a gum which was treated with 1. OM hydrogen chloride in diethyl ester to give the title compound as a yellow solid (80mg). Mass spectrum MH + (found) = 424 MH + (calculated) = 424 C.c.d. . { dichloromethane methanol 9: 1): Rf = 0.27.

The following Examples 2-4 were prepared in a manner similar to Example 1 from Intermediary 11: Example 2 Hydrochloride REI (3R, 3aR, 6aS) -3-Isopropyl-l-methanesulfonyl-4- (5-morpholin-4-ylmethyl-furan-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one Solid cream. Mass spectrum MH + (found) = 440 MH + (calculated) = 440 C.c.d. (dichloromethane: methanol 9: 1): Rf = 0.60.

Example 3 Hydrochloride REI (3R, 3aR, 6aS) -3-Isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-l-ylmethyl) -furan-2-carbonyl] -hexahydro-pyrrolo [ 3, 2-b] pyrrol-2-one Red solid. Mass spectrum MH + (found) = 515 MH + (calculated) = 515 C.c.d. (dichloromethane methanol 9: 1): Rf = 0.65.

EXAMPLE 4 RI- (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -furan-2-carbonyl] -hexahydro-pyrrolohydrochloride 3, 2-b] pyrrol-2-one White solid. Mass spectrum MH + (found) = 453 MH + (calculated) = 453 C.c.d. (dichloromethane: methanol 9: 1): Rf = 0.16.

EXAMPLE 5 Hydrochloride REI (3R, 3aR, 6aS) -3-Isopropyl-l-methanesulfonyl-4- (2-morpholin-4-ylmethyl-furan-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one A mixture of Intermediate 12 (50mg) and morpholine (13mg) in dichloromethane (3.5ml) was stirred for 1.5h. Sodium triacetoxyborohydride (43mg) was added and stirring was continued overnight. The reaction mixture was diluted with dichloromethane and extracted with 2M hydrochloric acid. The aqueous extracts were made basic with 6% aqueous sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane extracts were washed with brine, dried (Na2SO4) and the solvent was stirred in vacuo to leave a solid, which was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a solid cream (32mg). Mass spectrum MH + (found) = 440 MH + (calculated) = 440 C.c.d. (dichloromethane: methanol: ammonia 100: 8: 1): Rf = 0.68.

The following Examples 6-10 were prepared in a manner similar to Example 5 from Intermediary 12: EXAMPLE 6 REI (3R, 3aR, 6aS) -4- (2-dimethylaminomethyl-furan-3-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole-2- Ona Solid cream. Mass spectrum MH + (found) = 398 MH + (calculated) = 398 C.c.d. (dichloromethane: ethanol ammonia 100: 8: 1): Rf = 0.70.

EXAMPLE 7 Rehydrochloride (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethyl-furan-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] beige solid pyrrol-2-one. Mass spectrum MH + (found) = 438 MH + (calculated) = 438 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.68.

EXAMPLE 8 Rehydrochloride (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-furan-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one Yellow solid. Mass spectrum MH + (found) = 424 MH + (calculated) = 424 C.c.d. (dichloromethane: ethanol ammonia 100: 8: 1): Rf = 0.67.

EXAMPLE 9 REI (3R, 3aR, 6aS) -3-Isopropyl-l-methanesulfonyl-4- [2- (4-phenyl-piperazin-1-ylmethyl) -furan- 3-carbonyl] -hexahydro-pyrrolo [ 3, 2-b] pyrrol-2-one Yellow solid. Mass spectrum MH + (found) = 515 MH + (calculated) = 515 C.c.d. (dichloromethane: ethanol ammonia 100: 8: 1): Rf = 0.86.

EXAMPLE 10 Rehydrochloride (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- [2- (4-methyl-piperazin-1-ylmethyl) -furan-3-carbonyl] -hexahydro-pyrrolo [ 3, 2-b] pyrrol-2-one Solid cream. Mass spectrum MH + (found) = 453 MH + (calculated) = 453 C.c.d. (dichloromethane: ethanol: ammonia 100: 6: 1): Rf = 0.50.

EXAMPLE 11 REI (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-thiophene-2-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole-2- One mixture of the Intermediate • 13 (60mg), dimethylammonium chloride (36mg) and sodium triacetoxyborohydride (66mg) in dichloromethane (6ml) was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with 2M hydrochloric acid. The aqueous extracts were washed with dichloromethane then made basic with 2M sodium carbonate solution and extracted with dichloromethane. These dichloromethane extracts were washed with brine, dried (MgSO4) and the solvent was removed in vacuo to leave a gum, which was treated with 1.0M of hydrogen chloride in diethyl ether to give the title compound as a yellow solid. (15mg) Mass spectrum MH + (found) = 414 MH + (calculated) = 414 C.c.d. (dichloromethane: ethanol: ammonia 100: 6: 1): Rf = 0.44.

The following Example 12 was prepared in a manner similar to Example 11 from Intermediary 13: EXAMPLE 12 ReI- (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-piperidin-1-ylmethyl-thiophene-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one Yellow solid. Mass spectrum MH + (found) = 454 MH + (calculated) = 454 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.52.

