MXPA00005890A - Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors - Google Patents

Abstract

Compounds represented by formulae (I, II or III), wherein U is CH, O, or S;Z is -C(R2)(R3), -CH-N(R2)(R3), C(R3)[(CH2)nR2], CH-C(R3)(R8)(CH2)nR2, C[(CH2)nR2]-[CH(R3)(R8)], C[(R3)][CH[(CH2)nR2](R8)];R1 is H, (CH2)nOH, (CH2)nNH2, (CH2)nNR10R11, (CH2)nOR11, (CH2)nSR11, or (CH2)n halogen;R9 is (CH2)nCO2H, (CH2)nSO3H, (CH2)nPO3H2, (CH2)nNO2, CH(SCH3)3, esters thereof, or salts thereof.

Description

I CYCLOPENTAN AND CYCLOPENTENE COMPONENTS SUBSTITUTED THAT ARE USEFUL AS INHIBITORS OF NEURAMINIDASE Technical field This invention relates to novel cyclopentane and substituted cyclopentene compounds and derivatives thereof which are useful as inhibitors of neuraminidase, with pharmaceutical compositions containing said compounds useful for the prevention, treatment or amelioration of viral, bacterial and other infections. and with methods for using said compounds. The present invention also relates to novel intermediates or precursors for the production of the novel substituted cyclopentane and cyclopentene compounds of the present invention.

BACKGROUND OF THE INVENTION Despite the large amount of information available, influenza continues to be a potentially devastating disease for humans, lower mammals and birds. There is no effective vaccine and a cure is not available once the infection started. Influenza viruses consist of eight fragments of single-stranded RNA, packaged neatly within the virion. Each fragment encodes one of the major viral proteins. The replication complex is enclosed in a membrane formed by a matrix protein associated with a lipid bilayer. Two peaks of surface glycoproteins, hemagglutinin (HA) and the enzyme neuraminidase (NA) are embedded in said lipid bilayer. All the viral genes have been cloned and the three-dimensional structures of the surface glycoproteins have been determined. Influenza viruses continually suffer from antigenic variations in the two surface antigens, HA and NA, to which the neutralizing antibodies are directed. For this reason, the vaccines and the natural immune system of the subject have not been very effective. Currently attention is directed to the discovery of other potential antiviral agents that act in other sites of the virion. This invention is directed to new compounds that are useful in the inhibition of the NA viral surface enzyme. In addition, many other organisms also carry NA. Many of these NA organisms are also important pathogens for man and / or mammals, including Vibraeo cholerae, Clostridium perfringes, Streptococcus pneumonia, Arthrobacter sialophilas and other viruses, such as parainfluenza virus, mumps virus, the Newcastle disease virus, the bird pest virus and the Sendai virus. The compounds of this invention are also directed to the inhibition of the NA of these organisms. In the virus, NA exists as a tetramer consisting of four approximately spherical subunits and a centrally attached stem that contains a hydrophobic region through which it is imbedded in the body's membrane. Various roles for NA have been suggested. The enzyme catalyzes the cleavage of the α-ketosid bond between the terminal sialic acid and the adjacent sugar residue. The elimination of the sialic acid decreases the viscosity and allows the access of the virus to the epithelial cells. NA also destroys the HA receptor in the host cell, thereby allowing elution of the progeny of viral particles from the infected cells. Research indicates that the active site of influenza neuraminidase remains substantially unchanged in most influenza strains. For example, a sequence comparison of influenza A and B subtypes shows conserved residues with crucial structures and functional roles. Although the sequence homology is only about 30%, many of the catalytic residues are conserved. In addition, the three-dimensional structures of the neuraminidases of influenza A and B were determined. The superposition of the different structures shows a remarkable structural similarity of the active sites. Since the amino acids of the active site are conserved in all the influenza A neuraminidases sequenced so far, an inhibitor can be designed that is effective against the neuraminidase of the different strains of influenza A and / or B on the basis of the three-dimensional structure of neuraminidase. In general, it is believed that the role of NA is for the mobility of viruses both to and from the site of the infections. The compounds inhibiting the activity of neuraminidase can protect a subject from infection and / or cure said subject once the infection started. A further objective of this invention is to provide a method for using the compounds of this invention in the treatment and / or cure of a viral infection. It is known that neuramnoic acid analogs, such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives inhibit HA in vitro; however, these compounds are inactive in vivo. Palese and Schulman, IN CHEMOPROPHYLAXIX AND VIRUS INFECTIONS OF THE UPPER RESPIRATORY TRACT, Vol. 1 (J.S. Oxford, Ed.), CRC Press, 1977, p. 189-205. Von Itzstein et al., Describe cyclohexane analogs of the -D-neuraminic acid having the following formula & 004 where: A is O, C or S in formula (a) and N or C in formula (b); R1 is CO2H, PO3H2, NO2, SO2H, SO3H, tetrazolyl, CH2CHO, CHO or CH (CHO) 2; R2 - is H, OR6, F, Cl, Br, CN, NHR6, SR6 or CH2X, where X is halogen NHR6 or OR6; R3 and R3 'are H, CN, NHR5, SR6, = NOR6, OR6, guanidino, NR5; R4 is NHR6, SR6, OR6, C02R6, N02, C (R6) 3, CH2C02R6, CH2N02 or CH2NHR6; R5 is CH2YR6, CHYR6CH2YR6 or CHYR6CHYR6CH2YR6; R6 is H, acyl, alkyl, allyl or aryl; And it is O. S, NH or H; and salts for pharmaceutical use thereof, which are useful as antiviral agents.In addition, in U.S. Pat. Ns: 5,453,533 benzene derivatives are suggested as inhibitors of influenza virus neuraminidase and in U.S. Pat. NQ: 5,602,277 others are described. Yamamoto et al. describe various sialic acid isomers with inhibitory activity against neuraminidase in Synthesis of Sialic Acid Isomers With Inhibitory Activity Against Neuraminidase, Tertrahedron Letters, Vol. 33, No. 39, pgs. 5791-5794, 1992. In WO 96/26933 of Gilead Sciences, Inc., various 6-membered ring compounds are disclosed as possible inhibitors of neuraminidase. However, none of these references describe the cyclopentane and cyclopentene derivatives of the present invention.

SUMMARY OF THE INVENTION One aspect of the present invention is directed to compounds represented by the following formulas: & 005-1 where U is CH, O or S; Z is -C (R2) (R3), -CH-N (R2) (R3), C (R3) [(CH2) nR2], CH-C (R3) (R8) (CH2) nR2, C [( CH2) nR2] - [CH (R3) (R8)], C [(R3)] [CH [(CH2) nR2] (R8)]; R1 is H, (CH2) nOH, (CH2) nNH2) (CH2) nNR10R11, (CH2) nOR11, (CH2) nSR1 \ or (CH2) n halogen R9 is (CH2) nC02H, (CH2) nS03H, (CH2) nP03H2, (CH2) nN02, CH (SCH3) 3, esters thereof or salts thereof, or R1, R9 represent together = 0, or & 005-2 R2 is H, NHC (0) R5, NHC (S) R5, NHS02R5, C (0) NHR5, S02NHR5, CH2S (O) R5 or CH2S02R5 R and Rb are individually H, (CH2) nC (0) R 1? 0 ?, (CH2) nC02R) 10 (CH2) mOR10, CH (OR10) CH (R10) m, C (O) N (R10) m, C (O) N (OR10) R10 (CH2) nN (R10) m, CH (R10) m, (CH2) n (R10) m, CH2CH (OR10) CH2OR10 CH (OR, 1? 0?) 'CH (OR ??) CH2OR > 10 CH2OR 1 T0U CH (OR1,0u) CH2NHR 10 CH2CH (OR10) CH2NHR10, CH (OR10) CH (OR 0) CH2NHR10) C (= NR10) N (R10) m NHR10, NHC (= NR10) N (R10) m, (CH2) mXWY, CH2CH (XWY) CH2OR10"CH (XWY) CH (OR10) CH2OR10, CH (XWY) CH2 (OR10), CH (OR10) CH (XW- Y) CH2OR10, CH (OR10) CH2 (XWY), CH2CH (XWY) CH2NHR10, CH (X »WY) CH (OR10) CH2NHR10, CH (XWY) CH2 (NHR10), CH (OR10) CH (XW-Y) CH2NHR10 or CH (-NHR10) CH2 (XWY); with the proviso that at least one of R-2% D R 3, y, r R > 8a is different from H; R4 is H, (CH2) nOH, (CH2) nOR 11 (CH2) nOC (O) R (CH2) nNHC (NR11) NHR11, (CH2) nNR10R11, (CH2) nNH2, (CH2) nC (= NH) (NH2), (CH2) nNHC (= NR11) NH2, (CH2) nNHC (= NR7) NH2 , (CH2) nCN, (CH2) nN3 > C (= NH) NH2 < C (NR7) NH2, or C (NR11) NH2; R5 is H, lower alkyl, cycloalkyl, alkyl substituted with halogen, aryl, substituted aryl or CF3; R7 is H, (CH ^ nOH, (CH ^ CN, (CH2) nNH2 or (CH2) nNO2, R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, aromatic (CH2) n, aromatic substituted with ( CH2) no, when m is 2, both R10 groups can also be interconnected to form a N-substituted heterocyclic ring or other 5- or 6-membered heterocyclic rings, R11 is lower alkyl, branched alkyl, aromatic (CH2) m, S02R1 °, C (O) R10 or C (O) OR10; R12 and R13 is H, (CH2) nOH, (CH2) nNH2, (CH2) nNR10R11, (CH2) nOR1 \ (CH2) nF, (CH2) nOC (0) R11, (CH2) nNHC (0) R11 or XWY, m is 1 or 2, n is 0-4, p is 0 or 1, X is O, S, CH2 or NH, - -W is a spacer group formed by a chain of 1 to 100 atoms and also optionally comprising substituted carbon and / or nitrogen atoms and optionally including oxygen or sulfur atoms, and 'Y is H, OH, SH, NH2, CH = 0, CH = CH2l CO2H , CONHNH2 or a protected form of one of these terminal functionalities, acceptable salts for fa of the same. The present invention is also related to compositions for inhibiting influenza virus neuraminidase comprising a vehicle acceptable for pharmaceutical use and an effective amount for inhibiting influenza virus neuraminidase from one of the compounds defined above. Another aspect of the present invention comprises a method for inhibiting influenza virus comprising administering to a patient in need thereof one of the compounds defined above in an amount effective to inhibit influenza virus neuraminidase. Yet another aspect of the present invention relates to the treatment of an influenza virus infection comprising administering to a patient in need thereof one of the compounds defined above in an amount effective to inhibit the neuraminidase of the influenza virus. influenza. Another aspect of the present invention relates to intermediaries represented by the following formulas: &; 008-1 where R4 and R9 are as defined above; and &008-2 where R14 is individually H, O, (CH2) nC02H, (CH2) nSO3H, (CH2) nPO3H2, (OH2) nNO2, CH (SCH3) 3, &008-3"'esters of the same or salts thereof and with the proviso that • at least one of R14 is H and R3 and R4 are as defined above.

Diverse and better modes for carrying out the invention One aspect of the present invention relates to compounds represented by the formulas: &009-1 where U is CH, O or S; Z is -C (R2) (R3), -CH-N (R2) (R3), C (R3) [(CH2) nR2], CH-C (R3) (R8) (CH2) nR2J C [(CH2 ) nR2] - [CH (R3) (R8)] > C [(R3)] [CH [(CH2) nR2] (R8)]; R1 is H, (CH2) nOH, (CH2) nNH2) (CH2) nNR10R1 \ (CH2) nOR11, (CH2) nSR11, or (CH2) n halogen R9 is (CH2) nC02H, (CH2) nS03H, (CH2) nP03H2 > (CH2) nN02, CH (SCH3) 3, esters thereof or salts thereof, or R1, R9 represent together = 0, or &009-2 R2 is H, NHC (0) R5, NHC (S) R5, NHS02R5, C (0) NHR5, SO2NHR5, CH2S (O) R5 or CH2SO2R5 R3 and R8 are individually H, (CH2) nC (0) R1, (CH2) nC02R10 < CH2) mOR10, CH (OR10) CH (R10) m, C (O) N (R10) m) C (O) N (OR10) R10 (CH2) nN (R10) m, CH (R10) m, (CH2) n (R10) m > CH2CH (OR1Q) CH2OR10 CH (OR10) CH (OR10) CH2OR10, CH2OR10, CH (OR10) CH2NHR10 CH2CH (OR10) CH2NHR10, CH (OR10) CH (OR10) CH2NHR10, C (= NR10) N (R10) m NHR10, NHC (= NR10) N (R10) m, (CH2) mXWY, CH2CH (XWY) CH2OR10, CH (X- WY) CH (OR) CH2OR > 1l0u, CH (X-W-Y) CH2 (OR 1? 0?), CH (OR ??) CH (X-W) Y) CH2ORA CH (OR> 1? 0?) - CH2 (XWY), CH2CH (XWY) CH2NHR 1p0 ?, CH (XW- Y) CH (OR10) CH2NHR10, CH (XWY) CH2 (NHR10), CH ( OR10) CH (XW- Y) CH2NHR10 or CH (NHR10) CH2 (XWY); with the proviso that at least one of R2, R3, and R8 is different from H; R4 is H, (CH2) nOH, (CH2) nOR11, (CH2) nOC (0) R11, (CH2) nNHC (NR11) NHR11, (CH2) nNR10R11, (CH2) nNH2, (CH2) nC (= NH) (NH2), (CH2) nNHC (= NR11) NH2, (CH2) nNHC (= NR7) NH2, (CH2) nCN, (CH2) nN3, C (= NH) NH2) C (NR7) NH2 or C (NR11 ) NH2; R5 is H, lower alkyl, cycloalkyl, alkyl substituted with halogen, aryl, substituted aryl or CF3; R7 is H, (CH2) nOH, (CH2) nCN, (CH2) nNH2 or (CH2) nN02; R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, aromatic (CH2) n, aromatic substituted with (CH2) no, when m is 2, both groups R10 may also be interconnected to form a N-substituted heterocyclic ring or other 5 or 6 membered heterocyclic rings; R11 is lower alkyl, branched alkyl, aromatic (CH2) m, SO2R10, C (0) R10 or C (0) OR10; R12 and R13 is H, (CH2) nOH, (CH2) nNH2, (CH2) nNR10R11, (CH2) nOR11, (CH2) nF, (CH2) nOC (O) R11, (CH2) nNHC (O) R11 or XWY; m is 1 or 2; n is 0-4; "p is '0 or 1; •' 'X is O, S, CH2 or NH;' - W is a spacer group formed by a chain of 1 to 100 atoms and which also optionally comprises substituted carbon and / or nitrogen atoms and optionally including oxygen or sulfur atoms, and Y is H, OH, SH, NH2) CH = 0, CH = CH2, C02H, CONHNH2 or a protected form of one of these terminal functionalities, and salts acceptable for pharmaceutical use of The present invention also relates to intermediates represented by the following formulas: & 01 1 -1 where R and R are as defined above, and & 01 1-2 where R14 is individually H, O, (CH2) ), CO2H, (CH2) nSO3H, (CH2) nP03H2, (CH2) nNO2, CH (SCH3) 3, &1 1 -3 esters thereof or salts thereof and with the proviso that at least one of R 14 is H, and R 3 and R 4 are as defined above The lower alkyl groups contain about 1 to 8 carbon atoms and preferably 1 to 3 carbon atoms. approximately carbon, and can be straight chain or branched or cyclic saturated aliphatic hydrocarbon groups. Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. Examples of suitable cyclic aliphatic groups typically contain 3-8 carbon atoms and include cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably aromatic groups substituted with phenyl or alkyl (aralkyl), such as phenyl-C? -3-alkyl, such as benzyl or halo substituted aryl groups. Examples of substituted cycloalkyl groups include cyclic aliphatic groups typically containing 3-8 carbon atoms in the substituted ring with alkyl groups typically having 1-6 carbon atoms and / or hydroxy groups. Usually, there are 1 or 2 substituted groups. The esters are typically lower alkyl esters that possess 1 to 12 carbon atoms and, preferably, from 1 to about 3 carbon atoms and arylesters containing from 6 to 14 carbon atoms. The alkylesters may be saturated aliphatic straight-chain, branched-chain or cyclic hydrocarbons. Examples of some alkyl esters are the esters of methyl, ethyl, propyl, isopropyl, t-butyl, cyclopentyl and cyclohexyl. The aryl esters are preferably aromatic esters substituted with phenyl or alkyl (alkaryls) including phenyl substituted phenyl substituted with C? -3-alkyl, such as benzyl.

The lower alkylene group can be a straight chain, branched or cyclic unsaturated hydrocarbon group and contains 2-8 carbon atoms and preferably 2-3 carbon atoms. Examples of alkylene groups are vinyl, 1 -propenyl, allyl, isopropenyl, 2-methyl-2-propenyl and cyclopentenyl. N-heterocyclic rings contain 3-7 atoms in the ring. The heterocyclic rings may be substituted, such as with a lower alkyl group. Examples of suitable heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino. The spacer groups W include, but are not limited to, linear peptides, oligosaccharides, polyols, polyethylene glycol groups, hydrocarbon groups and hydrocarbon groups linked together with oxygen or sulfur atoms or with carbonyl, amide, urea or hydrazide functionalities. The spacer groups W may also comprise combinations of these various groups. The spacer groups may be straight or branched chain.

Protective groups for functionality Y include, but are not limited to, esters of OH, SH, C02H groups, carbamates of NH2 and CONHNH2 groups and acetals of the CH = O group. As used herein, the term "hydrocarbon group" includes saturated and unsaturated hydrocarbon groups, straight or branched chain, including aryl groups and combinations of said groups. Salts acceptable for pharmaceutical use of the compounds of formula (I) include those derived from inorganic and organic acids and bases acceptable for pharmaceutical use. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulfonic. Salts derived from the appropriate bases include alkalines, such as sodium and ammonia. • It should be understood that the compounds of the present invention relate to all optical isomers and stereo-isomers in the various possible atoms of the molecule. Examples of some particular formulas that fall within the scope of this invention are represented by the following: &015 The naming system used in this document for compounds of the following type is as follows: &016 In some cases the Greek letters a and ß were used to show that these groups are trans to each other. This is the case when there are more than two substituents on the cyclopentane ring and only two are fixed. In a fused cyclopent [d] isoxazole system, the numbering is as follows: &017 The examples of some specific intermediates and compounds according to the present application are identified in Examples 2, 3, 4, , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, '88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 111, 112, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and 209. The following schemes illustrate methods for preparing the compounds of the present invention. invention. SCHEME 1 &018 SCHEME 2 &019 SCHEME 3 &020 SCHEME 4 &021 SCHEME 5 &022 SCHEME 6 &023 SCHEME 7 &024 SCHEME 8 &025 SCHEME 9 &026 &027 53, 55, 62, 65, 72, 76, 80, 84: isomer A at C-1 '54, 56-61, 64, 66-71, 73-75, 77-79, 81 -83, 85-87: isomer B in C-1 '63: mixture of isomers A and B in C-1' 44, 49, 50, 51, 52, 58, 59, 60, 61 X = CH3 in the following compounds: 43, 45, 46, 47, 48, 53, 54, 55, 56, 57, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 X = C2H5 in the following compounds: 44, 49, 50 , 51, 52, 58, 59, 60, 61 SCHEME 10 &028 86-93: B isomer in C-1 'SCHEME 11 &029 80, 94, 98, 102: isomer A in C-1 '81-83, 96, 97, 99-101, 103-105: isomer B in Ct SCHEME 12 &030 92, 106-108: isomer B in C-1 'SCHEME 13 &031 SCHEME 14 &032 SCHEME 15 &033 SCHEME 16 &034 SCHEME 17 &035 SCHEME 18 &036 In addition, an important intermediate of the present invention, compounds 125-136, can be prepared by reacting a cyclopentene of formula &037 with the corresponding nitrile oxide (produced from phenyl isocyanate and a nitroalkane in the presence of triethylamine or from chloro-oxime and triethylamine) to produce a cyclopent [d] isoxazole ring system. The product can then be hydrogenated in the presence of PtO2 in an alcohol together with HCl to open the ring and form the corresponding amino compound. A description of a process for preparing the compounds of the present invention can also be found in US Pat. Serial No.9: 60 / 085,252, filed on May 13, 1998, under the title "Preparation of Substituted Cyclopentane and Cyclopentene Compounds and Certain Intermediates," by Chand et al, whose contents are fully incorporated herein by way of reference. The following non-limiting examples are offered to further illustrate the present invention.