Example 13 - (3S, 3aS,, 6aR) - 3-isopropyl-1-methyl sulphonyl 4- (5-: orf olin- 4 -i: Imethyl-IH- pyrrole -2-carbonyl) -hexahi .dro -pyrrolo [3, 2- -b] pyrrol-2-one -one A mixture of Intermediate 14 (80mg), paraformaldehyde (28mg) and morpholine (40mg) in ethanol (4ml) and glacial acetic acid (1.5ml) was stirred and heated to reflux by ldh. The mixture was cooled to room temperature and partitioned between 8% aqueous sodium bicarbonate solution (25ml) and ethyl acetate (25ml). The aqueous phase was further extracted with ethyl acetate (30ml). The combined organic phases were dried (Na 2 SO 4) and the solvent was evaporated in vacuo to leave a gum. The gum was purified by flash column chromatography (silica Merck 9385; eluant dichloromethane: ethanol: ammonia 200: 8: 1) to give a white powder (21mg) which was treated with 1. OM hydrogen chloride in diethyl ether give the title compound as a white powder (22mg). Melting point 184-ldd ° Mass spectrum MH + (found) = 439 MH + (calculated) = 439 The following Examples 14-20 were prepared in a manner similar to Example 13 from Intermediary 14: EXAMPLE 14 RI- (3S, 3aS, 6aR) -4- (5-dimethylaminomethyl-lH-pyrrole-2-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol- 2-one White powder. Melting point 233-236 ° C Mass spectrum MH + (found) = 397 MH + (calculated) = 397 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.45 Example 15 Rel- (3S, 3aS, 6aR) - • 3-isopropyl-1-methanesulfonyl- • 4- (5-piperidin-1-ylmethyl-lH-pyrrole-2-carbonyl) -hexahi .dro hydrochloride -pyrrolo [3,2-b] pyrrol-2-one White powder. Melting point 160-164 ° C Mass spectrum MH + (found) = 437 MH + (calculated) = 437 EXAMPLE 16 ReI- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (5-pyrrolidin-l-ylmethyl-lH-pyrrole-2-carbonyl) -hexahydro-pyrrolohydrochloride [3, 2- b] pyrrol-2-one White powder. Melting point 175-178 ° C Mass spectrum MH + (found) = 423 MH + (calculated) = 423 EXAMPLE 17 ReI- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) -1H-pyrrole-2-carbonyl] -hexahydroxyhydrochloride pyrrolo [3, 2-b] pyrrol-2-one (1: 2) Cream powder, Melting point 156-160 ° C Mass spectrum MH + (found) = 514 MH + (calculated) = 514 EXAMPLE 18 ReI- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [5- (4-methyl-piperazin-l-ylmethyl-lH-pyrrole-2-carbonyl] -hexahydro-pyrrolohydrochloride [3, 2-b] pyrro 1-2 -one (1: 2) Cream powder, Melting point 177-181 ° C Mass spectrum MH + (found) = 452 MH + (calculated) = 452 EXAMPLE 19 ReI- (3S, 3aS, 6aR) -4- (5-dibutylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole 2-one pale yellow powder. Melting point 116-120 ° C Mass spectrum MH + (found) = 481 MH + (calculated) = 481 EXAMPLE 20 ReI- (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (5-methylaminomethyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole 2-one Powder cream, Melting point 210-215 ° C Mass spectrum MH + (found) = 383 MH + (calculated) = 383 EXAMPLE 21 Rel- (3S, 3aS, 6aR) -3-isopropy-1-1-methanesulfonyl-4- (1- • methyl-5-p.iperidin-I-Í: lmethyl-lH-pyrrole-2-carboni hydrochloride D- • hexahydro-pyrrolo [3,2-b] pyrrol-2-one A mixture of Intermediate 15 (40mg), paraformaldehyde (15ml) and piperidine (23mg) in ethanol (3ml) and glacial acetic acid (1.5ml) was stirred and heated to reflux for 22h. The mixture was cooled to room temperature and partitioned between 8% aqueous sodium bicarbonate solution (30ml) and ethyl acetate (20ml). The organic phase was dried (Na2SO4) and the solvent was evaporated in vacuo to leave a gum. The gum was purified by flash column chromatography (Merck silica 9385; eluent dichloromethane: ethanol: 100: 8: 1 ammonia) to give a white solid (26mg) which was treated with 1.0M of hydrogen chloride in diethyl ether to give the title compound as a white powder (28mg). Melting point 149-153 ° C Mass spectrum MH + (found) = 451 MH + (calculated) = 451 The following Examples 22-25 were prepared in a manner similar to Example 21 from Intermediary 15: EXAMPLE 22 ReI- (3S, 3aS, 6aR) -3-iso? Ropil-l-methanesulfonyl-4- (l-methyl-5-morpholin-4-ylmethyl-lH-pyrrole-2-carbonyl) -hexahydroxyhydrochloride pyrrolo [3, 2-b] pyrrol-2-one pale yellow powder, melting point 150-154 ° C mass spectrum MH + (found) = 453 MH + (calculated) = 453 EXAMPLE 23 ReI- (3S, 3aS, 6aR) -4- (5-dimethylaminomethyl-1-methyl-1H-pyrrole-2-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3, 2-yl] hydrochloride. b] pyrrol-2-one White powder. Melting point 137-141 ° C Mass spectrum MH + (found) = 411 MH + (calculated) = 411 Example 24 Rel- (3S, 3aS, 6aR) -3-isopropy1-1-methanesulfonyl-4- (1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl D- hydrochloride) hexahydro-pyrrolo [3,2-b] pyrrol-2-one Yellow powder, Melting point 135-139 ° C Mass spectrum MH + (found) = 437 MH + (calculated) = 437 EXAMPLE 25 ReI- (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (l-methyl-5-methylaminomethyl-lH-pyrrole-2-carbonyl) -hexahydro-pyrrolohydrochloride [3, 2- b] pyrrol-2-one White powder, Melting point 216-218 ° C Mass spectrum MH + (found) = 397 MH + (calculated) = 397 EXAMPLE 26 ReI- (3S, 3aS, 6aR) -4- (4-Dimethylaminomethyl-lH-pyrrole-2-carbonyl) -3-isopropy1-1-methanesulfonyl-hexahydro-pyrrolo [3,2- b] pyrrole 2-one A mixture of Intermediary 14 (dOmg), paraformaldehyde (25mg) and dimethylammonium chloride (38mg) and activated 4 Angstrom molecular sieves (200 mg) in ethanol (10 ml) was stirred and heated to reflux for 24 h. The mixture was cooled to room temperature and the solvent was evaporated in vacuo to leave a gum. The gum was purified by flash column chromatography, using two columns (silica Merck 9385; eluent: dichloromethane: ethanol: ammonia 80: 8: 1 for the first column, 100: 8: 1 for the second column) to isolate or separate a powder white (16mg) which was treated with 1. OM of hydrogen chloride in diethyl ether to give the title compound as a white powder (16mg). Melting point 160-165 ° C Mass spectrum MH + (found) = 397 MH + (calculated) = 397 C.c.d (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.20 EXAMPLE 27 ReI- (3S, 3aS, 6aR) -3-isopropy1-1-methanesulfonyl-4- (2-pyrrolidin-1-yl-methyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3, 2-] hydrochloride b] pyrrol-2-one A mixture of Intermediate 18 (387mg), and triethylamine (202mg) in dichloromethane (42ml) was stirred and treated with methanesulfonyl chloride (172mg). The reaction mixture was stirred for 1.5 h. An aliquot (7ml) was removed and added to a stirred solution of pyrrolidine (30mg) in dichloromethane (2ml). The solution was stirred for 2 days. The aqueous 8% sodium bicarbonate solution was added, with vigorous stirring. The aqueous phase was separated and extracted with dichloromethane (15ml). The organic phases were combined and dried (Na2SO4). The solvent was removed in vacuo to leave a semi-solid, which was triturated in diethyl ether (10 ml) to give a solid suspension. Cyclohexane (lOml) was added to the suspension and the solvent decanted. The residual solid was dried in vacuo to leave a white solid which was treated with 1. OM hydrogen chloride in diethyl ester to give the title compound as a cream powder (51mg). Melting point 130-134 ° C Mass spectrum MH + (found) = 441 MH + (calculated) = 441 The following Examples 28-35 were prepared in a manner similar to Example 27 from Intermediary 18: Example 28 ReI- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-morpholin-4-ylmethyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one Pale-colored powder, melting point 138- 143 ° C Mass spectrum MH + (found) = 457 MH + (calculated) = 457 EXAMPLE 29 RI- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-piperidin-l-ylmethyl-thiazole-4-carbonyl) -hexahydro-pyrrolohydrochloride [3 , 2-b] pyrrol-2-one Cream-colored powder, Melting point 153-15d ° C Mass spectrum MH + (found) = 455 MH + (calculated) = 455 EXAMPLE 30 ReI- (3S, 3aS, 6aR) -3-isopropyl-l-methansul-4-fyl [2- (4-methyl-piperazin-1-ylmethyl) -thiazole-4-carbonyl] -hexahydro-pyrrolohydrochloride [3, 2-b] pyrrol-2-one (1: 2) White powder, Melting point 153-158 ° C Mass spectrum MH + (found) = 470 MH + (calculated) = 470 EXAMPLE 31 Re-1- (3S,, 3aS,, 6aR) -4- (2-cyclopropylaminomethyl-1-thiazole- • 4-carb-onyl) -3-isopropyl-1-methanesulfonyl-hexahydroxyhydrochloride -pirrc > [3, 2 - b] pirre »1--2-one Pale gray powder, Melting point 160-163 ° C Mass spectrum MH + (found) = 427 MH + (calculated) = 427 Example 32 Rel- (3S, 3aSir6aR) -4-- hydrochloride. { 2- [(4-Fluoro-benzylamino) -methyl] -thiazole-4-carbonyl} -3- • isopropyl-1-methanesulfoni 1-hexah: idro-pyrrolo [3,2-b] pyrrole-2-one Pale yellow powder, Melting point 141-145 ° C Mass spectrum MH + (found) = 495 MH + (calculated) = 495 EXAMPLE 33 Rel- (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4 - [2- (4-phenyl-piperazin-1-ylmethyl) -thiazole-4-carboni hydrochloride. 1] -hexahydro -pyrrolo [3,2-b] pyrrol-2-one (1: 2) Cream-colored powder, Melting point 156-161 ° C Mass spectrum MH + (found) = 532 MH + (calculated) = 532 EXAMPLE 34 ReI- (3S, 3aS, 6aR) -4- (2-dibutylaminomethyl-thiazole-4-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole-2-hydrochloride. ona Powder pale yellow, Melting point 81-86 ° C Mass spectrum MH + (found) = 499 MH + (calculated) = 499 Example 35: (3R, 3aR, 6aS) -3-iso? ropil-4- hydrochloride. { 2- [(1-isopropyl-2-methyl-propylamino) -methyl] -thiazole-4-carbonyl} -l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one Cream-colored powder, Melting point 192-195 ° C Mass spectrum MH + (found) = 485 MH + (calculated) = 485 EXAMPLE 36 ReI- (3S, 3aS, 6aR) -4- (2-Dimethylaminomethyl-thiazole-4-carbonyl) -3-iso-ro-pyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrole 2-one Oxalyl chloride (127 mg) was added to a stirred suspension of Intermediate 19 (125 mg) in dichloromethane (10 ml), followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1 h, then concentrated in vacuo. The residue was suspended in dichloromethane (15ml) and treated, with agitation, with Intermediate 10 (43mg) and sodium bicarbonate (175mg). After stirring the reaction mixture for 16 h, 8% sodium bicarbonate solution (12 ml) was added. The aqueous phase was separated and extracted with dichloromethane (15ml). The combined organic extracts were dried (Na2SO) and evaporated to give a brown gum. The gum was chromatographed on silica (Merck 9385), using a mixture of dichloromethane, ethanol, and ammonia (160: 8: 1) as the eluent, to give a brown gum, which was treated with 1. OM chloride. hydrogen in ether to give the title compound (23mg) as a cream solid. Melting point 122-127 ° C Mass spectrum MH + (found) = 415 MH + (calculated) = 415 EXAMPLE 37 ReI- (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-isoxazole-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one A mixture of Intermediary 21 (50mg) and morpholine (13mg) in dichloromethane (5ml) was stirred for 1.5h. Sodium triacetoxyborohydride (43 mg) was added and stirring was continued for 2.5 h. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution. The organic phase was passed through a mixed elution silica cartridge Varian SPE (which has been preconditioned by eluting a column volume of dichloromethane), eluting sequentially with dichloromethane, chloroform, diethyl ester, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give a foam which was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a white solid (39mg). Mass spectrum MH + (found) = 441 MH + (calculated) = 441 C.c.d. (dichloromethanemethanol 9: 1): Rf = 0.65.

The following Examples 38-44 were prepared in a manner similar to Example 37 from Intermediary 21: EXAMPLE 36 Re (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-isoxazole-3-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrole-2-hydrochloride. white solid ona. Mass spectrum MH + (found) = 399 MH + (calculated) = 399 C.c.d. (dichloromethane: methanol 9: 1): Rf = 0.5d.

Example 39 Rel- (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- (5-pyrrolidin-l-ylmethyl-isoxazole-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one Solid cream. Mass spectrum MH + (found) = 425 MH + (calculated) = 425 C.c.d. (dichloromethane: methanol 9: 1): Rf = 0.55.

EXAMPLE 40 Rel- (3R,, 3aR, 6aS) '-3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethyl-isoxazole-3-carbonyl) -hexahi. Dro- hydrochloride pyrrolo [3, 2-b] pyrrol-2-one. White solid. Mass spectrum MH + (found) = 439 MH + (calculated) = 439 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.52.

EXAMPLE 41 ReI- (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -isoxazole-3-carbonyl] -hexahydro-pyrrolo hydrochloride 3, 2-b] pyrrol-2-one White solid. Mass spectrum MH + (found) = 454 MH + (calculated) = 454 C.c.d. (dichloromethane: methanol 9: 1): Rf = 0.13.

Example 42 Rel- (3R, 3aR, r 6aS) -4-- hydrochloride. { 5- [(4-Fluoro-benzylamino) -methyl] -isoxazole-3-carbonyl} - 3-isop: ropil-1-methanesulfoni 1-hexahydro-pyrrolo [3, 2-b] pyrrole-2 - < Ona Solid cream. Mass spectrum MH + (found) = 479 MH + (calculated) = 479 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.59.

EXAMPLE 43 Rehydrochloride (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) -isoxazole-3-carbonyl] -hexahydro-pyrrolo [ 3, 2-b] pyrrol-2-one Solid cream. Mass spectrum MH + (found) = 516 MH + (calculated) = 516 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.62.

EXAMPLE 44 ReI- (3R, 3aR, 6aS) -4- (5-dibutylaminomethyl-isoxazole-3-carbonyl) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrole-2-hydrochloride. Ona Solid cream. Mass spectrum MH + (found) = 483 MH + (calculated) = 483 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.75.

EXAMPLE 45 Rehydrochloride (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-1-methyl-1H-pyrazole-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3, 2 b] pyrrol-2-one A mixture of Intermediate 26 (50mg) and dimethylammonium chloride (32mg) in dichloromethane (5ml) was stirred for 2h. Sodium triacetoxyborohydride was added (55mg) and stirring was continued for 3h. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution. The organic phase was passed through a Varian SPE cartridge (which had been preconditioned by eluting through a column volume of dichloromethane), eluting with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give a pale brown oil which was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a cream solid (28mg). Mass spectrum MH + (found) = 412 MH + (calculated) = 412 C.c.d. . { dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.68.

The following Examples 46-49 were prepared in a manner similar to Example 45 from Intermediary 26.

EXAMPLE 46 Rehydric hydrochloride (3R, 3aR, 6aS) -3-isopropyl-1-1-methansulfonyl-4- (1-methyl-5-pyrrole idin-1- ime ti 1-1 Hp i razol- 3- carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2-one Solid cream. Mass spectrum MH + (found) = 438 MH + (calculated) = 438 C.c.d. (dichloromethane: ethanol: ammonia 100: 6: 1): Rf = 0.65.

EXAMPLE 47 Rehydrochloride (3R, 3aR, 6aS) -3-isopropyl-1-1- methanesulfonyl-4- (1-methyl-5-morpholin-4-ylmethyl-1H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one Solid cream. Mass spectrum MH + (found) = 454 MH + (calculated) = 454 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.69.

EXAMPLE 48 Rel- (3R, 3aR, 6aS) -3-isopro-1-yl-1-methanesulfonyl-4- (1-methyl-5-piperidin-1-ylmethyl-1H-pyrazole-3- hydrochloride) carbonyl) -hexahydro-pyrrole or [3, 2-b] pyrrol-2-one Solid cream. Mass spectrum MH + (found) = 452 MH + (calculated) = 452 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.67.

EXAMPLE 49 Rehydric hydrochloride (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- [l-methyl-5- (4-methyl-piperidin-1-yl ethyl) -lH-pyrazole-3 carbonyl] -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one Solid cream. Mass spectrum - MH + (found) = 466 MH + (calculated) = 466 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1): Rf = 0.78.

Example 50 Re-(3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [2-methyl-5- (4-phenyl-piperazin-1-ylmethyl) -2H-pyrazole-3-carbonyl hydrochloride ] -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one A mixture of Intermediate 29 (50mg) and phenylpiperazine (28mg) in dichloromethane (5ml) was stirred for 2h. Sodium triacetoxyborohydride (50 mg) was added and stirring was continued overnight. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution. The organic phase was passed through a Varian SPE cartridge (which had been preconditioned by eluting through a column volume of dichloromethane), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give a gum which was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a dark yellow solid (16mg). Mass spectrum MH + (found) = 529 MH + (calculated) = 529 C.c.d. (dichloromethane: ethanol: ammonia 100: 8: 1.): Rf = 0.77.