Example 1 (+) 4-azidocyclopent-2-en-1 -one (2, Scheme 1) &038 To a solution of sodium azide (2.12 g, 32.6 mmol) in DMF (15 ml) cooled to 0 °. C 4 ~ bromocyclopent-2-en-1-one (1, 3.5 g, 21.7 mmol, prepared by the method of DePuy et al., J. Org. Chem. 29, 3503) was added dropwise with stirring. , 1964) in DMF (5 ml) over a period of 5 min. The reaction mixture was stirred at 0 ° C for 30 min and diluted with ethyl acetate (20 ml). The reaction mixture was washed with water (2 x 20 ml) and saline • (2 x 20 ml), dried (MgSO) and filtered. The filtrate was concentrated under vacuum to give an oily residue. Purification by flash column chromatography (silica gel, 10-15% ethyl acetate in hexane) allowed to obtain 1.9 g (71%) of compound 2, as an oil. 1 H NMR (CDCl 3): d 2.35 (dd, J = 18.6 and 2.4 Hz, 1 H), 2.77 (dd, J = 18.6 and 6.6 Hz, 1 H), 4.67 (dd, J = 4.9 and 2.6 Hz, 1 H), 6.35 (dd, J = 5.6 and 1.5 Hz, 1 H), 7.54 (dd, J = 5.5 and 2.4 Hz, 1 H). • Example 2 (+) 3ß- [1 '-acetylamin-1' -bi (ethoxycarbonyl)] methylene-4 (-azydrocyclopentan-1 -one (3, Scheme 1) &039 To a solution of diethyl acetamide malonate (1.25 g, 5.7 mmol) in ethanol (10 ml) under nitrogen atmosphere was added fresh sodium metal cut (0.03 g, 1.4 mmol). The reaction was stirred at room temperature until all of the sodium metal had dissolved. The reaction mixture was cooled to -40 ° C and a solution of compound 2 (0.7 g, 5.7 mmol) in ethanol (5 ml) was added dropwise. The reaction mixture was stirred at -40 ° C for 30 min and quenched with trifluoroacetic acid (0.1 mL, 1.4 mmol). The solvent25 was removed under vacuum to give the crude compound 3 as a white solid. The solid was dissolved in ethyl acetate and washed with water, dried and concentrated under vacuum and the solid obtained was crystallized from ether / hexane to result in 1.2 g (63%) of compound 3, as a white solid, mp 121-122 ° C. 1 H NMR (CDCl 3): d 1, 26 (t, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.2 Hz, 3 H), 2.05 (s, 3 H) , 2.27 (m, 2 H), 2.54 (dd, J = 18 and 8 Hz, 1 H), 2.78 (dd, J = 18 and 8 Hz, 1 H), 3.26 (m , 1 H), 4.30 (m, 4 H), 4.38 (m, 1 H), 6.78 (br s, 1 H); IR (KBr): 3331, 2981, 2107, 1744, 1605, 1525 cm "1; MS (ES): 341, 2 (100%, M + 1), Analysis: Cale, for C? 4H20N4O6: C: 49, 41; H: 5.92; N: 16.46 Found: C: 49.47; H: 5.95; N: 16.48 Example 3 (+) 3ß- [1 '-acetylamin-1' -bi (ethoxycarbonyl)] methyl-4-tert-butoxycarbonylamin-cyclopentan-1-one (4, Scheme 1) &040 A mixture of compound 3 (0) was hydrogenated. , 5 g, 1.5 mmol), di-tert-butyl dicarbonate (0.39 g, 1.77 mmol) and 10% Pd / C (0.14 g) in ethyl acetate (25 ml) at 45 ° C. psi for 1 h. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to yield crude compound 4. Recrystallization from ether / hexane allowed to obtain 0.28 g (45%) of compound 4, as a white solid, m.p. 135-136 ° C. 1 H NMR (CDCl 3): d 1.27 (m, 6 H), 1.45 (s, 9 H), 2.10 (s, 3 H), 2.33 (m, 2 H), 2.75 (m, 2 H), 3.25 (m, 1 H), 4.14 (m, 1 H), 4.28 (m, 4 H), 4.83 (s, 1 H), 6.98 (s) , 1 HOUR); IR (KBr) 3365, 2980, 1739, 1689, 1519, 1394, 1275 cm "1; MS (Cl-): 413 (10%, M-1). Analysis: Cale, for C? 9H30N2O8: C: 55, 06; H: 7.30; N: 6.76 Found: C: 54.63; H: 7.17; N: 6.74 Example 4 ( ) 2-. { 3β- [1 '-acetylamino-1' -bi (ethoxycarbonyl)] methyl-4-tert-butoxycarbonyl-amin-1-cyclopentylidene} -1, 3-dithiane (5, Scheme 1) &041 A mixture of 2-trimethylsilyl-1,3-dithiane (7.88 g, 41.5 mmol) in THF (100 ml) at 0 ° C was added. added, by drops and under a nitrogen atmosphere, n-BuLi (1.6 M solution in hexane, 28.6 mL, 45.7 mmol) and stirred at 0 ° C for 45 min. The anion was cooled to -40 ° C and a solution of compound 4 (4.3 g, 10.4 mmol) in THF (50 ml) was added dropwise and the reaction mixture was stirred at -40 ° C for 5 hours. hy was heated to -20 ° C. The reaction was quenched with saturated NH 4 Cl (50 mL) and warmed to room temperature, ether was added and the organic layer was separated. The aqueous layer was extracted with ether (2 x 50 ml). The organic layers were combined, dried (MgSO4) and concentrated. The obtained residue was purified by flash column chromatography (silica gel, 30-35% ethyl acetate in hexane) to yield 3.16 g (59%) of compound 5, as a colorless oil which solidified upon standing, pf 66-68 ° C. 1 H NMR (CDCl 3): d 1, 26 (m, 6 H), 1.44 (s, 9 H), 2.05 (s, 3 H), 2.1 1 (m, 2 H), 2, 22 (m, 2 H), 2.84 (m, 5 H), 2.98 (m, 2 H), 3.77 (m, 1 H), 4.23 (m, 4 H), 4, 85 (d, 1 H), 6.95 (br s, 1 H); IR (KBr): 3388, 2979, 2934, 1743, 1690, 1512, 1368, 1242, 1 169 cm "1; MS (ES +): 517.7 (35%, M + 1). Analysis: Cale, for C23H36N207S2 : C: 53.47; H: 7.02; N: 5.42 Found: C: 53.50; H: 7.07; N: 5.41 Example 5 (+) 2-. { 3β- (1 '-acetylamino-1' -carboxy) methyl-4-tert-butoxycarbonylamino-1-cyclopentylidene} -1, 3-dithiane (6, mixture of isomers in C-1 ', Scheme 1) &042 To a solution of compound 5 (7.5 g, 14.53 mmol) in ethanol (75 ml) and water ( 25 ml) was added 1 N NaOH (50.9 ml, 50.9 mmol) and heated to reflux for 2 h. The reaction mixture was quenched with glacial acetic acid (4.6 ml, 76.3 mmol) and heated to gentle reflux for 2 h. The solid obtained was collected by filtration, washed with water and dried under vacuum at the reflux temperature of toluene to yield 1.63 g (27%) of compound 6, as a white solid. The filtrate was extracted with ethyl acetate (3 x 100 ml), dried (MgSO4) and after filtration, the filtrate was concentrated under vacuum to yield 3.5 g (58%) of compound 6. Recrystallization from from ethanol allowed to obtain compound 6, as a white solid, mp 174-176 ° C. 1H NMR (CDCb): d 1.35 and 1.36 (two s, 9 H), 1.82 (s, 3 H), 2.08 (m, 5 Hj, 2.27 (m, 2 H) , 2.80 (m, 4 H), 3.54 (m, 1 H), 3.71 (m, 1 H), 4.06 (m, 0.6 H), 4.22 (m, 0 , 4 H), 6.48 (d, J = 6 Hz, 0.6 H), 6.98 (m, 0.4 H) 7.65 (d, J = 8 Hz, 1 H). The ratio of isomers in the carbon atom of NHAc (A and B) was 3: 2; IR (KBr): 3371, 2977, 1689, 1530, 1 172 cm "1. Analysis: Cale, for C? 8H28N2O5S2.0.75H2O: C: 50.27; H: 6.91; N: 6.51 Found: C: 50.03; H: 6.54; N: 6.41 Example 6 (+) 2-. { 3β- [1 '-acetylamin-1' - [(N-methoxy-N-methyl) amincarbonyl] methyl] -4a-tert-butoxycarbonylamin-1-cyclopentylidene} -1, 3-dithiane (7, isomer mixture in C-1 ', Scheme 1) &043 To a solution of compound 6 (5.13 g, 12.33 mmol) in THF (120 ml) at 0 ° C Methyl chloroformate (1.01 ml, 13.56 mmol) and triethylamine (2.2 ml, 15.42 mmol) were added dropwise and stirred at 0 ° C for 45 min. A solution of N-dimethylhydroxylamine hydrochloride (3.68 g, 17 mmol) and triethylamine (7 ml) in THF (25 ml) previously stirred for 30 min to the above mixture was added dropwise. The reaction mixture was further stirred at room temperature for 16 h. It was then concentrated and to the residue was added 0.1 N NaOH (100 ml) and ethyl acetate (100 ml). The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 75 ml). The organic layers were combined and dried (MgSO). After filtration, the filtrate was concentrated and the obtained residue was purified by flash column chromatography (silica gel, 90% ethyl acetate in hexane and 25% [c-Foroform: methanol: ammonium hydroxide (80: 18: 2)] in methylene chloride) to yield 4.2 g (74%) of compound 7, as a white solid, mp 122-126 ° C. An analytical sample was prepared by recrystallization from ether-hexane. H NMR (CDCl 3): d 1.44 (s, 9 x 0.5 H), 1.45 (s, 9 x 0.5 H), 2.02 (s, 3 x 0.5 H), 2 , 03 (s, 3 x 0.5 H), 2.17 (m, 4 H), 2.35 (m, 0.5 H), 2.59 (m, 2 H), 2.77 (m , 6 H), 3.19 (s, 3 x 0.5 H), 3.22 (s, 3 x 0.5 H), 3.57 (m, 0.5 H), 3.77 (s) , 3 x 0.5 H), 3.78 (s, 3 x 0.5 H), 3.90 (m, 0.5 H), 4.60 (d, J = 8 Hz, 0.5 H ), 4.89 (br s, 0.5 H), 5.01 (br s, 0.5 H), 5.16 (m, 0.5 H) 6.34 (br s, 0.5 H) ), 6.89 (br s, 0.5 H). The ratio of the isomers in the carbon atom of NHAc (A and B) was 1: 1; IR (KBr): 3341, 3269, 2978, 2936, 1715, 1681, 1653, 1521, 1156, 1 171 cm "1. Analysis: Cale, for C20H33N3O5S2: C: 52.26; H: 7.24; N. : 9.14 Found: C: 52.34; H: 7.20; N: 9.09 Example 7 & 044 (+) 2-. { 3β- (1'-acetylamin-1 '-formyl) methyl-4a-tert-butoxycarbonylamin-1-cyclopentinium} -1, 3-dithiane (8, isomer A in C-1 'and 9, isomer B in C-1', Scheme 1) &044 To a solution of compound 7 (0.23 g, 0.5 mmol) in THF (5 ml) at 0 ° C was added, by drops, lithium tri-tert-butoxyaluminohydride (1 M solution in THF, 1.1 ml, 1.1 mmol) and stirred at room temperature for 16 h. The reaction mixture was carefully quenched with 1 N HCl (1.0 mL, pH 4) and stirred for 5 min. To the reaction mixture was added ether (10 ml) and 1.0 M aqueous potassium sodium tartrate (10 ml) and stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with ether (2 x 10 ml). The organic layers were combined, dried (MgSO) and concentrated in vacuo to give a crude aldehyde as a white solid. The crude product was purified by flash column chromatography (silica gel, 50-80% ethyl acetate in hexane) to result in 0.08 g (40%, isomer A) of compound 8, as a white solid, m.p. 188-192 ° C (dec). 1 H NMR (CDCl 3): d 1, 41 (s, 9 H), 2.10 (m, 4 H), 2.16 (s, 3 H), 2.52 (m, 1 H), 2.69. (dd, J = 17.5 and 7.7 Hz, 1 H), 2.83 (m, 5 H), 3.73 (m, 1 H), 4.54 (d, J = 8.8 Hz , 1 H), 4.77 (dd, J = 9.6 and 2.1 Hz, 1 H), 7.45 (d, J = 9.6 Hz, 1 H), 9.49 (s, 1 H); IR (KBr): 3337, 2982, 1729, 1681, 1535, 1 166 cm "1; MS (ES +): 401, 4 (100%, M + 1). Analysis: Cale, for C? 8H25N204S2: C: 53 , 97; H: 7.05; N: 6.99 Found: C: 53.93; H: 7.09; N: 6.93 An additional elution allowed to obtain compound 9 (0.07g, 35%, isomer B), mp> 180 ° C. 1 H NMR (CDCl 3): d 1.45 (s, 9 H), 2.08 (s, 3 H), 2.13 (m, 3 H), 2.41 (m, 1 H), 2.55 (m, 1 H), 2.67 (dd, J = 17.2 and 8 Hz, 1 H), 2.84 (m, 5 H), 3.70 ( m, 1 H), 4.38 (m, 1 H), 4.79 (m, 1 H), 6.76 (br s, 1 H), 9.65 (s, 1 H), IR (KBr) ): 3335, 2979, 1730, 1686, 1533, 1 165 cm "1; MS (ES +): 401, 2 (20%, M + 1). Analysis: Cale, for C? 8H28N204S2: C: 53.97; H: 7.05; N: 6.99 Found: C: 54.03; H: 7.05; N: 6.97 Example 8 (±) 2-. { 3β- (1 '-acetylamin-1' -ethoxycarbonyl) methyl-4a-ler-butoxycarbonylamin-1-cyclopentylidene} -1, 3-dithiane (10, mixture of isomers in C-1 ', Scheme 2) &046 To a solution of compound 5 (3.06 g, 5.94 mmol) in ethanol (20 ml) and water ( 15 ml) was added 1N NaOH (19.29 ml, 19.29 mmol) and stirred at room temperature for 16 h. The reaction mixture was quenched with glacial acetic acid (1.74 ml, 28.94 mmol) and heated at 80-90 ° C for 1 h. The solid obtained was collected by filtration, washed with water and hexane and dried to yield 1.43 g (54%) of compound 10, as a white solid, m.p. 157-167 ° C. 1 H NMR (CDC1,): d 1.86 (m, 3 H), 144 (s, 9 H), 2.04 (s, 1.2 H), 2.09 (s, 1.8 h), 2.14 (m, 3 H), 2.57 (m, 2 H), 2.69 (m, 1 H), 2.87 (m, 5 H), 3.67 ( m, 0.4 Hj, 3.87 (m, 0.6 H), 4.19 (m, 2 H), 4.49 (d, J = 8.6 Hz, 0.6 H), 4, 68 (m, 0.4 H), 4.77 (dd, J = 8.9 and 3.6 Hz, 1 H), 6.48 (br s, 0.4 H), 6.99 (d, J = 8.5 Hz, 0.6 H) The ratio of isomers A and B was 3: 2, IR (KBr): 3338, 2982, 1740, 1681, 1545, 1530, 170 cm "1. (ES +): 445.6 (20%, M + 1) Analysis: Cale, for C20H32N2O5S2: C: 54.02, H: 7.25, N: 6.30 Found: C: 54.15, H: 7.26; N: 6.30 Example 9 (±) 2-. { 3β- (1 '-acetylamino-2'-hydroxy) ethyl-4-tert-butoxycarbonylamino-1-cyclopentylidene} -1, 3-dithiane (11, isomer mixture in C-1 ', Scheme 2) & 047 To a solution of compound 10 (0.44 g, 1 mmol) in THF (10 ml) at 0 ° C was added dropwise lithium borohydride (2 M solution in THF, 1.0 ml, 2.0 mmol) and Lithium 9-BBN (1 M solution in THF, 0.1 ml, 0.1 mmol). The reaction mixture was stirred at room temperature for 16 h and carefully stopped with 1 N NaOH (3 ml) and saline (3 ml) and stirred for 5 min. The reaction was acidified with glacial acetic acid and ether (10 ml) was added. The organic layer was separated and the aqueous layer was further extracted with ether (2 x 10 ml). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give a crude alcohol as a white solid. The crude was crystallized from ethanol to yield 0.09 g (22%) of compound 11, as a white solid, m.p. 222-226 ° C. The filtrate was purified by flash column chromatography (silica gel, 75% ethyl acetate, in hexane) to yield 0.21 g (52%) of compound 11, as a white solid. 1H NMR (DMSOd6): d 1.34 (s, 9 H), 1.81 (s, 3 H), 2.07 (m, 6 H), 2.69 (dd, J = 17.3 and 6 , 9 Hz, 1 H), 2.82 (m, 4 H), 3.62 (m, 2 H), 3.66 (t, J = 7.4 Hz, 1 H), 3.73 (m , 1 H), 4.59 (t, J = 5.2 Hz, 1 H), 6.80 (d, J = 7.1 Hz, 1 H), 7.43 (d, J = 9.0 Hz, 1 H); IR (KBr): 3350, 1685, 1535, 1 173, 1050 cm "1; MS (ES +): 403.5 (100%, M + 1). Analysis: Cale, for C18H30N2O4S2: C: 53.70; : 7.51; N: 6.96 Found: C: 53.69; H: 7.56; N: 6.88 Example 10 (±) 2-. { 3β- (1 '-acetylamino-2'-ethoxy) ethyl-4a- (tert-butoxycarbonyl) amin-1-cyclopentinium iden} -1, 3-dithiane (12, isomer A in C-1 ', and 13, mixture of isomers in C-1', Scheme 2) &048 To a stirred solution of compound 11 (1.5 g, 3, 73 mmol) in DMF (20 ml) at 0 ° C was added 95% NaH (0.125 g, 4.95 mmol). After stirring for 1 h, ethyl iodide (0.4 ml, 6.4 mmol) was added dropwise and the reaction mixture was stirred for 3 h. Water (20 ml) was added to the reaction mixture and the organic layer was separated. The aqueous layer was further extracted with EtOAc (4 x 15 ml). The combined organic extracts were washed with saline, dried (MgSO), filtered through Celite and the filtrate was concentrated under vacuum to give the crude product. Purification by radial PLC (Si02, 50% EtOAc / hexane) allowed first to obtain compound 12 (0.75 g, 47%, isomer A) as a white solid, followed by a mixture of isomers A & B, compound 13 (11%).

Example 1 1 (±) 3ß- (1 '-acetylamino-2'-ethoxy) ethyl-4 - (tert-butoxycarbonyl) amincyclopentan-1-methylcarboxylate (14, isomer A in C-1' and mixture in C-1, Scheme 3) and (±) 3ß- (1'-acetylamin-2'-ethoxy) ethyl-4a-amino-cyclopentan-r-1-methylcarboxylate (15, isomer A in C-1 'and mixture in C-1) , Scheme 3) &; 049 To a stirred solution of compound 12 (0.7 g, 1.63 mmol) in MeOH (48 ml) at room temperature was added 6N HCl (4.0 ml, 24 mmol) and the reaction mixture was stirred for 24 h. To this mixture was added NaOH (1.4 g, 35 mmol) and stirred for 1 h. The reaction mixture was acidified with glacial acetic acid, filtered and the filtrate was concentrated under vacuum to give the crude product. Purification by flash column chromatography (silica gel, 75% EtOAc / hexane) allowed to obtain 0.15 g (34%) of compound 14, as a brown oil. Further elution with (CHCl3 / MeOH / NH4OH, 8: 1, 8: 0.2) allowed to obtain 0.163 g (37%) of compound 15, as a yellow oil. 1 H NMR (DMSO-d 6): d 1, 11 (m, 3 H), 1.58 (m, 2 H), 1.82 (s, 3 H), 2.14-1, 83 (m, 3 H), 3.28-2.73 (m, 3 H), 3.49-3.30 (m, 3 H), 3.58 (s, 3 H), 3.84-3.78 (m , 2 H), 4.14 (m, 1 H), 7.79-7.94 (m, 1 H); IR (NaCl): 3256, 3065, 2975, 1732, 1657, 1556, 1440, 1376, 1298 cm "1; MS (ES +): 273.0 (100%, M + 1). Analysis: Cale, for C? 3H24N204: C: 57.33; H: 8.88; N: 10.29 Cale, for C13H24N204 • 0.2 CHCI3: C: 53.52; H: 8.23; N: 9.45 Found: C: 53.24; H: 8.46; N: 9.04Example 12 (+) 3β- (1 '-acetylamino-2'-ethoxy) ethyl-4a-amincyclopentane-1-carboxylic acid (16, isomer A in C-1' and mixture in C-1, Scheme 3) &050- 1 A mixture of compound 15 (0.124 g, 0.046 mmol), 1 N NaOH (0.2 mL, 0.2 mmol) and water (0.2 mL) was stirred at room temperature for 1 h. The reaction mixture was neutralized with glacial acetic acid and diluted with water to give compound 16 as a 29.2 mmolar aqueous solution. MS (ES +): 259.0 (100%, M + 1).

Example 13 (+) 3β- (1'-Acetylamin-2'-ethoxy) ethyl-4a - [(aminoimin) methyl] aminocyclopentane-1-carboxylic acid (17, isomer A in C-1 'and mixture in C-1, Scheme 3) &050-2 A mixture of compound 15 (0.0166 g, 0.0611 mmol), aminoiminmethanesulfonic acid (0.1 g, 0.81 mmol) and potassium carbonate was stirred ( 0.1 g, 0.72 mmol) in water at room temperature for 6 h. To this mixture was added 1 N NaOH (2 mL, 2 mmol) and the mixture was stirred for 45 min. The reaction mixture was neutralized with glacial acetic acid, filtered through a piece of cotton and diluted with water to give compound 17 as a 4.4 mmolar aqueous solution. MS (ES +): 301, 0 (100%, M + 1).

Example 14 (+) t-3- [1 '-acetylamino-1' -di (ethoxycarbonyl)] methyl-c-4-tert-butoxycarbonylamin-t-1 - [(trismethylthio) methyl] cyclopentan-r-1-ol (18) , Scheme 4) &051 A tris (methylthio) methane (1.6 ml, 12 mmol) in THF (20 ml) at -78 ° C was added dropwise, under nitrogen atmosphere, n-BuLi (solution 2, 5 M in hexane, 5.3 ml, 13.3 mmol) and stirred at -78 ° C for 30 min. To this anion, at -78 ° C, a solution of compound 4 (1.0 g, 2.4 mmol) in THF (15 ml) was added dropwise and the reaction mixture was stirred at -78 ° C for 3 hours. h. It was then neutralized with saturated NH 4 Cl (15 mL) and warmed to room temperature. Ether was added and the organic layer was separated. The aqueous layer was extracted with ether (4 x 10 ml). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue obtained was purified by radial PLC (50% ethyl acetate in hexane) to give compound 18 (0.48 g, 35%) as a colorless semi-solid. 1 H NMR (CDCl 3): d 1, 28 (m, 6 H), 1, 43 (s, 9 H), 1, 76 (d, J = 17 Hz, 1 H), 2.03 (s, 3 H) ), 2.13 (m, 1 H), 2.25 (s, 9 H), 2.42 (m, 1 H), 2.51 (m, 1 H), 2.98 (m, 1 H) ), 3.17 (s, 1 H), 3.93 (m, 1 H), 4.26 (m, 4 H), 5.40 (d, J = 9 Hz, 1 H), 7.57 (s, 1 H); IR (NaCl): 3383, 2981, 1738, 1688, 1526, 1369, 1274, 1206, 1168 cm "1 MS (ES +): 569.3 (100%, M + 1) Analysis: Cale, for C23H40N2O8S3: C: 48.57; H: 7.09; N: 4.93 Found: C: 48.74; H: 7.00; N: 4.91 Example 15 (+) t-3- [1 '-acetylamin-1' -carboxy)] methyl-c-4-tert-butoxycarbonylamin-t-1 - [(trismethyl thio) methyl] cyclopentan-r-1 -ol (19, mixture of isomers in C-1 ', Scheme 4) &052 The reaction of compound 18 (3.66 g, 6.4 mmol), described for compound 6, allowed to obtain 2.25 g (75%) of the compound 19 as a tan solid, mp 220-223 ° C (dec). 1 H NMR (CDCl 3): d 1, 36 (s, 9 H), 1.49 (m, 1 H), 1.81 (m, 5 H), 2.16 (s, 9 H), 2.48 (m, 2 H), 2.61 (m, 1 H), 3.66 (m, 1 H), 4.03 (m, 1 H), 4.93 (m, 1 H), 6.40 (m, 1 H), 7.52 (m, 1 H); IR (KBr) 3400, 2979, 2921, 1684, 1585, 1417, 1368, 1250, 1 168 cm "1; MS (ES +): 469.3 (20%, M + 1) Analysis: Cale, for C18H32N206S2, 1 , 5 H20: C: 43.62; H: 6.71; N: .65 Found: C: 43.88; H: 6.47; N: .28 Example 16 (+) t-3- [1 '-acetylamin-1' - [(N-methoxy-N-methyl) amincarbonyl] methyl] -c-4-tert-butoxycarbonylamin-t-1 - [(trismethylthio) methyl] cyclopentan -r-1 -ol (20, mixture of isomers in C-1 ', Scheme 4) &053-1 The reaction of compound 19 (6.34 g, 13.5 mmol) described for compound 7, allowed to obtain 3.85 g (56%) of compound 20, as a white solid, mp 142-143 ° C. 1 H NMR (CDCl 3): d 1, 41 (s, 9 H), 1.77 (m, 1 H), 2.01 (m, 5 H), 2.39 (s, 9 H), 2.49 (m, 2 H), 3.21 (s, 3 H), 3.36 (m, 1 H), 3.85 (s, 3 H), 4.34 (br s, 1 H), 5, 1 1 (br s, 1 H), 5.51 (m, 1 H), 7.26-7.69 (m, 1 H); IR (KBr): 3427, 3315, 1681, 1637 cm "1; MS (ES +): 512.5 (M + 1). Analysis: Cale, for C ^ Hs ^ OeSs: C: 46.94; H: 7.29; N: 9.21 Found: C: 47.13; H: 7.34; N: 8.16 Example 17 (+) t-3- (1 '-acetylamino-1' -formyl) methyl-c-4-tert-butoxycarbonylamin-t-1 - [(tris methylthio) methyl] cyclopentan-r- 1 -ol (21, isomer mixture in C-1 ', Scheme 4) &053 The reaction of compound 20 (1.12 g, 2.18 mmol) described for compounds 8 and 9, allowed obtaining 0.29 g (25%) of compound 21, as a light yellow solid, mp 78-79 ° C. : 1 H NMR (CDCl 3): d 1.44 (s, 9 H), 1.75-2.18 (m, 5 H), 2.08 (s, 9 H), 2.46 (m, 2 H) ), 2.58 (m, 1 H), 3.10 (s, 0.5 H), 3.26 (s, 0.5 H), 3.82 (m, 1 H), 4.13 ( m, 0.5 H), 4.53 (m, 0.5 H), 5.37 (d, J = 8.8 Hz, 0.5 H), 5.58 (d, J = 8.5 Hz, 0.5 H), 8.03 (m, 1 H), 9.42 (s, 0.5 H), 9.61 (s, 0.5 H); IR (KBr): 3329, 2979, 2921, 1683, 1527, 1367, 1 169 cm "1; MS (ES +): 453.4 (100%, M + 1) Analysis: Cale, for C? 8H37N205S3: C : 47.76, H: 7.13, N: 6.19 Found: C: 47.70, H: 7.17, N: 6.1 1 Example 18 (+) t-3 - [(1 '-acetylamino-3'-ethyl-2'-oxo) pentyl] -c-4-tert-butoxycarbonylamin-t-1 - [(trismethyl) methyl] cyclopentan -r-1 -ol (22, isomer mixture in C-1 ', Scheme 4) &054 Dry Mg (17.1 g, 704 mmol) and iodine (1 crystal) were heated on a dried balloon until sublimation of the iodine The heating was stopped and the purple vapors were allowed to settle on the Mg. THF (250 ml) and a few drops of 3-bromopentane were added to the reaction mixture, which was then heated to start the reaction. The remaining 3-bromopentane (100 ml, 805 mmol) was added dropwise to the reaction mixture at such a rate that a gentle reflux was maintained. After cooling to room temperature, the solution was transferred to a dry and clean bottle. To this mixture was added compound 21 (4.0 g, 8.84 mmol) in dry THF (100 ml) and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was quenched with water (100 ml) and extracted with Et20 (3 x 50 ml). The combined ether layers were washed with saline (3 x 50 ml) and dried (Na 2 SO). The solvent was removed under vacuum to give a crude mixture, which was purified by flash column chromatography (silica gel, 20% EtOAc / hexane) to obtain 1.44 g (33%) of compound 22.

Example 19 (+) t-3 - [(1 '-acetylamino-3'-ethyl-2'-hydroxy) pentyl] -c-4-tert-butoxycarbonylamin-t-1 - < [(trismethylthio) methyl] cyclopentan-r-1 -ol (23, mixture of isomers at C-1 'and C-2', Scheme 4) &055 Compound 22 (1.4 g, 2.62 was combined mmol) with NaBH (0.2 g, 5.29 mmol) in dry MeOH (20 ml), stirred at room temperature for 1 h and neutralized with glacial acetic acid. The solvent was removed under vacuum to give a residue, which was taken up in H0 and extracted with EtOAc (3 x 50 ml). The combined organic extracts were dried (MgSO4) and concentrated to give a crude reaction mixture that was purified by flash chromatography (silica gel, 50% EtOAc / hexane followed by 10% MeOH / EtOAc) which allowed compound 23 to be obtained. , 75 g, 53%).

Example 20 (+) c-3 - [(1'-Acetylamino-3'-ethyl-2'-hydroxy) pentyl] -t-4-tert-butoxycarbonyl-amin-t-1-hydroxycyclopentan-r-1-methylcarboxylate (24, mixture of isomers at C-1 'and C-2', Scheme 4) &056 A mixture of compound 23 (0.74 g, 1.38 mmol) was stirred in MeOH / H20 (12: 1, 35 ml), HgCl2 (1.43 g, 5.27 mmol) and HgO (0.49 g, 2.26 mmol) at room temperature for 2 h. The reaction mixture was filtered through Celite and the Celite was washed with MeOH (25 ml). The filtrate was concentrated under vacuum leaving a white residue, which was partitioned between H 0 (50 ml) and EtOAc (50 ml). The EtOAc layer was separated and the aqueous layer was further extracted with EtOAc (2 x 50 ml). The combined organic layers are • washed with saline (2 x 50 ml) and dried (MgSO4). After filtration, the filtrate was concentrated to give a crude reaction mixture.

Said crude mixture was purified by flash chromatography (silica gel, 60% ElOAc / hexane) to give compound 24 (0.27 g, 43%).

Example 21 (+) c-3 - [('1' -acetylamino-3'-ethyl-2'-hydroxy) pentyl] -t-4 - [(tert-butoxycarbonylamin-tert-butoxycarbonylimino) methyl] amin-t- 1-methylhydroxycyclopentan-r-1-methylcarboxylate (25, one isomer at C-1 'or C-2' and mix at another and 26, mix at both C-1 'and C-2', Scheme 5) &057 A mixture of compound 24 (0.23 g, 0.52 mmol) in CH2Cl2 (10 mL) and TFA (1 mL) was stirred for 16 h at room temperature. The mixture was concentrated under vacuum and traces of TFA were removed by co-evaporation with CH CI2 (2 x 5 mL). The residue was dried under high vacuum. To the residue was added dry DMF (5 ml), Et3N (0.5 ml, 3.6 mmol), bi- (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea (0.15 g, 0.52 mmol) and HgCl (0.15 g, 0.55 mmol). The mixture was stirred at room temperature for 4 h. Mix c with EtOAc and filter through Celite. The filtrate was washed with H20 (2 x 50 ml), saline (2 x 50 ml) and dried (Na2SO4). After filtration, the filtrate was concentrated to give the crude product, which was purified by radial PLC (SiO2) using 30% EtOAc / hexane as eluent to give first 0.06 g (20%) of compound 25, followed by 0.085 g. (28%) of compound 26.

Example 22 (+) c-3 - [(-acetylammon-3'-ethyl-2'-hydroxy) pentyl] -t-4- [aminoiminmethyl] -amin-t-1-hydroxycyclopentan-r-1 - acid carboxylic (27, isomer mixture in C-1 'and C-2', Scheme 5] &058 A mixture of compound 26 (0.075 g, 0.13 mmol) was stirred in CH2CI2 (3 ml) with TFA (0.5 ml) for 16 h at room temperature. The reaction mixture was concentrated and dried under high vacuum to give c-3 - [(1'-acetylamino-3'-ethyl-2'-hydroxy) pentl] -t-4- [aminoiminmethyl] amin-t-1-hydroxycyclopentan-r-1-methylcarboxylate; MS (ES +): 373 (M + 1). The above product (0.015 g, 0.04 mmol) was stirred with 1 N NaOH (0.1 mL, 0.1 mmol) and water (0.2 mL) for 16 h. The solution was neutralized with acetic acid, filtered through cotton and diluted with H20 to obtain a 13.2 mmolar solution of Compound 27.

Example 23 (+) c-3 - [(1'-Acetylamin-3'-ethyl-2'-hydroxy) pentyl] -t-4- [aminoiminmethyl] -amin-t-1-hydroxycyclopentan-r-1-carboxylic acid ( 28, one isomer in C-1 'or C-2' and mixed in another, Scheme 5) &059-1 The reaction of compound 25 (0.045 g, 0.078 mmol) described for compound 27 allowed to obtain a solution 5, 37 mmolar of compound 28.

Example 24 (+) 2-. { 3β- (1 '-acetylamino-3'-ethyl) -2'-pentenyl-4a-tert-butoxycarbonylamino-1-cyclopentylidene)} -1, 3-dithiane (29, isomer A in C-1 ', mixture in C-2', Scheme 6) &059 To a suspension of propyltriphenylphosphonium bromide (0.5 g, 1.3 mmol) in THF (15 ml) at -78 ° C was added dropwise sodium (trimethylsilyl) amide, NaHMDS (1 M solution in THF, 1.3 ml, 1.3 mmol). After stirring for 30 min, the reaction mixture was allowed to warm to 0 ° C and was stirred for 30 min. To this mixture was added compound 8 (0.21 g, 0.52 mmol) in THF (10 ml) and the reaction mixture was stirred for 1 h. An additional amount of NaHMDS (2.6 ml, 2.6 mmol) was added dropwise and the • reaction mixture was stirred for 30 min followed by dropwise addition of ethyl bromide (0.3 ml). The reaction mixture was allowed to reach room temperature and was stirred for 2 h. Water (20 ml) was added and the layers separated. The aqueous layer was extracted with ether (4 x 15 ml). The combined organic extracts were washed with saline, dried (MgSO), filtered through Celite and the filtrate was concentrated under vacuum to give the crude product. Purification by radial PLC (silica gel, 50-75% • EtOAc / hexane) allowed to obtain compound 29 (0.045 g, 20%) as a white solid. 1 H NMR (CDCl 3): d 0.99-0.94 (m, 3 H), 1, 19-1, 12 (m, 3 H), 1.48 (s, 9 H), 1, 74-1, 52 (m, 2 H), 2.00 (s, 3 H), 2.15-2.02 (m, 6 H), 2.78-2.55 ( m, 2 H), 2.99-2.82 (m, 4 H), 3.22-3.16 (m, 2 H), 5.13-4.93 (m, 1 H), 5, 49-5.47 (m, 1 H), 5.58-5.57 (m, 1 H), 6.96 (bs, 1 H); MS (ES +): 455.6 (100%, M + 1). Analysis: Cale, for C23H38N203S2; C: 60.75; H: 8.42; N: 6.16 20 Cale, for C23H38N203S2 • 0.2 CH2CI C: 59.08; H: 8.21; N: 5.94 Found C: 58.92; H: 8.2 1; N: 6.02 Example 25 25 (+) 3ß- (1'-acetylamino-3'-ethyl) -2'-pentenyl-4a- (tert-butoxycarbonyl) amin-cidopentan-1-methylcarboxylate (30, isomer A in C-1 ', mixture of isomers in C-1 and C-2', Scheme 6) &060 To a stirred solution of compound 29 (0.019 g, 0.042 mmol) in MeOH (1 ml) at room temperature was add 6 N HCl (0.1 mL, 0.6 mmol) and the reaction mixture was stirred for 24 h. The reaction mixture was concentrated under vacuum to give a brown residue of compound 30, which was used as it was in the reaction of the following example.

Example 26 (+) 3β- (1'-acetylamino-3'-ethyl) -2'-pentenyl-4-amyclopentane-1-methylcarboxylate (31, isomer A in C-1 ', mixture of isomers in C-1 and C-2 ', Schematic 6) &061-1 To a mixture of compound 30 (0.042 mmol) in CH 2 Cl 2 (1 mL) was added CF 3 CO 2 H (0.1 mL, 1.3 mmol) and the mixture was stirred for 4 h and concentrated in vacuo to give Resulting in compound 31 as a brown solid and used as it was in the reaction of the following example.

Example 27 (+) 3β- (1'-Acetylamino-3'-ethyl) -2'-pentenyl-4-amyclopentane-1-carboxylic acid (32, isomer A in C-1 ', mixture of isomers in C-1 and C -2 ', Scheme 6) &061 -2 To a solution of compound 31 (0.042 mmol) in MeOH (1 mL) was added 1 N NaOH (0.7 mL, 0.7 mmol) and stirred for 1 h room temperature. The reaction mixture was neutralized with glacial acetic acid and diluted with water to obtain a 20 mmolar solution of compound 32.

Example 28 (+) 3β- (1'-acetylamino-3'-ethyl) pentyl-4a-amino-cyclopentan-1-methyl-carboxylate (33, isomer A in C-1 ', mixture in C-1, Scheme 6) & 062 • A mixture of 31 (0.2 mmol) and Pt02 (0.1 g) in EtOH (10 mL) was hydrogenated under 45 psi pressure for 16 h. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to give compound 33 (59%) as a yellow oil. 1 H NMR (360 MHz, CDCl 3): d 8.40-8.45 (bs, 2 H), 7.73-7.70 (m, 1 H), 3.62 (s, 3 H), 3, 28-2.50 (m, 3 H), 2.10-1, 87 (m, 4 H), 1.83 (s, 3 H), 1, 44-1, 24 (m, 3 H), 1, 19-1, 15 (m, 8 H), 0.85-0.84 (m, 3 H); IR (NaCl): 3358, 2946, 2834, 1451, 1418, 1029 cm "1; MS (ES +): 299.0 (100%, M + 1). • 20 Analysis: Cale, for C16H3oN203: C: 64, 39; H: 10.13; N: 9.39 Cale, for C16H30N2O3"2.25 CF3C02H: C: 44.37; H: 5.86; N: 5.05 Found: C: 44.25; H: 6.04; N: 5.17 Example 29 (+) 3β- (1 '-acetylamino-3'-ethyl) pentyl-4 (x-amincyclopentane-1-carboxylate (34, isomer A in C-1', mixture in C-1, Scheme 6) &063 -1 A mixture of 33 (0.0089 g, 0.03 mmol) and 1 N NaOH (0.2 mL, 0.2 mmol) in water (0.4 mL) was stirred at room temperature for 1 h. The reaction mixture was neutralized with AcOH and diluted with water to give compound 34 as an aqueous solution 12.1 mmolar, MS (ES +): 285.1 (100%, M + 1).

• Example 30 (±) 3ß- (1 '-acetylamino-3'-ethyl) -2'-pentenyl-4-aminicyclopentan-1-carboxylate of Methyl (35, mixture of isomers in C-1, C-1 'and C-2', Scheme 7). &063-2 This was prepared from the mixture of compounds 8 and 9 (1.74 g, 4.5 mmol) following the same procedures as for compounds 29, 30 and 31. Obtained as a yellow oil . • 20 Example 31 (+) 3β- (1'-acetylamino-3'-ethyl) pentyl-4a-amino-cyclopentan-1-methylcarboxylate (36, mixture of isomers at C-1 'and C-1, Scheme 7) 25 &064 -1 This was prepared from 35 following the same procedures as for compound 33. 1 H NMR (360 MHz, CDCl 3): d 0.85-0.84 (m, 3 H), 1, 15-1, 51 (m, 11 H), 1.83 (s, 3 H), 2.10-1, 92 (m, 4 H), 3.01-2.86 (m, 3 H), 3.61 ( s, 3 H), 7.4-7.71 • (m, 1 H), 8.40-8.45 (bs, 2 H); IR (NaCl) 3358, 2946, 2834, 1451, 1418, 1029 cm "1; MS (ES +): 299.0 (100%, M + 1) Analysis: Cale, for C? 6H30N2O3; C: 64.39; H: 10.13; N: 9.39 Cale, for C? 6H3oN 03 »3 CF3C02He« 2 H20: C: 39.05; H: 5.51; N: 4.41 10 Found: C: 38, 79; H: 5.13; N: 4.34 • Example 32 (+) 3β- (1'-Acetylamino-3'-ethyl) pentyl-4a-amincyclopentane-1-carboxylic acid (37, mixture of isomers in C-1 and C-1 ', Scheme 7) &064-2 The reaction of compound 36 (0.010 g, 0.034 mmol) described for compound 34 allowed to obtain a 9.8 mmolar solution of compound 37 MS (ES +): 285.1 (100%, M + 1). 20 Example 33 (+) 2-. { 3β- (1'-acetylamino) -2'-pentenyl-4a-tert-butoxycarbonylamin-1-cyclopentylidene} -1, 3-dithiane (38, isomer A in C-1 ', mixture in C-2', Scheme 8) 25 &065 To a suspension of propyltriphenylphosphonium bromide (0.28 g, 0.73 mmol) in THF (10 mL) at -78 ° C was added NaHMDS (1 M solution in THF, 0.73 mL, 0.73 mmol) per drops. After stirring for 10 min., The reaction mixture was allowed to warm to 0 ° C, stirred for 20 min., And cooled to -78 ° C. To this mixture was added compound 8 (0.097 g, 0.24 mmol) in THF (6 ml) and the reaction mixture was stirred for 1 h. Water (10 ml) was added and the layers separated. The aqueous layer was extracted with ether (4 x 10 ml). The combined organic extracts were washed with saline, dried (MgSO), filtered through Celite. After the filtration, the filtrate was concentrated under vacuum to give 0.16 g of the crude product. Purification by radial PLC (silica gel, 50-75% EtOAc / hexane) allowed to obtain 0.093 g (91%) of compound 38 as a white solid, m.p. 175-177 ° C. 1 H NMR (360 MHz, CDCl 3): d 0.95-1, 0 (m, 3 H), 1.45 (s, 9 H), 1, 97-2.27 (m, 10 H), 2- 56-2.72 (m, 1 H), 2.82-2.86 (m, 5 H), 3.82-3.88 (m, 1 H), 4.45 (m, 1 H), 4.71 (m, 1 H), 5.33-5.44 (m, 1 H), 5.58-5.75 (m, 1 H) 6.54-6.61 (m, 1 H); IR (KBr): 3342, 2970, 2935, 1683, 1646, 1537, 1367, 1296, 1 170 cm "1; MS (ES +): 427.5 (100%, M + 1). Analysis: Cale, for C21H34N203S2 : C: 59.12; H: 8.03; N: 6.57 Found: C: 59.21; H: 8.04; N: 6.51 Example 34 (+) 3ß- (1'-acetylamin) -2'-pentenyl-4a-tert-butoxycarbonylamino-cyclopentan-1-methylcarboxylate (39, isomer A in C-1 'and mixture in C-2', Scheme 8) &; 066-1 The reaction of compound 38 (4.0 g, 9.4 mmol) described for compound 30 allowed to obtain 2.7 g (78%) of compound 39 as an oil.

Example 35 (+) 3ß- (1'-acetylamin) pentyl-4-tert-butoxycarbonylaminocyclopentane-1-methylcarboxylate (40, isomer A in C-1 ', mixture in C-1, Scheme 8) &066-2 reaction of compound 39 (0.145 g, 0.39 mmol) described for compound 33 allowed 0.94 g (97%) of compound 40 to be obtained as a thick oil.

Example 36 (+) 3ß- (1'-acetylamin) pentyl-4a-amino-cyclopentan-1-methylcarboxylate (41, isomer A in C-P, mixture in C-1, Scheme 8) &067-1 A mixture was stirred of compound 40 (0.08 g, 0.22 mmol) and TFA (0.5 mL, 6.5 mmol) in CH202 (8 mL) at room temperature for 16 h. The reaction mixture was concentrated under vacuum to give 0.1 12 g of compound 41.

Example 37 (+) 3β- (1 '-acetylamino) pentyl-4-amyclopentane-1-carboxylic acid (42, isomer A in C-1', mixture in C-1, Scheme 8) &067-2 The reaction of the compound 41 (0.1 12 g) described for compound 34 allowed to obtain a 31.9 mmolar solution of compound 42. MS (ES +): 257.4 (100%, M + 1).

Example 38 (+) methyl cyclopent-3-en-1-carboxylate (43, Scheme 9) and ethyl cyclopent-3-en-1-carboxylate (44, Scheme 9) &068-1 These compounds were prepared from cis-1, 4-dichloro-2-butene and dimethylmalonate using the procedure of Depres et. al., J. Org. Chem. 1984, 49, 928-931. The resulting acid was esterified according to standard methods to give 43 or 44.

Example 39 (+) 3-butyI-4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylic acid methyl ester (45, Scheme 9, the ester group and the ring sooxazoline are cis to each other) and (±) 3-Butyl-4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylic acid methyl ester (46, Scheme 9, the ester group and the isooxazoline ring are trans to each other) &068-2 To a refluxing solution of methyl 3-cyclopentene-1-carboxylate 43 (10.21 g, 80.9 mmol) and phenyl isocyanate (17.5 mL, 161 mmol) in dry benzene (50%). ml) was added, by drops, a mixture of 1-nitropentane (10.8 ml, 87.8 mmol) and Et3N (20 drops) in dry benzene (30 ml) over a period of 1 h. The mixture was heated to reflux for an additional hour. The solids were filtered off and washed with Et20. The combined filtrate was concentrated to give an orange oil, which was purified by flash chromatography (silica gel, 0 to 50% ethyl acetate in hexanes). The fractions containing the desired compound were pooled and evaporated to give 46 (8.1 g, 43%) as a yellow oil. 1 H NMR (CDCl 3): d ppm 0.83 (t, J = 7.2 Hz, 3 H), 1, 24-1, 38 (m, 2 H), 1, 39-1, 58 (m, 2 H), 1.85-2.20 (m, 4 H), 2.22-2.39 (m, 2 H), 2.62-2.73 (m, 1 H), 3.54-3 , 67 (m, 1 H), 3.63 (s, 3 H), 4.95-5.03 (m, 1 H); MS (ES +): 225.9 (M + -) - Analysis: Cale, for C12H19N03: C: 63.97; H: 8.52; N: 6.21 Found: C: 63.77; H: 8.46; N: 6.25 An additional elution allowed to obtain 45 (2.0 g, 11%), as a yellow oil. 1 H NMR (CDCl 3): d ppm 0.90 (t, J = 15.0 Hz, 3 H), 1, 27-1, 40 (m, 2 H), 1, 41 -1, 63 (m, 2 H), 1, 92-2.05 (m, 1 H), 2.13-2.45 (m, 5 H), 2.78-2.86 (m, 1 H), 3.48-3 , 58 (m, 1 H), 3.62 (s, 3 H), 4.91 -5.03 (m, 1 H); MS (ES +): 225.8 (M + 1) Analysis: Cale, for d2H19N03: C: 63.97; H: 8.52; N: 6.21 Found: C: 63.80; H: 8.54; N: 6.16 Example 40 (+) 3- (1'-ethylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylic acid methyl ester (47, Scheme 9, the ester group and the isooxazoline ring are trans each) & 069 Prepared using the procedure for compound 46 using 1-nitro-2-ethylbutane (20.3 g, 0.156 mol) and 43 (20 g, 0.158 mol) was obtained with 53% yield, like a yellow oil. 'H NMR (CDCl 3): d ppm 0.8 (m, 6 H), 1.5 (m, 4 H), 1.9 (m, 2 H), 2.0 (m, 1 H), 2 , 1 (m, 1 H), 2.2 (m, 1 H), 2.5 (m, 1 H), 3.6 (s, 3 H), 3.7 (m, 1 H), 4 8 (m, 1 H); MS (ES +): 240 (100%, M + 1). Analysis: Cale, for C? 3H21N03: C: 65.28; H: 8.78; N: 5.85 Found: C: 65.26; H: 8.78; N: 5.92 Example 41 (+) 3- (1 '-propylbutyl) -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylic acid methyl ester (48, Scheme 9, the ester group and the isooxazoline ring are trans each) & 070 Prepared using the procedure for compound 46 using 1-nitro-2-propylpentane (73.06 g, 460 mmol) and 43 (63 g, 515 mmol) was obtained with 45% yield as a yellow oil 1 H NMR (CDCl 3): d ppm 0.90 (t, J = 7.3 Hz, 6 H), 1, 24-1, 37 (m, 4 H), 1, 42-1, 55 (m, 3 H), 1.63 (m, 1 H), 1.98 (m, 2 H), 2.06 (m, 1 H), 2.39 (m, 2 H), 2.79 (m, 1 H), 3.61 (t, J = 8.4 Hz, 1 H), 3.69 (s, 3 H), 5.01 (dd, J = 8.5 and 5.3 Hz, 1 H); MS (ES +): 225.8 (M + 1). Analysis: Cale, for C15H25N03: C: 67.39; H: 9.42; N: 5.24 Found: C: 67.25; H: 9.36; N: 5.17 Example 42 (+) 3- (cyclohexylmethyl) -4,5,6,6a-tetrahydro-3aH-cyclopentane [d] isoxazot-5-carboxylic acid ethyl ester (49, Scheme 9, the ester group and the isooxazoline ring are trans to each other) &071 Prepared using the procedure for compound 46 using 1-nitro-2-cyclohexylethane (3.3 g, 21 mmol) and 44 (2.68 g, 19.1 mmol) was obtained with 31% yield , like a yellow oil. 1 H NMR (CDCl 3): d ppm 0.97 (m, 2 H), 1.22 (m, 6 H), 1.63 (m, 6 H), 2.01 (m, 4 H), 2, 23 (dd, J = 8.9 and 15 Hz, 1 H), 2.33 (dd, J = 6.2 and 14 Hz, 1 H), 2.74 (m, 1 H), 3.62 ( t, J = 8.6 Hz, 1 H), 4.13 (m, 2 H), 5.03 (dd, J = 5.5 and 8.6 Hz); MS (ES +): 280.4 (M + 1). Analysis: Cale, for C? 6H25N03: C: 68.79; H: 9.02; N: 5.01 Found: C: 68.81; H: 8.96; N: 5.06 41 Example 43 (+) Ethyl 3- (1'-ethylpentyl) -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylate (50, isomer mixture in C-1 ', Scheme 9, the ester group and the isooxazoline ring are trans to each other) &072-1 Prepared using the procedure for compound 46 using 1-nitro-ethylhexane (5.75 g, 36 mmol) and 44 (4.6 g , 33 mmol) with 34% yield, as a yellow oil.

Example 44 (+) Ethyl 3- (1'-methylethyl) -4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylate (51, Scheme 9, the ester group and the isooxazoline ring are trans each) & 072-2 Prepared using the procedure for compound 46 using 1-nitro-2-methylpropane (6.2 g, 60 mmol) and 44 (0.7 g, 50 mmol) was obtained with a 41 , 5% yield, as a yellow oil.

Example 45 (+) 3-cyclohexyl-4,5,6,6a-tetrahydro-3aH-cyclopenta [d] isoxazole-5-carboxylic acid ethyl ester (52, Scheme 9, the ester group and the isoxazoline ring are trans to each other) &; 073-1 was prepared using the procedure for compound 46 using 1-nitro-2-propylpentane (2.86 g, 20 mmol) and 44 (2.8 g, 20 mmol) was obtained with 39.6% of performance, like a yellow oil.