The following Examples 51-55 were prepared in a manner similar to Example 50 from Intermediary 29: EXAMPLE 51 RI- (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-2-methyl-2H-pyrazole-3-carbonyl) -3-isopropyl-1-ethanesulfonyl-hexahydro-pyrrolo [3, 2-] hydrochloride. b] yellow solid pyrrol-2-one. Mass spectrum MH + (found) = 412 Mrf (calculated) = 412 C.c.d (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.66, EXAMPLE 52 Rehydrochloride (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- (2-methyl-5-pyrrolidin-1-ylmethyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [ 3, 2-b] pyrrol-2-one Yellow solid. Mass spectrum MH + (found) = 436 MH (calculated) = 438 C.c.d [dichloromethane: ethanol: ammonia 100-: 8: 1) Rf = 0.63 EXAMPLE 53 Rei (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- (2-methyl-5-morpholin-4-ylmethyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo hydrochloride 3, 2-b] pyrrol-2-one Yellow solid. Mass spectrum MH + (found) = 454 MH + (calculated) = 454 C.c.d (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.65.

Example 54 Rehydric hydrochloride (3R, 3aR, 6aS) -3- isopropi 1-1-methanesulfonyl-4- (2-methyl-5-piperidin-l-ylmethyl-2H-pi-3-carbonyl) -hexahydro -pyrrolo [3, 2-b] pyrrole-2-one Yellow solid. Mass spectrum MH + (found) = 452 MH + (calculated) = 452 C.c.d (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.65 EXAMPLE 55 ReI- (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- [2-methyl-5- (4-methyl-? Iperazin-1-ylmethyl) -2H-pyrazole-3- hydrochloride. carbonyl] -hexahydro-pyrrolo [3,2-b] pyrrol-2-one Yellow solid. Mass spectrum MH + (found) = 467 MH + (calculated) = 467 C.c.d (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.29.

Example 56: (3R, 3aR, 6aS) -4- Hydrochloride. { 6- [(dicyclohexyl-amino) -methyl] -pyridine-3-carbonyl} -3-isopropy1-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one (1: 2) A mixture of Intermediary 31 (90mg), dicyclohexylamine (104.6 μl), sodium iodide (79mg) and potassium carbonate (169mg) in acetonitrile (2ml) was stirred for 5 days. The solvent was evaporated and the residue was partitioned between 2M of sodium carbonate solution (2ml) and dichloromethane (3ml). The phases separated. The organic phase was passed through a Varian SPE cartridge (which had been preconditioned by eluting through a column volume of dichloromethane), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give a colorless oil which was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a cream solid (60mg). Mass spectrum MH + (found) = 545 MH + (calculated) = 545 C.c.d. (ethyl acetate); Rf = 0.47.

The following Examples 57-64 were prepared in a manner similar to Example 56 from Intermediary 31: EXAMPLE 57 Rehydrochloride (3R, 3aR, 6aS) -4- (6-dibutylaminomethyl-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydro-pyrrolo [3,2-b] pyrrole-2-hydrochloride ona (1: 2) Brown glass. Mass spectrum MH + (found) = 493 MH + (calculated) = 493 C.c.d (ethyl acetate) Rf = 0.49.

EXAMPLE 58 ReI- (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- (6-morpholin-4-ylmethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one (1: 2) orange crystal. Mass spectrum MH + (found) = 451 MH + (calculated) = 451 C.c.d (ethyl acetate) Rf = 0.38.

EXAMPLE 59 Rel- (3R, 3aR, 6aS) -4- (6-Cyclopropylaminomethyl-1-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] hydrochloride ] pyrrole-2-one (1:29) Pale brown solid, Mass spectrum MH + (found) = 421 MH + 'calculated) = 421 C.c.d (ethyl acetate) Rf = 0.36.

EXAMPLE 60 Rel- (3R,, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl- 4- (6-piperidin-1-ylmethyl-p: iri.din-3-carbonyl) hydrochloride - hexaihydro-pyrrolo [3, 2 - b] pyrrol-2-one (1: 2) Green solid. Mass spectrum MH + (found) = 449 MH + (calculated) = 449 C.c.d (ethyl acetate) Rf = 0.36.

EXAMPLE 61 Rehydrochloride (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- [6- (4-methyl-piperazin-1-ylmethyl) -pyridine-3-carbonyl] -hexahydro-pyrrolo [ 3, 2-b] pyrrol-2-one (1: 2) Orange crystal. Mass spectrum MH + (found) = 464 MH + (calculated) = 464 C.c.d (ethyl acetate) Rf = 0.05.

EXAMPLE 62 RI- (3R, 3aR, 6aS) -3-iso? Ropil-4- hydrochloride. { 6- [(1-iso? Ropil-2-methyl-propylamino) -met l] -pyridine-3-carbonyl} -l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one (1: 2) yellow solid. Mass spectrum MH + (found) = 479 MH + (calculated) = 479 C.c.d (ethyl acetate) Rf = 0.42.

EXAMPLE 63 Rel- (3R, 3aR, 6aS) -4- (6-dimethylamino-methyl-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol- hydrochloride 2-one (1: 2) Pale yellow crystal. Mass spectrum MH + (found) = 409 MH + (calculated) = 409 C.c.d (ethyl acetate) Rf = 0.21.

Example 64 Relative hydrochloride (3R, r 3aR, 6aS) -4-. { 6- [(4-Fluoro-benzylamino) -methyl] -pyridin-3-carbonyl} - 3-isopropyl-1-ethansulfoni 1-hexah: idro-pyrrolo [3,2-b] pyrrole-2-one (1: 2) Yellow / brown solid. Mass spectrum MH + (found) = 489 MH + (calculated) = 489 C.c.d (ethyl acetate) Rf = 0.41.

EXAMPLE 65 RI- (3R, 3aR, 6aS) -4- (5-Cyclopropylamino-methyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrole 2-one (1: 2) A mixture of Intermediate 34 (45mg), cyclopropylamine (23.3 μl), and sodium iodide (25mg) in dichloromethane (lml) was stirred for 18h. More cyclopropylamine (23.3 μl) was added and stirring was continued for an additional 24h. The reaction mixture was partitioned between 2M sodium carbonate solution (3ml) and dichloromethane (3ml). The phases separated. The organic phase was passed through a Varian SPE cartridge (which had been preconditioned by eluting through a column volume of dichloromethane), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the required product were combined and evaporated to give a pale brown oil (17mg) which was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a brown solid (20mg). Mass spectrum MH + (found) = 422 MH + (calculated) = 422 C.c.d. (ethyl acetate); Rf = 0.12.

The following Examples 66-75 were prepared in a manner similar to Example 65 from Intermediary 34: EXAMPLE 66 ReI- (3R, 3aR, 6aS) -4- (5-dibutylaminomethyl-pyra-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole-2-hydrochloride -one (1: 2) Pale brown solid. Mass spectrum MH + (found) = 494 MH + (calculated) = 494 C.c.d (ethyl acetate) Rf = 0.63.

EXAMPLE 67 RI- (3R, 3aR, 6aS) -3-isopropy-1-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride ] pyrrol-2-one (1 2) Solid cream. Mass spectrum MH + (found) = 452 MH + (calculated) = 452 C.c.d (ethyl acetate) Rf = 0.12.

EXAMPLE 68 Rehydrochloride (3R, 3aR, 6aS) -4-. { 5- [(dicyclohexyl-a ino) -methyl] -pyrazine-2-carbonyl} -3-isopropyl-l-ethanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one (1: 2) Cream solid. Mass spectrum MH + (found) = 546 MH + (calculated) = 546 C.c.d (ethyl acetate) Rf = 0.65.