Example 46 (±) t-3- (1 '-acetylaminopentyl) -t-4-hydroxycyclopentan-r-1-methylcarboxylate (53, isomer A in C-1 ', Scheme 9) &073-2 To a solution of compound 46 (3.0 g, 13.3 mmol) in THF (10 ml) was added acetic anhydride (25 ml, 27 mmol) and Raney nickel (3 g). The mixture was hydrogenated at 35 psi for 16 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 40% to 100% EtOAc in hexanes). The desired fractions were pooled and concentrated. The residue was dissolved in MeOH (10 ml) and sodium pellets (10 mg) were added and the whole was stirred for 4 h. The reaction mixture was neutralized with AcOH and concentrated in vacuo. After addition of water (20 ml), the mixture was extracted with EtOAc (2 x 20 ml). The organic layers were combined, dried (MgSO) and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 50-80% EtOAc in hexanes). The appropriate fractions were pooled and concentrated to give compound 53 in 20% yield, as a colorless oil. 1 H NMR (CDCl 3): d ppm 0.90 (t, J = 6.5 Hz, 3 H), 1.32 (m, 6 H), 1.90 (m, 4 H), 2.05 (s) , 3 H), 2.09 (m, 1 H), 3.19 (m, 1 H), 3.67 (s, 3 H), 3.81 (m, 1 H), 4.07 (s) , 1 H), 4.52 (s, 1 H,), 5.38 (d, J = 8.71 Hz, 1 H); IR (NaCl) 3285, 2952, 1733, 1626, 1549, 1436, 1202 cm "1; MS (ES +): 272.3 (100%, M + 1) Analysis: Cale, for C? 4H25N04: C: 61 , 97; H: 9.29; N; 5.16 Cale, for C14H25NO4 »0.25 H20: C: 60.96; H: 9.31; N: 5.08 Found: C: 60.79; : 9.01; N: 5.13 Example 47 (±) t-3- (1'-acetylaminopentyl) -t-4-hydroxycyclopentan-r-1-methylcarboxylate (54, isomer B in C-1 ', Scheme 9) &074 - A, solution of the Compound 46 (3.5 g, 15.6 mmol) in THF (150 ml) was added acetic anhydride (29 ml, 31 mmol) and platinum oxide (0.8 g). The mixture was hydrogenated at 50 psi for 24 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated under vacuum. The crude product was dissolved in EtOAc (50 ml), neutralized with concentrated NH OH and water (25 ml) was added. The organic layer was separated, the aqueous layer was extracted further with EtOAc (2 X 20 ml). The organic layers were combined and dried (MgSO). After filtration, the filtrate was concentrated under vacuum. The residue was recrystallized from ether to give 54 with 24% yield, as a white solid. 1 H NMR (CDCl 3): d ppm 0.89 (t, J = 6.5 Hz, 3 H), 1.35 (m, 5 H), 1.97 (m, 6 H), 2. 00 (s) , 3 H), 2.73 (s, 1 H), 3.10 (m, 1 H), 3.67 (s, 3 H), 4.13 (m, 1 Hj, 4.28 (d, J = 2.6 Hz, 1 H), 5.28 (d, J = 9.2 Hz, 1 H); IR (KBr) 3537, 3286, 2951, 1700, 1640, 1559, 1219 cm "1; (ES +): 272.4 (100% M + 1).

Analysis Cale, for C? H25N0: C: 61, 97; H: 9.29; N: 5.16 Found: C: 61, 78; H: 9.09; N: 5.08 Example 48 (±) t-3- (1-Acetylamin-2-ethyl) butyl-t-4-hydroxycyclopentan-r-1-methylcarboxylate (55, isomer A in C-1 ', Scheme 9) &075 To a solution of compound 47 (0.5 g, 2 mmol) in a mixture of CH3CN: H20 (15: 1, 50 ml) was added Mo (CO) 6 (0.2 g, 0.8 mmol) and NaBH 4 (91 mg, 2.4 mmol). The reaction mixture was refluxed for 3 h, cooled to room temperature and evaporated to dryness. To the resulting mixture, EtOAc (50 ml), acetic anhydride (3.78 ml, 40 mmol) was added and - the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then evaporated to dryness and the residue was purified by flash column chromatography (silica gel, 0 to 100% EtOAc in hexanes). Appropriate fractions were pooled and concentrated to give compound 55 in 20% yield, as a white solid. 1 H NMR (DMSO-d 6): d ppm 0.8 (t, J = 7.2 Hz, 3 H), 0.9 (t, J = 7 Hz, 3 H), 1, 0 (m, 1 H) 1, 2 (m, 2 H), 1, 4 (m, 2 H), 1, 6 (m, 1 H), 1.7 (m, 2 H) ), 1, 8 (m, 2) H), 1.88 (s, 3 H), 3.0 (m, 1 H), 3.6 (s, 3 H), 3.9 (m, 2 H), 4.5 (s, 1 H), 7.5 (d, J) = 9.5 Hz, 1 H); MS (ES +): 244.13 (M + 1).

Example 49 (±) t-3 - [(1'-acetylamin-2'-ethyl) butyl-t-4-hydroxycyclopentan-r-1-methylcarboxylate (56, isomer B in C-1 ', Scheme 9) & 076 This compound was obtained with a 61% yield as a colorless oil from 47 (15 g, 62.7 mmol) using the same procedure as for compound 54. 1 H NMR (DMSO-d 6): d ppm 0, 8 (m, 6 H), 1, 0 (m, 2 H), 1, 3 (m, 2 H), 1, 4 (m, 1 H), 1, 7 (m, 1 H), 1, 8 (s, 3 H), 1, 9 (m, 3 H), 2.0 (m, 1 H), 3.0 (m, 1 H), 3.6 (s, 3 H), 4, 0 (m, 1 H), 4.1 (dd, J = 1, 4 and 10.4 Hz, 1 H), 4.5 (d, 1 H, J = 4.3 Hz), 7.3 ( d, J = 10.2 Hz, 1 H); MS (ES +): 286.3 (100% M + 1). Cale Analysis, for C? 5H27N04 0.75 H20: C: 60.31; H: 9.54; N: 4.69 Found: C: 60.24; H: 9.51; N: 4.59 Example 50 (+) t-3- (1'-acetylamin-2'-propyl) pentyl-4-hydroxycyclopentan-r-1-methylcarboxylate (57, isomer B in C-1 ', Scheme 9) &; 077 To a mixture of compound 48 (14 g, 52 mmol) dissolved in MeOH / H20 / AcOH (120/15/15 ml) was added Pt02 (1.4 g) and the mixture was hydrogenated at 50 psi for 16 h. The catalyst was removed by filtration and the filtrate was concentrated to give the amino derivative. The above crude product was dissolved in CH2Cl2 (250 ml), acetic anhydride (55 ml, 520 mmol) was added and the reaction mixture was stirred for 45 min at room temperature. Concentrated NH 4 OH was added to the mixture to pH 8. The organic layer was separated, washed with saline, dried and concentrated under vacuum. The residual oil was crystallized from ether / hexane to yield compound 57 in 64% yield, as a white solid. 1 H NMR (CDCl 3): d ppm 0.9 (m, 6 H), 1, 06 (m, 1 H), 1, 14 (m, 1 H), 1.32 (m, 4 H), 1, 44 (m, 2 H), 1, 52 (m, 1 H), 1, 96 (m, 5 H), 2.00 (s, 3 H), 2.59 (d, J = 3.1 HZ , 1 H), 3. 10 (m, 1 H), 3.67 (s, 3 H), 4.21 (m, 1 H), 4.27 (m 1 H), 5.29 (d, J = 10 Hz, 1 H); IR (KBr): 3493, 3277, 2955, 2930, 2870, 1734, 1713, 1642, 1560, 1442, 1372, 1216 cm "1; MS (ES +): 314.5 (20%, M + 1). : Cale, for C17H3iN04: C: 65.14; H: 9.97; N: 4.47 Found: C: 65.19; H: 10.04; N: 4.50 Example 51 (±) t-3- (1 '-acetylamin-2'-cyclohexyl) ethyl-t-4-hydroxycyclopentan-r-1-ethyl carboxylate (58, isomer B in C-1', Scheme 9) &; 078-1 This was obtained with a 68.5% yield as a yellow oil from 49 (0.5 g, 1.79 mmol) using the same procedure as for compound 54. 1 H NMR (CDCl 3): d ppm 0.82-0.99 (m, 2 H), 1, 10-1, 23 (m, 4 H), 1.25 (t, 3 H), 1, 28- 1, 42 (m, 4 H), 1, 58-1, 70 (m, 4 H), 1, 97-2.05 (m, 3 H), 2.00 (s, 3 H), 2, 80 (d, 1 H), 3.06 (m, 1 H), 4.12 (m, 3 H), 4.26 (m, 2 H), 5.18 (d, 1 H); MS (ES +): 326.5 (M + 1). Analysis: Cale, for C18H31N04, 0.25H20: C: 65.52; H: 9.62; N: 4.25 Found: C: 65.48; H: 9.63; N: 4.27.

Example 52 (+) 1 -3- (1'-acetylamin-2'-ethyl) hexyl-t-4-hydroxycyclopentan-r-1-ethylcarboxylate (59, isomer B in C-1 'and mixture in C-2' , Scheme 9) &078-2 This compound was obtained with 34% yield as an oil from 50 (1.0 g, 3.55 mmol) using the same procedure as for compound 54.

Example 53 (+) t-3- (1'-acetylamin-2'-methyl) propyl-t-4-hydroxycyclopentan-r-1-ethylcarboxylate (60, isomer B in C-1 ', Scheme 9) &079 -1 This compound was obtained with a 15.5% yield as an oil from 51 (0.98 g, 4.1 mmol) using the same procedure as for compound 54. MS (ES +): 272.1 (M +1), Example 54 (+) t-3- (1'-acetylamin-1'-cyclohexyl) methyl-t-4-hydroxycyclopentan-r-1-ethyl carboxylate (61, isomer B in C-1 ', Scheme 9) &079 -2 This compound was obtained with 17% yield as an oil from 52 (1 g, 3.77 mmol) using the same procedure as for compound 54. MS (FS +): 312.0 (M + 1 ) Example 55 (+) t-3- (1'-Acetylaminopentyl) -t-4-hydroxycyclopentan-r-1-carboxylic acid (62, isomer A in C-1 ', Scheme 9) &080 To a mixture of 53 ( , 1 g, 0.37 mmol) in THF (2 mL) and EtOH (2 mL) was added 1 N NaOH (0.93 mL, 0.93 mmol) and water (2 mL). The mixture was stirred for 30 min. The solvent was removed, the residue was taken up in H20 and extracted with EtOAc (5 ml). The aqueous layer was acidified (pH 4) and extracted with EtOAc (2 x 5 mL). The organic extracts of the acidic mixture were combined and dried (MgSO). After filtration, the filtrate was concentrated and triturated with ether / hexane to give compound 62 (84%) as a white solid. 1 H NMR (DMSO-d 6): d ppm 0.85 (t, J = 5.0 Hz, 3 H), 1.26 (m, 6 H), 1.74 (m, 5 H), 1.86 (s, 3 H), 2.92 (m, 1 H), 3.54 (m, 1 H), 3.90 (s, 1 H), 4.60 (s, 1 H), 7.87 (d, J = 8.6 Hz, 1 H), 1 1, 96 (s, 1 H); IR (KBr): 3259, 31 12, 1727, 1607, 1200 cm "1; MS (ES +) 258.4 (100%, M + 1) Analysis: Cale, for C? 3H23N04: C: 60.68; H: 9.01; N: 5.44 Found: C: 60.63; H: 9.00; N: 5.45 Example 56 (+) t-3- (1'-Acetylaminopentyl) -t-4-hydroxycyclopentan-r-1-carboxylic acid (63, isomer mixture in C-1 ', Scheme 9) &081 To a mixture of compound 46 (3.0 g, 13.3 mmol) in THF (100 ml) was added acetic anhydride (25 ml, 270 mmol) and Raney nickel (3 g). The mixture was hydrogenated at 35 psi for 16 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 40-100% EtOAc in hexanes). The appropriate fractions were combined and concentrated. To the ester obtained above (0.15 g), THF (2 ml), EtOH (2 ml) and 1 N NaOH (2 ml, 2 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and concentrated in vacuo to remove the organic solvent. The aqueous layer was washed with EtOAc and acidified to pH 4 using 1 N HCl. The aqueous layer was saturated with sodium chloride and extracted with EtOAc (2 x 5 mL). The organic extracts of the acidic layer were combined and dried (MgSO). After filtration, the filtrate was concentrated under vacuum. The residue was triturated with ether / hexane (1: 1) to give compound 63, as a white solid. H NMR (DMSO-de): d 0.83 (m, 3 H), 1.3 (m, 5 H), 1.9 (m, 6 H), 2.9 (m, 1 H), 3 , 35 (s, 3 H), 3.5 (m, 0.4 H), 3.85 (m, 0.6 H), 3.95 (s, 0.4 H), 4.05 (s) , 0.6 H), 4.6 (s, 0.6 H), 4.7 (s, 0.4 H), 7.44 (d, J = 9.5 Hz, 0.6 H), 8.0 (d, J = 9.5 Hz, 0.4 H), 12.0 (s, 1 H); IR (KBr) 3303, 2951, 2934, 1726, 1688, 1650, 1550, 1202 cm "1; MS (ES +): 258.4 (100%, M + 1) Analysis: Cale, for C13H23N04: C: 60 , 68; H: 9.01; N: 5.44 Found: C: 60.67; H: 8.96; N: 5.42 Example 57 (+) t-3- (1'-Acetyl-aminopentyl) -t-4-hydroxycyclopentan-r-1-carboxylic acid (64, isomer B in C-1 ', Scheme 9) &082 This compound was obtained with a % yield as a hygroscopic solid from 54 (0.15 g, mmol) using the same procedure as for compound 62. 1 H NMR (DMSO-d6): d ppm 0.83 (t, J = 6.5 Hz, 3 H), 1, 26 (m, 5 H), 1, 47 (m, 2 H), 1, 61 (m, 1 H), 1, 71 (m, 1 H), 1, 79 ( s, 3 H), 1, 91 (m, 1 H), 2.02 (m, 1 H), 2.56 (m, 1 H), 3.37 (m, 1 H), 3.68 ( m, 1 H), 3.80 (dd, J = 13.0 and 6.6 Hz, 1 H), 7.44 (d, J = 9.5 Hz, 1 H), 1 1, 8 (brs , 1 HOUR); IR (NaCl) 3303, 2957, 2934, 1708, 1628, 1556, 1376 and 1221 cm "1; MS (ES +): 258.3 (100%, M + 1) Analysis: Cale, for C13H23N04: C: 60 , 68; H: 9.01; N: 5.44 Cale, for Ci3H23N04, 0.33H2O: C: 59.30, H: 9.06, N: 5.32 Found: C: 59.08, H: 8.85; N: 5.13 Example 58 (+) 1 -3- (1'-Acetylamin-2'-ethyl) butyl-t-4-hydroxycyclopentan-r-1-carboxylic acid (65, isomer A in C-1 ', Scheme 9) &083- 1 A mixture of compound 55 (8.4 mg, 0.03 mmol), 1 N sodium hydroxide (0.1 ml, 0.1 mmol) and water (0.2 ml) was stirred at room temperature for 2 h . The mixture was neutralized with 1N hydrochloric acid and diluted with water to obtain a 29.4 mmolar solution. MS (ES +): 272.2 (M + 1).

Example 59 (+) t-3- (1 '-acetylamino-2'-ethyl) butyl-t-4-hydroxycyclopentan-r-1-carboxylic acid (66, isomer B in C-1 ', Scheme 9) &083-2 This compound was obtained as a 44.2 mmol solution from 56 (5.3 mg, 0.0177 mmol) using the same procedure as for compound 65.

MS (ES +): 272.2 (M + 1).

Example 60 (+) t-3- (1'-acetylamino ^ '- propylJpentyl-tA-hydroxycyclopentan-rl-carboxylic acid (67, isomer B in C-1', Scheme 9) &084 To a solution of compound 57 ( , 15 g, 0.48 mmol) in THF (2 ml) and MeOH (2 ml) was added 1N NaOH (1.9 ml, 1.9 mmol) and water (1 ml), after stirring at room temperature for 1 h, the mixture was acidified to pH 3 using 6 N HCl. The solid was collected by filtration and dried under vacuum to give compound 67 in 96% yield, as a white solid. • 1 H NMR (DMSO-) of): d ppm 0.80 (t, J = 7.0 Hz, 3 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.99 (m, 2 H), 1 ..1 1 (m, 1 H), 1, 22 (m, 2 H), 1, 41 (m, 3 H), 1, 52 (m, 1 H), 1, 66 (m, 1 H), 1, 78 (s, 3 H), 1, 83 (m, 3 H), 1, 92 (m, 1 H), 2.86 (m, 1 HOUR), 3.95 (d, J = 2.8 Hz, 1 H), 4.07 (dt, J = 10.8 and 1.4 Hz, 1 H), 4.42 (d, J = 4.2 Hz , i 1 H), 7.24 (d, J = 10.3 Hz, 1 H), 11, 92 (s, 1 H); IR (KBr) 3369, 2962, 2934, 1695, 1596, 1548, 1217 cm "1; MS (ES +): 300.4 (100%, M + 1) Analysis: Cale, for C? 6H29N04: C: 64 , 19; H: 9.76, N; 4.68 Found: C: 64.04; H: 9.73, N; 4.68 Example 61 (+) 1 -3- (1 '-acetylamino-2'-cyclohexyl) ethyl-t-4-hydroxycyclopentan-r-1-carboxylic acid (68, isomer B in C-1', Scheme 9) & 085-1 This compound was obtained as a 50 mmolar solution from 58 (6.5 mg, 0.02 mmol) using the same procedure as for compound 65. MS (ES +): 320.4 (M + Na) .

Example 62 (+) Acid t-3- (1'-Acetylamin-2'-ethyl) hexyl-t-4-hydroxy-cyclopentan-r-1-carboxylic acid (69, isomer B in C-1 'and mixture in C-2', Scheme 9) &085-2 This compound was obtained as a 76 mmolar solution from 59 (10 mg, 0.0306 mmol) using the same procedure as for compound 65. MS (ES +): 300.5 (M + 1).

Example 63 (+) t-3- (1'-acetylamin-2'-methyl) propyl-t-4-hydroxycyclopentan-r-1-carboxylic acid (70, isomer B in C-1 ', Scheme 9) &086-1 This compound was obtained as an 80 mmolar solution from 60 (10 mg, 0.032 mmol) using the same procedure as for compound 65. MS (ES +): 266.0 (M + Na).

Example 64 (+) t-3- (1'-acetylamin-1'-cyclohexyl) methyl-t-4-hydroxycyclopentan-r-1-carboxylic acid (71, isomer B in C-1 ', Scheme 9) &086- 2 This compound was obtained as an 80 mmolar solution from 61 (10 mg, 0.032 mmol) using the same procedure as for compound 65. MS (ES +): 305.9 (M + Na).

Example 65 (±) methyl t-3- (1'-acetylaminopentyl) -t-4-methanesulfonyloxycyclopentan-r-1-carboxylate (72, isomer A in C-1 ', Scheme 9) &087-1 methansulfoyl (0.3 ml, 3.87 mmol) and Et3N (0.75 ml, 5.38 mmol) to a mixture of 53 (0.59 g, 2.17 mmol) and DMAP (30 mg, 0 mg). , 24 mmol) in dry CH 2 Cl 2 (10 ml) cooled to 4 ° C. After stirring at this temperature overnight, the reaction was quenched with H20 and extracted with CH2CI (2 x 50 ml). The combined organic extracts were washed with saline and dried (MgSO). After filtration, the filtrate was concentrated under vacuum to give compound 72 (83%) as an oil.

Example 66 (+) t-3- (1'-Acetylaminopentyl) -1 -4-methansulfonyloxycyclopentan-r-1-methylcarboxylate (73, isomer B in C-1 ', Scheme 9). & amp; 087-2 This compound was prepared from 54 (2.13 g, 7.85 mmol) using the same procedure as for compound 72 with 41% yield. It was recrystallized from ether / hexane to give the desired compound as a white solid. 1 H NMR (CDCl 3): d ppm 0.91 (m, 3 H), 1, 20-1, 45 (m, 4 H), 1.53-1.80 (m, 2 H), 1.98 ( s, 3 H), 2.01-2.21 (m, 4 H), 2.48-2.51 (m, 1 H), 3.02 (s, 3 H), 3.04-3. 10 (m, 1 H), 3.65 (s, 3 H), 4.00-4.15 (m, 1 H), 5.15-5.25 (m, 2 H); MS (ES +): 350.4 (M + 1). Analysis: Cale, for C? 5H27N06S: C: 51, 56; H: 7.79; N: 4.01 Found: C: 51, 44; H: 7.75; N: 4.25 Example 67 (+) t-3- (1'-acetylamin-2'-ethyl) butyl-4-methanesulfonyloxycyclopentan-r-1-methylcarboxylate (74, isomer B in C-1 ', Scheme 9) &088 -1 This compound was prepared from 56 (5.18 g, 18.2 mmol), using the same procedure as for compound 72 in 20% yield, as a yellow oil.

Example 68 (+) t-3- (1'-Acetylamin-2'-propyl) pentyl-t-4-methanesulfonyloxycyclopentan-r-1-carboxylic acid methyl ester (75, isomer B in C-1 ', Scheme 9) &; 088-2 This compound was prepared from 57 (1.92 g, 6.13 mmol) using the same procedure as for compound 72 with 81% yield.

Example 69 (±) t-3- (1 '-acetylaminopentyl) -c-4-azidocyclopentan-r-1-methylcarboxylate (76, isomer A in C-1 ', Scheme 9) &089-1 To a mixture of compound 72 (0.6 g, 1.72 mmol) in dry DMF (6 ml) was added sodium azide (0, 47 g, 7.2 mmol) and heated at 80 ° C for 3 h. The reaction was quenched with H20 (5 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with H20 (2 x 5 ml) and dried (MgSO). After filtration, the filtrate was concentrated to give a crude oil which was separated on a flash silica gel separation column using a mixture of 8 parts of dichloromethane and 2 parts of [chloroform (80): methanol (18): ammonium (2)] as an eluent to give 0.45 g (88%) of 76, as a white solid.

Example 70 (+) t-3- (1'-Acetylaminopentyl) -c-4-azidocyclopentan-r-1-methylcarboxylate (77, isomer B in C-1 ', Scheme 9) &089-2 This compound was prepared from 73 (2.4 g, 6.87 mmol) using the same procedure as for compound 76 with a 85 % from . performance, like a white solid. 1 H NMR (CDCl 3): d ppm 0.90 (m, 3 H), 1, 20-1, 40 (m, 5 H), 1.58-1.19 (m, 2 H), 1.95- 2.13 (m, 3 H), 2.01 (s, 3 H), 2.29-2.39 (m, 1 H), 2.75-2.80 (m, 1 H), 3, 50-3.61 (m, 1 H), 3.65 (s, 3 H), 4.05-4.10 (m, 1 H), 5.20 (d, 1 H, J = 6 Hz); MS (ES +): 297.4 (M + 1); IR (KBr): 3200, 3085, 2091, 1737, 1645 cm "1. Analysis: Cale, for C14H24N403: C: 56.74, H: 8.16, N: 18.90 Found: C: 56, 83; H: 8.14; N: 18.81 Example 71 (+) t-3 - [(1'-Acetylamin-2'-ethyl) butyl] -c-4-azidocyclopentan-r-1-methylcarboxylate (78, isomer B in C-1 ', Scheme 9) &; 090 This compound was prepared from 74 (1 g, 2.7 mmol) using the same procedure as for compound 76 with 74% yield.

Example 72 (±) t-3- (1'-acetylamin-2'-propyl) pentyl-c-4-azidocyclopentan-r-1-methylcarboxylate (79, isomer B in C-1 ', Scheme 9) &; 091-1 This compound was prepared from 75 (0.56 g, 1.44 mmol) using the same procedure as for compound 76 with 31% yield. 1 H NMR (CDCl 3): d ppm 0.9 (m, 6 H), 1, 04 (m, 1 H), 1.17 (m, 2 H), 1.37 (m, 7 H), 1, 69 (m, 1 H), 2.01 (s, 3 H), 2.02 (m, 1 H), 2.08 (m, 1 H), 2.37 (m, 1 H), 2, 84 (m, 1 H), 3.52 (dd, J = 15 and 7.5 HZ, 1 H), 3.69 (s, 3 H), 4.07 (m, 1 H), 5.17 (d, J = 10 Hz, 1 H); IR (KBr): 3280, 2959, 2872, 2104.1725, 1645, 1560, 1438, 1372 cm "1; MS (ES +): 339.5 (100%, M + 1). Analysis: Cale, for C17H30N4O3: C: 60.33; H: 8.93; N: 16.55 Found: C: 60.60; H: 8.85; N: 16.31 Example 73 (+) t-3- (1'-acetylaminopentyl) -c-4-amincyclopentan-r-1-methylcarboxylate (80, isomer A in C-1 ', Scheme 9) &091 -2 To a mixture of compound 76 (0.45 g, 1.5 mmol) in MeOH (10 mL) was added Pt02 (50 mg) and the mixture was hydrogenated at 50 psi for 12 h. The catalyst was removed by filtration, washed with MeOH and the filtrate was concentrated to dryness. The residue was purified using column chromatography [silica gel, elution with EtOAc followed by a mixture of chloroform (80): methanol (18): ammonium hydroxide (2)] to give compound 78 (27%). MS (ES +): 257.4 (M + 1).

Example 74 (+) t-3- (1'-acetylaminopentyl) -c-4-amincyclopentan-r-1-methylcarboxylate (81, isomer B in C-1 ', Scheme 9) &092 This compound was prepared from of 77 (95 mg, 0.32 mmol) using the same procedure as for compound 80 in 65% yield, as hydrochloride. 1 H NMR (DMSO-d 6): d ppm 0.85 (t, 3 H), 1, 10-1, 45 (m, 5 H), 1.71-1.90 (m, 5 H), 1, 91 (s, 3 H), 2.00-2.09 (m, 1 H), 2.15-2.28 (m, 1 H), 2.75-2 , 85 (rn, 1 H), 2.92-3.05 (m, 1 H), 3.65 (s, 3 H), 3.90-4.01 (m, 1 H), 7.95 -8.15 (m, 3 H); MS (ES +): 271, 4 (M + 1); IR (KBr): 3400, 3240, 1733, 1645 cm "1. Analysis: Cale, for: d4H26N203.HCI: C: 54.80, H: 8.87, N: 9.1 1 Found: C: 54, 77; H: 8.80; N: 8.72 Example 75 (+) t-3 - [(1'-Acetylamino-2'-ethyl) butyl] -c-4-amincyclopentan-r-1-methylcarboxylate (82, isomer B in C-1 ', Scheme 9) &093-1 This compound was prepared from 78 (0.5 g, 1.6 mmol) using the same procedure as for compound 80 with a 35 % yield, as a white solid. 1 H NMR (DMSO-de): d ppm 0.75 (t, 3 H, J = 7.2 Hz), 0.8 (t, 3 H, J = 7.2 Hz), 1.2 (m, 2 H), 1, 3 (m, 1 H), 1, 4 (m, 2 H), 1, 8 (m, 3 H), 1, 9 (s, 3 H), 2.2 (m, 2 H), 2.9 (m, 2 H), 3.6 (m, 3 H), 3.8 (m, 1 H), 8.0 (m, 3 H).

Example 76 (±) t-3- (1'-acetylamin-2'-propyl) pentyl-c-4-amincyclopentan-r-1-methylcarboxylate (83, isomer B in C-1 ', Scheme 9) &093 -2 This compound was prepared from 79 (0.7 g, 2.1 mmol) using the same procedure as for compound 80 in 90% yield, as hydrochloride. 1 H NMR (DMSO-de): d ppm 0.85 (m, 6 H), 1.26 (m, 8 H), 1.4 (m, 1 H), 1.77 (m, 2 H), 1.84 (m, 1 H), 1.88 (s, 3 H), 2.20 (m, 2 H), 2.83 (m, 1 H), 2.92 (m, 1 H), 3.61 (s, 3 H), 3.83 (t, J = 8.5 Hz, 1 H), 7.92 (d, J = 9 Hz, 1 H), 7 , 98 (s, 2H); IR (KBr): 3321, 2958, 2933, 2872, 1725, 1641, 1614, 1368, 1166 cm "1; MS (ES +): 313.4 (100%, M + 1). Analysis: Cale, for C? 7H32N203.HCI: C: 58.52; H: 9.53; N: 8.03 Cale, for C17H32N203.HCI, 0.75H20: C: 56.50; H: 9.34; N: 7.75 Found: C: 56.33; H: 9.24; N: 7.48.

Example 77 (+) t-3- (1'-Acetylaminopentyl) -c-4-amincyclopentan-r-1-carboxylic acid (84, isomer A in C-1 ', Scheme 9) &094-1 A mixture of the compound 80 (4.6 mg, 0.0017 mmol), 1 N sodium hydroxide (0.1 ml, 0.1 mmol) and water (0.2 ml) at room temperature for 2 h. The mixture was neutralized with 1N hydrochloric acid and diluted with water to give the desired compound as a 10.6 mmolar solution. MS (ES +): 257.0 (M + 1).

Example 78 (+) t-3- (1'-Acetylaminopentyl) -c-4-amincyclopentan-r-1-carboxylic acid (85, isomer B in C-1 ', Scheme 9) &094-2 It was prepared from 81 (10.9 mg, 0.036 mmol) using the same procedure as for compound 84, as a 35.4 mmolar solution. MS (ES +): 257.3 (M + 1).

Example 79 (+) t-3 - [(1'-acetylamin-2'-ethyl) butyl-c-4-amincyclopentan-r-1-carboxylic acid (86, isomer B in C-1 ', Scheme 9) &095 It was prepared from 82 (10 mg, 0.036 mmol) using the same procedure as for compound 84, as a 35.9 mmolar solution. MS (ES +): 271, 4 (M + 1).

Example 80 (+) t-3- (1'-Acetylamin-2'-propyl) pentyl-c-4-amincyclopentan-r-1-carboxylic acid (87, isomer B in C-1 ', Scheme 9) &096- 1 It was prepared from 83 (10.5 mg, 0.03 mmol) using the same procedure as for compound 84, as a 13.4 mmolar solution. MS (ES +): 299.4 (M + 1).

Example 81 (+) c-3- (1'-Acetylaminopentyl) -c-4-hydroxycyclopentan-r-1-methylcarboxylate (88, isomer B in C-1 ', Scheme 10) &096-2 Prepared from 45 (2.0 g, 8.9 mmol) with 88% yield using the same procedure as for the compound 54. The product was recrystallized from ether.

Example 82 (+) c-3- (1'-Acetylaminopentyl) -c-4-hydroxy-cyclopentan-r-1-carboxylic acid (89, isomer B in C-1, Scheme 10) &096-3 To a mixture of 88 (174 mg, 0.64 mmol) in TyF / MeOy (4 mL, 1: 1) was added 1 N NaOH (1.6 mL, 1.6 mmol) and the mixture was stirred for 30 min. The solvent was removed, the residue was taken up in H20 (10 ml) and extracted with EtOAC (2 x 10 ml). The aqueous layer was acidified (pH 4), extracted with EtOAc (2 x 10 mL). The combined organic extracts of the acidic layer were dried (MgSO4). After filtration, the filtrate was concentrated. The residue was triturated with ether / hexane to give compound 89 in 69% yield, as a white solid. 1 H NMR (DMSO-de): d ppm 0.95 (t, 3 H), 1, 13-1, 28 (m, 5 H), 1.51 -1, 87 (m, 5 H), 1, 75 (s, 3 H), 1, 98-2.07 (m, 1 H), 2.52-2.68 (m, 1 H), 3.75-3.84 (m, 1 H), 3.89 (br s, 1 H), 4.39 (br s, 1 H), 7.41 (s, 1 H), 1 1, 90 (s, 1 H); MS (ES +): 258.0 (M + 1); IR (KBr): 3500-2850, 3529, 3318, 1700, 1601, 1565 cm "1. Analysis: Cale, for C13H23N04: C: 60.68; H: 9.01; N: 5.44 Found: C: 60.57; H: 8.95; N: 5.40 Example 83 (+) c-3- (1'-acetylaminopentyl) -c-4-methanesulfonyloxycyclopentan-1-methylcarboxylate (90, isomer B in C-1 ', Scheme 10) &097 Prepared from 88 (1.4 g, 5.16 mmol) with 20% yield using the same procedure as for compound 72. 1 H NMR (CDCl 3): d 0.90 (t, 3 H, J = 6 , 5 Hz), 1, 21 -1, 48 (m, 5 H), 1, 61 -1, 75 (m, 1 H), 1, 92-2.30 (m, 7 H), 2.50 (dd, 1 H, J = 4.0 and 1.1 Hz), 2.81-2.95 (m, 1 H), 3.09 (s, 3 H), 3.68 (s, 3 H) ), 4.02-4.15 (m, 1 H), 5.10 (s, 1 H), 5.45 (d, 8.7 Hz, 1 H); IR (KBr) 3327, 1725, 1648 cm "1; MS (ES +): 350.0 (M + 1) .Analysis: Cale, for C? 5H27N06S C: 51, 56; H: 7.79; N: 4 , 01 Found C: 51, 82; H: 7.84; N: 4.02 Example 84 (+) methyl c-3- (1'-acetylaminopentyl) -t-4-azidocyclopentan-r-1-carboxylate (91, isomer B in C-1 ', Scheme 10) &098-1 Prepared from of 90 (0.712 g, 2.04 mmol) with 68% yield using the same procedure as for compound 76.

Example 85 (+) c-3- (1'-acetylaminylpentyl) -t-4-amincyclopentan-r-1-methylcarboxylate (92, isomer B in C-1 ', Scheme 10) &098-2 Prepared from of 91 (50 mg, 0.17 mmol) with 90% yield using the same procedure as for compound 80 and obtained as hydrochloride. 1 H NMR (DMSO-de): d ppm 0.85 (m, 3 H), 1.3 (m, 6 H), 1.5 (m, 1 H), 1.8 (m, 4 H), 2.1 (m, 3 H), 3.1 (m, 2 H), 3.6 (s, 3 H), 4.0 (m, 1 H), 7.9 (m, 1 H), 8.2 (m, 3 H); IR (KBr): 3249, 2955, 2933, 2871, 2361, 1732, 1645, 1548, 1437; MS (ES +): 271, 0 (100%, M + 1). Analysis: Cale, for: C H26N203.HCI, 0.7 H20: C: 52.71; H: 8.99; N: 8.78 Found: C: 53.09; H: 8.59; N: 8.20 Example 86 (+) c-3- (1'-Acetylaminopentyl) -t-4-amincyclopentan-r-1-carboxylic acid (93, isomer B in C-1 ', Scheme 10) &099-1 Prepared to from 92 (9.3 mg, 0.029 mmol) using the same procedure as for compound 84, as a 28.5 mmolar solution. MS (ES +): 257.0 (M + 1).

Example 87 (+) t-3- (1'-acetyl-laminopentyl) -c-4 - [(tert-butoxycarbonyl-lamin-tert-butoxycarbonylimin) methyl] aminc'clopentan-r-1-methylcarboxylate (94, isomer A in C-1 ', Scheme 11) &099-2 To a mixture of compound 80 (0.1 g, 0.38 mmol) in dry DMF (4 ml) was added Et3N (0.19 ml, , 32 mmol), 1,3-bi (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea (0.42 g, 0.12 mmol) and HgCl2 (0.1 1 g, 0.42 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (20 ml) and filtered through Celite. The filtrate was washed with water, saline and dried (MgSO4). After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 60-70% EtOAc in hexane) to give compound 94 in 34% yield as a colorless oil. MS (ES +): 513.6 (M + 1).

.: Example 88 (+) t-4- (1 '-acetylaminopentyl) -c-4 - [(tert-butoxycarbonylamino-tert-butoxycarbonylimin) methyl] amincyclopentan-r-1-methylcarboxylate (95, isomer B in C- 1 ', Scheme 1 1) &100 was prepared from 81 (1.3 g, 4.81 mmol) in 64% yield using the same procedure as for compound 94 and was obtained as a white solid. 1 H NMR (CDCl 3): d 0.90 (m, 3 H), 1.4 (m, 6 H), 1.48 (s, 9 H), 1.50 (s, 9 H), 1, 71-1, 85 (m, 1 H), 1, 88 (s, 3 H), 2.15-2.30 (m, 3 H), 2.75-2.85 (m , 1 HOUR), 3.70 (s, 3 H), 3.91-4.00 (m, 1 H), 4.42-4.51 (m, 1 H), 7.10 (m, 1 H), 8, 25 (m, 1 H), 1 1, 30 (m, 1 H); IR (KBr) 3323, 1721, 1716.1612 cm "1; MS (ES +): 513.7 (M + 1).

Analysis: Cale, for C25H44N4O7 C: 58.57; H: 8.65; N: 10.93 Found C: 58.30; H: 8.57; N: 10.93 Example 89 (+) t-3 - [(1'-Acetylamin-2'-ethyl) butyl-c-4 - [(tert-butoxycarbonylamin-tert-butoxycarbonylimin) methyl] amincyclopentan-r-1-methylcarboxylate (96, isomer B in C-1 ', Scheme 1 1) &101 -1 was prepared from 82 (0.26 g, 1 mmol) in 50% yield using the same procedure as for compound 94 and was obtained as a white solid.

Example 90 (+) t-3- (1'-Acetylamin-2'-propyl) pentyl-c-4 - [(tert-butoxycarbonylamin-tert-butoxycarbonylimin) methyl] amincyclopentan-r-1-methylcarboxylate (97, isomer B in C-1 ', Scheme 1 1) &101-2 It was prepared from 83 (0.58 g, 1.87 mmol) with 91% yield and was obtained as a white solid using the same procedure than for compound 94. 1 H NMR (CDCl 3): d ppm 0.88 (m, 6 H), 0.97 (m, 1 H), 1, 10-1, 46 (m, 7 H), 1, 48 (s, 9 H), 1, 49 (s, 9 H), 1, 70 (m, 1 H), 1, 83 (m, 2 H), 1, 97 (s, 3 H), 2, 06 (m, 1 H), 2.13 (m 1 H), 2.42 (m, 1 H), 2.87 (m, 1 H), 3.70 (s, 3 H), 3.95 (m, 1 H), 4.43 (m, 1 H), 5.66 (d, J = 9.9 Hz, 1 H), 8.56 (d, J = 8.6 Hz, 1 H) , 1 1, 44 (s, 1 H); IR (KBr): 3323, 2958, 2932, 2872, 1724, 1641, 1614, 1418, 1368, 1 166, 1 126, 1056 cm "1; MS (ES +): 555.8 (100%, M + 1) Analysis: Cale, for C28H5oN407: C: 60.63; H: 9.09; N: 10.10 Found: C: 60.69; H: 9.01; N: 10.10 Example 91 (+) t-3- (1'-Acetylaminopentyl) -c-4 - [(aminoimin) methyl] amincyclopentan-r-1-methylcarboxylate (98, isomer A in C-1 ', Scheme 1 1) & To a mixture of compound 94 (66 mg, 0.13 mmol) in CH 2 Cl 2 (2 mL) was added trifluoroacetic acid (0.1 mL, 1.3 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then subjected to evaporation to dryness to give compound 98 (63%) as a hygroscopic solid. MS (ES +): 313.0 (100%, M + 1) Analysis: Cale, for C15H28N403.CF3COOH: C: 47.88; H: 6.85; N: 13.14 Cale, for C? 5H28N403.CF3COOH. 0.75 H20: C: 46.41; H: 6.99; N: 12.74 Found: C: 46.44; H: 6.88; N: 12.67 Example 92 (+) 1 -3- (r-acetylaminopentyl) -c-4 - [(aminoimin) methyl] amincyclopentan-r-1-methylcarboxylate (99, isomer B in C-1 ', Scheme 1 1) & amp;; 103 Prepared from 95 (0.3 g, 0.59 mmol) with 89% yield as a white solid using the same procedure as for compound 98. 1 H NMR (DMSO-de): d ppm 0 , 80 (m, 3 H), 1, 2 (m, 6 H), 1, 5 (m, 1 H), 1, 8 (m, 6 H), 2.2 (m, 1 H), 2 , 7 (m, 1 H), 3.5 (m, 1 H), 3.6 (s, 3 H), 3.8 (m, 1 H), 7.0 (br s, 3 H), 7.8 (m, 2 H); IR (KBr) 3365, 3182, 2958, 2873, 1675, 1655, 1552 cm "1; MS (ES +): 313 (100%, M + 1). Analysis: Cale, for C? 5H28N403 1, 15 CF3C02H: C : 46.84, H: 6.63, N: 12.62 Found: C: 47.19, H: 6.83, N: 12.33 Example 93 (+) t-3 - [(1'-Acetylamin-2'-ethyl) butyl] -c-4 - [(aminonin) methyl] aminonclopentan-r-1-methylcarboxylate (100, isomer B in C-1 ', Scheme 1 1) &104 Prepared from 96 (0.32 g, 0.55 mmol) with 85% yield as a hygroscopic solid white using the same procedure as for the compound 98. 1 H NMR (DMSO-de): d ppm 0.80 (m, 6H), 1.3 (m, 5 H), 1.6 (m, 1 H), 1, 8 (m, 2 H), 1, 9 (s, 3 H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.4 (m, 1 H), 3.6 (m, 3 H), 3.8 (m, 1 H), 7.0 (br s, 4 H), 7.8 (m, 2 H); MS (ES +): 327.5 (100%, M + 1).

Analysis: Cale, for C? 6H3oN403 0.75CF3CO2H: C: 47.40; H: 6.43; N: 1 1, 34 Found: C: 48.13; H: 6.94; N: 1 1, 58 • Example 94 (+) t-3- (1'-Acetylamin-2'-propyl) pentlc-4 - [(tert-butoxycarbonyllamide-tert-butoxycarbonylimin) methyl] amincyclopentan-r-1-carboxylic acid ( 101, isomer B in C-1 ', Scheme 11) 10 &105 To a mixture of compound 97 (0.3 g, 0.54 mmol) in THF (5 ml) and MeOH (5 ml) was added NaOH 1 N (2.2 ml, 2.2 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated under vacuum to remove MeOH and THF. The aqueous layer was acidified with glacial AcOH and the The obtained solid was collected by filtration, washed with water, hexane and dried under vacuum to yield compound 101 in 87% yield, as a white solid. z -. 1 H NMR (DMSO-de): d ppm 0.80 (m, 6 H), 0.95 (m, 2 H), 1, 06 (m, 2 H), 1, 28 (m, 5 H), 1, 37 (s, 9 H), 1, 46 (s, 9 H), 1, 58 (m, 1 H), 1, 70 (m, 1 H), 1, 78 (s, 3 H), 1, 93) (m, 1 H), 2, 16 (m 2 H), 2.70 (m, 1 H), 3.81 (m, 1 H), 4, 19 (m, 1 H), 7.35 (d, J = 9.9 Hz, 1 H), 8.42 (d, J = 8.7 Hz, 1 H), 1 1, 48 (s, 1 H), 12.19 (s, 1 H); IR (KBr): 3317, 2958, 2933, 2872, 1724, 1641, 1614, 1418, 1368, 1 156, 127, 1056 cm "1; MS (ES +): 541, 7 (100%, M + 1) Analysis: Cale, for C27H48N407: C: 59.97; H: 8.95; N: 10.36 Found: C: 59.54; H: 8.81; N: 10.29 Example 95 (+) t-3- (1'-Acetylaminopentyl) -c-4 - [(aminoimin) methyl] aminocyclopentan-r-1-carboxylic acid (102, isomer A in C-1 ', Scheme 11) & 106-1 'A mixture of compound 98 (4.2 mg, 0.0095 mmol), 1 N sodium hydroxide (0.1 ml, 0.1 mmol) and water (0.2 ml) was stirred at room temperature. for 2 h. The mixture was neutralized with 1 N hydrochloric acid and diluted with water to give compound 102 as a 9.5 mmol solution. MS (ES +): 299.2 (M + 1).

Example 96 (+) t-3- (1'-Acetylaminopentyl) -c-4 - [(aminoimin) methyl] aminocyclopentan-r-1-carboxylic acid (103, isomer B in C-F, Scheme 11) & 106-2 It was prepared from 99 (13 mg, 0.042 mmol) using the same procedure as for compound 102, as a 19.5 mmolar solution. MS (ES +): 299.2 (M + 1).

Example 97 (+) t-3 - [(1 '-acetylamino-2'-ethyl) butyl] -c-4 - [(aminoimin) methyl] amincyclopentan-r-1 -carboxylic acid (104, isomer B in C- 1 ', Scheme 1 1) &107 Prepared from 100 (10.9 mg, 0.029 mmol) using the same procedure as for compound 102, as a 33.4 mmolar solution. MS (ES +): 313.4 (M + 1).

Example 98 (+) t-3- (1'-Acetylamin-2'-propyl) pentyl-c-4- [(aminoimin) methyl] amincyclopentan-r-1-carboxylic acid (105, isomer B in C-1 ', Scheme 1 1) &108 Prepared from 101 (0.2 g, 0.37 mmol) using the same procedure as for compound 98. After trituration with ether, compound 105 was obtained as a white solid with 65% yield 1 H NMR (DMSO-de): d ppm 0.82 (m, 6 H), 1.22 (m, 9 H), 1.62 (m, 2 H),, 82 (m, 1 H), 1 , 87 (s, 3 H), 2.1 1 (m, 2 H), 3.38 (m, 1 H), 3.76 (m, 1 H), 7.43 (br s, 4 H), 7.67 (d, J = 9.7 Hz, 1 H), 8.43 (s, 1 H), 12.5 (s, 1 H); IR (KBr): 3318, 2959, 2933, 2872, 1724, 1641, 1615, 1419, 1369, 1 156, 1 126, 1056 cm "1; MS (ES +): 341.5 (100%, M + 1) Analysis: Cale, for C17H32N403; 0.5 CF3COOH: C: 54.39; H: 8.24; N: 14.10 Cale, for C17H32N403; 0.5 CF3COOH.0,25H2O: C: 53.78; H: 8.27; N: 13.94 Found: C: 53.89; H: 8.00; N: 13.92 Example 99 (+) c-3- (1'-Acetylaminopentyl) -t-4 - [(tert-butoxycarbonylamino-tert-butoxycarbonylimin) methyl] amincyclopentan-r-1-methylcarboxylate (106, isomer B in C-1 ' Scheme 12) &109-1 Prepared from 92 (0.4 g, 1.48 mmol) using the same procedure as for compound 94, and was obtained with 60% yield as a white solid. 10 Example 100 • (+) methyl c-3- (-acetylaminopentyl) -t-4 - [(aminoimin) methyl] amincyclopentan-1-carboxylate (107, isomer B in C-1 ', Scheme 12) 15 & 109-2 - Prepared from 106 (0.35 g, 0.68 mmol) using the same procedure as for compound 98 and was obtained with 80% yield as a tan solid. 1 H NMR (DMSO-d 6): d ppm 0.80 (m, 3 H), 1.3 (m, 6 H), 1.6 (m, 2 H), 1.8 (s, 3 H), 1, 9 (m, 2 H), 2.1 (m, 1 H), 2.9 (m, 1 H), 3.5 (m, 1 H), 3 , 6 (s, 3 H), 3. 9 (m, 2 H), 7.2 (br s, 3 H), 7.8 (m, 2 H); MS (ES +): 313.1 (100%, M + 1). Analysis: Cale, for C15H28N403.1, 15 CF3C02H: C: 46.84; H: 6.64; N: 12.62 Found: C: 46.83; H: 6.74; N: 12.4 25 Example 101 (+) c-3- (1-Acetylaminopentyl) -t-4 - [(aminoimin) methy1] aminocyclopentan-r-1-carboxylic acid (108, isomer B in C-1 ', Scheme 12) & amp; 110 was prepared from 107 (11 mg, 0.0248 mmol) using the same procedure as for compound 102 and 24.8 mmolar was obtained as a solution. MS (ES +): 299.5 (M + 1).

Example 102 (1 S, 4 R) - (-) - 4-amincyclopent-2-en-1-carboxylic acid, hydrochloride (112, Scheme 13) &111-1 A mixture of (-) - (1 R, 4 S) was heated ) -2-azabicyclo [2.2.1] hept-5-en-3-one (109, 15 g, 137 mmol) and 1 N HCl (375 ml) at reflux for 1 h. The mixture was concentrated and the residue was dried under vacuum to give compound 112 in 95% yield. It was used as it was in the next step.

Example 103 Acid (1 R, 4S) - (+) - 4-aminciclopent-2-en-1-carboxylic acid, hydrochloride (113, Scheme 13) &1 1 1-2 Prepared from (+) - (1 S , 4R) -2-azabicyclo [2.2.1] hept-5-en-3-one (4.9 g) according to the method used for compound 112.

• Example 104 (+) - cis-4-aminciclopent-2-en-1-carboxylic acid, hydrochloride (114, Scheme 13) &112-1? O Prepared from (+) - 2-azabicyclo [2.2, 1] hept-5-en-3-one (111, 3.2 g) according to the method used for corhpuesto 112. • Example 105 (1S, 4R) - (-) - methyI-4-amincyclopent-2-en-1-carboxylate, hydrochloride (115, Scheme 13) &12-2 A mixture of (-) - (1 R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one (109.600 g, 5.51 mol) and 1 N methanolic HCl (12 I) at reflux for 10 h. The solvent was evaporated under reduced pressure and ether (800 ml) was added to the residue and cooled. The solid obtained was collected by filtration, washed with ether and dried to give 956 g (98%) of compound 115, as a white crystalline solid, m.p. 106-108 ° C. 1 H NMR (DMSO-d 6): d 1.98 (m, 1 H), 2.52 (m, 1 H), 3.6 (s, 3 H), 3.68 (m, 1 H), 4 , 15 (m 1 H), 5.88 (d, 1 H), 6.08 (d, 1 H), 8.40 (m, 2 H); MS (ES +): 142.11 (100%, M + 1); IR (KBr): 3004, 1722, 1239, 1217 cm "1. Cale analysis, for C7H9N02: C: 47.33; H: 6.81; N: 7.89 Found: C: 47, 12; H: 7 , 12; N: 7.85 Example 106 (1S, 4R) - (-) - ethyl-4-aminciclopent-2-en-1-carboxylate, hydrochloride (116, Scheme 13) &1 13-1 Method A: Prepared from (-) - (1 R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one (109.4.9 g) and ethanolic HCl according to the method used for compound 115. Method B : Also prepared from compound 112 and elanolic HCl according to the method used for compound 115.