EXAMPLE 69 ReI- (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-piperidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride pyrrol-2-one (1 ¡2) Solid cream. Mass spectrum MH + (found) = 450 MH + (calculated) = 450 C.c.d (ethyl acetate) Rf = 0.12.

EXAMPLE 70 ReI- (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- [- (4-methyl-piperazin-1-ylmethyl) -pyrazine-2-carbonyl] -hexahydro-pyrrolohydrochloride [3 , 2-b] pyrrol-2-one (1: 2) Brown crystal. Mass spectrum MH + (found) = 465 MH + (calculated) = 465 C.c.d (ethyl acetate) Rf = 0.02.

EXAMPLE 71 Rehydrochloride (3R, 3aR, 6aS) -4-. { 5- [(l-isopropyl-2-methyl-propylamino) -methyl] -pyrazine-2-carbonyl) -1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one (1: 2) Solid cream. Mass spectrum MH + (found) = 480 MH + (calculated) = 480 C.c.d (ethyl acetate) Rf = 0.45.

EXAMPLE 72 Re (3R, 3aR, 6aS) -4-, (5-dimethylaminomethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrole-2-hydrochloride. -one (1: 2) Pale brown solid. Mass spectrum MH + (found) = 410 MH + (calculated) = 410 C.c.d (ethyl acetate) Rf = 0.06.

EXAMPLE 73 ReI- (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) pyrazine-2-carbonyl] -hexahydro-pyrrolohydrochloride [3 , 2-b] pyrrol-2-one (1: 2) Pale yellow crystal. Mass spectrum MH + (found) = 527 MH + (calculated) = 527 C.c.d (ethyl acetate) Rf = 0.27.

EXAMPLE 74 Rel- (3R, r 3aR, 6aS) -3- -isopropyl-1-methansulphonyl-4- (5- pyrrolidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahi hydrochloride. .dro -pyrrolo [3, 2- -b] pyrrol-2-one (1: 2) Solid orange / coffee Mass spectrum MH + (found) = 436 MH + (calculated) = 436 C.c.d (ethyl acetate) Rf = 0.05.

EXAMPLE 75 ReI- (3R, 3aR, 6aS) -3-isopropy1-1-methanesulfonyl-4- (5-methylaminomethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2-hydrochloride ona (1: 2) Pale brown solid. Mass spectrum MH + (found) = 396 MH + (calculated) = 396 C.c.d (ethyl acetate) Rf = 0.02.

Example 76 (3S, 3aS, 6aR) -4- (5-Cyclopropylaminomethyl-γ-irazin-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one hydrochloride A solution of Intermediate 48 (21.53g) and 4. OM of HCl in 1,4-dioxan (200ml) was stirred at room temperature for 2 hours. The solvent was stirred in vacuo to give a colorless solid. The solid was recrystallized from 5% hot water / 2-propanol (2.3 1) to give the title compound (single or single enantiomer) (15.54g) as a white solid. C.c.d. (Silica, eluent 200: 8: 1 dichloromethane: ethanol: 0.880 ammonia) Rf = 0.21. Mass spectrum MH + (found) = 422.19, MH + (calculated) = 422.19. [a] D20 +51.3 (c = 0.9, 1: 1 H20 / MeCN) P.f. 183-185 ° C Circular dichroism:? Má? 250.2nm (? E -1.34M "1cpf1)? Max285.4nm (? E +0. Sm ^ c '1), (MeCN / H20) Elemental analysis: Found C, 47.4; H, 6.4; N, 14.3; S, 6.5; Cl, 7.8; water, 4.9% (C? 9H27Cl N504S.HC1.1.3H20 requires C, 47.4; H, 6.4; N, 14.6; S, 6.7; Cl , 7.4, water, 4.9%).

Example 76 (alternative preparation) A mixture of Intermediate 46 (1.056g), cyclopropylamine (0.73ml) and potassium iodide (481mg) in acetonitrile (25ml) was stirred for 3 hours. The solvent was evaporated in vacuo and the mixture was partitioned between saturated sodium bicarbonate solution (20 ml) and dichloromethane (20 ml). The phases separated. The aqueous phase was further extracted with dichloromethane (2x20ml). The combined organic products were dried (MgSO4), they were filtered and the solvent removed in va cuo left an oil. The oil was purified by flash column chromatography (Merck 9385 silica) and eluted with 200: 8: 1 dichloromethane: ethanol: 0.880 ammonia. The fractions containing the required product were combined and evaporated to give a white solid (924mg) which was dissolved in dichloromethane (10ml) and treated with 1.0M of hydrogen chloride in diethyl ether (10ml) to give the title compound (single enantiomer) as a white solid (l.OOg).

Example 77 3S, 3aS, 6aR) -3- Isopropyl 1-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole hydrochloride 2-one Intermediate 56 (32.2g) was added rapidly to a stirred solution of 1-hydroxybenzotriazole (13. Og) in acetonitrile (350ml). A solution of (3S, 3aS, 6aR) -3-isopropy1-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one (Intermediary 122 of International Patent Application WO97 / 36903) (21.7g) and 1- (3-dimethylaminopro-yl) -3-ethylcarbodiimide hydrochloride (37.Og) in acetonitrile (70ml) was then added and the reaction mixture was stirred for 20h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (900ml) and 1. OM sodium carbonate solution (600ml). The aqueous phase was separated and extracted with dichloromethane (150ml). The combined organic substances were washed with brine (250ml), dried (MgSO 4) and concentrated in vacuo to leave a brown solid. The solid was purified by flash column chromatography (Merck silica 9385; dichloromethane: ethanol: ammonia 150: 8: 1 to 135: 8: 1 eluent) to give a cream solid (29.3g). The solid was dissolved in dichloromethane (150ml) and treated with 1. OM hydrogen chloride in ether (75ml). The solvent was removed in vacuo to leave a solid which was dissolved again in dichloromethane (150 ml) and treated with 1. OM hydrogen chloride in ether (75 ml). The solvent is 136 stirring in vacuo to leave a solid which was recrystallized from acetone to give the title compound (26.3g) as a white solid. Melting point 156-158 ° C. C.c.d. (silica, dichloromethane: ethanol: ammonia 100: 8: 1, double elution) Rf = 0.66. 1 H NMR (400 MHz, D-6 DMSO): d 8.78 (s, lH), 4.68 (s, 2H), 4.13 (ddd, J = ll, ll, 7 Hz, 1H), 4.08 (dd, J = ll , 10 Hz, 1H), 3.d0 (ddd, J = 12, 10.5, 5.5 Hz, 1H), 3.60 (m, 2H), 3.55 (dd, J = 12.10.5 Hz, 1H), 3.31 (s, 3H), 3.20 (, 2H), 3.03 (dd, J = 12.2.5 Hz, 1H), 2.88 (md, J = 2.5 Hz, 1H), 2.34 (m, 1H), 2.12 (m, 1H), 1.96 (m, 4H), 1.19 (d, J = 7 Hz, 3H), 0.98 (d, J = 7 Hz, 3H). Contains 0.16 Mol. % acetone. Infrared (diffuse reflectance of KBr) 3633, 3474, 3149, 3102, 2956, 2882, 2668, 2576, 2475, 1747, 1709, 1639, 1634, 1567, 1442, 1380, 1347, 1161, 1146, 967, 810, 547 cm "1. Mass spectrum MH + (found) = 425.186372. MH + (calculated) = 425.185867 (error 1.2 ppm) Combustion analysis Found: C, 48.65; H, 6.39; N, 11.41; S, 6.19; Cl 7.13 % C, 9H28N4O5S.HC1.0.75H2O.0.2Me2CO required: C, 48.43; H, 6.57; N, 11.53; S, 6.60; Cl, 7.29%.