Example 107 (1 R, 4S) - (+) - ethyl-4-aminciclopent-2-en-1-carboxylate, hydrochloride (117, Scheme 13) &113-2 Prepared from compound 113 (7.3 g) according to method B of compound 116.

Example 108 (+) - cis -methyl-4-aminciclopent-2-en-1-carboxylate, hydrochloride (118, Scheme 13) • &1 14-1 Prepared from (+) - 2-azabicyclo [2 , 2,1] hept-5-en-3-one (111.1 1 g) and methanolic HCl according to the method used for compound 115.

Example 109 • (+) - cis-ethyl-4-aminciclopent-2-en-1-carboxylate, hydrochloride (119, Scheme 13) &14-2 It was prepared from 114 (4.9 g) and ethanolic HCl of according to the method used for compound 116.

Example 1 10 (1S, 4R) - (-) - Methyl-4-tert-butoxycarbonylaminocyclopent-2-en-1-carboxylate (120, Scheme 13) &14-3 To a mixture of compound 115 (950 g, , 35 mol) and di-tert-butyldicarbonate (1226 g, 5.62 mol) in dichloromethane (12 I) at 0 ° C was added triethylamine over a period of 2.5 h and the reaction mixture was stirred additionally for 1 hr. h. The reaction mixture was washed with water (2 x 8 I) and saline (2 x 4 I) and the organic layer was separated and dried over MgSO4. After filtration, the filtrate was concentrated and the residual thick syrup was crystallized from hexane to give 1 196 g (92%) of compound 120 in 3 parts. 1 H NMR (CDCl 3): d 1.44 (s, 9 H), 1.85 (m, 1 H), 2.51 (m 1 H), 3.47 (m, 1 H), 3.71 ( s, 3 H), 4.78 (m, 1 H), 4.88 (br s, 1 H), 5.86 (m, 2 H); MS (ES +): 242.25 (80%, M + 1). Analysis: Cale, for C12H19N04: C: 59.73; H: 7.94; N: 5.80 Found: C: 59.57; H: 7.86; N: 5.79 Example 1 1 1 (1S, 4R) - (-) - etl-4-tert-butoxycarbonylaminocyclopent-2-en-1-carboxylate (121, Scheme 13) &1 15 Prepared from 116 (17.5 g) according to the method used for compound 120.

Example 1 12 (1, R, 4S) - (+) - Ethyl-4-tert-butoxycarbonylamino-cyclopent-2-en-1-carboxylate (122, Scheme 13) &1 16-1 Prepared from 117 (8.4 g) according to the method used for compound 120.

Example 1 13 (+) - cis-methyl-4-tert-butoxycarbonylaminocyclopent-2-en-1-carboxylate (123, Scheme 13) &1 16-2 Prepared from 118 (17.8 g) according to the method used for compound 120.

Example 1 14 (+) - cis-etl-4-tert-butoxycarbonylaminocyclopent-2-en-1-carboxylate (124, Scheme 13) &116-3 Prepared from 119 (20.8 g) according to the method used for compound 120.

Example 1 15 (3aR, 4R, 6S, 6a, S) - (+) - methyl-4-tert-butoxycarbonylamin-3- (1'-ethylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d ] isoxazole-6-carboxylate (125, Scheme 13) &117 Method A: A mixture of 120 (949 g, 3.93 mol) and phenyl isocyanate (1.5 I, 13.8) was heated under reflux. mol) in benzene (10 I). To this mixture was added a mixture of 2-ethyl-1-nitrobutane (918 g, 5.92 mol, 95% pure by 1 H NMR) and triethylamine (55 ml, 0.40 mol) in benzene (2 I) over a period of 5 h. The reaction mixture was further stirred under reflux for 24 h. After cooling, the solid was removed by filtration, the filtrate was concentrated and ethyl ether (2 I) was added to the residue. The mixture was allowed to stand overnight, again the solids were separated by filtration and the filtrate was concentrated under vacuum to give 1.991 kg of a dark brown syrup. The product obtained above was dissolved in THF (5.0 L) and ethanol (7.5 L). To this mixture was added NaOH (454 g in 5 l of cold water) and the mixture was stirred at room temperature for 3 h. The mixture was then concentrated under vacuum. The residue was dissolved in water (10 L), extracted with ethyl ether (2 x 2 L) and the organic layers were discarded. The aqueous layer was acidified with acid Acetic acid was extracted with ethyl acetate (2 x 7 I), the combined organic extracts were dried (MgSO 4) and the organic layer was concentrated to give 1.75 Kg of crude acid. To the above product in methanol (19.5 I) conc. HCl was added. (162 ml) and the mixture was stirred at room temperature for 16 h. The mixture was neutralized with ammonium hydroxide and the solvent was evaporated under vacuum to give 1, 422 Kg of the crude ester. The crude product was dissolved in ethyl acetate (5 L), washed with water (5 L) and saline (5 L) and dried (MgSO). After filtration, the filtrate was concentrated and the residue was purified by passing it through a silica gel column using a hexane / ethyl acetate mixture (95/5 to 85/15) as eluent. The appropriate fractions were pooled and concentrated to give 984 g (70.5%) of 125, m.p. 66 ° C. Analysis: Cale, for C? 8H3oN205: C: 61, 00; H: 8.53; N: 7.90 Found: C: 61, 13; H: 8.45; N: 7.84 1 H NMR (CDCl 3): d ppm 0.87-0.95 (m, 6H), 1.44 (s, 9 H), 1.58-1.78 (m, 4 H); 2.0-2.15 (m, 2H), 2.51 (bs, 1 H), 3.21 (d, J = 8.1 Hz, 1 H), 3.58 (d, J = 8, 8 Hz, 1 H), 3.76 (s, 3 H), 4.23 (bs, 1 H), 5.21 (d, 1 H, J = 8.8 Hz), 5.59 (bs, • 5 1 H); MS (HS +): 355.64 (M + 1). Method B: The reaction of the compound cyclopentene 120 with 1-nitro-2-elilbutane and phenyl-socianate was carried out as described in Method A. After completion of the reaction (24 h reflux), the solids were separated by filtration and the filtrate was concentrated. The residue was purified two times by passing it through a column of silica gel using a mixture of ethyl acetate: hexane as eluent. • Method C: A mixture of 120 (1.08 kg, 4.46 mol) and 2-ethylbutyrhydroximinoyl chloride (prepared from 2-ethyl butyraldoxime and N-chlorosuccinimide, 614 g, 4.1 mol) was heated to reflux. in THF (8 I). To this mixture was added a mixture of triethylaniline (340 ml., 2.4 mol) in THF over a period of 1.5 h. An additional amount of chloro-oxime (550 g, 3.7 mol) was added followed by a mixture of triethylamine (340 ml, 2.4 mol) in THF (340 ml) on a pepod of 1 h. This exact addition was repeated twice. Additional triethylamine (100 ml, 0.7 mol) was added for 30 min. The reaction mixture was further heated to reflux for 16 h. The reaction mixture was cooled and the insoluble solid was removed by filtration. The filtrate was concentrated and the residue was purified either by chromatography or through an acid-base treatment as described in Methods A and B.

Example 116 (3aR, 4R, 6S, 6a, S) - (+) - methyl-4-tert-butoxycarbonylamin-3- (1'-propylbutyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d ] isoxazole-6-carboxylate (126, Scheme 13) &119 Prepared from 120 (171 g) using the same procedure as for compound 125 (Method A).

Example 117 (3a, R, 4R, 6S, 6aS) - (+) - ethyl-4-tert-butoxycarbonylamin-3- (1'-ethylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole -6-carboxylate (127, Scheme 13) &120-1 Prepared from 121 (5.64 g) using the same procedure as for 125 (Method B).

Example 118 (3aR, 4R, 6S, 6aS) - (+) - ethyl-4-tert-butoxycarbonylamin-3- (1'-propylbutyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole -6-carboxylate (128, Scheme 13) & 120-2 Prepared from 121 (16.1 g) using the same procedure as for compound 125 (Method B).

Example 119 (3aS, 4S, 6R, 6aR) - (-) - ethyl-4-tert-butoxycarbonylamin-3- (1'-ethylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole-6 carboxylate (129, Scheme 13) &121-1 Prepared from 122 (5.1 g) using the same procedure as for compound 125 (Method B).

Example 120 (+) 4-tert-butoxycarbonylamino-3- (1'-ethylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole-6-carboxylic acid methyl ester (The NHBoc and ester groups are cis yes but trans with respect to the isooxazoline ring, 130, Scheme 13) &121-2 Prepared from 123 (4.8 g) using the same procedure as for compound 125 (Method B).

Example 121 (+) 4-tert-Butoxycarbonylamino-3- (1'-propylbutyl) -4,5,6,6a-tetrahydro-3aH-cyclopentyl [d] isoxazole-6-carboxylic acid ester (the NHBoc and ester groups are cis yes but trans with respect to the isooxazoline ring, 131, Scheme 13) &122-1 Prepared from 123 (4.0 g) using the same procedure as for compound 125 (Method B).

Example 122 (+) 4-tert-Butoxycarbonylamino-3- (2'-ethylbutyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole-6-carboxylic acid methyl ester (the NHBoc and ester groups are cis yes but trans with respect to the isooxazoline ring, 132, Scheme 13) &122-2 Prepared from 123 (1.18 g) using the same procedure as for compound 125 (Method B).

Example 123 (+) 4-tert-butoxycarbonylamino-3- (n-butyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole-6-carboxylic acid methyl ester (the NHBoc and ester groups are cis to each other but trans to the isooxazoline ring, 133, Scheme 13) &123-1 Prepared from 123 (1.2 g) using the same procedure as for compound 125 (Method B).

Example 124 (+) 4-tert-butoxycarbonylamino-3- (1'-ethylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole-6-carboxylic acid ethyl ester (the NHBoc and ester groups are cis yes but trans with respect to the isooxazoline ring, 134, Scheme 13) & 123-2 It was prepared from 124 (4.8 g) using the same procedure as for compound 125 (Method B).

Example 125 (+) - 4-tert-butoxycarbonylamino-3- (1'-methylpropyl) -4,5,6,6a-tetrahydro-3aH-cyclopent [d] isoxazole-6-carboxylic acid ethyl ester (mixture in C-1 ', the NHBoc and ester groups are cis to each other but trans to the ring, sooxazoline, 135, Scheme 13) &124-1 was prepared from 124 (3.5 g) using the same procedure as for compound 125 ( Method B).

Example 126 (+) - ethyl 4-tert-butoxycarbonylamino-3- (1'-methylethyl) -4,5,6,6a-tetrahydro-3aH-cyclopentyl [d] isoxazole-6-carboxylate (the NHBoc and ester groups are cis each other but trans with respect to the isooxazoline ring, 136, Scheme 13) & 124-2 It was prepared from 124 (2.9 g) using the same procedure as for compound 125 (Method B).

Example 127 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl-3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amine-2-hydroxycyclopentan-1 carboxylate (137, Scheme 14) &125 To a mixture of 125 (80 g, 0.226 mol) in methanol (1.6 I) conc. HCl was added. (18.8 ml, 0.226 mol) and Adam catalyst (Pt02, 8.0 g) and the mixture was stirred vigorously at 100 psi hydrogen pressure for 4 h. The catalyst was removed by filtration and the filtrate was concentrated to give 82, 7 g (93%) of (1 S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1' -amin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amin -2-hydroxycyclopentane-1-carboxylate, which was used as it was for acetylation. To the amine hydrochloride obtained above (66.2 g, 0.168 mol) in dichloromethane (600 ml), triethylamine (23.4 ml, 0.168 mol) and acetic anhydride (17.5 ml, 0.184 mol) were added at room temperature and it was stirred for 2 h. The reaction mixture was washed with water (600 ml). The water layer was re-extracted with dichloromethane (200 ml). The combined organic layers were washed with water (300 ml) and saline (300 ml) and dried over magnesium sulfate. After filtration, the filtrate was concentrated and the residue was purified by passing through a column of silica gel using hexane / ethyl acetate (1: 1) as eluent. The appropriate fractions were pooled and concentrated to give 45 g (67%) of compound 137. Analysis: Cale, for C2oH36N206: C: 59.98; H: 9.06; N: 6.99, Found: C: 59.89; H: 8.91; N: 6.94 1 H NMR (CDCl 3): d ppm 0.77-0.87 (m, 6 H), 1.19-1.44 (m, 15 H), 1.66-1.72 (m , 1 H), 1, 96-2.00 (m, 1 H), 2.08 (s, 3 H), 2.45-2.53 (m, 1 H), 2.80-2.84 (m, 1 H), 3.70 (s, 3 H), 3.99-4.04 (m, 1 H), 4.11 -4.15 (m, 1 H), 4.23 (d) , J = 5.2 Hz, 1 H), 4.78 (d, J = 9.3 Hz, 1 H), 7.55 (d, J = 10.0 Hz, 1 H); MS (ES +): 401, 75 (M + 1).

Example 128 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) pentyl-4-tert-butoxycarbonyl-amin-2-hydroxycyclopentane-1-carboxylate (138, Scheme 14) &126-1 Prepared from 126 (77 g) using the same procedure as for compound 137.

Example 129 (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-2-amin-2 -hydroxycyclopentan-1-carboxylate (139, Scheme 14) & 126-2 It was prepared from 127 (5 g) using the same procedure as for compound 137.

Example 130 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) pentyl-4-tert-butoxycarbonyl-amin-2-hydroxycyclopentane-1-carboxylate (140, Scheme 14) &127-1 Prepared from 128 (15 g) using the same procedure as for compound 137.

Example 131 (1 R, 2R, 3S, 4S, 1 'R) - (±) -ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amin-2-hydroxycyclopentan-1-carboxylate (141, Scheme 14) &127-2 Prepared from 129 (5.9 g) using the same procedure as for compound 137.

Example 132 (+) t-3- (1 '-acetylamin-2'-ethyl) butyl-c-4-tert-butoxycarbonylamino-t-2-hydroxy-cyclopentan-r-1-methylcarboxylate (142, isomer A in C- 1 ', Scheme 14) &128-1 Prepared from 130 (2.6 g) using the same procedure as for compound 137.

Example 133 (+) t-3- (1'-Acetylamin-2'-propyl) pentyl-c-4-tert-butoxycarbonylamino-t-2-hydroxycyclopentan-r-1-methylcarboxylate (143, isomer A in C-1 ', Scheme 14) &128-2 Prepared from 131 (6.2 g) using the same procedure as for compound 137.

Example 134 (+) t-3- (1 '-acetylamino-3'-ethyl) pentyl-c-4-tert-butoxycarbonylamino-t-2-acetyloxycyclopentan-r-1-methylcarboxylate (144, isomer A in C-1) ', Scheme 14) & 129-1 Prepared from 132 (2.4 g) using the same procedure as for compound 137, except that during acetylation an excess of acetic anhydride (2.5 equivalents) and triethylamine (2.5 equivalents) was used. ).

Example 135 (+) t-3- (1'-Acetylamin-n-butyl) -c-4-tert-butoxycarbonylamino-1-acetyloxy-cyclopentan-r-1-methyl carboxylate (145, isomer A in C- 1 ', Scheme 14) & 129-2 It was prepared from 133 (0.45 g) using the same procedure as for compound 137, except that during acetylation an excess of acetic anhydride (2.5 equivalents) and triethylamine (2.5 equivalents) was used. ). • Example 136 (+) t-3- (1'-Acetylamin-2'-ethyl) butyl-c-4-tert-butoxycarbonylamino-t-2-hydroxycyclopentan-r-1-ethyl carboxylate (146, isomer A in C-1 ', Scheme 10 14) &130-1 • Prepared from 134 (2.6 g) using the same procedure as for compound 137.

Example 137 (+) t-3- (1'-Acetylamin-2'-methyl) butyl-c-4-tert-butoxycarbonylamin-t-2-hydroxycyclopentan-r-1-ethyl carboxylate (147, isomer A in C-1 ', mixture in C-2', Scheme 14) 20 &130-2 Prepared from 135 (1.3 g) using the same procedure as for compound 137.

Example 138 25 (+) t-3- (1'-Acetylamin-2'-methyl) propyl-c-4-tert-butoxycarbonylamin-t-2-hydroxycyclopentan-r-l-carboxylic acid ethyl ester (148, isomer A in C-1 ', Scheme 14) &131 -1 Prepared from 136 (1.39 g) using the same procedure as for compound 137.

Example 139 (1S, 2S, 3R, 4R, 1 ', S) - (-) - methyl 3- (1'-acetylamin-2'-ethyl) butyl-4-amin-2-hydroxy-cyclopentan-1-carboxylate, hydrochloride (149, Scheme 14) &131-2 To a mixture of 137 (150 g, 0.375 mol) in ether (800 ml) was added 1N HCl in ether (1 170 mL, 1.17 mole) and stirred at room temperature for 24 h and then heated to reflux for 2 h. After cooling, the solid was collected by filtration, washed with ether and dried under vacuum to give 126 g of 149. This compound was used as it was in the next step.

Example 140 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) pentyl-4-amin-2-hydroxycyclopentan-1-carboxylate, hydrochloride (150 , Scheme 14) &132-1 Prepared from 138 (10.4 g) using the same procedure as for compound 149.

Example 141 (1S, 2S, 3R, 4R, 1 'S) - (-) - eti 3- (1'-acetylamin-2'-ethyl) butyl-4-amin-2-hydroxycyclopentan-1 - carboxylate, trifluoroacetate (151, Scheme 14) &132-2 To a mixture of 139 (1.3 g, 3.14 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (4.0 ml) and stirred room temperature for 6 h. It was concentrated and co-evaporated 2 times with dichloromethane and 2 times with ether. The residue was dried under vacuum to give 151, which was used as it was in the next step.

Example 142 (1R, 2R, 3S, 4S, rR) - (+) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4-amin-2-hydroxy-cyclopentan-1-carboxylate, trifluoroacetate (152 , Scheme 14) &133-1 Prepared from 141 (0.6 g) using the same procedure as for compound 151.

Example 143 (±) -methyl 1 -3- (1'-acetylamin-2'-ethyl) butyl-c-4-amin-t-2-hydroxy-cyclopentan-r-1-carboxylate, trifluoroacetate (153, isomer A in C -1 ', Scheme 14) &133-2 Prepared from 142 (0.8 g) using the same procedure as for compound 151.

Example 144 (±) -methyl t-3- (1'-acetylamin-2'-propyl) pentyl-c-4-amin-t-2-hydroxycyclopentan-r-1-carboxylate, trifluoroacetate (154, isomer A in C-1 ', Scheme 14) &134-1 Prepared from 143 (0.39 g) using the same procedure as for compound 151.

Example 145 (+) - methyl t-3- (1'-acetylamin-3'-etl) pentlc-4-amin-t-2-acetyloxycyclopentan-r-1-carboxylate, trifluoroacetate (155, isomer A in C-1 ', Scheme 14) & 134-2 Prepared from 144 (0.47 g) using the same procedure as for compound 151.

Example 146 (+) - methyl t-3- (1'-acetylamin-n-butyl) -c-4-amin-t-2-acetyloxycyclopentan-r-1-methylcarboxylic acid trifluoroacetate (156, isomer A in C- 1 ', Scheme 14) &135-1 Prepared from 145 (0.27 g) using the same procedure as for compound 151.

Example 147 (+) - ethyl 1 -3- (1'-acetylamin-2'-ethyl) butyl-4-amin-1 -2-hydroxycyclopentan-r-1-carboxylate, trifluoroacetate (157, isomer A in C-1 ', Scheme 14) & 135-2 It was prepared from 146 (0.8 g) using the same procedure as for compound 151.

Example 148 (+) - ethyl t-3- (1'-acetylamin-2'-methyl) butyl-c-4-amynt-2-hydroxyclopentan-r-1-carboxylate, trifluoroacetate (158, isomer A in C -1 ', mix in C-2', Scheme 14) &136-1 Prepared from 147 (0.74 g) using the same procedure as for compound 151.

I0I Example 149 (+) - ethyl t-3- (1'-acetylamin-2'-meth1) propyl-c-4-amynt-2-hydroxycyclopentan-r-1-carboxylate, trifluoroacetate (159, isomer A in C -1 ', Scheme 14) &136-2 Prepared from 148 (1.0 g) using the same procedure as for compound 151.

Example 150 Acid (1 S, 2.5.3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4-amin-2-hydroxycyclo] -. Pentan-1-carboxylic acid (160, Scheme 14) &137-1 A mixture of 151 (14 mg, 0.0327 mmol) in 1 N NaOH (0.1 mL) and water (0.2 mL) was stirred room temperature for 2 h. The reaction mixture was neutralized with 1 N HCl and diluted with water to give a> 0.degree. 32.7 mmolar solution. MS (ES +): 297.4 (100%, M + 1) " Example 151 Acid (1 R, 2R, 3S, 4S, 1 'R) - (±) -3- (1'-acetylamin-2'-etyl) butyl-4-amin-2-hydroxy-pentane-1-carboxylic acid ( 161, Scheme 14) & 137-2 It was prepared from 152 (100 mg, 0.234 mmol) using the same procedure as for compound 160 and 93.6 mmolar was obtained as a solution. MS (ES +): 287.4 (100%, M + 1).

Example 152 Acid (±) -t-3- (1'-acetylamin-2'-ethyl) butyI-c-4-amin-t-2-hydroxycyclopentan-r-1-carboxylic acid (162, isomer A in C -1 ', Scheme 14) &138-1 Prepared from 153 (12.5 mg, 0.030 mmol) using the same procedure as for compound 160 and 30.0 mmolar was obtained as a solution. MS (ES +): 287.4 (100%, M + 1).

Example 153 (+) - T-3- (1'-Acetylamin-2'-propyl) pentyl-c-4-amin-t-2-hydroxycyclopentan-r-1-carboxylic acid (163, isomer A in C-1 ', Scheme 14) &138-2 Prepared from 154 (7.5 mg, 0.017 mmol) using the same procedure as for compound 160 and 7.7 mmol was obtained as a solution. MS (FS +): 315.5 (100%, M + 1).

Example 154 Acid "(+) - t-3- (1 '-acetylamino-3'-ethyl) pentyl-c-4-amin-t-2-hydroxycyclopentan-r-1 -carboxylic acid (164, isomer A in C- 1 ', Scheme 14) &139-1 was prepared from 155 (10.6 mg, 0.0225 mmol) using the same procedure as for compound 160 and 21.5 mmolar was obtained as a solution. ES +): 301, 4 (100%, M + 1).

Example 155 Acid (±) t-3- (1 '-acetylamin-n-butyl) -c-4-amin-t-2-hydroxycyclopentan-r-1 -carboxylic (165, isomer A in C-1', Scheme 14) &139-2 Prepared from 156 (5.0 mg, 0.01 mmol) using the same procedure as for compound 160 and a 1.0 mmol solution was obtained as a solution. MS (ES +): 273.0 (100%, M + 1).

Example 156 (±) -t-3- (1'-Acetylamin-2'-methyl) butyl-c-4-amin-t-2-hydroxycyclopentan-r-1-carboxylic acid (166, isomer A in C-1 ', mixture in C-2 ', Scheme 14) &140-1 Prepared from 158 (9.5 mg, 0.0229 mmol) using the same procedure as for compound 160 and obtained as a solution 9.36 mmolar. MS (ES +): 273.5 (100%, M + 1).

Example 157 (+) - t-3- (1'-Acetylamin-2'-methyl) propyl-c-4-amin-t-2-hydroxycyclopentan-r-1-carboxylic acid (167, isomer A in C-1) ', Scheme 14) & 140-2 Prepared from 159 (9.5 mg, 0.0237 mmol) using the same procedure as for compound 160 and 12.9 mmol was obtained as a solution. MS (ES +): 259.4 (100%, M + 1).

Example 158 (1S, 2S, 3R, 4R, l'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(tert-butoxycarbonyl-amin-tert-butoxycarbonylimin) methyl] amin -2-hydroxycyclopentane-1-carboxylate (168, Scheme 15) &141-1 Prepared from 151 (0.65 g) using the same procedure as for compound 94. Example 159 (+) - methyl t- 3- (1'-Acetylamin-2'-ethyl) butyl-c-4 - [(tert-butoxycarbonylamin-tert-butoxycarbonylimin) methyl] amin-1-2-hydroxy-cyclopentan-r-1-carboxylate ( 169, isomer A in C-1 ', Scheme 15) &141-2 Prepared from 153 (0.6 g) using the same procedure as for compound 94.

Example 160 (+) - methyl t-3- (1'-acetylamin-3'-ethyl) pentyl-c-4-r (tert-butoxycarbonylamino-tert-butoxycarbonylimin) methyl] amin-t-2-acetyloxycyclopentan-r- 1-carboxylate (170, isomer A in C-1 ', Scheme 15) &142-1 - Prepared from 155 (0.25 g) using the same procedure as for compound 94.

Example 161 (+) - methyl t-3- (1 '-acetylamin-n-butyl) -c-4 - [(tert-butoxycarbonylamin-tert-butoxycarbonyl imin) methyl] amin-t-2-acetyloxy-cyclopentan-r-1-carboxylate (171, isomer A in C-1 ', Scheme 15) &142-2 Prepared from 156 (0.26 g) using the same procedure as for compound 94.

Example 162 (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(N-tert-butoxycarbonyl-N-ter) -N-methylamin-N'-tert-butoxycarbonylimin) methyl] amin-2-hydroxycyclopentane-1-carboxylate (172, Scheme 15) &143-1 Prepared from 151 (0.46 g) using the same procedure as for compound 94. The reagent used was 1, 3-bi (tert-butoxycarbonyl) -N-methyl-2- (2,4-dinitrophenyl) -2-thiopseudourea instead of 1, 3 -bi (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea and RgCI2 was not needed.

Example 163 (1S, 2S, 3R, 4R, 1 'S) - (-) - et! 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminimin) metit] -amin-2-hydroxycyclopentane-1-carboxylate (173, Scheme 15) & 143-2 It was prepared from 168 (0.1 g) using the same procedure as for compound 151.

Example 164 (+) - met? I t -3- (1 '-acetylamino-2'-ethyl) butyl-c-4 - [(aminimin) methyl] amin-t-2-hydroxycyclo pentan-r-1-carboxylate (174 , isomer A in C-1 ', Scheme 14) &144-1 Prepared from 169 (0.38 g) using the same procedure as for compound 151.

Example 165 (+) - methyI-3- (1'-acetylamin-3'-ethyl) pentyl-c-4 - [(aminimin) methyl] amin-1-acetyloxy-2-acetyloxy-r-1-carboxylate (175, isomer A in C-1 ', Scheme 15) &144-2 Prepared from 170 (0.1 g) using the same procedure as for compound 151.

Example 166 (+) - methyl t-3- (1 '-acetylamin-n-butyl) -c-4 - [(aminimin) methyl] amin-t-2-acetyloxycyclo pentan-r-1-carboxylate (176, isomer A in C-1 ', Scheme 15) &145-1 Prepared from 171 (0.08 g) using the same procedure as for compound 151.

Example 167 (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4 - [(N-methylaminimin) methyl] amin-2- hydroxycyclopentane-1-carboxylate (177, Scheme 15) & 145-2 It was prepared from 172 (0.3 g) using the same procedure as for compound 151.

Example 168 Acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin) methylene] amine -2-hydroxycyclopentane-1-carboxylic acid (178, Scheme 15) &146 Method A: Prepared from 173 (7.8 mg, 0.0166 mmol) using the same procedure as for compound 160 and was obtained as a 7.2 mmolar solution. MS (ES +): 329.5 (M + 1). Method B: To a mixture of 149 (3.0 g, 8.9 mmol) in DMF (20 ml) was • added pyrazolecarboxamidine hydrochloride (1.56 g, 10.6 mmol) and diisopropylethylamine (3.9 ml, 22.4 mmol) and heated at 60 ° C for 36 h. An additional amount of pyrazolecarboxamidine hydrochloride (0.65 g) and diisopropylethylamine (1 ml) was added and heated at 60 ° C for a further 12 h. The solvent was evaporated under reduced pressure. To the residue was added 1 N NaOH (22 ml, 22 mmol) and stirred at room temperature for 5 h. The reaction mixture was extracted with ethyl acetate (3 x 25 ml) and the aqueous layer was concentrated. A solid was obtained which was collected by filtration and dried to give 1.22 g (39%) of compound 178. 1 H NMR (D20): 1 H NMR (D20): d ppm 0.90 (m, 3 H), 0.95 (m, 3 H), 1.05 ( m, 2 H), 1, 5 (m, 3 H), 1, 8 (m, 1 H), 2.0 (s, 3 H), 2.3 (m, 1 H); 2.55 (m, 1 H), 2.75 (m, 1 H), 3.9 (m, 1 H), 4.4 (m, 2H).

Analysis: Cale, for C? 5H28N 04.H20: C: 52.01; H: 8.73; N: 16.17 Found: C: 51, 64; H: 8.57; N: 16.14 Example 169 (±) -t-3- (1'-Acetyl-2'-ethyl) butyl-c-4 - [(aminoimin) methyl] amin-1-hydroxy-cyclopentan-1-carboxylic acid (179, isomer) A in C-1 ', Scheme 15) &147 Prepared from 174 (12.0 mg, 0.0263 mmol) using the same procedure as for compound 160 (Method A) and was obtained as a solution. , 3 mmolar. MS (ES +): 329.5 (M + 1).

Example 170 (+) - t-3- (1'-Acetylamino-3'-ethyl) pentyl-c-4 - [(aminoimin) methyl] amin-t-2-hydroxycyclopentan-r-1-carboxylic acid (180, isomer A in O-1 ', Scheme 15) "&148-1 was prepared from 175 (9.0 mg, 0.0176 mmol) using the same procedure as for compound 160 (Method A) and was obtained as a 17.6 mmolar solution MS (ES +): 343.5 (M + 1).

Example 171 (+) - t-3- (1'-Acetylamin-n-butyl) -c-4 - [(aminoimin) methyl] amynt-2-hydroxycyclopentan-r-1-carboxylic acid (181, isomer A in C-1 ', Scheme 15) &148-2 Prepared from 176 (4.9 mg, 0.010 mmol) using the same procedure as for compound 160 (Method A) and obtained as a 10 solution, 0 mmolar. MS (ES +): 315.0 (M + 1).

Example 172 Acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2, -ethyl) butyl-4 - [(N-methylaminoim) methyl] amin-2 -hydroxycyclopentane-1-carboxylic acid (182, Scheme I 5) &149-1 was prepared from 177 (10.4 mg, 0.0203 mmol) using the same procedure as for compound 160 (Method A) and obtained as a 20.3 mmolar solution. MS (ES +): 343.6 (M + 1).

Example 173 Acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-propyl) pentyl-4 - [(aminonin) methyl] amin-2-hydroxycyclopentan -1-carboxylic (183, Scheme 15) & 149-2 It was prepared from 150 (8.7 g) using the same procedure as for compound 178 (Method B).

Example 174 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amin -2- (N- imidazolyl thiocarbonyloxy) cyclopentane-1-carboxylate (184, Scheme 16) &150 A mixture of 137 (100 g, 0.25 mol) and 1,1'-thiocarbonyldiimidazole (90 g, 0%) was heated at reflux temperature. 5 mol) in THF anh. (1, 3 I) for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (1 L) and washed with 0.5 N HCl (3 x 1 L). The ethyl acetate layer was dried over MgSO, and after filtration, the filtrate was concentrated. The residue was recrystallized from ethyl acetate / hexane to give 76 g (59, 6%) of compound 184. The filtrate was concentrated and the residue was purified by passing through a silica gel column using ethyl acetate / hexane as eluent to give another 14 g (11%) of 184. 1H NMR (CDCl 3): d 0.75 (m, 3 H), 0.9. (m, 3 H), 1, 15 (m, 3 H), 1, 4 (m, 9 H), 1, 9 (m, 2 H), 2.0 (s, 3 H), 2.5 (m, 2 H), 3, 1 (m, 1 H), 3.75 (s, 3 H), 4.25 (m, 1 H), 4.5 (m, 1 H), 5.0 (m, 1 H) 6.0 (m, 1 H), 6.4 (m, 1 H), 7.05 (s, 1 H), 7.7 (s, 1 H), 8.4 ( s, 1 H). Analysis: Cale, for C24H38N406S: C: 56,45; H: 7.50; N: 10.97 Found: C: 56.40; H: 7.50; N: 10.98 Example 175 (1S, 2S, 3R, 4, R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) pentyl-4-tert-butoxycarbonyl amin-2- (N-imidazolyl) -thiocarbonyloxy) cyclopentan-1-carboxylate (185, Scheme 16) &151-1 Prepared from 138 (17.1 g) according to the same procedure used for compound 184.

Example 176 (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amin-2- (N-imidazolyl) thiocarbonyloxy) cyclopentane-1-carboxylate (186, Scheme 16) &151-2 Prepared from 139 (2.8 g) according to the same procedure used for compound 184.

Example 177 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) pentyl-4-tert-butoxycarbonyl-amin-2- (N-imidazolyl) thiocarbonyloxy) cyclopentan-1-carboxylate (187, Scheme 16) &152-1 Prepared from 140 (3.43 g) according to the same procedure used for compound 184.

Example 178 • (+) - methyl t-3- (1'-acetylamin-2'-ethyl) butyl-c-4-tert-butoxycarbonylamin-1 -2- (N-imidazolyl-thiocarbonyloxy) cyclopentan-r-1-carboxylate (188, isomer A in C-1 ', Scheme 16) 8.152-2 10 Prepared from 142 (0.4 g) according to the same procedure used for compound 184. • Example 179 (1 R, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamino-2'-ethyl) butyl-4-ter-1-butoxycarbonyl-amin-cyclopentan-1-carboxylate (189 , Scheme 16) &153 To a mixture of 184 (50 g, 0.098 mol) in toluene (1.3 g) at 70 ° C was added tributyltin hydride (34 ml, 0.126 mol) followed by azobiisobutyronitrile (AIBN, 0.1 g, 0.06 mmol) and the mixture was stirred at 70 ° C for 10 min. The solvent was removed under vacuum and the residue was dissolved in acetonitrile (1 L) and washed with hexanes (3 x 1 L). The acetonitrile layer was concentrated and the residue was purified by passing it through a silica gel column using ethyl acetate: hexanes (0-50% mixture) as eluent. Appropriate fractions were pooled and concentrated to give 36 g (95%) of compound 189. 1 H NMR (DMSO-de): d 0.8 (m, 6 H), 1.2 (m, 5 H), 1 , 4 (s, 9 H), 1, 6 (m, 2 H), 1, 85 3 H), 1, 9 (m, 1 H), 2.1 (m, 2 H), 2.7 ( m, 1 H), 3.55 (s, 3 H), 3.7 (m, 1 H), 3.8 (m, 1 H), 6.72 (d, J = 7.5 Hz, 1 H), 7.20 (d, J = 9.9 Hz, 1 H) Analysis: Cale, for C2oH36N205.0.75 H20: C: 60.35; H: 9.50; N: 7.04 Found: C: 60.60; H: 9.49; N: 7.05 Example 180 (1 R, 3R, 4R, 1 'S) - (-) - methyl 1 - (1'-acetylamin-2'-propyl) pentyl-4-tert-butoxycarbonyl-amincyclopentane-1-carboxylate (190, Scheme 16) &154-1 Prepared from 185 (16.0 g) according to the same procedure as was used for compound 189.

Example 181 (1 R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amin-cyclopentan-1-carboxylate (191, Scheme 16) & 154-2 It was prepared from 186 (1.9 g) according to the same procedure used for compound 189.

Example 182 (1 R, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) penti-4-tert-butoxycarbonyl-amincyclopentane-1-carboxylate (192 , Scheme 16) &155-1 Prepared from 187 (1.2 g) according to the same procedure used for compound 189.

Example 183 (+) - methyl t-3- (1'-acetylamin-2'-ethyl) butyl-c-4-tert-butoxycarbonylaminyl-1-pentan-1-carboxylate (193, isomer A in C-1 ', Scheme 16 ) &155-2. It was prepared from 188 (0.2 g) according to the same procedure used for compound 189.

Example 184 (1R, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-ethyl) butyl-4-amincyclopentane-1-carboxylate, hydrochloride (194, Scheme 16) & 156-1 was prepared from 189 (10.0 g) according to the same procedure as for compound 149.

Example 185 (1R, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-propyl) pentyl-4-amincyclopentane-1-carboxylate, hydrochloride (195, Scheme 16) & 156-2 It was prepared from 190 (10.0 g) according to the same procedure as that used for compound 149.

Example 186 (1R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4-aminocyclopentane-1-carboxylate, trifluoroacetate (196, Scheme 16) &157-1 v /. It was prepared from 191 (1, 4 g) according to the same procedure used for compound 151.

Example 187 (1R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-propyl) pentyl-4-amincyclopentane-1-carboxylate, trifluoroacetate (197, Scheme 16) & 157-2 Prepared from 192 (0.84 g) according to the same procedure used for compound 151.

Example 188 • (+) - methyl t-3- (1'-acetylamin-2'-ethyl) butyl-c-4-amincyclopentan-1-carboxylate, trifluoroacetate (198, isomer A in C-1 ', Scheme 16) 8.158- 1 Prepared from 193 (5-7 mg) according to the same procedure used for compound 151. 10 Example 189 Acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-Acetylamin-2'-ethyl) butyl-4-a-aminocyclopentane-1-carboxylic acid (199, Scheme 16) 15 8.158-2 It was prepared from 196 (8.3 mg, 0.0233 mmol) using the same procedure as for compound 160 and 23.3 mmolar was obtained as a solution. MS (ES +): 271, 4 (100%, M + 1). 20 Example 190 (+) - t-3- (1'-Acetylamino-2'-ethyl) butyl-c-4-aminocyclopentane-1-carboxylic acid (200, isomer A in C-1 ', Scheme 16) 25 &159-1 was prepared from 198 (4.21 mg, 0.0148 mmol) using the same procedure as for compound 160 and was obtained as a 14.8 mmolar solution. MS (ES +): 271, 4 (100%, M + 1).

Example 191 (1 R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(tert-butoxycarbonyl-tert-butoxycarbonylimino) methyl) ] amincyclopentane-1-carboxylate (201, Scheme 17) 8.159-2 Prepared from 196 (1.52 g) using the same procedure as for compound 94.

Example 192 i (1 R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamino-2'-propyl) pentyl-4 - [(tert-butoxycarbonylamino-tert-butoxycarbonylimin) methyl] amincyclopentan- 1-carboxylate (202, Scheme 17) &160-1 Prepared from 197 (0.87 g) using the same procedure as for compound 94. 19 Example 193 (+) - methyl t-3- (1'-acetylamin-2'-ethyl) butyl-c-4 - [(tert-butoxycarbonylamin-tert-butoxycarbonylimin) methyl] amincyclopentan-r-1-carboxylate (203, isomer A in C-1 ', Scheme 17) & 160-2 It was prepared from 198 (0.093 g) using the same procedure as for compound 94.

Example 194 (1 R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-et? L) butyl-4 - [(N-tert-butoxycarbonyl-N-methylamino-N '-ter-butoxycarbonylimin) methyl] amincyclopentane-1-carboxylate (204, Scheme 17) 8.161 Prepared from 196 (0.33 g) using the same procedure as for compound 94. The reagent used was 1, 3- bi (tert-butoxycarbonyl) -N-methyl-2- (2,4-dinitrophenyl) -2-thiopseudourea in place of 1,1-bi (tert-butoxycarbonii) -2-methyl-2-thiopseudourea.

Example 195 (1 R, 3R, 4R, 1 'S) - (-) - Ethyl 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin) methyl] -aminocyclopentan-1-carboxylate, trifluoroacetate ( 205, Scheme 17) 8.162-1 Prepared from 201 (0.9 g) using the same procedure as for compound 151.

Example 196 • (1 R, 3R, 4R, 1 'S) - (-) - ethyl 3- (1'-acetylamin-2'-propyl) pentyl-4 - [(aminoimin) -methyl] amincyclopentane-1-carboxylate, trifluoroacetate ( 206, Scheme 17) &162-2 Prepared from 202 (0.8 g) using the same procedure than for compound 151.

• - ". ' ', • Example 197 (+) - methyl t-3- (1'-acetylamin-2'-ethyl) butyl-c-4 - [(aminoimin) methyl-aminocyclo-pentan-r-1-carboxylate, trifluoroacetate (207, isomer A in C-1 ', Scheme 17) • 8.163-1 • 'Prepared from 203 (0.055 g) using the same procedure as for compound 151.

Example 198 (1 R, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4 - [(N-methylaminoimin) methyl] amincyclopentan-1-carboxylate, trifluoroacetate (208, Scheme 17) &163-2 Prepared from 204 (0.35 g) using the same procedure as for compound 151.

Example 199 Acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4- (aminoimin) methyl-amino-cydopentane-1-carboxylic acid (209) , Scheme 17) &164-1 Method A: Prepared from 205 (7.6 mg, 0.0167 mmol) using the same procedure as for compound 160 and obtained as a 16.7 mmol solution. MS (ES +): 3 13.4 (100%, M + 1). Method B: Prepared from 194 (15.02 g) using the same procedure as for compound 178 (Method B). 1R NMR (D20): d 0.90 (m, 6 H), 1.1 (m, 2 H), 1.4 (m, 1 H), 1.5 (m, 2 H); 1.75 (m, 2 H); 2.05 (s, 3 H), 2.15 (m, 1 H), 2.35 (m, 2 H), 2.8 (m, 1 H), 3.65 (m, 1 H), 4.0 (m, 1 H).

Example 200 Acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-propyl) pentyl-4 - [(aminoimin) methyl] am? Ncyclopentan-1 -carboxylic acid (210 , Scheme 17) 8.164-2 Method A: Prepared from 206 (9.69 mg, 0.0197 mmol) using the same procedure as for compound 160 and a 14.9 mmol solution was obtained. MS (ES +): 341, 7 (100%, M + 1). Method B: Prepared from 153 (8.4 g) using the same procedure as for compound 178 (Method B). 1 NMR (D20): d 0.90 (m, 6 H), 1.1 (m, 2 H), 1.4 (m, 6 H), 1.6 (m, 1 H), 1.75 (m, 2 H), 2.05 (s, 3 H), 2.15 (m, 1 H), 2.3 (m, 1 H), 2.4 (m, 1 H), 2.78 (m, 1 H), 3.6 H), 3.9 (m, 1 H) Example 201 (+) - T-3- (1'-Acetylamino-2'-ethyl) butyl-c-4 - [(aminoimin) methylamine-cyclopentan-r-1-carboxylic acid (211, isomer A in C-1 ', Scheme 17) & 65 was prepared from 207 (18 mg, 0.0342 mmol) using the same procedure as for compound 160 and 34.2 mmolar was obtained as a solution. MS (ES +): 313.4 (100%, M + 1).

Example 202 Acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamino-2'-ethyl) butl-4 - [(N-methylaminoimin) methyl] amincyclopentan-1 -carboxylic acid (212, Scheme 17) 8.166-1 Prepared from 208 (10.7 mg, 0.0235 mmol) using the same procedure as for compound 160 and 30.18 mmol was obtained as a solution. MS (ES +): 327.6 (100%, M + 1).

Example 203 (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl 3- (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxy-carbonylamino-2-methanesulfonyloxycyclopentan-1 -carboxylate (213, Scheme 18) 8.166-2 To a mixture of 137 (1.0 g, 2.4 mmol) in dichloromethane (40 ml) was added methanesulfonyl chloride (0.37 ml, 4.8 mmol) and triethylamine (1.0 ml, 7.2 mmol) at 4 ° C. The reaction mixture was stirred for 16 h at 4 ° C. Water (10 ml) was added to the mixture and extracted with dichloromethane (3 x 10 ml). The combined organic extracts were washed with saline (20 ml) and dried (MgSO). After filtration, the filtrate was concentrated and the residue was purified by passing through a silica gel column to give 0.8 g (68%) of compound 213. MS (ES + I): 493.8 (M + 1 ).

Example 204 (3R, 4R, 1 ', S) - (-) - methyl-3 (1'-acetylamin-2'-ethyl) butyl-4-tert-butoxycarbonyl-amine-cyclopent-1-en-1-carboxylate (214, Scheme 18) 8.167. To a mixture of 213 (0.4 g, 0.81 mmol) in THF (5 ml) at 4 ° C was added freshly prepared sodium ethoxide (2.43 mmol) in ethanol (1.5 ml) and stirred for 30 min. The mixture was neutralized with acetic acid and concentrated. The residue was taken up in dichloromethane (20 ml) and washed with water and saline and dried (MgSO 4). After filtration, the filtrate was concentrated and the residue was purified on a silica gel column to give 0.1 1 g (37%) of 214. MS (ES +): 397.8 (M + 1).

Example 205 (3R, 4R, 1 'S) - (-) - methyI 3- (1'-acetylamin-2'-ethyl) butyl-4-aminciclopent-1-en-1-carboxylate, hydrochloride (215, Scheme 18) 8.168 -1 was prepared from 214 (23 mg, 0.81 mmol) according to the method used for compound 149 and used as it was in the next step. MS (ES +): 297.5 (M + 1).

Example 206 Acid (3R.4R, 1 'S) - (-) 3- (1'-Acetylamino-2'-ethyl) butyl-4-aminciclopent-1-en-1 -carboxylic acid (216, Scheme 18) & 168-2 The mixture of 216, obtained above, was treated in the same manner as compound 160 and obtained as a 58 mmolar solution.

Example 207 (3R, 4R, 1 ', S) - (-) - methyl 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(tert-butoxycarbonyl-aminoter-butoxycarbonylimin) methyl] ] aminciclopent-1-en-1-carboxylate (217, Scheme 18) 8.169 A mixture of 215 (4.23 g, 13.6 mmol), N-tert-butoxycarbonyl-N'-tert-butoxycarbonyl-N "-trifluoromethanesulfonylguanidine (5.87 g, 15 mmol) and triethylamine ( 4.1 ml, 29.2 mmol) in dichloromethane (70 ml) at room temperature for 16 h The reaction mixture was washed with saturated sodium bicarbonate solution, water and saline and dried (MgSO). After filtration, the filtrate was concentrated and the residue was purified by passing through a silica gel column to give 3.9 g (60%) of compound 217.

MS (ES +): 526.08 (M + 1).

Example 208 Acid (3R, 4R, 1 'S) - (-) - 3- (1'-acetylamino-2'-ethyl) butyl-4 - [(tert-butoxycarbonylaminoter-butoxycarbonylimin) methyl] amincyclopent-1-en- 1-carboxylic acid (218, Scheme 18) 8.170-1 A mixture of 217 (1.8 g, 3.4 mmol), TF (10 mL), ethanol (10 mL), water (10 mL) and NaOH 1 was stirred. N (10 ml) at room temperature for 8 h. The reaction mixture was concentrated and the residual aqueous layer was washed with ether (20 ml) and acidified with acetic acid. The solid was collected by filtration, washed with water and dried to give 1.6 g (92%) of compound 218. MS (ES +): 512.0 (M + 1).

Example 209 Acid (3R.4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin) methyl] amin-cyclopent-1-en-1 -carboxylic acid, hydrochloride (219, Scheme 18) & 170-2 A mixture of 218 (1.52 g, 2.98 mmol) and 3 N HCl (20 mL, 60 mmol) was stirred for 24 h. The reaction mixture was concentrated and dried. The residue was recrystallized from ethanol / ether and 0.85 g (83%) of compound 219 was obtained. MS (ES +): 31.1.4 (M + 1). Analysis: Cale, for C? 5H26N 03. HCI: C: 51, 94; H: 7.56; N: 16.15 Found: C: 51, 84; H: 7.75; N: 16.03 Biochemistry The in vitro test is based on the method described by von Itzstein et al. (Patent Application EP 92309634.6). The neuraminidase of strain H1 N9 of influenza was obtained by the method described by Laver et al. Virology 1984, 137, p. 314-323. The IC50 values were measured by spectrofluorometry techniques employing the fluorogenic substrate, 2 '- (4-methylumbelliferyl) - - D -acetylneuramic acid. This substrate is divated with neuraminidase to give a fluorescent product which can then be quantified. The assay mixture contains inhibitors at various concentrations (four to six points) and enzyme in MES buffer [32 (2- (N-morpholine) ethanesulfonic acid] 32.5mM, 4mM CaCl2 at pH = 6.5 (total volume = 80 μ [) The reaction starts with the addition of 20 μl of substrate to a final concentration of 75 μM After 10 min at 37 ° C, 150 μl of 0.2 M glycine / NaOH is added (pH = 10 , 2) to 0.1 ml of the reaction mixture to terminate the reaction A target is also run with the same substrate solution but without enzyme Fluorescence is read using a Spectrafluor Fluorometer (excitation: 360 nm and emission: 450 nm) and the readings of the "substrate targets were subtracted from the values of the sample readings, the IC or is calculated by plotting the percentage of inhibition of NA activity versus the concentration of the inhibitor, and the determination of each point. It is done in duplicate.

Biological data The following table shows the inhibition data of the enzyme neuraminidase (IC50 values). + > 100 μM; ++ 1 -100 μM; +++ < 1 μM.