Example 78: Rehydrochloride (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl) -hexahydro-pyrrolo [3, 2-b ] pyrrol-2-one (1: 2) A stirred suspension of Intermediary 56 (second preparation: 40mg), in dichloromethane (4ml) was treated with oxalyl chloride (63mg) followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1.5 h. The solvent was removed in vacuo and replaced with toluene (10 ml). The resulting suspension was vigorously ground for 10 min. The toluene was removed in vacuo to leave a gum which was suspended in dichloromethane (5 ml) and treated with Intermediate 10 (20 mg) and sodium bicarbonate (35 mg). The reaction mixture was stirred for 3.75 h., Then it was partitioned between dichloromethane (2xl0ml) and water (5ml). The combined organics were dried (Na2SO) and concentrated in vacuo to leave a solid. The solid was triturated in ether (4ml) for 10 min. The ether decanted. The residue was dried in vacuo to leave a white powder. The powder was treated with 1.0M of hydrogen chloride in diethyl ether to give the title compound as a cream powder (17mg). Melting point 116-120 ° C.

Mass spectrum MH "(found) = 425 MH + (calculated) = 425.

The following Examples 79-81 were prepared in a manner similar to Example 78 from Intermediary 10 and Intermediates 57-59 respectively: Example 79: RI- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-piperidin-1-ylmethyl-oxazol-4-carbonyl) -hexahydro-pyrrolo [3, 2-b] hydrochloride ] pyrrole -2 -one White powder, melting point 140-143 ° C. Mass spectrum MH + (found) = 439. MH + (calculated) = 439.

Example 80: Lacyl hydrochloride (3S, 3aS, 6aR) -3-iso? Ropil-l-methanesulfonyl-4- [2- (4-phenyl-pipe razi nl -ylmethyl) -oxazole-4-carbonyl] -hexahydro -pyrrolo [3, 2-b] pyrro 1-2 -one Solid cream, melting point 156-160 ° C. Mass spectrum MH + (found) = 516. MH + (calculated) = 516.

EXAMPLE 81 ReI- (3S, 3aS, 6aR) -4- (2-dibutylaminomethyl-oxazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrole-2-hydrochloride. ona White powder, melting point 122-126 ° C. Mass spectrum MH + (found) = 483. MH + (calculated) = 483.

Example 82: Rehydrochloride (3S, 3aS, 6aR) -4-. { 2- [(cyclopropyl-methyl-amino) -methyl] -oxazole-4-carbonyl} -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3, 2-b]? Irrol-2-one A solution of Intermediate 51 (21mg) in dioxane (1.5ml) and 1. OM sodium hydroxide (0.4ml) ) was stirred for 3.5h. Hydrochloric acid (0.35ml) was added with stirring. The solvents were removed in va cuo. The residue was triturated in dioxane (3ml) for 5 min. The solvent was removed in vacuo. The trituration was repeated using more dioxane (3ml). The solvent was removed in vacuo and the residue was dried under vacuum to give a solid. A stirred suspension of this solid in dichloromethane (3ml) was treated with oxalyl chloride (50mg) followed by dimethylformamide (1 drop). The reaction mixture was stirred for 1 hour. The solvent was removed in vacuo and the residue triturated vigorously in a mixture (1: 1) of dichloromethane and toluene (10 ml) for 5 min. The solvents were removed in vacuo to leave a gum which was suspended in dichloromethane (5 ml) and treated with Intermediate 10 (18 mg) and sodium bicarbonate (35 mg). The reaction mixture was stirred for 0.75 h, left at room temperature for 3 days, diluted with dichloromethane (10 ml) and washed with water (10 ml). The organic phase was dried (Na 2 SO 4) and concentrated in vacuo to leave a gum. The gum was purified by flash column chromatography (silica Merck 9385; eluant dichloromethane: ethanol: ammonia 150: 8: 1) to give a white powder. The powder was treated with 1. OM hydrogen chloride in diethyl ether to give the title compound as a white powder (7mg). Melting point 116-119 ° C. Mass spectrum MH + (found) = 425. MH + (calculated) = 425.

The following Example 83 was prepared in a manner similar to Example 82 from Intermediary 10 and Intermediary 52: Example 83: Rehydrochloride (3S, 3aS, 6aR) -4-. { 2- [(dicyclohexyl-amino) -methyl] -oxazole-4-carbonyl} -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one White powder, mp 130-133 ° C. Mass spectrum MH + (found) = 535. MH + (calculated) = 535.

Biological Data 1. The compounds of Examples 1-83 were tested in the in vitro elastase test described at the beginning of the description. The IC50 values are given in the following table: Example IC50 (μM) Example IC50 (μM) 1 0 .123 39 0 .021 2 0 .081 40 0 .030 3 0 .164 41 0 .014 4 0 .065 42 0 .057 5 0 .039 43 0 .051 6 0 .071 44 0 .099 7 0 .082 45 0 .019 8 0 .086 46 0 .014 9 0 .129 47 0 .024 0 .114 48 0 .030 11 0 .139 49 0 .051 12 0, .104 50 0. .054 13 0, .032 51 0 .021 14 0, .021 52 0, .012 15 0, .021 53 0. .015 16 0. .019 54 0, .011 17 0, .068 55 0. .020 18 0. .022 56 0, .038 19 0. .057 57 0., 041 20 0. .013 58 0. .045 21 0., 029 59 0. .028 22 0., 043 60 0. .037 23 0., 026 61 0. 030 24 0., 024 62 0. 041 25 0. 009 63 0. 025 26 0. 017 64 0. 048 27 0. 008 65 0. 013 28 0. 011 66 0. 076 29 0. 014 67 0. 019 30 0. 017 68 0. 087 31 0. 016 69 0. 022 32 0. 009 70 0. 013 33 0. 005 71 0. 050 34 0. 013 72 0. 012 35 0. 056 73 0. 074 36 0. 013 74 0. 012 37 0. 017 75 0. 093 38 0. 014 76 0. 011 Example IC50 (μM) 77 0.010 78 0.014 79 0.016 80 0.100 81 0.076 62 0.084 83 0.137 2. The compounds of Examples 1, 2, 11, 12, 13, 15, 16, 17, 27, 28, 29, 31, 33, 34, 35, 37-50, 56, 57, 59, 60, 62-69 , 72, 73, 76, 78, 80 and 81 were tested in an in vivo test with hamsters described above at an effective dose of less than 10mg / kg, and giving a duration of effect at least 6 hours. 3. The compounds of Examples 1 to 83 were tested in the fully human blood elastase inhibition assay described at the beginning in the description. The IC 50 values are given in the following table.

Example ICso (μM) Example ICso (μM) 1 0.355 41 1.76 2 1,882 42 0.43 3 2,195 43 0.429 4 4.185 44 0.52d 3 45 0.518 6 4.015 46 0.524 7 3.04 47 1.043 8 3.46 48 0.414 9 3.615 49 0.539 ,555 50 1.92 11 1.16 51 > 10 12 2.4 52 7.637 13 1.103 53 8.23 14 1,885 54 4,205 0.452 55 > 10 16 0.774 56 0.293 17 0.316 57 0.193 18 2.925 58 2.44 18 0.408 59 0.394 6.405 60 0.605 21 0.317 61 5.898 22 0.453 62 0.252 23 0.364 63 1.62 24 0.306 64 0.521 1.64 65 0.333 26 > 10 66 0.217 26 0.704 67 0.876 28 1.125 68 0.221 29 0.311 69 0.264 1,683 70 3,215 31 0.896 71 0.205 32 0.427 72 0.322 33 0.257 73 0.282 34 0.546 74 0.205 0.81 75 5.025 36 0.296 76 0.139 37 1,187 77 0.245 38 0.224 78 0.411 39 0.358 79 0.502 40 0.222 60 0.4 Example IC50 (μM) 81 0.296 82 0.717 83 0.55 It is noted that in relation to this date, the best method known to the applicant for carrying out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (32)

1. A compound of the formula (I) (indicated relative stereochemistry) characterized in that: R1 represents alkyl of 1 to 6 carbon atoms; R2 represents alkyl of 2 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; X represents CO or S02; Het represents an optionally substituted monocyclic or bicyclic aromatic ring system of 5 to 10 elements, containing 1 to 4 heteroatoms selected from 0, N and S; n represents an integer from 0 to 4; R3 and R4 independently represent hydrogen, alkyl of 1 to 8 carbon atoms, - (CH2)? -4CONR5R6, COC? -alkyl or (CH2) or-2Fen wherein Fen represents phenyl optionally substituted by one or more alkyl groups of 1 to 4 carbon atoms or halogen or NR3R4 groups together represent azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl optionally N-substituted by alkyl of 1 to 6 carbon atoms, phenyl (optionally substituted by halogen or alkyl of 1 to 4 atoms) carbon) or benzyl (optionally substituted on the benzene ring by halogen or alkyl of 1 to 4 carbon atoms) or NR3R4 together represent a ring as described so far except that it is substituted on the carbon by one or more alkyl groups from 1 to 4 carbon atoms, CONR5R6 or COOR6. R5 and R6 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and salts and solvates thereof. •

2. A compound of the formula (I) according to claim 1, characterized in that Het represents a monocyclic aromatic ring with 5-6 elements containing 1 6 2 heteroatoms selected from O, N and S.

3. A compound of the formula (I) according to claim 2, characterized in that Het represents thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl.

4. A compound of the formula (I) according to claim 2, characterized in that Het represents pyridin-3-yl.

5. A compound of the formula (I) according to claim 2, characterized in that Het represents oxazolyl.

6. A compound of the formula (I) according to claim 1, 2 6 5, characterized in that it is a compound of the formula (IA) (indicated relative stereochemistry) 7.

A compound of the formula (I) according to any of the preceding claims, characterized in that it represents isopropyl propyl.

6. A compound of the formula (I) according to any of the preceding claims, characterized in that R 2 represents isopropyl.

9. A compound of the formula (I) according to any of the preceding claims, characterized in that R 1 represents methyl or ethyl.

10. A compound of the formula (I) according to claim 9, characterized in that R 1 represents methyl.

11. A compound of the formula (I) according to any of the preceding claims, characterized in that X represents CO.

12. A compound of the formula (I) according to any of the preceding claims, characterized in that n represents 1 to 3.

13. A compound of the formula (I) according to any of the preceding claims, characterized in that R3 and R4 independently represent hydrogen or alkyl of 1 to 8 carbon atoms or NR3R4 represent pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted in N by alkyl from 1 to 8 carbon atoms or phenyl (optionally substituted by halogen or alkyl of 1 to 4 carbon atoms).

14. A compound of the formula (I) according to claim 1, characterized in that it is rel- (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-furan-2) -carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-orpholin-4-ylmethyl-furan-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) -furan-2-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one '; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -furan-2-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopro-yl-l-methanesulfonyl-4- (2-orpholin-4-ylmethyl-furan-3-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrol- 2-one; (3R, 3aR, 6aS) -4- (2-dimethylaminomethyl-furan-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethyl-furan-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-furan-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [2- (4-phenyl-piperazin-1-ylmethyl) -furan-3-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [2- (4-methyl-piperazin-1-ylmethyl) -furan-3-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (5-Dimethylaminomethyl-thiophene-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-piperidin-1-ylmethyl-thiophene-2-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrole-2 ona; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (5-morpholin-4-ylmethyl-lH-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrol- 2-one; (3S, 3aS, 6aR) -4- (5-Dimethylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol- 2-one; (3S, 3aS, 6aR) -3-isopropyl-l-metansuJ "fonyl-4- (5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2-one; re- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) -lH-pyrrole-2-carbonyl] - hexahydro-pyrrolo [3,2-b] pyrrol-2-one; re- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -lH-pyrrole-2-carbonyl] -hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -4- (5-dibutylaminomethyl-lH-pyrrole-2-carbonyl ) -3-isopropyl-l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (5-methylaminomethyl) -lH-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (1-methy1-5-? iperidin-l-ylmethyl-lH-pyrrole-2-carbonyl) -hexahydrp-pyrrolo [3, 2 -b] pyrrol-2-one; (3S, 3aS, 6aR) -3-iso? ropil-l-methanesulfonyl-4- (1-methyl-5-morpholin-4-ylmethyl-lH-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one; (3S, 3aS, 6aR) -4- (5-Dimethylaminomethyl-1-methyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3, 2-b] pyrrol- 2-one; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (1-methyl-5-methylaminomethyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 2-b] 2-one; (3S, 3aS, 6aR) -4- (4-Dimethylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-morpholin-4-ylmethyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrole-2 ona; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-piperidin-1-ylmethyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrole-2- ona; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [2- (4-methyl-piperazin-1-ylmethyl) -thiazole-4-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3S, 3aS, 6aR) -4- (2-Cyclopropylaminomethyl-thiazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydropyrrolo [3,2-b] pyrrol-2-one; reí- (3S, 3aS, 6aR) -4-. { 2- [(4-Fluoro-benzylamino) -methyl] -thiazole-4-carbonyl} -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [2- (4-phenyl-piperazin-1-ylmethyl) -thiazole-4-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3S, 3aS, 6aR) -4- (2-dibutylaminomethyl-thiazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydropyrrolo [3,2-b] pyrrol-2-one; 'reí- (3R, 3aR, 6aS) -3-isopropyl-4-. { 2- [(l-isopropyl-2-methyl-propylamino) -methyl] -thiazole-4-carbonyl} -l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3S, 3aS, 6aR) -4- (2-Dimethylaminomethyl-thiazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydropyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-isoxazole-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3R, 3aR, 6aS) -4- (5-Dimethylaminomethyl-isoxazole-3-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-isoxazole-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-piperidin-1-ylmethyl-isoxazole-3-carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrole-2- ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -isoxazole-3-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; laugh- (3R, 3aR, 6aS) -4-. { 5- [(4-Fluoro-benzylamino) -methyl] -isoxazole-3-carbonyl} -3-isopropy1-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) -isoxazole-3-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (5-dibutylaminomethyl-isoxazole-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-1-methyl-1H-pyrazo-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2- b] pyrrol- 2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (1-methy1-5-morpholin-4-ylmethyl-1H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (1-methyl-5-piperidin-1-ylmethyl-1H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2] b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [1-methyl-5- (4-methyl-piperidin-1-ylmethyl) -lH-? irazol-3-carbonyl) -hexahydro -pyrrolo [3, 2-b] -pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [2-methyl-5- (4-phenyl-piperazin-1-ylmethyl) -lH-pyrazole-3-carbonyl] -hexahydro- pyrrolo [3, 2-b] pyrro1-2-one; (3R, 3aR, 6aS) -4- (5-Dimethylaminomethyl-2-methyl-2H-pyrazole-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2- b] pyrrol- 2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (2-methyl-5-pyrrolidin-1-ylmethyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (2-methyl-5-morpholin-4-ylmethyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (2-methyl-5-piperidin-1-ylmethyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [2-methyl-5- (4-methyl-piperazin-1-ylmethyl) -2H-pyrazole-3-carbonyl] -hexahydro- pyrrolo [3, 2-b] pyrrol-2-one; laugh- (3R, 3aR, 6aS) -4-. { 6- [(dicyclohexylamino) -methyl] -pyridine-3-carbonyl} -3-isopropy1-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (6-dibutylaminomethyl-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl- (6-morpholin-4-ylmethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (6-cyclopropylaminomethyl-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (6-piperidin-l-ylmethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrole-2 ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [6- (4-methyl-piperazin-1-ylmethyl) -pyridine-3-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; RI- (3R, 3aR, 6aS) -3-isopropyl-4-. { 6- [(1-isopropy1-2-methyl-1-propylamino) -methyl] -pyridine-3-carbonyl} -l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (6-Dimethylaminomethyl-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; laugh- (3R, 3aR, 6aS) -4-. { 6- [(4-Fluoro-benzylamino) -methyl] -pyridine-3-carbonyl} -3-isopropy1-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -4- (5-cyclopropylaminomethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; rel- (3R, 3aR, 6aS) -4- (5-dibutylaminomyl-pyrazin-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-morpholin-4-ylmethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrole-2 ona; laugh- (3R, 3aR, 6aS) -4-. { 5- [(-dicyclohexylamino) -methyl] -pyrazine-2-carbonyl} -3-isopropy1-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-piperidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrole-2 ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -pyrazine-2-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; RI- (3R, 3aR, 6aS) -3-isopropyl-4-. { 5- [(1-isopropy1-2-methyl-propylamino) -methyl] -pyrazine-2-carbonyl} -l-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-pyrazine-2-carbonyl) 3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- [5- (4-phenyl-piperazin-1-ylmethyl) -pyrazine-2-carbonyl] -hexahydro-pyrrolo [3, 2- b] pyrrol-2-one; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3,2- b] pyrrole-2 ona; (3R, 3aR, 6aS) -3-isopropyl-l-methanesulfonyl-4- (5-methylaminomethyl-pyrazine-2-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrol-2-one; or a salt or solvate of any of these.