NQ Compound Flu A FluB 65 ++ ++ 86 ++ ++ 160 +++ +++ 162 +++ +++ 163 +++ +++ 165 ++ ++ 166 +++ ++ 178 +++ +++ 179 +++ +++ 180 +++ +++ • 181 +++ +++ 182 +++ +++ 183 +++ +++ 199 +++ +++ 200 +++ +++ 209 +++ +++ 210 +++ +++ 211 +++ +++ • 212 +++ +++ 219 +++ +++ Crystallography The complexes between the inhibition and neuraminidase molecules were prepared by transferring crystals of neuraminidase H1 N9 in 2 ml of the phosphate buffer solution in which the inhibitor was dissolved. The concentration of the inhibitor compound was adjusted to 2 mM. The crystals were allowed to equilibrate in the buffer solution for about a day and then they were separated from the solution and mounted in a glass capillary for the collection of the X-ray diffraction data. All measurements of the intensity of the rays X were recorded with a Siemens X-100 area detector on a Rigaku RU-300 rotary anode generator operating at 100 • mA and 50 KV and a copper anode. The distance of the crystals to the detector was 160 mm and the detector was adjusted to receive data of 2.2 A. The intensity data were measured with oscillation frames of 0.1 ° to 240 sec. exposure per frame. Each crystal made it possible to obtain 600-700 frames of data before radiation damage to the crystals impeded data collection. The intensity data were processed using the XENGEN program package. The integrated intensities were brought to scale and • 20 were grouped to produce a final data set that only contained unique reflections. All adjustments were made using the XPLOR program. The initial model for the adjustment was 2.0 A adjusted to the native structure N9. The representations of the differentiated Fourier at 2.2 A were calculated using the phases calculated from the model adjusted. The electronic intensity map analysis was carried out with a Silicon Graphics indigo Extreme 2 computerized graphics workstation using the QUANTA graphics program. The idealized models of the inhibitory molecules were manually adjusted based on the differential electronic density. These inhibitor models are then included in the setting with the XPLOR.

Dosage and formulation The antiviral compounds of this invention can be administered as a treatment for viral infections with any of the means that • cause a contact between the site of action of the active agent and viral neuraminidase in the body of a human being, a mammal, a bird or other animal. They can be administered by conventional means available for use with pharmaceutical products, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. • The dosage administered varies, of course, depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of symptoms, the type of concurrent treatment; of the frequency of the treatment; and the effect desired. The daily dosage of the active ingredient may be from about 0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight, with the preferred dose being about 0.1 to 30 mg / kg. - Dosage forms (compositions suitable for administration) contain from about 1 mg to 500 mg of active ingredient per unit. In these pharmaceutical compositions, the amount of active ingredient that is usually present will be about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in liquid dosage forms • • sterile. The active ingredient can also be administered via • Intranasal (nasal drops) or by inhalation of a cloud of powder with the drug Other dosage forms are potentially possible, such as transdermal administration, by means of a patch mechanism or an ointment.The gelatin capsules contain the active ingredient and powdered vehicles, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid and the like Similar diluents can be used for the manufacture of compressed tablets. manufacture as sustained release products to provide a continuous release of the medication over a period of hours.The compressed tablets can be coated with sugar or with films to mask any unpleasant taste and protect the tablet from the atmosphere or have an enteric coating for the selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavors to increase patient acceptance. They may also contain regulatory agents, agents 'Surfactants and preservatives. Oral liquid products can be developed to exhibit sustained release properties. They may also contain cyclodextrin derivatives to increase the solubility of the active ingredient and to promote its oral uptake. In general, water, a suitable oil, saline, aqueous dextrose (glucose) and solutions of related sugars and glycol, such as • propylene glycol or polyethylene glycol, are suitable vehicles for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, regulatory agents. Antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. The citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propylparaben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company and Handbook of Pharmaceuticals Excipients, American Pharmaceutical. Association, both standard reference texts in this field.

The pharmaceutical dosage forms that are useful for the administration of the compounds according to the present invention can be illustrated as follows: Hard coating capsules A large number of unit capsules can be prepared by filling each standard two-piece hard gelatin capsule with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules A mixture of active ingredient is prepared in an edible oil, such as soybean oil, cottonseed oil or olive oil and is injected by means of a positive displacement pump in melted gelative to form soft gelative capsules containing 100 mg of active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water-miscible medicinal mixture.

Tablets A large number of tablets can be prepared by conventional procedures such that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose. , 1 1 mg of starch and 98.8 mg of lactose. Suitable aqueous and non-aqueous coatings can be applied to increase acceptance, improve elegance and stability or delay absorption.

Tablets / capsules for immediate release These are solid oral dosage forms made by conventional and new processes. These units are taken orally without water for immediate dissolution and distribution of the medication. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids solidify into solid tablets or capsules by means of freeze-drying and solid-state extraction techniques. The compounds of the drug can be compressed with effervescent components, sugars and viscoelastic and thermoelastic polymers to produce porous matrices intended for immediate release, without the need for water. Moreover, the compounds of the present invention can be administered in the form of nasal drops or metered doses and nasal or buccal inhalers. The drug is administered from the nasal solution as a fine cloud or from a powder as an aerosol. Those skilled in the art will understand that various modifications of the invention can be made in addition to those which are shown and described in this document from the foregoing description. Said modifications are also encompassed by the scope of the appended claims. The above description includes all the information considered essential to enable those skilled in the art to practice the invention claimed. Since the aforementioned request may elicit additional useful information, the cited materials are fully incorporated herein by way of reference. •

Claims (46)

CLAIMS:

1. A compound, CHARACTERIZED BECAUSE it is represented by the following formulas: &179-1 where U is CH, O or S; Z is -C (R2) (R3), -CH-N (R2) (R3), C (R3) [(CH2) nR2], CH-C (R3) (R8) (CH2) nR2, C [( CH2) nR2] - [CH (R3) (R8)], C [(R3)] [CH [(CH2) nR2] (R8)]; R1 is H, (CH2) nOH, (CH2) nNH2, (CH2) nNR10R11, (CH2) nOR11, (CH2) nSR11, or (CH2) n halogen R9 is (CH2) nC02H, (CH2) nS03H, (CH2) nP03H2, (CH2) nN02, CH (SCH3) 3, esters thereof or salts thereof, or R, R9 represent together = 0, or 8. 179-2 R2 is H, NHC (0) R5, NHC (S) R5, NHS02R5, C (0) NHR5, S02NHR5, CH2S (0) R5 or CH2S02R5 R3 and R8 are individually H, (CH2) nC (0) R10, (CH2) nC02R1 ° (CH2) mOR10, CH (OR10) CH (R10) m, C (O) N (R10) ) m, C (O) N (OR10) R10 (CH2) nN (R10) m, CH (R10) m, (CH2) n (R10) m, CH2CH (OR10) CH2OR10 CH (OR10) CH (OR10) CH2OR10, CH2OR10, CH (OR10) CH2NHR10 CH2CH (OR 0) CH2NHR10, CH (OR10) CH (OR10) CH2NHR10, C (= NR10) N (R10) m NHR10, NHC (= NR10) N (R10) m, (CH2) mXWY, CH2CH (XWY) CH2OR10 , CH (XWY) CH (OR10) CH2OR10, CH (XWY) CH2 (OR10), CH (OR10) CH (XWY) CH2OR10, CH (OR10) CH2 (XWY), CH2CH (XWY) CH2NHR10, CH (XWY) CH (OR10) CH2NHR10, CH (XWY) CH2 (NHR10), CH (OR10) CH (XW-Y) CH2NHR10 or CH (-NHR10) CH2 (XWY); with the proviso that at least one of R2, R3 and R8 is different from H; R4 is H, (CH2) nOH, (CH2) nOR11, (CH2) nOC (0) R11, (CH2) nNHC (NR11) NHR11, (CH2) nNR10R11, (CH2) nNH2, (CH2) nC (= NH) (NH2), (CH2) nNHC (= NR11) NH2, (CH2) nNHC (= NR7) NH2, (CH2) nCN, (CH2) nN3, C (= NH) NH2, C (NR7) NH2, or C ( NR11) NH2; R5 is H, lower alkyl, cycloalkyl, alkyl substituted with halogen, aryl, substituted aryl or CF3; R7 is H, (CH2) nOH, (CH2) nCN, (CH2) nNH2 or (CH2) nN02; R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, aromatic (CH2) n, aromatic substituted with (CH2) no, when m is 2, both groups R10 may also be interconnected to form an N-substituted heterocyclic ring or other 5 or 6 membered heterocyclic rings; R11 is lower alkyl, branched alkyl, aromatic (CH2) m, S02R10, C (0) R10 or C (0) OR10; • - R12 and R13 is H, (CH2) nOH, (CH2) nNH2, (CH2) nNR10R11, (CH2) nOR11, (CH2) nF, (CH2) nOC (0) R11, (CH2) nNHC (0) R11 or XWY; m is 1 or 2; n is 0-4; p is 0 or 1; X is O, S, CH2 or NH; W is a spacer group formed by a chain of 1 to 100 atoms and also optionally comprises substituted carbon and / or nitrogen atoms and optionally including oxygen or sulfur atoms; and Y is H, OH, SH, NH2, CH = 0, CH = CH2, COZH, CONHNH2 or a protected form of one of these terminal functionalities; acceptable salts for pharmaceutical use thereof.

2. The compound of clause 1, CHARACTERIZED BECAUSE said lower alkyl group contains from 1 to about 8 carbon atoms; and said lower alkylene group contains from 2 to about 8 carbon atoms.

3. The compound of clause 1, CHARACTERIZED BECAUSE said lower alkyl group contains from 1 to about 3 carbon atoms; and said lower alkylene group contains from 2 to 3 carbon atoms.

4. The compound of clause 1, CHARACTERIZED BECAUSE said alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, t-butyl, cyclopentyl and cyclohexyl, the aromatic group is selected from the group consisting of aromatic groups substituted with phenyl and alkyl; substituted cycloalkyl groups contain 3-8 carbon atoms in the ring and are substituted with 1 or 2 alkyl groups possessing 1-6 carbon atoms, hydroxy groups or both; and the alkylene group is selected from the group consisting of vinyl, 1-propenyl, 2-methyl-2-propenyl and cyclopentenyl.

5. The compound of clause 1, CHARACTERIZED BECAUSE said salt comes from an acid selected from the group consisting of hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p sulphonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulfonic.

6. The compound of clause 1, CHARACTERIZED BECAUSE said salt is a sodium or ammonium salt.

7. A compound, CHARACTERIZED BECAUSE it is represented by the following formulas: 8.182 or 8.183 where R3 is H, (CH2) nC (O) R10, (CH2) nC02R10, (CH2) mOR10, CH (OR10) CH (R10) m, C (O) N (R10) m, C (O) N (OR10) R10, (CH2) nN (R10) m, CH (R10) m, (CH2) n ( R10) m, CH2CH (OR10) CH2OR10, CH (OR10) CH (OR10) CH2OR10, CH2OR10, CH (OR10) CH2NHR10, CH2CH (OR10) CH2NHR10, CH (OR10) CH (OR10) CH2NHR10, C (= NR10) N (R10) m, NHR10, NHC (= NR10) N (R10) m, (CH2) mXWY, CH2CH (XWY) CH2OR10, CH (XW- Y) CH (OR10) CH2OR10, CH (XWY) CH2 (OR10), CH (OR10) CH (XWY) ) CH2OR10, CH (OR10) CH2 (XWY), CH2CH (XWY) CH2NHR10, CH (XW- Y) CH (OR10) CH2NHR10, CH (XWY) CH2 (NHR10), CH (OR10) CH (XW- Y) CH2NHR10 or CH (NHR10) CH2 (XWY); R4 is H, (CH2) nOH, (CH2) nOC (0) R11, (CH2) nOR11, (CH2) nNHC (NR11) NHR11, (CH2) nNR10R11, (CH2) nNH2, (CH2) nC (= NH) (NH2), (CH2) nNHC (= NR1) NH2, (CH2) nNHC (= NR7) N-H2, (CH2) nCN, (CH2) nN3, C (= NH) NH2, C (NR7) NH2 or C (NR1) NH2; R9 is (CH2) nC02H, (CH2) nS03H, (CH2) nP03H2, (CH2) nN02, CH (SCH3) 3, = O or &183-2 5 esters thereof or salts thereof, each R14 is individually H, (CH2) nC02H, (CH2) nS03H, (CH2) nP03H2, (CH2) nN02, CH (SCH3) 3, = O or &184 esters thereof or salts thereof, and with the proviso that at least one of R14 is H; R7 is H, (CH2) nOH, (CH2) nCN, (CH2) nNH2 or (CH2) nN02; R10 is H, a lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, aromatic (CH2) n, aromatic (CH2) n substituted group or, when m is 2, both R10 groups can also be interconnected to form a substituted N-heterocyclic ring or other 5 or 6 heterocyclic rings '15 members; "R11 is a lower alkyio group, branched alkyl, aromatic (CH2) m, S02R10, C (0) R10 or C (0) OR10; m is 1 or 2; n is 0-4; 20 W is a spacer group formed by a chain of 1 to 100 atoms, and also optionally comprising carbon and / or substituted nitrogen atoms and optionally including oxygen or sulfur atoms, and Y is H, OH, SH, NH2, CH = 0, CH = CH2, C02H, CONHNH2 or a protected form of one of these terminal functionalities;

8. The compound of clause 7, CHARACTERIZED BECAUSE said lower alkyl group contains from 1 to about 8 carbon atoms; and said lower alkylene group contains from 2 to about 8 carbon atoms. •

9. The compound of clause 7, CHARACTERIZED BECAUSE said lower alkyl group contains from 1 to about 3 carbon atoms; and said lower alkylene group contains from 2 to 3 carbon atoms.

10. The compound of clause 7, CHARACTERIZED BECAUSE , alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, t-butyl, cyclopentyl and cyclohexyl, the aromatic group is selected from the group consisting of aromatic groups substituted with phenyl and alkyl; substituted cycloalkyl groups contain 3-8 carbon atoms in the 15 and are substituted with 1 or 2 alkyl groups possessing 1-6 carbon atoms, hydroxy groups or both; and the alkylene group is selected from the group consisting of vinyl, 1-propenyl, 2-methyl-2-propenyl and cyclopentenyl.

11. The compound of clause 1, CHARACTERIZED BECAUSE it is selected from the group consisting of the compounds and intermediates according to the present application which are identified in Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 , 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 25 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 1 , 1 1 1, 1 12, 1 13, 1 14, 1 15, 1 16, 1 17, 1 18, 1 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130 , 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155 , 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 and 209; and salts of the same

12. The compound of clause 1, CHARACTERIZED BECAUSE it is selected from the group consisting of the compounds and intermediates according to the present application identified in Examples 58, 79, 150, 152, 153, 155, 156, 168, 169, 170, 171 , 172, 173, 189, 190, 199, 200, 201, 202, 209; and salts acceptable for pharmaceutical use thereof.

13. The compound of clause 1, CHARACTERIZED BECAUSE (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl-3- (1-acetylamin-2'-ethyl) butyl-4-amin-2 -hydroxy-cydopentan-1-carboxylate; or an acceptable salt for pharmaceutical use thereof.

14. The compound of clause 1, CHARACTERIZED BECAUSE (1S, 2S, 3R, 4R, 1 'S) - (-) - methyl-3- (1'-acetylamin-2'-propyl) pentyl-4-amino- 2-hydroxy-cyclopentan-1-carboxylate; or an acceptable salt for pharmaceutical use thereof.

15. The compound of clause 1, CHARACTERIZED BECAUSE (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4-amin-2 -hydroxy-cyclopentan-1-carboxylate; or an acceptable salt for pharmaceutical use thereof. •

16. The compound of clause 1, CHARACTERIZED BECAUSE (1 R, 2R, 3S, 4S, 1 'R) - (+) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4-amin- 2-hydroxy-cyclopentan-1-carboxylate; or an acceptable salt for pharmaceutical use thereof. 10 17.

The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4- amin-2-hydroxy-c-dopentan-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof. . . 15.

The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 2R, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-ethyl) butyl-4- amin-2-hydroxy-cyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

19. The compound of clause 1, CHARACTERIZED BECAUSE it is (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin) -methyl] amin-2-hydroxy-cyclopentan-1-carboxylate; or an acceptable salt for pharmaceutical use thereof. 25

20. The compound of clause 1, CHARACTERIZED BECAUSE (1S, 2S, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4 - [( N-methylaminoimin) -methyl] amin-2-hydroxy-cyclopentan-1-carboxylate; or an acceptable salt for pharmaceutical use thereof.

21. The compound of clause 1, CHARACTERIZED BECAUSE (3R, 4R, 1 'S) - (-) - methyl-3- (1'-acetylamin-2'-ethyl) butyl-4-aminciclopent-1-en-1 -carboxylate; or an acceptable salt for pharmaceutical use thereof.

22. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (3R, 4R, 1'S) - (-) - 3- (1'-acetylamin-2'-ethyl) buti-4-amynccyclopent-1-en- 1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

23. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(amino-min) methyl] amin-cyclopent-1-en-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

24. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(am Noimin) methyl] amine-2-hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

25. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamino-2'-ethyl) but-1-4 - [(N-methylaminoim) methyl] amin-2-hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

26. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-propyl) pentyl-4 - [(amino N) methyl] amin-2-hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

27. The compound of clause 1, CHARACTERIZED BECAUSE (1 R, 3R, 4R, 1 'S) - (-) - methyl-3- (1'-acetylamin-2'-ethyl) butyl-4-amincyclopentan-1- carboxylate; or an acceptable salt for pharmaceutical use thereof.

28. The compound of clause 1, CHARACTERIZED BECAUSE (1 R, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4-aminocyclopentan- 1- 'carboxylate; or an acceptable salt for pharmaceutical use thereof.

29. The compound of clause 1, CHARACTERIZED BECAUSE (1 R, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-propyl) pentyl-4-amincyclopentan-1- carboxylate; or an acceptable salt for pharmaceutical use thereof.

30. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4-amincyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

31. The compound of clause 1, CHARACTERIZED BECAUSE (1 R, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin) -methyl] amincyclopentane-1-carboxylate; or an acceptable salt for pharmaceutical use thereof.

32. The compound of clause 1, CHARACTERIZED BECAUSE (1 R, 3R, 4R, 1 'S) - (-) - ethyl-3- (1'-acetylamin-2'-ethyl) butyl-4 - [(N- methylamino) -methyl] aminocyclopentane-1-carboxylate; or an acceptable salt for pharmaceutical use thereof.

33. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 3R, 4R, 1'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin) -methyl] amincyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

34. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-propyl) pentyl-4 - [(amino-min) -methyl] aminocyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

35. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(N-methylaminoimin ) -methyl] aminocyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

36. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 2S, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-propyl) pentyl-4-amin-2 -hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

37. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 2R, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-propyl) pentyl-4-amin-2 -hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

38. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 2R, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin ) methyl] -amin-2-hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

39. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 2R, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-propyl) pentyl 4- [ (aminoimin) methyl] -amin-2-hydroxycyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

40. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1 R, 3R, 4R, 1 'S) - (-) - 3- (1'-acetylamin-2'-propyl) pentyl-4-ann'cyclopentan-1 -carboxylic; or an acceptable salt for pharmaceutical use thereof.

41. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-ethyl) butyl-4-amincyclopentane-1-carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

42. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-ethyl) butyl-4 - [(aminoimin ) metl] -amiciclopentan-1 -carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

43. The compound of clause 1, CHARACTERIZED BECAUSE it is acid (1S, 3S, 4S, 1 'R) - (+) - 3- (1'-acetylamin-2'-propyl) pentyl-4 - [(aminoimin ) metl] -amiciclopentan-1 -carboxylic acid; or an acceptable salt for pharmaceutical use thereof.

44. A composition for inhibiting influenza virus neuraminidase, CHARACTERIZED BECAUSE comprises: a vehicle acceptable for pharmaceutical use and an effective amount for inhibiting influenza virus neuraminidase of a compound according to clause 1.

45. A method for inhibiting influenza virus neuraminidase, CHARACTERIZED BECAUSE it comprises a step of administering to a patient in need thereof a composition containing a vehicle acceptable for pharmaceutical use and an amount effective to inhibit influenza virus neuraminidase from a compound according to clause 1.

46. A method for treating an influenza virus infection, CHARACTERIZED BECAUSE it comprises a step of administration to a patient in need of a vehicle acceptable for pharmaceutical use and • an amount effective to inhibit the neuraminidase of the influenza virus of a compound according to clause 1. • CICLOPENTAN AND CYCLOPENTENE COMPONENTS SUBSTITUTED THAT ARE OF UTILITY AS INHIBITORS OF NEURAMINIDASE Summary Compounds represented by the following formulas are provided: 8.192-1 where U is CH, O or S; Z is -C (R2) (R3), -CH-N (R2) (R3), C (R3) [(CH2) nR2], CH-C (R3) (R8) (CH2) nR2, C [( CH2) nR2] - [CH (R3) (R8)], C [(R3)] [CH [(CH2) nR2] (R8)]; R1 is H, (CH2) nOH, (CH2) nNH2, (CH2] nNR10R11, (CH2) nOR11, (CH2) nSR11, or (CH2) n halogen R9 is (CH2) nC02H, (CH2) nS03H, (CH2) nP03H2, (CH2) nN02, CH (SCH3) 3, esters thereof or salts thereof, or R1, R9 represent together = 0, or &192-2 R2 is H, NHC (0) R5, NHC ( S) R5, NHS02R5, C (0) NHR5, S02NHR5, CH2S (0) R5 or CH2S02R5 R3 and R8 are individually H, (CH2) nC (0) R10, (CH2) nC02R10, (CH2) mOR10, CH (OR ??) CH (R) 1? 0?) M, C (0) N (R.). 1? 0u) m, C (0) N (OR 1l0u) \ DR1p0 ?, (CH2) nN (R> 1? 0?) \ m, CH (R) 1? 0?) \ mi (CH2) n (R10) m, CH2CH (OR10) CH2OR10, CH (OR10) CH (OR10) CH2OR10, CH2OR10, CH (OR10) CH2NHR10, CH2CH (OR10) CH2NHR10, CH (OR10) CH (OR10) CH2NHR10, C (= NR10) N (R10) m, NHR10, NHC (= NR10) N (R10) m, (CH2) mXWY, CH2CH (XW- Y) CH2OR10, CH (XWY) CH (OR10) CH2OR10, CH (XWY) CH2 (OR10), CH (OR10) CH (XWY) CH2OR10, CH (OR10) CH2 (XWY), CH2CH (XWY) CH2NHR10, CH (XWY) CH (OR 0) CH2NHR10, CH (XWY) CH2 (NHR10), CH (OR10) CH (XWY) CH2NHR10 or CH (-NHR10) CH2 (XWY); with the proviso that at least one of R2, R3 and R8 is different from H; R4 is H, (CH2) nOH, (CH2) nOR11, (CH2) nOC (0) R11, (CH2) nNHC (NR11) NHR11, (CH2) nNR10R11, (CH2) nNH2, (CH2) nC (= NH) (NH2), (CH2) nNHC (= NR11) NH2, (CH2) nNHC (= NR7) NH2, (CH2) nCN, (CH2) nN3, C (= NH) NH2, C (NR7) NH2 or C (NR11 ) NH2; R 5 is H, lower alkyl, cycloalkyl, alkyl substituted with halogen, aryl, substituted aiyl or CF 3; R7 is H, (CH2) nOH, (CH2) nCN, (CH2) nNH2 or (CH2) nN02; R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, aromatic (CH2) n, aromatic substituted with (CH2) no, when m is 2, both groups R10 may also be interconnected to form a N-substituted heterocyclic ring or other 5 or 6 membered heterocyclic rings; R11 is lower alkyl, branched alkyl, aromatic (CH2) m, S0 R10, C (0) R10 or C (0) OR10; R12 and R13 is H, (CH2) nOH, (CH2) nNH2, (CH2) nNR10R11, (CH2) nOR11, (CH2) nF, (CH2) nOC (0) R11, (CH2) nNHC (0) R11 or XWY; m is 1 or 2; n is 0-4; p is 0 or 1; X is O, S, CH2 or NH; W is a spacer group formed by a chain of 1 to 100 atoms and also optionally comprises substituted carbon and / or nitrogen atoms and optionally including oxygen or sulfur atoms; and Y is H, OH, SH, NH2, CH = 0, CH = CH2, C02H, CONHNH2 or a protected form of one of these terminal functionalities; salts acceptable for pharmaceutical use thereof and the method for their preparation. The compounds of the formulas described are inhibitors of influenza virus neuraminidase and can be used in the treatment of patients infected with the influenza virus. Intermediaries represented by the formulas are also provided: Another aspect of the present invention relates to intermediates represented by the following formulas: 8.194 where R4 and R9 are as defined above; and 8.195-1 where each R14 is individually H, O, (CH2) nC02H, (CH2) nS03H, (CH2) nP03H, (CH2) nN02, CH (SCH3) 3, &195-2 esters thereof or salts thereof, and with the proviso that at least one of the R14 is H, and R3 and R4 are as defined above.