15. A compound of the formula (I) according to claim 1, characterized in that it is (3S, 3aS, 6aR) -4- (5-cyclopropylaminomethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-1-hexahydro- pyrrolo [3, 2-b] pyrrol-2-one or a salt or solvate thereof.

16. A compound of the formula (I) according to claim 1, characterized in that it is rel- (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4) -carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-piperidin-l-ylmethyl-oxazole-4-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrole -2 -one; (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- [2- (4-f-enyl-piperazin-1-ylmethyl) -oxazole -carbonyl] -hexahydro-pyrrolo [3, 2 -b] pyrrol-2-one; (3S, 3aS, 6aR) -4- (2-dibutylaminomethyl-oxazole-4-carbonyl) -3-isopropyl-1-methylsulfonyl-1-hexahydro-pyrrolo [3, 2-b] pyrrole-2 - ona; rel- (3S, 3aS, 6aR) -4-. { 2- [(cyclopropyl-me thi-amino) -methyl] -oxazole-4-carbonyl} -3- isopropyl 1-1-methansulfonyl 1-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; rel- (3S, 3aS, 6aR) -4-. { 2- [(di-ciciohexyl-amino) -methyl] -oxazole-4-carbonyl} -3-isopropyl-1-met ansulf onyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one; or a salt or solvate of any of these.

17. A compound of the formula (I) according to claim 1, characterized in that it is (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl) ) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one or a salt or solvate thereof.

18. A compound of the formula (I) according to claim 1, characterized in that it is (3S, 3aS, 6aR) -3-isopropyl-l-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4 hydrochloride. -carbonyl) -hexahydro-pyrrolo [3, 2-b] pyrrol-2-one.

19. A simple purified enantiomer of a compound of the formula (I) according to any of claims 1 to 14 and 16 having the absolute stereochemistry as illustrated in formula (I).

20. A compound of the formula (I) according to any of claims 1 to 19, characterized in that it is used as a pharmaceutical product.

21. A pharmaceutical composition characterized in that it comprises a compound of the formula (I) according to any of claims 1 to 19, in admixture with one or more diluent or physiologically acceptable carriers.

22. The use of a compound of the formula (I) according to any of claims 1 to 19 for the manufacture or production of a medicament for the treatment of chronic bronchitis or chronic obstructive pulmonary disease.

23. A method of treating chronic bronchitis or chronic obstructive pulmonary disease in a human or animal subject, characterized in that it comprises administering to the human or animal subject an effective amount of a compound of the formula (I) according to any of claims 1 to 19 .

24. The use of a compound of the formula (I) according to any of claims 1 to 19, in the manufacture or production of a medicament for the treatment of asthma.

25. A method of treating asthma in a human or animal subject characterized in that it comprises administering to the human or animal subject an effective amount of a compound of the formula (I) according to any of claims 1 to 19.

26. A process for preparing a compound of the formula (I) as defined in claim 1, characterized in that it comprises: (i) condensation of a compound of the formula (II): (relative stereochemistry indicated) with a compound R4R3N (CH2) nHetCOOH or an acid derivative thereof such as an acid chloride, activated ester, acid anhydride, or a mixed anhydride or with a compound R4R3N (CH2) nHetXY, wherein y is a reactive group such as halogen , for example, chlorine, or a protected derivative thereof; or (ii) sulfonylation of a compound of the formula (III): (indicated relative stereochemistry) or a protected derivative thereof with a compound Y02SRx wherein Y is a reactive group such as halogen, for example, chloro; or (iii) cyclizing a compound of the formula (IV): (relative stereochemistry indicated) or a carboxylic acid ester thereof; or (iv) oxidation of a corresponding compound of the formula (V) R1 (Relative stereochemistry indicated) where Xa is sulfur or SO; or (v) reaction of a corresponding compound of the formula (VI) (Relative stereochemistry indicated) wherein L is a separation group with a compound of the formula R 4 R 3 NH; or (vi) preparation of a compound of the formula I in which n represents an integer from 1 to 4 by reduction of the reaction product of a corresponding compound of the formula (VII) (Relative stereochemistry indicated) with a compound of the formula RR3NH; or (vi) preparation of a compound of the formula I in which n represents 1 by reaction of a corresponding compound of the formula (VIII) (indicated relative stereochemistry) with formaldehyde or paraformaldehyde together with a compound of the formula R4R3NH under acidic conditions; or (viii) deprotection of a compound of the formula (I) which is protected; or (ix) purifying an enantiomer of the compound of the formula (I) from a mixture of enantiomers; and wherein it is desired or necessary to convert a resulting free base compound of formula I into a physiologically acceptable salt form or vice versa or to convert one salt form into another physiologically acceptable salt form.

27. A compound of the formula (III, ' (indicated relative stereochemistry) characterized in that R2, R3, R4, n, Het and X are as defined in claim 1 or a protected derivative thereof.

28. A compound of the formula (IV) (indicated relative stereochemistry) characterized in that R1, R2, R3, R4, n, Het and X are as defined in claim 1 or a carboxylic acid ester thereof.

29. A compound of the formula (V) (indicated relative stereochemistry) characterized in that R1, R2, R3, R4, n, Het and X are as defined in claim 1 and Xa represents sulfur or SO.

30. A compound of the formula (VI) (indicated relative stereochemistry) characterized in that R1, R2, n, Het and X are as defined in claim 1 and L represents a separation group.

31. A compound of the formula (VII) (indicated relative stereochemistry) characterized in that R1, R2, Het and X are as defined in claim 1 and n represents an integer from 1 to 4.

32. A compound of the formula (VIII) Het-X H R2 (VIII) N i SO, R ' (indicated relative stereochemistry) characterized in that R1, R2, X - and Het are as defined in claim 1.